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10,683	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:35.455617	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/6188s018s019Lbl.pdf', 'application_number': 6188, 'submission_type': 'SUPPL ', 'submission_number': 19}
10,682	2.5 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction 2.6 Titration and Maintenance Treatment of Opioid Dependence Detoxification 2.7 Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DOLOPHINE® safely and effectively. See full prescribing information for DOLOPHINE. DOLOPHINE (methadone hydrochloride ) tablets, for oral use, CII Initial U.S. Approval: 1947 WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; LIFE-THREATENING QT PROLONGATION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and TREATMENT FOR OPIOID ADDICTION See full prescribing information for complete boxed warning • DOLOPHINE exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1, 9) • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. (5.2) • Accidental ingestion of DOLOPHINE, especially in children, can result in fatal overdose of methadone. (5.2) • QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred during treatment with methadone. (5.3) • Prolonged use of DOLOPHINE during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life- threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (5.4). • Methadone products, when used for the treatment of opioid addiction in detoxification or maintenance programs, shall be dispensed only by certified opioid treatment programs as stipulated in 42 CFR 8.12. (1) -------------------------- RECENT MAJOR CHANGES ------------------------- Boxed Warning 04/2014 Indications and Usage (1) 04/2014 Dosage and Administration (2) 04/2015 Warnings and Precautions (5) 04/2014 --------------------------- INDICATIONS AND USAGE ------------------------- DOLOPHINE is an opioid agonist indicated for the: • Management of pain severe enough to require daily, around-the clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Use • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with long-acting opioids, reserve DOLOPHINE for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. • DOLOPHINE is not indicated as an as-needed (prn) analgesic. • Detoxification treatment of opioid addiction (heroin or other morphine-like drugs). • Maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services. (1) ---------------------- DOSAGE AND ADMINISTRATION --------------------- • Management of Pain: • For opioid naïve patients, initiate DOLOPHINE treatment with 2.5 mg every 8 to 12 hours. (2.2) • Titrate slowly with dose increases no more frequent than every 3 to 5 days. (2.3) • To convert to DOLOPHINE from another opioid, use available conversion factors to obtain estimated dose. (2.2) • Initiation of Detoxification and Maintenance Treatment: A single dose of 20 to 30 mg may be sufficient to suppress withdrawal syndrome. (2.5) • Do not abruptly discontinue DOLOPHINE in a physically dependent patient. (2.4, 5.12) --------------------- DOSAGE FORMS AND STRENGTHS ------------------- Tablets: 5 mg and 10 mg. (3) ------------------------------ CONTRAINDICATIONS ---------------------------- • Significant respiratory depression (4) • Acute or severe bronchial asthma (4) • Known or suspected paralytic ileus (4) • Hypersensitivity to methadone (4) ----------------------- WARNINGS AND PRECAUTIONS --------------------- • Respiratory Depression: The peak respiratory depressant effect typically occurs later, and persists longer than the peak analgesic effect. (5.2) • May cause QT interval prolongation and serious arrhythmia. (5.3) • Interactions with CNS depressants: Concomitant use may cause profound sedation, respiratory depression, and death. If coadministration is required, consider dose reduction of one or both drugs because of additive pharmacological effects. (5.5, 7.1) • Elderly, cachectic, debilitated patients, and those with chronic pulmonary disease: Monitor closely because of increased risk for life-threatening respiratory depression. (5.6, 5.7) • Hypotensive effect: Monitor during dose initiation and titration (5.8) • Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of DOLOPHINE in patients with impaired consciousness or coma susceptible to intracranial effects of CO 2 retention. (5.9) ------------------------------ ADVERSE REACTIONS ---------------------------- Most common adverse reactions are: lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. (6) To report SUSPECTED ADVERSE REACTIONS, contact Roxane Laboratories, Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ------------------------------ DRUG INTERACTIONS ---------------------------- • CYP3A4 Inducers: Increased risk of more rapid metabolism and decreased effects of methadone. (7.2) • CYP3A4 Inhibitors: Increased risk of reduced metabolism and methadone toxicity. (7.2) • Anti-retroviral Agents: May result in increased clearance and decreased plasma levels of methadone or in certain cases, increased plasma levels and risk of toxicity. (7.2) • Potentially Arrhythmogenic Agents: Extreme caution is necessary when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with methadone. (7.3) • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with DOLOPHINE because they may reduce analgesic effect of DOLOPHINE or precipitate withdrawal symptoms. (5.12, 7.4) ----------------------- USE IN SPECIFIC POPULATIONS --------------------- • Pregnancy: Based on animal data, may cause fetal harm. (8.1) • Nursing mothers: Methadone has been detected in human milk. Closely monitor infants of nursing women receiving DOLOPHINE. (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 04/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important General Information 2.2 Initial Dosing for Management of Pain 2.3 Titration and Maintenance of Therapy for Pain 2.4 Discontinuation of DOLOPHINE for Pain Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2.8 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction 2.9 Considerations for Management of Acute Pain During Methadone Maintenance Treatment 2.10 Dosage Adjustment During Pregnancy 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Addiction, Abuse and Misuse 5.2 Life Threatening Respiratory Depression 5.3 Life-Threatening QT Prolongation 5.4 Neonatal Opioid Withdrawal Syndrome 5.5 Interactions with Central Nervous System Depressants 5.6 Use in Elderly, Cachectic, and Debilitated Patients 5.7 Use in Patients with Chronic Pulmonary Disease 5.8 Hypotensive Effect 5.9 Use in Patients with Head Injury or Increased Intracranial Pressure 5.10 Use in Patients with Gastrointestinal Conditions 5.11 Use in Patients with Convulsive or Seizure Disorders 5.12 Avoidance of Withdrawal 5.13 Driving and Operating Machinery 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 7.1 CNS Depressants 7.2 Drugs Affecting Cytochrome P450 Isoenzymes 7.3 Potentially Arrhythmogenic Agents 7.4 Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics 7.5 Antidepressants 7.6 Anticholinergics 7.7 Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Storage and Handling 16.2 How Supplied 17 PATIENT COUNSELING INFORMATION MEDICATION GUIDE *Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION WARNING: ADDICTION, ABUSE AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; LIFE-THREATENING QT PROLONGATION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and TREATMENT FOR OPIOID ADDICTION Addiction, Abuse, and Misuse DOLOPHINE exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing DOLOPHINE, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)]. Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of DOLOPHINE. Monitor for respiratory depression, especially during initiation of DOLOPHINE or following a dose increase [see Warnings and Precautions (5.2)]. Accidental Ingestion Accidental ingestion of even one dose of DOLOPHINE, especially by children, can result in a fatal overdose of methadone [see Warnings and Precautions (5.2)]. Life-threatening QT Prolongation QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred during treatment with methadone. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Closely monitor patients for changes in cardiac rhythm during initiation and titration of DOLOPHINE [see Warnings and Precautions (5.3)]. Neonatal Opioid Withdrawal Syndrome Prolonged use of DOLOPHINE during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.4)]. Conditions For Distribution And Use Of Methadone Products For The Treatment Of Opioid Addiction For detoxification and maintenance of opioid dependence, methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8, including limitations on unsupervised administration [see Indications and Usage (1)]. Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 INDICATIONS AND USAGE DOLOPHINE is indicated for the: • Management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Use • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with long-acting opioids, reserve DOLOPHINE for use in patients for whom alternative analgesic treatment options (e.g., non-opioid analgesics or immediate- release opioid analgesics) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. • DOLOPHINE is not indicated as an as-needed (prn) analgesic. • Detoxification treatment of opioid addiction (heroin or other morphine-like drugs). • Maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services. Conditions For Distribution And Use Of Methadone Products For The Treatment Of Opioid Addiction Code of Federal Regulations, Title 42, Sec 8 Methadone products when used for the treatment of opioid addiction in detoxification or maintenance programs, shall be dispensed only by opioid treatment programs (and agencies, practitioners or institutions by formal agreement with the program sponsor) certified by the Substance Abuse and Mental Health Services Administration and approved by the designated state authority. Certified treatment programs shall dispense and use methadone in oral form only and according to the treatment requirements stipulated in the Federal Opioid Treatment Standards (42 CFR 8.12). See below for important regulatory exceptions to the general requirement for certification to provide opioid agonist treatment. Failure to abide by the requirements in these regulations may result in criminal prosecution, seizure of the drug supply, revocation of the program approval, and injunction precluding operation of the program. Regulatory Exceptions To The General Requirement For Certification To Provide Opioid Agonist Treatment: During inpatient care, when the patient was admitted for any condition other than concurrent opioid addiction (pursuant to 21CFR 1306.07(c)), to facilitate the treatment of the primary admitting diagnosis). During an emergency period of no longer than 3 days while definitive care for the addiction is being sought in an appropriately licensed facility (pursuant to 21CFR 1306.07(b)). 2 DOSAGE AND ADMINISTRATION 2.1 Important General Information • The peak respiratory depressant effect of methadone occurs later and persists longer than its peak therapeutic effect. • A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists. • With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity. • Methadone has a narrow therapeutic index, especially when combined with other drugs. 2.2 Initial Dosing for Management of Pain DOLOPHINE should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Consider the following important factors that differentiate methadone from other opioid analgesics: • There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals. • The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma elimination half-life is 8 to 59 hours. • Steady-state plasma concentrations, and full analgesic effects, are not attained until at least 3 to 5 days on a dose, and may take longer in some patients. Initiate the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with DOLOPHINE [see Warnings and Precautions (5.2)]. Use of DOLOPHINE as the First Opioid Analgesic: Initiate treatment with DOLOPHINE with 2.5 mg orally every 8 to 12 hours. Conversion from Other Oral Opioids to DOLOPHINE: Discontinue all other around-the-clock opioid drugs when DOLOPHINE therapy is initiated. Deaths have occurred in opioid-tolerant patients during conversion to methadone. While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient’s 24-hour oral methadone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral methadone requirements which could result in adverse reactions. With repeated dosing, the potency of methadone increases due to systemic accumulation. Consider the following when using the information in Table 1: • This is not a table of equinalgesic doses. • The conversion factors in this table are only for the conversion from another oral opioid analgesic to DOLOPHINE. • The table cannot be used to convert from DOLOPHINE to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose. Table 1: Conversion Factors to DOLOPHINE Total Daily Baseline Oral Morphine Equivalent Dose < 100 mg 100 to 300 mg Reference ID: 3725185 Estimated Daily Oral Methadone Requirement as Percent of Total Daily Morphine Equivalent Dose 20% to 30% 10% to 20% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 300 to 600 mg 8% to 12% 600 mg to 1000 mg 5% to 10% > 1000 mg < 5 % To calculate the estimated DOLOPHINE dose using Table 1: • For patients on a single opioid, sum the current total daily dose of the opioid, convert it to a Morphine Equivalent Dose according to specific conversion factor for that specific opioid, then multiply the Morphine Equivalent Dose by the corresponding percentage in the above table to calculate the approximate oral methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). • For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and sum the totals to obtain the approximate total methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). • For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion. Always round the dose down, if necessary, to the appropriate DOLOPHINE strength(s) available. Example conversion from a single opioid to DOLOPHINE: Step 1: Sum the total daily dose of the opioid (in this case, Morphine Extended Release Tablets 50 mg twice daily) 50 mg Morphine Extended Release Tablets 2 times daily = 100 mg total daily dose of Morphine Step 2: Calculate the approximate equivalent dose of DOLOPHINE based on the total daily dose of Morphine using Table 1. 100 mg total daily dose of Morphine x 15% (10% to 20% per Table 1) = 15 mg DOLOPHINE daily Step 3: Calculate the approximate starting dose of DOLOPHINE to be given every 12 hours. Round down, if necessary, to the appropriate DOLOPHINE tablets strengths available. 15 mg daily / 2 = 7.5 mg DOLOPHINE every 12 hours Then 7.5 mg is rounded down to 5 mg DOLOPHINE every 12 hours Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to DOLOPHINE. Conversion from Parenteral Methadone to DOLOPHINE: Use a conversion ratio of 1:2 mg for parenteral to oral methadone (e.g., 5 mg parenteral methadone to 10 mg oral methadone). 2.3 Titration and Maintenance of Therapy for Pain Individually titrate DOLOPHINE to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving DOLOPHINE to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics. Because of individual variability in the pharmacokinetic profile (i.e., terminal half-life (T 1/2 ) from 8 to 59 hours in different studies [see Clinical Pharmacology (12.3)]), titrate DOLOPHINE slowly, with dose increases no more frequent than every 3 to 5 days. However, because of this high variability, some patients may require substantially longer periods between dose increases (up to 12 days). Monitor patients closely for the development of potentially life-threatening adverse reactions (e.g., CNS and respiratory depression). Patients who experience breakthrough pain may require a dose increase of DOLOPHINE, or may need rescue medication with an appropriate dose of an immediate-release medication. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the DOLOPHINE dose. If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced and/or the dosing interval adjusted (i.e., every 8 hours or every 12 hours). Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.4 Discontinuation of DOLOPHINE for Pain When a patient no longer requires therapy with DOLOPHINE for pain, use a gradual downward titration, of the dose every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue DOLOPHINE. 2.5 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction For detoxification and maintenance of opioid dependence methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration. Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. An initial single dose of 20 to 30 mg of DOLOPHINE will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg. To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have been reached. Provide an additional 5 to 10 mg of DOLOPHINE if withdrawal symptoms have not been suppressed or if symptoms reappear. The total daily dose of DOLOPHINE on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone levels will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Instruct patients that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate. Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment episodes or dollars spent per day on illicit drug use. Short-term Detoxification: For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization, gradually decrease the dose of DOLOPHINE. Decrease the dose of DOLOPHINE on a daily basis or at 2-day intervals, keeping the amount of DOLOPHINE sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule. Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2.6 Titration and Maintenance Treatment of Opioid Dependence Detoxification Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day. 2.7 Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment. 2.8 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms [see Drug Abuse and Dependence (9.3)]. Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients. 2.9 Considerations for Management of Acute Pain During Methadone Maintenance Treatment Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone. 2.10 Dosage Adjustment During Pregnancy Methadone clearance may be increased during pregnancy. During pregnancy, a woman’s methadone dose may need to be increased or the dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)]. 3 DOSAGE FORMS AND STRENGTHS DOLOPHINE Tablets are available in 5 mg and 10 mg dosage strengths. The 5 mg tablets are round, white and are debossed with tablet identifier “54 162” on one side and scored on the other side. The 10 mg tablets are round, white and are debossed with tablet identifier “54 549” on one side and scored on the other side. 4 CONTRAINDICATIONS DOLOPHINE is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected paralytic ileus • Hypersensitivity (e.g., anaphylaxis) to methadone[see Adverse Reactions (6)]. 5 WARNINGS AND PRECAUTIONS 5.1 Addiction, Abuse and Misuse Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOLOPHINE contains methadone, a Schedule II controlled substance. As an opioid, DOLOPHINE exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. As long-acting opioids such as DOLOPHINE have pharmacological effects over an extended period of time, there is a greater risk for overdose and death. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed DOLOPHINE and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing DOLOPHINE, and monitor all patients receiving DOLOPHINE for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of DOLOPHINE for the proper management of pain in any given patient. Patients at increased risk may be prescribed long-acting opioids such as DOLOPHINE, but use in such patients necessitates intensive counseling about the risks and proper use of DOLOPHINE along with the intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of DOLOPHINE by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the methadone and can result in overdose and death [see Overdosage (10)]. Opioid agonists such as DOLOPHINE are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing DOLOPHINE. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug[see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of long-acting opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status[see Overdosage (10)]. Carbon dioxide (CO 2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of DOLOPHINE, the risk is greatest during the initiation of therapy or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing period. Closely monitor patients for respiratory depression when initiating therapy with DOLOPHINE and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of DOLOPHINE are essential [see Dosage and Administration (2.2, 2.3)]. Overestimating the DOLOPHINE dose when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of DOLOPHINE, especially by children, can result in respiratory depression and death due to overdose of methadone. 5.3 Life-Threatening QT Prolongation Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200 mg/day). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In most Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda patients on the lower doses typically used for maintenance, concomitant medications and/or clinical conditions such as hypokalemia were noted as contributing factors. However, the evidence strongly suggests that methadone possesses the potential for adverse cardiac conduction effects in some patients. The effects of methadone on the QT interval have been confirmed in in vivo laboratory studies, and methadone has been shown to inhibit cardiac potassium channels in in vitro studies. Closely monitor patients with risk factors for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia), a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction. QT prolongation has also been reported in patients with no prior cardiac history who have received high doses of methadone. Evaluate patients developing QT prolongation while on methadone treatment for the presence of modifiable risk factors, such as concomitant medications with cardiac effects, drugs that might cause electrolyte abnormalities, and drugs that might act as inhibitors of methadone metabolism. Only initiate DOLOPHINE therapy for pain in patients for whom the anticipated benefit outweighs the risk of QT prolongation and development of dysrhythmias that have been reported with high doses of methadone. The use of methadone in patients already known to have a prolonged QT interval has not been systematically studied. 5.4 Neonatal Opioid Withdrawal Syndrome Prolonged use of DOLOPHINE during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn [see Use in Special Populations (8.1)]. 5.5 Interactions with Central Nervous System Depressants Hypotension, profound sedation, coma, respiratory depression, and death may result if DOLOPHINE is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of DOLOPHINE in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that cause CNS depression. If the decision to begin DOLOPHINE is made, start with DOLOPHINE 2.5 mg every 12 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.1)]. 5.6 Use in Elderly, Cachectic, and Debilitated Patients Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating DOLOPHINE and when DOLOPHINE is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)]. Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.7 Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with DOLOPHINE, as in these patients, even usual therapeutic doses of DOLOPHINE may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2)]. Consider the use of alternative non-opioid analgesics in these patients if possible. 5.8 Hypotensive Effect DOLOPHINE may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions (7.1)]. Monitor these patients for signs of hypotension after initiating or titrating the dose of DOLOPHINE. 5.9 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking DOLOPHINE who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with DOLOPHINE. DOLOPHINE may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of DOLOPHINE in patients with impaired consciousness or coma. 5.10 Use in Patients with Gastrointestinal Conditions DOLOPHINE is contraindicated in patients with paralytic ileus. Avoid the use of DOLOPHINE in patients with other gastrointestinal obstruction. The methadone in DOLOPHINE may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase. 5.11 Use in Patients with Convulsive or Seizure Disorders The methadone in DOLOPHINE may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during DOLOPHINE therapy. 5.12 Avoidance of Withdrawal Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) and partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including DOLOPHINE. In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7.4)]. When discontinuing DOLOPHINE, gradually taper the dose [see Dosage and Administration (2.4)]. Do not abruptly discontinue DOLOPHINE. 5.13 Driving and Operating Machinery DOLOPHINE may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of DOLOPHINE and know how they will react to the medication. Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] • Life Threatening Respiratory Depression [see Warnings and Precautions (5.2)] • QT Prolongation[see Warnings and Precautions (5.3)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)] • Interactions with Other CNS Depressants[see Warnings and Precautions (5.5)] • Hypotensive Effect [see Warnings and Precautions (5.8)] • Gastrointestinal Effects [see Warnings and Precautions (5.10)] • Seizures [see Warnings and Precautions (5.11)] The major hazards of methadone are respiratory depression and, to a lesser degree, systemic hypotension. Respiratory arrest, shock, cardiac arrest, and death have occurred. The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not suffering severe pain. In such individuals, lower doses are advisable. Other adverse reactions include the following: Body as a Whole: asthenia (weakness), edema, headache Cardiovascular: arrhythmias, bigeminal rhythms, bradycardia, cardiomyopathy, ECG abnormalities, extrasystoles, flushing, heart failure, hypotension, palpitations, phlebitis, QT interval prolongation, syncope, T-wave inversion, tachycardia, torsades de pointes, ventricular fibrillation, ventricular tachycardia Central Nervous System: agitation, confusion, disorientation, dysphoria, euphoria, insomnia, hallucinations, seizures, visual disturbances Endocrine: hypogonadism Gastrointestinal: abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis Hematologic: reversible thrombocytopenia has been described in opioid addicts with chronic hepatitis Metabolic: hypokalemia, hypomagnesemia, weight gain Renal: antidiuretic effect, urinary retention or hesitancy Reproductive: amenorrhea, reduced libido and/or potency, reduced ejaculate volume, reduced seminal vesicle and prostate secretions, decreased sperm motility, abnormalities in sperm morphology Respiratory: pulmonary edema, respiratory depression Skin and Subcutaneous Tissue: pruritus, urticaria, other skin rashes, and rarely, hemorrhagic urticaria Hypersensitivity: Anaphylaxis has been reported with ingredients contained in DOLOPHINE. Advise patients how to recognize such a reaction and when to seek medical attention. Maintenance on a Stabilized Dose: During prolonged administration of methadone, as in a methadone maintenance treatment program, constipation and sweating often persist and hypogonadism, decreased serum testosterone and reproductive effects are thought to be related to chronic opioid use. Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOLOPHINE for the Detoxification and Maintenance Treatment of Opioid Dependence: During the induction phase of methadone maintenance treatment, patients are being withdrawn from illicit opioids and may have opioid withdrawal symptoms. Monitor patients for signs and symptoms including: lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose-flesh, fever, chilling alternating with flushing, restlessness, irritability, weakness, anxiety, depression, dilated pupils, tremors, tachycardia, abdominal cramps, body aches, involuntary twitching and kicking movements, anorexia, nausea, vomiting, diarrhea, intestinal spasms, and weight loss and consider dose adjustment as indicated. 7 DRUG INTERACTIONS 7.1 CNS Depressants The concomitant use of DOLOPHINE with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and DOLOPHINE for signs of respiratory depression, sedation and hypotension. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced [Warnings and Precautions (5.5)]. Deaths have been reported when methadone has been abused in conjunction with benzodiazepines. 7.2 Drugs Affecting Cytochrome P450 Isoenzymes Methadone undergoes hepatic N-demethylation by cytochrome P450 (CYP) isoforms, principally CYP3A4, CYP2B6, CYP2C19, and to a lesser extent by CYP2C9 and CYP2D6 [see Clinical Pharmacology (12.3)]. Inhibitors of CYP3A4 and 2C9: Because the CYP3A4 isoenzyme plays a major role in the metabolism of methadone, drugs that inhibit CYP3A4 activity may cause decreased clearance of methadone which could lead to an increase in methadone plasma concentrations and result in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of CYP 2C9 and 3A4 inhibitors. If co-administration with DOLOPHINE is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)]. Inducers of CYP3A4: CYP450 3A4 inducers may induce the metabolism of methadone and, therefore, may cause increased clearance of the drug which could lead to a decrease in methadone plasma concentrations, lack of efficacy or, possibly, development of a withdrawal syndrome in a patient who had developed physical dependence to methadone. If co-administration with DOLOPHINE is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)]. After stopping the treatment of a CYP3A4 inducer, as the effects of the inducer decline, methadone plasma concentration will increase which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. If co-administration or discontinuation of a CYP3A4 inducer with DOLOPHINE is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved[see Clinical Pharmacology (12.3)]. Paradoxical Effects of Antiretroviral Agents on DOLOPHINE: Concurrent use of certain antiretroviral agents with CYP3A4 inhibitory activity, alone and in combination, such as abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, and tipranvir+ritonavir, has resulted in increased clearance or decreased plasma levels of methadone. This may result in reduced efficacy of DOLOPHINE and could precipitate a withdrawal syndrome. Monitor methadone-maintained patients receiving any of these anti retroviral therapies closely for evidence of withdrawal effects and adjust the methadone dose accordingly. Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effects of DOLOPHINE on Antiretroviral Agents: Didanosine and Stavudine: Experimental evidence demonstrated that methadone decreased the area under the concentration-time curve (AUC) and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered. Zidovudine: Experimental evidence demonstrated that methadone increased the AUC of zidovudine, which could result in toxic effects. 7.3 Potentially Arrhythmogenic Agents Monitor patients closely for cardiac conduction changes when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with methadone. Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents such as class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Similarly, monitor patients closely when prescribing methadone concomitantly with drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia) that may prolong the QT interval, including diuretics, laxatives, and, in rare cases, mineralocorticoid hormones. 7.4 Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Mixed agonist/antagonist (i.e., pentazocine, nalbuphine and butorphanol) and partial agonist (buprenorphine) analgesics may reduce the analgesic effect of DOLOPHINE or precipitate withdrawal symptoms. Avoid the use of mixed agonist/antagonist and partial agonist analgesics in patients receiving DOLOPHINE. 7.5 Antidepressants Monoamine Oxidase (MAO) Inhibitors: Therapeutic doses of meperidine have precipitated severe reactions in patients concurrently receiving monoamine oxidase inhibitors or those who have received such agents within 14 days. Similar reactions thus far have not been reported with methadone. However, if the use of methadone is necessary in such patients, a sensitivity test should be performed in which repeated small, incremental doses of methadone are administered over the course of several hours while the patient’s condition and vital signs are carefully observed. Desipramine: Blood levels of desipramine have increased with concurrent methadone administration. 7.6 Anticholinergics Anticholinergics or other drugs with anticholinergic activity when used concurrently with opioids may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when DOLOPHINE is used concurrently with anticholinergic drugs. 7.7 Laboratory Test Interactions False positive urine drug screens for methadone have been reported for several drugs including diphenhydramine, doxylamine, clomipramine, chlorpromazine, thioridazine, quetiapine, and verapamil. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Clinical Considerations: Fetal/neonatal adverse reactions: Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly [see Warnings and Precautions (5.4)]. Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Teratogenic Effects - Pregnancy Category C: There are no adequate and well controlled studies in pregnant women. DOLOPHINE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Methadone has been shown to be teratogenic in the hamster at doses 2 times the human daily oral dose (120 mg/day on a mg/m2 basis) and in mice at doses equivalent to the human daily oral dose (120 mg/day on a mg/m2 basis). Increased neonatal mortality and significant differences in behavioral tests have been reported in the offspring of male rodents that were treated with methadone prior to mating when compared to control animals. Methadone has been detected in human amniotic fluid and cord plasma at concentrations proportional to maternal plasma and in newborn urine at lower concentrations than corresponding maternal urine. Dosage Adjustment during Pregnancy: The disposition of oral methadone has been studied in approximately 30 pregnant patients in 2nd and 3rd trimesters. Total body clearance of methadone was increased in pregnant patients compared to the same patients postpartum or to non-pregnant opioid-dependent women. The terminal half-life of methadone is decreased during 2nd and 3rd trimesters. The decrease in plasma half-life and increased clearance of methadone resulting in lower methadone trough levels during pregnancy can lead to withdrawal symptoms in some pregnant patients. The dosage may need to be increased or the dosing interval decreased in pregnant patients receiving methadone to achieve therapeutic effect [see Dosage and Administration (2.10)]. Effects on the Neonate: Babies born to mothers who have been taking opioids regularly prior to delivery may be physically dependent. Onset of withdrawal symptoms in infants is usually in the first days after birth. Monitor newborn for withdrawal signs and symptoms including: poor feeding, irritability, excessive crying, tremors, rigidity, hyper-active reflexes, increased respiratory rate, diarrhea, sneezing, yawning, vomiting, fever, and seizures. The intensity of the neonatal withdrawal syndrome does not always correlate with the maternal dose or the duration of maternal exposure. The duration of the withdrawal signs may vary from a few days to weeks or even months. There is no consensus on the appropriate management of infant withdrawal [see Warnings and Precautions (5.4)]. Human Data: Reported studies have generally compared the benefit of methadone to the risk of untreated addiction to illicit drugs; the relevance of these findings to pain patients prescribed methadone during pregnancy is unclear. Pregnant women involved in methadone maintenance programs have been reported to have significantly improved prenatal care leading to significantly reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality when compared to women using illicit drugs. Several factors, including maternal use of illicit drugs, nutrition, infection and psychosocial circumstances, complicate the interpretation of investigations of the children of women who take methadone during pregnancy. Information is limited regarding dose and duration of methadone use during pregnancy, and most maternal exposure appears to occur after the first trimester of pregnancy. A review of published data on experiences with methadone use during pregnancy by the Teratogen Information System (TERIS) concluded that maternal use of methadone during pregnancy as part of a supervised, therapeutic regimen is unlikely to pose a substantial teratogenic risk (quantity and quality of data assessed as “limited to fair”). However, the data are insufficient to state that there is no risk (TERIS, last reviewed October, 2002). A retrospective case series of 101 pregnant, opioid-dependent women who underwent inpatient opioid detoxification with methadone did not demonstrate any increased risk of miscarriage in the 2nd trimester or premature delivery in the 3rd trimester. Recent studies suggest an increased risk of premature delivery in opioid-dependent women exposed to methadone during pregnancy, although the presence of confounding factors makes it difficult to determine a causal relationship. Several studies have suggested that infants born to narcotic-addicted women treated with methadone during all or part of pregnancy have been found to have decreased fetal growth with reduced birth weight, length, and/or head circumference compared to controls. This growth deficit does not appear to persist into later childhood. Children prenatally exposed to methadone have been reported to demonstrate mild but persistent deficits in performance on psychometric and behavioral tests. In addition, several studies suggest that children born to opioid-dependent women exposed to methadone during pregnancy may have an increased risk of visual development anomalies; however, a causal relationship has not been assigned. Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There are conflicting reports on whether Sudden Infant Death Syndrome occurs with an increased incidence in infants born to women treated with methadone during pregnancy. Abnormal fetal non-stress tests have been reported to occur more frequently when the test is performed 1 to 2 hours after a maintenance dose of methadone in late pregnancy compared to controls. Animal Data: Methadone did not produce teratogenic effects in rat or rabbit models. Methadone produced teratogenic effects following large doses, in the guinea pig, hamster and mouse. One published study in pregnant hamsters indicated that a single subcutaneous dose of methadone ranging from 31 to 185 mg/kg (the 31 mg/kg dose is approximately 2 times a human daily oral dose of 120 mg/day on a mg/m2 basis) on day 8 of gestation resulted in a decrease in the number of fetuses per litter and an increase in the percentage of fetuses exhibiting congenital malformations described as exencephaly, cranioschisis, and “various other lesions.” The majority of the doses tested also resulted in maternal death. In another study, a single subcutaneous dose of 22 to 24 mg/kg methadone (estimated exposure was approximately equivalent to a human daily oral dose of 120 mg/day on a mg/m2 basis) administered on day 9 of gestation in mice also produced exencephaly in 11% of the embryos. However, no effects were reported in rats and rabbits at oral doses up to 40 mg/kg (estimated exposure was approximately 3 and 6 times, respectively, a human daily oral dose of 120 mg/day on a mg/m2 basis) administered during days 6 to 15 and 6 to 18, respectively. Published animal data have reported increased neonatal mortality in the offspring of male rodents that were treated with methadone prior to mating. In these studies, the female rodents were not treated with methadone, indicating paternally- mediated developmental toxicity. Specifically, methadone administered to the male rat prior to mating with methadone- naïve females resulted in decreased weight gain in progeny after weaning. The male progeny demonstrated reduced thymus weights, whereas the female progeny demonstrated increased adrenal weights. Behavioral testing of these male and female progeny revealed significant differences in behavioral tests compared to control animals, suggesting that paternal methadone exposure can produce physiological and behavioral changes in progeny in this model. Other animal studies have reported that perinatal exposure to opioids including methadone alters neuronal development and behavior in the offspring. Perinatal methadone exposure in rats has been linked to alterations in learning ability, motor activity, thermal regulation, nociceptive responses and sensitivity to drugs. Additional animal data demonstrates evidence for neurochemical changes in the brains of methadone-treated offspring, including changes to the cholinergic, dopaminergic, noradrenergic and serotonergic systems. Studies demonstrated that methadone treatment of male rats for 21 to 32 days prior to mating with methadone-naïve females did not produce any adverse effects, suggesting that prolonged methadone treatment of the male rat resulted in tolerance to the developmental toxicities noted in the progeny. Mechanistic studies in this rat model suggest that the developmental effects of “paternal” methadone on the progeny appear to be due to decreased testosterone production. These animal data mirror the reported clinical findings of decreased testosterone levels in human males on methadone maintenance therapy for opioid addiction and in males receiving chronic intraspinal opioids. Additional data have been published indicating that methadone treatment of male rats (once a day for three consecutive days) increased embryolethality and neonatal mortality. Examination of uterine contents of methadone-naïve female mice bred to methadone-treated mice indicated that methadone treatment produced an increase in the rate of preimplantation deaths in all post-meiotic states. 8.2 Labor and Delivery Opioids cross the placenta and may produce respiratory depression in neonates. DOLOPHINE is not for use in women during and immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8.3 Nursing Mothers Methadone is secreted into human milk. At maternal oral doses of 10 to 80 mg/day, methadone concentrations from 50 to 570 mcg/L in milk have been reported, which, in the majority of samples, were lower than maternal serum drug concentrations at steady state. Peak methadone levels in milk occur approximately 4 to 5 hours after an oral dose. Based on an average milk consumption of 150 mL/kg/day, an infant would consume approximately 17.4 mcg/kg/day which is approximately 2 to 3% of the oral maternal dose. Methadone has been detected in very low plasma concentrations in some infants whose mothers were taking methadone. Cases of sedation and respiratory depression in infants exposed to methadone through breast milk have been reported. Caution should be exercised when methadone is administered to a nursing woman. Advise women who are being treated with methadone and who are breastfeeding or express a desire to breastfeed of the presence of methadone in human milk. Instruct breastfeeding mothers how to identify respiratory depression and sedation in their babies and when it may be necessary to contact their healthcare provider or seek immediate medical care. Breastfed infants of mothers using methadone should be weaned gradually to prevent development of withdrawal symptoms in the infant. 8.4 Pediatric Use The safety, effectiveness, and pharmacokinetics of methadone in pediatric patients below the age of 18 years have not been established. 8.5 Geriatric Use Clinical studies of methadone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, start elderly patients at the low end of the dosing range, taking into account the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients. Closely monitor elderly patients for signs of respiratory and central nervous system depression. 8.6 Renal Impairment Methadone pharmacokinetics have not been extensively evaluated in patients with renal insufficiency. Since unmetabolized methadone and its metabolites are excreted in urine to a variable degree, start these patients on lower doses and with longer dosing intervals and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression. 8.7 Hepatic Impairment Methadone has not been extensively evaluated in patients with hepatic insufficiency. Methadone is metabolized by hepatic pathways; therefore, patients with liver impairment may be at risk of increased systemic exposure to methadone after multiple dosing. Start these patients on lower doses and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Methadone is a mu-agonist opioid with an abuse liability similar to other opioid agonists and is a Schedule II controlled substance. Methadone can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)]. Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9.2 Abuse All patients treated with opioids for pain management require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the counter drug to get “high”, or the use of steroids for performance enhancement and muscle build up. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of lost prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. DOLOPHINE, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record- keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state law, is strongly advised. Risks Specific to Abuse of DOLOPHINE: Abuse of DOLOPHINE poses a risk of overdose and death. This risk is increased with concurrent abuse of methadone and alcohol or other substances. DOLOPHINE is for oral use only and must not be injected. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Proper assessment and selection of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. 9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. DOLOPHINE should not be abruptly discontinued [see Dosage and Administration (2.4)]. If DOLOPHINE is abruptly discontinued in a physically dependent patient, an abstinence syndrome may occur. Some or all of the following can Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1) and Warnings and Precautions (5.4)]. 10 OVERDOSAGE Clinical Presentation Acute overdosage of methadone is manifested by respiratory depression, somnolence progressing to stupor or coma, maximally constricted pupils, skeletal-muscle flaccidity, cold and clammy skin, and sometimes, bradycardia and hypotension. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. The opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to methadone overdose. Such agents should be administered cautiously to patients who are known, or suspected to be, physically dependent on DOLOPHINE. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome. Because the duration of reversal would be expected to be less than the duration of action of methadone in DOLOPHINE, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be given as directed in the product’s prescribing information. In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal. The severity of the withdrawal produced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. 11 DESCRIPTION Methadone hydrochloride is chemically described as 6-(dimethylamino)-4,4-diphenyl-3-hepatanone hydrochloride. Methadone hydrochloride is a white, crystalline material that is water-soluble. Its molecular formula is C21H27NO• HCl and it has a molecular weight of 345.91. Methadone hydrochloride has a melting point of 235°C, and a pKa of 8.25 in water at 20°C. Its octanol/water partition coefficient at pH 7.4 is 117. A solution (1:100) in water has a pH between 4.5 and 6.5. It has the following structural formula: Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula Each DOLOPHINE tablet contains 5 or 10 mg of methadone hydrochloride, USP and the following inactive ingredients: magnesium stearate, microcrystalline cellulose, and starch. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methadone hydrochloride is a mu-agonist; a synthetic opioid analgesic with multiple actions qualitatively similar to those of morphine, the most prominent of which involves the central nervous system and organs composed of smooth muscle. The principal therapeutic uses for methadone are for analgesia and for detoxification or maintenance in opioid addiction. The methadone withdrawal syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe. Some data also indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor. The contribution of NMDA receptor antagonism to methadone’s efficacy is unknown. Other NMDA receptor antagonists have been shown to produce neurotoxic effects in animals. 12.3 Pharmacokinetics Absorption: Following oral administration the bioavailability of methadone ranges between 36 to 100% and peak plasma concentrations are achieved between 1 to 7.5 hours. Dose proportionality of methadone pharmacokinetics is not known. However, after administration of daily oral doses ranging from 10 to 225 mg, the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food on the bioavailability of methadone has not been evaluated. Distribution: Methadone is a lipophilic drug and the steady-state volume of distribution ranges between 1.0 to 8.0 L/kg. In plasma, methadone is predominantly bound to α1-acid glycoprotein (85% to 90%). Methadone is secreted in saliva, breast milk, amniotic fluid and umbilical cord plasma. Metabolism: Methadone is primarily metabolized by N-demethylation to an inactive metabolite, 2-ethylidene-1,5 dimethyl-3,3-diphenylpyrrolidene (EDDP). Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, and CYP2C19 and to a lesser extent CYP2C9 and CYP2D6, are responsible for conversion of methadone to EDDP and other inactive metabolites, which are excreted mainly in the urine. Methadone appears to be a substrate for P-glycoprotein but its pharmacokinetics do not appear to be significantly altered in case of P-glycoprotein polymorphism or inhibition. Excretion: The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Published reports indicate that after multiple dose administration the apparent plasma clearance of methadone ranged between 1.4 and 126 L/h, and the terminal half-life (T 1/2 ) was highly variable and ranged between 8 to 59 hours in different studies. Methadone is a basic (pKa=9.2) compound and the pH of the urinary tract can alter its disposition in plasma. Also, since methadone is lipophilic, it has been known to persist in the liver and other tissues. The slow release from the liver and other tissues may prolong the duration of methadone action despite low plasma concentrations. Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions: Cytochrome P450 Interactions: Methadone undergoes hepatic N-demethylation by cytochrome P450 (CYP) isoforms, principally CYP3A4, CYP2B6, CYP2C19, and to a lesser extent by CYP2C9 and CYP2D6. Coadministration of methadone with CYP inducers may result in more rapid metabolism and potential for decreased effects of methadone, whereas administration with CYP inhibitors may reduce metabolism and potentiate methadone’s effects. Although antiretroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination are known to inhibit some CYPs, they are shown to reduce the plasma levels of methadone, possibly due to CYP induction activity [see Drug Interactions (7.2)]. Therefore, drugs administered concomitantly with methadone should be evaluated for interaction potential; clinicians are advised to evaluate individual response to drug therapy. Cytochrome P450 Inducers: The following drug interactions were reported following coadministration of methadone with known inducers of cytochrome P450 enzymes: Rifampin: In patients well-stabilized on methadone, concomitant administration of rifampin resulted in a marked reduction in serum methadone levels and a concurrent appearance of withdrawal symptoms. Phenytoin: In a pharmacokinetic study with patients on methadone maintenance therapy, phenytoin administration (250 mg twice daily initially for 1 day followed by 300 mg daily for 3 to 4 days) resulted in an approximately 50% reduction in methadone exposure and withdrawal symptoms occurred concurrently. Upon discontinuation of phenytoin, the incidence of withdrawal symptoms decreased and methadone exposure increased to a level comparable to that prior to phenytoin administration. St. John’s Wort, Phenobarbital, Carbamazepine: Administration of methadone with other CYP3A4 inducers may result in withdrawal symptoms. Cytochrome P450 Inhibitors: Since the metabolism of methadone is mediated primarily by CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of methadone. Voriconazole: Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days) increased the peak plasma concentration (C max ) and AUC of (R)-methadone by 31% and 47%, respectively, in subjects receiving a methadone maintenance dose (30 to 100 mg daily. The C max and AUC of (S) methadone increased by 65% and 103%, respectively. Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed [see Drug Interactions (7.2)]. Antiretroviral drugs: Although antiretroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir combination are known to inhibit some CYPs, they are shown to reduce the plasma levels of methadone, possibly due to CYP induction activity. Abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, tipranvir+ritonavir combination: Coadministration of these anti-retroviral agents resulted in increased clearance or decreased plasma levels of methadone[see Drug Interactions (7.2)]. Didanosine and Stavudine: Methadone decreased the AUC and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered[see Drug Interactions (7.2)]. Zidovudine: Methadone increased the AUC of zidovudine which could result in toxic effects [see Drug Interactions (7.2)]. Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: The results of carcinogenicity assessment in B6C2F1 mice and Fischer 344 rats following dietary administration of two doses of methadone HCl have been published. Mice consumed 15 mg/kg/day or 60 mg/kg/day methadone for two years. These doses were approximately 0.6 and 2.5 times a human daily oral dose of 120 mg/day on a body surface area basis (mg/m2). There was a significant increase in pituitary adenomas in female mice treated with 15 mg/kg/day but not with 60 mg/kg/day. Under the conditions of the assay, there was no clear evidence for a treatment- related increase in the incidence of neoplasms in male rats. Due to decreased food consumption in males at the high dose, male rats consumed 16 mg/kg/day and 28 mg/kg/day of methadone for two years. These doses were approximately 1.3 and 2.3 times a human daily oral dose of 120 mg/day, based on body surface area comparison. In contrast, female rats consumed 46 mg/kg/day or 88 mg/kg/day for two years. These doses were approximately 3.7 and 7.1 times a human daily oral dose of 120 mg/day, based on body surface area comparison. Under the conditions of the assay, there was no clear evidence for a treatment-related increase in the incidence of neoplasms in either male or female rats. Mutagenesis: There are several published reports on the potential genetic toxicity of methadone. Methadone tested positive in the in vivo mouse dominant lethal assay and the in vivo mammalian spermatogonial chromosome aberration test. Additionally, methadone tested positive in the E. coli DNA repair system and Neurospora crassa and mouse lymphoma forward mutation assays. In contrast, methadone tested negative in tests for chromosome breakage and disjunction and sex-linked recessive lethal gene mutations in germ cells of Drosophila using feeding and injection procedures. Fertility: Published animal studies show that methadone treatment of males can alter reproductive function. Methadone produces a significant regression of sex accessory organs and testes of male mice and rats. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Storage and Handling DOLOPHINE contains methadone which is a controlled substance. Like fentanyl, morphine, oxycodone, hydromorphone, and oxymorphone, methadone is controlled under Schedule II of the Federal Controlled Substances Act. DOLOPHINE may be targeted for theft and diversion by criminals [see Warnings and Precautions (5.1)]. Dispense in a tight, light-resistant container as defined in the USP/NF. Store at 25ºC (77ºF); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. 16.2 How Supplied DOLOPHINE Tablets, USP 5 mg Tablets: round, white tablets debossed with tablet identifier 54 162 on one side and scored on the other side. NDC 0054-4218-25: Bottles of 100 tablets. 10 mg Tablets: round, white tablet debossed with tablet identifier 54 549 on one side and scored on the other side. NDC 0054-4219-25: Bottles of 100 tablets. DEA order form required. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Addiction, Abuse, and Misuse: Inform patients that the use of DOLOPHINE, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see Warnings and Precautions (5.1)]. Instruct patients not to share DOLOPHINE with others and to take steps to protect DOLOPHINE from theft or misuse. Life-threatening Respiratory Depression: Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting DOLOPHINE or when the dose is increased, and that it can occur even at recommended doses [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Ingestion: Inform patients that accidental ingestion, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store DOLOPHINE securely and to dispose of unused DOLOPHINE by flushing the tablets down the toilet. Symptoms of Arrhythmia: Instruct patients to seek medical attention immediately if they experience symptoms suggestive of an arrhythmia (such as palpitations, near syncope, or syncope) when taking methadone. Neonatal Opioid Withdrawal Syndrome: Inform female patients of reproductive potential that prolonged use of DOLOPHINE during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4)]. Interactions with Alcohol and other CNS Depressants: Inform patients that potentially serious additive effects may occur if DOLOPHINE is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a health care provider. Important Administration Instructions: Instruct patients how to properly take DOLOPHINE, including the following: • Use DOLOPHINE exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) • Do not discontinue DOLOPHINE without first discussing the need for a tapering regimen with the prescriber Hypotension: Inform patients that DOLOPHINE may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position). Driving or Operating Heavy Machinery: Inform patients that DOLOPHINE may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication. Constipation: Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention. Anaphylaxis: Inform patients that anaphylaxis has been reported with ingredients contained in DOLOPHINE. Advise patients how to recognize such a reaction and when to seek medical attention. Breastfeeding: Instruct nursing mothers using DOLOPHINE to watch for signs of methadone toxicity in their infants, which include increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby’s healthcare provider immediately if they notice these signs. If they cannot reach the healthcare provider right away, instruct them to take the baby to the emergency room or call 911 (or local emergency services). Disposal of Unused DOLOPHINE: Advise patients to flush the unused tablets down the toilet when DOLOPHINE is no longer needed. Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Roxane Laboratories, Inc. Columbus, Ohio 43216 www.Roxane.com, or call 1-800-962-8364 4077444//07 Revised March 2015 © RLI, 2015 Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE DOLOPHINE® (DOL-o-feen) (methadone hydrochloride) tablets, CII DOLOPHINE is: • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require daily around-the-clock, long-term treatment with an opioid, when other pain treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them. • A long-acting opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse than can lead to death. • Not for use to treat pain that is not around-the-clock. • Also used to manage drug addiction. Important information about DOLOPHINE: • Get emergency help right away if you take too much DOLOPHINE (overdose). When you first start taking DOLOPHINE, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. • Never give anyone your DOLOPHINE. They could die from taking it. Store DOLOPHINE away from children and in a safe place to prevent stealing or abuse. Selling or giving away DOLOPHINE is against the law. Do not take DOLOPHINE if you have: • severe asthma, trouble breathing, or other lung problems. • a bowel blockage or have narrowing of the stomach or intestines. Before taking DOLOPHINE, tell your healthcare provider if you have a history of: • head injury, seizures • liver, kidney, thyroid problems • problems urinating • heart rhythm problems (Long QT syndrome) • pancreas or gallbladder problems • abuse of street or prescription drugs, alcohol addiction, or mental health problems. Tell your healthcare provider if you are: • pregnant or planning to become pregnant. Prolonged use of DOLOPHINE during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. • breastfeeding. DOLOPHINE passes into breast milk and may harm your baby. • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking DOLOPHINE with certain other medicines may cause serious side effects. When taking DOLOPHINE: • Do not change your dose. Take DOLOPHINE exactly as prescribed by your healthcare provider. • Do not take more than your prescribed dose in 24 hours. If you take DOLOPHINE for pain and miss a dose, take DOLOPHINE as soon as possible and then take your next dose 8 or 12 hours later as directed by your healthcare provider. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. • If you take DOLOPHINE for opioid addiction and miss a dose, take your next dose the following day as scheduled. Do not take extra doses. Taking more than the prescribed dose may cause you to overdose because DOLOPHINE builds up in your body over time. • Do not crush, dissolve, snort or inject DOLOPHINE because this may cause you to overdose and die. • Call your healthcare provider if the dose you are taking does not control your pain. • Do not stop taking DOLOPHINE without talking to your healthcare provider. • After you stop taking DOLOPHINE, flush any unused tablets down the toilet. While taking DOLOPHINE DO NOT: • Drive or operate heavy machinery, until you know how DOLOPHINE affects you. DOLOPHINE can make you sleepy, dizzy, or lightheaded. • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with DOLOPHINE may cause you to overdose and die. The possible side effects of DOLOPHINE are: • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe. Get emergency medical help if you have: • trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, light-headedness when changing positions, or you are feeling faint. These are not all the possible side effects of DOLOPHINE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov. Manufactured by: Roxane Laboratories, Inc., Columbus, Ohio 43216, www.Roxane.com, or call 1-800-962-8364 This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: April 2014 Reference ID: 3725185 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:35.494187	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/006134s038lbl.pdf', 'application_number': 6134, 'submission_type': 'SUPPL ', 'submission_number': 38}
10,684	PROPYLTHIOURACIL TABLETS, USP PROPYLTHIOURACIL TABLETS, USP DESCRIPTION WARNING: Severe liver injury and acute liver failure, in some cases fatal, have been reported in patients treated with propylthiouracil. These reports of hepatic reactions include cases requiring liver transplantation in adult and pediatric patients. Propylthiouracil should be reserved for patients who can not tolerate methimazole and in whom radioactive iodine therapy or surgery are not appropriate treatments for the management of hyperthyroidism. Because of the risk of fetal abnormalities associated with methimazole, propylthiouracil may be the treatment of choice when an antithyroid drug is indicated during or just prior to the first trimester of pregnancy (see Warnings and Precautions). Propylthiouracil is one of the thiocarbamide compounds. It is a white, crystalline substance that has a bitter taste and is very slightly soluble in water. Propylthiouracil is an antithyroid drug administered orally. The structural formula is: Each tablet contains propylthiouracil 50 mg and the following inactive ingredients: corn starch, docusate sodium, magnesium stearate, microcrystalline cellulose, modified food starch, sodium benzoate, and sodium starch glycolate. CLINICAL PHARMACOLOGY Propylthiouracil inhibits the synthesis of thyroid hormones and thus is effective in the treatment of hyperthyroidism. The drug does not inactivate existing thyroxine and triiodothyronine that are stored in the thyroid or circulating in the blood, nor does it interfere with the effectiveness of thyroid hormones given by mouth or by injection. Propylthiouracil inhibits the conversion of thyroxine to triiodothyronine in peripheral tissues and may therefore be an effective treatment for thyroid storm. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Propylthiouracil is readily absorbed and is extensively metabolized. Approximately 35% of the drug is excreted in the urine, in intact and conjugated forms, within 24 hours. INDICATIONS AND USAGE Propylthiouracil is indicated: • in patients with Graves’ disease with hyperthyroidism or toxic multinodular goiter who are intolerant of methimazole and for whom surgery or radioactive iodine therapy is not an appropriate treatment option • to ameliorate symptoms of hyperthyroidism in preparation for thyroidectomy or radioactive iodine therapy in patients who are intolerant of methimazole CONTRAINDICATION Propylthiouracil is contraindicated in patients who have demonstrated hypersensitivity to the drug or any of the other product components. WARNINGS Liver Toxicity Liver injury resulting in liver failure, liver transplantation, or death, has been reported with propylthiouracil therapy in adult and pediatric patients. No cases of liver failure have been reported with the use of methimazole in pediatric patients. For this reason, propylthiouracil is not recommended for pediatric patients except when methimazole is not well-tolerated and surgery or radioactive iodine therapy are not appropriate therapies. There are cases of liver injury, including liver failure and death, in women treated with propylthiouracil during pregnancy. Two reports of in utero exposure with liver failure and death of a newborn have been reported. The use of an alternative antithyroid medication (e.g., methimazole) may be advisable following the first trimester of pregnancy (see Precautions, Pregnancy). Biochemical monitoring of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT, AST) is not expected to attenuate the risk of severe liver injury due to its rapid and unpredictable onset. Patients should be informed of the risk of liver failure. Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, right upper quadrant pain, etc.), particularly in the first six months of therapy. When these symptoms occur, propylthiouracil should be discontinued immediately This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and liver function tests and ALT and AST levels obtained. Agranulocytosis Agranulocytosis occurs in approximately 0.2% to 0.5% of patients and is a potentially life-threatening side effect of propylthiouracil therapy. Agranulocytosis typically occurs within the first 3 months of therapy. Patients should be instructed to immediately report any symptoms suggestive of agranulocytosis, such as fever or sore throat. Leukopenia, thrombocytopenia, and aplastic anemia (pancytopenia) may also occur. Propylthiouracil should be discontinued if agranulocytosis, aplastic anemia (pancytopenia), ANCA- positive vasculitis, hepatitis, interstitial pneumonitis, fever, or exfoliative dermatitis is suspected, and the patient's bone marrow indices should be obtained. Hypothyroidism Propylthiouracil can cause hypothyroidism necessitating routine monitoring of TSH and free T4 levels with adjustments in dosing to maintain a euthyroid state. Because the drug readily crosses placental membranes, propylthiouracil can cause fetal goiter and cretinism when administered to a pregnant woman (see Precautions, Pregnancy). PRECAUTIONS General Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, jaundice, light colored stools, dark urine, right upper quadrant pain, etc.), particularly in the first six months of therapy. When these symptoms occur, measurement should be made of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT/AST levels). Patients who receive propylthiouracil should be under close surveillance and should be counseled regarding the necessity of immediately reporting any evidence of illness, particularly sore throat, skin eruptions, fever, headache, or general malaise. In such cases, white blood cell and differential counts should be obtained to determine whether agranulocytosis has developed. Particular care should be exercised with patients who are receiving concomitant drugs known to be associated with agranulocytosis. Information for Patients Patients should be advised that if they become pregnant or intend to become pregnant while taking an antithyroid drug, they should contact their physician immediately about their therapy. Patients should report immediately any evidence of illness, in particular sore This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda throat, skin eruptions, fever, headache, or general malaise. They also should report symptoms suggestive of hepatic dysfunction (anorexia, pruritus, right upper quadrant pain, etc.). Laboratory Tests Because propylthiouracil may cause hypoprothrombinemia and bleeding, monitoring of prothrombin time should be considered during therapy with the drug, especially before surgical procedures. Thyroid function tests should be monitored periodically during therapy. Once clinical evidence of hyperthyroidism has resolved, the finding of an elevated serum TSH indicates that a lower maintenance dose of propylthiouracil should be employed. Drug Interactions Anticoagulants (oral): Due to the potential inhibition of vitamin K activity by propylthiouracil, the activity of oral anticoagulants (e.g., warfarin) may be increased; additional monitoring of PT/INR should be considered, especially before surgical procedures. Beta-adrenergic blocking agents: Hyperthyroidism may cause an increased clearance of beta blockers with a high extraction ratio. A reduced dose of beta- adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid. Digitalis glycosides: Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; a reduced dose of digitalis glycosides may be needed. Theophylline: Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed. Carcinogenesis, Mutagenesis, Impairment of Fertility Laboratory animals treated with propylthiouracil for >1 year have demonstrated thyroid hyperplasia and carcinoma formation. Such animal findings are seen with continuous suppression of thyroid function by sufficient doses of a variety of antithyroid agents, as well as in dietary iodine deficiency, subtotal thyroidectomy, and implantation of autonomous thyrotropic hormone-secreting pituitary tumors. Pituitary adenomas have also been described. Pregnancy Because propylthiouracil readily crosses placental membranes and can induce goiter and even cretinism in the developing fetus, it is important that a sufficient, but not excessive, dose be given during pregnancy. In many This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda pregnant women, the thyroid dysfunction diminishes as the pregnancy proceeds; consequently a reduction of dosage may be possible. In some instances, propylthiouracil can be withdrawn several weeks or months before delivery. If propylthiouracil is used during pregnancy, or if the patient becomes pregnant while taking propylthiouracil, the patient should be warned of the rare potential hazard to the mother and fetus of liver damage. Since methimazole may be associated with the rare development of fetal abnormalities such as aplasia cutis and choanal atresia, propylthiouracil may be the preferred agent during organogenesis, in the first trimester of pregnancy. Given the potential maternal adverse effects of propylthiouracil (e.g., hepatotoxicity), it may be preferable to switch from propylthiouracil to methimazole for the second and third trimesters. Pregnancy Category D. See WARNINGS. Nursing Mothers Propylthiouracil is transferred to breast milk to a small extent and therefore likely results in clinically insignificant doses to the suckling infant. In one study, nine lactating women were administered 400 mg of propylthiouracil by mouth. The mean amount of propylthiouracil excreted during 4 hours after drug administration was 0.025% of the administered dose. Pediatric Use Postmarketing reports of severe liver injury including hepatic failure requiring liver transplantation or resulting in death have been reported in the pediatric population. No such reports have been observed with methimazole. As such, propylthiouracil is not recommended for use in the pediatric population except in rare instances in which methimazole is not well-tolerated and surgery or radioactive iodine therapy are not appropriate. When used in children, parents and patients should be informed of the risk of liver failure. If patients taking propylthiouracil develop tiredness, nausea, anorexia, fever, pharyngitis, or malaise, propylthiouracil should be discontinued immediately by the patient, a physician should be contacted, and a white blood cell count, liver function tests, and transaminase levels obtained. ADVERSE REACTIONS Major adverse reactions (much less common than the minor adverse reactions) include liver injury resulting in hepatitis, liver failure, a need for liver transplantation or death. Inhibition of myelopoiesis (agranulocytosis, granulopenia, and thrombocytopenia), aplastic anemia, drug fever, a lupus-like syndrome (including splenomegaly and vasculitis), This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hepatitis, periarteritis, and hypoprothrombinemia and bleeding have been reported. Nephritis, glomerulonephritis, interstitial pneumonitis, exfoliative dermatitis, and erythema nodosum have been reported. Reports of a vasculitis syndrome associated with the presence of anti-neutrophilic cytoplasmic antibodies (ANCA) have also been received. Manifestations of ANCA-positive vasculitis may include rapidly progressive glomerulonephritis (crescentic and pauci-immune necrotizing glomerulonephritis), sometimes leading to acute renal failure; pulmonary infiltrates or alveolar hemorrhage; skin ulcers; and leukocytoclastic vasculitis. Minor adverse reactions include skin rash, urticaria, nausea, vomiting, epigastric distress, arthralgia, paresthesias, loss of taste, taste perversion, abnormal loss of hair, myalgia, headache, pruritus, drowsiness, neuritis, edema, vertigo, skin pigmentation, jaundice, sialadenopathy, and lymphadenopathy. It should be noted that about 10% of patients with untreated hyperthyroidism 3 have leukopenia (white blood cell count of less than 4,000/mm ), often with relative granulopenia. OVERDOSAGE Signs and Symptoms Nausea, vomiting, epigastric distress, headache, fever, arthralgia, pruritus, edema, and pancytopenia. Agranulocytosis is the most serious effect. Rarely, exfoliative dermatitis, hepatitis, neuropathies or CNS stimulation or depression may occur. No information is available on the following: LD50; concentration of propylthiouracil in biologic fluids associated with toxicity and/or death; the amount of drug in a single dose usually associated with symptoms of overdosage; or the amount of propylthiouracil in a single dose likely to be life-threatening. Treatment To obtain up-to-date information about the treatment of overdose, a good resource is the certified Regional Poison Control Center. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in the patient. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s medical status. DOSAGE AND ADMINISTRATION Propylthiouracil is administered orally. The total daily dosage is usually given in 3 equal doses at approximately 8 hour intervals. Adults This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The initial dose is 300 mg daily. In patients with severe hyperthyroidism, very large goiters, or both, the initial dose may be increased to 400 mg daily; an occasional patient will require 600 to 900 mg daily initially. The usual maintenance dose is 100 to 150 mg daily. Pediatric Patients Propylthiouracil is generally not recommended for use in the pediatric patient population except in rare instances in which other alternative therapies are not appropriate options. Studies evaluating appropriate dosing regimen have not been conducted in the pediatric population although general practice would suggest initiation of therapy in patients 6 years or older at a dosage of 50 mg daily with careful upward titration based on clinical response and evaluation of TSH and free T4 levels. Although cases of severe liver injury have been reported with doses as low as 50 mg/day, most cases were associated with doses of 300 mg/day and higher. HOW SUPPLIED Propylthiouracil Tablets, USP, 50 mg, are round, white, scored tablets, engraved LL and P33, supplied as: NDC 67253-651-10 Bottle of 100; NDC 67253-651-11 Bottle of 1000. Store at controlled room temperature 15°-30°C (59° -86°F). REFERENCE 1. International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. 1974; 7; 67-76. DAVA Pharmaceuticals, Inc. Fort Lee, NJ 07024 Rev. 1 - January 2010 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:35.519781	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/006188s020lbl.pdf', 'application_number': 6188, 'submission_type': 'SUPPL ', 'submission_number': 20}
10,685	PROPYLTHIOURACIL - propylthiouracil tablet DAVA International Inc. WARNING: Severe liver injury and acute liver failure, in some cases fatal, have been reported in patients treated with propylthiouracil. These reports of hepatic reactions include cases requiring liver transplantation in adult and pediatric patients. Propylthiouracil should be reserved for patients who can not tolerate methimazole and in whom radioactive iodine therapy or surgery are not appropriate treatments for the management of hyperthyroidism. Because of the risk of fetal abnormalities associated with methimazole, propylthiouracil may be the treatment of choice when an antithyroid drug is indicated during or just prior to the first trimester of pregnancy (see Warnings and Precautions). DESCRIPTION Propylthiouracil is one of the thiocarbamide compounds. It is a white, crystalline substance that has a bitter taste and is very slightly soluble in water. Propylthiouracil is an antithyroid drug administered orally. The structural formula is: structural formula Each tablet contains propylthiouracil 50 mg and the following inactive ingredients: corn starch, docusate sodium, magnesium stearate, microcrystalline cellulose, modified food starch, sodium benzoate, and sodium starch glycolate. CLINICAL PHARMACOLOGY Propylthiouracil inhibits the synthesis of thyroid hormones and thus is effective in the treatment of hyperthyroidism. The drug does not inactivate existing thyroxine and triiodothyronine that are stored in the thyroid or circulating in the blood, nor does it interfere with the effectiveness of thyroid hormones given by mouth or by injection. Propylthiouracil inhibits the conversion of thyroxine to triiodothyronine in peripheral tissues and may therefore be an effective treatment for thyroid storm. Propylthiouracil is readily absorbed and is extensively metabolized. Approximately 35% of the drug is excreted in the urine, in intact and conjugated forms, within 24 hours. INDICATIONS AND USAGE Propylthiouracil is indicated: • in patients with Graves’ disease with hyperthyroidism or toxic multinodular goiter who are intolerant of methimazole and for whom surgery or radioactive iodine therapy is not an appropriate treatment option • to ameliorate symptoms of hyperthyroidism in preparation for thyroidectomy or radioactive iodine therapy in patients who are intolerant of methimazole CONTRAINDICATIONS Propylthiouracil is contraindicated in patients who have demonstrated hypersensitivity to the drug or any of the other product components. WARNINGS Liver Toxicity Liver injury resulting in liver failure, liver transplantation, or death, has been reported with propylthiouracil therapy in adult and pediatric patients. No cases of liver failure have been reported with the use of methimazole in pediatric patients. For this reason, propylthiouracil is not recommended for pediatric patients except when methimazole is not well-tolerated and surgery or radioactive iodine therapy are not appropriate therapies. There are cases of liver injury, including liver failure and death, in women treated with propylthiouracil during pregnancy. Two reports of in utero exposure with liver failure and death of a newborn have been reported. The use of an alternative antithyroid medication (e.g., methimazole) may be advisable following the first trimester of pregnancy (see Precautions, Pregnancy). Biochemical monitoring of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT, AST) is not expected to attenuate the risk of severe liver injury due to its rapid and unpredictable onset. Patients should be informed of the risk of liver failure. Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, right upper quadrant pain, page 1 of 8 Reference ID: 2979531 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda etc.), particularly in the first six months of therapy. When these symptoms occur, propylthiouracil should be discontinued immediately and liver function tests and ALT and AST levels obtained. Agranulocytosis Agranulocytosis occurs in approximately 0.2% to 0.5% of patients and is a potentially life-threatening side effect of propylthiouracil therapy. Agranulocytosis typically occurs within the first 3 months of therapy. Patients should be instructed to immediately report any symptoms suggestive of agranulocytosis, such as fever or sore throat. Leukopenia, thrombocytopenia, and aplastic anemia (pancytopenia) may also occur. Propylthiouracil should be discontinued if agranulocytosis, aplastic anemia (pancytopenia), ANCA- positive vasculitis, hepatitis, interstitial pneumonitis, fever, or exfoliative dermatitis is suspected, and the patient's bone marrow indices should be obtained. Hypothyroidism Propylthiouracil can cause hypothyroidism necessitating routine monitoring of TSH and free T4 levels with adjustments in dosing to maintain a euthyroid state. Because the drug readily crosses placental membranes, propylthiouracil can cause fetal goiter and cretinism when administered to a pregnant woman (see Precautions, Pregnancy). PRECAUTIONS General Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, jaundice, light colored stools, dark urine, right upper quadrant pain, etc.), particularly in the first six months of therapy. When these symptoms occur, measurement should be made of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT/AST levels). Patients who receive propylthiouracil should be under close surveillance and should be counseled regarding the necessity of immediately reporting any evidence of illness, particularly sore throat, skin eruptions, fever, headache, or general malaise. In such cases, white blood cell and differential counts should be obtained to determine whether agranulocytosis has developed. Particular care should be exercised with patients who are receiving concomitant drugs known to be associated with agranulocytosis. Information for Patients Patients should be advised that if they become pregnant or intend to become pregnant while taking an antithyroid drug, they should contact their physician immediately about their therapy. Patients should report immediately any evidence of illness, in particular sore throat, skin eruptions, fever, headache, or general malaise. They also should report symptoms suggestive of hepatic dysfunction (anorexia, pruritus, right upper quadrant pain, etc.). Laboratory Tests Because propylthiouracil may cause hypoprothrombinemia and bleeding, monitoring of prothrombin time should be considered during therapy with the drug, especially before surgical procedures. Thyroid function tests should be monitored periodically during therapy. Once clinical evidence of hyperthyroidism has resolved, the finding of an elevated serum TSH indicates that a lower maintenance dose of propylthiouracil should be employed. Drug Interactions Anticoagulants (oral): Due to the potential inhibition of vitamin K activity by propylthiouracil, the activity of oral anticoagulants (e.g., warfarin) may be increased; additional monitoring of PT/INR should be considered, especially before surgical procedures. Beta-adrenergic blocking agents: Hyperthyroidism may cause an increased clearance of beta blockers with a high extraction ratio. A reduced dose of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid. Digitalis glycosides: Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; a reduced dose of digitalis glycosides may be needed. Theophylline: Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed. Carcinogenesis, Mutagenesis, Impairment of Fertility Laboratory animals treated with propylthiouracil for >1 year have demonstrated thyroid hyperplasia and carcinoma formation. Such animal findings are seen with continuous suppression of thyroid function by sufficient doses of a variety of antithyroid agents, as well as in dietary iodine deficiency, subtotal thyroidectomy, and implantation of autonomous thyrotropic hormone-secreting pituitary tumors. Pituitary adenomas have also been described. Pregnancy Because propylthiouracil readily crosses placental membranes and can induce goiter and even cretinism in the developing fetus, it is important that a sufficient, but not excessive, dose be given during pregnancy. In many pregnant women, the thyroid dysfunction diminishes as the pregnancy proceeds; consequently a reduction of dosage may be possible. In some instances, propylthiouracil can be withdrawn several weeks or months before delivery. page 2 of 8 Reference ID: 2979531 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If propylthiouracil is used during pregnancy, or if the patient becomes pregnant while taking propylthiouracil, the patient should be warned of the rare potential hazard to the mother and fetus of liver damage. Since methimazole may be associated with the rare development of fetal abnormalities such as aplasia cutis and choanal atresia, propylthiouracil may be the preferred agent during organogenesis, in the first trimester of pregnancy. Given the potential maternal adverse effects of propylthiouracil (e.g., hepatotoxicity), it may be preferable to switch from propylthiouracil to methimazole for the second and third trimesters. Pregnancy Category D. See WARNINGS. Nursing Mothers Propylthiouracil is transferred to breast milk to a small extent and therefore likely results in clinically insignificant doses to the suckling infant. In one study, nine lactating women were administered 400 mg of propylthiouracil by mouth. The mean amount of propylthiouracil excreted during 4 hours after drug administration was 0.025% of the administered dose. Pediatric Use Postmarketing reports of severe liver injury including hepatic failure requiring liver transplantation or resulting in death have been reported in the pediatric population. No such reports have been observed with methimazole. As such, propylthiouracil is not recommended for use in the pediatric population except in rare instances in which methimazole is not well-tolerated and surgery or radioactive iodine therapy are not appropriate. When used in children, parents and patients should be informed of the risk of liver failure. If patients taking propylthiouracil develop tiredness, nausea, anorexia, fever, pharyngitis, or malaise, propylthiouracil should be discontinued immediately by the patient, a physician should be contacted, and a white blood cell count, liver function tests, and transaminase levels obtained. ADVERSE REACTIONS Major adverse reactions (much less common than the minor adverse reactions) include liver injury resulting in hepatitis, liver failure, a need for liver transplantation or death. Inhibition of myelopoiesis (agranulocytosis, granulopenia, and thrombocytopenia), aplastic anemia, drug fever, a lupus-like syndrome (including splenomegaly and vasculitis), hepatitis, periarteritis, and hypoprothrombinemia and bleeding have been reported. Nephritis, glomerulonephritis, interstitial pneumonitis, exfoliative dermatitis, and erythema nodosum have been reported. Reports of a vasculitis syndrome associated with the presence of anti-neutrophilic cytoplasmic antibodies (ANCA) have also been received. Manifestations of ANCA-positive vasculitis may include rapidly progressive glomerulonephritis (crescentic and pauci-immune necrotizing glomerulonephritis), sometimes leading to acute renal failure; pulmonary infiltrates or alveolar hemorrhage; skin ulcers; and leukocytoclastic vasculitis. Minor adverse reactions include skin rash, urticaria, nausea, vomiting, epigastric distress, arthralgia, paresthesias, loss of taste, taste perversion, abnormal loss of hair, myalgia, headache, pruritus, drowsiness, neuritis, edema, vertigo, skin pigmentation, jaundice, sialadenopathy, and lymphadenopathy. It should be noted that about 10% of patients with untreated hyperthyroidism have leukopenia (white blood cell count of less than 4,000/mm3 ), often with relative granulopenia. OVERDOSAGE Signs and Symptoms Nausea, vomiting, epigastric distress, headache, fever, arthralgia, pruritus, edema, and pancytopenia. Agranulocytosis is the most serious effect. Rarely, exfoliative dermatitis, hepatitis, neuropathies or CNS stimulation or depression may occur. No information is available on the following: LD50; concentration of propylthiouracil in biologic fluids associated with toxicity and/ or death; the amount of drug in a single dose usually associated with symptoms of overdosage; or the amount of propylthiouracil in a single dose likely to be life-threatening. Treatment To obtain up-to-date information about the treatment of overdose, a good resource is the certified Regional Poison Control Center. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in the patient. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s medical status. DOSAGE AND ADMINISTRATION Propylthiouracil is administered orally. The total daily dosage is usually given in 3 equal doses at approximately 8-hour intervals. Adults The initial dose is 300 mg daily. In patients with severe hyperthyroidism, very large goiters, or both, the initial dose may be increased to 400 mg daily; an occasional patient will require 600 to 900 mg daily initially. The usual maintenance dose is 100 to 150 mg daily. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. page 3 of 8 Reference ID: 2979531 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Use Propylthiouracil is generally not recommended for use in the pediatric patient population except in rare instances in which other alternative therapies are not appropriate options. Studies evaluating appropriate dosing regimen have not been conducted in the pediatric population although general practice would suggest initiation of therapy in patients 6 years or older at a dosage of 50 mg daily with careful upward titration based on clinical response and evaluation of TSH and free T4 levels. Although cases of severe liver injury have been reported with doses as low as 50 mg/day, most cases were associated with doses of 300 mg/day and higher. Geriatric Use Clinical studies of propylthiouracil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. HOW SUPPLIED Propylthiouracil Tablets, USP, 50 mg, are round, white, scored tablets, engraved LL and P33, supplied as: NDC 67253-651-10 Bottle of 100 NDC 67253-651-11 Bottle of 1000 Store at controlled room temperature 15°-30°C (59° -86°F). REFERENCE 1. International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. 1974; 7; 67-76. DAVA Pharmaceuticals, Inc. Fort Lee, NJ 07024 Rev. 2 - February 2010 MEDICATION GUIDE PROPYLTHIOURACIL TABLETS, USP (Pro-pil-thi-o-ur-a-sil) Read this Medication Guide before you start taking Propylthiouracil and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. What is the most important information I should know about Propylthiouracil? Propylthiouracil can cause serious side effects, including: Severe liver problems. In some cases, these liver problems can lead to liver failure, the need for liver transplant, or death. Stop taking Propylthiouracil and call your doctor right away if you have: • fever • loss of appetite • nausea • vomiting • tiredness • itchiness • pain or tenderness in your right upper stomach area (abdomen) • dark (tea colored) urine • pale or light colored bowel movements (stools) • yellowing of your skin or whites of your eyes What is Propylthiouracil? Propylthiouracil is a prescription medicine used to treat people who have Graves’ disease with hyperthyroidism or toxic multinodular goiter. Propylthiouracil is used when: • certain other antithyroid medicines do not work well. • thyroid surgery or radioactive iodine therapy is not a treatment option. page 4 of 8 Reference ID: 2979531 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • to decrease symptoms of hyperthyroidism in preparation for a thyroidectomy (removal of the thyroid gland) or radioactive iodine therapy. Propylthiouracil is not recommended for use in children. Propylthiouracil may be used when an antithyroid drug is needed during or just before the first trimester of pregnancy. Who should not take Propylthiouracil? Do not take Propylthiouracil if you are allergic to Propylthiouracil or any of its ingredients. See the end of this Medication Guide for a complete list of ingredients in Propylthiouracil. What should I tell my doctor before taking Propylthiouracil? Before you take Propylthiouracil, tell your doctor if you: • plan to have surgery. • have any other medical conditions • are pregnant or plan to become pregnant. Talk to your doctor right away if you are pregnant or plan to become pregnant. • Propylthiouracil may cause liver problems, liver failure and death in pregnant women. • Propylthiouracil may harm your unborn baby. • are breast-feeding or plan to breast-feed. Propylthiouracil can pass into your breast milk. talk to your doctor about the best way to feed your baby if you take Propylthiouracil. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Propylthiouracil may affect the way other medicines work. Especially, tell your doctor if you take: • a blood thinner medicine warfarin sodium (Coumadin, Jantoven) • medicine for heart problems • medicine for high blood pressure • Digoxin (Lanoxicaps, Lanoxin) • Theophylline (Elixophyllin, Theolair, Theochron, Theo-24, Uniphyl) Ask your doctor if you are not sure if your medicine is one of these. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I take Propylthiouracil? • Take Propylthiouracil exactly as your doctor tells you to take it. • Your doctor may change your dose if needed. • Propylthiouracil is usually taken 3 times a day (every 8 hours). • If you take too much Propylthiouracil, call your Regional Poison Control Center or go to the nearest hospital emergency room right away. • If you take too much Propylthiouracil you may have the following symptoms: • nausea • fever • vomiting • joint pain • upper stomach pain or tenderness • swelling of your body, arms, and legs • headache page 5 of 8 Reference ID: 2979531 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • If you miss a dose of Propylthiouracil, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Just take the next dose at your regular time. Do not double your dose. What are the possible side effects of Propylthiouracil? Propylthiouracil may cause serious side effects, including: • liver problems. See “What is the most important information I should know about Propylthiouracil?” • low white blood cell counts. This usually happens within the first 3 months of treatment and can be life-threatening. You may have a higher chance of getting an infection when your white blood cell count is low. Tell your doctor right away if you have: • a fever • chills • sore throat • hypothyroidism. Your doctor should do blood tests regularly during treatment to check your thyroid. • increased bleeding especially with surgical procedures and particularly if you are taking blood thinners. The most common side effects of Propylthiouracil include: • skin rash or hives • headache • nausea • sleepiness • vomiting • nerve pain • upper stomach pain or tenderness • swelling (edema) • joint pain • dizziness • itching or tingling • enlarged salivary glands or enlarged lymph nodes • loss or change in taste • loss of hair • muscle pain Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of Propylthiouracil. For more information, ask our doctor or pharmacist. page 6 of 8 Reference ID: 2979531 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Propylthiouracil? Store Propylthiouracil at 59ºF to 86º F (15º-30ºC). Keep Propylthiouracil and all medicines out of the reach of children. General information about the safe and effective use of Propylthiouracil: Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Propylthiouracil for a condition for which it was not prescribed. Do not give Propylthiouracil to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about Propylthiouracil. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Propylthiouracil that is written for health professionals. www.davapharma.com 1-877-963-8422 What are the ingredients in Propylthiouracil? Active ingredient: propylthouracil Inactive ingredients: corn starch, docusate sodium, magnesium stearate,microcrystalline cellulose, modified food starch, sodium benzoate, and sodium starch glycolate. DAVA Pharmaceuticals, Inc, Fort Lee, NJ 07024 This Medication Guide has been approved by the U.S. Food and Drug Administration. 03/2010 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:35.688221	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/006188s021s022lbl.pdf', 'application_number': 6188, 'submission_type': 'SUPPL ', 'submission_number': 22}
10,687	1 721566-04 451175A/Revised February 2010 ® 2 Xylocaine (lidocaine HCl Injection, USP) ® 3 Xylocaine (lidocaine HCl and epinephrine Injection, USP) 4 For Infiltration and Nerve Block 5 Rx only 6 DESCRIPTION : 7 Xylocaine (lidocaine HCl) Injections are sterile, nonpyrogenic, aqueous solutions that contain a 8 local anesthetic agent with or without epinephrine and are administered parenterally by injection. 9 See INDICATIONS for specific uses. Xylocaine solutions contain lidocaine HCl, which is chemically designated as acetamide, 10 11 12 2-(diethylamino)-N-(2,6-dimethylphenyl)-, monohydrochloride and has the molecular wt. 270.8. Lidocaine HCl (C14H22N2O • HCl) has the following structural formula: 13 14 15 16 Structural Formula Epinephrine is (-) -3, 4-Dihydroxy-α-[(methylamino) methyl] benzyl alcohol and has the molecular wt. 183.21. Epinephrine (C9H13NO3) has the following structural formula: 17 Structural Formula 18 Dosage forms listed as Xylocaine-MPF indicate single dose solutions that are Methyl 19 Paraben Free (MPF). 20 Xylocaine MPF is a sterile, nonpyrogenic, isotonic solution containing sodium chloride. Xylocaine in multiple dose vials: Each mL also contains 1 mg methylparaben as antiseptic 21 22 23 preservative. The pH of these solutions is adjusted to approximately 6.5 (5.0–7.0) with sodium hydroxide and/or hydrochloric acid. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Xylocaine MPF with Epinephrine is a sterile, nonpyrogenic, isotonic solution containing 2 sodium chloride. Each mL contains lidocaine hydrochloride and epinephrine, with 0.5 mg 3 sodium metabisulfite as an antioxidant and 0.2 mg citric acid as a stabilizer. Xylocaine with 4 Epinephrine in multiple dose vials: Each mL also contains 1 mg methylparaben as antiseptic 5 preservative. The pH of these solutions is adjusted to approximately 4.5 (3.3–5.5) with sodium 6 hydroxide and/or hydrochloric acid. Filled under nitrogen. 7 CLINICAL PHARMACOLOGY: 8 Mechanism of Action: 9 Lidocaine HCl stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the 10 initiation and conduction of impulses thereby effecting local anesthetic action. 11 Hemodynamics: Excessive blood levels may cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. With central neural blockade these changes may be attributable to block of autonomic fibers, a direct depressant effect of the local anesthetic agent on various 12 13 14 15 16 17 components of the cardiovascular system, and/or the beta-adrenergic receptor stimulating action of epinephrine when present. The net effect is normally a modest hypotension when the recommended dosages are not exceeded. 18 Pharmacokinetics and Metabolism: Information derived from diverse formulations, concentrations and usages reveals that lidocaine HCl is completely absorbed following parenteral administration, its rate of absorption depending, 19 20 21 22 23 for example, upon various factors such as the site of administration and the presence or absence of a vasoconstrictor agent. Except for intravascular administration, the highest blood levels are obtained following intercostal nerve block and the lowest after subcutaneous administration. The plasma binding of lidocaine HCl is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At concentrations of 1 to 4 mcg of free base per 24 25 26 27 mL 60 to 80 percent of lidocaine HCl is protein bound. Binding is also dependent on the plasma concentration of the alpha-1-acid glycoprotein. Lidocaine HCl crosses the blood-brain and placental barriers, presumably by passive 28 29 diffusion. 30 Lidocaine HCl is metabolized rapidly by the liver, and metabolites and unchanged drug 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 are excreted by the kidneys. Biotransformation includes oxidative N-dealkylation, ring 2 hydroxylation, cleavage of the amide linkage, and conjugation. N-dealkylation, a major pathway 3 of biotransformation, yields the metabolites monoethylglycinexylidide and glycinexylidide. The 4 pharmacological/toxicological actions of these metabolites are similar to, but less potent than, 5 those of lidocaine HCl. Approximately 90% of lidocaine HCl administered is excreted in the 6 form of various metabolites, and less than 10% is excreted unchanged. The primary metabolite 7 in urine is a conjugate of 4-hydroxy-2,6-dimethylaniline. 8 The elimination half-life of lidocaine HCl following an intravenous bolus injection is 9 typically 1.5 to 2.0 hours. Because of the rapid rate at which lidocaine HCl is metabolized, any condition that affects liver function may alter lidocaine HCl kinetics. The half-life may be 10 11 12 prolonged two-fold or more in patients with liver dysfunction. Renal dysfunction does not affect lidocaine HCl kinetics but may increase the accumulation of metabolites. Factors such as acidosis and the use of CNS stimulants and depressants affect the CNS levels of lidocaine HCl required to produce overt systemic effects. Objective adverse 13 14 15 16 17 manifestations become increasingly apparent with increasing venous plasma levels above 6.0 µg free base per mL. In the rhesus monkey arterial blood levels of 18–21 µg/mL have been shown to be threshold for convulsive activity. INDICATIONS AND USAGE: Xylocaine (lidocaine HCl) Injections are indicated for production of local or regional anesthesia by infiltration techniques such as percutaneous injection and intravenous regional anesthesia by 18 19 20 21 22 23 peripheral nerve block techniques such as brachial plexus and intercostal and by central neural techniques such as lumbar and caudal epidural blocks, when the accepted procedures for these techniques as described in standard textbooks are observed. CONTRAINDICATIONS : 24 25 26 Lidocaine HCl is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type. WARNINGS: 3 XYLOCAINE INJECTIONS FOR INFILTRATION AND NERVE BLOCK SHOULD BE 27 28 29 30 31 EMPLOYED ONLY BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES THAT MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED AND THEN ONLY AFTER This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 ENSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE 2 DRUGS, CARDIOPULMONARY EQUIPMENT AND THE PERSONNEL NEEDED FOR 3 PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES. (See 4 also ADVERSE REACTIONS and PRECAUTIONS.) DELAY IN PROPER 5 MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANY 6 CAUSE AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF 7 ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH. 8 Intra-articular infusions of local anesthetics following arthroscopic and other surgical 9 procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether 10 11 12 13 14 15 16 17 18 shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. To avoid intravascular injection, aspiration should be performed before the local anesthetic solution is injected. The needle must be repositioned until no return of blood can be 19 20 21 22 elicited by aspiration. Note, however, that the absence of blood in the syringe does not guarantee that intravascular injection has been avoided. Local anesthetic solutions containing antimicrobial preservatives (eg, methylparaben) 23 24 25 should not be used for epidural or spinal anesthesia because the safety of these agents has not been established with regard to intrathecal injection, either intentional or accidental. Xylocaine with epinephrine solutions contain sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe 26 27 28 29 30 asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people. 31 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 PRECAUTIONS: 2 General 3 The safety and effectiveness of lidocaine HCl depend on proper dosage, correct technique, 4 adequate precautions, and readiness for emergencies. Standard textbooks should be consulted 5 for specific techniques and precautions for various regional anesthetic procedures. 6 Resuscitative equipment, oxygen, and other resuscitative drugs should be available for 7 immediate use. (See WARNINGS and ADVERSE REACTIONS.) The lowest dosage that 8 results in effective anesthesia should be used to avoid high plasma levels and serious adverse 9 effects. Syringe aspirations should also be performed before and during each supplemental injection when using indwelling catheter techniques. During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and that the patient be monitored for central nervous system toxicity and cardiovascular toxicity, as well as for signs of unintended intrathecal administration, before proceeding. When clinical conditions permit, consideration should be given to employing local anesthetic solutions that contain epinephrine for the test dose because circulatory changes compatible with epinephrine may also serve as a 10 11 12 13 14 15 16 17 18 19 20 21 22 warning sign of unintended intravascular injection. An intravascular injection is still possible even if aspirations for blood are negative. Repeated doses of lidocaine HCl may cause significant increases in blood levels with each repeated dose because of slow accumulation of the drug or its metabolites. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their age and physical condition. Lidocaine HCl should also be used with caution in patients with severe shock or heart block. Lumbar and caudal epidural anesthesia should be used with extreme caution in persons 23 24 25 with the following conditions: existing neurological disease, spinal deformities, septicemia, and severe hypertension. Local anesthetic solutions containing a vasoconstrictor should be used cautiously and in carefully circumscribed quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply. Patients with peripheral vascular disease and those with 26 27 28 29 30 31 32 hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result. Preparations containing a vasoconstrictor should be used with caution in patients during or following the administration of potent general anesthetic agents, since cardiac arrhythmias may occur under such conditions. 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Careful and constant monitoring of cardiovascular and respiratory (adequacy of 2 ventilation) vital signs and the patient’s state of consciousness should be accomplished after each 3 local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, 4 tinnitus, dizziness, blurred vision, tremors, depression or drowsiness may be early warning signs 5 of central nervous system toxicity. 6 Since amide-type local anesthetics are metabolized by the liver, Xylocaine Injection 7 should be used with caution in patients with hepatic disease. Patients with severe hepatic 8 disease, because of their inability to metabolize local anesthetics normally, are at greater risk of 9 developing toxic plasma concentrations. Xylocaine Injection should also be used with caution in patients with impaired cardiovascular function since they may be less able to compensate for 10 11 functional changes associated with the prolongation of A-V conduction produced by these drugs. Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Since it is not known whether amide-type local anesthetics may trigger this reaction and since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for the management of 12 13 14 15 16 17 18 19 20 malignant hyperthermia should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene (consult dantrolene sodium intravenous package insert before using). Proper tourniquet technique, as described in publications and standard textbooks, is 21 22 23 essential in the performance of intravenous regional anesthesia. Solutions containing epinephrine or other vasoconstrictors should not be used for this technique. Lidocaine HCl should be used with caution in persons with known drug sensitivities. 24 25 26 Patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc) have not shown cross-sensitivity to lidocaine HCl. 27 Use in the Head and Neck Area Small doses of local anesthetics injected into the head and neck area, including retrobulbar, dental and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity 28 29 30 31 seen with unintentional intravascular injections of larger doses. Confusion, convulsions, respiratory depression and/or respiratory arrest, and cardiovascular stimulation or depression 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 have been reported. These reactions may be due to intra-arterial injection of the local anesthetic 2 with retrograde flow to the cerebral circulation. Patients receiving these blocks should have their 3 circulation and respiration monitored and be constantly observed. Resuscitative equipment and 4 personnel for treating adverse reactions should be immediately available. Dosage 5 recommendations should not be exceeded. (See DOSAGE AND ADMINISTRATION.) 6 Information for Patients 7 When appropriate, patients should be informed in advance that they may experience temporary 8 loss of sensation and motor activity, usually in the lower half of the body, following proper 9 administration of epidural anesthesia. 10 11 Clinically Significant Drug Interactions The administration of local anesthetic solutions containing epinephrine or norepinephrine to 12 13 14 patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of 15 16 epinephrine. Concurrent use of these agents should generally be avoided. In situations when 17 18 concurrent therapy is necessary, careful patient monitoring is essential. Concurrent administration of vasopressor drugs (for the treatment of hypotension related 19 20 21 to obstetric blocks) and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. 22 Drug/Laboratory Test Interactions The intramuscular injection of lidocaine HCl may result in an increase in creatine phosphokinase levels. Thus, the use of this enzyme determination, without isoenzyme 23 24 25 26 separation, as a diagnostic test for the presence of acute myocardial infarction may be compromised by the intramuscular injection of lidocaine HCl. 27 Carcinogenesis, Mutagenesis, Impairment of Fertility 28 Studies of lidocaine HCl in animals to evaluate the carcinogenic and mutagenic potential or the 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 effect on fertility have not been conducted. 2 Pregnancy 3 Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in rats 4 at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus 5 caused by lidocaine HCl. There are, however, no adequate and well-controlled studies in 6 pregnant women. Animal reproduction studies are not always predictive of human response. 7 General consideration should be given to this fact before administering lidocaine HCl to women 8 of childbearing potential, especially during early pregnancy when maximum organogenesis takes 9 place. 10 11 Labor and Delivery Local anesthetics rapidly cross the placenta and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.) The potential for toxicity 12 13 14 15 16 17 depends upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function. Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce 18 19 20 vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal 21 22 monitoring is highly advisable. Epidural, spinal, paracervical, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and 23 24 25 26 27 28 29 facilitation of cervical dilation. However, spinal and epidural anesthesia have also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 The use of some local anesthetic drug products during labor and delivery may be 2 followed by diminished muscle strength and tone for the first day or two of life. The long-term 3 significance of these observations is unknown. Fetal bradycardia may occur in 20 to 30 percent 4 of patients receiving paracervical nerve block anesthesia with the amide-type local anesthetics 5 and may be associated with fetal acidosis. Fetal heart rate should always be monitored during 6 paracervical anesthesia. The physician should weigh the possible advantages against risks when 7 considering a paracervical block in prematurity, toxemia of pregnancy, and fetal distress. 8 Careful adherence to recommended dosage is of the utmost importance in obstetrical 9 paracervical block. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth, which correlates with high local anesthetic serum levels, and often manifest seizures within six hours. Prompt use of supportive measures combined with forced 10 11 12 13 14 15 16 17 18 19 20 urinary excretion of the local anesthetic has been used successfully to manage this complication. Case reports of maternal convulsions and cardiovascular collapse following use of some local anesthetics for paracervical block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The recommended maximum dose of each drug should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a 5-minute interval between sides. 21 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted 22 23 24 in human milk, caution should be exercised when lidocaine HCl is administered to a nursing woman. 25 Pediatric Use Dosages in children should be reduced, commensurate with age, body weight and physical 26 27 condition. See DOSAGE AND ADMINISTRATION. 28 29 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 ADVERSE REACTIONS Systemic Adverse experiences following the administration of lidocaine HCl are similar in nature to those observed with other amide local anesthetic agents. These adverse experiences are, in general, dose-related and may result from high plasma levels caused by excessive dosage, rapid absorption or inadvertent intravascular injection, or may result from a hypersensitivity, idiosyncrasy or diminished tolerance on the part of the patient. Serious adverse experiences are generally systemic in nature. The following types are those most commonly reported: Central Nervous System CNS manifestations are excitatory and/or depressant and may be characterized by lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest. Drowsiness following the administration of lidocaine HCl is usually an early sign of a high blood level of the drug and may occur as a consequence of rapid absorption. Cardiovascular System Cardiovascular manifestations are usually depressant and are characterized by bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac arrest. Allergic Allergic reactions are characterized by cutaneous lesions, urticaria, edema or anaphylactoid reactions. Allergic reactions may occur as a result of sensitivity either to local anesthetic agents or to the methylparaben used as a preservative in the multiple dose vials. Allergic reactions as result of sensitivity to lidocaine HCl are extremely rare and, if they occur, should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value. Neurologic The incidences of adverse reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration and the physical status of the patient. In a prospective review of 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 10,440 patients who received lidocaine HCl for spinal anesthesia, the incidences of adverse reactions were reported to be about 3 percent each for positional headaches, hypotension and backache; 2 percent for shivering; and less than 1 percent each for peripheral nerve symptoms, nausea, respiratory inadequacy and double vision. Many of these observations may be related to local anesthetic techniques, with or without a contribution from the local anesthetic. In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter may occur. Subsequent adverse effects may depend partially on the amount of drug administered subdurally. These may include spinal block of varying magnitude (including total spinal block), hypotension secondary to spinal block, loss of bladder and bowel control, and loss of perineal sensation and sexual function. Persistent motor, sensory and/or autonomic (sphincter control) deficit of some lower spinal segments with slow recovery (several months) or incomplete recovery have been reported in rare instances when caudal or lumbar epidural block has been attempted. Backache and headache have also been noted following use of these anesthetic procedures. There have been reported cases of permanent injury to extraocular muscles requiring surgical repair following retrobulbar administration. OVERDOSAGE: Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution (see ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS). Management of Local Anesthetic Emergencies The first consideration is prevention best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered. The first step in the management of convulsions, as well as underventilation or apnea due to unintended subarachnoid injection of drug solution, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such 2 as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered 3 intravenously. The clinician should be familiar, prior to the use of local anesthetics, with these 4 anticonvulsant drugs. Supportive treatment of circulatory depression may require administration 5 of intravenous fluids and, when appropriate, a vasopressor as directed by the clinical situation 6 (eg, ephedrine). 7 If not treated immediately, both convulsions and cardiovascular depression can result in 8 hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. Underventilation or apnea due to 9 unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should 10 11 occur, standard cardiopulmonary resuscitative measures should be instituted. Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the 12 13 14 15 maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated. Dialysis is of negligible value in the treatment of acute overdosage with lidocaine HCl. 16 17 18 The oral LD50 of lidocaine HCl in non-fasted female rats is 459 (346–773) mg/kg (as the salt) and 214 (159–324) mg/kg (as the salt) in fasted female rats. DOSAGE AND ADMINISTRATION: Table 1 (Recommended Dosages) summarizes the recommended volumes and concentrations of Xylocaine Injection for various types of anesthetic procedures. The dosages suggested in this table are for normal healthy adults and refer to the use of epinephrine-free solutions. When larger 19 20 21 22 23 24 25 26 27 volumes are required, only solutions containing epinephrine should be used except in those cases where vasopressor drugs may be contraindicated. There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. Xylocaine is not approved for this use (see WARNINGS and DOSAGE and ADMINISTRATION). These recommended doses serve only as a guide to the amount of anesthetic required for most routine procedures. The actual volumes and concentrations to be used depend on a number 28 29 30 31 of factors such as type and extent of surgical procedure, depth of anesthesia and degree of muscular relaxation required, duration of anesthesia required, and the physical condition of the 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 patient. In all cases the lowest concentration and smallest dose that will produce the desired 2 result should be given. Dosages should be reduced for children and for the elderly and debilitated 3 patients and patients with cardiac and/or liver disease. 4 The onset of anesthesia, the duration of anesthesia and the degree of muscular relaxation 5 are proportional to the volume and concentration (ie, total dose) of local anesthetic used. Thus, 6 an increase in volume and concentration of Xylocaine Injection will decrease the onset of 7 anesthesia, prolong the duration of anesthesia, provide a greater degree of muscular relaxation 8 and increase the segmental spread of anesthesia. However, increasing the volume and 9 concentration of Xylocaine Injection may result in a more profound fall in blood pressure when used in epidural anesthesia. Although the incidence of side effects with lidocaine HCl is quite low, caution should be exercised when employing large volumes and concentrations, since the 10 11 12 13 incidence of side effects is directly proportional to the total dose of local anesthetic agent injected. For intravenous regional anesthesia, only the 50 mL single dose vial containing 14 15 Xylocaine (lidocaine HCl) 0.5% Injection should be used. Epidural Anesthesia 16 17 18 For epidural anesthesia, only the following dosage forms Xylocaine Injection are recommended: 1% without epinephrine 19 1% without epinephrine 20 1% with epinephrine 21 1:200,000 22 1.5% without epinephrine 23 1.5% without epinephrine 24 1.5% with epinephrine 25 1:200,000 26 2% without epinephrine 2% with epinephrine 27 28 1:200,000 10 mL Polyamp DuoFit™ 30 mL single dose solutions 30 mL single dose solutions 10 mL Polyamp DuoFit™ 20 mL Polyamp DuoFit™ 30 mL ampules, 30 mL single dose solutions 10 mL Polyamp DuoFit™ 20 mL ampules, 20 mL single dose solutions Although these solutions are intended specifically for epidural anesthesia, they may also be 29 30 used for infiltration and peripheral nerve block, provided they are employed as single dose units. 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 These solutions contain no bacteriostatic agent. 2 In epidural anesthesia, the dosage varies with the number of dermatomes to be anesthetized 3 (generally 2–3 mL of the indicated concentration per dermatome). 4 Caudal and Lumbar Epidural Block 5 As a precaution against the adverse experience sometimes observed following unintentional 6 penetration of the subarachnoid space, a test dose such as 2 to 3 mL of 1.5% lidocaine HCl 7 should be administered at least 5 minutes prior to injecting the total volume required for a lumbar 8 or caudal epidural block. The test dose should be repeated if the patient is moved in a manner 9 that may have displaced the catheter. Epinephrine, if contained in the test dose (10 to 15 mcg have been suggested), may serve as a warning of unintentional intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or 10 11 12 13 14 15 16 17 18 19 more seconds. Patients on beta blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure. Adequate time should be allowed for onset of anesthesia after administration of each test dose. The rapid injection of a large volume of Xylocaine Injection through the catheter should be avoided, and, when feasible, fractional doses should be administered. In the event of the known injection of a large volume of local anesthetic solution into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting 20 21 22 23 the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter. 24 MAXIMUM RECOMMENDED DOSAGES: Adults For normal healthy adults, the individual maximum recommended dose of lidocaine HCl with epinephrine should not exceed 7 mg/kg (3.5 mg/lb) of body weight, and in general it is 25 26 27 28 29 30 31 recommended that the maximum total dose not exceed 500 mg. When used without epinephrine the maximum individual dose should not exceed 4.5 mg/kg (2 mg/lb) of body weight, and in general it is recommended that the maximum total dose does not exceed 300 mg. For continuous epidural or caudal anesthesia, the maximum recommended dosage should not be administered at 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 intervals of less than 90 minutes. When continuous lumbar or caudal epidural anesthesia is used 2 for non-obstetrical procedures, more drug may be administered if required to produce adequate 3 anesthesia. 4 The maximum recommended dose per 90 minute period of lidocaine hydrochloride for 5 paracervical block in obstetrical patients and non-obstetrical patients is 200 mg total. One half of 6 the total dose is usually administered to each side. Inject slowly, five minutes between sides. 7 (See also discussion of paracervical block in PRECAUTIONS.) 8 For intravenous regional anesthesia, the dose administered should not exceed 4mg/kg in 9 adults. 10 Children It is difficult to recommend a maximum dose of any drug for children, since this varies as a function of age and weight. For children over 3 years of age who have a normal lean body mass and normal body development, the maximum dose is determined by the child’s age and weight. 11 12 13 14 15 16 17 18 For example, in a child of 5 years weighing 50 lbs the dose of lidocaine HCl should not exceed 75–100 mg (1.5 to 2 mg/lb). The use of even more dilute solutions (ie, 0.25 to 0.5%) and total dosages not to exceed 3 mg/kg (1.4 mg/lb) are recommended for induction of intravenous regional anesthesia in children. In order to guard against systemic toxicity, the lowest effective concentration and lowest effective dose should be used at all times. In some cases it will be necessary to dilute available 19 20 21 22 concentrations with 0.9% sodium chloride injection in order to obtain the required final concentration. NOTE: Parenteral drug products should be inspected visually for particulate matter and 23 24 25 discoloration prior to administration whenever the solution and container permit. The Injection is not to be used if its color is pinkish or darker than slightly yellow or if it contains a precipitate. 26 27 28 29 30 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Table 1. Recommended Dosages Procedure Conc (%) Xylocaine (lidocaine hydrochloride) Injection (without epinephrine) Vol (mL) Total Dose (mg) Infiltration Percutaneous 0.5 or 1 1-60 5-300 Intravenous regional Peripheral Nerve Blocks, eg 0.5 10-60 50-300 Brachial 1.5 15-20 225-300 Dental 2 1-5 20-100 Intercostal 1 3 30 Paravertebral 1 3-5 30-50 Pudendal (each side) Paracervical Obstetrical analgesia 1 10 100 (each side) Sympathetic Nerve Blocks, eg, 1 10 100 Cervical (stellate ganglion) 1 5 50 Lumbar Central Neural Blocks Epidural* 1 5-10 50-100 Thoracic Lumbar 1 20-30 200-300 Analgesia 1 25-30 250-300 Anesthesia 1.5 15-20 225-300 Caudal 2 10-15 200-300 Obstetrical analgesia 1 20-30 200-300 Surgical anesthesia 1.5 15-20 225-300 2 *Dose determined by number of dermatomes to be anesthetized (2–3 mL/dermatome). 3 THE ABOVE SUGGESTED CONCENTRATIONS AND VOLUMES SERVE ONLY AS A 4 GUIDE. OTHER VOLUMES AND CONCENTRATIONS MAY BE USED PROVIDED THE 5 TOTAL MAXIMUM RECOMMENDED DOSE IS NOT EXCEEDED. 6 STERILIZATION, STORAGE AND TECHNICAL PROCEDURES: 7 Disinfecting agents containing heavy metals, which cause release of respective ions (mercury, 8 zinc, copper, etc) should not be used for skin or mucous membrane disinfection as they have 9 been related to incidents of swelling and edema. When chemical disinfection of multi-dose vials is desired, either isopropyl alcohol (91%) or ethyl alcohol (70%) is recommended. Many 10 11 commercially available brands of rubbing alcohol, as well as solutions of ethyl alcohol not of 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 USP grade, contain denaturants which are injurious to rubber and therefore are not to be used. 2 Dosage forms listed as Xylocaine-MPF indicate single dose solutions that are Methyl 3 Paraben Free (MPF). 4 HOW SUPPLIED: H ow Supplied Chart All solutions should be stored at room temperature, approximately 25°C (77°F). Protect from 7 light. 8 All trademarks are the property of the APP Pharmaceuticals, LLC. © 9 Manufactured for: 451175A Revised: February 2010 Co mp any logo 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:35.825373	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/006488s074lbl.pdf', 'application_number': 6488, 'submission_type': 'SUPPL ', 'submission_number': 74}
10,688	NDA 6-927/S-030 NDA 9-112/S-021 Page 3 Rx only Eurax (crotamiton USP) Lotion/Cream FOR TOPICAL USE ONLY NOT FOR OPHTHALMIIC, ORAL, OR INTRAVAGINAL USE DESCRIPTION Eurax (crotamiton USP) is a scabicidal and antipruritic agent available as a cream or lotion for topical use only. Eurax provides 10% (w/w) of the synthetic, crotamiton USP, in a vanishing-cream or emollient-lotion base containing: water, petrolatum, propylene glycol, steareth-2, cetyl alcohol, dimethicone, laureth-23, fragrance, magnesium aluminum silicate, carbomer-934, sodium hydroxide, diazolidinylurea, methylchloroisothiazolinone, methylisothiazolinone and magnesium nitrate. In addition, the cream contains glyceryl stearate. Crotamiton is N-ethyl-N-(o-methylphenyl) -2- butenamide and its structural formula is: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 6-927/S-030 NDA 9-112/S-021 Page 4 Crotamiton USP is a colorless to slightly yellowish oil, having a faint amine-like odor. It is miscible with alcohol and with methanol. Crotamiton is a mixture of the cis and trans isomers. Its molecular weight is 203.28. CLINICAL PHARMACOLOGY Eurax has scabicidal and antipruritic actions. The mechanisms of these actions are not known. The pharmacokinetics of crotamiton and its degree of systemic absorption following topical application have not been determined. INDICATIONS AND USAGE For eradication of scabies (Sarcoptes scabiei) and for symptomatic treatment of pruritic skin. CONTRAINDICATIONS Eurax should not be applied topically to patients who develop a sensitivity or are allergic to it or who manifest a primary irritation response to topical medications. WARNINGS If severe irritation or sensitization develops, treatment with this product should be discontinued and appropriate therapy instituted. PRECAUTIONS General Eurax should not be applied in the eyes or mouth because it may cause irritation. It should not be applied to acutely inflamed skin or raw or weeping surfaces until the acute inflammation has subsided. lnformation for Patients See DIRECTIONS FOR PATIENTS WITH SCABIES. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 6-927/S-030 NDA 9-112/S-021 Page 5 Drug interactions None known. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies in animals have not been conducted. Pregnancy (Category C) Animal reproduction studies have not been conducted with Eurax. It is also not known whether Eurax can cause fetal harm when applied topically to a pregnant woman or can affect reproduction capacity. Eurax should be given to a pregnant woman only if clearly needed. Pediatric Use Safety and effectiveness in children have not been established. Geriatric Use Clinical studies with Eurax (crotamiton USP) Lotion/Cream did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS Primary irritation reactions, such as dermatitis, pruritus, and rash, and allergic sensitivity reactions have been reported in a few patients. OVERDOSAGE There is no specific information on the effect of overtreatment with repeated topical applications in humans. A death was reported but cause was not confirmed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 6-927/S-030 NDA 9-112/S-021 Page 6 Accidental oral ingestion may be accompanied by burning sensation in the mouth, irritation of the buccal, esophageal and gastric mucosa, nausea, vomiting, abdominal pain. If accidental ingestion occurs, call your Poison Control Center. DOSAGE AND ADMINISTRATION In Scabies: Thoroughly massage into the skin of the whole body from the chin down, paying particular attention to all folds and creases. A second application is advisable 24 hours later. Clothing and bed linen should be changed the next morning. A cleansing bath should be taken 48 hours after the last application. In Pruritus: Massage gently into affected areas until medication is completely absorbed. Repeat as needed. LOTION: Shake well before using. DIRECTIONS FOR PATIENTS WITH SCABIES: 1. Take a routine bath or shower. Thoroughly massage Eurax cream or lotion into the skin from the chin to the toes including folds and creases. 2. Put Eurax cream or lotion under fingernails after trimming the fingernails short, because scabies are very likely to remain there. A toothbrush can be used to apply the Eurax cream or lotion under the fingernails. Immediately after use, the toothbrush should be wrapped in paper and thrown away. Use of the same brush in the mouth could lead to poisoning. 3. A second application is advisable 24 hours later. 4. This 60 gram tube or bottle is sufficient for two applications. 5. Clothing and bed linen should be changed the next day. Contaminated clothing and bed linen may be dry-cleaned, or washed in the hot cycle of the washing machine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 6-927/S-030 NDA 9-112/S-021 Page 7 6. A cleansing bath should be taken 48 hours after the last application. HOW SUPPLIED Eurax (crotamiton USP) Cream: 60g tubes (NDC 0072-2103-60; NSN 6505-00-116-0200). Lotion: 60g (2 oz.) bottles (NDC 0072-2203-60, NSN 6505-01-153- 4423). 454g (16 oz.) bottles (NDC 0072-2203-16). SHAKE WELL before using. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 6-927/S-030 NDA 9-112/S-021 Page 8 Store at room temperature. Keep out of reach of children. Westwood-Squibb Pharmaceuticals, Inc. A Bristol-Myers Squibb Company Princeton, NJ 08543 USA Insert code TBD Revised TBD This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:35.828713	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/06927slr030,09112slr021_eurax_lbl.pdf', 'application_number': 6927, 'submission_type': 'SUPPL ', 'submission_number': 30}
10,686	PROPYLTHIOURACIL TABLETS, USP WARNING: Severe liver injury and acute liver failure, in some cases fatal, have been reported in patients treated with propylthiouracil. These reports of hepatic reactions include cases requiring liver transplantation in adult and pediatric patients. Propylthiouracil should be reserved for patients who can not tolerate methimazole and in whom radioactive iodine therapy or surgery are not appropriate treatments for the management of hyperthyroidism. Because of the risk of fetal abnormalities associated with methimazole, propylthiouracil may be the treatment of choice when an antithyroid drug is indicated during or just prior to the first trimester of pregnancy (see Warnings and Precautions). DESCRIPTION Propylthiouracil is one of the thiocarbamide compounds. It is a white, crystalline substance that has a bitter taste and is very slightly soluble in water. Propylthiouracil is an antithyroid drug administered orally. The structural formula is: structural formula Each tablet contains propylthiouracil 50 mg and the following inactive ingredients: corn starch, docusate sodium, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium benzoate, and sodium starch glycolate. CLINICAL PHARMACOLOGY Propylthiouracil inhibits the synthesis of thyroid hormones and thus is effective in the treatment of hyperthyroidism. The drug does not inactivate existing thyroxine and triiodothyronine that are stored in the thyroid or circulating in the blood, nor does it interfere with the effectiveness of thyroid hormones given by mouth or by injection. Propylthiouracil inhibits the conversion of thyroxine to triiodothyronine in peripheral tissues and may therefore be an effective treatment for thyroid storm. 1 Reference ID: 3699805 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Propylthiouracil is readily absorbed and is extensively metabolized. Approximately 35% of the drug is excreted in the urine, in intact and conjugated forms, within 24 hours. INDICATIONS AND USAGE Propylthiouracil is indicated: • in patients with Graves’ disease with hyperthyroidism or toxic multinodular goiter who are intolerant of methimazole and for whom surgery or radioactive iodine therapy is not an appropriate treatment option • to ameliorate symptoms of hyperthyroidism in preparation for thyroidectomy or radioactive iodine therapy in patients who are intolerant of methimazole CONTRAINDICATIONS Propylthiouracil is contraindicated in patients who have demonstrated hypersensitivity to the drug or any of the other product components. WARNINGS Liver Toxicity Liver injury resulting in liver failure, liver transplantation, or death, has been reported with propylthiouracil therapy in adult and pediatric patients. No cases of liver failure have been reported with the use of methimazole in pediatric patients. For this reason, propylthiouracil is not recommended for pediatric patients except when methimazole is not well-tolerated and surgery or radioactive iodine therapy are not appropriate therapies. There are cases of liver injury, including liver failure and death, in women treated with propylthiouracil during pregnancy. Two reports of in utero exposure with liver failure and death of a newborn have been reported. The use of an alternative antithyroid medication (e.g., methimazole) may be advisable following the first trimester of pregnancy (see Precautions, Pregnancy). Biochemical monitoring of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT, AST) is not expected to attenuate the risk of severe liver injury due to its rapid and unpredictable onset. Patients should be informed of the risk of liver failure. Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, right upper quadrant pain, etc.), particularly in the first six months of therapy. When these symptoms occur, propylthiouracil should be discontinued immediately and liver function tests and ALT and AST levels obtained. Agranulocytosis Agranulocytosis occurs in approximately 0.2% to 0.5% of patients and is a potentially life-threatening side effect of propylthiouracil therapy. Agranulocytosis typically occurs within the first 3 months of therapy. Patients should be instructed to immediately report any symptoms suggestive of agranulocytosis, such as fever or sore throat. Leukopenia, thrombocytopenia, and aplastic anemia (pancytopenia) may also occur. Propylthiouracil should be discontinued if agranulocytosis, aplastic 2 Reference ID: 3699805 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda anemia (pancytopenia), ANCA-positive vasculitis, hepatitis, interstitial pneumonitis, fever, or exfoliative dermatitis is suspected, and the patient's bone marrow indices should be obtained. Hypothyroidism Propylthiouracil can cause hypothyroidism necessitating routine monitoring of TSH and free T4 levels with adjustments in dosing to maintain a euthyroid state. Because the drug readily crosses placental membranes, propylthiouracil can cause fetal goiter and cretinism when administered to a pregnant woman (see Precautions, Pregnancy). PRECAUTIONS General Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, jaundice, light colored stools, dark urine, right upper quadrant pain, etc.), particularly in the first six months of therapy. When these symptoms occur, measurement should be made of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT/AST levels). Patients who receive propylthiouracil should be under close surveillance and should be counseled regarding the necessity of immediately reporting any evidence of illness, particularly sore throat, skin eruptions, fever, headache, or general malaise. In such cases, white blood cell and differential counts should be obtained to determine whether agranulocytosis has developed. Particular care should be exercised with patients who are receiving concomitant drugs known to be associated with agranulocytosis. Information for Patients Patients should be advised that if they become pregnant or intend to become pregnant while taking an antithyroid drug, they should contact their physician immediately about their therapy. Patients should report immediately any evidence of illness, in particular sore throat, skin eruptions, fever, headache, or general malaise. They also should report symptoms suggestive of hepatic dysfunction (anorexia, pruritus, right upper quadrant pain, etc.). Laboratory Tests Because propylthiouracil may cause hypoprothrombinemia and bleeding, monitoring of prothrombin time should be considered during therapy with the drug, especially before surgical procedures. Thyroid function tests should be monitored periodically during therapy. Once clinical evidence of hyperthyroidism has resolved, the finding of an elevated serum TSH indicates that a lower maintenance dose of propylthiouracil should be employed. 3 Reference ID: 3699805 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Anticoagulants (oral): Due to the potential inhibition of vitamin K activity by propylthiouracil, the activity of oral anticoagulants (e.g., warfarin) may be increased; additional monitoring of PT/INR should be considered, especially before surgical procedures. Beta-adrenergic blocking agents: Hyperthyroidism may cause an increased clearance of beta blockers with a high extraction ratio. A reduced dose of beta adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid. Digitalis glycosides: Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; a reduced dose of digitalis glycosides may be needed. Theophylline: Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed. Carcinogenesis, Mutagenesis, Impairment of Fertility Laboratory animals treated with propylthiouracil for >1 year have demonstrated thyroid hyperplasia and carcinoma formation. Such animal findings are seen with continuous suppression of thyroid function by sufficient doses of a variety of antithyroid agents, as well as in dietary iodine deficiency, subtotal thyroidectomy, and implantation of autonomous thyrotropic hormone-secreting pituitary tumors. Pituitary adenomas have also been described. Pregnancy Because propylthiouracil readily crosses placental membranes and can induce goiter and even cretinism in the developing fetus, it is important that a sufficient, but not excessive, dose be given during pregnancy. In many pregnant women, the thyroid dysfunction diminishes as the pregnancy proceeds; consequently a reduction of dosage may be possible. In some instances, propylthiouracil can be withdrawn several weeks or months before delivery. If propylthiouracil is used during pregnancy, or if the patient becomes pregnant while taking propylthiouracil, the patient should be warned of the rare potential hazard to the mother and fetus of liver damage. Since methimazole may be associated with the rare development of fetal abnormalities such as aplasia cutis and choanal atresia, propylthiouracil may be the preferred agent during organogenesis, in the first trimester of pregnancy. Given the potential maternal adverse effects of propylthiouracil (e.g., hepatotoxicity), it may be preferable to switch from propylthiouracil to methimazole for the second and third trimesters. Pregnancy Category D. See WARNINGS. 4 Reference ID: 3699805 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nursing Mothers Propylthiouracil is transferred to breast milk to a small extent and therefore likely results in clinically insignificant doses to the suckling infant. In one study, nine lactating women were administered 400 mg of propylthiouracil by mouth. The mean amount of propylthiouracil excreted during 4 hours after drug administration was 0.025% of the administered dose. Pediatric Use Postmarketing reports of severe liver injury including hepatic failure requiring liver transplantation or resulting in death have been reported in the pediatric population. No such reports have been observed with methimazole. As such, propylthiouracil is not recommended for use in the pediatric population except in rare instances in which methimazole is not well-tolerated and surgery or radioactive iodine therapy are not appropriate. When used in children, parents and patients should be informed of the risk of liver failure. If patients taking propylthiouracil develop tiredness, nausea, anorexia, fever, pharyngitis, or malaise, propylthiouracil should be discontinued immediately by the patient, a physician should be contacted, and a white blood cell count, liver function tests, and transaminase levels obtained. ADVERSE REACTIONS The following adverse reactions have been reported with the use of propylthiouracil. Because these events generally come from voluntary reporting from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a casual relationship to drug exposure. Severe adverse reactions include liver injury presenting as hepatitis, liver failure necessitating liver transplantation or resulting in death. Inhibition of myelopoiesis (agranulocytosis, granulopenia, aplastic anemia, and thrombocytopenia), drug fever, a lupus-like syndrome (including splenomegaly and vasculitis), periarteritis, hypoprothrombinemia, and bleeding have been reported. Nephritis, glomerulonephritis, interstitial pneumonitis, exfoliative dermatitis, and erythema nodosum have also been reported. There are reports of a vasculitis syndrome associated with the presence of anti neutrophilic cytoplasmic antibodies (ANCA). Manifestations of ANCA-positive vasculitis may include rapidly progressive glomerulonephritis (crescentric and pauci immune necrotizing glomerulonephritis), sometimes leading to acute renal failure; pulmonary infiltrates or alveolar hemorrhage; skin ulcers; and leukocytoclastic vasculitis. There have been rare reports of serious hypersensitivity reactions (e.g., Stevens Johnson syndrome and toxic epidermal necrolysis) in patients treated with propylthiouracil. Other adverse reactions include skin rash, uticaria, nausea, vomiting, epigastric distress, arthralgia, paresthesias, loss of taste, taste perversion, 5 Reference ID: 3699805 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda abnormal loss of hair, myalgia, headache, pruritus, drowsiness, neuritis, edema, vertigo, skin pigmentation, jaundice, sialadenopathy, and lymphadenopathy. OVERDOSAGE Signs and Symptoms Nausea, vomiting, epigastric distress, headache, fever, arthralgia, pruritus, edema, and pancytopenia. Agranulocytosis is the most serious effect. Rarely, exfoliative dermatitis, hepatitis, neuropathies or CNS stimulation or depression may occur. No information is available on the following: LD50; concentration of propylthiouracil in biologic fluids associated with toxicity and/or death; the amount of drug in a single dose usually associated with symptoms of overdosage; or the amount of propylthiouracil in a single dose likely to be life-threatening. Treatment To obtain up-to-date information about the treatment of overdose, a good resource is the certified Regional Poison Control Center. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in the patient. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s medical status. DOSAGE AND ADMINISTRATION Propylthiouracil is administered orally. The total daily dosage is usually given in 3 equal doses at approximately 8 hour intervals. Adults The initial dose is 300 mg daily. In patients with severe hyperthyroidism, very large goiters, or both, the initial dose may be increased to 400 mg daily; an occasional patient will require 600 to 900 mg daily initially. The usual maintenance dose is 100 to 150 mg daily. Pediatric Patients Propylthiouracil is generally not recommended for use in the pediatric patient population except in rare instances in which other alternative therapies are not appropriate options. Studies evaluating appropriate dosing regimen have not been conducted in the pediatric population although general practice would suggest initiation of therapy in patients 6 years or older at a dosage of 50 mg daily with careful upward titration based on clinical response and evaluation of TSH and free T4 levels. Although cases of severe liver injury have been reported with doses as low as 50 mg/day, most cases were associated with doses of 300 mg/day and higher. Geriatric Patients Clinical studies of propylthiouracil did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. 6 Reference ID: 3699805 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. HOW SUPPLIED Propylthiouracil Tablets, USP, 50 mg, are round, white, scored tablets, engraved P33, supplied as: NDC 67253-651-10 Bottle of 100 NDC 67253-651-11 Bottle of 1000 Store at controlled room temperature 15°-30°C (59°-86°F). REFERENCE 1. International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. 1974; 7; 67-76. Manufactured for: DAVA Pharmaceuticals, Inc. Fort Lee, NJ 07024 By: Chartwell Pharmaceuticals Congers, NY 10920 Rev. 2/2015 7 Reference ID: 3699805 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE PROPYLTHIOURACIL TABLETS, USP (Pro-pil-thi-o-ur-a-sil) Read this Medication Guide before you start taking Propylthiouracil and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. What is the most important information I should know about Propylthiouracil? Propylthiouracil can cause serious side effects, including: Severe liver problems. In some cases, these liver problems can lead to liver failure, the need for liver transplant, or death. Stop taking Propylthiouracil and call your doctor right away if you have: • fever • loss of appetite • nausea • vomiting • tiredness • itchiness • pain or tenderness in your right upper stomach area (abdomen) • dark (tea colored) urine • pale or light colored bowel movements (stools) • yellowing of your skin or whites of your eyes What is Propylthiouracil? Propylthiouracil is a prescription medicine used to treat people who have Graves’ disease with hyperthyroidism or toxic multinodular goiter. Propylthiouracil is used when: • certain other antithyroid medicines do not work well. • thyroid surgery or radioactive iodine therapy is not a treatment option. • to decrease symptoms of hyperthyroidism in preparation for a thyroidectomy (removal of the thyroid gland) or radioactive iodine therapy. Propylthiouracil is not recommended for use in children. Reference ID: 3699805 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Propylthiouracil may be used when an antithyroid drug is needed during or just before the first trimester of pregnancy. Who should not take Propylthiouracil? Do not take Propylthiouracil if you are allergic to Propylthiouracil or any of its ingredients. See the end of this Medication Guide for a complete list of ingredients in Propylthiouracil. What should I tell my doctor before taking Propylthiouracil? Before you take Propylthiouracil, tell your doctor if you: • plan to have surgery. • have any other medical conditions • are pregnant or plan to become pregnant. Talk to your doctor right away if you are pregnant or plan to become pregnant. • Propylthiouracil may cause liver problems, liver failure and death in pregnant women. • Propylthiouracil may harm your unborn baby. • are breast-feeding or plan to breast-feed. Propylthiouracil can pass into your breast milk. talk to your doctor about the best way to feed your baby if you take Propylthiouracil. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Propylthiouracil may affect the way other medicines work. Especially, tell your doctor if you take: • a blood thinner medicine warfarin sodium (Coumadin, Jantoven) • medicine for heart problems • medicine for high blood pressure • Digoxin (Lanoxicaps, Lanoxin) • Theophylline (Elixophyllin, Theolair, Theochron, Theo-24, Uniphyl) Ask your doctor if you are not sure if your medicine is one of these. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. Reference ID: 3699805 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda How should I take Propylthiouracil? • Take Propylthiouracil exactly as your doctor tells you to take it. • Your doctor may change your dose if needed. • Propylthiouracil is usually taken 3 times a day (every 8 hours). • If you take too much Propylthiouracil, call your Regional Poison Control Center or go to the nearest hospital emergency room right away. • If you take too much Propylthiouracil you may have the following symptoms: • nausea • fever • vomiting • joint pain • upper stomach pain • swelling of your body, or tenderness arms, and legs • headache • If you miss a dose of Propylthiouracil, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Just take the next dose at your regular time. Do not double your dose. What are the possible side effects of Propylthiouracil? Propylthiouracil may cause serious side effects, including: • liver problems. See “What is the most important information I should know about Propylthiouracil?” • low white blood cell counts. This usually happens within the first 3 months of treatment and can be life-threatening. You may have a higher chance of getting an infection when your white blood cell count is low. Tell your doctor right away if you have: • a fever • chills • sore throat • hypothyroidism. Your doctor should do blood tests regularly during treatment to check your thyroid. • increased bleeding especially with surgical procedures and particularly if you are taking blood thinners. The most common side effects of Propylthiouracil include: Reference ID: 3699805 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • skin rash or hives • headache • nausea • sleepiness • vomiting • nerve pain • upper stomach pain • swelling (edema) or tenderness • joint pain • dizziness • itching or tingling • enlarged salivary glands or enlarged lymph nodes • loss or change in taste • loss of hair • muscle pain Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of Propylthiouracil. For more information, ask our doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1 800-FDA-1088. How should I store Propylthiouracil? Store Propylthiouracil at 59ºF to 86º F (15º-30ºC). Keep Propylthiouracil and all medicines out of the reach of children. General information about the safe and effective use of Propylthiouracil: Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Propylthiouracil for a condition for which it was not prescribed. Do not give Propylthiouracil to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about Propylthiouracil. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Propylthiouracil that is written for health professionals. Reference ID: 3699805 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda www.davapharma.com 1-877-963-8422 What are the ingredients in Propylthiouracil? Active ingredient: propylthiouracil Inactive ingredients: corn starch, docusate sodium, magnesium stearate,microcrystalline cellulose, pregelatinized starch, sodium benzoate, and sodium starch glycolate. Rx only Manufactured for: By: DAVA Pharmaceuticals, Inc. Chartwell Pharmaceuticals Fort Lee, NJ 07024 Congers, NY 10920 This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev. 2/2015 Reference ID: 3699805 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:35.893692	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/006188s024lbl.pdf', 'application_number': 6188, 'submission_type': 'SUPPL ', 'submission_number': 24}
10,689	Azulfidine® sulfasalazine tablets, USP DESCRIPTION AZULFIDINE Tablets contain sulfasalazine, 500 mg, for oral administration. Therapeutic Classification: Anti-inflammatory agent. Chemical Designation: 5-([p-(2-pyridylsulfamoyl)phenyl]azo) salicylic acid. Chemical Structure: structural formula Molecular Formula: C18H14N4O5S CLINICAL PHARMACOLOGY Pharmacodynamics The mode of action of sulfasalazine (SSZ) or its metabolites, 5-aminosalicylic acid (5 ASA) and sulfapyridine (SP), is still under investigation, but may be related to the anti- inflammatory and/or immunomodulatory properties that have been observed in animal and in vitro models, to its affinity for connective tissue, and/or to the relatively high concentration it reaches in serous fluids, the liver and intestinal walls, as demonstrated in autoradiographic studies in animals. In ulcerative colitis, clinical studies utilizing rectal administration of SSZ, SP, and 5-ASA have indicated that the major therapeutic action may reside in the 5-ASA moiety. Pharmacokinetics In vivo studies have indicated that the absolute bioavailability of orally administered SSZ is less than 15% for parent drug. In the intestine, SSZ is metabolized by intestinal bacteria to SP and 5-ASA. Of the two species, SP is relatively well absorbed from the intestine and highly metabolized, while 5-ASA is much less well absorbed. Absorption: Following oral administration of 1 g of SSZ to 9 healthy males, less than 15% of a dose of SSZ is absorbed as parent drug. Detectable serum concentrations of SSZ have been found in healthy subjects within 90 minutes after the ingestion. Maximum concentrations of SSZ occur between 3 and 12 hours post-ingestion, with the mean peak concentration (6 μg/mL) occurring at 6 hours. In comparison, peak plasma levels of both SP and 5-ASA occur approximately 10 hours after dosing. This longer time to peak is indicative of gastrointestinal transit to the lower intestine where bacteria mediated metabolism occurs. SP apparently is well absorbed from the colon with an estimated bioavailability of 60%. In this same study, 5-ASA is much less well absorbed from the gastrointestinal tract with an estimated bioavailability of from 10 to 30%. Reference ID: 3463739 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Distribution: Following intravenous injection, the calculated volume of distribution (Vdss) for SSZ was 7.5 ± 1.6 L. SSZ is highly bound to albumin (>99.3%) while SP is only about 70% bound to albumin. Acetylsulfapyridine (AcSP), the principal metabolite of SP, is approximately 90% bound to plasma proteins. Metabolism: As mentioned above, SSZ is metabolized by intestinal bacteria to SP and 5 ASA. Approximately 15% of a dose of SSZ is absorbed as parent and is metabolized to some extent in the liver to the same two species. The observed plasma half-life for intravenous sulfasalazine is 7.6 ± 3.4 hours. The primary route of metabolism of SP is via acetylation to form AcSP. The rate of metabolism of SP to AcSP is dependent upon acetylator phenotype. In fast acetylators, the mean plasma half-life of SP is 10.4 hours while in slow acetylators, it is 14.8 hours. SP can also be metabolized to 5-hydroxy sulfapyridine (SPOH) and N-acetyl-5-hydroxy-sulfapyridine. 5-ASA is primarily metabolized in both the liver and intestine to N-acetyl-5-aminosalicylic acid via a non acetylation phenotype dependent route. Due to low plasma levels produced by 5-ASA after oral administration, reliable estimates of plasma half-life are not possible. Excretion: Absorbed SP and 5-ASA and their metabolites are primarily eliminated in the urine either as free metabolites or as glucuronide conjugates. The majority of 5-ASA stays within the colonic lumen and is excreted as 5-ASA and acetyl-5-ASA with the feces. The calculated clearance of SSZ following intravenous administration was 1 L/hr. Renal clearance was estimated to account for 37% of total clearance. Special Populations Elderly: Elderly patients with rheumatoid arthritis showed a prolonged plasma half-life for SSZ, SP, and their metabolites. The clinical impact of this is unknown. Pediatric: Small studies have been reported in the literature in children down to the age of 4 years with ulcerative colitis and inflammatory bowel disease. In these populations, relative to adults, the pharmacokinetics of SSZ and SP correlated poorly with either age or dose. Acetylator Status: The metabolism of SP to AcSP is mediated by polymorphic enzymes such that two distinct populations of slow and fast metabolizers exist. Approximately 60% of the Caucasian population can be classified as belonging to the slow acetylator phenotype. These subjects will display a prolonged plasma half-life for SP (14.8 hours vs 10.4 hours) and an accumulation of higher plasma levels of SP than fast acetylators. The clinical implication of this is unclear; however, in a small pharmacokinetic trial where acetylator status was determined, subjects who were slow acetylators of SP showed a higher incidence of adverse events. Gender: Gender appears not to have an effect on either the rate or the pattern of metabolites of SSZ, SP, or 5-ASA. 2 Reference ID: 3463739 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE AZULFIDINE Tablets are indicated: a) in the treatment of mild to moderate ulcerative colitis, and as adjunctive therapy in severe ulcerative colitis; and b) for the prolongation of the remission period between acute attacks of ulcerative colitis. CONTRAINDICATIONS AZULFIDINE Tablets are contraindicated in: Patients with intestinal or urinary obstruction, Patients with porphyria as sulfonamides have been reported to precipitate an acute attack, Patients hypersensitive to sulfasalazine, its metabolites, sulfonamides, or salicylates. WARNINGS Only after critical appraisal should AZULFIDINE Tablets be given to patients with hepatic or renal damage or blood dyscrasias. Deaths associated with the administration of sulfasalazine have been reported from hypersensitivity reactions, agranulocytosis, aplastic anemia, other blood dyscrasias, renal and liver damage, irreversible neuromuscular and central nervous system changes, and fibrosing alveolitis. The presence of clinical signs such as sore throat, fever, pallor, purpura, or jaundice may be indications of serious blood disorders or hepatotoxicity. Complete blood counts, as well as urinalysis with careful microscopic examination, should be done frequently in patients receiving AZULFIDINE (see PRECAUTIONS, Laboratory Tests). Discontinue treatment with sulfasalazine while awaiting the results of blood tests. Oligospermia and infertility have been observed in men treated with sulfasalazine; however, withdrawal of the drug appears to reverse these effects. Serious infections, including fatal sepsis and pneumonia, have been reported. Some infections were associated with agranulocytosis, neutropenia, or myelosuppression. Discontinue AZULFIDINE if a patient develops a serious infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with AZULFIDINE. For a patient who develops a new infection during treatment with AZULFIDINE, perform a prompt and complete diagnostic workup for infection and myelosuppression. Caution should be exercised when considering the use of sulfasalazine in patients with a history of recurring or chronic infections or with underlying conditions or concomitant drugs which may predispose patients to infections. Severe hypersensitivity reactions may include internal organ involvement, such as hepatitis, nephritis, myocarditis, mononucleosis-like syndrome (i.e., pseudomononucleosis), hematological abnormalities (including hematophagic histiocytosis), and/or pneumonitis including eosinophilic infiltration. Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome, and toxic epidermal necrolysis, have been reported in association with the use of sulfasalazine. Patients are at highest risk for these events early in therapy, with most events occurring within the first month of treatment. Sulfasalazine should be 3 Reference ID: 3463739 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. Severe, life-threatening, systemic hypersensitivity reactions such as drug rash with eosinophilia and systemic symptoms have been reported in patients taking sulfasalazine. Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Sulfasalazine should be discontinued if an alternative etiology for the signs or symptoms cannot be established. PRECAUTIONS General: AZULFIDINE Tablets should be given with caution to patients with severe allergy or bronchial asthma. Adequate fluid intake must be maintained in order to prevent crystalluria and stone formation. Patients with glucose-6 phosphate dehydrogenase deficiency should be observed closely for signs of hemolytic anemia. This reaction is frequently dose related. If toxic or hypersensitivity reactions occur, the drug should be discontinued immediately. Information for Patients: Patients should be informed of the possibility of adverse reactions and of the need for careful medical supervision. The occurrence of sore throat, fever, pallor, purpura, or jaundice may indicate a serious blood disorder. Should any of these occur, the patient should seek medical advice. They should also be made aware that ulcerative colitis rarely remits completely, and that the risk of relapse can be reduced by continued administration of AZULFIDINE at a maintenance dosage. Patients should be instructed to take AZULFIDINE in evenly divided doses preferably after meals. Additionally, patients should be advised that sulfasalazine may produce an orange-yellow discoloration of the urine or skin. Laboratory Tests: Complete blood counts, including differential white cell count and liver function tests, should be performed before starting AZULFIDINE and every second week during the first three months of therapy. During the second three months, the same tests should be done once monthly and thereafter once every three months, and as clinically indicated. Urinalysis and an assessment of renal function should also be done periodically during treatment with AZULFIDINE. The determination of serum sulfapyridine levels may be useful since concentrations greater than 50 μg/mL appear to be associated with an increased incidence of adverse reactions. Drug Interactions: Reduced absorption of folic acid and digoxin have been reported when those agents were administered concomitantly with sulfasalazine. Drug/Laboratory Test Interactions: Several reports of possible interference with measurements, by liquid chromatography, of urinary normetanephrine causing a false-positive test result have been observed in patients exposed to sulfasalazine or its metabolite, mesalamine/mesalazine. Reference ID: 3463739 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, Mutagenesis, Impairment of Fertility: Two-year oral carcinogenicity studies were conducted in male and female F344/N rats and B6C3F1 mice. Sulfasalazine was tested at 84 (496 mg/m2), 168 (991 mg/m2), and 337.5 (1991 mg/m2) mg/kg/day doses in rats. A statistically significant increase in the incidence of urinary bladder transitional cell papillomas was observed in male rats. In female rats, two (4%) of the 337.5 mg/kg rats had transitional cell papilloma of the kidney. The increased incidence of neoplasms in the urinary bladder and kidney of rats was also associated with an increase in the renal calculi formation and hyperplasia of transitional cell epithelium. For the mouse study, sulfasalazine was tested at 675 (2025 mg/m2), 1350 (4050 mg/m2), and 2700 (8100 mg/m2) mg/kg/day. The incidence of hepatocellular adenoma or carcinoma in male and female mice was significantly greater than the control at all doses tested. Sulfasalazine did not show mutagenicity in the bacterial reverse mutation assay (Ames test) and in L51784 mouse lymphoma cell assay at the HGPRT gene. However, sulfasalazine showed equivocal mutagenic response in the micronucleus assay of mouse and rat bone marrow and mouse peripheral RBC and in the sister chromatid exchange, chromosomal aberration, and micronucleus assays in lymphocytes obtained from humans. Impairment of male fertility was observed in reproductive studies performed in rats at a dose of 800 mg/kg/day (4800 mg/m2). Oligospermia and infertility have been described in men treated with sulfasalazine. Withdrawal of the drug appears to reverse these effects. Pregnancy: Pregnancy Category B. There are no adequate and well-controlled studies of sulfasalazine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 6 times the human maintenance dose of 2 g/day based on body surface area and have revealed no evidence of impaired female fertility or harm to the fetus due to sulfasalazine. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. There have been case reports of neural tube defects (NTDs) in infants born to mothers who were exposed to sulfasalazine during pregnancy, but the role of sulfasalazine in these defects has not been established. However, oral sulfasalazine inhibits the absorption and metabolism of folic acid which may interfere with folic acid supplementation (see Drug Interactions) and diminish the effect of periconceptional folic acid supplementation that has been shown to decrease the risk of NTDs. A national survey evaluated the outcome of pregnancies associated with inflammatory bowel disease (IBD). In a group of 186 women treated with sulfasalazine alone or sulfasalazine and concomitant steroid therapy, the incidence of fetal morbidity and mortality was comparable to that for 245 untreated IBD pregnancies as well as to pregnancies in the general population.1 A study of 1,455 pregnancies associated with 5 Reference ID: 3463739 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda exposure to sulfonamides indicated that this group of drugs, including sulfasalazine, did not appear to be associated with fetal malformation.2 A review of the medical literature covering 1,155 pregnancies in women with ulcerative colitis suggested that the outcome was similar to that expected in the general population.3 No clinical studies have been performed to evaluate the effect of sulfasalazine on the growth development and functional maturation of children whose mothers received the drug during pregnancy. Clinical Considerations: Sulfasalazine and its metabolite, sulfapyridine pass through the placenta. Sulfasalazine and its metabolite are also present in human milk. In the newborn, sulfonamides compete with bilirubin for binding sites on the plasma proteins and may cause kernicterus. Although sulfapyridine has been shown to have a poor bilirubin-displacing capacity, monitor the newborn for the potential for kernicterus. A case of agranulocytosis has been reported in an infant whose mother was taking both sulfasalazine and prednisone throughout pregnancy. Nursing Mothers: Sulfonamides, including sulfasalazine, are present in human milk (see Pregnancy, Clinical Considerations). Insignificant amounts of sulfasalazine have been found in milk, whereas levels of the active metabolite sulfapyridine in milk are about 30 to 60 percent of those in the maternal serum. Caution should be exercised when AZULFIDINE is administered to a nursing mother. There are reports with limited data of bloody stools or diarrhea in human milk fed infants of mothers taking sulfasalazine. In cases where the outcome was reported, bloody stools or diarrhea resolved in the infant after discontinuation of sulfasalazine in the mother or discontinuation of breastfeeding. Due to limited data, a causal relationship between sulfasalazine exposure and bloody stools or diarrhea cannot be confirmed or denied. Monitor human milk fed infants of mothers taking sulfasalazine for signs and symptoms of diarrhea and/or bloody stools. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 2 years have not been established. ADVERSE REACTIONS The most common adverse reactions associated with sulfasalazine are anorexia, headache, nausea, vomiting, gastric distress, and apparently reversible oligospermia. These occur in about one-third of the patients. Less frequent adverse reactions are skin rash, pruritus, urticaria, fever, Heinz body anemia, hemolytic anemia, and cyanosis, which may occur at a frequency of one in every thirty patients or less. Experience suggests that with a daily dosage of 4 g or more, or total serum sulfapyridine levels above 50 μg/mL, the incidence of adverse reactions tends to increase. Although the listing which follows includes a few adverse reactions which have not been reported with this specific drug, the pharmacological similarities among the sulfonamides 6 Reference ID: 3463739 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda require that each of these reactions be considered when AZULFIDINE Tablets are administered. Less common or rare adverse reactions include: Blood dyscrasias: aplastic anemia, agranulocytosis, leukopenia, megaloblastic (macrocytic) anemia, purpura, thrombocytopenia, hypoprothrombinemia, methemoglobinemia, congenital neutropenia, and myelodysplastic syndrome. Hypersensitivity reactions: erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis, epidermal necrolysis (Lyell´s syndrome) with corneal damage, drug rash with eosinophilia and systemic symptoms (DRESS), anaphylaxis, serum sickness syndrome, interstitial lung disease, pneumonitis with or without eosinophilia, vasculitis, fibrosing alveolitis, pleuritis, pericarditis with or without tamponade, allergic myocarditis, polyarteritis nodosa, lupus erythematosus-like syndrome, hepatitis and hepatic necrosis with or without immune complexes, fulminant hepatitis, sometimes leading to liver transplantation, parapsoriasis varioliformis acuta (Mucha-Haberman syndrome), rhabdomyolysis, photosensitization, arthralgia, periorbital edema, conjunctival and scleral injection, and alopecia. Gastrointestinal reactions: hepatitis, hepatic failure, pancreatitis, bloody diarrhea, impaired folic acid absorption, impaired digoxin absorption, stomatitis, diarrhea, abdominal pains, and neutropenic enterocolitis. Central nervous system reactions: transverse myelitis, convulsions, meningitis, transient lesions of the posterior spinal column, cauda equina syndrome, Guillian-Barre syndrome, peripheral neuropathy, mental depression, vertigo, hearing loss, insomnia, ataxia, hallucinations, tinnitus, and drowsiness. Renal reactions: toxic nephrosis with oliguria and anuria, nephritis, nephrotic syndrome, urinary tract infections, hematuria, crystalluria, proteinuria, and hemolytic-uremic syndrome. Other reactions: urine discoloration and skin discoloration. The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides), and oral hypoglycemic agents. Goiter production, diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides. Cross-sensitivity may exist with these agents. Rats appear to be especially susceptible to the goitrogenic effects of sulfonamides and long-term administration has produced thyroid malignancies in this species. Postmarketing Reports The following events have been identified during post-approval use of products which contain (or are metabolized to) mesalamine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to mesalamine: Reference ID: 3463739 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Blood dyscrasias: pseudomononucleosis Cardiac disorders: myocarditis Hepatobiliary disorders: reports of hepatotoxicity, including elevated liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, hepatitis cholestatic, cholestasis and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. One case of Kawasaki-like syndrome, which included hepatic function changes, was also reported. Immune system disorders: anaphylaxis Metabolism and nutrition system disorders: folate deficiency Renal and urinary disorders: nephrolithiasis Respiratory, thoracic and mediastinal disorders: oropharyngeal pain Skin and subcutaneous tissue disorders: angioedema, purpura Vascular disorders: pallor DRUG ABUSE AND DEPENDENCE None reported. OVERDOSAGE There is evidence that the incidence and severity of toxicity following overdosage are directly related to the total serum sulfapyridine concentration. Symptoms of overdosage may include nausea, vomiting, gastric distress, and abdominal pains. In more advanced cases, central nervous system symptoms such as drowsiness, convulsions, etc., may be observed. Serum sulfapyridine concentrations may be used to monitor the progress of recovery from overdosage. There are no documented reports of deaths due to ingestion of large single doses of sulfasalazine. Doses of Azulfidine tablets of 16 g per day have been given to patients without mortality. A single oral dose of 12 g/kg was not lethal to mice. Instructions for Overdosage: Gastric lavage or emesis plus catharsis as indicated. Alkalinize urine. If kidney function is normal, force fluids. If anuria is present, restrict fluids and salt, and treat appropriately. Catheterization of the ureters may be indicated for complete renal blockage by crystals. The low molecular weight of sulfasalazine and its metabolites may facilitate their removal by dialysis. 8 Reference ID: 3463739 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION The dosage of AZULFIDINE Tablets should be adjusted to each individual’s response and tolerance. Initial Therapy: Adults: 3 to 4 g daily in evenly divided doses with dosage intervals not exceeding eight hours. In some cases, it is advisable to initiate therapy with a smaller dosage, e.g., 1 to 2 g daily, to reduce possible gastrointestinal intolerance. If daily doses exceeding 4 g are required to achieve desired effects, the increased risk of toxicity should be kept in mind. Children, six years of age and older: 40 to 60 mg/kg body weight in each 24-hour period, divided into 3 to 6 doses. Maintenance Therapy: Adults: 2 g daily. Children, six years of age and older: 30 mg/kg body weight in each 24-hour period, divided into 4 doses. The response of acute ulcerative colitis to AZULFIDINE Tablets can be evaluated by clinical criteria, including the presence of fever, weight changes, and degree and frequency of diarrhea and bleeding, as well as by sigmoidoscopy and the evaluation of biopsy samples. It is often necessary to continue medication even when clinical symptoms, including diarrhea, have been controlled. When endoscopic examination confirms satisfactory improvement, the dosage of AZULFIDINE should be reduced to a maintenance level. If diarrhea recurs, the dosage should be increased to previously effective levels. If symptoms of gastric intolerance (anorexia, nausea, vomiting, etc.) occur after the first few doses of AZULFIDINE, they are probably due to increased serum levels of total sulfapyridine and may be alleviated by halving the daily dose of AZULFIDINE and subsequently increasing it gradually over several days. If gastric intolerance continues, the drug should be stopped for 5 to 7 days, then reintroduced at a lower daily dose. Some patients may be sensitive to treatment with sulfasalazine. Various desensitization- like regimens have been reported to be effective in 34 of 53 patients,4 7 of 8 patients,5 and 19 of 20 patients.6 These regimens suggest starting with a total daily dose of 50 to 250 mg sulfasalazine initially, and doubling it every 4 to 7 days until the desired therapeutic level is achieved. If the symptoms of sensitivity recur, AZULFIDINE should be discontinued. Desensitization should not be attempted in patients who have a history of agranulocytosis, or who have experienced an anaphylactoid reaction while previously receiving sulfasalazine. 9 Reference ID: 3463739 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED AZULFIDINE Tablets, 500 mg, are round, gold-colored, scored tablets, monogrammed ”101” on one side and ”KPh” on the other. They are available in the following package sizes: Bottles of 100 NDC 0013-0101-01 Bottles of 300 NDC 0013-0101-20 Store at 25° C (77° F); excursions permitted to 15–30° C (59–86° F) [see USP Controlled Room Temperature]. Sulfasalazine is also available as AZULFIDINE EN-tabs® brand of sulfasalazine delayed release tablets, USP, 500 mg, in the following package sizes: Bottles of 100 NDC 0013-0102-01 Bottles of 300 NDC 0013-0102-20 REFERENCES 1. Mogadam M, et al. Pregnancy in inflammatory bowel disease: effect of sulfasalazine and corticosteroids on fetal outcome. Gastroenterology 1981;80:72–6. 2. Kaufman DW, editor. Birth defects and drugs during pregnancy. Littleton, MA: Publishing Sciences Group, Inc, 1977: 296–313. 3. Jarnerot G. Fertility, sterility and pregnancy in chronic inflammatory bowel disease. Scand J Gastroenterol 1982;17:1–4. 4. Korelitz B, et al. Desensitization to sulfasalazine in allergic patients with IBD: an important therapeutic modality. Gastroenterology 1982;82:1104. 5. Holdworth CG. Sulphasalazine desensitization. Br Med J 1981;282:110. 6. Taffet SL, Das KM. Desensitization of patients with inflammatory bowel disease to sulfasalazine. Am J Med 1982;73:520–4. This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com. company logo LAB-0241-7.0 Revised February 2014 Reference ID: 3463739 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Azulfidine EN-tabs® sulfasalazine delayed release tablets, USP Enteric-coated Tablets DESCRIPTION AZULFIDINE EN-tabs Tablets contain sulfasalazine, formulated in a delayed release tablet (enteric-coated), 500 mg, for oral administration. AZULFIDINE EN-tabs Tablets are film coated with cellulose acetate phthalate to retard disintegration of the tablet in the stomach and reduce potential irritation of the gastric mucosa. Therapeutic Classification: Anti-inflammatory agent and/or immunomodulatory agent. Chemical Designation: 5-([p-(2-pyridylsulfamoyl)phenyl]azo) salicylic acid. Chemical Structure: structural formula Molecular Formula: C18H14N4O5S CLINICAL PHARMACOLOGY Pharmacodynamics The mode of action of sulfasalazine (SSZ) or its metabolites, 5-aminosalicylic acid (5 ASA) and sulfapyridine (SP), is still under investigation, but may be related to the anti- inflammatory and/or immunomodulatory properties that have been observed in animal and in vitro models, to its affinity for connective tissue, and/or to the relatively high concentration it reaches in serous fluids, the liver and intestinal walls, as demonstrated in autoradiographic studies in animals. In ulcerative colitis, clinical studies utilizing rectal administration of SSZ, SP and 5-ASA have indicated that the major therapeutic action may reside in the 5-ASA moiety. The relative contribution of the parent drug and the major metabolites in rheumatoid arthritis is unknown. Pharmacokinetics In vivo studies have indicated that the absolute bioavailability of orally administered SSZ is less than 15% for parent drug. In the intestine, SSZ is metabolized by intestinal bacteria to SP and 5-ASA. Of the two species, SP is relatively well absorbed from the intestine and highly metabolized, while 5-ASA is much less well absorbed. Absorption: Following oral administration of 1 g of SSZ to 9 healthy males, less than 15% of a dose of SSZ is absorbed as parent drug. Detectable serum concentrations of SSZ have been found in healthy subjects within 90 minutes after the ingestion. Maximum Reference ID: 3463739 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda concentrations of SSZ occur between 3 and 12 hours post-ingestion, with the mean peak concentration (6 μg/mL) occurring at 6 hours. In comparison, peak plasma levels of both SP and 5-ASA occur approximately 10 hours after dosing. This longer time to peak is indicative of gastrointestinal transit to the lower intestine, where bacteria-mediated metabolism occurs. SP apparently is well absorbed from the colon, with an estimated bioavailability of 60%. In this same study, 5-ASA is much less well absorbed from the gastrointestinal tract, with an estimated bioavailability of from 10% to 30%. Distribution: Following intravenous injection, the calculated volume of distribution (Vdss) for SSZ was 7.5 ± 1.6 L. SSZ is highly bound to albumin (>99.3%), while SP is only about 70% bound to albumin. Acetylsulfapyridine (AcSP), the principal metabolite of SP, is approximately 90% bound to plasma proteins. Metabolism: As mentioned above, SSZ is metabolized by intestinal bacteria to SP and 5 ASA. Approximately 15% of a dose of SSZ is absorbed as parent and is metabolized to some extent in the liver to the same two species. The observed plasma half-life for intravenous sulfasalazine is 7.6 ± 3.4 hrs. The primary route of metabolism of SP is via acetylation to form AcSP. The rate of metabolism of SP to AcSP is dependent upon acetylator phenotype. In fast acetylators, the mean plasma half-life of SP is 10.4 hrs, while in slow acetylators it is 14.8 hrs. SP can also be metabolized to 5-hydroxy sulfapyridine (SPOH) and N-acetyl-5-hydroxy-sulfapyridine. 5-ASA is primarily metabolized in both the liver and intestine to N-acetyl-5-aminosalicylic acid via a nonacetylation phenotype dependent route. Due to low plasma levels produced by 5-ASA after oral administration, reliable estimates of plasma half-life are not possible. Excretion: Absorbed SP and 5-ASA and their metabolites are primarily eliminated in the urine either as free metabolites or as glucuronide conjugates. The majority of 5-ASA stays within the colonic lumen and is excreted as 5-ASA and acetyl-5-ASA with the feces. The calculated clearance of SSZ following intravenous administration was 1 L/hr. Renal clearance was estimated to account for 37% of total clearance. Special Populations Elderly: Elderly patients with rheumatoid arthritis showed a prolonged plasma half-life for SSZ, SP, and their metabolites. The clinical impact of this is unknown. Pediatric: Small studies have been reported in the literature in children down to the age of 4 years with ulcerative colitis and inflammatory bowel disease. In these populations, relative to adults, the pharmacokinetics of SSZ and SP correlated poorly with either age or dose. To date, comparative pharmacokinetic trials have not been conducted to determine whether or not significant pharmacokinetic differences exist between children with juvenile rheumatoid arthritis and adults with rheumatoid arthritis. Acetylator Status: The metabolism of SP to AcSP is mediated by polymorphic enzymes such that two distinct populations of slow and fast metabolizers exist. Approximately 2 Reference ID: 3463739 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 60% of the Caucasian population can be classified as belonging to the slow acetylator phenotype. These subjects will display a prolonged plasma half-life for SP (14.8 hrs vs. 10.4 hrs) and an accumulation of higher plasma levels of SP than fast acetylators. The clinical implication of this is unclear; however, in a small pharmacokinetic trial where acetylator status was determined, subjects who were slow acetylators of SP showed a higher incidence of adverse events. Gender: Gender appears not to have an effect on either the rate or the pattern of metabolites of SSZ, SP, or 5-ASA. INDICATIONS AND USAGE AZULFIDINE EN-tabs Tablets are indicated: a) in the treatment of mild to moderate ulcerative colitis, and as adjunctive therapy in severe ulcerative colitis; b) for the prolongation of the remission period between acute attacks of ulcerative colitis; c) in the treatment of patients with rheumatoid arthritis who have responded inadequately to salicylates or other nonsteroidal anti-inflammatory drugs (e.g., an insufficient therapeutic response to, or intolerance of, an adequate trial of full doses of one or more nonsteroidal anti-inflammatory drugs); and d) in the treatment of pediatric patients with polyarticular-course1 juvenile rheumatoid arthritis who have responded inadequately to salicylates or other nonsteroidal anti- inflammatory drugs. AZULFIDINE EN-tabs is particularly indicated in patients with ulcerative colitis who cannot take uncoated sulfasalazine tablets because of gastrointestinal intolerance, and in whom there is evidence that this intolerance is not primarily the result of high blood levels of sulfapyridine and its metabolites, e.g., patients experiencing nausea and vomiting with the first few doses of the drug, or patients in whom a reduction in dosage does not alleviate the adverse gastrointestinal effects. In patients with rheumatoid arthritis or juvenile rheumatoid arthritis, rest and physiotherapy as indicated should be continued. Unlike anti-inflammatory drugs, AZULFIDINE EN-tabs does not produce an immediate response. Concurrent treatment with analgesics and/or nonsteroidal anti-inflammatory drugs is recommended at least until the effect of AZULFIDINE EN-tabs is apparent. CONTRAINDICATIONS AZULFIDINE EN-tabs Tablets are contraindicated in: Hypersensitivity to sulfasalazine, its metabolites, sulfonamides or salicylates, Patients with intestinal or urinary obstruction, Patients with porphyria, as the sulfonamides have been reported to precipitate an acute attack. 3 Reference ID: 3463739 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS Only after critical appraisal should AZULFIDINE EN-tabs Tablets be given to patients with hepatic or renal damage or blood dyscrasias. Deaths associated with the administration of sulfasalazine have been reported from hypersensitivity reactions, agranulocytosis, aplastic anemia, other blood dyscrasias, renal and liver damage, irreversible neuromuscular and central nervous system changes, and fibrosing alveolitis. The presence of clinical signs such as sore throat, fever, pallor, purpura or jaundice may be indications of serious blood disorders or hepatotoxicity. Complete blood counts, as well as urinalysis with careful microscopic examination, should be done frequently in patients receiving AZULFIDINE EN-tabs (see PRECAUTIONS, Laboratory Tests). Discontinue treatment with sulfasalazine while awaiting the results of blood tests. Oligospermia and infertility have been observed in men treated with sulfasalazine; however, withdrawal of the drug appears to reverse these effects. Serious infections, including fatal sepsis and pneumonia, have been reported. Some infections were associated with agranulocytosis, neutropenia, or myelosuppression. Discontinue AZULFIDINE EN tabs if a patient develops a serious infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with AZULFIDINE EN tabs. For a patient who develops a new infection during treatment with AZULFIDINE EN tabs, perform a prompt and complete diagnostic workup for infection and myelosuppression. Caution should be exercised when considering the use of sulfasalazine in patients with a history of recurring or chronic infections or with underlying conditions or concomitant drugs which may predispose patients to infections. Severe hypersensitivity reactions may include internal organ involvement, such as hepatitis, nephritis, myocarditis, mononucleosis-like syndrome (i.e., pseudomononucleosis), hematological abnormalities (including hematophagic histiocytosis), and/or pneumonitis including eosinophilic infiltration. Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome, and toxic epidermal necrolysis, have been reported in association with the use of sulfasalazine. Patients are at highest risk for these events early in therapy, with most events occurring within the first month of treatment. Sulfasalazine should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. Severe, life-threatening, systemic hypersensitivity reactions such as drug rash with eosinophilia and systemic symptoms have been reported in patients taking sulfasalazine. Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Sulfasalazine should be discontinued if an alternative etiology for the signs or symptoms cannot be established. PRECAUTIONS 4 Reference ID: 3463739 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda General: AZULFIDINE EN-tabs Tablets should be given with caution to patients with severe allergy or bronchial asthma. Adequate fluid intake must be maintained in order to prevent crystalluria and stone formation. Patients with glucose-6-phosphate dehydrogenase deficiency should be observed closely for signs of hemolytic anemia. This reaction is frequently dose related. If toxic or hypersensitivity reactions occur, AZULFIDINE EN-tabs should be discontinued immediately. Isolated instances have been reported when AZULFIDINE EN-tabs Tablets have passed undisintegrated. If this is observed, the administration of AZULFIDINE EN-tabs should be discontinued immediately. Information For Patients: Patients should be informed of the possibility of adverse effects and of the need for careful medical supervision. The occurrence of sore throat, fever, pallor, purpura or jaundice may indicate a serious blood disorder. Should any of these occur, the patient should seek medical advice. Patients should be instructed to take AZULFIDINE EN-tabs in evenly divided doses, preferably after meals, and to swallow the tablets whole. Additionally, patients should be advised that sulfasalazine may produce an orange-yellow discoloration of the urine or skin. Ulcerative Colitis: Patients with ulcerative colitis should be made aware that ulcerative colitis rarely remits completely, and that the risk of relapse can be substantially reduced by continued administration of AZULFIDINE EN-tabs at a maintenance dosage. Rheumatoid Arthritis: Rheumatoid arthritis rarely remits. Therefore, continued administration of AZULFIDINE EN-tabs is indicated. Patients requiring sulfasalazine should follow up with their physicians to determine the need for continued administration. Laboratory Tests: Complete blood counts, including differential white cell count and liver function tests, should be performed before starting AZULFIDINE EN-tabs and every second week during the first three months of therapy. During the second three months, the same tests should be done once monthly and thereafter once every three months, and as clinically indicated. Urinalysis and an assessment of renal function should also be done periodically during treatment with AZULFIDINE EN-tabs. The determination of serum sulfapyridine levels may be useful since concentrations greater than 50 μg/mL appear to be associated with an increased incidence of adverse reactions. Drug Interactions: Reduced absorption of folic acid and digoxin have been reported when those agents were administered concomitantly with sulfasalazine. 5 Reference ID: 3463739 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda When daily doses of sulfasalazine 2 g and weekly doses of methotrexate 7.5 mg were coadministered to 15 rheumatoid arthritis patients in a drug-drug interaction study, the pharmacokinetic disposition of the drugs was not altered. Daily doses of sulfasalazine 2 g (maximum 3 g) and weekly doses of methotrexate 7.5 mg (maximum 15 mg) were administered alone or in combination to 310 rheumatoid arthritis patients in two controlled 52-week clinical studies. The overall toxicity profile of the combination revealed an increased incidence of gastrointestinal adverse events, especially nausea, when compared to the incidence associated with either drug administered alone. Drug/Laboratory Test Interactions: Several reports of possible interference with measurements, by liquid chromatography, of urinary normetanephrine causing a false- positive test result have been observed in patients exposed to sulfasalazine or its metabolite, mesalamine/mesalazine. Carcinogenesis, Mutagenesis, Impairment of Fertility: Two year oral carcinogenicity studies were conducted in male and female F344/N rats and B6C3F1 mice. Sulfasalazine was tested at 84 (496 mg/m2), 168 (991 mg/m2) and 337.5 (1991 mg/m2) mg/kg/day doses in rats. A statistically significant increase in the incidence of urinary bladder transitional cell papillomas was observed in male rats. In female rats, two (4%) of the 337.5 mg/kg rats had transitional cell papilloma of the kidney. The increased incidence of neoplasms in the urinary bladder and kidney of rats was also associated with an increase in the renal calculi formation and hyperplasia of transitional cell epithelium. For the mouse study, sulfasalazine was tested at 675 (2025 mg/m2), 1350 (4050 mg/m2) and 2700 (8100 mg/m2) mg/kg/day. The incidence of hepatocellular adenoma or carcinoma in male and female mice was significantly greater than the control at all doses tested. Sulfasalazine did not show mutagenicity in the bacterial reverse mutation assay (Ames test) or in the L51784 mouse lymphoma cell assay at the HGPRT gene. However, sulfasalazine showed equivocal mutagenic response in the micronucleus assay of mouse and rat bone marrow and mouse peripheral RBC and in the sister chromatid exchange, chromosomal aberration, and micronucleus assays in lymphocytes obtained from humans. Impairment of male fertility was observed in reproductive studies performed in rats at a dose of 800 mg/kg/day (4800 mg/m2). Oligospermia and infertility have been described in men treated with sulfasalazine. Withdrawal of the drug appears to reverse these effects. Pregnancy: Pregnancy Category B. There are no adequate and well-controlled studies of sulfasalazine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 6 times the human maintenance dose of 2 g/day based on body surface area and have revealed no evidence of impaired female fertility or harm to the fetus due to sulfasalazine. Because 6 Reference ID: 3463739 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. There have been case reports of neural tube defects (NTDs) in infants born to mothers who were exposed to sulfasalazine during pregnancy, but the role of sulfasalazine in these defects has not been established. However, oral sulfasalazine inhibits the absorption and metabolism of folic acid which may interfere with folic acid supplementation (see Drug Interactions) and diminish the effect of periconceptional folic acid supplementation that has been shown to decrease the risk of NTDs. A national survey evaluated the outcome of pregnancies associated with inflammatory bowel disease (IBD). In 186 pregnancies in women treated with sulfasalazine alone or sulfasalazine and concomitant steroid therapy, the incidence of fetal morbidity and mortality was comparable both to that of 245 untreated IBD pregnancies, and to pregnancies in the general population.2 A study of 1455 pregnancies associated with exposure to sulfonamides including sulfasalazine, indicated that this group of drugs did not appear to be associated with fetal malformation.3 A review of the medical literature covering 1155 pregnancies in women with ulcerative colitis suggested that the outcome was similar to that expected in the general population.4 No clinical studies have been performed to evaluate the effect of sulfasalazine on the growth development and functional maturation of children whose mothers received the drug during pregnancy. Clinical Considerations: Sulfasalazine and its metabolite, sulfapyridine, pass through the placenta. Sulfasalazine and its metabolite are also present in human milk. In the newborn, sulfonamides compete with bilirubin for binding sites on the plasma proteins and may cause kernicterus. Although sulfapyridine has been shown to have poor bilirubin-displacing capacity, monitor the newborn for the potential for kernicterus. A case of agranulocytosis has been reported in an infant whose mother was taking both sulfasalazine and prednisone throughout pregnancy. Nursing Mothers: Sulfonamides, including sulfasalazine, are present in human milk (see Pregnancy, Clinical Considerations). Insignificant amounts of sulfasalazine have been found in milk, whereas levels of the active metabolite sulfapyridine in milk are about 30 to 60 percent of those in the maternal serum. Caution should be exercised when AZULFIDINE EN-tabs is administered to a nursing mother. There are reports with limited data of bloody stools or diarrhea in human milk fed infants of mothers taking sulfasalazine. In cases where the outcome was reported, bloody stools or diarrhea resolved in the infant after discontinuation of sulfasalazine in the mother or discontinuation of breastfeeding. Due to limited data, a causal relationship between sulfasalazine exposure and bloody stools or diarrhea cannot be , confirmed or denied. 7 Reference ID: 3463739 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Monitor human milk fed infants of mothers taking sulfasalazine for signs and symptoms of diarrhea and/or bloody stools. Pediatric Use: The safety and effectiveness of AZULFIDINE EN-tabs in pediatric patients below the age of 2 years with ulcerative colitis have not been established. The safety and effectiveness of AZULFIDINE EN-tabs for the treatment of the signs and symptoms of polyarticular-course juvenile rheumatoid arthritis in pediatric patients aged 6–16 years is supported by evidence from adequate and well-controlled studies in adult rheumatoid arthritis patients. The extrapolation from adults with rheumatoid arthritis to children with polyarticular-course juvenile rheumatoid arthritis is based on similarities in disease and response to therapy between these two patient populations. Published studies support the extrapolation of safety and effectiveness for sulfasalazine to polyarticular-course juvenile rheumatoid arthritis1,5 (see ADVERSE REACTIONS). It has been reported that the frequency of adverse events in patients with systemic-course of juvenile arthritis is high.6 Use in children with systemic-course juvenile rheumatoid arthritis has frequently resulted in a serum sickness-like reaction.5 This reaction is often severe and presents as fever, nausea, vomiting, headache, rash, and abnormal liver function tests. Treatment of systemic-course juvenile rheumatoid arthritis with sulfasalazine is not recommended. ADVERSE REACTIONS The most common adverse reactions associated with sulfasalazine in ulcerative colitis are anorexia, headache, nausea, vomiting, gastric distress, and apparently reversible oligospermia. These occur in about one-third of the patients. Less frequent adverse reactions are pruritus, urticaria, rash, fever, Heinz body anemia, hemolytic anemia and cyanosis, which may occur at a frequency of 1 in 30 patients or less. Experience suggests that with a daily dose of 4 g or more, or total serum sulfapyridine levels above 50 μg/mL, the incidence of adverse reactions tends to increase. Similar adverse reactions are associated with sulfasalazine use in adult rheumatoid arthritis, although there was a greater incidence of some reactions. In rheumatoid arthritis studies, the following common adverse reactions were noted: nausea (19%), dyspepsia (13%), rash (13%), headache (9%), abdominal pain (8%), vomiting (8%), fever (5%), dizziness (4%), stomatitis (4%), pruritis (4%), abnormal liver function tests (4%), leukopenia (3%), and thrombocytopenia (1%). One report7 showed a 10% rate of immunoglobulin suppression, which was slowly reversible and rarely accompanied by clinical findings. In general, the adverse reactions in juvenile rheumatoid arthritis patients are similar to those seen in patients with adult rheumatoid arthritis except for a high frequency of serum sickness-like syndrome in systemic-course juvenile rheumatoid arthritis (see PRECAUTIONS, Pediatric Use). One clinical trial showed an approximate 10% rate of immunoglobulin suppression.1 8 Reference ID: 3463739 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Although the listing which follows includes a few adverse reactions which have not been reported with this specific drug, the pharmacological similarities among the sulfonamides require that each of these reactions be considered when AZULFIDINE EN-tabs is administered. Less common or rare adverse reactions include: Blood dyscrasias: aplastic anemia, agranulocytosis, megaloblastic (macrocytic) anemia, purpura, hypoprothrombinemia, methemoglobinemia, congenital neutropenia, and myelodysplastic syndrome. Hypersensitivity reactions: erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis, epidermal necrolysis (Lyell’s syndrome) with corneal damage, drug rash with eosinophilia and systemic symptoms (DRESS), anaphylaxis, serum sickness syndrome, interstitial lung disease, pneumonitis with or without eosinophilia, vasculitis, fibrosing alveolitis, pleuritis, pericarditis with or without tamponade, allergic myocarditis, polyarteritis nodosa, lupus erythematosus-like syndrome, hepatitis and hepatic necrosis with or without immune complexes, fulminant hepatitis, sometimes leading to liver transplantation, parapsoriasis varioliformis acuta (Mucha-Haberman syndrome), rhabdomyolysis, photosensitization, arthralgia, periorbital edema, conjunctival and scleral injection and alopecia. Gastrointestinal reactions: hepatitis, hepatic failure, pancreatitis, bloody diarrhea, impaired folic acid absorption, impaired digoxin absorption, stomatitis, diarrhea, abdominal pains, and neutropenic enterocolitis. Central Nervous System reactions: transverse myelitis, convulsions, meningitis, transient lesions of the posterior spinal column, cauda equina syndrome, Guillain-Barre syndrome, peripheral neuropathy, mental depression, vertigo, hearing loss, insomnia, ataxia, hallucinations, tinnitus and drowsiness. Renal reactions: toxic nephrosis with oliguria and anuria, nephritis, nephrotic syndrome, urinary tract infections, hematuria, crystalluria, proteinuria, and hemolytic-uremic syndrome. Other reactions: urine discoloration and skin discoloration. The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides), and oral hypoglycemic agents. Goiter production, diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides. Cross-sensitivity may exist with these agents. Rats appear to be especially susceptible to the goitrogenic effects of sulfonamides and long-term administration has produced thyroid malignancies in this species. Postmarketing Reports Reference ID: 3463739 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The following events have been identified during post-approval use of products which contain (or are metabolized to) mesalamine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to mesalamine: Blood dyscrasias: pseudomononucleosis Cardiac disorders: myocarditis Hepatobiliary disorders: reports of hepatotoxicity, including elevated liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, hepatitis cholestatic, cholestasis and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. One case of Kawasaki-like syndrome, which included hepatic function changes, was also reported. Immune system disorders: anaphylaxis Metabolism and nutrition system disorders: folate deficiency Renal and urinary disorders: nephrolithiasis Respiratory, thoracic and mediastinal disorders: oropharyngeal pain Skin and subcutaneous tissue disorders: angioedema, purpura Vascular disorders: pallor DRUG ABUSE AND DEPENDENCE None reported. OVERDOSAGE There is evidence that the incidence and severity of toxicity following overdosage is directly related to the total serum sulfapyridine concentration. Symptoms of overdosage may include nausea, vomiting, gastric distress and abdominal pains. In more advanced cases, central nervous system symptoms such as drowsiness, convulsions, etc., may be observed. Serum sulfapyridine concentrations may be used to monitor the progress of recovery from overdosage. There are no documented reports of deaths due to ingestion of large single doses of sulfasalazine. It has not been possible to determine the LD50 in laboratory animals such as mice, since the highest oral daily dose of sulfasalazine which can be given (12 g/kg) is not lethal. Doses of regular sulfasalazine tablets of 16 g per day have been given to patients without mortality. 10 Reference ID: 3463739 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Instructions for Overdosage: Gastric lavage or emesis plus catharsis as indicated. Alkalinize urine. If kidney function is normal, force fluids. If anuria is present, restrict fluids and salt, and treat appropriately. Catheterization of the ureters may be indicated for complete renal blockage by crystals. The low molecular weight of sulfasalazine and its metabolites may facilitate their removal by dialysis. DOSAGE AND ADMINISTRATION The dosage of AZULFIDINE EN-tabs Tablets should be adjusted to each individual’s response and tolerance. Patients should be instructed to take AZULFIDINE EN-tabs in evenly divided doses, preferably after meals, and to swallow the tablets whole. Initial Therapy Adults: 3 to 4 g daily in evenly divided doses with dosage intervals not exceeding eight hours. It may be advisable to initiate therapy with a lower dosage, e.g., 1 to 2 g daily, to reduce possible gastrointestinal intolerance. If daily doses exceeding 4 g are required to achieve the desired therapeutic effect, the increased risk of toxicity should be kept in mind. Children, six years of age and older: 40 to 60 mg/kg of body weight in each 24-hour period, divided into 3 to 6 doses. Maintenance Therapy Adults: 2 g daily. Children, six years of age and older: 30 mg/kg of body weight in each 24-hour period, divided into 4 doses. The response of acute ulcerative colitis to AZULFIDINE EN-tabs can be evaluated by clinical criteria, including the presence of fever, weight changes, and degree and frequency of diarrhea and bleeding, as well as by sigmoidoscopy and the evaluation of biopsy samples. It is often necessary to continue medication even when clinical symptoms, including diarrhea, have been controlled. When endoscopic examination confirms satisfactory improvement, dosage of AZULFIDINE EN-tabs should be reduced to a maintenance level. If diarrhea recurs, dosage should be increased to previously effective levels. AZULFIDINE EN-tabs is particularly indicated in patients who cannot take uncoated sulfasalazine tablets because of gastrointestinal intolerance (e.g., anorexia, nausea). If symptoms of gastric intolerance (anorexia, nausea, vomiting, etc.) occur after the first few doses of AZULFIDINE EN-tabs, they are probably due to increased serum levels of total sulfapyridine, and may be alleviated by halving the daily dose of AZULFIDINE EN-tabs and subsequently increasing it gradually over several days. If gastric intolerance continues, the drug should be stopped for 5 to 7 days, then reintroduced at a lower daily dose. Adult Rheumatoid Arthritis : 11 Reference ID: 3463739 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 g daily in two evenly divided doses. It is advisable to initiate therapy with a lower dosage of AZULFIDINE EN-tabs, e.g., 0.5 to 1.0 g daily, to reduce possible gastrointestinal intolerance. A suggested dosing schedule is given below. In rheumatoid arthritis, the effect of AZULFIDINE EN-tabs can be assessed by the degree of improvement in the number and extent of actively inflamed joints. A therapeutic response has been observed as early as 4 weeks after starting treatment with AZULFIDINE EN-tabs, but treatment for 12 weeks may be required in some patients before clinical benefit is noted. Consideration can be given to increasing the daily dose of AZULFIDINE EN-tabs to 3 g if the clinical response after 12 weeks is inadequate. Careful monitoring is recommended for doses over 2 g per day. Suggested Dosing Schedule for Adult Rheumatoid Arthritis: Week of Number of AZULFIDINE EN-tabs Tablets Treatment Morning Evening 1 - One 2 One One 3 One Two 4 Two Two Juvenile Rheumatoid Arthritis - polyarticular course Children, six years of age and older: 30 to 50 mg/kg of body weight daily in two evenly divided doses. Typically, the maximum dose is 2 g per day. To reduce possible gastrointestinal intolerance, begin with a quarter to a third of the planned maintenance dose and increase weekly until reaching the maintenance dose at one month. Some patients may be sensitive to treatment with sulfasalazine. Various desensitization- like regimens have been reported to be effective in 34 of 53 patients,8 7 of 8 patients,9 and 19 of 20 patients.10 These regimens suggest starting with a total daily dose of 50 to 250 mg sulfasalazine initially, and doubling it every 4 to 7 days until the desired therapeutic level is achieved. If the symptoms of sensitivity recur, AZULFIDINE EN- tabs should be discontinued. Desensitization should not be attempted in patients who have a history of agranulocytosis, or who have experienced an anaphylactoid reaction while previously receiving sulfasalazine. HOW SUPPLIED AZULFIDINE EN-tabs Tablets, 500 mg, are elliptical, gold-colored, film enteric-coated tablets, monogrammed “102” on one side and “KPh” on the other. They are available in the following package sizes: Bottles of 100 NDC 0013-0102-01 Bottles of 300 NDC 0013-0102-20 Storage: Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. 12 Reference ID: 3463739 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda REFERENCES 1. van Rossum MAJ, et al. Sulfasalazine in the treatment of juvenile chronic arthritis: a randomized, double-blind, placebo-controlled, multicenter study. Arth Rheum 1998;41:808–816. 2. Mogadam M, et al. Pregnancy in inflammatory bowel disease: effect of sulfasalazine and corticosteroids on fetal outcome. Gastroenterology 1981;80:726. 3. Kaufman DW, editor. Birth defects and drugs during pregnancy. Littleton, MA: Publishing Sciences Group, Inc., 1977:296–313. 4. Jarnerot G. Fertility, sterility and pregnancy in chronic inflammatory bowel disease. Scand J Gastroenterol 1982;17:1–4. 5. Imundo LF, Jacobs JC. Sulfasalazine therapy for juvenile rheumatoid arthritis. J Rheumatol 1996;23:360–366. 6. Hertzberger-ten Cate R, Cats A. Toxicity of sulfasalazine in systemic juvenile chronic arthritis. Clin Exp Rheumatol 1991;9:85–8. 7. Farr M, et al. Immunodeficiencies associated with sulphasalazine therapy in inflammatory arthritis. British Jnl Rheum 1991;30:413–417. 8. Korelitz B, et al. Desensitization to sulfasalazine in allergic patients with IBD: an important therapeutic modality. Gastroenterology 1982;82:1104. 9. Holdworth CG. Sulphasalazine desensitization. Br Med J 1981;282:110. 10. Taffet SL, Das KM. Desensitization of patients with inflammatory bowel disease to sulfasalazine. Am J Med 1982;73:520–4. This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com. company logo LAB-0237-7.0 Revised February 2014 Reference ID: 3463739 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:36.025721	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/007073s128lbl.pdf', 'application_number': 7073, 'submission_type': 'SUPPL ', 'submission_number': 128}
10,690	NDA 7-337/S-029 Page 3 PERCODAN® (Oxycodone and Aspirin Tablets, USP) CII Rx only DESCRIPTION Each PERCODAN Tablet contains: Oxycodone Hydrochloride 4.5 mg* Oxycodone Terephthalate 0.38 mg* Aspirin, USP 325 mg The total of 4.5 mg oxycodone HCl and 0.38 mg oxycodone terephthalate is equivalent to 4.33 mg of oxycodone as the free base. PERCODAN Tablets also contain the following inactive ingredients: D&C Yellow 10, FD&C Yellow 6, microcrystalline cellulose and corn starch. The oxycodone hydrochloride component is Morphinan-6-one, 4,5-epoxy-14-hydroxy-3-methoxy-17- methyl-, hydrochloride, (5a)-., a white to off-white, hygroscopic crystals or powder, odorless, soluble in water; slightly soluble in alcohol. Oxycodone Terephthalate is freely soluble in water and slightly soluble in alcohol and is represented by the following structural formula: C18H21NO4●HCl MW 351.82 The aspirin component is 2-(acetyloxy)-, Benzoic acid, a white crystal, commonly tabular or needle- like, or white, crystalline powder. Is odorless or has a faint odor. Is stable in dry air; in moist air it gradually hydrolyzes to salicylic and acetic acids. Slightly soluble in water; freely soluble in alcohol; soluble in chloroform and in ether; sparingly soluble in absolute ether and is represented by the following structural formula: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 4 C9H8O 4 MW 180.16 CLINICAL PHARMACOLOGY Central Nervous System Oxycodone is a semisynthetic pure opioid agonist whose principal therapeutic action is analgesia. Other pharmacological effects of oxycodone include anxiolysis, euphoria and feelings of relaxation. These effects are mediated by receptors (notably µ and κ) in the central nervous system for endogenous opioid-like compounds such as endorphins and enkephalins. Oxycodone produces respiratory depression through direct activity at respiratory centers in the brain stem and depresses the cough reflex by direct effect on the center of the medulla. Aspirin (acetylsalicylic acid) works by inhibiting the body’s production of prostaglandins, including prostaglandins involved in inflammation. Prostaglandins cause pain sensations by stimulating muscle contractions and dilating blood vessels throughout the body. In the CNS, aspirin works on the hypothalamus heat-regulating center to reduce fever, however, other mechanisms may be involved. Gastrointestinal Tract and Other Smooth Muscle Oxycodone reduces motility by increasing smooth muscle tone in the stomach and duodenum. In the small intestine, digestion of food is delayed by decreases in propulsive contractions. Other opioid effects include contraction of biliary tract smooth muscle, spasm of the Sphincter of Oddi, increased ureteral and bladder sphincter tone, and a reduction in uterine tone. Aspirin can produce gastrointestinal injury (lesions, ulcers) through a mechanism that is not yet completely understood, but may involve a reduction in eicosanoid synthesis by the gastric mucosa. Decreased production of prostaglandins may compromise the defenses of the gastric mucosa and the activity of substances involved in tissue repair and ulcer healing. Cardiovascular System Oxycodone may produce a release of histamine and may be associated with orthostatic hypotension, and other symptoms, such as pruritus, flushing, red eyes, and sweating. Platelet Aggregation Aspirin affects platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating factor thromboxane A2. Nonacetylated salicylates do not inhibit this enzyme and have no effect on platelet aggregation. At somewhat higher doses, aspirin reversibly inhibits the formation of prostaglandin 12 (prostacyclin), which is an arterial vasodilator and inhibits platelet aggregation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 5 Pharmacokinetics Absorption and Distribution The mean absolute oral bioavailability of oxycodone in cancer patients was reported to be about 87%. Oxycodone has been shown to be 45% bound to human plasma proteins in vitro. The volume of distribution after intravenous administration is 211.9 ±186.6 L. Aspirin is hydrolyzed primarily to salicylic acid in the gut wall and during first-pass metabolism through the liver. Salicylic acid is absorbed rapidly from the stomach, but most of the absorption occurs in the proximal small intestine. Following absorption, salicylate is distributed to most body tissues and fluids, including fetal tissues, breast milk, and the CNS. High concentrations are found in the liver and kidneys. Salicylate is variably bound to serum proteins, particularly albumin. Metabolism and Elimination A high portion of oxycodone is N-dealkylated to noroxycodone during first-pass metabolism. Oxymorphone, is formed by the O-demethylation of oxycodone. The metabolism of oxycodone to oxymorphone is catalyzed by CYP2D6. Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. Approximately 8% to 14% of the dose is excreted as free oxycodone over 24 hours after administration. Following a single, oral dose of oxycodone, the mean ± SD elimination half-life is 3.51 ± 1.43 hours. The biotransformation of aspirin occurs primarily in the liver by the microsomal enzyme system. With a plasma half-life of approximately 15 minutes, aspirin is rapidly hydrolyzed to salicylate. At low doses, salicylate elimination follows first-order kinetics. The plasma half-life of salicylate is approximately 2 to 3 hours. Approximately 10% of aspirin is excreted as unchanged salicylate in the urine. The major metabolites excreted in the urine are salicyluric acid (75%), salicyl phenolic glucuronide (10%), salicyl acyl glucuronide (5%), and gentisic and gentisuric acid (less than 1%) each. Eighty to 100% of a single dose is excreted in the urine within 24 to 72 hours. INDICATIONS AND USAGE PERCODAN tablets are indicated for the management of moderate to moderately severe pain. CONTRAINDICATIONS PERCODAN tablets are contraindicated in patients with known hypersensitivity to oxycodone or aspirin, and in any situation where opioids or aspirin are contraindicated. Aspirin is contraindicated for patients with hemophilia. Reye Syndrome: Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye syndrome with concomitant use of aspirin in certain viral illnesses. Allergy: Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema, or bronchospasm (asthma). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 6 Oxycodone is contraindicated in patients with known hypersensitivity to oxycodone. Oxycodone is contraindicated in any situation where opioids are contraindicated including patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment) and patients with acute or severe bronchial asthma or hypercarbia. Oxycodone is contraindicated in the setting of suspected or known paralytic ileus. WARNINGS Misuse, Abuse and Diversion of Opioids Oxycodone is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Oxycodone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing PERCODAN tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Concerns about misuse, addiction, and diversion should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Administration of PERCODAN (Oxycodone and Aspirin Tablets, USP) tablets should be closely monitored for the following potentially serious adverse reactions and complications: Respiratory Depression Respiratory depression is a hazard with the use of oxycodone, one of the active ingredients in PERCODAN tablets, as with all opioid agonists. Elderly and debilitated patients are at particular risk for respiratory depression as are non-tolerant patients given large initial doses of oxycodone or when oxycodone is given in conjunction with other agents that depress respiration. Oxycodone should be used with extreme caution in patients with acute asthma, chronic obstructive pulmonary disorder (COPD), cor pulmonale, or preexisting respiratory impairment. In such patients, even usual therapeutic doses of oxycodone may decrease respiratory drive to the point of apnea. In these patients alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose. In case of respiratory depression, a reversal agent such as naloxone hydrochloride may be utilized (see OVERDOSAGE). Head Injury and Increased Intracranial Pressure The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Oxycodone produces effects on pupillary response and consciousness which may obscure neurologic signs of worsening in patients with head injuries. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 7 Hypotensive Effect Oxycodone may cause severe hypotension particularly in individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs which compromise vasomotor tone such as phenothiazines. Oxycodone, like all opioid analgesics of the morphine-type, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. Oxycodone may produce orthostatic hypotension in ambulatory patients. Alcohol Warning Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. Coagulation Abnormalities Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited (hemophilia) or acquired (liver disease or vitamin K deficiency) bleeding disorders. GI Side Effects GI side effects include stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur. Peptic Ulcer Disease Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation and bleeding. PRECAUTIONS General Opioid analgesics should be used with caution when combined with CNS depressant drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression, altered mental state, and postural hypotension. PERCODAN tablets should be given with caution to patients with CNS depression, elderly or debilitated patients, patients with severe impairment of hepatic, pulmonary, or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy, urethral stricture, acute alcoholism, delirium tremens, kyphoscoliosis with respiratory depression, myxedema, and toxic psychosis. PERCODAN tablets may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Oxycodone may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings. Following administration of PERCODAN tablets, anaphylactic reactions have been reported in patients with a known hypersensitivity to codeine, a compound with a structure similar to morphine and oxycodone. The frequency of this possible cross-sensitivity is unknown. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 8 Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time. Hemorrhage Aspirin may increase the likelihood of hemorrhage due to its effect on the gastric mucosa and platelet function (prolongation of bleeding time). Salicylates should be used with caution in the presence of peptic ulcer or coagulation abnormalities. Pregnancy Aspirin can cause fetal harm when administered to a pregnant woman. Salicylates readily cross the placenta and by inhibiting prostaglandin synthesis, may cause constriction of ductus arteriosus, resulting in pulmonary hypertension and increased fetal mortality and, possibly other untoward fetal effects. Aspirin use in pregnancy can also result in alteration in maternal and neonatal hemostasis mechanisms. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths and neonatal death. The use of aspirin during pregnancy especially in the third trimester should be avoided. If PERCODAN tablets are used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Renal Failure Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute). Hepatic Insufficiency Avoid aspirin in patients with severe hepatic insufficiency. Interactions with Other CNS Depressants Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with PERCODAN tablets may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Interactions with Mixed Agonist/Antagonist Opioid Analgesics Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as oxycodone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone and/or may precipitate withdrawal symptoms in these patients. Ambulatory Surgery and Postoperative Use Oxycodone and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common postoperative complication, especially after intra-abdominal surgery with use of opioid analgesia. Caution should be taken to monitor for decreased bowel motility in postoperative patients receiving opioids. Standard supportive therapy should be implemented. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 9 Use in Pancreatic/Biliary Tract Disease Oxycodone may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like oxycodone may cause increases in the serum amylase level. Tolerance and Physical Dependence Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: Cessation of Therapy). Information for Patients/Caregivers The following information should be provided to patients receiving PERCODAN tablets by their physician, nurse, pharmacist, or caregiver: 1. Patients should be aware that PERCODAN tablets contain oxycodone, which is a morphine- like substance. 2. Patients should be instructed to keep PERCODAN tablets in a secure place out of the reach of children. In the case of accidental ingestions, emergency medical care should be sought immediately. 3. When PERCODAN tablets are no longer needed, the unused tablets should be destroyed by flushing down the toilet. 4. Patients should be advised not to adjust the medication dose themselves. Instead, they must consult with their prescribing physician. 5. Patients should be advised that PERCODAN tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery). 6. Patients should not combine PERCODAN tablets with alcohol, opioid analgesics, tranquilizers, sedatives, or other CNS depressants unless under the recommendation and guidance of a physician. When co-administered with another CNS depressant, PERCODAN tablets can cause dangerous additive central nervous system or respiratory depression, which can result in serious injury or death. 7. The safe use of PERCODAN tablets during pregnancy has not been established; thus, women who are planning to become pregnant or are pregnant should consult with their physician before taking PERCODAN tablets. 8. Nursing mothers should consult with their physicians about whether to discontinue nursing or discontinue PERCODAN tablets because of the potential for serious adverse reactions to nursing infants. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 10 9. Patients who are treated with PERCODAN tablets for more than a few weeks should be advised not to abruptly discontinue the medication. Patients should consult with their physician for a gradual discontinuation dose schedule to taper off the medication. 10. Patients should be advised that PERCODAN tablets are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed. Laboratory Tests Although oxycodone may cross-react with some drug urine tests, no available studies were found which determined the duration of detectability of oxycodone in urine drug screens. However, based on pharmacokinetic data, the approximate duration of detectability for a single dose of oxycodone is roughly estimated to be one to two days following drug exposure. Urine testing for opiates may be performed to determine illicit drug use and for medical reasons such as evaluation of patients with altered states of consciousness or monitoring efficacy of drug rehabilitation efforts. The preliminary identification of opiates in urine involves the use of an immunoassay screening and thin-layer chromatography (TLC). Gas chromatography/mass spectrometry (GC/MS) may be utilized as a third-stage identification step in the medical investigational sequence for opiate testing after immunoassay and TLC. The identities of 6-keto opiates (e.g., oxycodone) can further be differentiated by the analysis of their methoxime-trimethylsilyl (MO-TMS) derivative. Drug/Drug Interactions with Oxycodone Opioid analgesics may enhance the neuromuscular-blocking action of skeletal muscle relaxants and produce an increase in the degree of respiratory depression. Patients receiving CNS depressants such as other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with PERCODAN tablets may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, naltrexone, and butorphanol) should be administered with caution to a patient who has received or is receiving a pure opioid agonist such as oxycodone. These agonist/antagonist analgesics may reduce the analgesic effect of oxycodone or may precipitate withdrawal symptoms. Drug/Drug Interactions with Aspirin Angiotensin Converting Enzyme (ACE) Inhibitors: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin-angiotensin conversion pathway. Acetazolamide: Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion. Anticoagulant Therapy (Heparin and Warfarin): Patients on anticoagulation therapy are at increased risk for bleeding because of drug-drug interactions and the effect on platelets. Aspirin can displace This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 11 warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk. Anticonvulsants: Salicylate can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels. Beta Blockers: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention. Diuretics: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. Methotrexate: Aspirin may enhance the serious side and toxicity of methotrexate due to displacement from its plasma protein binding sites and/or reduced renal clearance. Nonsteroidal Anti-inflammatory Drugs (NSAID's): The concurrent use of aspirin with other NSAID's should be avoided because this may increase bleeding or lead to decreased renal function. Aspirin may enhance the serious side effects and toxicity of ketorolac, due to displacement from its plasma protein binding sites and/or reduced renal clearance. Oral Hypoglycemics Agents: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia. Uricosuric Agents: Salicylates antagonize the uricosuric action of probenecid or sulfinpyrazone. Drug/Laboratory Test Interactions Depending on the sensitivity/specificity and the test methodology, the individual components of PERCODAN tablets may cross-react with assays used in the preliminary detection of cocaine (primary urinary metabolite, benzoylecgonine) or marijuana (cannabinoids) in human urine. A more specific alternate chemical method must be used in order to obtain a confirmed analytical result. The preferred confirmatory method is gas chromatography/mass spectrometry (GC/MS). Moreover, clinical considerations and professional judgment should be applied to any drug-of-abuse test result, particularly when preliminary positive results are used. Salicylates may increase the protein bound iodine (PBI) result by competing for the protein binding sites on pre-albumin and possibly thyroid-binding globulins. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Animal studies to evaluate the carcinogenic potential of oxycodone and aspirin have not been performed. Mutagenesis The combination of oxycodone and aspirin has not been evaluated for mutagenicity. Oxycodone alone was negative in a bacterial reverse mutation assay (Ames), an in vitro chromosome aberration assay This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 12 with human lymphocytes without metabolic activation and an in vivo mouse micronucleus assay. Oxycodone was clastogenic in the human lymphocyte chromosomal assay in the presence of metabolic activation and in the mouse lymphoma assay with or without metabolic activation. Aspirin induced chromosome aberrations in cultured human fibroblasts. Fertility Animal studies to evaluate the effects of oxycodone on fertility have not been performed. Aspirin has been shown to inhibit ovulation in rats. Pregnancy Teratogenic Effects Oxycodone: Pregnancy Category B Reproduction studies in rats and rabbits demonstrated that oral administration of oxycodone was not teratogenic or embryo-fetal toxic. Aspirin: Pregnancy Category D (see PRECAUTIONS) Salicylates readily cross the placenta and by inhibiting prostaglandin synthesis, may cause constriction of ductus arteriosus resulting in pulmonary hypertension and increased fetal mortality and, possibly other untoward fetal effects. Aspirin use in pregnancy can also result in alteration in maternal and neonatal hemostasis mechanisms. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths and neonatal death. Use during pregnancy, especially in the third trimester, should be avoided. Safe use of PERCODAN (Oxycodone and Aspirin Tablets, USP) in pregnancy has not been established relative to possible adverse effects on fetal development. Therefore, PERCODAN tablets should not be used in pregnant women unless, in the judgment of the physician, the potential benefits outweigh the possible hazards. Nonteratogenic Effects Opioids can cross the placental barrier and have the potential to cause neonatal respiratory depression. Opioid use during pregnancy may result in a physically drug-dependent fetus. After birth, the neonate may suffer severe withdrawal symptoms. Aspirin may produce anemia, ante- or postpartum hemorrhage, prolonged gestation and labor, and oligohydramnios. Labor and Delivery PERCODAN tablets are not recommended for use in women during and immediately prior to labor and delivery due to its potential effects on respiratory function in the newborn. Aspirin should be avoided one week prior to and during labor and delivery because it can result in excessive blood loss at delivery. Prolonged gestation and prolonged labor due to prostaglandin inhibition have been reported. Nursing Mothers Ordinarily, nursing should not be undertaken while a patient is receiving PERCODAN tablets because of the possibility of sedation and/or respiratory depression in the infant. Oxycodone is excreted in breast milk in low concentrations, and there have been rare reports of somnolence and lethargy in babies of nursing mothers taking an oxycodone/acetaminophen product. Salicylic acid has also been detected in breast milk. Adverse effects on platelet function in the nursing infant exposed to aspirin in breast milk may be a potential risk. Furthermore, the risk of Reye Syndrome caused by salicylate in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 13 breast milk is unknown. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the potential benefits to the woman and the possible hazards to the nursing infant. Pediatric Use PERCODAN tablets should not be administered to pediatric patients. Reye Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin (or salicylates) may increase the risk of developing this disease. Geriatric Use Special precaution should be given when determining the dosing amount and frequency of PERCODAN tablets for geriatric patients, since clearance of oxycodone may be slightly reduced in this patient population when compared to younger patients. Hepatic Impairment In a pharmacokinetic study of oxycodone in patients with end-stage liver disease, oxycodone plasma clearance decreased and the elimination half-life increased. Care should be exercised when oxycodone is used in patients with hepatic impairment. Renal Impairment In a study of patients with end stage renal impairment, mean elimination half-life was prolonged in uremic patients due to increased volume of distribution and reduced clearance. Oxycodone should be used with caution in patients with renal impairment. ADVERSE REACTIONS Serious adverse reactions that may be associated with PERCODAN tablet use include respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, and shock (see OVERDOSAGE). The most frequently observed non-serious adverse reactions include lightheadedness, dizziness, drowsiness or sedation, nausea, and vomiting. These effects seem to be more prominent in ambulatory than in nonambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include euphoria, dysphoria, constipation and pruritus. Aspirin may increase the likelihood of hemorrhage due to its effect on the gastric mucosa and platelet function. Furthermore, aspirin has the potential to cause anaphylaxis in hypersensitive patients as well as angioedema especially in patients with chronic urticaria. Other adverse reactions due to aspirin use include anorexia, reversible hepatotoxicity, leukopenia, thrombocytopenia, purpura, decreased plasma iron concentration, and shortened erythrocyte survival time. Other adverse reactions obtained from postmarketing experiences with PERCODAN tablets are listed by organ system and in decreasing order of severity and/or frequency as follows: Body as a Whole allergic reaction, malaise, asthenia, headache, anaphylaxis, fever, hypothermia, thirst, increased sweating, accident, accidental overdose, non-accidental overdose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 14 Cardiovascular tachycardia, dysrhythmias, hypotension, orthostatic hypotension, bradycardia, palpitations Central and Peripheral Nervous System stupor, paresthesia, agitation, cerebral edema, coma, confusion, dizziness, headache, subdural or intracranial hemorrhage, lethargy, seizures, anxiety, mental impairment Fluid and Electrolyte dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis Gastrointestinal hemorrhagic gastric/duodenal ulcer, gastric/peptic ulcer, dyspepsia, abdominal pain, diarrhea, eructation, dry mouth, gastrointestinal bleeding, intestinal perforation, nausea, vomiting, transient elevations of hepatic enzymes, hepatitis, Reye syndrome, pancreatitis, intestinal obstruction, ileus Hearing and Vestibular hearing loss, tinnitus. Patients with high frequency loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism. Hematologic unspecified hemorrhage, purpura, reticulocytosis, prolongation of prothrombin time, disseminated intravascular coagulation, ecchymosis, thrombocytopenia. Hypersensitivity acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema, urticaria, anaphylactoid reaction Metabolic and Nutritional hypoglycemia, hyperglycemia, acidosis, alkalosis Musculoskeletal rhabdomyolysis Ocular miosis, visual disturbances, red eye Psychiatric drug dependence, drug abuse, somnolence, depression, nervousness, hallucination Reproductive prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding, closure of patent ductus arteriosis Respiratory System bronchospasm, dyspnea, hyperpnea, pulmonary edema, tachypnea, aspiration, hypoventilation, laryngeal edema This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 15 Skin and Appendages urticaria, rash, flushing Urogenital interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure, urinary retention OVERDOSAGE Signs and Symptoms Serious overdose with PERCODAN (Oxycodone and Aspirin Tablets, USP) is characterized by signs and symptoms of opioid and salicylate overdose. Oxycodone overdosage can be manifested by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, pupillary constriction (pupils may be dilated in the setting of hypoxia), and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. Early signs of acute aspirin (salicylate) overdose including tinnitus occur at plasma concentrations approaching 200 mcg/mL. Plasma concentrations of aspirin above 300 mcg/mL are toxic. Severe toxic effects are associated with levels above 400 mcg/mL. A single lethal dose of aspirin in adults is not known with certainty but death may be expected at 30 g. For real or suspected overdose, a Poison Control Center should be contacted immediately. In acute salicylate overdose, severe acid-base and electrolyte disturbances may occur and are complicated by hyperthermia and dehydration, and coma. Respiratory alkalosis occurs early while hyperventilation is present, but is quickly followed by metabolic acidosis. Serious symptoms such as depression, coma, and respiratory failure progress rapidly. Salicylism (chronic salicylate toxicity) may be noted by symptoms such as dizziness, tinnitus, difficulty hearing, nausea, vomiting, diarrhea, and mental confusion. More severe salicylism may result in respiratory alkalosis. Treatment Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. Supportive measures (including oxygen, intravenous fluids, and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Treatment of acid-base disturbances and electrolyte disorders is also important. Because of the concern over salicylate toxicity, acid-base status should be followed closely with serial blood gas and serum pH determinations. The opioid antagonist naloxone hydrochloride (NARCAN) is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to opioids including oxycodone. Therefore, an appropriate dose of naloxone hydrochloride should be administered (usual initial adult dose 0.4 mg-2 mg) preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. Since the duration of action of oxycodone may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. Opioid antagonists should not be administered in the absence of clinically significant respiratory of circulatory depression secondary to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 16 oxycodone overdose. In patients who are physically dependent on any opioid agonist including oxycodone, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use. Gastric emptying and/or lavage may be useful in removing unabsorbed drug. This procedure is recommended as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal, as a slurry, is beneficial, if less than three hours have passed since ingestion. Charcoal adsorption should not be employed prior to lavage and emesis. In severe cases of salicylate overdose, hyperthermia and hypovolemia are the major immediate threats to life. Children should be sponged with tepid water. Replacement fluid should be administered intravenously and augmented with correction of acidosis. Plasma electrolytes and pH should be monitored to promote alkaline diuresis of salicylate if renal function is normal. Infusion of glucose may be required to control hypoglycemia. With more severe acute toxicity respiratory alkalosis may occur. Hemodialysis and peritoneal dialysis can be performed to reduce the body content of aspirin. In patients with renal insufficiency or in cases of life-threatening salicylate intoxication dialysis is usually required. Exchange transfusion may be indicated in infants and young children. In case of real or suspected overdose, a poison control center should be consulted for the treatment of salicylism. The toxicity of oxycodone and aspirin in combination is unknown. DOSAGE AND ADMINISTRATION Dosage should be adjusted according to the severity of the pain and the response of the patient. It may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of opioids. If pain is constant, the opioid analgesic should be given at regular intervals on an around-the-clock schedule. PERCODAN tablets are given orally. The usual dosage is one tablet every 6 hours as needed for pain. The maximum daily dose of aspirin should not exceed 4 grams or 12 tablets. Cessation of Therapy In patients treated with PERCODAN tablets for more than a few weeks who no longer require therapy, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient. DRUG ABUSE AND DEPENDENCE PERCODAN tablets are a Schedule II controlled substance. Oxycodone is a mu-agonist opioid with an abuse liability similar to morphine. Oxycodone, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 17 Drug addiction is defined as an abnormal, compulsive use, use for non-medical purposes of a substance despite physical, psychological, occupational or interpersonal difficulties resulting from such use, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common. Opioid addiction is relatively rare in patients with chronic pain but may be more common in individuals who have a past history of alcohol or substance abuse or dependence. Pseudoaddiction refers to pain relief seeking behavior of patients whose pain is poorly managed. It is considered an iatrogenic effect of ineffective pain management. The health care provider must assess continuously the psychological and clinical condition of a pain patient in order to distinguish addiction from pseudoaddiction and thus, be able to treat the pain adequately. Physical dependence on a prescribed medication does not signify addiction. Physical dependence involves the occurrence of a withdrawal syndrome when there is sudden reduction or cessation in drug use or if an opiate antagonist is administered. Physical dependence can be detected after a few days of opioid therapy. However, clinically significant physical dependence is only seen after several weeks of relatively high dosage therapy. In this case, abrupt discontinuation of the opioid may result in a withdrawal syndrome. If the discontinuation of opioids is therapeutically indicated, gradual tapering of the drug over a 2-week period will prevent withdrawal symptoms. The severity of the withdrawal syndrome depends primarily on the daily dosage of the opioid, the duration of therapy and medical status of the individual. The withdrawal syndrome of oxycodone is similar to that of morphine. This syndrome is characterized by yawning, anxiety, increased heart rate and blood pressure, restlessness, nervousness, muscle aches, tremor, irritability, chills alternating with hot flashes, salivation, anorexia, severe sneezing, lacrimation, rhinorrhea, dilated pupils, diaphoresis, piloerection, nausea, vomiting, abdominal cramps, diarrhea and insomnia, and pronounced weakness and depression. “Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor Shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated infection. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Oxycodone, like other opioids, has been diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Like other opioid medications, PERCODAN tablets are subject to the Federal Controlled Substances Act. After chronic use, PERCODAN tablets should not be discontinued abruptly when it is thought that the patient has become physically dependent on oxycodone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 18 Interactions with Alcohol and Drugs of Abuse Oxycodone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. HOW SUPPLIED PERCODAN (Oxycodone and Aspirin Tablets, USP), tablets are supplied as a yellow round tablet, scored and debossed with “PERCODAN” on one side and plain on the other side. Available in: Bottles of 100 NDC 63481-135-70 Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). DEA Order Form Required. Manufactured for: Endo Pharmaceuticals Inc. Chadds Ford, Pennsylvania 19317 PERCODAN® is a Registered Trademark of Endo Pharmaceuticals Inc. NARCAN® is a Registered Trademark of Endo Pharmaceuticals Inc. Copyright © Endo Pharmaceuticals Inc. 2003 Printed in U.S.A. 414342/December, 2003 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 19 PERCODAN®-DEMI (Oxycodone and Aspirin Tablets, USP) CII Rx only DESCRIPTION Each PERCODAN-Demi Tablet contains: Oxycodone Hydrochloride 2.25 mg Oxycodone Terephthalate 0.19 mg* Aspirin, USP 325 mg *The total of 2.25 mg oxycodone HCl and 0.19 mg oxycodone terephthalate is equivalent to 2.1673 mg of oxycodone as the free base. PERCODAN-Demi Tablets also contain: microcrystalline cellulose and starch (corn). The oxycodone hydrochloride component is Morphinan-6-one, 4,5-epoxy-14-hydroxy-3-methoxy-17- methyl-, hydrochloride, (5a)-., a white to off-white, hygroscopic crystals or powder, odorless, soluble in water; slightly soluble in alcohol. Oxycodone Terephthalate is freely soluble in water and slightly soluble in alcohol and is represented by the following structural formula: C18H21NO4●HCl M.W. 351.82 The aspirin component is 2-(acetyloxy)-, Benzoic acid, a white crystal, commonly tabular or needle- like, or white, crystalline powder. Is odorless or has a faint odor. Is stable in dry air; in moist air it gradually hydrolyzes to salicylic and acetic acids. Slightly soluble in water; freely soluble in alcohol; soluble in chloroform and in ether; sparingly soluble in absolute ether and is represented by the following structural formula: C9H 8O 4 M.W. 180.16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 20 CLINICAL PHARMACOLOGY Central Nervous System Oxycodone is a semisynthetic pure opioid agonist whose principal therapeutic action is analgesia. Other pharmacological effects of oxycodone include anxiolysis, euphoria and feelings of relaxation. These effects are mediated by receptors (notably µ andκ) in the central nervous system for endogenous opioid-like compounds such as endorphins and enkephalins. Oxycodone produces respiratory depression through direct activity at respiratory centers in the brain stem and depresses the cough reflex by direct effect on the center of the medulla. Aspirin (acetylsalicylic acid) works by inhibiting the body’s production of prostaglandins, including prostaglandins involved in inflammation. Prostaglandins cause pain sensations by stimulating muscle contractions and dilating blood vessels throughout the body. In the CNS, aspirin works on the hypothalamus heat-regulating center to reduce fever, however, other mechanisms may be involved. Gastrointestinal Tract and Other Smooth Muscle Oxycodone reduces motility by increasing smooth muscle tone in the stomach and duodenum. In the small intestine, digestion of food is delayed by decreases in propulsive contractions. Other opioid effects include contraction of biliary tract smooth muscle, spasm of the Sphincter of Oddi, increased ureteral and bladder sphincter tone, and a reduction in uterine tone. Aspirin can produce gastrointestinal injury (lesions, ulcers) through a mechanism that is not yet completely understood, but may involve a reduction in eicosanoid synthesis by the gastric mucosa. Decreased production of prostaglandins may compromise the defenses of the gastric mucosa and the activity of substances involved in tissue repair and ulcer healing. Cardiovascular System Oxycodone may produce a release of histamine and may be associated with orthostatic hypotension, and other symptoms, such as pruritus, flushing, red eyes, and sweating. Platelet Aggregation Aspirin affects platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating factor thromboxane A2. Nonacetylated salicylates do not inhibit this enzyme and have no effect on platelet aggregation. At somewhat higher doses, aspirin reversibly inhibits the formation of prostaglandin 12 (prostacyclin), which is an arterial vasodilator and inhibits platelet aggregation. Pharmacokinetics Absorption and Distribution The mean absolute oral bioavailability of oxycodone in cancer patients was reported to be about 87%. Oxycodone has been shown to be 45% bound to human plasma proteins in vitro. The volume of distribution after intravenous administration is 211.9 ±186.6 L. Aspirin is hydrolyzed primarily to salicylic acid in the gut wall and during first-pass metabolism through the liver. Salicylic acid is absorbed rapidly from the stomach, but most of the absorption occurs in the proximal small intestine. Following absorption, salicylate is distributed to most body This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 21 tissues and fluids, including fetal tissues, breast milk, and the CNS. High concentrations are found in the liver and kidneys. Salicylate is variably bound to serum proteins, particularly albumin. Metabolism and Elimination A high portion of oxycodone is N-dealkylated to noroxycodone during first-pass metabolism. Oxymorphone, is formed by the O-demethylation of oxycodone. The metabolism of oxycodone to oxymorphone is catalyzed by CYP2D6. Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. Approximately 8% to 14% of the dose is excreted as free oxycodone over 24 hours after administration. Following a single, oral dose of oxycodone, the mean ± SD elimination half-life is 3.51 ± 1.43 hours. The biotransformation of aspirin occurs primarily in the liver by the microsomal enzyme system. With a plasma half-life of approximately 15 minutes, aspirin is rapidly hydrolyzed to salicylate. At low doses, salicylate elimination follows first-order kinetics. The plasma half-life of salicylate is approximately 2 to 3 hours. Approximately 10% of aspirin is excreted as unchanged salicylate in the urine. The major metabolites excreted in the urine are salicyluric acid (75%), salicyl phenolic glucuronide (10%), salicyl acyl glucuronide (5%), and gentisic and gentisuric acid (less than 1%) each. Eighty to 100% of a single dose is excreted in the urine within 24 to 72 hours. INDICATIONS AND USAGE PERCODAN-Demi tablets are indicated for the management of moderate to moderately severe pain. CONTRAINDICATIONS PERCODAN-Demi tablets are contraindicated in patients with known hypersensitivity to oxycodone or aspirin, and in any situation where opioids or aspirin are contraindicated. Aspirin is contraindicated for patients with hemophilia. Reye Syndrome: Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye syndrome with concomitant use of aspirin in certain viral illnesses. Allergy: Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema, or bronchospasm (asthma). Oxycodone is contraindicated in patients with known hypersensitivity to oxycodone. Oxycodone is contraindicated in any situation where opioids are contraindicated including patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment) and patients with acute or severe bronchial asthma or hypercarbia. Oxycodone is contraindicated in the setting of suspected or known paralytic ileus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 22 WARNINGS Misuse, Abuse and Diversion of Opioids Oxycodone is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Oxycodone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing PERCODAN-Demi tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Concerns about misuse, addiction, and diversion should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Administration of PERCODAN- Demi (Oxycodone and Aspirin Tablets, USP) tablets should be closely monitored for the following potentially serious adverse reactions and complications: Respiratory Depression Respiratory depression is a hazard with the use of oxycodone, one of the active ingredients in PERCODAN- Demi tablets, as with all opioid agonists. Elderly and debilitated patients are at particular risk for respiratory depression as are non-tolerant patients given large initial doses of oxycodone or when oxycodone is given in conjunction with other agents that depress respiration. Oxycodone should be used with extreme caution in patients with acute asthma, chronic obstructive pulmonary disorder (COPD), cor pulmonale, or preexisting respiratory impairment. In such patients, even usual therapeutic doses of oxycodone may decrease respiratory drive to the point of apnea. In these patients alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose. In case of respiratory depression, a reversal agent such as naloxone hydrochloride may be utilized (see OVERDOSAGE). Head Injury and Increased Intracranial Pressure The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Oxycodone produces effects on pupillary response and consciousness which may obscure neurologic signs of worsening in patients with head injuries. Hypotensive Effect Oxycodone may cause severe hypotension particularly in individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs which compromise vasomotor tone such as phenothiazines. Oxycodone, like all opioid analgesics of the morphine-type, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. Oxycodone may produce orthostatic hypotension in ambulatory patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 23 Alcohol Warning Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. Coagulation Abnormalities Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited (hemophilia) or acquired (liver disease or vitamin K deficiency) bleeding disorders. GI Side Effects GI side effects include stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur. Peptic Ulcer Disease Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation and bleeding. PRECAUTIONS General Opioid analgesics should be used with caution when combined with CNS depressant drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression, altered mental state, and postural hypotension. PERCODAN- Demi tablets should be given with caution to patients with CNS depression, elderly or debilitated patients, patients with severe impairment of hepatic, pulmonary, or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy, urethral stricture, acute alcoholism, delirium tremens, kyphoscoliosis with respiratory depression, myxedema, and toxic psychosis. PERCODAN- Demi tablets may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Oxycodone may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings. Following administration of PERCODAN- Demi tablets, anaphylactic reactions have been reported in patients with a known hypersensitivity to codeine, a compound with a structure similar to morphine and oxycodone. The frequency of this possible cross-sensitivity is unknown. Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time. Hemorrhage Aspirin may increase the likelihood of hemorrhage due to its effect on the gastric mucosa and platelet function (prolongation of bleeding time). Salicylates should be used with caution in the presence of peptic ulcer or coagulation abnormalities. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 24 Pregnancy Aspirin can cause fetal harm when administered to a pregnant woman. Salicylates readily cross the placenta and by inhibiting prostaglandin synthesis, may cause constriction of ductus arteriosus, resulting in pulmonary hypertension and increased fetal mortality and, possibly other untoward fetal effects. Aspirin use in pregnancy can also result in alteration in maternal and neonatal hemostasis mechanisms. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths and neonatal death. The use of aspirin during pregnancy especially in the third trimester should be avoided. If PERCODAN- Demi tablets are used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Renal Failure Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute). Hepatic Insufficiency Avoid aspirin in patients with severe hepatic insufficiency. Interactions with Other CNS Depressants Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with PERCODAN- Demi tablets may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Interactions with Mixed Agonist/Antagonist Opioid Analgesics Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as oxycodone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone and/or may precipitate withdrawal symptoms in these patients. Ambulatory Surgery and Postoperative Use Oxycodone and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common postoperative complication, especially after intra-abdominal surgery with use of opioid analgesia. Caution should be taken to monitor for decreased bowel motility in postoperative patients receiving opioids. Standard supportive therapy should be implemented. Use in Pancreatic/Biliary Tract Disease Oxycodone may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like oxycodone may cause increases in the serum amylase level. Tolerance and Physical Dependence Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 25 The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: Cessation of Therapy ). Information for Patients/Caregivers The following information should be provided to patients receiving PERCODAN- Demi tablets by their physician, nurse, pharmacist, or caregiver: 11. Patients should be aware that PERCODAN-Demi tablets contain oxycodone, which is a morphine-like substance. 12. Patients should be instructed to keep PERCODAN- Demi tablets in a secure place out of the reach of children. In the case of accidental ingestions, emergency medical care should be sought immediately. 13. When PERCODAN- Demi tablets are no longer needed, the unused tablets should be destroyed by flushing down the toilet. 14. Patients should be advised not to adjust the medication dose themselves. Instead, they must consult with their prescribing physician. 15. Patients should be advised that PERCODAN- Demi tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery). 16. Patients should not combine PERCODAN- Demi tablets with alcohol, opioid analgesics, tranquilizers, sedatives, or other CNS depressants unless under the recommendation and guidance of a physician. When co-administered with another CNS depressant, PERCODAN- Demi tablets can cause dangerous additive central nervous system or respiratory depression, which can result in serious injury or death. 17. The safe use of PERCODAN- Demi tablets during pregnancy has not been established; thus, women who are planning to become pregnant or are pregnant should consult with their physician before taking PERCODAN- Demi tablets. 18. Nursing mothers should consult with their physicians about whether to discontinue nursing or discontinue PERCODAN- Demi tablets because of the potential for serious adverse reactions to nursing infants. 19. Patients who are treated with PERCODAN- Demi tablets for more than a few weeks should be advised not to abruptly discontinue the medication. Patients should consult with their physician for a gradual discontinuation dose schedule to taper off the medication. 20. Patients should be advised that PERCODAN- Demi tablets are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed. Laboratory Tests Although oxycodone may cross-react with some drug urine tests, no available studies were found which determined the duration of detectability of oxycodone in urine drug screens. However, based on pharmacokinetic data, the approximate duration of detectability for a single dose of oxycodone is roughly estimated to be one to two days following drug exposure. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 26 Urine testing for opiates may be performed to determine illicit drug use and for medical reasons such as evaluation of patients with altered states of consciousness or monitoring efficacy of drug rehabilitation efforts. The preliminary identification of opiates in urine involves the use of an immunoassay screening and thin-layer chromatography (TLC). Gas chromatography/mass spectrometry (GC/MS) may be utilized as a third-stage identification step in the medical investigational sequence for opiate testing after immunoassay and TLC. The identities of 6-keto opiates (e.g., oxycodone) can further be differentiated by the analysis of their methoxime-trimethylsilyl (MO-TMS) derivative. Drug/Drug Interactions with Oxycodone Opioid analgesics may enhance the neuromuscular-blocking action of skeletal muscle relaxants and produce an increase in the degree of respiratory depression. Patients receiving CNS depressants such as other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with PERCODAN- Demi tablets may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, naltrexone, and butorphanol) should be administered with caution to a patient who has received or is receiving a pure opioid agonist such as oxycodone. These agonist/antagonist analgesics may reduce the analgesic effect of oxycodone or may precipitate withdrawal symptoms. Drug/Drug Interactions with Aspirin Angiotensin Converting Enzyme (ACE) Inhibitors: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin-angiotensin conversion pathway. Acetazolamide: Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion. Anticoagulant Therapy (Heparin and Warfarin): Patients on anticoagulation therapy are at increased risk for bleeding because of drug-drug interactions and the effect on platelets. Aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk. Anticonvulsants: Salicylate can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels. Beta Blockers: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention. Diuretics: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 27 Methotrexate: Aspirin may enhance the serious side and toxicity of methotrexate due to displacement from its plasma protein binding sites and/or reduced renal clearance. Nonsteroidal Anti-inflammatory Drugs (NSAID's): The concurrent use of aspirin with other NSAID's should be avoided because this may increase bleeding or lead to decreased renal function. Aspirin may enhance the serious side effects and toxicity of ketorolac, due to displacement from its plasma protein binding sites and/or reduced renal clearance. Oral Hypoglycemics Agents: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia. Uricosuric Agents: Salicylates antagonize the uricosuric action of probenecid or sulfinpyrazone. Drug/Laboratory Test Interactions Depending on the sensitivity/specificity and the test methodology, the individual components of PERCODAN- Demi tablets may cross-react with assays used in the preliminary detection of cocaine (primary urinary metabolite, benzoylecgonine) or marijuana (cannabinoids) in human urine. A more specific alternate chemical method must be used in order to obtain a confirmed analytical result. The preferred confirmatory method is gas chromatography/mass spectrometry (GC/MS). Moreover, clinical considerations and professional judgment should be applied to any drug-of-abuse test result, particularly when preliminary positive results are used. Salicylates may increase the protein bound iodine (PBI) result by competing for the protein binding sites on pre-albumin and possibly thyroid-binding globulins. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Animal studies to evaluate the carcinogenic potential of oxycodone and aspirin have not been performed. Mutagenesis The combination of oxycodone and aspirin has not been evaluated for mutagenicity. Oxycodone alone was negative in a bacterial reverse mutation assay (Ames), an in vitro chromosome aberration assay with human lymphocytes without metabolic activation and an in vivo mouse micronucleus assay. Oxycodone was clastogenic in the human lymphocyte chromosomal assay in the presence of metabolic activation and in the mouse lymphoma assay with or without metabolic activation. Aspirin induced chromosome aberrations in cultured human fibroblasts. Fertility Animal studies to evaluate the effects of oxycodone on fertility have not been performed. Aspirin has been shown to inhibit ovulation in rats. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 28 Pregnancy Teratogenic Effects Oxycodone: Pregnancy Category B Reproduction studies in rats and rabbits demonstrated that oral administration of oxycodone was not teratogenic or embryo-fetal toxic. Aspirin: Pregnancy Category D (see PRECAUTIONS) Salicylates readily cross the placenta and by inhibiting prostaglandin synthesis, may cause constriction of ductus arteriosus resulting in pulmonary hypertension and increased fetal mortality and, possibly other untoward fetal effects. Aspirin use in pregnancy can also result in alteration in maternal and neonatal hemostasis mechanisms. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths and neonatal death. Use during pregnancy, especially in the third trimester, should be avoided. Safe use of PERCODAN- Demi (Oxycodone and Aspirin Tablets, USP) in pregnancy has not been established relative to possible adverse effects on fetal development. Therefore, PERCODAN- Demi tablets should not be used in pregnant women unless, in the judgment of the physician, the potential benefits outweigh the possible hazards. Nonteratogenic Effects Opioids can cross the placental barrier and have the potential to cause neonatal respiratory depression. Opioid use during pregnancy may result in a physically drug-dependent fetus. After birth, the neonate may suffer severe withdrawal symptoms. Aspirin may produce anemia, ante- or postpartum hemorrhage, prolonged gestation and labor, and oligohydramnios. Labor and Delivery PERCODAN- Demi tablets are not recommended for use in women during and immediately prior to labor and delivery due to its potential effects on respiratory function in the newborn. Aspirin should be avoided one week prior to and during labor and delivery because it can result in excessive blood loss at delivery. Prolonged gestation and prolonged labor due to prostaglandin inhibition have been reported. Nursing Mothers Ordinarily, nursing should not be undertaken while a patient is receiving PERCODAN- Demi tablets because of the possibility of sedation and/or respiratory depression in the infant. Oxycodone is excreted in breast milk in low concentrations, and there have been rare reports of somnolence and lethargy in babies of nursing mothers taking an oxycodone/acetaminophen product. Salicylic acid has also been detected in breast milk. Adverse effects on platelet function in the nursing infant exposed to aspirin in breast milk may be a potential risk. Furthermore, the risk of Reye Syndrome caused by salicylate in breast milk is unknown. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the potential benefits to the woman and the possible hazards to the nursing infant. Pediatric Use PERCODAN- Demi tablets should not be administered to pediatric patients. Reye Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin (or salicylates) may increase the risk of developing this disease. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 29 Geriatric Use Special precaution should be given when determining the dosing amount and frequency of PERCODAN- Demi tablets for geriatric patients, since clearance of oxycodone may be slightly reduced in this patient population when compared to younger patients. Hepatic Impairment In a pharmacokinetic study of oxycodone in patients with end-stage liver disease, oxycodone plasma clearance decreased and the elimination half-life increased. Care should be exercised when oxycodone is used in patients with hepatic impairment. Renal Impairment In a study of patients with end stage renal impairment, mean elimination half-life was prolonged in uremic patients due to increased volume of distribution and reduced clearance. Oxycodone should be used with caution in patients with renal impairment. ADVERSE REACTIONS Serious adverse reactions that may be associated with PERCODAN- Demi tablet use include respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, and shock (see OVERDOSAGE). The most frequently observed non-serious adverse reactions include lightheadedness, dizziness, drowsiness or sedation, nausea, and vomiting. These effects seem to be more prominent in ambulatory than in nonambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include euphoria, dysphoria, constipation and pruritus. Aspirin may increase the likelihood of hemorrhage due to its effect on the gastric mucosa and platelet function. Furthermore, aspirin has the potential to cause anaphylaxis in hypersensitive patients as well as angioedema especially in patients with chronic urticaria. Other adverse reactions due to aspirin use include anorexia, reversible hepatotoxicity, leukopenia, thrombocytopenia, purpura, decreased plasma iron concentration, and shortened erythrocyte survival time. Other adverse reactions obtained from postmarketing experiences with PERCODAN- Demi tablets are listed by organ system and in decreasing order of severity and/or frequency as follows: Body as a Whole allergic reaction, malaise, asthenia, headache, anaphylaxis, fever, hypothermia, thirst, increased sweating, accident, accidental overdose, non-accidental overdose. Cardiovascular tachycardia, dysrhythmias, hypotension, orthostatic hypotension, bradycardia, palpitations Central and Peripheral Nervous System stupor, paresthesia, agitation, cerebral edema, coma, confusion, dizziness, headache, subdural or intracranial hemorrhage, lethargy, seizures, anxiety, mental impairment Fluid and Electrolyte dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 30 Gastrointestinal hemorrhagic gastric/duodenal ulcer, gastric/peptic ulcer, dyspepsia, abdominal pain, diarrhea, eructation, dry mouth, gastrointestinal bleeding, intestinal perforation, nausea, vomiting, transient elevations of hepatic enzymes, hepatitis, Reye syndrome, pancreatitis, intestinal obstruction, ileus Hearing and Vestibular hearing loss, tinnitus. Patients with high frequency loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism. Hematologic unspecified hemorrhage, purpura, reticulocytosis, prolongation of prothrombin time, disseminated intravascular coagulation, ecchymosis, thrombocytopenia. Hypersensitivity acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema, urticaria, anaphylactoid reaction Metabolic and Nutritional hypoglycemia, hyperglycemia, acidosis, alkalosis Musculoskeletal rhabdomyolysis Ocular miosis, visual disturbances, red eye. Psychiatric drug dependence, drug abuse, somnolence, depression, nervousness, hallucination Reproductive prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding, closure of patent ductus arteriosis Respiratory System bronchospasm, dyspnea, hyperpnea, pulmonary edema, tachypnea, aspiration, hypoventilation, laryngeal edema Skin and Appendages urticaria, rash, flushing Urogenital interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure, urinary retention OVERDOSAGE Signs and Symptoms Serious overdose with PERCODAN- Demi (Oxycodone and Aspirin Tablets, USP) is characterized by signs and symptoms of opioid and salicylate overdose. Oxycodone overdosage can be manifested by This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 31 respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, pupillary constriction (pupils may be dilated in the setting of hypoxia), and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. Early signs of acute aspirin (salicylate) overdose including tinnitus, occur at plasma concentrations approaching 200 mcg/mL. Plasma concentrations of aspirin above 300 mcg/mL are toxic. Severe toxic effects are associated with levels above 400 mcg/mL. A single lethal dose of aspirin in adults is not known with certainty but death may be expected at 30 g. For real or suspected overdose, a Poison Control Center should be contacted immediately. In acute salicylate overdose, severe acid-base and electrolyte disturbances may occur and are complicated by hyperthermia and dehydration, and coma. Respiratory alkalosis occurs early while hyperventilation is present, but is quickly followed by metabolic acidosis. Serious symptoms such as depression, coma, and respiratory failure progress rapidly. Salicylism (chronic salicylate toxicity) may be noted by symptoms such as dizziness, tinnitus, difficulty hearing, nausea, vomiting, diarrhea, and mental confusion. More severe salicylism may result in respiratory alkalosis. Treatment Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. Supportive measures (including oxygen, intravenous fluids, and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Treatment of acid-base disturbances and electrolyte disorders is also important. Because of the concern over salicylate toxicity, acid-base status should be followed closely with serial blood gas and serum pH determinations. The opioid antagonist naloxone hydrochloride (NARCAN) is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to opioids including oxycodone. Therefore, an appropriate dose of naloxone hydrochloride should be administered (usual initial adult dose 0.4 mg-2 mg) preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. Since the duration of action of oxycodone may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. Opioid antagonists should not be administered in the absence of clinically significant respiratory of circulatory depression secondary to oxycodone overdose. In patients who are physically dependent on any opioid agonist including oxycodone, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use. Gastric emptying and/or lavage may be useful in removing unabsorbed drug. This procedure is recommended as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal, as a slurry, is beneficial, if less than three hours have passed since ingestion. Charcoal adsorption should not be employed prior to lavage and emesis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 32 In severe cases of salicylate overdose, hyperthermia and hypovolemia are the major immediate threats to life. Children should be sponged with tepid water. Replacement fluid should be administered intravenously and augmented with correction of acidosis. Plasma electrolytes and pH should be monitored to promote alkaline diuresis of salicylate if renal function is normal. Infusion of glucose may be required to control hypoglycemia. With more severe acute toxicity respiratory alkalosis may occur. Hemodialysis and peritoneal dialysis can be performed to reduce the body content of aspirin. In patients with renal insufficiency or in cases of life-threatening salicylate intoxication dialysis is usually required. Exchange transfusion may be indicated in infants and young children. In case of real or suspected overdose, a poison control center should be consulted for the treatment of salicylism. The toxicity of oxycodone and aspirin in combination is unknown. DOSAGE AND ADMINISTRATION Dosage should be adjusted according to the severity of the pain and the response of the patient. It may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of opioids. If pain is constant, the opioid analgesic should be given at regular intervals on an around-the-clock schedule. PERCODAN- Demi tablets are given orally. The usual dosage is one tablet every 6 hours as needed for pain. The maximum daily dose of aspirin should not exceed 4 grams or 12 tablets. Cessation of Therapy In patients treated with PERCODAN- Demi tablets for more than a few weeks who no longer require therapy, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient. DRUG ABUSE AND DEPENDENCE PERCODAN- Demi tablets are a Schedule II controlled substance. Oxycodone is a mu-agonist opioid with an abuse liability similar to morphine. Oxycodone, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion. Drug addiction is defined as an abnormal, compulsive use, use for non-medical purposes of a substance despite physical, psychological, occupational or interpersonal difficulties resulting from such use, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common. Opioid addiction is relatively rare in patients with chronic pain but may be more common in individuals who have a past history of alcohol or substance abuse or dependence. Pseudoaddiction refers to pain relief seeking behavior of patients whose pain is poorly managed. It is considered an iatrogenic effect of ineffective pain management. The health care provider must assess continuously the psychological and clinical condition of a pain patient in order to distinguish addiction from pseudoaddiction and thus, be able to treat the pain adequately. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 33 Physical dependence on a prescribed medication does not signify addiction. Physical dependence involves the occurrence of a withdrawal syndrome when there is sudden reduction or cessation in drug use or if an opiate antagonist is administered. Physical dependence can be detected after a few days of opioid therapy. However, clinically significant physical dependence is only seen after several weeks of relatively high dosage therapy. In this case, abrupt discontinuation of the opioid may result in a withdrawal syndrome. If the discontinuation of opioids is therapeutically indicated, gradual tapering of the drug over a 2-week period will prevent withdrawal symptoms. The severity of the withdrawal syndrome depends primarily on the daily dosage of the opioid, the duration of therapy and medical status of the individual. The withdrawal syndrome of oxycodone is similar to that of morphine. This syndrome is characterized by yawning, anxiety, increased heart rate and blood pressure, restlessness, nervousness, muscle aches, tremor, irritability, chills alternating with hot flashes, salivation, anorexia, severe sneezing, lacrimation, rhinorrhea, dilated pupils, diaphoresis, piloerection, nausea, vomiting, abdominal cramps, diarrhea and insomnia, and pronounced weakness and depression. “Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor Shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated infection. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Oxycodone, like other opioids, has been diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Like other opioid medications, PERCODAN- Demi tablets are subject to the Federal Controlled Substances Act. After chronic use, PERCODAN- Demi tablets should not be discontinued abruptly when it is thought that the patient has become physically dependent on oxycodone. Interactions with Alcohol and Drugs of Abuse Oxycodone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. HOW SUPPLIED PERCODAN- Demi (Oxycodone and Aspirin Tablets, USP), tablets are supplied as a white standard biconvex tablet, scored and debossed with “PERCODAN- Demi” on one side and plain on the other side. Available in: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 7-337/S-029 Page 34 Bottles of 100 NDC 63481-166-70 Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). DEA Order Form Required. Manufactured for: Endo Pharmaceuticals Inc. Chadds Ford, Pennsylvania 19317 PERCODAN is a Registered Trademark of Endo Pharmaceuticals Inc. NARCAN® is a Registered Trademark of Endo Pharmaceuticals Inc. Copyright © Endo Pharmaceuticals Inc. 2003 Printed in U.S.A. 6484-01/December, 2003 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:36.254532	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/07337slr029_percodan_lbl.pdf', 'application_number': 7337, 'submission_type': 'SUPPL ', 'submission_number': 29}
10,692	Structural Formula CII Company logo PERCODAN® (Oxycodone and Aspirin Tablets, USP) Rx only DESCRIPTION Each PERCODAN Tablet contains: Oxycodone Hydrochloride, USP 4.8355 mg* Aspirin, USP 325 mg *4.8355 mg oxycodone HCl is equivalent to 4.3346 mg of oxycodone as the free base. PERCODAN Tablets also contain the following inactive ingredients: D&C Yellow 10, FD&C Yellow 6, microcrystalline cellulose and corn starch. The oxycodone hydrochloride component is Morphinan-6-one, 4,5-epoxy-14-hydroxy-3 methoxy-17-methyl-, hydrochloride, (5a)-., a white to off-white, hygroscopic crystals or powder, odorless, soluble in water; slightly soluble in alcohol and is represented by the following structural formula: The aspirin component is 2-(acetyloxy)-, Benzoic acid, a white crystal, commonly tabular or needle-like, or white, crystalline powder. Is odorless or has a faint odor. Is stable in dry air; in moist air it gradually hydrolyzes to salicylic and acetic acids. Slightly soluble in water; freely soluble in alcohol; soluble in chloroform and in ether; sparingly soluble in absolute ether and is represented by the following structural formula: 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda S tructural Formula CLINICAL PHARMACOLOGY Central Nervous System Oxycodone is a semisynthetic pure opioid agonist whose principal therapeutic action is analgesia. Other pharmacological effects of oxycodone include anxiolysis, euphoria and feelings of relaxation. These effects are mediated by receptors (notably μ and κ) in the central nervous system for endogenous opioid-like compounds such as endorphins and enkephalins. Oxycodone produces respiratory depression through direct activity at respiratory centers in the brain stem and depresses the cough reflex by direct effect on the center of the medulla. Aspirin (acetylsalicylic acid) works by inhibiting the body’s production of prostaglandins, including prostaglandins involved in inflammation. Prostaglandins cause pain sensations by stimulating muscle contractions and dilating blood vessels throughout the body. In the CNS, aspirin works on the hypothalamus heat-regulating center to reduce fever, however, other mechanisms may be involved. Gastrointestinal Tract and Other Smooth Muscle Oxycodone reduces motility by increasing smooth muscle tone in the stomach and duodenum. In the small intestine, digestion of food is delayed by decreases in propulsive contractions. Other opioid effects include contraction of biliary tract smooth muscle, spasm of the Sphincter of Oddi, increased ureteral and bladder sphincter tone, and a reduction in uterine tone. Aspirin can produce gastrointestinal injury (lesions, ulcers) through a mechanism that is not yet completely understood, but may involve a reduction in eicosanoid synthesis by the gastric mucosa. Decreased production of prostaglandins may compromise the defenses of the gastric mucosa and the activity of substances involved in tissue repair and ulcer healing. Cardiovascular System Oxycodone may produce a release of histamine and may be associated with orthostatic hypotension, and other symptoms, such as pruritus, flushing, red eyes, and sweating. Platelet Aggregation Aspirin affects platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda factor thromboxane A2. Nonacetylated salicylates do not inhibit this enzyme and have no effect on platelet aggregation. At somewhat higher doses, aspirin reversibly inhibits the formation of prostaglandin 12 (prostacyclin), which is an arterial vasodilator and inhibits platelet aggregation. Pharmacokinetics Absorption and Distribution The mean absolute oral bioavailability of oxycodone in cancer patients was reported to be about 87%. Oxycodone has been shown to be 45% bound to human plasma proteins in vitro. The volume of distribution after intravenous administration is 211.9 ±186.6 L. Aspirin is hydrolyzed primarily to salicylic acid in the gut wall and during first-pass metabolism through the liver. Salicylic acid is absorbed rapidly from the stomach, but most of the absorption occurs in the proximal small intestine. Following absorption, salicylate is distributed to most body tissues and fluids, including fetal tissues, breast milk, and the CNS. High concentrations are found in the liver and kidneys. Salicylate is variably bound to serum proteins, particularly albumin. Metabolism and Elimination A high portion of oxycodone is N-dealkylated to noroxycodone during first-pass metabolism. Oxymorphone, is formed by the O-demethylation of oxycodone. The metabolism of oxycodone to oxymorphone is catalyzed by CYP2D6. Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. Approximately 8% to 14% of the dose is excreted as free oxycodone over 24 hours after administration. Following a single, oral dose of oxycodone, the mean ± SD elimination half-life is 3.51 ± 1.43 hours. The biotransformation of aspirin occurs primarily in the liver by the microsomal enzyme system. With a plasma half-life of approximately 15 minutes, aspirin is rapidly hydrolyzed to salicylate. At low doses, salicylate elimination follows first-order kinetics. The plasma half-life of salicylate is approximately 2 to 3 hours. Approximately 10% of aspirin is excreted as unchanged salicylate in the urine. The major metabolites excreted in the urine are salicyluric acid (75%), salicyl phenolic glucuronide (10%), salicyl acyl glucuronide (5%), and gentisic and gentisuric acid (less than 1%) each. Eighty to 100% of a single dose is excreted in the urine within 24 to 72 hours. INDICATIONS AND USAGE PERCODAN tablets are indicated for the management of moderate to moderately severe pain. CONTRAINDICATIONS PERCODAN tablets are contraindicated in patients with known hypersensitivity to oxycodone or aspirin, and in any situation where opioids or aspirin are contraindicated. Aspirin is contraindicated for patients with hemophilia. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reye Syndrome: Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye syndrome with concomitant use of aspirin in certain viral illnesses. Allergy: Aspirin is contraindicated in patients with known allergy to nonsteroidal anti inflammatory drug products and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema, or bronchospasm (asthma). Oxycodone is contraindicated in patients with known hypersensitivity to oxycodone. Oxycodone is contraindicated in any situation where opioids are contraindicated including patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment) and patients with acute or severe bronchial asthma or hypercarbia. Oxycodone is contraindicated in the setting of suspected or known paralytic ileus. WARNINGS Misuse and Abuse of Opioids Oxycodone is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion (see DRUG ABUSE AND DEPENDENCE). Oxycodone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing PERCODAN tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Concerns about misuse, addiction, and diversion should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Administration of PERCODAN (Oxycodone and Aspirin Tablets, USP) tablets should be closely monitored for the following potentially serious adverse reactions and complications: Respiratory Depression Respiratory depression is a hazard with the use of oxycodone, one of the active ingredients in PERCODAN tablets, as with all opioid agonists. Elderly and debilitated patients are at particular risk for respiratory depression as are non-tolerant patients given large initial doses of oxycodone or when oxycodone is given in conjunction with other agents that depress respiration. Oxycodone should be used with extreme caution in patients with acute asthma, chronic obstructive pulmonary disorder (COPD), cor pulmonale, or preexisting respiratory impairment. In such patients, even usual therapeutic doses of oxycodone may decrease respiratory drive to the point of apnea. In these patients alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In case of respiratory depression, a reversal agent such as naloxone hydrochloride may be utilized (see OVERDOSAGE). Head Injury and Increased Intracranial Pressure The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Oxycodone produces effects on pupillary response and consciousness which may obscure neurologic signs of worsening in patients with head injuries. Hypotensive Effect Oxycodone may cause severe hypotension particularly in individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs which compromise vasomotor tone such as phenothiazines. Oxycodone, like all opioid analgesics of the morphine-type, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. Oxycodone may produce orthostatic hypotension in ambulatory patients. Alcohol Warning Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. Coagulation Abnormalities Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited (hemophilia) or acquired (liver disease or vitamin K deficiency) bleeding disorders. GI Side Effects GI side effects include stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur. Peptic Ulcer Disease Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation and bleeding. PRECAUTIONS General Opioid analgesics should be used with caution when combined with CNS depressant drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression, altered mental state, and postural hypotension. 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PERCODAN tablets should be given with caution to patients with CNS depression, elderly or debilitated patients, patients with severe impairment of hepatic, pulmonary, or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy, urethral stricture, acute alcoholism, delirium tremens, kyphoscoliosis with respiratory depression, myxedema, and toxic psychosis. PERCODAN tablets may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Oxycodone may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings. Following administration of PERCODAN tablets, anaphylactic reactions have been reported in patients with a known hypersensitivity to codeine, a compound with a structure similar to morphine and oxycodone. The frequency of this possible cross-sensitivity is unknown. Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time. Hemorrhage Aspirin may increase the likelihood of hemorrhage due to its effect on the gastric mucosa and platelet function (prolongation of bleeding time). Salicylates should be used with caution in the presence of peptic ulcer or coagulation abnormalities. Pregnancy Aspirin can cause fetal harm when administered to a pregnant woman. Salicylates readily cross the placenta and by inhibiting prostaglandin synthesis, may cause constriction of ductus arteriosus, resulting in pulmonary hypertension and increased fetal mortality and, possibly other untoward fetal effects. Aspirin use in pregnancy can also result in alteration in maternal and neonatal hemostasis mechanisms. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths and neonatal death. The use of aspirin during pregnancy especially in the third trimester should be avoided. If PERCODAN tablets are used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Renal Failure Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute). Hepatic Insufficiency Avoid aspirin in patients with severe hepatic insufficiency. Interactions with Other CNS Depressants Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with PERCODAN tablets may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Interactions with Mixed Agonist/Antagonist Opioid Analgesics Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as oxycodone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone and/or may precipitate withdrawal symptoms in these patients. Ambulatory Surgery and Postoperative Use Oxycodone and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common postoperative complication, especially after intra-abdominal surgery with use of opioid analgesia. Caution should be taken to monitor for decreased bowel motility in postoperative patients receiving opioids. Standard supportive therapy should be implemented. Use in Pancreatic/Biliary Tract Disease Oxycodone may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like oxycodone may cause increases in the serum amylase level. Tolerance and Physical Dependence Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: Cessation of Therapy). Information for Patients/Caregivers The following information should be provided to patients receiving PERCODAN tablets by their physician, nurse, pharmacist, or caregiver: 1. Patients should be aware that PERCODAN tablets contain oxycodone, which is a morphine-like substance. 2. Patients should be instructed to keep PERCODAN tablets in a secure place out of the reach of children. In the case of accidental ingestions, emergency medical care should be sought immediately. 3. When PERCODAN tablets are no longer needed, the unused tablets should be destroyed by flushing down the toilet. 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4. Patients should be advised not to adjust the medication dose themselves. Instead, they must consult with their prescribing physician. 5. Patients should be advised that PERCODAN tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery). 6. Patients should not combine PERCODAN tablets with alcohol, opioid analgesics, tranquilizers, sedatives, or other CNS depressants unless under the recommendation and guidance of a physician. When co-administered with another CNS depressant, PERCODAN tablets can cause dangerous additive central nervous system or respiratory depression, which can result in serious injury or death. 7. The safe use of PERCODAN tablets during pregnancy has not been established; thus, women who are planning to become pregnant or are pregnant should consult with their physician before taking PERCODAN tablets. 8. Nursing mothers should consult with their physicians about whether to discontinue nursing or discontinue PERCODAN tablets because of the potential for serious adverse reactions to nursing infants. 9. Patients who are treated with PERCODAN tablets for more than a few weeks should be advised not to abruptly discontinue the medication. Patients should consult with their physician for a gradual discontinuation dose schedule to taper off the medication. 10. Patients should be advised that PERCODAN tablets are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed. 11. Patients should be advised that PERCODAN tablets may cause or worsen constipation, as generally occurs with all opioids. They should discuss any past history of constipation with their prescribing physician so a management plan may be initiated. Laboratory Tests Although oxycodone may cross-react with some drug urine tests, no available studies were found which determined the duration of detectability of oxycodone in urine drug screens. However, based on pharmacokinetic data, the approximate duration of detectability for a single dose of oxycodone is roughly estimated to be one to two days following drug exposure. Urine testing for opiates may be performed to determine illicit drug use and for medical reasons such as evaluation of patients with altered states of consciousness or monitoring efficacy of drug rehabilitation efforts. The preliminary identification of opiates in urine involves the use of an immunoassay screening and thin-layer chromatography (TLC). Gas chromatography/mass spectrometry (GC/MS) may be utilized as a third-stage identification step in the medical investigational sequence for opiate testing after immunoassay and TLC. The identities of 6-keto opiates (e.g., oxycodone) can further be differentiated by the analysis of their methoxime trimethylsilyl (MO-TMS) derivative. Drug/Drug Interactions with Oxycodone Opioid analgesics may enhance the neuromuscular-blocking action of skeletal muscle relaxants and produce an increase in the degree of respiratory depression. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients receiving CNS depressants such as other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with PERCODAN tablets may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, naltrexone, and butorphanol) should be administered with caution to a patient who has received or is receiving a pure opioid agonist such as oxycodone. These agonist/antagonist analgesics may reduce the analgesic effect of oxycodone or may precipitate withdrawal symptoms. Drug/Drug Interactions with Aspirin Angiotensin Converting Enzyme (ACE) Inhibitors: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin-angiotensin conversion pathway. Acetazolamide: Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion. Anticoagulant Therapy (Heparin and Warfarin): Patients on anticoagulation therapy are at increased risk for bleeding because of drug-drug interactions and the effect on platelets. Aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk. Anticonvulsants: Salicylate can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels. Beta Blockers: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention. Diuretics: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. Methotrexate: Aspirin may enhance the serious side and toxicity of methotrexate due to displacement from its plasma protein binding sites and/or reduced renal clearance. Nonsteroidal Anti-inflammatory Drugs (NSAID's): The concurrent use of aspirin with other NSAID's should be avoided because this may increase bleeding or lead to decreased renal function. Aspirin may enhance the serious side effects and toxicity of ketorolac, due to displacement from its plasma protein binding sites and/or reduced renal clearance. 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Oral Hypoglycemics Agents: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia. Uricosuric Agents: Salicylates antagonize the uricosuric action of probenecid or sulfinpyrazone. Drug/Laboratory Test Interactions Depending on the sensitivity/specificity and the test methodology, the individual components of PERCODAN tablets may cross-react with assays used in the preliminary detection of cocaine (primary urinary metabolite, benzoylecgonine) or marijuana (cannabinoids) in human urine. A more specific alternate chemical method must be used in order to obtain a confirmed analytical result. The preferred confirmatory method is gas chromatography/mass spectrometry (GC/MS). Moreover, clinical considerations and professional judgment should be applied to any drug-of abuse test result, particularly when preliminary positive results are used. Salicylates may increase the protein bound iodine (PBI) result by competing for the protein binding sites on pre-albumin and possibly thyroid-binding globulins. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Animal studies to evaluate the carcinogenic potential of oxycodone and aspirin have not been performed. Mutagenesis The combination of oxycodone and aspirin has not been evaluated for mutagenicity. Oxycodone alone was negative in a bacterial reverse mutation assay (Ames), an in vitro chromosome aberration assay with human lymphocytes without metabolic activation and an in vivo mouse micronucleus assay. Oxycodone was clastogenic in the human lymphocyte chromosomal assay in the presence of metabolic activation and in the mouse lymphoma assay with or without metabolic activation. Aspirin induced chromosome aberrations in cultured human fibroblasts. Fertility Animal studies to evaluate the effects of oxycodone on fertility have not been performed. Aspirin has been shown to inhibit ovulation in rats. Pregnancy Teratogenic Effects Oxycodone: Pregnancy Category B Reproduction studies in rats and rabbits demonstrated that oral administration of oxycodone was not teratogenic or embryo-fetal toxic. Aspirin: Pregnancy Category D (see PRECAUTIONS) Salicylates readily cross the placenta and by inhibiting prostaglandin synthesis, may cause constriction of ductus arteriosus resulting in pulmonary hypertension and increased fetal 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda mortality and, possibly other untoward fetal effects. Aspirin use in pregnancy can also result in alteration in maternal and neonatal hemostasis mechanisms. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths and neonatal death. Use during pregnancy, especially in the third trimester, should be avoided. Safe use of PERCODAN (Oxycodone and Aspirin Tablets, USP) in pregnancy has not been established relative to possible adverse effects on fetal development. Therefore, PERCODAN tablets should not be used in pregnant women unless, in the judgment of the physician, the potential benefits outweigh the possible hazards. Nonteratogenic Effects Opioids can cross the placental barrier and have the potential to cause neonatal respiratory depression. Opioid use during pregnancy may result in a physically drug-dependent fetus. After birth, the neonate may suffer severe withdrawal symptoms. Aspirin may produce anemia, ante- or postpartum hemorrhage, prolonged gestation and labor, and oligohydramnios. Labor and Delivery PERCODAN tablets are not recommended for use in women during and immediately prior to labor and delivery due to its potential effects on respiratory function in the newborn. Aspirin should be avoided one week prior to and during labor and delivery because it can result in excessive blood loss at delivery. Prolonged gestation and prolonged labor due to prostaglandin inhibition have been reported. Nursing Mothers Ordinarily, nursing should not be undertaken while a patient is receiving PERCODAN tablets because of the possibility of sedation and/or respiratory depression in the infant. Oxycodone is excreted in breast milk in low concentrations, and there have been rare reports of somnolence and lethargy in babies of nursing mothers taking an oxycodone/acetaminophen product. Salicylic acid has also been detected in breast milk. Adverse effects on platelet function in the nursing infant exposed to aspirin in breast milk may be a potential risk. Furthermore, the risk of Reye Syndrome caused by salicylate in breast milk is unknown. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the potential benefits to the woman and the possible hazards to the nursing infant. Pediatric Use PERCODAN tablets should not be administered to pediatric patients. Reye Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin (or salicylates) may increase the risk of developing this disease. Geriatric Use Special precaution should be given when determining the dosing amount and frequency of PERCODAN tablets for geriatric patients, since clearance of oxycodone may be slightly reduced in this patient population when compared to younger patients. 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatic Impairment In a pharmacokinetic study of oxycodone in patients with end-stage liver disease, oxycodone plasma clearance decreased and the elimination half-life increased. Care should be exercised when oxycodone is used in patients with hepatic impairment. Renal Impairment In a study of patients with end stage renal impairment, mean elimination half-life was prolonged in uremic patients due to increased volume of distribution and reduced clearance. Oxycodone should be used with caution in patients with renal impairment. ADVERSE REACTIONS Serious adverse reactions that may be associated with PERCODAN tablet use include respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, and shock (see OVERDOSAGE). The most frequently observed non-serious adverse reactions include lightheadedness, dizziness, drowsiness or sedation, nausea, and vomiting. These effects seem to be more prominent in ambulatory than in nonambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include euphoria, dysphoria, constipation and pruritus. Aspirin may increase the likelihood of hemorrhage due to its effect on the gastric mucosa and platelet function. Furthermore, aspirin has the potential to cause anaphylaxis in hypersensitive patients as well as angioedema especially in patients with chronic urticaria. Other adverse reactions due to aspirin use include anorexia, reversible hepatotoxicity, leukopenia, thrombocytopenia, purpura, decreased plasma iron concentration, and shortened erythrocyte survival time. Other adverse reactions obtained from postmarketing experiences with PERCODAN tablets are listed by organ system and in decreasing order of severity and/or frequency as follows: Body as a Whole allergic reaction, malaise, asthenia, headache, anaphylaxis, fever, hypothermia, thirst, increased sweating, accident, accidental overdose, non-accidental overdose. Cardiovascular tachycardia, dysrhythmias, hypotension, orthostatic hypotension, bradycardia, palpitations Central and Peripheral Nervous System stupor, paresthesia, agitation, cerebral edema, coma, confusion, dizziness, headache, subdural or intracranial hemorrhage, lethargy, seizures, anxiety, mental impairment Fluid and Electrolyte dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Gastrointestinal hemorrhagic gastric/duodenal ulcer, gastric/peptic ulcer, dyspepsia, abdominal pain, diarrhea, eructation, dry mouth, gastrointestinal bleeding, intestinal perforation, nausea, vomiting, transient elevations of hepatic enzymes, hepatitis, Reye syndrome, pancreatitis, intestinal obstruction, ileus Hearing and Vestibular hearing loss, tinnitus. Patients with high frequency loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism. Hematologic unspecified hemorrhage, purpura, reticulocytosis, prolongation of prothrombin time, disseminated intravascular coagulation, ecchymosis, thrombocytopenia Hypersensitivity acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema, urticaria, anaphylactoid reaction Metabolic and Nutritional hypoglycemia, hyperglycemia, acidosis, alkalosis Musculoskeletal rhabdomyolysis Ocular miosis, visual disturbances, red eye Psychiatric drug dependence, drug abuse, somnolence, depression, nervousness, hallucination Reproductive prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding, closure of patent ductus arteriosis Respiratory System bronchospasm, dyspnea, hyperpnea, pulmonary edema, tachypnea, aspiration, hypoventilation, laryngeal edema Skin and Appendages urticaria, rash, flushing Urogenital interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure, urinary retention 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OVERDOSAGE Signs and Symptoms Serious overdose with PERCODAN (Oxycodone and Aspirin Tablets, USP) is characterized by signs and symptoms of opioid and salicylate overdose. Oxycodone overdosage can be manifested by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, pupillary constriction (pupils may be dilated in the setting of hypoxia), and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. Early signs of acute aspirin (salicylate) overdose including tinnitus occur at plasma concentrations approaching 200 mcg/mL. Plasma concentrations of aspirin above 300 mcg/mL are toxic. Severe toxic effects are associated with levels above 400 mcg/mL. A single lethal dose of aspirin in adults is not known with certainty but death may be expected at 30 g. For real or suspected overdose, a Poison Control Center should be contacted immediately. In acute salicylate overdose, severe acid-base and electrolyte disturbances may occur and are complicated by hyperthermia and dehydration, and coma. Respiratory alkalosis occurs early while hyperventilation is present, but is quickly followed by metabolic acidosis. Serious symptoms such as depression, coma, and respiratory failure progress rapidly. Salicylism (chronic salicylate toxicity) may be noted by symptoms such as dizziness, tinnitus, difficulty hearing, nausea, vomiting, diarrhea, and mental confusion. More severe salicylism may result in respiratory alkalosis. Treatment Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. Supportive measures (including oxygen, intravenous fluids, and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Treatment of acid-base disturbances and electrolyte disorders is also important. Because of the concern over salicylate toxicity, acid-base status should be followed closely with serial blood gas and serum pH determinations. The opioid antagonist naloxone hydrochloride is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to opioids including oxycodone. Therefore, an appropriate dose of naloxone hydrochloride should be administered (usual initial adult dose 0.4 mg-2 mg) preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. Since the duration of action of oxycodone may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdose. In patients who are physically dependent on any opioid agonist including oxycodone, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use. Gastric emptying and/or lavage may be useful in removing unabsorbed drug. This procedure is recommended as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal, as a slurry, is beneficial, if less than three hours have passed since ingestion. Charcoal adsorption should not be employed prior to lavage and emesis. In severe cases of salicylate overdose, hyperthermia and hypovolemia are the major immediate threats to life. Children should be sponged with tepid water. Replacement fluid should be administered intravenously and augmented with correction of acidosis. Plasma electrolytes and pH should be monitored to promote alkaline diuresis of salicylate if renal function is normal. Infusion of glucose may be required to control hypoglycemia. With more severe acute toxicity respiratory alkalosis may occur. Hemodialysis and peritoneal dialysis can be performed to reduce the body content of aspirin. In patients with renal insufficiency or in cases of life-threatening salicylate intoxication dialysis is usually required. Exchange transfusion may be indicated in infants and young children. In case of real or suspected overdose, a poison control center should be consulted for the treatment of salicylism. The toxicity of oxycodone and aspirin in combination is unknown. DOSAGE AND ADMINISTRATION Dosage should be adjusted according to the severity of the pain and the response of the patient. It may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of opioids. If pain is constant, the opioid analgesic should be given at regular intervals on an around-the clock schedule. PERCODAN tablets are given orally. The usual dosage is one tablet every 6 hours as needed for pain. The maximum daily dose of aspirin should not exceed 4 grams or 12 tablets. Cessation of Therapy In patients treated with PERCODAN tablets for more than a few weeks who no longer require therapy, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient. DRUG ABUSE AND DEPENDENCE PERCODAN tablets are a Schedule II controlled substance. Oxycodone is a mu-agonist opioid with an abuse liability similar to morphine. Oxycodone, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion. 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug addiction is defined as an abnormal, compulsive use, use for non-medical purposes of a substance despite physical, psychological, occupational or interpersonal difficulties resulting from such use, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common. Opioid addiction is relatively rare in patients with chronic pain but may be more common in individuals who have a past history of alcohol or substance abuse or dependence. Pseudoaddiction refers to pain relief seeking behavior of patients whose pain is poorly managed. It is considered an iatrogenic effect of ineffective pain management. The health care provider must assess continuously the psychological and clinical condition of a pain patient in order to distinguish addiction from pseudoaddiction and thus, be able to treat the pain adequately. Physical dependence on a prescribed medication does not signify addiction. Physical dependence involves the occurrence of a withdrawal syndrome when there is sudden reduction or cessation in drug use or if an opiate antagonist is administered. Physical dependence can be detected after a few days of opioid therapy. However, clinically significant physical dependence is only seen after several weeks of relatively high dosage therapy. In this case, abrupt discontinuation of the opioid may result in a withdrawal syndrome. If the discontinuation of opioids is therapeutically indicated, gradual tapering of the drug over a 2-week period will prevent withdrawal symptoms. The severity of the withdrawal syndrome depends primarily on the daily dosage of the opioid, the duration of therapy and medical status of the individual. The withdrawal syndrome of oxycodone is similar to that of morphine. This syndrome is characterized by yawning, anxiety, increased heart rate and blood pressure, restlessness, nervousness, muscle aches, tremor, irritability, chills alternating with hot flashes, salivation, anorexia, severe sneezing, lacrimation, rhinorrhea, dilated pupils, diaphoresis, piloerection, nausea, vomiting, abdominal cramps, diarrhea and insomnia, and pronounced weakness and depression. “Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Oxycodone, like other opioids, has been diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Like other opioid medications, PERCODAN tablets are subject to the Federal Controlled Substances Act. After chronic use, PERCODAN tablets should not be discontinued abruptly when it is thought that the patient has become physically dependent on oxycodone. Interactions with Alcohol and Drugs of Abuse Oxycodone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. HOW SUPPLIED PERCODAN (Oxycodone and Aspirin Tablets, USP), tablets are supplied as a yellow round tablet, scored and debossed with “PERCODAN” on one side and plain on the other side. Available in: Bottles of 100 NDC 63481-121-70 Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). DEA Order Form Required. Manufactured for: Endo Pharmaceuticals Inc. Chadds Ford, Pennsylvania 19317 PERCODAN® is a Registered Trademark of Endo Pharmaceuticals © 2009 Endo Pharmaceuticals Printed in U.S.A. 2005700 / September, 2009 Company logo 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:36.333304	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/007337s045lbl.pdf', 'application_number': 7337, 'submission_type': 'SUPPL ', 'submission_number': 45}
10,691	1 PERCODAN® (Oxycodone and Aspirin Tablets, USP) CII Rx only DESCRIPTION Each PERCODAN Tablet contains: Oxycodone Hydrochloride, USP 4.8355 mg* Aspirin, USP 325 mg 4.8355 mg oxycodone HCl is equivalent to 4.3346 mg of oxycodone as the free base. PERCODAN Tablets also contain the following inactive ingredients: D&C Yellow 10, FD&C Yellow 6, microcrystalline cellulose and corn starch. The oxycodone hydrochloride component is Morphinan-6-one, 4,5-epoxy-14-hydroxy-3- methoxy-17-methyl-, hydrochloride, (5a)-., a white to off-white, hygroscopic crystals or powder, odorless, soluble in water; slightly soluble in alcohol and is represented by the following structural formula: C18H21NO4●HCl MW 351.82 The aspirin component is 2-(acetyloxy)-, Benzoic acid, a white crystal, commonly tabular or needle-like, or white, crystalline powder. Is odorless or has a faint odor. Is stable in dry air; in moist air it gradually hydrolyzes to salicylic and acetic acids. Slightly soluble in water; freely soluble in alcohol; soluble in chloroform and in ether; sparingly soluble in absolute ether and is represented by the following structural formula: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 C9H8O 4 MW 180.16 CLINICAL PHARMACOLOGY Central Nervous System Oxycodone is a semisynthetic pure opioid agonist whose principal therapeutic action is analgesia. Other pharmacological effects of oxycodone include anxiolysis, euphoria and feelings of relaxation. These effects are mediated by receptors (notably μ and κ) in the central nervous system for endogenous opioid-like compounds such as endorphins and enkephalins. Oxycodone produces respiratory depression through direct activity at respiratory centers in the brain stem and depresses the cough reflex by direct effect on the center of the medulla. Aspirin (acetylsalicylic acid) works by inhibiting the body’s production of prostaglandins, including prostaglandins involved in inflammation. Prostaglandins cause pain sensations by stimulating muscle contractions and dilating blood vessels throughout the body. In the CNS, aspirin works on the hypothalamus heat-regulating center to reduce fever, however, other mechanisms may be involved. Gastrointestinal Tract and Other Smooth Muscle Oxycodone reduces motility by increasing smooth muscle tone in the stomach and duodenum. In the small intestine, digestion of food is delayed by decreases in propulsive contractions. Other opioid effects include contraction of biliary tract smooth muscle, spasm of the Sphincter of Oddi, increased ureteral and bladder sphincter tone, and a reduction in uterine tone. Aspirin can produce gastrointestinal injury (lesions, ulcers) through a mechanism that is not yet completely understood, but may involve a reduction in eicosanoid synthesis by the gastric mucosa. Decreased production of prostaglandins may compromise the defenses of the gastric mucosa and the activity of substances involved in tissue repair and ulcer healing. Cardiovascular System Oxycodone may produce a release of histamine and may be associated with orthostatic hypotension, and other symptoms, such as pruritus, flushing, red eyes, and sweating. Platelet Aggregation Aspirin affects platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 factor thromboxane A2. Nonacetylated salicylates do not inhibit this enzyme and have no effect on platelet aggregation. At somewhat higher doses, aspirin reversibly inhibits the formation of prostaglandin 12 (prostacyclin), which is an arterial vasodilator and inhibits platelet aggregation. Pharmacokinetics Absorption and Distribution The mean absolute oral bioavailability of oxycodone in cancer patients was reported to be about 87%. Oxycodone has been shown to be 45% bound to human plasma proteins in vitro. The volume of distribution after intravenous administration is 211.9 ±186.6 L. Aspirin is hydrolyzed primarily to salicylic acid in the gut wall and during first-pass metabolism through the liver. Salicylic acid is absorbed rapidly from the stomach, but most of the absorption occurs in the proximal small intestine. Following absorption, salicylate is distributed to most body tissues and fluids, including fetal tissues, breast milk, and the CNS. High concentrations are found in the liver and kidneys. Salicylate is variably bound to serum proteins, particularly albumin. Metabolism and Elimination A high portion of oxycodone is N-dealkylated to noroxycodone during first-pass metabolism. Oxymorphone, is formed by the O-demethylation of oxycodone. The metabolism of oxycodone to oxymorphone is catalyzed by CYP2D6. Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. Approximately 8% to 14% of the dose is excreted as free oxycodone over 24 hours after administration. Following a single, oral dose of oxycodone, the mean ± SD elimination half-life is 3.51 ± 1.43 hours. The biotransformation of aspirin occurs primarily in the liver by the microsomal enzyme system. With a plasma half-life of approximately 15 minutes, aspirin is rapidly hydrolyzed to salicylate. At low doses, salicylate elimination follows first-order kinetics. The plasma half-life of salicylate is approximately 2 to 3 hours. Approximately 10% of aspirin is excreted as unchanged salicylate in the urine. The major metabolites excreted in the urine are salicyluric acid (75%), salicyl phenolic glucuronide (10%), salicyl acyl glucuronide (5%), and gentisic and gentisuric acid (less than 1%) each. Eighty to 100% of a single dose is excreted in the urine within 24 to 72 hours. INDICATIONS AND USAGE PERCODAN tablets are indicated for the management of moderate to moderately severe pain. CONTRAINDICATIONS PERCODAN tablets are contraindicated in patients with known hypersensitivity to oxycodone or aspirin, and in any situation where opioids or aspirin are contraindicated. Aspirin is contraindicated for patients with hemophilia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Reye Syndrome: Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye syndrome with concomitant use of aspirin in certain viral illnesses. Allergy: Aspirin is contraindicated in patients with known allergy to nonsteroidal anti- inflammatory drug products and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema, or bronchospasm (asthma). Oxycodone is contraindicated in patients with known hypersensitivity to oxycodone. Oxycodone is contraindicated in any situation where opioids are contraindicated including patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment) and patients with acute or severe bronchial asthma or hypercarbia. Oxycodone is contraindicated in the setting of suspected or known paralytic ileus. WARNINGS Misuse, Abuse and Diversion of Opioids Oxycodone is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Oxycodone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing PERCODAN tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Concerns about misuse, addiction, and diversion should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Administration of PERCODAN (Oxycodone and Aspirin Tablets, USP) tablets should be closely monitored for the following potentially serious adverse reactions and complications: Respiratory Depression Respiratory depression is a hazard with the use of oxycodone, one of the active ingredients in PERCODAN tablets, as with all opioid agonists. Elderly and debilitated patients are at particular risk for respiratory depression as are non-tolerant patients given large initial doses of oxycodone or when oxycodone is given in conjunction with other agents that depress respiration. Oxycodone should be used with extreme caution in patients with acute asthma, chronic obstructive pulmonary disorder (COPD), cor pulmonale, or preexisting respiratory impairment. In such patients, even usual therapeutic doses of oxycodone may decrease respiratory drive to the point of apnea. In these patients alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose. In case of respiratory depression, a reversal agent such as naloxone hydrochloride may be utilized (see OVERDOSAGE). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Head Injury and Increased Intracranial Pressure The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Oxycodone produces effects on pupillary response and consciousness which may obscure neurologic signs of worsening in patients with head injuries. Hypotensive Effect Oxycodone may cause severe hypotension particularly in individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs which compromise vasomotor tone such as phenothiazines. Oxycodone, like all opioid analgesics of the morphine-type, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. Oxycodone may produce orthostatic hypotension in ambulatory patients. Alcohol Warning Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. Coagulation Abnormalities Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited (hemophilia) or acquired (liver disease or vitamin K deficiency) bleeding disorders. GI Side Effects GI side effects include stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur. Peptic Ulcer Disease Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation and bleeding. PRECAUTIONS General Opioid analgesics should be used with caution when combined with CNS depressant drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression, altered mental state, and postural hypotension. PERCODAN tablets should be given with caution to patients with CNS depression, elderly or debilitated patients, patients with severe impairment of hepatic, pulmonary, or renal function, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 hypothyroidism, Addison's disease, prostatic hypertrophy, urethral stricture, acute alcoholism, delirium tremens, kyphoscoliosis with respiratory depression, myxedema, and toxic psychosis. PERCODAN tablets may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Oxycodone may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings. Following administration of PERCODAN tablets, anaphylactic reactions have been reported in patients with a known hypersensitivity to codeine, a compound with a structure similar to morphine and oxycodone. The frequency of this possible cross-sensitivity is unknown. Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time. Hemorrhage Aspirin may increase the likelihood of hemorrhage due to its effect on the gastric mucosa and platelet function (prolongation of bleeding time). Salicylates should be used with caution in the presence of peptic ulcer or coagulation abnormalities. Pregnancy Aspirin can cause fetal harm when administered to a pregnant woman. Salicylates readily cross the placenta and by inhibiting prostaglandin synthesis, may cause constriction of ductus arteriosus, resulting in pulmonary hypertension and increased fetal mortality and, possibly other untoward fetal effects. Aspirin use in pregnancy can also result in alteration in maternal and neonatal hemostasis mechanisms. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths and neonatal death. The use of aspirin during pregnancy especially in the third trimester should be avoided. If PERCODAN tablets are used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Renal Failure Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute). Hepatic Insufficiency Avoid aspirin in patients with severe hepatic insufficiency. Interactions with Other CNS Depressants Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with PERCODAN tablets may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Interactions with Mixed Agonist/Antagonist Opioid Analgesics Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as oxycodone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone and/or may precipitate withdrawal symptoms in these patients. Ambulatory Surgery and Postoperative Use Oxycodone and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common postoperative complication, especially after intra-abdominal surgery with use of opioid analgesia. Caution should be taken to monitor for decreased bowel motility in postoperative patients receiving opioids. Standard supportive therapy should be implemented. Use in Pancreatic/Biliary Tract Disease Oxycodone may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like oxycodone may cause increases in the serum amylase level. Tolerance and Physical Dependence Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: Cessation of Therapy). Information for Patients/Caregivers The following information should be provided to patients receiving PERCODAN tablets by their physician, nurse, pharmacist, or caregiver: 1. Patients should be aware that PERCODAN tablets contain oxycodone, which is a morphine-like substance. 2. Patients should be instructed to keep PERCODAN tablets in a secure place out of the reach of children. In the case of accidental ingestions, emergency medical care should be sought immediately. 3. When PERCODAN tablets are no longer needed, the unused tablets should be destroyed by flushing down the toilet. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 4. Patients should be advised not to adjust the medication dose themselves. Instead, they must consult with their prescribing physician. 5. Patients should be advised that PERCODAN tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery). 6. Patients should not combine PERCODAN tablets with alcohol, opioid analgesics, tranquilizers, sedatives, or other CNS depressants unless under the recommendation and guidance of a physician. When co-administered with another CNS depressant, PERCODAN tablets can cause dangerous additive central nervous system or respiratory depression, which can result in serious injury or death. 7. The safe use of PERCODAN tablets during pregnancy has not been established; thus, women who are planning to become pregnant or are pregnant should consult with their physician before taking PERCODAN tablets. 8. Nursing mothers should consult with their physicians about whether to discontinue nursing or discontinue PERCODAN tablets because of the potential for serious adverse reactions to nursing infants. 9. Patients who are treated with PERCODAN tablets for more than a few weeks should be advised not to abruptly discontinue the medication. Patients should consult with their physician for a gradual discontinuation dose schedule to taper off the medication. 10. Patients should be advised that PERCODAN tablets are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed. Laboratory Tests Although oxycodone may cross-react with some drug urine tests, no available studies were found which determined the duration of detectability of oxycodone in urine drug screens. However, based on pharmacokinetic data, the approximate duration of detectability for a single dose of oxycodone is roughly estimated to be one to two days following drug exposure. Urine testing for opiates may be performed to determine illicit drug use and for medical reasons such as evaluation of patients with altered states of consciousness or monitoring efficacy of drug rehabilitation efforts. The preliminary identification of opiates in urine involves the use of an immunoassay screening and thin-layer chromatography (TLC). Gas chromatography/mass spectrometry (GC/MS) may be utilized as a third-stage identification step in the medical investigational sequence for opiate testing after immunoassay and TLC. The identities of 6-keto opiates (e.g., oxycodone) can further be differentiated by the analysis of their methoxime- trimethylsilyl (MO-TMS) derivative. Drug/Drug Interactions with Oxycodone Opioid analgesics may enhance the neuromuscular-blocking action of skeletal muscle relaxants and produce an increase in the degree of respiratory depression. Patients receiving CNS depressants such as other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with PERCODAN tablets may exhibit an This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, naltrexone, and butorphanol) should be administered with caution to a patient who has received or is receiving a pure opioid agonist such as oxycodone. These agonist/antagonist analgesics may reduce the analgesic effect of oxycodone or may precipitate withdrawal symptoms. Drug/Drug Interactions with Aspirin Angiotensin Converting Enzyme (ACE) Inhibitors: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin-angiotensin conversion pathway. Acetazolamide: Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion. Anticoagulant Therapy (Heparin and Warfarin): Patients on anticoagulation therapy are at increased risk for bleeding because of drug-drug interactions and the effect on platelets. Aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk. Anticonvulsants: Salicylate can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels. Beta Blockers: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention. Diuretics: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. Methotrexate: Aspirin may enhance the serious side and toxicity of methotrexate due to displacement from its plasma protein binding sites and/or reduced renal clearance. Nonsteroidal Anti-inflammatory Drugs (NSAID's): The concurrent use of aspirin with other NSAID's should be avoided because this may increase bleeding or lead to decreased renal function. Aspirin may enhance the serious side effects and toxicity of ketorolac, due to displacement from its plasma protein binding sites and/or reduced renal clearance. Oral Hypoglycemics Agents: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia. Uricosuric Agents: Salicylates antagonize the uricosuric action of probenecid or sulfinpyrazone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 Drug/Laboratory Test Interactions Depending on the sensitivity/specificity and the test methodology, the individual components of PERCODAN tablets may cross-react with assays used in the preliminary detection of cocaine (primary urinary metabolite, benzoylecgonine) or marijuana (cannabinoids) in human urine. A more specific alternate chemical method must be used in order to obtain a confirmed analytical result. The preferred confirmatory method is gas chromatography/mass spectrometry (GC/MS). Moreover, clinical considerations and professional judgment should be applied to any drug-of- abuse test result, particularly when preliminary positive results are used. Salicylates may increase the protein bound iodine (PBI) result by competing for the protein binding sites on pre-albumin and possibly thyroid-binding globulins. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Animal studies to evaluate the carcinogenic potential of oxycodone and aspirin have not been performed. Mutagenesis The combination of oxycodone and aspirin has not been evaluated for mutagenicity. Oxycodone alone was negative in a bacterial reverse mutation assay (Ames), an in vitro chromosome aberration assay with human lymphocytes without metabolic activation and an in vivo mouse micronucleus assay. Oxycodone was clastogenic in the human lymphocyte chromosomal assay in the presence of metabolic activation and in the mouse lymphoma assay with or without metabolic activation. Aspirin induced chromosome aberrations in cultured human fibroblasts. Fertility Animal studies to evaluate the effects of oxycodone on fertility have not been performed. Aspirin has been shown to inhibit ovulation in rats. Pregnancy Teratogenic Effects Oxycodone: Pregnancy Category B Reproduction studies in rats and rabbits demonstrated that oral administration of oxycodone was not teratogenic or embryo-fetal toxic. Aspirin: Pregnancy Category D (see PRECAUTIONS) Salicylates readily cross the placenta and by inhibiting prostaglandin synthesis, may cause constriction of ductus arteriosus resulting in pulmonary hypertension and increased fetal mortality and, possibly other untoward fetal effects. Aspirin use in pregnancy can also result in alteration in maternal and neonatal hemostasis mechanisms. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths and neonatal death. Use during pregnancy, especially in the third trimester, should be avoided. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Safe use of PERCODAN (Oxycodone and Aspirin Tablets, USP) in pregnancy has not been established relative to possible adverse effects on fetal development. Therefore, PERCODAN tablets should not be used in pregnant women unless, in the judgment of the physician, the potential benefits outweigh the possible hazards. Nonteratogenic Effects Opioids can cross the placental barrier and have the potential to cause neonatal respiratory depression. Opioid use during pregnancy may result in a physically drug-dependent fetus. After birth, the neonate may suffer severe withdrawal symptoms. Aspirin may produce anemia, ante- or postpartum hemorrhage, prolonged gestation and labor, and oligohydramnios. Labor and Delivery PERCODAN tablets are not recommended for use in women during and immediately prior to labor and delivery due to its potential effects on respiratory function in the newborn. Aspirin should be avoided one week prior to and during labor and delivery because it can result in excessive blood loss at delivery. Prolonged gestation and prolonged labor due to prostaglandin inhibition have been reported. Nursing Mothers Ordinarily, nursing should not be undertaken while a patient is receiving PERCODAN tablets because of the possibility of sedation and/or respiratory depression in the infant. Oxycodone is excreted in breast milk in low concentrations, and there have been rare reports of somnolence and lethargy in babies of nursing mothers taking an oxycodone/acetaminophen product. Salicylic acid has also been detected in breast milk. Adverse effects on platelet function in the nursing infant exposed to aspirin in breast milk may be a potential risk. Furthermore, the risk of Reye Syndrome caused by salicylate in breast milk is unknown. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the potential benefits to the woman and the possible hazards to the nursing infant. Pediatric Use PERCODAN tablets should not be administered to pediatric patients. Reye Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin (or salicylates) may increase the risk of developing this disease. Geriatric Use Special precaution should be given when determining the dosing amount and frequency of PERCODAN tablets for geriatric patients, since clearance of oxycodone may be slightly reduced in this patient population when compared to younger patients. Hepatic Impairment In a pharmacokinetic study of oxycodone in patients with end-stage liver disease, oxycodone plasma clearance decreased and the elimination half-life increased. Care should be exercised when oxycodone is used in patients with hepatic impairment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Renal Impairment In a study of patients with end stage renal impairment, mean elimination half-life was prolonged in uremic patients due to increased volume of distribution and reduced clearance. Oxycodone should be used with caution in patients with renal impairment. ADVERSE REACTIONS Serious adverse reactions that may be associated with PERCODAN tablet use include respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, and shock (see OVERDOSAGE). The most frequently observed non-serious adverse reactions include lightheadedness, dizziness, drowsiness or sedation, nausea, and vomiting. These effects seem to be more prominent in ambulatory than in nonambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include euphoria, dysphoria, constipation and pruritus. Aspirin may increase the likelihood of hemorrhage due to its effect on the gastric mucosa and platelet function. Furthermore, aspirin has the potential to cause anaphylaxis in hypersensitive patients as well as angioedema especially in patients with chronic urticaria. Other adverse reactions due to aspirin use include anorexia, reversible hepatotoxicity, leukopenia, thrombocytopenia, purpura, decreased plasma iron concentration, and shortened erythrocyte survival time. Other adverse reactions obtained from postmarketing experiences with PERCODAN tablets are listed by organ system and in decreasing order of severity and/or frequency as follows: Body as a Whole allergic reaction, malaise, asthenia, headache, anaphylaxis, fever, hypothermia, thirst, increased sweating, accident, accidental overdose, non-accidental overdose. Cardiovascular tachycardia, dysrhythmias, hypotension, orthostatic hypotension, bradycardia, palpitations Central and Peripheral Nervous System stupor, paresthesia, agitation, cerebral edema, coma, confusion, dizziness, headache, subdural or intracranial hemorrhage, lethargy, seizures, anxiety, mental impairment Fluid and Electrolyte dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis Gastrointestinal hemorrhagic gastric/duodenal ulcer, gastric/peptic ulcer, dyspepsia, abdominal pain, diarrhea, eructation, dry mouth, gastrointestinal bleeding, intestinal perforation, nausea, vomiting, transient elevations of hepatic enzymes, hepatitis, Reye syndrome, pancreatitis, intestinal obstruction, ileus This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Hearing and Vestibular hearing loss, tinnitus. Patients with high frequency loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism. Hematologic unspecified hemorrhage, purpura, reticulocytosis, prolongation of prothrombin time, disseminated intravascular coagulation, ecchymosis, thrombocytopenia Hypersensitivity acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema, urticaria, anaphylactoid reaction Metabolic and Nutritional hypoglycemia, hyperglycemia, acidosis, alkalosis Musculoskeletal rhabdomyolysis Ocular miosis, visual disturbances, red eye Psychiatric drug dependence, drug abuse, somnolence, depression, nervousness, hallucination Reproductive prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding, closure of patent ductus arteriosis Respiratory System bronchospasm, dyspnea, hyperpnea, pulmonary edema, tachypnea, aspiration, hypoventilation, laryngeal edema Skin and Appendages urticaria, rash, flushing Urogenital interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure, urinary retention OVERDOSAGE Signs and Symptoms Serious overdose with PERCODAN (Oxycodone and Aspirin Tablets, USP) is characterized by signs and symptoms of opioid and salicylate overdose. Oxycodone overdosage can be manifested by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 flaccidity, cold and clammy skin, pupillary constriction (pupils may be dilated in the setting of hypoxia), and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. Early signs of acute aspirin (salicylate) overdose including tinnitus occur at plasma concentrations approaching 200 mcg/mL. Plasma concentrations of aspirin above 300 mcg/mL are toxic. Severe toxic effects are associated with levels above 400 mcg/mL. A single lethal dose of aspirin in adults is not known with certainty but death may be expected at 30 g. For real or suspected overdose, a Poison Control Center should be contacted immediately. In acute salicylate overdose, severe acid-base and electrolyte disturbances may occur and are complicated by hyperthermia and dehydration, and coma. Respiratory alkalosis occurs early while hyperventilation is present, but is quickly followed by metabolic acidosis. Serious symptoms such as depression, coma, and respiratory failure progress rapidly. Salicylism (chronic salicylate toxicity) may be noted by symptoms such as dizziness, tinnitus, difficulty hearing, nausea, vomiting, diarrhea, and mental confusion. More severe salicylism may result in respiratory alkalosis. Treatment Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. Supportive measures (including oxygen, intravenous fluids, and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Treatment of acid-base disturbances and electrolyte disorders is also important. Because of the concern over salicylate toxicity, acid-base status should be followed closely with serial blood gas and serum pH determinations. The opioid antagonist naloxone hydrochloride is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to opioids including oxycodone. Therefore, an appropriate dose of naloxone hydrochloride should be administered (usual initial adult dose 0.4 mg-2 mg) preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. Since the duration of action of oxycodone may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdose. In patients who are physically dependent on any opioid agonist including oxycodone, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use. Gastric emptying and/or lavage may be useful in removing unabsorbed drug. This procedure is recommended as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal, as a slurry, is beneficial, if less This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 than three hours have passed since ingestion. Charcoal adsorption should not be employed prior to lavage and emesis. In severe cases of salicylate overdose, hyperthermia and hypovolemia are the major immediate threats to life. Children should be sponged with tepid water. Replacement fluid should be administered intravenously and augmented with correction of acidosis. Plasma electrolytes and pH should be monitored to promote alkaline diuresis of salicylate if renal function is normal. Infusion of glucose may be required to control hypoglycemia. With more severe acute toxicity respiratory alkalosis may occur. Hemodialysis and peritoneal dialysis can be performed to reduce the body content of aspirin. In patients with renal insufficiency or in cases of life-threatening salicylate intoxication dialysis is usually required. Exchange transfusion may be indicated in infants and young children. In case of real or suspected overdose, a poison control center should be consulted for the treatment of salicylism. The toxicity of oxycodone and aspirin in combination is unknown. DOSAGE AND ADMINISTRATION Dosage should be adjusted according to the severity of the pain and the response of the patient. It may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of opioids. If pain is constant, the opioid analgesic should be given at regular intervals on an around-the- clock schedule. PERCODAN tablets are given orally. The usual dosage is one tablet every 6 hours as needed for pain. The maximum daily dose of aspirin should not exceed 4 grams or 12 tablets. Cessation of Therapy In patients treated with PERCODAN tablets for more than a few weeks who no longer require therapy, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient. DRUG ABUSE AND DEPENDENCE PERCODAN tablets are a Schedule II controlled substance. Oxycodone is a mu-agonist opioid with an abuse liability similar to morphine. Oxycodone, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion. Drug addiction is defined as an abnormal, compulsive use, use for non-medical purposes of a substance despite physical, psychological, occupational or interpersonal difficulties resulting from such use, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common. Opioid addiction is relatively rare in patients with chronic pain but may be more common in individuals who have a past history of alcohol or substance abuse or dependence. Pseudoaddiction refers to pain relief seeking behavior of patients whose pain is poorly managed. It is considered an iatrogenic effect This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 of ineffective pain management. The health care provider must assess continuously the psychological and clinical condition of a pain patient in order to distinguish addiction from pseudoaddiction and thus, be able to treat the pain adequately. Physical dependence on a prescribed medication does not signify addiction. Physical dependence involves the occurrence of a withdrawal syndrome when there is sudden reduction or cessation in drug use or if an opiate antagonist is administered. Physical dependence can be detected after a few days of opioid therapy. However, clinically significant physical dependence is only seen after several weeks of relatively high dosage therapy. In this case, abrupt discontinuation of the opioid may result in a withdrawal syndrome. If the discontinuation of opioids is therapeutically indicated, gradual tapering of the drug over a 2-week period will prevent withdrawal symptoms. The severity of the withdrawal syndrome depends primarily on the daily dosage of the opioid, the duration of therapy and medical status of the individual. The withdrawal syndrome of oxycodone is similar to that of morphine. This syndrome is characterized by yawning, anxiety, increased heart rate and blood pressure, restlessness, nervousness, muscle aches, tremor, irritability, chills alternating with hot flashes, salivation, anorexia, severe sneezing, lacrimation, rhinorrhea, dilated pupils, diaphoresis, piloerection, nausea, vomiting, abdominal cramps, diarrhea and insomnia, and pronounced weakness and depression. “Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Oxycodone, like other opioids, has been diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Like other opioid medications, PERCODAN tablets are subject to the Federal Controlled Substances Act. After chronic use, PERCODAN tablets should not be discontinued abruptly when it is thought that the patient has become physically dependent on oxycodone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 Interactions with Alcohol and Drugs of Abuse Oxycodone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. HOW SUPPLIED PERCODAN (Oxycodone and Aspirin Tablets, USP), tablets are supplied as a yellow round tablet, scored and debossed with “PERCODAN” on one side and plain on the other side. Available in: Bottles of 100 NDC 63481-121-70 Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). DEA Order Form Required. Manufactured for: Endo Pharmaceuticals Inc. Chadds Ford, Pennsylvania 19317 PERCODAN® is a Registered Trademark of Endo Pharmaceuticals Inc. Copyright © Endo Pharmaceuticals Inc. 2005 Printed in U.S.A. 2000390 / July, 2005 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lot: EXP: ® 2000391 NDC 63481-121-70 100 tablets NSN 6505-01-030-9493 Rx only Each tablet contains: Oxycodone Hydrochloride, USP. . . 4.8355 mg Aspirin, USP. . . . . . . . . . . . . . . . . . . . . 325 mg * 4.8355 mg oxycodone HCl is equivalent to 4.3346 mg of oxycodone. Usual Dosage: See package insert for complete prescribing information. Store at 25°C (77°F); excursions permitted to 15°-30°C (59° to 86°F). REPLACE CAP IMMEDIATELY. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). This is a bulk package and not intended for dispensing. DEA ORDER FORM REQUIRED. Manufactured for: Endo Pharmaceuticals Inc. Chadds Ford, PA 19317 Manufactured by: Novartis, Lincoln, NE 68501 PERCODAN ® (oxycodone and aspirin tablets, USP) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:36.433564	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/007337s043lbl.pdf', 'application_number': 7337, 'submission_type': 'SUPPL ', 'submission_number': 43}
10,693	structural formula CII company logo PERCODAN® (Oxycodone and Aspirin Tablets, USP) Rx only DESCRIPTION Each PERCODAN Tablet contains: Oxycodone Hydrochloride, USP 4.8355 mg* Aspirin, USP 325 mg *4.8355 mg oxycodone HCl is equivalent to 4.3346 mg of oxycodone as the free base. PERCODAN Tablets also contain the following inactive ingredients: D&C Yellow 10, FD&C Yellow 6, microcrystalline cellulose and corn starch. The oxycodone hydrochloride component is Morphinan-6-one, 4,5-epoxy-14-hydroxy-3 methoxy-17-methyl-, hydrochloride, (5α)-., a white to off-white, hygroscopic crystals or powder, odorless, soluble in water; slightly soluble in alcohol and is represented by the following structural formula: The aspirin component is 2-(acetyloxy)-, Benzoic acid, a white crystal, commonly tabular or needle-like, or white, crystalline powder. Is odorless or has a faint odor. Is stable in dry air; in moist air it gradually hydrolyzes to salicylic and acetic acids. Slightly soluble in water; freely soluble in alcohol; soluble in chloroform and in ether; sparingly soluble in absolute ether and is represented by the following structural formula: 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda s tructural formula CLINICAL PHARMACOLOGY Central Nervous System Oxycodone is a semisynthetic pure opioid agonist whose principal therapeutic action is analgesia. Other pharmacological effects of oxycodone include anxiolysis, euphoria and feelings of relaxation. These effects are mediated by receptors (notably μ and κ) in the central nervous system for endogenous opioid-like compounds such as endorphins and enkephalins. Oxycodone produces respiratory depression through direct activity at respiratory centers in the brain stem and depresses the cough reflex by direct effect on the center of the medulla. Aspirin (acetylsalicylic acid) works by inhibiting the body’s production of prostaglandins, including prostaglandins involved in inflammation. Prostaglandins cause pain sensations by stimulating muscle contractions and dilating blood vessels throughout the body. In the CNS, aspirin works on the hypothalamus heat-regulating center to reduce fever, however, other mechanisms may be involved. Gastrointestinal Tract and Other Smooth Muscle Oxycodone reduces motility by increasing smooth muscle tone in the stomach and duodenum. In the small intestine, digestion of food is delayed by decreases in propulsive contractions. Other opioid effects include contraction of biliary tract smooth muscle, spasm of the Sphincter of Oddi, increased ureteral and bladder sphincter tone, and a reduction in uterine tone. Aspirin can produce gastrointestinal injury (lesions, ulcers) through a mechanism that is not yet completely understood, but may involve a reduction in eicosanoid synthesis by the gastric mucosa. Decreased production of prostaglandins may compromise the defenses of the gastric mucosa and the activity of substances involved in tissue repair and ulcer healing. Cardiovascular System Oxycodone may produce a release of histamine and may be associated with orthostatic hypotension, and other symptoms, such as pruritus, flushing, red eyes, and sweating. Platelet Aggregation Aspirin affects platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda factor thromboxane A2. Nonacetylated salicylates do not inhibit this enzyme and have no effect on platelet aggregation. At somewhat higher doses, aspirin reversibly inhibits the formation of prostaglandin 12 (prostacyclin), which is an arterial vasodilator and inhibits platelet aggregation. Pharmacokinetics Absorption The mean absolute oral bioavailability of oxycodone in cancer patients was reported to be about 87%. This high oral bioavailability is due to low pre-systemic elimination and/or first-pass metabolism. Distribution The volume of distribution after intravenous administration is 211.9 ±186.6 L. Oxycodone has been shown to be 45% bound to human plasma proteins in vitro. Oxycodone has been found in breast milk [see PRECAUTIONS]. Aspirin is hydrolyzed primarily to salicylic acid in the gut wall and during first-pass metabolism through the liver. Salicylic acid is absorbed rapidly from the stomach, but most of the absorption occurs in the proximal small intestine. Following absorption, salicylate is distributed to most body tissues and fluids, including fetal tissues, breast milk, and the CNS. High concentrations are found in the liver and kidneys. Salicylate is variably bound to serum proteins, particularly albumin. Metabolism Oxycodone is extensively metabolized by multiple metabolic pathways to produce noroxycodone, oxymorphone and noroxymorphone, which are subsequently glucuronidated. Noroxycodone and noroxymorphone are the major circulating metabolites. CYP3A mediated N demethylation to noroxycodone is the primary metabolic pathway of oxycodone with a lower contribution from CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs (see Drug- Drug Interactions). Noroxycodone exhibits very weak anti-nociceptive potency compared to oxycodone, however, it undergoes further oxidation to produce noroxymorphone, which is active at opioid receptors. Although noroxymorphone is an active metabolite and present at relatively high concentrations in circulation, it does not appear to cross the blood-brain barrier to a significant extent. Oxymorphone, is present in the plasma only at low concentrations and undergoes further metabolism to form its glucuronide and noroxymorphone. Oxymorphone has been shown to be active and possessing analgesic activity but its contribution to analgesia following oxycodone administration is thought to be clinically insignificant, based on the amount formed. Other metabolites (α- and ß-oxycodol, noroxycodol and oxymorphol) may be present at very low concentrations and demonstrate limited penetration into the brain as compared to oxycodone. The enzymes responsible for keto-reduction and glucuronidation pathways in oxycodone metabolism have not been established. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The biotransformation of aspirin occurs primarily in the liver by the microsomal enzyme system. With a plasma half-life of approximately 15 minutes, aspirin is rapidly hydrolyzed to salicylate. At low doses, salicylate elimination follows first-order kinetics. The plasma half-life of salicylate is approximately 2 to 3 hours. Excretion Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. Approximately 8% to 14% of the dose is excreted as free oxycodone over 24 hours after administration. Approximately 10% of aspirin is excreted as unchanged salicylate in the urine. The major metabolites excreted in the urine are salicyluric acid (75%), salicyl phenolic glucuronide (10%), salicyl acyl glucuronide (5%), and gentisic and gentisuric acid (less than 1%) each. Eighty to 100% of a single dose is excreted in the urine within 24 to 72 hours. DRUG-DRUG INTERACTIONS (SEE PRECAUTIONS) Inhibitors of CYP3A4: Since the CYP3A4 isoenzyme plays a major role in the metabolism of PERCODAN, drugs that inhibit CYP3A4 activity, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations. A published study showed that the co-administration of the antifungal drug, voriconazole, increased oxycodone AUC and Cmax by 3.6 and 1.7 fold, respectively. The expected clinical results would be increased or prolonged opioid effects. Inducers of CYP450: CYP450 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the metabolism of oxycodone, may cause increased clearance of the drug which could lead to a decrease in oxycodone plasma concentrations. A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone (oral) AUC and Cmax by 86% and 63% respectively. The expected clinical results would be lack of efficacy or, possibly, development of abstinence syndrome in a patient who had developed physical dependence to oxycodone. Induction of CYP3A4 may be of greatest importance given oxycodone’s metabolic pathways. INDICATIONS AND USAGE PERCODAN tablets are indicated for the management of moderate to moderately severe pain. CONTRAINDICATIONS PERCODAN tablets are contraindicated in patients with known hypersensitivity to oxycodone or aspirin, and in any situation where opioids or aspirin are contraindicated. Aspirin is contraindicated for patients with hemophilia. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reye Syndrome: Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye syndrome with concomitant use of aspirin in certain viral illnesses. Allergy: Aspirin is contraindicated in patients with known allergy to nonsteroidal anti inflammatory drug products and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema, or bronchospasm (asthma). Oxycodone is contraindicated in patients with known hypersensitivity to oxycodone. Oxycodone is contraindicated in any situation where opioids are contraindicated including patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment) and patients with acute or severe bronchial asthma or hypercarbia. Oxycodone is contraindicated in the setting of suspected or known paralytic ileus. WARNINGS Misuse and Abuse of Opioids Oxycodone is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion (see DRUG ABUSE AND DEPENDENCE). Oxycodone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing PERCODAN tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Concerns about misuse, addiction, and diversion should not prevent the proper management of pain. PERCODAN tablets may be abused by crushing, snorting, or injecting the product. These practices pose a significant risk to the abuser that could result in overdose and death. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Administration of PERCODAN (Oxycodone and Aspirin Tablets, USP) tablets should be closely monitored for the following potentially serious adverse reactions and complications: Respiratory Depression Respiratory depression is a hazard with the use of oxycodone, one of the active ingredients in PERCODAN tablets, as with all opioid agonists. Elderly and debilitated patients are at particular risk for respiratory depression as are non-tolerant patients given large initial doses of oxycodone or when oxycodone is given in conjunction with other agents that depress respiration. Oxycodone should be used with extreme caution in patients with acute asthma, chronic obstructive pulmonary disorder (COPD), cor pulmonale, or preexisting respiratory impairment. In such patients, even usual therapeutic doses of oxycodone may decrease respiratory drive to the 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda point of apnea. In these patients alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose. In case of respiratory depression, a reversal agent such as naloxone hydrochloride may be utilized (see OVERDOSAGE). Head Injury and Increased Intracranial Pressure The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Oxycodone produces effects on pupillary response and consciousness which may obscure neurologic signs of worsening in patients with head injuries. Hypotensive Effect Oxycodone may cause severe hypotension particularly in individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs which compromise vasomotor tone such as phenothiazines. Oxycodone, like all opioid analgesics of the morphine-type, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. Oxycodone may produce orthostatic hypotension in ambulatory patients. Alcohol Warning Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. Coagulation Abnormalities Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited (hemophilia) or acquired (liver disease or vitamin K deficiency) bleeding disorders. GI Side Effects GI side effects include stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur. Peptic Ulcer Disease Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation and bleeding. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General Opioid analgesics should be used with caution when combined with CNS depressant drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression, altered mental state, and postural hypotension. PERCODAN tablets should be given with caution to patients with CNS depression, elderly or debilitated patients, patients with severe impairment of hepatic, pulmonary, or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy, urethral stricture, acute alcoholism, delirium tremens, kyphoscoliosis with respiratory depression, myxedema, and toxic psychosis. PERCODAN tablets may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Oxycodone may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings. Following administration of PERCODAN tablets, anaphylactic reactions have been reported in patients with a known hypersensitivity to codeine, a compound with a structure similar to morphine and oxycodone. The frequency of this possible cross-sensitivity is unknown. Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time. Hemorrhage Aspirin may increase the likelihood of hemorrhage due to its effect on the gastric mucosa and platelet function (prolongation of bleeding time). Salicylates should be used with caution in the presence of peptic ulcer or coagulation abnormalities. Interactions with Other CNS Depressants Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with PERCODAN tablets may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Interactions with Mixed Agonist/Antagonist Opioid Analgesics Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as oxycodone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone and/or may precipitate withdrawal symptoms in these patients. Ambulatory Surgery and Postoperative Use Oxycodone and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common postoperative complication, especially after intra-abdominal surgery with use of 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda opioid analgesia. Caution should be taken to monitor for decreased bowel motility in postoperative patients receiving opioids. Standard supportive therapy should be implemented. Use in Pancreatic/Biliary Tract Disease Oxycodone may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like oxycodone may cause increases in the serum amylase level. Tolerance and Physical Dependence Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: Cessation of Therapy). Information for Patients/Caregivers The following information should be provided to patients receiving PERCODAN tablets by their physician, nurse, pharmacist, or caregiver: 1. Patients should be aware that PERCODAN tablets contain oxycodone, which is a morphine-like substance. 2. Patients should be instructed to keep PERCODAN tablets in a secure place out of the reach of children. In the case of accidental ingestions, emergency medical care should be sought immediately. 3. When PERCODAN tablets are no longer needed, the unused tablets should be destroyed by flushing down the toilet. 4. Patients should be advised not to adjust the medication dose themselves. Instead, they must consult with their prescribing physician. 5. Patients should be advised that PERCODAN tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery). 6. Patients should not combine PERCODAN tablets with alcohol, opioid analgesics, tranquilizers, sedatives, or other CNS depressants unless under the recommendation and guidance of a physician. When co-administered with another CNS depressant, PERCODAN tablets can cause dangerous additive central nervous system or respiratory depression, which can result in serious injury or death. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7. The safe use of PERCODAN tablets during pregnancy has not been established; thus, women who are planning to become pregnant or are pregnant should consult with their physician before taking PERCODAN tablets. 8. Nursing mothers should consult with their physicians about whether to discontinue nursing or discontinue PERCODAN tablets because of the potential for serious adverse reactions to nursing infants. 9. Patients who are treated with PERCODAN tablets for more than a few weeks should be advised not to abruptly discontinue the medication. Patients should consult with their physician for a gradual discontinuation dose schedule to taper off the medication. 10. Patients should be advised that PERCODAN tablets are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed. 11. Patients should be advised that PERCODAN tablets may cause or worsen constipation, as generally occurs with all opioids. They should discuss any past history of constipation with their prescribing physician so a management plan may be initiated. Laboratory Tests Although oxycodone may cross-react with some drug urine tests, no available studies were found which determined the duration of detectability of oxycodone in urine drug screens. However, based on pharmacokinetic data, the approximate duration of detectability for a single dose of oxycodone is roughly estimated to be one to two days following drug exposure. Urine testing for opiates may be performed to determine illicit drug use and for medical reasons such as evaluation of patients with altered states of consciousness or monitoring efficacy of drug rehabilitation efforts. The preliminary identification of opiates in urine involves the use of an immunoassay screening and thin-layer chromatography (TLC). Gas chromatography/mass spectrometry (GC/MS) may be utilized as a third-stage identification step in the medical investigational sequence for opiate testing after immunoassay and TLC. The identities of 6-keto opiates (e.g., oxycodone) can further be differentiated by the analysis of their methoxime trimethylsilyl (MO-TMS) derivative. Drug/Drug Interactions with Oxycodone CYP3A4 Inhibitors and CYP450 Inducers: Oxycodone is extensively metabolized by multiple metabolic pathways. CYP3A4 is the major enzyme involved in noroxycodone formation followed by CYP2B6, CYP2C9/19 and CYP2D6. Drugs that inhibit CYP3A4 activity, such as macrolide antibiotics (e.g., erythromycin), azole- antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations and prolonged opioid effects. Similarly, CYP450 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the metabolism of oxycodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in oxycodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone. If co-administration with PERCODAN is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing CYP3A4 inhibitors or CYP450 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Skeletal Muscle Relaxants: Opioid analgesics may enhance the neuromuscular-blocking action of skeletal muscle relaxants and produce an increase in the degree of respiratory depression. CNS Depressants: Patients receiving CNS depressants such as other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with PERCODAN tablets may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, naltrexone, and butorphanol) should be administered with caution to a patient who has received or is receiving a pure opioid agonist such as oxycodone. These agonist/antagonist analgesics may reduce the analgesic effect of oxycodone or may precipitate withdrawal symptoms. Drug/Drug Interactions with Aspirin Angiotensin Converting Enzyme (ACE) Inhibitors: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin-angiotensin conversion pathway. Acetazolamide: Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion. Anticoagulant Therapy (Heparin and Warfarin): Patients on anticoagulation therapy are at increased risk for bleeding because of drug-drug interactions and the effect on platelets. Aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk. Anticonvulsants: Salicylate can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels. Beta Blockers: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention. Diuretics: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. Methotrexate: Aspirin may enhance the serious side and toxicity of methotrexate due to displacement from its plasma protein binding sites and/or reduced renal clearance. 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nonsteroidal Anti-inflammatory Drugs (NSAID's): The concurrent use of aspirin with other NSAID's should be avoided because this may increase bleeding or lead to decreased renal function. Aspirin may enhance the serious side effects and toxicity of ketorolac, due to displacement from its plasma protein binding sites and/or reduced renal clearance. Oral Hypoglycemics Agents: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia. Uricosuric Agents: Salicylates antagonize the uricosuric action of probenecid or sulfinpyrazone. Drug/Laboratory Test Interactions Depending on the sensitivity/specificity and the test methodology, the individual components of PERCODAN tablets may cross-react with assays used in the preliminary detection of cocaine (primary urinary metabolite, benzoylecgonine) or marijuana (cannabinoids) in human urine. A more specific alternate chemical method must be used in order to obtain a confirmed analytical result. The preferred confirmatory method is gas chromatography/mass spectrometry (GC/MS). Moreover, clinical considerations and professional judgment should be applied to any drug-of abuse test result, particularly when preliminary positive results are used. Salicylates may increase the protein bound iodine (PBI) result by competing for the protein binding sites on pre-albumin and possibly thyroid-binding globulins. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Animal studies to evaluate the carcinogenic potential of oxycodone and aspirin have not been performed. Mutagenesis The combination of oxycodone and aspirin has not been evaluated for mutagenicity. Oxycodone alone was negative in a bacterial reverse mutation assay (Ames), an in vitro chromosome aberration assay with human lymphocytes without metabolic activation and an in vivo mouse micronucleus assay. Oxycodone was clastogenic in the human lymphocyte chromosomal assay in the presence of metabolic activation and in the mouse lymphoma assay with or without metabolic activation. Aspirin induced chromosome aberrations in cultured human fibroblasts. Fertility Animal studies to evaluate the effects of oxycodone on fertility have not been performed. Aspirin has been shown to inhibit ovulation in rats. Pregnancy Teratogenic Effects Oxycodone: Pregnancy Category B Reproduction studies in rats and rabbits demonstrated that oral administration of oxycodone was not teratogenic or embryo-fetal toxic. 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Aspirin: Pregnancy Category D (see PRECAUTIONS) Salicylates readily cross the placenta and by inhibiting prostaglandin synthesis, may cause constriction of ductus arteriosus resulting in pulmonary hypertension and increased fetal mortality and, possibly other untoward fetal effects. Aspirin use in pregnancy can also result in alteration in maternal and neonatal hemostasis mechanisms. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths and neonatal death. Use during pregnancy, especially in the third trimester, should be avoided. Safe use of PERCODAN (Oxycodone and Aspirin Tablets, USP) in pregnancy has not been established relative to possible adverse effects on fetal development. Therefore, PERCODAN tablets should not be used in pregnant women unless, in the judgment of the physician, the potential benefits outweigh the possible hazards. Nonteratogenic Effects Opioids can cross the placental barrier and have the potential to cause neonatal respiratory depression. Opioid use during pregnancy may result in a physically drug-dependent fetus. After birth, the neonate may suffer severe withdrawal symptoms. Aspirin may produce anemia, ante- or postpartum hemorrhage, prolonged gestation and labor, and oligohydramnios. Labor and Delivery PERCODAN tablets are not recommended for use in women during and immediately prior to labor and delivery due to its potential effects on respiratory function in the newborn. Aspirin should be avoided one week prior to and during labor and delivery because it can result in excessive blood loss at delivery. Prolonged gestation and prolonged labor due to prostaglandin inhibition have been reported. Nursing Mothers Ordinarily, nursing should not be undertaken while a patient is receiving PERCODAN tablets because of the possibility of sedation and/or respiratory depression in the infant. Oxycodone is excreted in breast milk in low concentrations, and there have been rare reports of somnolence and lethargy in babies of nursing mothers taking an oxycodone/acetaminophen product. Salicylic acid has also been detected in breast milk. Adverse effects on platelet function in the nursing infant exposed to aspirin in breast milk may be a potential risk. Furthermore, the risk of Reye Syndrome caused by salicylate in breast milk is unknown. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the potential benefits to the woman and the possible hazards to the nursing infant. Pediatric Use PERCODAN tablets should not be administered to pediatric patients. Reye Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin (or salicylates) may increase the risk of developing this disease. 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Geriatric Use Special precaution should be given when determining the dosing amount and frequency of PERCODAN tablets for geriatric patients, since clearance of oxycodone may be slightly reduced in this patient population when compared to younger patients. Hepatic Impairment In a pharmacokinetic study of oxycodone in patients with end-stage liver disease, oxycodone plasma clearance decreased and the elimination half-life increased. Care should be exercised when oxycodone is used in patients with hepatic impairment. Avoid aspirin in patients with severe hepatic impairment. Renal Impairment In a study of patients with end stage renal impairment, mean elimination half-life of oxycodone was prolonged in uremic patients due to increased volume of distribution and reduced clearance. Oxycodone should be used with caution in patients with renal impairment. Avoid aspirin in patients with severe renal impairment (glomerular filtration rate less than 10 mL/minute). ADVERSE REACTIONS Serious adverse reactions that may be associated with PERCODAN tablet use include respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, and shock (see OVERDOSAGE). The most frequently observed non-serious adverse reactions include lightheadedness, dizziness, drowsiness or sedation, nausea, and vomiting. These effects seem to be more prominent in ambulatory than in nonambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include euphoria, dysphoria, constipation and pruritus. Aspirin may increase the likelihood of hemorrhage due to its effect on the gastric mucosa and platelet function. Furthermore, aspirin has the potential to cause anaphylaxis in hypersensitive patients as well as angioedema especially in patients with chronic urticaria. Other adverse reactions due to aspirin use include anorexia, reversible hepatotoxicity, leukopenia, thrombocytopenia, purpura, decreased plasma iron concentration, and shortened erythrocyte survival time. Other adverse reactions obtained from postmarketing experiences with PERCODAN tablets are listed by organ system and in decreasing order of severity and/or frequency as follows: Body as a Whole allergic reaction, malaise, asthenia, headache, anaphylaxis, fever, hypothermia, thirst, increased sweating, accident, accidental overdose, non-accidental overdose. 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cardiovascular tachycardia, dysrhythmias, hypotension, orthostatic hypotension, bradycardia, palpitations Central and Peripheral Nervous System stupor, paresthesia, agitation, cerebral edema, coma, confusion, dizziness, headache, subdural or intracranial hemorrhage, lethargy, seizures, anxiety, mental impairment Fluid and Electrolyte dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis Gastrointestinal hemorrhagic gastric/duodenal ulcer, gastric/peptic ulcer, dyspepsia, abdominal pain, diarrhea, eructation, dry mouth, gastrointestinal bleeding, intestinal perforation, nausea, vomiting, transient elevations of hepatic enzymes, hepatitis, Reye syndrome, pancreatitis, intestinal obstruction, ileus Hearing and Vestibular hearing loss, tinnitus. Patients with high frequency loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism. Hematologic unspecified hemorrhage, purpura, reticulocytosis, prolongation of prothrombin time, disseminated intravascular coagulation, ecchymosis, thrombocytopenia Hypersensitivity acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema, urticaria, anaphylactoid reaction Metabolic and Nutritional hypoglycemia, hyperglycemia, acidosis, alkalosis Musculoskeletal rhabdomyolysis Ocular miosis, visual disturbances, red eye Psychiatric drug dependence, drug abuse, somnolence, depression, nervousness, hallucination Reproductive prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding, closure of patent ductus arteriosis 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Respiratory System bronchospasm, dyspnea, hyperpnea, pulmonary edema, tachypnea, aspiration, hypoventilation, laryngeal edema Skin and Appendages urticaria, rash, flushing Urogenital interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure, urinary retention OVERDOSAGE Signs and Symptoms Serious overdose with PERCODAN (Oxycodone and Aspirin Tablets, USP) is characterized by signs and symptoms of opioid and salicylate overdose. Oxycodone overdosage can be manifested by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, pupillary constriction (pupils may be dilated in the setting of hypoxia), and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. Early signs of acute aspirin (salicylate) overdose including tinnitus occur at plasma concentrations approaching 200 mcg/mL. Plasma concentrations of aspirin above 300 mcg/mL are toxic. Severe toxic effects are associated with levels above 400 mcg/mL. A single lethal dose of aspirin in adults is not known with certainty but death may be expected at 30 g. For real or suspected overdose, a Poison Control Center should be contacted immediately. In acute salicylate overdose, severe acid-base and electrolyte disturbances may occur and are complicated by hyperthermia and dehydration, and coma. Respiratory alkalosis occurs early while hyperventilation is present, but is quickly followed by metabolic acidosis. Serious symptoms such as depression, coma, and respiratory failure progress rapidly. Salicylism (chronic salicylate toxicity) may be noted by symptoms such as dizziness, tinnitus, difficulty hearing, nausea, vomiting, diarrhea, and mental confusion. More severe salicylism may result in respiratory alkalosis. Treatment Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. Supportive measures (including oxygen, intravenous fluids, and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Treatment of acid-base disturbances and electrolyte disorders is also important. Because of the concern over salicylate toxicity, acid-base status should be followed closely with serial blood gas and serum pH determinations. 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The opioid antagonist naloxone hydrochloride is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to opioids including oxycodone. Therefore, an appropriate dose of naloxone hydrochloride should be administered (usual initial adult dose 0.4 mg-2 mg) preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. Since the duration of action of oxycodone may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdose. In patients who are physically dependent on any opioid agonist including oxycodone, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use. Gastric emptying and/or lavage may be useful in removing unabsorbed drug. This procedure is recommended as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal, as a slurry, is beneficial, if less than three hours have passed since ingestion. Charcoal adsorption should not be employed prior to lavage and emesis. In severe cases of salicylate overdose, hyperthermia and hypovolemia are the major immediate threats to life. Children should be sponged with tepid water. Replacement fluid should be administered intravenously and augmented with correction of acidosis. Plasma electrolytes and pH should be monitored to promote alkaline diuresis of salicylate if renal function is normal. Infusion of glucose may be required to control hypoglycemia. With more severe acute toxicity respiratory alkalosis may occur. Hemodialysis and peritoneal dialysis can be performed to reduce the body content of aspirin. In patients with renal insufficiency or in cases of life-threatening salicylate intoxication dialysis is usually required. Exchange transfusion may be indicated in infants and young children. In case of real or suspected overdose, a poison control center should be consulted for the treatment of salicylism. The toxicity of oxycodone and aspirin in combination is unknown. DOSAGE AND ADMINISTRATION Dosage should be adjusted according to the severity of the pain and the response of the patient. It may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of opioids. If pain is constant, the opioid analgesic should be given at regular intervals on an around-the clock schedule. PERCODAN tablets are given orally. The usual dosage is one tablet every 6 hours as needed for pain. The maximum daily dose of aspirin should not exceed 4 grams or 12 tablets. 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cessation of Therapy In patients treated with PERCODAN tablets for more than a few weeks who no longer require therapy, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient. DRUG ABUSE AND DEPENDENCE PERCODAN tablets are a Schedule II controlled substance. Oxycodone is a mu-agonist opioid with an abuse liability similar to morphine. Oxycodone, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion. Drug addiction is defined as an abnormal, compulsive use, use for non-medical purposes of a substance despite physical, psychological, occupational or interpersonal difficulties resulting from such use, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common. Opioid addiction is relatively rare in patients with chronic pain but may be more common in individuals who have a past history of alcohol or substance abuse or dependence. Pseudoaddiction refers to pain relief seeking behavior of patients whose pain is poorly managed. It is considered an iatrogenic effect of ineffective pain management. The health care provider must assess continuously the psychological and clinical condition of a pain patient in order to distinguish addiction from pseudoaddiction and thus, be able to treat the pain adequately. Physical dependence on a prescribed medication does not signify addiction. Physical dependence involves the occurrence of a withdrawal syndrome when there is sudden reduction or cessation in drug use or if an opiate antagonist is administered. Physical dependence can be detected after a few days of opioid therapy. However, clinically significant physical dependence is only seen after several weeks of relatively high dosage therapy. In this case, abrupt discontinuation of the opioid may result in a withdrawal syndrome. If the discontinuation of opioids is therapeutically indicated, gradual tapering of the drug over a 2-week period will prevent withdrawal symptoms. The severity of the withdrawal syndrome depends primarily on the daily dosage of the opioid, the duration of therapy and medical status of the individual. The withdrawal syndrome of oxycodone is similar to that of morphine. This syndrome is characterized by yawning, anxiety, increased heart rate and blood pressure, restlessness, nervousness, muscle aches, tremor, irritability, chills alternating with hot flashes, salivation, anorexia, severe sneezing, lacrimation, rhinorrhea, dilated pupils, diaphoresis, piloerection, nausea, vomiting, abdominal cramps, diarrhea and insomnia, and pronounced weakness and depression. “Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Oxycodone, like other opioids, has been diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Like other opioid medications, PERCODAN tablets are subject to the Federal Controlled Substances Act. After chronic use, PERCODAN tablets should not be discontinued abruptly when it is thought that the patient has become physically dependent on oxycodone. Interactions with Alcohol and Drugs of Abuse Oxycodone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. HOW SUPPLIED PERCODAN (Oxycodone and Aspirin Tablets, USP), tablets are supplied as a yellow round tablet, scored and debossed with “PERCODAN” on one side and plain on the other side. Available in: Bottles of 100 NDC 63481-121-70 Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). DEA Order Form Required. Manufactured for: Endo Pharmaceuticals Inc. Chadds Ford, Pennsylvania 19317 PERCODAN® is a Registered Trademark of Endo Pharmaceuticals © 2010 Endo Pharmaceuticals company logo Printed in U.S.A. 2006560 / June 2010 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:36.446319	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/007337s046lbl.pdf', 'application_number': 7337, 'submission_type': 'SUPPL ', 'submission_number': 46}
10,694	I PV 0373 UCP TABLETS TAPAz()LECI METHIMAZOLE'., . TABLETS, USP ~ I)ESCRIPTION rapazole~(Mathlmazole Tablets, USP) (1-methylimlrlazole-2-thiol) is a white, crystallne súbstance that Is freely soluble in water. It differs chemically from the drugs oftt:e.thiouracll series primarily because it has as-Instead of a 6-memberedring. Each tablet'contains S or10m9T43.8or 87:6 ~rnol) methimazole.an'orally' admin- Istered antihyroid drug. Ei,cl\ tablet also contains lactose, màgn~sium stearatè, starch, and talc. Themolècularweight is 114.16, and the empirical formulals.C4HsN:iS. The structural formulaIs as fôllows: . CI;3 I .'. C't' cLiNICAL PHAR.MACOLOGY. ,; Methimazole inhibits the synthesis of thyroid hormones and .thus .is. effective in the treatment of hyperthyroidism. The drug does not inactivate existing.thyroxlne and triiodothyronine that are, storedin the . thyroid or circulating in, the blood nordoiis It interfere with the effecii,veniiss. pf thyroid hormones given, by mouth '0,1' byinìeëtion. The actions and use of methimazole are simila(to'thôse ofpropylthiour¡¡cil.' On a weighibàsis, the, drug is at le¡¡st10 times !l~ potent as prc:pylthiôìJr!lcil, but methimazole maybe 'Iess consistent in acïiòri.' ". . from the gastrointestinal. tract. Itis metabolized rapidly andreqljires frequent admin istration. Methimazole is excreted in the Methimazolels readily absorbed urlnè.' . In laboratory anlmåls" various' regirtims that c0lÍtinuouelys~PRress thyroid flJJ)cilon and thereby iocrease.TSH secrètionresull in thyroid tissue hypertrophy; Uncl!lreyqh conditions, the' apPiiwanc.e ofthyrbid"àrld pituitary neoRliismst:as, 'alsooèi;in reported. . ens thatliàve beèn stydled in this incl~deantlthyroid agents as wella . . aryiodine deficiency, subtotal thyroldectomy, implantation of autonomous thyrotropic hormonii-secrèting pituitary tumorsòandadhilnlstrat.ion of chemical goiirogens.. . '. ..... .... ..... INDICATIONS AND USAGE Tapaiole is indicated in,thiimedièal t.reatmentof hyperthyroidism. Long-term therapy may lead to remission of the disease.. Tapazole may, be used .to amelic:ratehyperthyroldism in preparation This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda for. subtotal thyroidectomy or radioactive Iodine therapy. Tapazolels.also used when thyroidectomy is contraindicated or not advisable. CONTRAINDICATIONS ; Tapazoleis. conirain'dicateèl in the presence, of hypersllnsitivlty to the dr~g and In n~rslng mothers because the drug I,S excreted in milk. . " , . WARNINGS AgranulocytQsisis potentiaily.a s!lrious side effect. Patients should, be instructed to report to theirppysici¡¡ìie,any symptomsof agranulocytosis, such..as,.everor sore throat. LeuknP!lnla, thrombocytopenia, and aplastic anemi¡¡(pal)cyiopenia) may also occur. The drug 'should be discontinued in the presence of agran~locytosis, aplastic anemiå (pancyic:penia),' hepatiis,or exfoliative dermatitis. Thepatlents bone marrow function shouid be monitored. . Due to the similar hepatic toxicity profiles' ofTapazole and propylthiouracil, attention is drawn to 'the severe hepatic reactions which have occurred with both drugs: There have been rareirepórts of fulminant hepatitis, hep.atic necrosis, encephalop¡ithy, and death,Symptòms suggestive of' hepatic dysfunction (anorexia,pr~ritus,Jight upper quadrant pain, etc) sho~ld prompt evaluation of Iìver function. Drug treatment should' b.e discontín~edprom¡:llyin .'lh~ . eVent ofclinicallysignlficantevldènce of liliet' abnormality inciudinghepalic transliminase valuEisèxceeding 3 times the upper limitof norma!.' '.' .. '., .... ..... . Tapazblecancausefetal harm. when adminlsÎered to apregnarltwoman. Tapazolereiidilycrosses the pl¡¡cental nierni;ranes aM can Inducegditerand even cretinism in the devèlòplng'f!ltus. In addition,,;rare .instances' ofC(ingenital defiicts;.apl¡¡sia cutis, as manifested by scalpde'j!lèts; !lsophag!lal atresia w.ith traç~èbesóphageäl fistùla; and êhoanal atresia wlth¡ibtlentlhYPClPlasti,c ol,pples, h;ive qccurred iii jofeints born tq mothiirs who .receii(e~" TaR~~ole;(jLlring. pregnancx. IfTapazole,ls ,ùsedtlur1ng pregnancY qrif the. patient.bJlcè1mèspiè90a,i;I,wni1etakìng this drlJg, tpep¡¡tient stiould Iiè warned of the potential hazarcltó the fetlsc. Sin,Cf'th8 above conge~ita!dèieè:š haVe been ,reported ¡rioffspring oj,paiients tre.e.teci ,witi: . Tapazc:ie;i\ mày):ie approwi¡ite to 'use other, agents in, preg. nanf, ..o!Oiin requiring trii,atniëÌ)(Jor hYPei:~yroidism.' ." . POSip¡irtul'peitients rece!yirig Tapazql!l shoulcl not.nurse their i;¡ibiiis, . PRECAUTIONS Geneial--Patiérts Whìp receive Tapazole' should 'bèLinde'r close surveilance ¡¡nd.should bè cautioned to report immediately any evidènce. of ilness, particularly sOre throat, 'skin eruptions; felièr, headache, or' general malaise. In such cases," white-blood-cell. and differential counts should be made to determine whether.. agrànul()cytosis has developecL Pa'rcularcare should be exercised with patients iNho arerécelving additlo'nal drugsknown.to' "caUse agranulocytosis. 'L?oboratory Tèsts--Because Tapàzole may 'cause hypoprothrombinemia' and bleeding, prothrombin time. should be monitored duringtherapywith.the drug, espiiciallybeforesurgical pro.c, edu. .r.e. s (see General' under Precautions)., function ,is, Periodic. monitoring of thyroid warranted, and the finding 'oLan elevated TSH.warrants a decrease in the, dosage of Tapazole. Drug Interactions.. Anticoagulants (orall The activity of anticoàgulanismay b!l:pôtentlatedby anti vitamln-K activity attrlbutedtQTapazole. i Ii II l ,. I: I I This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ',,' TAPAZOLE~ (Methimazole Tablets, USP) ß-adrenergjc blocking agents-Hyper thyroidism may cause an increased clearance of beta blockers with ahigh extraction ratio. A dos!l reduction of beta- adrenergic blockers maybe needed when a hyperthyroidpatient be.comes euthyroid. Digital is glycosides..Serum digitalis 'levels may be increased when hyperthyroid patients on a stablè digitàlls glycoside regimai become euthyroid; a reduced dosage of digitalis glycosides rray be required: Theophyllne-Theophylline 'clearance may decrease when hyperthyroid'patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed~ Carcinogenesis, Mutagenesis, impair ment of Fertilty-In a 2 year study, rats were given methimazole at doses of 0.5, 3, and 18 mg/kg/day. These doses were 0.3, 2,and12 times the 15 mg/day maximum human malntenancè dose (when calculated on the basis of 'surfiice"aiea).'Thyrold hyperplasia, adenom,a, and carcinoma deveioped InJatsat the tw,o higher doses. The 'clinicalsignificance of.these findings Is unclear. ,,',', ' PregnafJcy Category Q-Sea, V\amings T¡¡pazòl!l~sed"judiclo~sly,is ,an !lffeçtiye drug,in hyperthyrçidismcomplicated, by pregnancy. In. many pregnant womeri, the thyroid dysfunction diminisl)es as lhe pregnancy prpceeds; consequently, a redl,ctlonin dosag!l may be.posslble. In som!linstal)ce$, use of ,TapazoJe caii be disconiinued 2 or :3 we!lks -b!lforedelivery. , Nursing /,Îtot/lers""The drùg,appears in hÙrran bre-ast milk and its use, is contralndicàt~d In nursing mnth!lrs(~ee Warnings).,' 'Co' ' Pediatric, Use-Sae Dosage and Administration. ' ADVERSE REACTIONS Major adverse reactiohs (wliichoccur with much, less frequency thfln the minor adverse'ree.ctions) incl.ude inhibition of myelop'òiesis(agranúloëytosis, granulocytopenia', and thrombocytopenia), apiastic anemia, drug fever, a lupuslike syndrome, insulin autoimmune, syndrome can result In, hypoglycemic 'coma), (which hepatitis Uaundicem¡¡y persist for sev,eral wéeks after discontinuation of the drug), pèrlarlerltis, and hy¡:oprothrornbinemla. Nephritis occurs very 'ràrely. " ,',_ Minor adverse' reactions' incl~de skin rash: ' urticaria, nausea;' Vomiting, epigastric distrèss" arthralgia, paresthesia, loss bftaste, abnormal loss of hair, mýàlgia, headache, pruritus, drowsiness, neuritis', edema, vertigo, skin pigmen tation, jaundice, sialadenopathy, and lymphadenopathy: ," , , . It should be noted that about 1 0% of patients with ~ntreated hyperthyroidism have leukopenia (white-blood-cell count of less'than 4,OOO/mm3), often with relative granuiopenia. ,,' OVl:f:ObSAGE Signsan~ Sympt(Íms..Symptoms may include, na~sea, xpmiting,!lpigastric distress,: headache, feyer,,jQint pain, pruritus, andedemii, ,A¡:lasticaniirnla (pancytopenia) or agran~locytQSls may be manifested in hours .to diiys. Less frequent events are hepatitis;' nephrotic syndrome, exfoliative'dérmatitis, neuropamie,s,and eNS stlmulationorde¡:ression. Although not well stuoied; methlmazole~lnduced agranulocytosis Is generaiiy associated with doses of 40 mg,ormore in patients oli;er lnan 40 years of age. No Information is available, on the median lethal dose of thedrug or the concentration of methimazole In biologic fluids associated This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda I with toxlcityandlor .death, Treatment-To obtain up-to,date infor mation abo~t the treatment of overdose, a good reiio~rce is your certified Regional Poison Control Center. Telephone numbers of certified poison çontrQI,centers are listed in ,he, Physicians' Desk 'Reference (PDR). In managing overdosage, consider the pc:sslbility of miHtlple dr~g overdoses, interaction among drugs, and unusual drug kinetics in your patient. " Proiectlhe patient's airway and support ventiiation arld perfusion. MetièiJlo~,sly monitor and' maintain, within' acceptable limits, the, patient's vital signs, blood gases, serum electrolytes, etc. The patient's bone marrow function'should be monltorëd. Absorption of drllgs troni the gastro- Intestinallractinay be decreaSed by,giving activatedchàrcoal, Which, inmany cases; is more effective than emesis or lavage; consider charcoal Instead of or In addition to of gastric emptying.' Repeated, doses elimination of some drugs that have been absorbed. charcoal overtime niay hasten Safeguard the patient's airway when employiriggastric emptyiniior charcoal. Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal heniQllerfusion have not been established as beneficial for an overdose of methimazole. ' DOSAGe AND,A~MINI$TRAT¡()N "Tapazo'le is administered oraÌly, 'It is usually given" in S equal doses at approximately 8-hour Intervals,. Adult-TheinitiaLdally, dosage is 15,mg for. mild, hyperthyroidism, 30 to 40 mg for moderately severe hyperthyroidism, and 60 mg forsevere hyperthyròidism, divided into 3 doses at 8-ho~r intervals. The maintenance dosage isS to 15 mg daily. Pediatric-Initially, the daily dosage is 0.4 mglkg of body weight divided into 3 doses and given at 8-hour intervals. The maintenance dosage is approximately 1/2 of the initial dose. HOW SUPPLIED Tapazole~ Tablets, are available in: The 5-mg tableis(UCõ3å$) are white,in color; round, beveled, scored, and debossed with "J94". , , ' ' They are available as follows: " Bottiesof'100 NDC 52604-1094-1 1765) (No. The 10-mg tablets (UC5386)afë white in color; rourid:beveled, scOred,;' and debòssed with "J95". " They are available as folloWs: BottåsoHOO' NDC52604'1095-1 (No: 1770) Store'at c:ontrolled room temperat~re, 15-30'C (59-B6'F). Literature revi¡;éd July 24, 1999 .. ' , ; '" DiSt Exclusively by JONES; RHARMA INCORPORATED .. ,',', St Louis, fy063146 Lilly a,r1,C, onìpariy" ','.;',',Mf"d',b,',I,'Y', i:,.",Ii, ;. Indianàpohs, It'A6285 PV'0373lJGR PRINTED IN USA i i ~ \ This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:36.583005	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/007517s022lbl.pdf', 'application_number': 7517, 'submission_type': 'SUPPL ', 'submission_number': 22}
10,696	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda BENOQUIN ® CREAM 20% (Monobenzone Cream, USP) Only. FOR EXTERNAL USE ONLY DESCRIPTION: Monobenzone is the monobenzyl ether of hydroquinone. Monobenzone occurs as a white, almost tasteless crystalline powder, soluble in alcohol and practically insoluble in water. Chemically, monobenzone is designated as p-(benzyloxy) phenol; the empirical formula is C13H12O2; molecular weight 200.24. The structural formula is: C13H12O2 200.24 Each gram of Benoquin Cream contains 200 mg of monobenzone USP, in a water-washable base consisting of purified water USP, cetyl alcohol NF, propylene glycol USP, sodium lauryl sulfate NF and white wax NF. CLINICAL PHARMACOLOGY: Benoquin Cream 20% is a depigmenting agent whose mechanism of action is not fully understood. The topical application of monobenzone in animals, increases the excretion of melanin from the melanocytes. The same action is thought to be responsible for the depigmenting effect of the drug in humans. Monobenzone may cause destruction of melanocytes and permanent depigmentation. This effect is erratic and may take one to four months to occur while existing melanin is lost with normal sloughing of the stratum corneum. Hyperpigmented skin appears to fade more rapidly than does normal skin, and exposure to sunlight reduces the depigmenting effect of the drug. The histology of the skin after depigmentation with topical monobenzone is the same as that seen in vitiligo; the epidermis is normal except for the absence of identifiable melanocytes. INDICATIONS AND USAGE: Benoquin Cream 20% is indicated for final depigmentation in extensive Vitiligo. Benoquin Cream 20% is applied topically to permanently depigment normal skin surrounding vitiliginous lesions in patients with disseminated (greater than 50 percent of body surface area) idiopathic vitiligo. Benoquin Cream 20% is not recommended in freckling; hyperpigmentation caused by photosensitization following the use of certain perfumes (berlock dermatitis); melasma (chloasma) of pregnancy; or hyperpigmentation resulting from inflammation of the skin. Benoquin Cream 20% is not effective for the treatment of cafe-au-lait spots, pigmented nevi, malignant melanoma or pigmentation resulting from pigments other than melanin (e.g.: bile, silver, or artificial pigments). CONTRAINDICATIONS: Benoquin Cream 20% contains a potent depigmenting agent and is not a cosmetic skin bleach. Use of Benoquin Cream 20% is contraindicated in any conditions other than disseminated vitiligo. Benoquin Cream 20% frequently produces irreversible depigmentation, and it must not be used as a substitute for hydroquinone. Benoquin Cream 20% is also contraindicated in individuals with a history of sensitivity or allergic reactions to this product, or any of its ingredients. WARNINGS: Benoquin Cream 20% is a potent depigmenting agent, not a mild cosmetic bleach. Do not use except for final depigmentation in extensive vitiligo. 2393-05 EL Rev. 8-00 O OH This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Keep this, and all medications out of the reach of children. In case of accidental ingestion, call a physician or a Poison Control Center immediately. PRECAUTIONS (See Warnings): General. Benoquin Cream 20% is for External Use Only. Following therapy with Benoquin Cream 20%, the skin will be sensitive for the rest of the patient’s life. He/she must use sunscreens during exposure to the sun. Information for the Patient. Benoquin Cream 20% contains a potent depigmenting agent and is not a cosmetic skin bleach. Use of Benoquin Cream 20% is contraindicated in any conditions other than disseminated vitiligo. Use only for final depigmentation in extensive vitiligo. Areas of normal skin distant to the site of Benoquin Cream 20% application may become depigmented, and irregular, excessive, unsightly, and frequently permanent depigmentation may occur. Carcinogenesis, mutagenesis, impairment of fertility. No long term studies have been performed to evaluate carcinogenic potential. Pregnancy: Category C. Animal reproduction studies have not been conducted with Benoquin Cream 20%. It is also not known whether Benoquin Cream 20% can cause fetal harm when administered to a pregnant woman, or can affect reproduction capacity. Benoquin Cream 20% should be given to a pregnant woman only if clearly needed. Nursing Mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Benoquin Cream 20% is administered to a nursing woman. Pediatric Use. The safety and effectiveness of Benoquin Cream 20% in pediatric patients below the age of 12 years have not been established. ADVERSE REACTIONS: Mild, transient skin irritation and sensitization, including erythematous and eczematous reactions have occurred following topical application of Benoquin Cream 20%. Although those reactions are usually transient, treatment with Benoquin Cream 20% should be discontinued if irritation, a burning sensation, or dermatitis occur. Areas of normal skin distant to the site of Benoquin Cream 20% application frequently have become depigmented, and irregular, excessive, unsightly, and frequently permanent depigmentation has occurred. DOSAGE AND ADMINISTRATION: A thin layer of Benoquin Cream 20% should be applied and rubbed into the pigmented area two or three times daily, or as directed by physician. Prolonged exposure to sunlight should be avoided during treatment with Benoquin Cream 20%, or a sunscreen should be used. Depigmentation is usually accomplished after one to four months of Benoquin Cream 20% treatment. If satisfactory results are not obtained after four months of Benoquin Cream 20% treatment, the drug should be discontinued. When the desired degree of depigmentation is obtained, Benoquin Cream 20% should be applied only as often as needed to maintain depigmentation (usually only two times weekly). HOW SUPPLIED: Benoquin Cream 20% in 1 1/4 oz. tubes (35.4 g) (NDC 0187-0380-34). Benoquin Cream 20% should be stored at 25°C (77°F); excursion permitted to 15°C - 30°C (59°F - 86°F). ICN Pharmaceuticals, Inc. 3300 Hyland Ave. Costa Mesa, CA 92626 (714)545-0100 2393-05 EL Rev. 8-00 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:36.647736	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/08173slr015_benoquin_lbl.pdf', 'application_number': 8173, 'submission_type': 'SUPPL ', 'submission_number': 15}
10,697	Apresoline hydrochloride(ß Apresoline(ß hydrochloride hydralazine hydrochloride USP Tablets Prescribing Information DESCRIPTION - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - _. ~.. - _. - _. - - - - - - - - - - - - - - - - - - - - - - - _. - - - - -. - -. - - - - - - - - - - -- # Strength Form 1 10: 1 TABLET, COATED (C42897) TABLET, COATED (C42897) TABLET, COATED (C42897) 4 100: 1 TABLET, Acacia, FD&C Yellow No.5, FD&C Yellow No.6, lactose, magnesium stearate, COATED mannitol, polyethylene glycol, sodium starch glycolate, starch, stearic acid _ _ _ _ _ _ _ _ _ _ _ _ ~C_~~J!2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ___ Proprietary name: Established name: Route of administration: Active ingredients (moiety): 2 25: 1 3 50: 1 Apresoline hydrochloride hydralazine hydrochloride ORAL (C38288) hydralazine hydrochloride (hydralazine) Inactive ingredients Acacia, D&C Yellow No. 10, lactose, magnesium stearate, mannitol, polyethylene glycol, sodium starch glycolate, starch, stearic acid Acacia, FD&C Blue No.1, lactose, magnesium stearate, mannitol, polyethylene glycol, sodium starch glycolate, starch, stearic acid Acacia, FD&C Blue No.1, lactose, magnesium stearate, mannitol, polyethylene glycol, sodium starch glycolate, starch, stearic acid Apresoline, hydralazine hydrochloride USP, is an antihypertensive, available as 10-, 25-, 50-, and 1 OO-mg tablets for oral administration. Its chemical name is 1-hydrazinophthalazine monohydrochloride, and its structural formula is: NHNH2 /' ./~ r~J..'.~O....... l '~N . HGI Hydralazine hydrochloride USP is a white to off-white, odorless crystalline powder. It is soluble in water, slightly soluble in alcohol, and very slightly soluble in ether. It melts at about 275°C, with decomposition, and has a molecular weight of 196.64. Inactive Ingredients. Acacia, D&C Yellow NO.1 0 (1 O-mg tablets), FD&C Blue NO.1 (25-mg and 50-mg tablets), FD&C Yellow No.5 and FD&C Yellow NO.6 (100-mg tablets), lactose, magnesium stearate, mannitol, polyethylene glycol, sodium starch glycolate, starch, and stearic acid. CLINICAL PHARMACOLOGY Although the precise mechanism of action of hydralazine is not fully understood, the major effects are on the cardiovascularsystem. Hydralazine apparently lowers blood pressure by exerting a peripheral vasodilating effect through a direct relaxation of vascular smooth muscle. Hydralazine, by altering cellular calcium metabolism, interferes with the calcium movements within the vascular smooth muscle that are responsible for initiating or maintaining the contractile state. The peripheral vasodilating effect of hydralazine results in decreased arterial blood pressure (diastolic more than systolic); decreased peripheral vascular resistance; and an increased heart rate, stroke volume, and cardiac output. The preferential dilatation of arterioles, as compared to veins, minimizes postural hypotension and promotes the increase in cardiac output. Hydralazine usually increases renin activity in plasma, presumably as a result of increased secretion of renin by the renal juxtaglomerular cells in response to reflex sympathetic discharge. This increase in renin activity leads to the production of angiotensin II, which then causes stimulation of aldosterone and consequent sodium reabsorption. Hydralazine also maintains or increases renal and cerebral blood flow. Hydralazine is rapidly absorbed after oral administration, and peak plasma levels are reached at 1-2 hours. Plasma levels of apparent hydralazine decline with a half-life of 3-7 hours. Binding to human plasma protein is 87% Plasma levels of hydralazine vary widely among individuals. Hydralazine is subject to polymorphic acetylation; slow acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain colilrölolölöoa pressure. Hydralazine undergoes extensive hepatic metabolism; it is excreted mainly in the form of metabolites in the urine. INDICATIONS AND USAGE Essential hypertension, alone or as an adjunct. CONTRAINDICATIONS Hypersensitivity to hydralazine; coronary artery disease; mitral valvular rheumatic heart disease. WARNINGS In a few patients hydralazine may produce a clinical picture simulating systemic lupus erythematosus including glomerulonephritis. In such patients hydralazine should be discontinued unless the benefit-to-risk determination requires continued antihypertensive therapy with this drug. Symptoms and signs usually regress when the drug is discontinued but residua have been detected many years later. Long-term treatment with steroids may be necessary. (See PRECAUTIONS, Laboratory Tests.) PRECAUTIONS General Myocardial stimulation produced by Apresoline can cause anginal attacks and ECG changes of myocardial ischemia. The drug has been implicated in the production of myocardial infarction. It must, therefore, be used with caution in patients with suspected coronary artery disease. The "hyperdynamic" circulation caused by Apresoline may accentuate specific cardiovascular inadequacies. For example, Apresoline may increase pulmonary artery pressure in patients with mitral valvular disease. The drug may reduce the pressor responses to epinephrine. Postural hypotension may result from Apresoline but is less common than with ganglionic blocking agents. It should be used with caution in patients with cerebral vascular accidents In hypertensive patients with normal kidneys who are treated with Apresoline, there is evidence of increased renal blood flow and a maintenance of glomerular filtration rate. In some instances where control values were below normal, improved renal function has been noted after administration of Apresoline. However, as with any antihypertensive agent, Apresoline should be used with caution in patients with advanced renal damage. Peripheral neuritis, evidenced by paresthesia, numbness, and tingling, has been observed. Published evidence suggests an antipyridoxine effect, and that pyridoxine should be added to the regimen if symptoms develop. The Apresoline tablets (100 mg) contain FD&C Yellow NO.5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow NO.5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who are also hypersensitive to aspirin. I Information For Patient Patients should be informed of possible side effects and advised to take the medication regularly and continuously as directed. Laboratory Tests Complete blood counts and antinuclear antibody titer determinations are indicated before and periodically during prolonged therapy with hydralazine even though the patient is asymptomatic. These studies are also indicated if the patient develops arthralgia, fever, chest pain, continued malaise, or other unexplained signs or symptoms. A positive antinuclear antibody titer requires that the physician carefully weigh the implications of the test results against. the benefits to be derived from antihypertensive therapy with hydralazine. Blood dyscrasias, consisting of reduction in hemoglobin and red cell count, leukopenia, agranulocytosis, and purpura have been reported. If such abnormalities develop, therapy should be discontinued. Drug/Drug Interactions MAO inhibitors should be used with caution in patients receiving hydralazine. When other potent parenteral antihypertensive drugs, such as diazoxide, are used in combination with hydralazine, patients should be continuously observed for several hours for any excessive fall in blood pressure. Profound hypotensive episodes may occur when diazoxide injection and Apresoline are used concomitantly. Drug/Food Interactions Administration of hydralazine with food results in higher plasma levels. Carcinogenesis, Mutagenesis, Impairment Of Fertility In a lifetime study in Swiss albino mice, there was a statistically significant increase in the incidence of lung tumors (adenomas and adenocarcinomas) of both male and female mice given hydralazine continuously in their drinking water at a dosage of about 250 mg/kg per day (about 80 times the maximum recommended human dose). In a 2-year carcinogenicity study of rats given hydralazine by gavage at dose levels of 15, 30, and 60 mg/kg/day (approximately 5 to 20 times the recommended human daily dosage), microscopic examination of the liver revealed a small, but statistically significant, increase in benign neoplastic nodules in male and female rats from the high-dose group and in female rats from the intermediate-dose group. Benign interstitial cell tumors of the testes were also significantly increased in male rats from the high-dose group. The tumors observed are common in aged rats and a significantly increased incidence was not observed until 18 months of treatment, Hydralazine was shown to be mutagenic in bacterial systems (Gene Mutation and DNA Repair) and in one of two rat and one rabbit hepatocyte in vitro DNA repair studies. Additional in vivo and in vitro studies using lymphoma cells, germinal cells, and fibroblasts from mice, bone marrow cells from Chinese hamsters and fibroblasts from human cell lines did not demonstrate any mutagenic potential for hydralazine. The extent to which these findings indicate a risk to man is uncertain. While long-term clinical observation has not suggested that human cancer is associated with hydralazine use, epidemiologic studies have so far been insufficient to arrive at any conclusions. Pregnancy Category C Animal studies indicate that hydralazine is teratogenic in mice at 20-30 times the maximum daily human dose of 200-300 mg and possibly in rabbits at 10- 15 times the maximum daily human dose, but that it is nonteratogenic in rats. Teratogenic effects observed were cleft palate and malformations of facial and cranial bones. There are no adequate and well-controlled studies in pregnant women. Although clinical experience does not include any positive evidence of adverse effects on the human fetus, hydralazine should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus. Nursing Mothers Hydralazine has been shown to be excreted in breast milk. Pediatric Use Safety and effectiveness in pediatric patients have not been established in controlled clinical trials, although there is experience with the use of Apresoline in these patients. The usual recommended oral starting dosagé is 0.75 mg/kg of body weight daily in four divided doses. Dosage may be increased gradually over the next 3-4 weeks to a maximum of 7.5 mg/kg or 200 mg daily. ADVERSE REACTIONS Adverse reactions with Apresoline are usually reversible when dosage is reduced. However, in some cases it may be necessary to discontinue the drug. The following adverse reactions have been observed, but there has not been enough systematic collection of data to support an estimate of their frequency. Common Headache, anorexia, nausea, vomiting, diarrhea, palpitations, tachycardia, angina pectoris. Less Frequent Digestive: Constipation, Paralytic Ileus. Cardiovascular. Hypotension, Paradoxical Pressor Response, Edema.. Respiratory Dyspnea. Neurologic. Peripheral Neuritis Evidenced By Paresthesia, Numbness, And Tingling, Dizziness: Tremors; Muscle Cramps; Psychotic Reactions . Characterized By Depression, Disorientation, Or Anxiety. Genitourinary: Difficulty In Urination. Hematologic: Blood Dyscrasias, Consisting Of Reduction In Hemoglobin And Red Cell Count, Leukopenia, Agranulocytosis, Purpura, Lymphadenopathy; Splenomegaly. Hypersensitive Reactions: Rash, Urticaria, Pruritus, Fever, Chils, Arthralgia, Eosinophila, And, Rarely, Hepatitis. Other: Nasal Congestion, Flushing, Lacrimation, Conjunctivitis. OVERDOSAGE Acute Toxicity No deaths due to acute poisoning have been reported. Highest known dose survived: adults, 10g orally. Oral LD50 in rats: 173 and 187 mg/kg. Signs And Symptoms Signs and symptoms of overdosage include hypotension, tachycardia, head- ache, and generalized skin flushing. Complications can include myocardial ischemia and subsequent myocardial infarction, cardiac arrhythmia, and profound shock. Treatment There is no specific antidote. The gastric contents should be evacuated, taking adequate precautions against aspiration and for protection of the airway. An activated charcoal slurry may be instilled if conditions permit. These manipulations may have to be omitted or carried out after cardiovascular status has been stabilized, since they might precipitate cardiac arrhythmias or increase the depth of shock. Support of the cardiovascular system is of primary importance. Shock should be treated with plasma expanders. If possible, vasopressors should not be given, but if a vasopressor is required, care should be taken not to precipitate or aggravate cardiac arrhythmia. Tachycardia responds to beta blockers. Digitalization may be necessary, and renal function should be monitored and supported as required. No experience has been reported with extracorporeal or peritoneal dialysis. DOSAGE AND ADMINISTRATION Initiate therapy in gradually increasing dosages; adjust according to individual response. Start with 10 mg four times daily for the first 2-4 days, increase to 25 mg four times daily for the balance of the first week. For the second and subsequent weeks, increase dosage to 50 mg four times daily. For maintenance, adjust dosage to the lowest effective levels. The incidence of toxic reactions, particularly the L.E. cell syndrome, is high in the group of patients receiving large doses of Apresoline. In a few resistant patients, up to 300 mg of Apresoline daily may be required for a significant antihypertensive effect. In such cases, a lower dosage of Apresoline combined with a thiazide and/or reserpine or a beta blocker may be considered. However, when combining therapy, individual titration is essential to ensure the lowest possible therapeutic dose of each drug. HOW SUPPLIED - - - - - - - - - - - - - - - - - - -. - - -. - - - - - - - - - - - - - - - - - - - - _. _. - - -- - - - - - - - - - - - - - - - -- - - - - - - - _. - - - - - - - - - -- -- # Name Strength Dosage Form Appearance Package Type Package NDC Qty 1 Apresoline 10: 1 TABLET, COATED BOTTLE 100: 1 0083-. hydrochloride (C42897) (C43169) 0037-30 2 Apresoline 25: 1 TABLET, COATED BOTTLE 100: 1 0083- hydrochloride (C42897) (C43169) 0039-30 3 Apresoline 50: 1 TABLET, COATED BOTTLE 100: 1 0083- hydrochloride (C42897) (C43169) 0073-30 4 Apresoline 100: 1 TABLET, COATED BOTTLE 100: 1 0083- _ _ _ ~J3~~~~~~~: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ~~~~~~7) _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ~~~~~ ~~ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _~~OJ~~~ _ __ Tab/ets 10 mg - round, pale yellow, dry-coated (imprinted CIBA 37) Bottes of 100 ........................... N DC 0083-0037-30 Tablets 25 mg - round, deep blue, dry-coated (imprinted CIBA 39) Bottes of 100 ............;.............. N DC 0083-0039-30 Tablets 50 mg - round, light blue, dry-coated (imprinted CIBA 73) Bottles of 100 ........................... N DC 0083-0073-30 Tablets 100 mg - round, peach, dry-coated (imprinted CIBA 101) Bottles of 100 ........................... N DC 0083-0101-30 Samples, when available, are identified by the word SAMPLE appearing on each tablet. Do not store above 86°F (30 C). Dispense in tight, light-resistant container (USP). 666692 CI BA Ciba-Geigy Corporation C95-14 (Rev. 5/95) Pharmaceuticals Division Summit, New Jersey 07901	custom-source	2025-02-12T13:43:36.690966	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/1996/008303s068lbl.pdf', 'application_number': 8303, 'submission_type': 'SUPPL ', 'submission_number': 68}
10,695	_______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BENTYL safely and effectively. See full prescribing information for BENTYL. BENTYL (dicyclomine hydrochloride) capsules, for oral use BENTYL (dicyclomine hydrochloride) tablets, for oral use BENTYL (dicyclomine hydrochloride) oral syrup BENTYL (dicyclomine hydrochloride) injection, for intramuscular use Initial U.S. Approval: 1950 ----------------------------INDICATIONS AND USAGE--------------------------- BENTYL is an antispasmodic and anticholinergic (antimuscarinic) agent indicated for the treatment of functional bowel/irritable bowel syndrome (1) ----------------------DOSAGE AND ADMINISTRATION----------------------- Dosage for BENTYL must be adjusted to individual patient needs (2). If a dose is missed, patients should continue the normal dosing schedule (2). Oral in adults (2.1): • Starting dose: 20 mg four times a day. After a week treatment with the starting dose, the dose may be escalated to 40 mg four times a day, unless side effects limit dosage escalation • Discontinue BENTYL if efficacy not achieved or side effects require doses less than 80 mg per day after two weeks of treatment Intramuscular in adults (2.2): • Intramuscular administration recommended no longer than 1 or 2 days when patients cannot take oral administration • Recommended dose: 10 mg to 20 mg four times a day ---------------------DOSAGE FORMS AND STRENGTHS---------------------- • BENTYL capsules 10 mg (3) • BENTYL syrup 10 mg/5 mL (3) • BENTYL tablets 20 mg (3) • BENTYL injection 20 mg/2 mL (10 mg/mL) (3) ------------------------------- CONTRAINDICATIONS----------------------------- • Infants less than 6 months of age (4) • Glaucoma (4) • Nursing mothers (4) • Obstructive uropathy (4) • Unstable cardiovascular status in • Obstructive disease of the acute hemorrhage (4) gastrointestinal tract (4) • Myasthenia gravis (4) • Severe ulcerative colitis (4) • Reflux esophagitis (4) -----------------------WARNINGS AND PRECAUTIONS----------------------- • For Intramuscular injection only; should not be administered by any other route. Intravenous injection may result in thrombosis or thrombophlebitis and injection site reactions (5.1) • Cardiovascular conditions: worsening of conditions (5.2) • Peripheral and central nervous system: heat prostration can occur with drug use (fever and heat stroke due to decreased sweating); drug should be discontinued and supportive measures instituted (5.3) • Psychosis in patients sensitive to anticholinergic drugs: signs and symptoms resolve within 12 to 24 hours after discontinuation of BENTYL (5.3) • Myasthenia Gravis: overdose may lead to muscular weakness and paralysis. BENTYL should be given to patients with myasthenia gravis only to reduce adverse muscarinic effects of an anticholinesterase (5.4) • Incomplete intestinal obstruction: diarrhea may be an early symptom especially in patients with ileostomy or colostomy. Treatment with BENTYL would be inappropriate and possibly fatal (5.5) • Salmonella dysenteric patients: due to risk of toxic megacolon (5.6) • Ulcerative colitis: BENTYL should be used with caution in these patients; large doses may suppress intestinal motility or aggravate the serious complications of toxic megacolon (5.7) • Prostatic hypertrophy: BENTYL should be used with caution in these patients; may lead to urinary retention (5.8) • Hepatic and renal disease: should be used with caution (5.9) • Geriatric: use with caution in elderly who may be more susceptible to BENTYL’s adverse events (5.10) ------------------------------ADVERSE REACTIONS------------------------------- The most serious adverse reactions include cardiovascular and central nervous system symptoms. The most common adverse reactions (> 5% of patients) are dizziness, dry mouth, vision blurred, nausea, somnolence, asthenia and nervousness (6) To report SUSPECTED ADVERSE REACTIONS, contact AXCAN Pharma US, Inc. at 1-800-472-2634 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------ • Antiglaucoma agents: anticholinergics antagonize antiglaucoma agents and may increase intraoccular pressure (7) • Anticholinergic agents: may affect the gastrointestinal absorption of various drugs; may also increase certain actions or side effects of other anticholinergic drugs (7) • Antacids: interfere with the absorption of anticholinergic agents (7) -----------------------USE IN SPECIFIC POPULATIONS----------------------- • Pregnancy: use only if clearly needed (8.1) • Pediatric Use: Safety and effectiveness not established (8.4) • Hepatic and renal impairment: caution must be taken with patients with significantly impaired hepatic and renal function (8.6) See 17 for PATIENT COUNSELING INFORMATION. Revised: 07/2011 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Oral Dosage and Administration in Adults 2.2 Intramuscular Dosage and Administration in Adults 2.3 Preparation for Intramuscular Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Inadvertent Intravenous Administration 5.2 Cardiovascular Conditions 5.3 Peripheral and Central Nervous System 5.4 Myasthenia Gravis 5.5 Intestinal Obstruction 5.6 Toxic Dilatation of Intestinemegacolon 5.7 Ulcerative Colitis 5.8 Prostatic Hypertrophy 5.9 Hepatic and Renal Disease 5.10 Geriatric Population 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 6.3 Adverse Reactions Reported with Similar Drugs with Anticholinergic/Antispasmodic Action 7 DRUG INTERACTIONS 7.1 Antiglaucoma Agents 7.2 Other Drugs with Anticholinergic Activity 7.3 Other Gastrointestinal Motility Drugs 7.4 Effect of Antacids 7.5 Effect on Absorption of Other Drugs 7.6 Effect on Gastric Acid Secretion 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Inadvertent Intravenous Administration 17.2 Use in Infants 17.3 Use in Nursing Mothers 17.4 Peripheral and Central Nervous System *Sections or subsections omitted from the full prescribing information are not listed Reference ID: 2981284 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE BENTYL® (dicyclomine hydrochloride ) is indicated for the treatment of patients with functional bowel/irritable bowel syndrome. 2 DOSAGE AND ADMINISTRATION Dosage must be adjusted to individual patient needs. 2.1 Oral Dosage and Administration in Adults The recommended initial dose is 20 mg four times a day. After one week treatment with the initial dose, the dose may be increased to 40 mg four times a day unless side effects limit dosage escalation. If efficacy is not achieved within 2 weeks or side effects require doses below 80 mg per day, the drug should be discontinued. Documented safety data are not available for doses above 80 mg daily for periods longer than 2 weeks. 2.2 Intramuscular Dosage and Administration in Adults BENTYL Intramuscular Injection must be administered via intramuscular route only. Do not administer by any other route. The recommended intramuscular dose is 10mg to 20 mg four times a day [see Clinical Pharmacology (12)]. The intramuscular injection is to be used only for 1 or 2 days when the patient cannot take oral medication. Intramuscular injection is about twice as bioavailable as oral dosage forms. 2.3 Preparation for Intramuscular Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Aspirate the syringe before injecting to avoid intravascular injection, since thrombosis may occur if the drug is inadvertently injected intravascularly. 3 DOSAGE FORMS AND STRENGTHS • BENTYL 10 mg capsules: blue, imprinted BENTYL 10 • BENTYL 20 mg tablets: compressed, light blue, round, debossed BENTYL 20 • BENTYL syrup 10mg/5ml • BENTYL injection 20mg/2ml (10mg/ml) 4 CONTRAINDICATIONS BENTYL is contraindicated in infants less than 6 months of age [see Use in Specific Populations (8.4)], nursing mothers [see Use in Specific Populations (8.3)], and in patients with: • unstable cardiovascular status in acute hemorrhage • myasthenia gravis [see Warnings and Precautions (5.4)] • glaucoma [see Adverse Reactions (6.3) and Drug Interactions (7.1)] • obstructive uropathy [see Warnings and Precautions (5.8)] • obstructive disease of the gastrointestinal tract [see Warnings and Precautions (5.5)] • severe ulcerative colitis [see Warnings and Precautions (5.7)] • reflux esophagitis 5 WARNINGS AND PRECAUTIONS 5.1 Inadvertent Intravenous Administration BENTYL solution is for intramuscular administration only. Do not administer by any other route. Inadvertent intravenous administration may result in thrombosis, thrombophlebitis, and injection site reactions such as pain, edema, skin color change, and reflux sympathetic dystrophy syndrome [see Adverse Reactions (6.2)]. 5.2 Cardiovascular Conditions Dicyclomine hydrochloride needs to be used with caution in conditions characterized by tachyarrhythmia such as thyrotoxicosis, congestive heart failure and in cardiac surgery, where they may further accelerate the heart rate. Investigate any tachycardia before administration of dicyclomine hydrochloride. Care is required in patients with coronary heart disease, as ischemia and infarction may be worsened, and in patients with hypertension [see Adverse Reactions (6.3)]. 5.3 Peripheral and Central Nervous System The peripheral effects of dicyclomine hydrochloride are a consequence of their inhibitory effect on muscarinic receptors of the autonomic nervous system. They include dryness of the mouth with difficulty in swallowing and talking, thirst, reduced bronchial secretions, dilatation of the pupils (mydriasis) with loss of accommodation (cycloplegia) and photophobia, flushing and dryness of the skin, transient bradycardia followed by tachycardia, with palpitations and arrhythmias, and difficulty in micturition, as well as reduction in the tone and motility of the gastrointestinal tract leading to constipation [see Adverse Reactions (6)]. In the presence of high environmental temperature heat prostration can occur with drug use (fever and heat stroke due to decreased sweating). It should also be used cautiously in patients with fever. If symptoms occur, the drug should be discontinued and supportive measures instituted. Because of the inhibitory effect on muscarinic receptors within the autonomic nervous system, caution should be taken in patients with autonomic neuropathy. Central nervous system (CNS) signs and symptoms include confusion, disorientation, short-term amnesia, hallucinations, dysarthria, ataxia, coma, euphoria, fatigue, insomnia, agitation and mannerisms, and inappropriate affect. Psychosis has been reported in sensitive individuals given anticholinergic drugs. These CNS signs and symptoms usually resolve within 12 to 24 hours after discontinuation of the drug. BENTYL may produce drowsiness, dizziness or blurred vision. The patient should be warned not to engage in activities requiring mental alertness, such as operating a motor vehicle or other machinery or performing hazardous work while taking BENTYL. 5.4 Myasthenia Gravis With overdosage, a curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). It should not be given to patients with myasthenia gravis except to reduce adverse muscarinic effects of an anticholinesterase [see Contraindications (4)]. 5.5 Intestinal Obstruction Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance, treatment with this drug would be inappropriate and possibly harmful [see Contraindications (4)]. Rarely development of Ogilvie’s syndrome (colonic pseudo- obstruction) has been reported. Ogilvie’s syndrome is a clinical disorder with signs, symptoms, and radiographic appearance of an acute large bowel obstruction but with no evidence of distal colonic obstruction 5.6 Toxic Dilatation of Intestinemegacolon Toxic dilatation of intestine and intestinal perforation is possible when anticholinergic agents are administered in patients with Salmonella dysentery. 5.7 Ulcerative Colitis Caution should be taken in patients with ulcerative colitis. Large doses may suppress intestinal motility to the point of producing a paralytic ileus and the use of this drug may precipitate or aggravate the serious complication of toxic megacolon [see Adverse Reactions (6.3)]. BENTYL is contraindicated in patients with severe ulcerative colitis [see Contraindications (4)]. Reference ID: 2981284 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.8 Prostatic Hypertrophy BENTYL should be used with caution in patients with known or suspected prostatic enlargement, in whom prostatic enlargement may lead to urinary retention [see Adverse Reactions (6.3)]. 5.9 Hepatic and Renal Disease BENTYL should be used with caution in patients with known hepatic and renal impairment. 5.10 Geriatric Population Dicyclomine hydrochloride should be used with caution in elderly who may be more susceptible to its adverse effects. 6 ADVERSE REACTIONS The pattern of adverse effects seen with dicylomine is mostly related to its pharmacological actions at muscarinic receptors [see Clinical Pharmacology (12)]. They are a consequence of the inhibitory effect on muscarinic receptors within the autonomic nervous system. These effects are dose-related and are usually reversible when treatment is discontinued. The most serious adverse reactions reported with dicyclomine hydrochloride include cardiovascular and central nervous system symptoms [see Warnings and Precautions (5.2, 5.3)]. 6.3 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure in controlled clinical trials involving over 100 patients treated for functional bowel/irritable bowel syndrome with dicyclomine hydrochloride at initial doses of 160 mg daily (40 mg four times a day) In these trials most of the side effects were typically anticholinergic in nature and were reported by 61% of the patients. Table 1 presents adverse reactions (MedDRA 13.0 preferred terms) by decreasing order of frequency in a side-by-side comparison with placebo. Table 1: Adverse reactions experienced in controlled clinical trials with decreasing order of frequency MedDRA Preferred Term Dicyclomine Hydrochloride (40 mg four times a day) % Placebo % Dry Mouth 33 5 Dizziness 40 5 Vision blurred 27 2 Nausea 14 6 Somnolence 9 1 Asthenia 7 1 Nervousness 6 2 Nine percent (9%) of patients were discontinued from BENTYL because of one or more of these side effects (compared with 2% in the placebo group). In 41% of the patients with side effects, side effects disappeared or were tolerated at the 160 mg daily dose without reduction. A dose reduction from 160 mg daily to an average daily dose of 90 mg was required in 46% of the patients with side effects who then continued to experience a favorable clinical response; their side effects either disappeared or were tolerated. 6.4 Postmarketing Experience The following adverse reactions, presented by system organ class in alphabetical order, have been identified during post approval use of BENTYL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Cardiac disorders: palpitations, tachyarrhythmias • Eye disorders: cycloplegia, mydriasis, vision blurred • Gastrointestinal disorders: abdominal distension, abdominal pain, constipation, dry mouth, dyspepsia, nausea, vomiting • General disorders and administration site conditions: fatigue, malaise • Immune System Disorders: drug hypersensitivity including face oedema, angioedema, anaphylactic shock • Nervous system disorders: dizziness, headache, hallucinations insomnia, somnolence, syncope • Psychiatric disorders: confusional state, nervousness • Reproductive system and breast disorders: suppressed lactation • Respiratory, thoracic and mediastinal disorders: dyspnoea, nasal congestion • Skin and subcutaneous tissue disorder: dermatitis allergic, erythema, rash 6.5 Adverse Reactions Reported with Similar Drugs with Anticholinergic/Antispasmodic Action Gastrointestinal: anorexia, Central Nervous System: tingling, numbness, dyskinesia, speech disturbance, insomnia Peripheral Nervous System: With overdosage, a curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). Ophthalmologic: diplopia, increased ocular tension Dermatologic/Allergic: urticaria, itching, and other dermal manifestations; Genitourinary: urinary hesitancy, urinary retention in patients with prostatic hypertrophy Cardiovascular: hypertension Respiratory: apnea Other: decreased sweating,sneezing, throat congestion, impotence. With the injectable form, there may be temporary sensation of light-headedness. Some local irritation and focal coagulation necrosis may occur following the intramuscular injection of BENTYL. 7 DRUG INTERACTIONS 7.3 Antiglaucoma Agents Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Use of BENTYL in patients with glaucoma is not recommended [see Contraindications (4)]. 7.4 Other Drugs with Anticholinergic Activity The following agents may increase certain actions or side effects of anticholinergic drugs including BENTYL: amantadine, antiarrhythmic agents of Class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. 7.5 Other Gastrointestinal Motility Drugs Interaction with other gastrointestinal motility drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. 7.6 Effect of Antacids Because antacids may interfere with the absorption of anticholinergic agents including BENTYL, simultaneous use of these drugs should be avoided. 7.7 Effect on Absorption of Other Drugs Anticholinergic agents may affect gastrointestinal absorption of various drugs by affecting on gastrointestinal motility, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentration may result. 7.8 Effect on Gastric Acid Secretion The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. Reference ID: 2981284 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B Adequate and well-controlled studies have not been conducted with BENTYL in pregnant women at the recommended doses of 80 to 160 mg/day. However, epidemiologic studies did not show an increased risk of structural malformations among babies born to women who took products containing dicyclomine hydrochloride at doses up to 40 mg/day during the first trimester of pregnancy. Reproduction studies have been performed in rats and rabbits at doses up to 33 times the maximum recommended human dose based on 160 mg/day (3 mg/kg) and have revealed no evidence of harm to the fetus due to dicyclomine. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers BENTYL is contraindicated in women who are human milk feeding. Dicyclomine hydrochloride is excreted in human milk. Because of the potential for serious adverse reactions in human milk- fed infants from BENTYL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother [see Use in Specific Populations (8.4)]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. BENTYL is contraindicated in infants less than 6 months of age [see Contraindications (4)]. There are published cases reporting that the administration of dicyclomine hydrochloride syrup to infants has been followed by serious respiratory symptoms (dyspnea, shortness of breath, breathlessness, respiratory collapse, apnea and asphyxia), seizures, syncope, pulse rate fluctuations, muscular hypotonia, and coma, and death, however; no causal relationship has been established. 8.5 Geriatric Use Clinical studies of BENTYL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range in adults, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Renal Impairment Effects of renal impairment on PK, safety and efficacy of BENTYL have not been studied. BENTYL drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. BENTYL should be administered with caution in patients with renal impairment. 8.7 Hepatic Impairment Effects of renal impairment on PK, safety and efficacy of BENTYL have not been studied. BENTYL should be administered with caution in patients with hepatic impairment. 10 OVERDOSAGE In case of an overdose, patients should contact a physician, poison control center (1-800-222-1222), or emergency room. The signs and symptoms of overdosage include: headache; nausea; vomiting; blurred vision; dilated pupils; hot, dry skin; dizziness; dryness of the mouth; difficulty in swallowing; and CNS stimulation including convulsion. A curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). One reported event included a 37-year-old who reported numbness on the left side, cold fingertips, blurred vision, abdominal and flank pain, decreased appetite, dry mouth, and nervousness following ingestion of 320 mg daily (four 20 mg tablets four times daily). These events resolved after discontinuing the dicyclomine. The acute oral LD50 of the drug is 625 mg/kg in mice. The amount of drug in a single dose that is ordinarily associated with symptoms of overdosage or that is likely to be life- threatening, has not been defined. The maximum human oral dose recorded was 600 mg by mouth in a 10-month-old child and approximately 1500 mg in an adult, each of whom survived. In three of the infants who died following administration of dicyclomine hydrochloride [see Warnings and Precautions (5.1)], the blood concentrations of drug were 200, 220, and 505 ng/mL. It is not known if BENTYL is dialyzable. Treatment should consist of gastric lavage, emetics, and activated charcoal. Sedatives (e.g., short-acting barbiturates, benzodiazepines) may be used for management of overt signs of excitement. If indicated, an appropriate parenteral cholinergic agent may be used as an antidote. 11 DESCRIPTION BENTYL is an antispasmodic and anticholinergic (antimuscarinic) agent available in the following dosage forms: • BENTYL capsules for oral use contain 10 mg dicyclomine hydrochloride USP. BENTYL 10 mg capsules also contain inactive ingredients: calcium sulfate, corn starch, FD&C Blue No. 1, FD&C Red No. 40, gelatin, lactose, magnesium stearate, pregelatinized corn starch, and titanium dioxide. • BENTYL tablets for oral use contain 20 mg dicyclomine hydrochloride USP. BENTYL 20 mg tablets also contain inactive ingredients: acacia, dibasic calcium phosphate, corn starch, FD&C Blue No. 1, lactose, magnesium stearate, pregelatinized corn starch, and sucrose. • BENTYL syrup for oral use contains 10 mg dicyclomine hydrochloride USP in each 5 mL (1 teaspoonful). BENTYL syrup also contains inactive ingredients: citric acid, D&C Red No. 33, FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6, flavors, glucose, methylparaben, propylene glycol, propylparaben, saccharin sodium, and water. • BENTYL injection is a sterile, pyrogen-free, aqueous solution for intramuscular injection (NOT FOR INTRAVENOUS USE) supplied as an ampoule containing 20 mg/2 mL (10 mg/mL). Each mL contains 10 mg dicyclomine hydrochloride USP in sterile water for injection, made isotonic with sodium chloride. BENTYL (dicyclomine hydrochloride) is [bicyclohexyl]-1 carboxylic acid, 2-(diethylamino) ethyl ester, hydrochloride, with a molecular formula of C19H35NO2•HCl and the following structural formula: structural formulastructural formula O structural formula CH2 CH3 C O CH2 CH2 N structural formula . HCl CH2 CH3 structural formula Molecular weight: 345.95 Dicyclomine hydrochloride occurs as a fine, white, crystalline, practically odorless powder with a bitter taste. It is soluble in water, freely soluble in alcohol and chloroform, and very slightly soluble in ether. Reference ID: 2981284 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 CLINICAL PHARMACOLOGY 12.3 Mechanism of Action Dicyclomine relieves smooth muscle spasm of the gastrointestinal tract. Animal studies indicate that this action is achieved via a dual mechanism: • a specific anticholinergic effect (antimuscarinic) at the acetylcholine-receptor sites with approximately 1/8 the milligram potency of atropine (in vitro, guinea pig ileum); and • a direct effect upon smooth muscle (musculotropic) as evidenced by dicyclomine’s antagonism of bradykinin- and histamine-induced spasms of the isolated guinea pig ileum. Atropine did not affect responses to these two agonists. In vivo studies in cats and dogs showed dicyclomine to be equally potent against acetylcholine (ACh)- or barium chloride (BaCl2)-induced intestinal spasm while atropine was at least 200 times more potent against effects of ACh than BaCl2. Tests for mydriatic effects in mice showed that dicyclomine was approximately 1/500 as potent as atropine; antisialagogue tests in rabbits showed dicyclomine to be 1/300 as potent as atropine. 12.4 Pharmacodynamics BENTYL can inhibit the secretion of saliva and sweat, decrease gastrointestinal secretions and motility, cause drowsiness, dilate the pupils, increase heart rate, and depress motor function 12.5 Pharmacokinetics Absorption and Distribution In man, dicyclomine is rapidly absorbed after oral administration, reaching peak values within 60-90 minutes. Mean volume of distribution for a 20 mg oral dose is approximately 3.65 L/kg suggesting extensive distribution in tissues. Elimination The metabolism of dicyclomine was not studied The principal route of excretion is via the urine (79.5% of the dose). Excretion also occurs in the feces, but to a lesser extent (8.4%). Mean half-life of plasma elimination in one study was determined to be approximately 1.8 hours when plasma concentrations were measured for 9 hours after a single dose. In subsequent studies, plasma concentrations were followed for up to 24 hours after a single dose, showing a secondary phase of elimination with a somewhat longer half-life. 13 NONCLINICAL TOXICOLOGY 13.3 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of dicyclomine. In studies in rats at doses of up to 100 mg/kg/day, dicyclomine produced no deleterious effects on breeding, conception, or parturition. 14 CLINICAL STUDIES In controlled clinical trials involving over 100 patients who received drug, 82% of patients treated for functional bowel/irritable bowel syndrome with dicyclomine hydrochloride at initial doses of 160 mg daily (40 mg four times daily) demonstrated a favorable clinical response compared with 55% treated with placebo (p<0.05). 16 HOW SUPPLIED/STORAGE AND HANDLING BENTYL Capsules 10 mg blue capsules, imprinted BENTYL 10, supplied in bottles of 100. Store at room temperature, preferably below 86°F (30°C). NDC number: 58914-012-10. BENTYL Tablets 20 mg compressed, light blue, round tablets, debossed BENTYL 20, supplied in bottles of 100. To prevent fading, avoid exposure to direct sunlight. Store at room temperature, preferably below 86°F (30°C). NDC 58914-013-10. BENTYL Syrup 10 mg/5 mL pink syrup, supplied in 16 ounce bottles. Store at room temperature, preferably below 86°F (30°C). Protect from excessive heat. NDC 58914-015-16. BENTYL Injection 20 mg/2 mL (10 mg/mL) injection supplied in boxes of five 20 mg/2 mL ampules (10 mg/mL). Store at room temperature, preferably below 86°F (30°C). Protect from freezing. NDC 58914-080-52. 17 PATIENT COUNSELING INFORMATION 17.1 Inadvertent Intravenous Administration BENTYL Injection is for intramuscular administration only. Do not administer by any other route. Inadvertent administration may result in thrombosis or thrombophlebitis, and injection site such as pain, edema, skin color change and even reflex sympathetic dystrophy syndrome [see Adverse Reactions (6.2)]. 17.2 Use in Infants Inform parents and caregivers not to administer BENTYL in infants less than 6 months of age [see Use in Specific Populations (8.4) ]. 17.3 Use in Nursing Mothers Advise lactating women that BENTYL should not be used while human milk feeding their infants [see Use in Specific Populations (8.3,8.4)]. 17.4 Peripheral and Central Nervous System In the presence of a high environmental temperature, heat prostration can occur with BENTYL use (fever and heat stroke due to decreased sweating). If symptoms occur, the drug should be discontinued and a physician contacted. BENTYL may produce drowsiness or blurred vision. The patient should be warned not to engage in activities requiring mental alertness, such as operating a motor vehicle or other machinery or to perform hazardous work while taking BENTYL [see Warnings and Precautions (5.3)]. Manufactured for: Axcan Pharma US, Inc. 22 Inverness Center Parkway Suite 310 Birmingham, AL 35242 USA www.axcan.com BENTYL® is a registered trademark owned by Axcan Pharma Inc., an affiliated company of Axcan Pharma US, Inc. Reference ID: 2981284 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:36.746923	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/007961s028lbl.pdf', 'application_number': 7961, 'submission_type': 'SUPPL ', 'submission_number': 28}
10,700	PRIMAQUINE PHOSPHATE TABLETS, USP DESCRIPTION Primaquine phosphate is 8-[(4-Amino-1-methylbutyl) amino]-6-methoxyquinoline phosphate, a synthetic compound with potent antimalarial activity. Each tablet contains 26.3 mg of primaquine phosphate (equivalent to 15 mg of primaquine base). The dosage is customarily expressed in terms of the base. Inactive Ingredients: Carnauba Wax, Hydroxypropyl Methylcellulose, Lactose, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol 400, Polysorbate 80, Pregelatinized Starch, Red Ferric Oxide, Talc, Titanium Dioxide. CLINICAL PHARMACOLOGY Primaquine phosphate is an 8-amino-quinoline compound which eliminates tissue (exoerythrocytic) infection. Thereby, it prevents the development of the blood (erythrocytic) forms of the parasite which are responsible for relapses in vivax malaria. Primaquine phosphate is also active against gametocytes of Plasmodium falciparum. INDICATIONS AND USAGE Primaquine phosphate is indicated for the radical cure (prevention of relapse) of vivax malaria. CONTRAINDICATIONS Primaquine phosphate is contraindicated in acutely ill patients suffering from systemic disease manifested by tendency to granulocytopenia, such as rheumatoid arthritis and lupus erythematosus. The drug is also contraindicated in patients receiving concurrently other potentially hemolytic drugs or depressants of myeloid elements of the bone marrow. Because quinacrine hydrochloride appears to potentiate the toxicity of antimalarial compounds which are structurally related to primaquine, the use of quinacrine in patients receiving primaquine is contraindicated. Similarly, primaquine should not be administered to patients who have received quinacrine recently, as toxicity is increased. WARNINGS Discontinue the use of primaquine phosphate promptly if signs suggestive of hemolytic anemia occur (darkening of the urine, marked fall of hemoglobin or erythrocytic count). Hemolytic reactions (moderate to severe) may occur in individuals with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and in individuals with a family or personal history of favism. Areas of high prevalence of G-6-PD deficiency are Africa, Southern Europe, Mediterranean region, Middle East, South-East Asia, and Oceania. People from these regions have a greater tendency to develop hemolytic anemia (due to a congenital deficiency of erythrocytic glucose-6-phosphate dehydrogenase) while receiving primaquine and related drugs. Reference ID: 3733735 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Usage in Pregnancy Safe usage of this preparation in pregnancy has not been established. Therefore, use of it during pregnancy should be avoided except when in the judgment of the physician the benefit outweighs the possible hazard. PRECAUTIONS Since anemia, methemoglobinemia, and leukopenia have been observed following administration of large doses of primaquine, the adult dosage of 1 tablet (= 15 mg base) daily for fourteen days should not be exceeded. It is also advisable to make routine blood examinations (particularly blood cell counts and hemoglobin determinations) during therapy. If primaquine phosphate is prescribed for (1) an individual who has shown a previous idiosyncrasy to primaquine phosphate (as manifested by hemolytic anemia, methemoglobinemia, or leukopenia), (2) an individual with a family or personal history of favism, or (3) an individual with erythrocytic glucose-6-phosphate dehydrogenase (G-6-PD) deficiency or nicotinamide adenine dinucleotide (NADH) methemoglobin reductase deficiency, the person should be observed closely for tolerance. The drug should be discontinued immediately if marked darkening of the urine or sudden decrease in hemoglobin concentration or leukocyte count occurs. Due to potential for QT interval prolongation, monitor ECG when using primaquine in patients with cardiac disease, long QT syndrome, a history of ventricular arrhythmias, uncorrected hypokalemia and/or hypomagnesemia, or bradycardia (<50 bpm), and during concomitant administration with QT interval prolonging agents (see PRECAUTIONS, Drug Interactions, ADVERSE REACTIONS, and OVERDOSAGE). Drug Interactions Caution is advised if primaquine is used concomitantly with other drugs that prolong the QT interval (see PRECAUTIONS, ADVERSE REACTIONS, and OVERDOSAGE). Geriatric Use Clinical studies of primaquine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS Gastrointestinal: nausea, vomiting, epigastric distress, and abdominal cramps. Hematologic: leukopenia, hemolytic anemia in glucose-6-phosphate dehydrogenase (G-6-PD) deficient individuals, and methemoglobinemia in nicotinamide adenine dinucleotide (NADH) methemoglobin reductase deficient individuals. Reference ID: 3733735 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cardiac: Cardiac arrhythmia and QT interval prolongation (see PRECAUTIONS, OVERDOSAGE). OVERDOSAGE Symptoms of overdosage of primaquine phosphate include abdominal cramps, vomiting, burning epigastric distress, central nervous system and cardiovascular disturbances, including cardiac arrhythmia and QT interval prolongation, cyanosis, methemoglobinemia, moderate leukocytosis or leukopenia, and anemia. The most striking symptoms are granulocytopenia and acute hemolytic anemia in sensitive persons. Acute hemolysis occurs, but patients recover completely if the dosage is discontinued. DOSAGE AND ADMINISTRATION Primaquine phosphate is recommended only for the radical cure of vivax malaria, the prevention of relapse in vivax malaria, or following the termination of chloroquine phosphate suppressive therapy in an area where vivax malaria is endemic. Patients suffering from an attack of vivax malaria or having parasitized red blood cells should receive a course of chloroquine phosphate, which quickly destroys the erythrocytic parasites and terminates the paroxysm. Primaquine phosphate should be administered concurrently in order to eradicate the exoerythrocytic parasites in a dosage of 1 tablet (equivalent to 15 mg base) daily for 14 days. HOW SUPPLIED Primaquine phosphate is supplied as pink, convex, discoid, film-coated tablets of 26.3 mg (= 15 mg base), printed with a “W” and “P97” on one side. Available in bottles of 100. (NDC 0024-1596-01) Store at 25° C (77° F); excursions permitted to 15° C - 30° C (59° F - 86° F) [see USP Controlled Room Temperature] Dispense in tight, light-resistant container as defined in the USP/NF. CLINICAL STUDIES Persons with acute attacks of vivax malaria, provoked by the release of erythrocytic forms of the parasite, respond readily to therapy, particularly to chloroquine phosphate. Primaquine eliminates tissue (exoerythrocytic) infection and prevents relapses in experimentally induced vivax malaria in human volunteers and in persons with naturally occurring infections and is a valuable adjunct to conventional therapy in vivax malaria. Rx Only Revised April 2015 Manufactured for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 A SANOFI COMPANY Reference ID: 3733735 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ©2015 sanofi-aventis U.S. LLC Reference ID: 3733735 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:37.181392	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/008316s021lbl.pdf', 'application_number': 8316, 'submission_type': 'SUPPL ', 'submission_number': 21}
10,699	NDA 8-316/S-015 Page 3 GERIATRIC MARKED/ANNOTATED - PSW-11D PRIMAQUINE PHOSPHATE TABLETS, USP WARNING: PHYSICIANS SHOULD COMPLETELY FAMILIARIZE THEMSELVES WITH THE COMPLETE CONTENTS OF THIS LEAFLET BEFORE PRESCRIBING PRIMAQUINE PHOSPHATE. DESCRIPTION Primaquine phosphate is 8-[(4-Amino-1-methylbutyl) amino]-6-methoxyquinoline phosphate, a synthetic compound with potent antimalarial activity. Each tablet contains 26.3 mg of Primaquine phosphate (equivalent to 15 mg of primaquine base). The dosage is customarily expressed in terms of the base. Inactive Ingredients: Carnauba Wax, Hydroxypropyl Methylcellulose, Lactose, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol 400, Polysorbate 80, Pregelatinized Starch, Red Ferric Oxide , Talc, Titanium Dioxide. CLINICAL PHARMACOLOGY Primaquine phosphate is an 8-amino-quinoline compound which eliminates tissue (exoerythrocytic) infection. Thereby, it prevents the development of the blood (erythrocytic) forms of the parasite which are responsible for relapses in vivax malaria. Primaquine phosphate is also active against gametocytes of Plasmodium falciparum. INDICATIONS AND USAGE Primaquine phosphate is indicated for the radical cure (prevention of relapse) of vivax malaria. CONTRAINDICATIONS Primaquine phosphate is contraindicated in acutely ill patients suffering from systemic disease manifested by tendency to granulocytopenia, such as rheumatoid arthritis and lupus erythematosus. The drug is also contraindicated in patients receiving concurrently other potentially hemolytic drugs or depressants of myeloid elements of the bone marrow. Because quinacrine hydrochloride appears to potentiate the toxicity of antimalarial compounds which are structurally related to primaquine, the use of quinacrine in patients receiving primaquine is contraindicated. Similarly, Primaquine should not be administered to patients who have received quinacrine recently, as toxicity is increased. WARNINGS Discontinue the use of Primaquine phosphate promptly if signs suggestive of hemolytic anemia occur (darkening of the urine, marked fall of hemoglobin or erythrocytic count). Hemolytic reactions (moderate to severe) may occur in glucose-6-phosphate dehydrogenase (G-6-PD) deficient Caucasians (particularly in Sardinians and in individuals with a family or personal This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-316/S-015 Page 4 history of favism). Dark-skinned persons (Negroes, for example) have a great tendency to develop hemolytic anemia (due to congenital deficiency of erythrocytic glucose-6-phosphate dehydrogenase) while receiving Primaquine and related drugs. Usage in Pregnancy. Safe usage of this preparation in pregnancy has not been established. Therefore, use of it during pregnancy should be avoided except when in the judgment of the physician the benefit outweighs the possible hazard. PRECAUTIONS Since anemia, methemoglobinemia, and leukopenia have been observed following administration of large doses of primaquine, the adult dosage of 1 tablet (= 15 mg base) daily for fourteen days should not be exceeded. It is also advisable to make routine blood examinations (particularly blood cell counts and hemoglobin determinations) during therapy. If primaquine phosphate is prescribed for (1) an individual who has shown a previous idiosyncrasy to primaquine phosphate (as manifested by hemolytic anemia, methemoglobinemia, or leukopenia), (2) an individual with a family or personal history of favism, or (3) an individual with erythrocytic glucose-6-phosphate dehydrogenase (G-6-PD) deficiency or nicotinamide adenine dinucleotide (NADH) methemoglobin reductase deficiency, the person should be observed closely for tolerance. The drug should be discontinued immediately if marked darkening of the urine or sudden decrease in hemoglobin concentration or leukocyte count occurs. Geriatric Use: Clinical studies of Primaquine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.'' ADVERSE REACTIONS Gastrointestinal: nausea, vomiting, epigastric distress, and abdominal cramps. Hematologic: leukopenia, hemolytic anemia in glucose-6-phosphate dehydrogenase (G-6-PD) deficient individuals, and methemoglobinemia in nicotinamide adenine dinucleotide (NADH) methemoglobin reductase deficient individuals. OVERDOSAGE Symptoms of overdosage of primaquine phosphate are similar to those seen after overdosage of pamaquine. They include abdominal cramps, vomiting, burning epigastric distress, central nervous system and cardiovascular disturbances, cyanosis, methemoglobinemia, moderate leukocytosis or leukopenia, and anemia. The most striking symptoms are granulocytopenia and acute hemolytic anemia in sensitive persons. Acute hemolysis occurs, but patients recover completely if the dosage is discontinued. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-316/S-015 Page 5 DOSAGE AND ADMINISTRATION Primaquine phosphate is recommended only for the radical cure of vivax malaria, the prevention of relapse in vivax malaria, or following the termination of chloroquine phosphate suppressive therapy in an area where vivax malaria is endemic. Patients suffering from an attack of vivax malaria or having parasitized red blood cells should receive a course of chloroquine phosphate, which quickly destroys the erythrocytic parasites and terminates the paroxysm. Primaquine phosphate should be administered concurrently in order to eradicate the exoerythrocytic parasites in a dosage of 1 tablet (equivalent to 15 mg base) daily for 14 days. HOW SUPPLIED Primaquine phosphate is supplied in tablets of 26.3 mg (= 15 mg base), bottles of 100. (NDC 0024-1596-01) Store at 25° C (77° F); excursions permitted to 15° - 30° C (59° - 86° F) [see USP Controlled Room Temperature] CLINICAL STUDIES Malariologists agree that malaria produced by Plasmodium vivax is the most difficult form to treat. This is ascribed to the ability of the parasite to develop extremely resistant tissue forms which are not eradicated by ordinary antimalarial compounds. Thus, persons with acute attacks of vivax malaria, provoked by the release of erythrocytic forms of the parasite, respond readily to therapy, particularly to Chloroquine phosphate. However, prior to the discovery of primaquine phosphate, no antimalarial drug was available that could be relied on to eliminate tissue (exoerythrocytic) infection and to prevent relapses. The various investigations made with primaquine in experimentally induced vivax malaria in human volunteers and in persons with naturally occurring infections have demonstrated that the drug is a valuable adjunct to conventional therapy in this refractory form of the disease. Manufactured for Sanofi-Synthelabo Inc. New York, NY 10016 by Bayer Corporation Myerstown, PA 17067 Made In USA Revised September 1999 Copyright, Sanofi-Synthelabo Inc., 1993, 1999 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:37.229499	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/08316slr015_primaquine_lbl.pdf', 'application_number': 8316, 'submission_type': 'SUPPL ', 'submission_number': 15}
10,698	.7789 Promethazine HCI and Codeine Phosphate Oral Solution C- V Page 1 of 13 PROMETHAZINE HCL AND CODEINE PHOSPHATE ORAL SOLUTION - promethazine hydrochloride and codeine phosphate solution ANI Pharmaceuticals, Inc. 7789 Promethazine HCI and Codeine Phosphate Oral Solution C-V Rx Only DESCRIPTION Each 5 mL (one teaspoonful), for oral administration contains: Promethazine hydrochloride 6.25 mg; codeine phosphate 10 mg. in a flavored syrup base with a pH between 4.8 and 5.4. Alcohol 7%. Inactive ingredients: Artificial and natural flavors, citric acid, D&C Red 33, FD&C Blue 1, FD&C Yellow 6, glycerin, saccharin sodium, sodium benzoate, sodium citrate, sodium propionate, water, and other ingredients. Codeine is one of the naturally occurring phenanthrene alkaloids of opium derived from the opium poppy, it is classified pharmacologically as a narcotic analgesic. Codeine phosphate may be chemically designated as 7,8-Didehydro-4, 5a-epoxy-3-methoxy-17 -methylmorphinan-6-a-ol phosphate (1:1 )(salt)hemihydrate. The phosphate salt of codeine occurs as white, needle-shaped crystals or white crystalline powder. Codeine phosphate is freely soluble in water and slightly soluble in alcohoL. It has a molecular weight of 406.37, a molecular formula of C18H21 N03.H3P04 · ~ H20, and the following structural formula: · 1hH20 OH Promethazine hydrochloride, a phenothiazine derivative, is chemically designated as (:t)-10-(2- (Dimethylamino )propyl) phenothiazine monohydrochloride. Promethazine hydrochloride occurs as a white to faint yellow, practically odorless, crystalline powder which slowly oxidizes and turns blue on prolonged exposure to air. It is freely soluble in water and soluble in alcohoL. It is soluble in water and freely soluble in alcohoL. It has a molecular weight of 320.88, a molecular formula of C17H20N2S · HCI, and the following structural formula fie:/I\\Fdswa150\nonectd\N08306\S _ 030\2008-05-23\Promethazine with Codeine\SPL\prom... 1112412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7789 Promethazine HCl and Codeine Phosphate Oral Solution C- V Page 2 of 13 CH 2CH(CHs)N(CHs)2 oc~)O · Hei CLINICAL PHARMACOLOGY Codeine: Narcotic analgesics, including codeine, exert their primary effects on the central nervous system and gastrointestinal tract. The analgesic effects of codeine are due to its central action; however, the precise sites of action have not been determined, and the mechanisms involved appear to be quite complex. Codeine resembles morphine both structurally and pharmacologically, but its actions at the doses of codeine used therapeutically are milder, with less sedation, respiratory depression, and gastrointestinal, urinary, and pupillary effects. Codeine produces an increase in biliary tract pressure, but less than morphine or meperidine. Codeine is less constipating than morphine. Codeine has good antitussive activity, although less than that of morphine at equal doses. It is used in preference to morphine, because side effects are infrequent at the usual antitussive dose of codeine. Codeine in oral therapeutic dosage does not usually exert major effects on the cardiovascular system. Narcotic analgesics may cause nausea and vomiting by stimulating the chemoreceptor trigger zone (CTZ); however, they also depress the vomiting center, so that subsequent doses are unlikely to produce vomiting. Nausea is minimal after usual oral doses of codeine. Narcotic analgesics cause histamine release, which appears to be responsible for wheals or urticaria sometimes seen at the site of injection on parenteral administration. Histamine release may also produce dilation of cutaneous blood vessels, with resultant flushing of the face and neck, pruritus, and sweating. Codeine and its salts are well absorbed following both oral and parenteral administration. Codeine is about 2/3 as effective orally as parenterally. Codeine is metabolized primarily in the liver by enzymes of the endoplasmic reticulum, where it undergoes O-demethylation, N-demethylation, and partial conjugation with glucuronic acid. The drug is excreted primarily in the urine, largely as inactive metabolites and small amounts of free and conjugated morphine. Negligible amounts of codeine and its metabolites are found in the feces. Following oral or subcutaneous administration of codeine, the onset of analgesia occurs within 15 to 30 minutes and lasts for four to six hours. The cough-depressing action, in animal studies, was observed to occur 15 minutes after oral administration of codeine, peak action at 45 to 60 minutes after ingestion. The duration of action, which is dose-dependent, usually did not exceed 3 hours. Promethazine: Promethazine is a phenothiazine derivative which differs structurally from the antipsychotic fie :/1\ \F dswa 15 0\nonectd\N08 3 06\S _ 030\2008 -05 - 23 \Promethazine with Codeine\SPL \prom... 11/24/2008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7789 Promethazine HCl and Codeine Phosphate Oral Solution C- V Page 3 of 13 phenothiazines by the presence of a branched side chain and no ring substitution. It is thought that this configuration is responsible for its lack (1/10 that of chlorpromazine) of dopamine antagonist properties. Promethazine is an H1 receptor blocking agent. In addition to its antihistaminicaction, it provides clinically useful sedative and antiemetic effects. Promethazine is well absorbed from the gastrointestinal tract. Clinical effects are apparent within 20 minutes after oral administration and generally last four to six hours, although they may persist as long as 12 hours. Promethazine is metabolized by the liver to a variety of compounds; the sulfoxides of promethazine and N-demethylpromethazine are the predominant metabolites appearing in the urine. INDICATIONS AND USAGE Promethazine HCI and Codeine Phosphate Oral Solution is indicated for the temporary relief of coughs and upper respiratory symptoms associated with allergy or the common cold. CONTRAINDICATIONS Codeine is contraindicated in patients with a known hypersensitivity to the drug. Promethazine hydrochloride is contraindicated in comatose states, and in individuals known to be hypersensitive or to have had an idiosyncratic reaction to promethazine or to other phenothiazines. The combination of promethazine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age, because the combination may cause fatal respiratory depression in this age population. Antihistamines and codeine are both contraindicated for use in the treatment of lower respiratory tract symptoms, including asthma. WARNINGS The combination of promethazine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age. Concomitant administration of promethazine products with other respiratory depressants has an association with respiratory depression, and sometimes death, in pediatric patients. Postmarketing cases of respiratory depression, including fatalities, have been reported with use of promethazine hydrochloride in pediatric patients less than 2 years of age. A wide range of weight-based doses of promethazine hydrochloride have resulted in respiratory depression in these patients. Codeine: Dosage of codeine SHOULD NOT BE INCREASED if cough fails to respond; an unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease. file:/I\\FdswaI50\nonectd\N08306\S_030\2008-05-23\Promethazine with Codeine\SPL\prom... 1112412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7789 Promethazine HCl and Codeine Phosphate Oral Solution C- V Page 4 of 13 Codeine may cause or aggravate constipation. Respiratory depression leading to arrest, coma, and death has occurred with the use of codeine antitussives in young children, particularly in the under-one-year infants whose ability to deactivate the drug is not fully developed. Administration of codeine may be accomplished by histamine release and should be used with caution in atopic children. Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of narcotic analgesics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, intracranial lesions, or a preexisting increase in intracranial pressure. Narcotics may produce adverse reactions which may obscure the clinical course of patients with head injuries. Asthma and Other Respiratory Conditions: Narcotic analgesics or cough suppressants, including codeine, should not be used in asthmatic patients (see CONTRAINDICATIONS). Nor should they be used in acute febrile illness associated with productive cough or in chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient's respiratory function. Hypotensive Effect: Codeine may produce orthostatic hypotension in ambulatory patients. Promethazine: CNS Depression - Promethazine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The impairment may be amplified by concomitant use of other central-nervous-system depressants such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore such agents should either be eliminated or given in reduced dosage in the presence of promethazine HCI (see PRECAUTIONS - Information for Patients and Drug Interactions). Respiratory Depression - Promethazine may lead to potentially fatal respiratory depression. Use of Promethazine in patients with compromised respiratory function (e.g. COPD, sleep apnea) should be avoided. Lower Seizure Threshold - Promethazine may lower seizure threshold. It should be used with caution in persons with seizure disorder or in persons who are using concomitant medications, such as narcotics or local anesthetics, which may also affect seizure threshold. Bone-Marrow Depression - Promethazine should be used with caution in patients with bone- marrow depression. Leukopenia and agranulocytosis have been reported, usually when promethazine HCI has been' used in association with other known marrow-toxic agents. Neuroleptic Malignant Syndrome - A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with promethazine HCI alone or in combination with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias). The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated file:/1\ \FdswaI50\nonectd\N08306\S _ 030\2008-05-23\Promethazine with Codeine\SPL\prom... 1112412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7789 Promethazine HCl and Codeine Phosphate Oral Solution C- V Page 5 of 13 extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of promethazine HCI, antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. Since recurrences of NMS have been reported with phenothiazines, the reintroduction of promethazine HCI should be carefully considered. Use in Pediatric Patients The combination of promethazine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age. Concomitant administration of promethazine products with other respiratory depressants has an association with respiratory depression, and sometimes death, in pediatric patients. The association does not directly relate to individualized weight-based dosing, which might otherwise permit safe administration. Excessively large dosages of antihistamines, including promethazine hydrochloride, in pediatric patients may cause sudden death (see OVERDOSAGE). Hallucinations and convulsions have occurred with therapeutic doses and overdoses of promethazine hydrochloride in pediatric patients. In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonias with the use of promethazine HCI. Other Considerations Administration of promethazine has been associated with reported cholestatic jaundice. PRECAUTIONS General Narcotic analgesics, including codeine, should be administered with caution and the initial dose reduced in patients with acute abdominal conditions, convulsive disorders, significant hepatic or renal impairment, fever, hypothyroidism, Addison's disease, ulcerative colitis, prostatic hypertrophy, in patients with recent gastrointestinal or urinary tract surgery, and in the very young or elderly or debilitated patients. Drugs having anticholinergic properties should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, and bladder- neck obstruction. Promethazine should be used cautiously in persons with cardiovascular disease or with impairment of liver function. Ultra-rapid Metabolizers of Codeine Some individuals may be ultra-rapid metabolizers due to a specific CYP2D62x2 genotype. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regiments, individuals who are ultra-rapid metabolizers may experience file:/1\ \FdswaI50\nonectd\N08306\S _ 030\2008-,05-23\Promethazine with Codeine\SPL\prom... 11/2412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7789 Promethazine HCl and Codeine Phosphate Oral Solution C- V Page 6 of 13 overdose symptoms such as extreme sleepiness, confusion or shallow breathing. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1 % in Chinese and Japanese, 0.5 to 1% in Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups. When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and should inform their patients about the risks and the signs of morphine overdose. (See PRECAUTIONS-Nursing Mothers). Information for Patients Patients should be advised to measure Promethazine HCI and Codeine Phosphate Oral Solution with an accurate measuring device. A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when a half a teaspoon is measured. A pharmacist can recommend an appropriate measuring device and can provide instructions for measuring the correct dose. Promethazine and codeine may cause marked drowsiness or may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. Ambulatory patients should be told to avoid engaging in such activities until it is known that they do not become drowsy or dizzy from promethazine and codeine therapy. Pediatric patients should be supervised to avoid potential harm in bike riding or in other hazardous activities. The concomitant use of alcohol or other central nervous system depressants, including narcotic analgesics, sedatives, hypnotics and tranquilizers, may have an additive effect and should be avoided or their dosage reduced. Patients should be advised to report any involuntary muscle movements. Avoid prolonged exposure to the sun. Codeine, like other narcotic analgesics, may produce orthostatic hypotension in some ambulatory patients. Patients should be cautioned accordingly. Caution patients that some people have a variation in a liver enzyme and change codeine into morphine more rapidly and completely than other people. These people are ultra-rapid metabolizers and are more likely to have higher-than-normal levels of morphine in their blood after taking codeine which can result in overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer. Nursing mothers taking codeine can also have higher morphine levels in their breast milk if they are ultra-rapid metabolizers. These higher levels of morphine in breast milk may lead to life- threatening or fatal side effects in nursing babies. Instruct nursing mothers to watch for signs of morphine toxicity in their infants including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby's doctor immediately if they notice these signs and, if they can not reach the doctor right away, to take the baby to an emergency room or call 911 (or local emergency services). I nteracti ons Drug Interactions Codeine: In patients receiving MAO inhibitors, an initial small test dose is advisable to allow fie:/1\ \FdswaI50\nonectd\N08306\S _ 030\2008-05-23\Promethazine with Codeine\SPL\prom... 1112412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7789 Promethazine HCl and Codeine Phosphate Oral Solution C~ V Page 7 of 13 observation of any excessive narcotic effects or MAOI interaction. Promethazine: CNS Depressants - Promethazine may increase, prolong or intensify the sedative action of other central nervous system depressants, such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore, such agents should be avoided or administered in reduced dosage to patients receiving promethazine HCI. When given concomitantly with promethazine, the dose of barbiturates should be reduced by at least one-half, and the dose of narcotics should be reduced by one-quarter to one-half. Dosage must be individualized. Excessive amounts of promethazine HCI relative to a narcotic may lead to restlessness and motor hyperactivity in the patient with pain; these symptoms usually disappear with adequate control of the pain. Epinephrine -Because of the potential for promethazine to reverse epinephrine's vasopressor effect, epinephrine should NOT be used to treat hypotension associated with promethazine overdose. Anticholinergics- Concomitant use of other agents with anticholinergic properties should be undertaken with caution. Monoamine Oxidase Inhibitors (MAOI) - Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly. Drug/Laboratory Test Interactions Because narcotic analgesics may increases biliary tract pressure, with resultant increase in plasma amylase or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after a narcotic analgesic has been given. The following laboratory tests may be affected in patients who are receiving therapy with promethazine hydrochloride. Pregnancy Tests: Diagnostic pregnancy tests based on immunological reactions between HCG and anti-HCG mayresult in false-negative or false-positive interpretations. Glucose Tolerance Test' An increase in blood glucose has been reported in patients receiving promethazine. Pregnancy Teratogenic Effects Pregnancy Category C: fie :/1\ \F dswa 15 0\nonectd\N08 3 06\S _ 030\2008-05 - 23 \Promethazine with Codeine\SPL \prom... 1112412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7789 Promethazine HCl and Codeine Phosphate Oral Solution C- V Page 8 òf 13 Codeine: A study in rats and rabbits reported no teratogenic effect of codeine administerèd during the period of organogenesis in doses ranging from 5 to 120 mg/kg. In the rat, doses at the 120- mg/kg level, in the toxic range for the adult animal were associated with an increase in embryo resorption at the time of implantation. In another study a single 100-mg/kg dose of codeine administered to pregnant mice reportedly resulted in delayed ossification in the offspring. There are no studies in humans, and the significance of these findings to humans, if any, is not known. Promethazine: Teratogenic effects have not been demonstrated in rat-feeding studies at doses of 6.25 and 12.5 mg/kg of promethazine HCI. These doses are from approximately 2.1 to 4.2 times the maximum recommended total daily dose of promethazine for a 50-kg subject depending upon the indication for which the drug is prescribed. Daily doses of 25 mg/kg intraperitoneally have been found to produce fetal mortality in rats. Specific studies to test the action of the drug on parturition"lactation, and development of the animal neonate were not done, but a general preliminary study in rats indicated no effect on these parameters. Although antihistamines have been found to produce fetal mortality in rodents, the pharmacological effects of histamine in the rodent do not parallel those in man. There are no adequate and well-controlled studies of promethazine in pregnant women. Animal reproduction studies have not been conducted with the drug combination - promethazine and codeine. It is not known whether this drug combination can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Promethazine HCI and Codeine Phosphate Oral Solution should be given to a pregnant woman only if clearly needed. Promethazine HCI and Codeine Phosphate Oral Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Dependence has been reported in newborns whose mothers took opiates regularly during pregnancy. Withdrawal signs include irritability, excessive crying, tremors, hyperreflexia, fever, vomiting, and diarrhea. Signs usually appear during the first few days of life. Promethazine administered to a pregnant woman within two weeks of delivery may inhibit platelet aggregation in the newborn. Labor and Delivery Narcotic analgesics cross the placental barrier. The closer to the delivery and the larger the dose used, the greater the possibility of respiratory depression in the newborn. Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required (see OVERDOSAGE). Limited data suggests that use of promethazine hydrochloride during labor and delivery does not have an appreciable effect on the duration of labor or delivery and does not increase the risk of need for intervention in the newborn. The effect of promethazine and/or codeine on later growth and development of the newborn is unknown. Nursing Mothers file:/1\ \FdswaI50\nonectd\N08306\S _ 030\2008-05-23\Promethazine with Codeine\SPL\prom... 1112412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7789 Promethazine HCl and Codeine Phosphate Oral Solution C- V Page 9 of 13 Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine excreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher- than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1 % in Chinese and Japanese, 0.5 to 1 % in Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups. The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and the baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, diffculty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding. (See PRECAUTIONS-General-Ultra-rapid Metabolizers of Codeine). Geriatric Use Clinical studies of Promethazine HCI and Codeine Phosphate Oral Solution did not include suffcient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of promethazine hydrochloride and codeine phosphate oral solution and observed closely. ADVERSE REACTIONS Codeine: Nervous System - CNS depression, particularly respiratory depression, and to a lesser extent circulatory depression; light-headedness, dizziness, sedation, euphoria, dysphoria, headache, fie:II\\FdswaI50\nonectd\N08306\S_030\2008-05-23\Promethazine with Codeine\SPL\prom... 11/2412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7789 Promethazine HCl and Codeine Phosphate Oral Solution C- V Page 10 of 13 transient hallucination, disorientation, visual disturbances, and convulsions. Cardiovascular - Tachycardia, bradycardia, palpitation, faintness, syncope, orthostatic hypotension (common to narcotic analgesics). Gastrointestinal- Nausea, vomiting, constipation, and biliary tract spasm. Patients with chronic ulcerative colitis may experience increased colonic motility; in patients with acute ulcerative colitis, toxic dilation has been reported. Genitourinary - Oliguria, urinary retention, antidiuretic effect has been reported (common to narcotic analgesics). Allergic - Infrequent pruritus, giant urticaria, angioneurotic edema, and laryngeal edema. Other - Flushing of the face, sweating and pruritus (due to opiate-induced histamine release); weakness. Promethazine: Central Nervous System - Drowsiness is the most prominent CNS effect of this drug. Sedation, somnolence, blurred vision, dizziness, confusion, disorientation and extrapyramidal symptoms such as oculogyric crisis, torticollis, and tongue protrusion; lassitude, tinnitus, incoordination, fatigue, euphoria, nervousness, diplopia, insomnia, tremors, convulsive seizures, excitation, catatonic-like states, hysteria. Hallucinations have also been reported. Cardiovascular - Increased or decreased blood pressure, tachycardia, bradycardia, faintness. Dermatologic - Dermatitis, photosensitivity, urticaria. Hematologic - Leukopenia, thrombocytopenia, thrombocytopenic purpura, agranulocytosis. Gastrointestinal- Dry mouth, nausea, vomiting, jaundice. Respiratory - Asthma, nasal stuffness, respiratory depression (potentially fatal) and apnea (potentially fatal) (see WARNINGS - Promethazine; Respiratory Depression). Other - Angioneurotic edema. Neuroleptic malignant syndrome (potentially fatal) has also been reported (see WARNINGS - Promethazine; Neuroleptic Malignant Syndrome). Paradoxical Reactions - Hyperexcitability and abnormal movements have been reported in patients following a single administration of promethazine HCI. Consideration should be given to the discontinuation of promethazine HCI and to the use of other drugs if these reactions occur. Respiratory depression, nightmares, delirium and agitated behavior have also been reported in some of these patients. DRUG ABUSE AND DEPENDENCE Controlled Substance Promethazine HCI and Codeine Phosphate Oral Solution is a Schedule V Controlled Substance. Abuse Codeine is known to be subject to abuse; however, the abuse potential of oral codeine appears to be quite low. Even parenteral codeine does not appear to offer the psychic effects sought by addicts to the same degree as heroin or morphine. However, codeine must be administered only file :/1\ \F dswa 15 0\nonectd\N08 3 06\S _ 030\2008 -0 5 - 23 \Promethazine with Codeine\SPL\prom... 1112412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7789 Promethazine HCl and Codeine Phosphate Oral Solution C- V Page 11 of 13 under close supervision to patients with a history of drug abuse or dependence. Dependence Psychological dependence, physical dependence and tolerance are known to occur with codeine. OVERDOSAGE Codeine: Serious overdose with codeine is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. The triad of coma, pinpoint pupils, and respiratory depression is strongly suggestive of opiate poisoning. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. Promethazine is additive to the depressant effects of codeine. It is difficult to determine what constitutes a standard toxic or lethal dose. However, the lethal oral dose of codeine in an aduit is reported to be in the range of 0.5 to 1 gram. Infants and children are believed to be relatively more sensitive to opiates on a body-weight basis. Elderly patients are also comparatively intolerant to opiates. Promethazine: Signs and symptoms of overdosage with promethazine range from mild depression of the central nervous system and cardiovascular system to profound hypotension, respiratory depression, unconsciousness and sudden death. Other reported reactions include hyperreflexia, hypertonia, ataxia, athetosis a.nd extensor-plantar reflexes (Babinski reflex). Stimulation may be evident, especially in children and geriatric patients. Convulsions may rarely occur. A paradoxical reaction has been reported in children receiving single doses of 75 mg to 125 mg orally, characterized by hyperexcitability and nightmares. Atropine-like signs and symptoms - dry mouth, fixed dilated pupils, flushing, as well as gastrointestinal symptoms, may occur. Treatment: Treatment of overdosage with promethazine and codeine is essentially symptomatic and supportive. Only in cases of extreme overdosage or individual sensitivity do vital signs including respiration, pulse, blood -pressure, temperature, and EKG need to be monitored. Activated charcoal orally or by lavage may be given, or sodium or magnesium sulfate orally as a cathartic. Attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. The narcotic antagonist, naloxone hydrochloride, may be administered when significant respiratory depression occurs with promethazine and codeine; any depressant effects of promethazine are not reversed with naloxone. Diazepam may be used to control convulsions. Avoid analeptics, which may cause convulsions. Acidosis and electrolyte losses should be corrected. A rise in temperature or pulmonary complications may signal the need for institution of antibiotic therapy. Severe hypotension usually responds to the administration of norepinephrine or phenylephrine. EPINEPHRINE SHOULD NOT BE USED, since its use in a patient with partial adrenergic file:/1\ \FdswaI50\nonectd\N08306\S _ 030\2008-05-23\Promethazine with Codeine\SPL\prom... 1112412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7789 Promethazine HCl and Codeine Phosphate Oral Solution C-V Page 12 of 13 blockade may further lower the blood pressure. Limited experience with dialysis indicates that it is not helpfuL. DOSAGE AND ADMINISTRATION It is important that Promethazine HCI and Codeine Phosphate Oral Solution is measured with an accurate measuring device (see PRECAUTIONS-Information for Patients). A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when half a teaspoon is to be measured. It is strongly recommended that an accurate measuring device be used. A pharmacist can provide an appropriate device and can provide instructions for measuring the correct dose. The combination of promethazine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age, because the combination may cause fatal respiratory depression in this age population. The average effective dose is given in the following table: Adults (12 years of age and 5 mL (1 teaspoonful) every 4 to 6 hours, not to exceed 30.0 mL in 24 ove0 hou~. Children 6 years to under 2.5 mL to 5 mL (~ to 1 teaspoonful) every 4 to 6 hours, not to exceed 12 years 30.0 mL in 24 hours. HOW SUPPLIED Promethazine HCI and Codeine Phosphate Oral Solution is a clear, purple solution supplied as follows: NDC 42769-7781-4 - bottles of 4 fl. oz. (118 mL) NDC 42769-7781-6 - bottles of 16 fl. oz. (473 mL) Keep bottes tightly closed. Store at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature.) Protect from light. Dispense in tight, light-resistant container (USP/NF) with a child-resistant closure. Manufactured for BaýPharma TM, Inc. Baltimore, MD 21244 501-78816-0 Rev 05/08 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7889 Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution C- V Page 1 of 16 PROMETHAZINE HCL, PHENYLEPHRINE HCL AND CODEINE PHOSPHATE ORAL SOLUTION - promethazine hydrochloride, codeine phosphate and phenylephrine hcl solution ANI Pharmaceuticals, Inc. 7889 Promethazine HCI, Phenylephrine HCI and Codeine Phosphate Oral Solution C-V Rx Only DESCRIPTION Each 5 mL (one teaspoonful), for oral administration contains: Codeine phosphate 10 mg; promethazine hydrochloride 6.25 mg; phenylephrine hydrochloride 5 mg in a flavored syrup base with a pH between 4.8 and 5.4. Alcohol 7%. Inactive ingredients: Artificial and natural flavors, citric acid, D&C Red 33, FD&C Yellow 6, glycerin, saccharin sodium, sodium benzoate, sodium citrate, sodium propionate, water, and other ingredients. Codeine is one of the naturally occurring phenanthrene alkaloids of opium derived from the opium poppy, it is classified pharmacologically as a narcotic analgesic. Codeine phosphate may be chemically designated as 7,8-Didehydro-4, 5a-epoxy-3-methoxy-17 -methylmorphinan-6a-ol phosphate (1:1 )(salt)hemi hydrate. The phosphate salt of codeine occurs as white, needle-shaped crystals or white crystalline powder. Codeine phosphate is freely soluble in water and slightly soluble in alcohoL. It has a molecular weight of 406.37, a molecular formula of C18H21 N03 · H3P04 · % H20 and the following structural formula: · 'hH20 Promethazine hydrochloride, a phenothiazine derivative, is chemically designated as (:!)-10-(2- (Dimethylamino)propyl) phenothiazine monohydrochloride. Promethazine hydrochloride occurs as a white to faint yellow, practically odorless, crystalline powder which slowly oxidizes and turns blue on prolonged exposure to air. It is soluble in water and freely soluble in alcohoL. It has a molecular weight of 320.88, a molecular formula of C17H20N2S · HCI, and the following structural formula . ~ fie:1 /\ \F dswa 15 0\nonectd\N08 3 06\S _ 03 0\2008-0 5 - 23 \Promethazine, phenylephrine & Codei... 11124/2008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7889 Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution C-V Page 2 of 16 CM2CH (CH;j)Ni(C HS)2 i 0(::0 · Hei Phenylephrine hydrochloride is a sympathomimetic amine salt which is chemically designated as (-)-m-hydroxy-a-((methyl-amino)methyl) benzyl alcohol hydrochloride. It occurs as white or nearly white crystals, having a bitter taste. It is freely soluble in water and alcohoL. Phenylephrine hydrochloride is subject to oxidation and must be protected from light and air. It has. a molecular weight of 203.67, a molecular formula of C9H13N02 · HCI and the following structural formula: OH \O)-~"CH2NHCH3 · HC OlH Fl CLINICAL PHARMACOLOGY Codeine: Narcotic analgesics, including codeine, exert their primary effects on the central nervous system and gastrointestinal tract. The analgesic effects of codeine are due to its central action; however, the precise sites of action have not been determined, and the mechanisms involved appear to be quite complex. Codeine resembles morphine both structurally and pharmacologically, but its actions at the doses of codeine used therapeutically are milder, with less sedation, respiratory depression and gastrointestinal, urinary, and pupillary effects. Codeine produces an increase in biliary tract pressure, but less than morphine or meperidine. Codeine is less constipating than morphine. Codeine has good antitussive activity, although less than that of morphine at equal doses. It is used in preference to morphine, because side effects are infrequent at the usual antitussive dose of codeine. Codeine in oral therapeutic dosage does not usually exert major effects on the cardiovascular system. Narcotic analgesics may cause nausea and vomiting by stimulating the chemoreceptor trigger zone (CTZ); however, they also depress the vomiting center, so that subsequent doses are unlikely to produce vomiting. Nausea is minimal after usual oral doses of codeine. Narcotic analgesics cause histamine release, which appears to be responsible for wheals or . urticaria sometimes seen at the site of injection on parenteral administration. Histamine release may also produce dilation of cutaneous blood vessels, with resultant flushing of the face and neck, pruritus, and sweating. Codeine and its salts are well absorbed following both oral and parenteral administration. Codeine file://\ \FdswaI50\nonectd\N08306\S _ 030\2008-05-23\Promethazine, phenylephrine & Codei... 1112412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7889 Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution C-V Page 3 of 16 is about 2/3 as effective orally as parenterally. Codeine is metabolized primarily in the liver by enzymes of the endoplasmic reticulum, where it undergoes O-demethylation, N-demethylation, and partial conjugation with glucuronic acid. The drug is excreted primarily in the urine, largely as inactive metabolites and small amounts offree and conjugated morphine. Negligible amounts of codeine and its metabolites are found in the feces. Following oral or subcutaneous administration of codeine, the onset of analgesia occurs within 15 to 30 minutes and lasts for four to six hours. The cough-depressing action, in animal studies, was observed to occur 15 minutes after oral administration of codeine, peak action at 45 to 60 minutes after ingestion. The duration of action, which is dose-dependent, usually did not exceed 3 hours. Promethazine: Promethazine is a phenothiazine derivativewhich differs structurally from the antipsychotic phenothiazines by the presence of a branched side chain and no ring substitution. It is thought that this configuration is responsible for its relative lack (1/10 that of chlorpromazine) of dopamine antagonist properties. Promethazine is an H1 receptor blocking agent. In addition to its antihistaminic action, it provides clinically useful sedative and antiemetic effects. Promethazine is well absorbed from the gastrointestinal tract. Clinical effects are apparent within 20 minutes after oral administration and generally last fòur to six hours, although they may persist as long as 12 hours. Promethazine is metabolized by the liver to a variety of compounds; the sulfoxides of promethazine and N-demethylpromethazine are the predominant metabolites appearing in the urine. Phenylephrine: Phenylephrine is a potent postsynaptic-a-receptor agonist with little effect on ß receptors of the heart. Phenylephrine has no effect on ß-adrenergic receptors of the bronchi or peripheral blood vessels. A direct action at receptors accounts for the greater part of its effects, only a small part being due to its ability to release norepinephrine. Therapeutic doses of phenylephrine mainly cause vasoconstriction. Phenylephrine increases resistance and, toa lesser extent, decreases capacitance of blood vessels. Total peripheral resistance is increased, resulting in increased systolic and diastolic blood pressure. Pulmonary arterial pressure is usually increased, and renal blood flow is usually decreased. Local vasoconstriction and hemostasis occur following topical application or infitration of phenylephrine into tissues. The main effect of phenylephrine on the heart is bradycardia; it produces a positive inotropic effect on the myocardium in doses greater than those usually used therapeutically. Rarely, the drug may increase the irritability of the heart, causing arrhythmias. Cardiac output is decreased slightly. Phenylephrine increases the work of the heart by increasing peripheral arterial resistance. Phenylephrine has a mild central stimulant effect. Following oral administration or topical application of phenylephrine to the mucosa, constriction of blood vessels in the nasal mucosa relieves nasal congestion associated with allergy or head colds. Following oral administration, nasal decongestion may occur within 15 or 20 minutes and may persist for up to 4 hours. file://\ \FdswaI50\nonectd\N08306\S _ 030\2008-05-23\Promethazine, phenylephrine & Codei... 11124/2008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7889 Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution C- V Page 4 of 16 Phenylephrine is irregularly absorbed from and readily metabolized in the gastrointestinal tract. Phenylephrine is metabolized in the liver and intestine by monoamine oxidase. The metabolites and their route and rate of excretion have not been identified. The pharmacologic action of phenylephrine is terminated at least partially by uptake of the drug into tissues. INDICATIONS AND USAGE Promethazine HCI, Phenylephrine HCI and Codeine Phosphate Oral Solution is indicated for the temporary relief of coughs and upper respiratory symptoms, including nasal congestion, associated with allergy or the common cold. CONTRAINDICATIONS Codeine is contraindicated in patients with a known hypersensitivity to the drug. Promethazine is contraindicated in comatose states, and in individuals known to be hypersensitive or to have had an idiosyncratic reaction to promethazine or to other phenothiazines. The combination of promethazine hydrochloride, phenylephrine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age, because the combination may cause fatal respiratory depression in this age population. Antihistamines and codeine are both contraindicated for use in the treatment of lower respiratory tract symptoms, including asthma. Phenylephrine is contraindicated in patients with hypertension or with peripheral vascular insufficiency (ischemia may result with risk of gangrene or thrombosis of compromised vascular beds). Phenylephrine should not be used in patients known to be hypersensitive to the drug or in those receiving a monoamine oxidase inhibitor (MAOI). WARNINGS The combination of promethazine hydrochloride, phenylephrine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age. Concomitant administration of promethazine products with other respiratory depressants has an association with respiratory depression, and sometimes death, in pediatric patients. Postmarketing cases of respiratory depression, including fatalities, have been reported with use of promethazine hydrochloride in pediatric patients less than 2 years of age. A wide range of weight-based doses of promethazine hydrochloride have resulted in respiratory depression in these patients. Codeine: Dosage of codeine SHOULD NOT BE INCREASED if cough fails to respond; an unresponsive cough should be re-evaluated in 5 days or sooner for possible underlying pathology, such as a foreign body or lower respiratory tract disease. file://\ \FdswaI50\nonectd\N08306\S _ 030\2008-05-23\Promethazine, phenylephrne & Codei... 1112412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7889 Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution C- V Page 5 of 16 Codeine may cause or aggravate constipation. Respiratory depression leading to arrest, coma and death has occurred with the use of codeine antitussives in young children, particularly in the under-one-year infants whose ability to deactivate the drug is not fully developed. Administration of codeine may be accomplished by histamine release and should be used with caution in atopic children. Head Injury and Increased Intracranial Pressure: The respiratory-depressant effects of narcotic analgesics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, intracranial lesions, or a pre-existing increase in intracranial pressure. Narcotics may produce adverse reactions which may obscure the clinical course of patients with head injuries. Asthma and Other Respiratory Conditions: Narcotic analgesics or cough suppressants, including codeine, should not be used in asthmatic patients (see CONTRAINDICATIONS). Nor should they be used in acute febrile illness associated with productive cough or in chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient's respiratory function. Hypotensive Effect: Codeine may produce orthostatic hypotension in ambulatory patients. Promethazine: eNS Depression - Promethazine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The impairment may be amplified by concomitant use of other central nervous system depressants such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore such agents should either be eliminated or given in reduced dosage in the presence of promethazine HCI (see PRECAUTIONS -Information for Patients and Drug Interactions). Respiratory Depression Promethazine may lead to potentially fatal respiratory depression. Use of promethazine in patients with compromised respiratory function (e.g. COPD, sleep apnea) should be avoided. Lower Seizure Threshold Promethazine may lower seizure threshold. It should be used with caution in persons with seizure disorders or in persons who are using concomitant medications, such as narcotics or local anesthetics, which may also affect seizure threshold. Bone-Marrow Depression Promethazine should be used with caution in patients with bone marrow depression. Leukopenia and agranulocytosis have been reported, usually when promethazine HCI has been used in association with other known marrow toxic agents. Neuroleptic Malignant Syndrome fie://\\FdswaI50\nonectd\N08306\S_030\2008-05-23\Promethazine, phenylephrine & Codei... 1112412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7a89 Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral S?lution C- V Page 6 of 16 A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with promethazine HCI alone or in combination with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias). The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of promethazine HCI, antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. Since recurrences of NMS have been reported with phenothiazines, the reintroduction of promethazine HCI should be carefully considered. Use in Pediatric Patients The combination of promethazine hydrochloride, phenylephrine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age. Concomitant administration of promethazine products with other respiratory depressants has an association with respiratory depression, and sometimes death, in pediatric patients. The association does not directly relate to individualized weight-based dosing, which might otherwise permit safe administration. Excessively large dosages of antihistamines, including promethazine hydrochloride, in pediatric patients may cause sudden death (see OVERDOSAGE). Hallucinations and convulsions have occurred with therapeutic doses and overdoses of promethazine hydrochloride in pediatric patients. In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonias with the use of promethazine HCI. . Other Considerations Administration of promethazine has been associated with reported cholestatic jaundice. Phenylephrine: Because phenylephrine is an adrenergic agent, it should be given with caution to patients with thyroid diseases, diabetes mellitus and heart diseases or those receiving tricyclic antidepressants. Men with symptomatic, benign prostatic hypertrophy can experience urinary retention when given oral nasal decongestants. Phenylephrine can cause a decrease in cardiac output, and extreme caution should be used when administering the drug parenterally or orally to patients with arteriosclerosis, to elderly individuals, and/or to patients with initially poor cerebral or coronary circulation. file://\ \FdswaI50\nonectd\N08306\S _ 030\2008-05-23\Promethazine, phenylephrne & Codei... 11/2412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7889 Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution C- V Page 7 of 16 Phenylephrine should be used with caution in patients taking diet preparations, such as amphetamines or phenylpropanolamine, because synergistic adrenergic effects could result in serious hypertensive response and possible stroke. PRECAUTIONS General Narcotic analgesics, including codeine, should be administered with caution and the initial dose reduced in patients with acute abdominal conditions, convulsive disorders, significant hepatic or renal impairment, fever, hypothyroidism, Addison's disease, ulcerative colitis, prostatic hypertrophy, in patients with recent gastrointestinal or urinary tract surgery and in the very young or elderly or debilitated patients. Drugs having anticholinergic properties should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, and bladder- neck obstruction. Promethazine should be used cautiously in persons with cardiovascular disease, or with impairment of liver function. Phenylephrine should be used with caution in patients with cardiovascular disease. Ultra-rapid Metabolizers of Codeine Some individuals may be ultra-rapid metabolizers due to a specific CYP2D62x2 genotype. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regiments, individuals who are ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1 % in Chinese and Japanese, 0.5 to 1 % in Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopian.s and Arabs. Data is not available for other ethnic groups. When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and should inform their patients about these risks and the signs of morphine overdose. (See PRECAUTIONS-Nursing Mothers). Information for Patients Patients should be advised to measure Promethazine HCI, Phenylephrine HCI and Codeine Phosphate Oral Solution with an accurate measuring device. A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when a half a teaspoon is measured. A pharmacist can recommend an appropriate measuring device and can provide instructions for measuring the correct dose. Promethazine, phenylephrine and codeine may cause marked drowsiness or may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehiCle or operating machinery. Ambulatory patients should be told to avoid engaging in such activities until it is known that they do not become drowsy or dizzy from promethazine, phenylephrine and codeine therapy. Pediatric patients should be supervised to avoid potential harm in bike riding or in other hazardous activities. . fie://\ \FdswaI50\nonectd\N08306\S _ 030\2008-05-23\Promethazine, phenylephrine & Codei... 1112412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7889 Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution C- V Page 8 of 16 The concomitant use of alcohol or other central nervous system depressants, including narcotic analgesics, sedatives, hypnotics and tranquilizers, may have an additive effect and should be avoided or their dosage reduced. Patients should be advised to report any involuntary muscle movements. Avoid prolonged exposure to the sun. Codeine, like other narcotic analgesics, may produce orthostatic hypotension in some ambulatory patients. Patients should be cautioned accordingly. Caution patients that some people have a variation in a liver enzyme and change codeine into morphine more rapidly and completely than other people. These people are ultra-rapid metabolizers and are more likely to have higher-than-normal levels of morphine in their blood after taking codeine which can result in overdose symptoms such as e~treme sleepiness, confusion, or shallow breathing. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer. Nursing mothers taking codeine can also have higher morphine levels in their breast milk if they are ultra-rapid metabolizers. These bigher levels of morphine in breast milk may lead to life- threatening or fatal side effects in nursing babies. Instruct nursing mothers to watch for signs of morphine toxicity in their infants including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby's doctor immediately if they notice these signs and, if they can not reach the doctor right away, to take the baby to an emergency room or call 911 (or local emergency services). Drug Interactions Codeine: In patients receiving MAO inhibitors, an initial small test dose is advisable to allow observation of any excessive narcotic effects or MAOI interaction. Promethazine: eNS Depressants - Promethazine may increase, prolong or intensify the sedative action of other central nervous system depressants, such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore, such agents should be avoided or administered in reduced dosage to patients receiving promethazine HCI. When given concomitantly with promethazine, the dose of barbiturates should be reduced by at least one-half, and the dose of narcotics should be reduced by one-quarter to one-half. Dosage must be individualized. Excessive amounts of promethazine HCI relative to a narcotic may lead to restlessness and motor hyperactivity in the patient with pain; these symptoms usually disappear with adequate control of the pain. Epinephrine -Because of the potential for promethazine to reverse epinephrine's vasopressor effect, epinephrine should NOT be used to treat hypotension associated with promethazine overdose. Anticholinergics- Concomitant use of other agents with anticholinergic properties should be undertaken with caution. Monoamine Oxidase Inhibitors (MAO!) - Drug interactions, including an increased incjdence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly. . file ://\ \F dswa 15 0\nonectd\N08 3 06\S _030\2008-05 - 23 \Promethazine, phenylephrine & Codei... 1112412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7889 Promethazine HCl, Phenylephrne HCl and Codeine Phosphate Oral Solution C- V Page 9 of16 Phenylephrine: Drug Effect Phenylephrine with prior administration of . Cardiac pressor response monoamine oxidase inhibitors (MAOI). potentiated. May cause acute hypertensive crisis. Phenylephrine with tricyclic antidepressant$. Pressor response increased. Phenylephrine with ergot alkaloids. Excessive rise in blood pressure. Phenylephrine with bronchodilator Tachycardia or other arrhythmias sympathomimetic agents and with may occur. epinephrine or other sympathomimetics. Phenylephrine with prior administration of Cardiostimulating effects propranolol or other ß-adrenergic blockers. blocked. Phenylephrine with atropine sulfate. Reflex bradycardia blocked; pressor response enhanced. Phenylephrine with prior administration of Pressor response decreased. phentolamine or other a-adrenergic blockers. Phenylephrine with diet preparations, such as Synergistic adrenergic response. amphetamines or phenylpropanolamine. Drug/Laboratory Test Interactions Because narcotic analgesics may increases biliary tract pressure, with resultant increase in plasma amylase or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after a narcotic analgesic has been given. The following laboratory tests may be affected in patients who are receiving therapy with promethazine hydrochloride. Pregnancy Tests: Diagnostic pregnancy tests based on immunological reactions between HCG and anti-HCG may result in false-negative or false-positive interpretations. Glucose Tolerance Test: An increase in blood glucose has been reported in patients receiving promethazine. Carcinogenesis, Mutagenesis, Impairment of Fertiliy Codeine and Promethazine: Long-term animal studies have not been performed to assess the carcinogenic potential of codeine or of promethazine, nor are there other animal or human data concerning carginogenicity, mutagenicity, or impairment of fertility with these agents. Codeine has been reported to show no evidence of carcinogenicity or mutagenicity in a variety of test systems, including the micronucleus and sperm abnormality assays and the Salmonella assay. Promethazine was nonmutagenic in the Salmonella test system of Ames. Phenylephrine: A study which followed the development of cancer in 143,574 patients over a four- file://\ \FdswaI50\nonectd\N08306\S _ 030\2008-05-23\Promethazine, phenylephrine & Codei... 11/2412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7889 Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution C-V Page 10 of 16 year period indicated that in 11,981 patients who received phenylephrine (systemic or topical), there was no statistically significant association between the drug and cancer at any or all sites. Long-term animal studies have not been performed to assess the carcinogenic potential of phenylephrine, nor are there other animal or human data concerning mutagenicity. A study of the effects of adrenergic drugs on ovum transport in rabbits indicated that treatment with phenylephrine did not alter incidence of pregnancy; the number of implantations was significantly reduced when high doses of the drug were used. Pregnancy Teratogenic Effects Pregnancy Category C: Codeine: A study in rats and rabbits reported no teratogenic effect of codeine administered during the period of organogenesis in doses ranging from 5 to 120 mg/kg. In the rat, doses at the 120- mg/kg level, in the toxic range for the aduit animal, were associated with an increase in embryo resorption at the time of implantation. In another study a single 100-mg/kg dose of codeine administered to pregnant mice reportedly resulted in delayed ossification in the offspring. There are no studies in humans, and the significance of these findings to humans, if any, is not known. Promethazine: Teratogenic effects have not been demonstrated in rat-feeding studies at doses of 6.25 and 12.5 mg/kg of promethazine HCI. These doses are from approximately 2.1 to 4.2 times the maximum recommended total daily dose of promethazine for a 50-kg subject, depending on the indication for which the drug is prescribed. Daily doses of 25 mg/kg intraperitoneally have been found to produce fetal mortality in rats. Specific studies to test the action of the drug on parturition, lactation, and development of the animal neonate were not done, but a general preliminary study in rats indicated no effect on these parameters. Although antihistamines have been found to produce fetal mortality in rodents, the pharmacological effects of histamine in the rodent do not parallel those in man. There are no adequate and well-controlled studies of promethazine in pregnant women. Phenylephrine: A study in rabbits indicated that continued moderate overexposure to phenylephrine (3 mg/day) during the second half of the pregnancy (22nd day of gestation to delivery) may contribute to perinatal wastage, prematurity, premature labor, and possibly fetal anomalies; when phenylephrine (3 mg/day) was given to rabbits during the first half of the pregnancy (3rd day after mating for seven days), a significant number gave birth to litters of low birth weight. Another study showed that phenylephrine was associated with anomalies of aortic arch and with ventricular septal defect in the chick embryo. Animal reproduction studies have not been conducted with the drug combination - promethazine, phenylephrine and codeine. It is not known whether this drug combination can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Promethazine HCI, Phenylephrine HCI and Codeine Phosphate Oral Solution should be given to a pregnant woman only if clearly needed. Promethazine HCI, Phenylephrine HCI and Codeine Phosphate Oral Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. fie://\ \FdswaI50\nonectd\N08306\S _ 030\2008-05-23\Promethazine, phenylephrine & Codei... 11124/2008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7889 Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution C- V Page 11 of 16 Nonteratogenic Effects Dependence has been reported in newborns whose mothers took opiates regularly during pregnancy. Withdrawal signs include irritability, excessive crying, tremors, hyperreflexia, fever, vomiting and diarrhea. Signs usually appear during the first few days of life. Promethazine administered to a pregnant woman within two weeks of delivery may inhibit platelet aggregation in the newborn. Labor and Delivery Narcotic analgesics cross the placental barrier. The closer to delivery and the larger the dose used, the greater the possibility of respiratory depression in the newborn. Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mOther has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required (see OVERDOSAGE). Limited data suggest that use of promethazine hydrochloride during labor and delivery does not have an appreciable effect on the duration of labor or delivery and does not increase the risk of need for intervention in the newborn. The effect of promethazine and/or codeine on later growth and development of the newborn is unknown. Administration of phenylephrine to patients in late pregnancy or labor may cause fetal anoxia or bradycardia by increasing contractility of the uterus and decreasing uterine blood flow. See also "Nonteratogenic Effects". Nursing Mothers Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine excreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher- than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1 % in Chinese and Japanese, 0.5 to 1 % in Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups. The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and the baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. Prescribers should closely monitor file:! /\ \FdswaI50\nonectd\N08306\S _ 030\2008-05-23\Promethazine, phenylephrine & Codei... 1112412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7889 Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution C- V Page 12 of 16 mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding. (See PRECAUTIONS-General-Ultra-rapid Metabolizers of Codeine). It is not known whether phenylephrine or promethazine are excreted in human milk. Pediatric Use The combination of promethazine hydrochloride, phenylephrine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age, because the combination may cause fatal respiratory depression in this age population (see WARNINGS- Boxed Warning and Use in Pediatric Patients). Geriatric Use Clinical studies of Promethazine HCI, Phenylephrine HCI and Codeine Phosphate Oral Solution did not include suffcient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of Promethazine HCI, Phenylephrine HCI and Codeine Phosphate Oral Solution and observed closely. ADVERSE REACTIONS Codeine: Central Nervous System - CNS depression, particularly respiratory depression, and to a lesser extent circulatory depression; light-headedness, dizziness, sedation, euphoria, dysphoria, headache, transient hallucination, disorientation, visual disturbances and convulsions. Cardiovascular - Tachycardia, bradycardia, palpitation, faintness, syncope, orthostatic hypotension (common to narcotic analgesics). Gastrointestinal- Nausea, vomiting, constipation, and biliary tract spasm. Patients with chronic ulcerative colitis may experience increased colonic motility; in patients with acute ulcerative colitis, toxic dilation has been reported. Genitourinary - Oliguria, urinary retention; antidiuretic effect has been reported (common to narcotic analgesics). Allergic - Infrequent pruritus, giant urticaria, angioneurotic edema, and laryngeal edema. Other - Flushing of the face, sweating and pruritus (due to opiate-induced histamine release); weakness. Promethazine: Central Nervous System - Drowsiness is the most prominent CNS effect of this drug. Sedation, somnolence, blurred vision, dizziness; confusion, disorientation and extrapyramidal symptoms such as oculogyric crisis, torticollis, and tongue protrusion; lassitude, tinnitus, incoordination, fie://\ \FdswaI50\noneCtd\N08306\S _ 030\2008-05-23\Promethazine, phenylephrine & Codei... 1112412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7889 Promethazine HCl, Phenylephrne HCl and Codeine Phosphate Oral Solution C- V Page 13 of 16 fatigue, euphoria, nervousness, diplopia, insomnia, tremors, convulsive seizures, excitation, catatonic-like states, hysteria. Hallucinations have also been reported. Cardiovascular - Increased or decreased blood pressure, tachycardia, bradycardia, faintness. Dermatologic - Dermatitis, photosensitivity, urticaria. Hematologic - Leukopenia, thrombocytopenia, thrombocytopenic purpura, agranulocytosis. Gastrointestinal- Dry mouth, nausea, vomiting, jaundice. Respiratory - Asthma, nasal stuffiness, respiratory depression (potentially fatal) and apnea (potentially fatal) (see WARNINGS - Promethazine; Respiratory Depression). Other - Angioneurotic edema. Neuroleptic malignant syndrome (potentially fatal) has also been reported (see WARNINGS - Promethazine; Neuroleptic Malignant Syndrome). Paradoxical Reactions - Hyperexcitability and abnormal movements have been reported in patients following a single administration of promethazine HCI. Consideration should be given to the discontinuation of promethazine HCI and to the use of other drugs if these reactions occur. Respiratory depression, nightmares, delirium and agitated behavior have also been reported in some of these patients. Phenylephrine: Central Nervous System - Restlessness, anxiety, nervousness and dizziness. Cardiovascular - Hypertension (see WARNINGS). Other - Primordial pain, respiratory distress, tremor and weakness. DRUG ABUSE AND DEPENDENCE Controlled Substance Promethazine HCI, Phenylephrine HCI and Codeine Phosphate Oral Solution ¡sa Schedule V Controlled Substance. Abuse Codeine is known to be subject to abuse; however, the abuse potential of oral codeine appears to be quite low. Even parenteral codeine does not appear to offer the psychic effects sought by addicts to the same degree as heroin or morphine. However, codeine must be administered only under close supervision to patients with a history of drug abuse or dependence. Dependence Psychological dependence, physical dependence and tolerance are known to occur with codeine. OVERDOSAGE Codeine Serious overdose with codeine is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence fie://\\FdswaI50\nonectd\N08306\S_030\2008-05-23\Promethazine, phenylephrine & Codei... 11/2412008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7889 Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution C- V Page 14 of 16 progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin and sometimes bradycardia and hypotension. The triad of coma, pinpoint pupils and respiratory depression is strongly suggestive of opiate poisoning. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. Promethazine is additive to the depressant effects of codeine. It is difficult to determine what constitutes a standard toxic or lethal dose. However, the lethal oral dose of codeine in an aduit is reported to be in the range of 0.5 to 1.0 gram. Infants and children are believed to be relatively more sensitive to opiates on a body-weight basis. Elderly patients are also comparatively intolerant to opiates. Promethazine Signs and symptoms of overdosage with promethazine HCI range from mild depression of the central nervous system and cardiovascular system to profound hypotension, respiratory depression, unconsciousness and sudden death. Other reported reactions include hyperreflexia, hypertonia, ataxia, athetosis and extensor-plantar reflexes (Babinski reflex). Stimulation may be evident, especially in children and geriatric patients. Convulsions may rarely occur. A paradoxical reaction has been reported in children receiving single doses of 75 mg to 125 mg orally, characterized by hyperexcitability and nightmares. Atropine-like signs and symptoms - dry mouth, fixed dilated pupils, flushing, as well as gastrointestinal symptoms, may occur. Phenylephrine Signs and symptoms of overdosage with phenylephrine include hypertension, headache, convulsions, cerebral hemorrhage, and vomiting. Ventricular premature beats and short paroxysms of ventricular tachycardia may also occur. Headache may be a symptom of hypertension. Bradycardia may also be seen early in phenylephrine overdosage through stimulation of baroreceptors. . Treatment: The treatment of overdosage with promethazine, phenylephrine and codeine is essentially symptomatic and supportive. Only in cases of extreme overdosage or individual sensitivity do vital signs including respiration, pulse, blood pressure, temperature, and EKG need to be monitored. Activated charcoal orally or by lavage may be given, or sodium or magnesium sulfate orally as a cathartic. Attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. The narcotic antagonist, naloxone hydrochloride, may be administered when significant respiratory depression occurs with promethazine, phenylephrine and codeine; any depressant effects of promethazine are not reversed by naloxone. Diazepam may be used to control convulsions. Avoid analeptics, which may cause convulsions. Acidosis and electrolyte losses should be corrected. A rise in temperature or pulmonary complications may signal the need for institution of antibiotic therapy. Severe hypotension usually responds to the administration of norepinephrine or phenylephrine. EPINEPHRINE SHOULD NOT BE USED, since its use in a patient with partial adrenergic blockade may further lower the blood pressure. Limited experience with dialysis indicates that it is not helpfuL. fie://\ \FdswaI50\nonectd\N08306\S _ 030\2008-05-23\Promethazine, phenylephrine & Codei... 11124/2008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7889 Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution C- V Page 15 of 16 DOSAGE AND ADMINISTRATION It is important that Promethazine HC/, Phenylephrine HCI and Codeine Phosphate Oral Solution is measured with an accurate measuring device (see PRECAUTIONS-Information for Patients). A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when half a teaspoon is to be measured. It is strongly recommended that an accurate measuring device be used. A pharmacist can provide an appropriate device and can provide instructions for measuring the correct dose. The combination of promethazine hydrochloride, phenylephrine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age, because the combination may cause fatal respiratory depression in this age population. The average effective dose is given in the following table: Adults (12 years of age and 5 mL (1 teaspoonful) every 4 to 6 hours, not to exceed 30.0 mL in 24 over) hours. Children 6 years to under 2.5 mL to 5 mL (% to 1 teaspoonful) every 4 to 6 hours, not to exceed 12 years 30.0 mL in 24 hours. HOW SUPPLIED Promethazine HCI, Phenylephrine HCI and Codeine Phosphate Oral Solution is a clear, reddish- orange solution supplied as follows: NDC 42769-7881-4 - bottles of 4 fl. oz. (118 mL) NDC 42769-7881-6 - bottles of 16 fl. oz. (473 mL) Keep bottles tightly closed. Store at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature.) Protect from light. Dispense in tight, light-resistant container (USP/NF) with a child-resistant closure. Manufactured for BayPharma TM, Inc. Baltimore, MD 21244 501-78816-0 Rev 05/08 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:37.233936	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/008306s030lbl.pdf', 'application_number': 8306, 'submission_type': 'SUPPL ', 'submission_number': 30}
10,701	_______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BENTYL safely and effectively. See full prescribing information for BENTYL. BENTYL (dicyclomine hydrochloride) capsules, for oral use BENTYL (dicyclomine hydrochloride) tablets, for oral use BENTYL (dicyclomine hydrochloride) oral syrup BENTYL (dicyclomine hydrochloride) injection, for intramuscular use Initial U.S. Approval: 1950 ----------------------------INDICATIONS AND USAGE--------------------------- BENTYL is an antispasmodic and anticholinergic (antimuscarinic) agent indicated for the treatment of functional bowel/irritable bowel syndrome (1) ----------------------DOSAGE AND ADMINISTRATION----------------------- Dosage for BENTYL must be adjusted to individual patient needs (2). If a dose is missed, patients should continue the normal dosing schedule (2). Oral in adults (2.1): • Starting dose: 20 mg four times a day. After a week treatment with the starting dose, the dose may be escalated to 40 mg four times a day, unless side effects limit dosage escalation • Discontinue BENTYL if efficacy not achieved or side effects require doses less than 80 mg per day after two weeks of treatment Intramuscular in adults (2.2): • Intramuscular administration recommended no longer than 1 or 2 days when patients cannot take oral administration • Recommended dose: 10 mg to 20 mg four times a day ---------------------DOSAGE FORMS AND STRENGTHS---------------------- • BENTYL capsules 10 mg (3) • BENTYL syrup 10 mg/5 mL (3) • BENTYL tablets 20 mg (3) • BENTYL injection 20 mg/2 mL (10 mg/mL) (3) ------------------------------- CONTRAINDICATIONS----------------------------- • Infants less than 6 months of age (4) • Glaucoma (4) • Nursing mothers (4) • Obstructive uropathy (4) • Unstable cardiovascular status in • Obstructive disease of the acute hemorrhage (4) gastrointestinal tract (4) • Myasthenia gravis (4) • Severe ulcerative colitis (4) • Reflux esophagitis (4) -----------------------WARNINGS AND PRECAUTIONS----------------------- • For Intramuscular injection only; should not be administered by any other route. Intravenous injection may result in thrombosis or thrombophlebitis and injection site reactions (5.1) • Cardiovascular conditions: worsening of conditions (5.2) • Peripheral and central nervous system: heat prostration can occur with drug use (fever and heat stroke due to decreased sweating); drug should be discontinued and supportive measures instituted (5.3) • Psychosis in patients sensitive to anticholinergic drugs: signs and symptoms resolve within 12 to 24 hours after discontinuation of BENTYL (5.3) • Myasthenia Gravis: overdose may lead to muscular weakness and paralysis. BENTYL should be given to patients with myasthenia gravis only to reduce adverse muscarinic effects of an anticholinesterase (5.4) • Incomplete intestinal obstruction: diarrhea may be an early symptom especially in patients with ileostomy or colostomy. Treatment with BENTYL would be inappropriate and possibly fatal (5.5) • Salmonella dysenteric patients: due to risk of toxic megacolon (5.6) • Ulcerative colitis: BENTYL should be used with caution in these patients; large doses may suppress intestinal motility or aggravate the serious complications of toxic megacolon (5.7) • Prostatic hypertrophy: BENTYL should be used with caution in these patients; may lead to urinary retention (5.8) • Hepatic and renal disease: should be used with caution (5.9) • Geriatric: use with caution in elderly who may be more susceptible to BENTYL’s adverse events (5.10) ------------------------------ADVERSE REACTIONS------------------------------- The most serious adverse reactions include cardiovascular and central nervous system symptoms. The most common adverse reactions (> 5% of patients) are dizziness, dry mouth, vision blurred, nausea, somnolence, asthenia and nervousness (6) To report SUSPECTED ADVERSE REACTIONS, contact AXCAN Pharma US, Inc. at 1-800-472-2634 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------ • Antiglaucoma agents: anticholinergics antagonize antiglaucoma agents and may increase intraoccular pressure (7) • Anticholinergic agents: may affect the gastrointestinal absorption of various drugs; may also increase certain actions or side effects of other anticholinergic drugs (7) • Antacids: interfere with the absorption of anticholinergic agents (7) -----------------------USE IN SPECIFIC POPULATIONS----------------------- • Pregnancy: use only if clearly needed (8.1) • Pediatric Use: Safety and effectiveness not established (8.4) • Hepatic and renal impairment: caution must be taken with patients with significantly impaired hepatic and renal function (8.6) See 17 for PATIENT COUNSELING INFORMATION. Revised: 07/2011 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Oral Dosage and Administration in Adults 2.2 Intramuscular Dosage and Administration in Adults 2.3 Preparation for Intramuscular Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Inadvertent Intravenous Administration 5.2 Cardiovascular Conditions 5.3 Peripheral and Central Nervous System 5.4 Myasthenia Gravis 5.5 Intestinal Obstruction 5.6 Toxic Dilatation of Intestinemegacolon 5.7 Ulcerative Colitis 5.8 Prostatic Hypertrophy 5.9 Hepatic and Renal Disease 5.10 Geriatric Population 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 6.3 Adverse Reactions Reported with Similar Drugs with Anticholinergic/Antispasmodic Action 7 DRUG INTERACTIONS 7.1 Antiglaucoma Agents 7.2 Other Drugs with Anticholinergic Activity 7.3 Other Gastrointestinal Motility Drugs 7.4 Effect of Antacids 7.5 Effect on Absorption of Other Drugs 7.6 Effect on Gastric Acid Secretion 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Inadvertent Intravenous Administration 17.2 Use in Infants 17.3 Use in Nursing Mothers 17.4 Peripheral and Central Nervous System *Sections or subsections omitted from the full prescribing information are not listed Reference ID: 2981284 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE BENTYL® (dicyclomine hydrochloride ) is indicated for the treatment of patients with functional bowel/irritable bowel syndrome. 2 DOSAGE AND ADMINISTRATION Dosage must be adjusted to individual patient needs. 2.1 Oral Dosage and Administration in Adults The recommended initial dose is 20 mg four times a day. After one week treatment with the initial dose, the dose may be increased to 40 mg four times a day unless side effects limit dosage escalation. If efficacy is not achieved within 2 weeks or side effects require doses below 80 mg per day, the drug should be discontinued. Documented safety data are not available for doses above 80 mg daily for periods longer than 2 weeks. 2.2 Intramuscular Dosage and Administration in Adults BENTYL Intramuscular Injection must be administered via intramuscular route only. Do not administer by any other route. The recommended intramuscular dose is 10mg to 20 mg four times a day [see Clinical Pharmacology (12)]. The intramuscular injection is to be used only for 1 or 2 days when the patient cannot take oral medication. Intramuscular injection is about twice as bioavailable as oral dosage forms. 2.3 Preparation for Intramuscular Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Aspirate the syringe before injecting to avoid intravascular injection, since thrombosis may occur if the drug is inadvertently injected intravascularly. 3 DOSAGE FORMS AND STRENGTHS • BENTYL 10 mg capsules: blue, imprinted BENTYL 10 • BENTYL 20 mg tablets: compressed, light blue, round, debossed BENTYL 20 • BENTYL syrup 10mg/5ml • BENTYL injection 20mg/2ml (10mg/ml) 4 CONTRAINDICATIONS BENTYL is contraindicated in infants less than 6 months of age [see Use in Specific Populations (8.4)], nursing mothers [see Use in Specific Populations (8.3)], and in patients with: • unstable cardiovascular status in acute hemorrhage • myasthenia gravis [see Warnings and Precautions (5.4)] • glaucoma [see Adverse Reactions (6.3) and Drug Interactions (7.1)] • obstructive uropathy [see Warnings and Precautions (5.8)] • obstructive disease of the gastrointestinal tract [see Warnings and Precautions (5.5)] • severe ulcerative colitis [see Warnings and Precautions (5.7)] • reflux esophagitis 5 WARNINGS AND PRECAUTIONS 5.1 Inadvertent Intravenous Administration BENTYL solution is for intramuscular administration only. Do not administer by any other route. Inadvertent intravenous administration may result in thrombosis, thrombophlebitis, and injection site reactions such as pain, edema, skin color change, and reflux sympathetic dystrophy syndrome [see Adverse Reactions (6.2)]. 5.2 Cardiovascular Conditions Dicyclomine hydrochloride needs to be used with caution in conditions characterized by tachyarrhythmia such as thyrotoxicosis, congestive heart failure and in cardiac surgery, where they may further accelerate the heart rate. Investigate any tachycardia before administration of dicyclomine hydrochloride. Care is required in patients with coronary heart disease, as ischemia and infarction may be worsened, and in patients with hypertension [see Adverse Reactions (6.3)]. 5.3 Peripheral and Central Nervous System The peripheral effects of dicyclomine hydrochloride are a consequence of their inhibitory effect on muscarinic receptors of the autonomic nervous system. They include dryness of the mouth with difficulty in swallowing and talking, thirst, reduced bronchial secretions, dilatation of the pupils (mydriasis) with loss of accommodation (cycloplegia) and photophobia, flushing and dryness of the skin, transient bradycardia followed by tachycardia, with palpitations and arrhythmias, and difficulty in micturition, as well as reduction in the tone and motility of the gastrointestinal tract leading to constipation [see Adverse Reactions (6)]. In the presence of high environmental temperature heat prostration can occur with drug use (fever and heat stroke due to decreased sweating). It should also be used cautiously in patients with fever. If symptoms occur, the drug should be discontinued and supportive measures instituted. Because of the inhibitory effect on muscarinic receptors within the autonomic nervous system, caution should be taken in patients with autonomic neuropathy. Central nervous system (CNS) signs and symptoms include confusion, disorientation, short-term amnesia, hallucinations, dysarthria, ataxia, coma, euphoria, fatigue, insomnia, agitation and mannerisms, and inappropriate affect. Psychosis has been reported in sensitive individuals given anticholinergic drugs. These CNS signs and symptoms usually resolve within 12 to 24 hours after discontinuation of the drug. BENTYL may produce drowsiness, dizziness or blurred vision. The patient should be warned not to engage in activities requiring mental alertness, such as operating a motor vehicle or other machinery or performing hazardous work while taking BENTYL. 5.4 Myasthenia Gravis With overdosage, a curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). It should not be given to patients with myasthenia gravis except to reduce adverse muscarinic effects of an anticholinesterase [see Contraindications (4)]. 5.5 Intestinal Obstruction Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance, treatment with this drug would be inappropriate and possibly harmful [see Contraindications (4)]. Rarely development of Ogilvie’s syndrome (colonic pseudo- obstruction) has been reported. Ogilvie’s syndrome is a clinical disorder with signs, symptoms, and radiographic appearance of an acute large bowel obstruction but with no evidence of distal colonic obstruction 5.6 Toxic Dilatation of Intestinemegacolon Toxic dilatation of intestine and intestinal perforation is possible when anticholinergic agents are administered in patients with Salmonella dysentery. 5.7 Ulcerative Colitis Caution should be taken in patients with ulcerative colitis. Large doses may suppress intestinal motility to the point of producing a paralytic ileus and the use of this drug may precipitate or aggravate the serious complication of toxic megacolon [see Adverse Reactions (6.3)]. BENTYL is contraindicated in patients with severe ulcerative colitis [see Contraindications (4)]. Reference ID: 2981284 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.8 Prostatic Hypertrophy BENTYL should be used with caution in patients with known or suspected prostatic enlargement, in whom prostatic enlargement may lead to urinary retention [see Adverse Reactions (6.3)]. 5.9 Hepatic and Renal Disease BENTYL should be used with caution in patients with known hepatic and renal impairment. 5.10 Geriatric Population Dicyclomine hydrochloride should be used with caution in elderly who may be more susceptible to its adverse effects. 6 ADVERSE REACTIONS The pattern of adverse effects seen with dicylomine is mostly related to its pharmacological actions at muscarinic receptors [see Clinical Pharmacology (12)]. They are a consequence of the inhibitory effect on muscarinic receptors within the autonomic nervous system. These effects are dose-related and are usually reversible when treatment is discontinued. The most serious adverse reactions reported with dicyclomine hydrochloride include cardiovascular and central nervous system symptoms [see Warnings and Precautions (5.2, 5.3)]. 6.3 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure in controlled clinical trials involving over 100 patients treated for functional bowel/irritable bowel syndrome with dicyclomine hydrochloride at initial doses of 160 mg daily (40 mg four times a day) In these trials most of the side effects were typically anticholinergic in nature and were reported by 61% of the patients. Table 1 presents adverse reactions (MedDRA 13.0 preferred terms) by decreasing order of frequency in a side-by-side comparison with placebo. Table 1: Adverse reactions experienced in controlled clinical trials with decreasing order of frequency MedDRA Preferred Term Dicyclomine Hydrochloride (40 mg four times a day) % Placebo % Dry Mouth 33 5 Dizziness 40 5 Vision blurred 27 2 Nausea 14 6 Somnolence 9 1 Asthenia 7 1 Nervousness 6 2 Nine percent (9%) of patients were discontinued from BENTYL because of one or more of these side effects (compared with 2% in the placebo group). In 41% of the patients with side effects, side effects disappeared or were tolerated at the 160 mg daily dose without reduction. A dose reduction from 160 mg daily to an average daily dose of 90 mg was required in 46% of the patients with side effects who then continued to experience a favorable clinical response; their side effects either disappeared or were tolerated. 6.4 Postmarketing Experience The following adverse reactions, presented by system organ class in alphabetical order, have been identified during post approval use of BENTYL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Cardiac disorders: palpitations, tachyarrhythmias • Eye disorders: cycloplegia, mydriasis, vision blurred • Gastrointestinal disorders: abdominal distension, abdominal pain, constipation, dry mouth, dyspepsia, nausea, vomiting • General disorders and administration site conditions: fatigue, malaise • Immune System Disorders: drug hypersensitivity including face oedema, angioedema, anaphylactic shock • Nervous system disorders: dizziness, headache, hallucinations insomnia, somnolence, syncope • Psychiatric disorders: confusional state, nervousness • Reproductive system and breast disorders: suppressed lactation • Respiratory, thoracic and mediastinal disorders: dyspnoea, nasal congestion • Skin and subcutaneous tissue disorder: dermatitis allergic, erythema, rash 6.5 Adverse Reactions Reported with Similar Drugs with Anticholinergic/Antispasmodic Action Gastrointestinal: anorexia, Central Nervous System: tingling, numbness, dyskinesia, speech disturbance, insomnia Peripheral Nervous System: With overdosage, a curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). Ophthalmologic: diplopia, increased ocular tension Dermatologic/Allergic: urticaria, itching, and other dermal manifestations; Genitourinary: urinary hesitancy, urinary retention in patients with prostatic hypertrophy Cardiovascular: hypertension Respiratory: apnea Other: decreased sweating,sneezing, throat congestion, impotence. With the injectable form, there may be temporary sensation of light-headedness. Some local irritation and focal coagulation necrosis may occur following the intramuscular injection of BENTYL. 7 DRUG INTERACTIONS 7.3 Antiglaucoma Agents Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Use of BENTYL in patients with glaucoma is not recommended [see Contraindications (4)]. 7.4 Other Drugs with Anticholinergic Activity The following agents may increase certain actions or side effects of anticholinergic drugs including BENTYL: amantadine, antiarrhythmic agents of Class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. 7.5 Other Gastrointestinal Motility Drugs Interaction with other gastrointestinal motility drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. 7.6 Effect of Antacids Because antacids may interfere with the absorption of anticholinergic agents including BENTYL, simultaneous use of these drugs should be avoided. 7.7 Effect on Absorption of Other Drugs Anticholinergic agents may affect gastrointestinal absorption of various drugs by affecting on gastrointestinal motility, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentration may result. 7.8 Effect on Gastric Acid Secretion The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. Reference ID: 2981284 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B Adequate and well-controlled studies have not been conducted with BENTYL in pregnant women at the recommended doses of 80 to 160 mg/day. However, epidemiologic studies did not show an increased risk of structural malformations among babies born to women who took products containing dicyclomine hydrochloride at doses up to 40 mg/day during the first trimester of pregnancy. Reproduction studies have been performed in rats and rabbits at doses up to 33 times the maximum recommended human dose based on 160 mg/day (3 mg/kg) and have revealed no evidence of harm to the fetus due to dicyclomine. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers BENTYL is contraindicated in women who are human milk feeding. Dicyclomine hydrochloride is excreted in human milk. Because of the potential for serious adverse reactions in human milk- fed infants from BENTYL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother [see Use in Specific Populations (8.4)]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. BENTYL is contraindicated in infants less than 6 months of age [see Contraindications (4)]. There are published cases reporting that the administration of dicyclomine hydrochloride syrup to infants has been followed by serious respiratory symptoms (dyspnea, shortness of breath, breathlessness, respiratory collapse, apnea and asphyxia), seizures, syncope, pulse rate fluctuations, muscular hypotonia, and coma, and death, however; no causal relationship has been established. 8.5 Geriatric Use Clinical studies of BENTYL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range in adults, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Renal Impairment Effects of renal impairment on PK, safety and efficacy of BENTYL have not been studied. BENTYL drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. BENTYL should be administered with caution in patients with renal impairment. 8.7 Hepatic Impairment Effects of renal impairment on PK, safety and efficacy of BENTYL have not been studied. BENTYL should be administered with caution in patients with hepatic impairment. 10 OVERDOSAGE In case of an overdose, patients should contact a physician, poison control center (1-800-222-1222), or emergency room. The signs and symptoms of overdosage include: headache; nausea; vomiting; blurred vision; dilated pupils; hot, dry skin; dizziness; dryness of the mouth; difficulty in swallowing; and CNS stimulation including convulsion. A curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). One reported event included a 37-year-old who reported numbness on the left side, cold fingertips, blurred vision, abdominal and flank pain, decreased appetite, dry mouth, and nervousness following ingestion of 320 mg daily (four 20 mg tablets four times daily). These events resolved after discontinuing the dicyclomine. The acute oral LD50 of the drug is 625 mg/kg in mice. The amount of drug in a single dose that is ordinarily associated with symptoms of overdosage or that is likely to be life- threatening, has not been defined. The maximum human oral dose recorded was 600 mg by mouth in a 10-month-old child and approximately 1500 mg in an adult, each of whom survived. In three of the infants who died following administration of dicyclomine hydrochloride [see Warnings and Precautions (5.1)], the blood concentrations of drug were 200, 220, and 505 ng/mL. It is not known if BENTYL is dialyzable. Treatment should consist of gastric lavage, emetics, and activated charcoal. Sedatives (e.g., short-acting barbiturates, benzodiazepines) may be used for management of overt signs of excitement. If indicated, an appropriate parenteral cholinergic agent may be used as an antidote. 11 DESCRIPTION BENTYL is an antispasmodic and anticholinergic (antimuscarinic) agent available in the following dosage forms: • BENTYL capsules for oral use contain 10 mg dicyclomine hydrochloride USP. BENTYL 10 mg capsules also contain inactive ingredients: calcium sulfate, corn starch, FD&C Blue No. 1, FD&C Red No. 40, gelatin, lactose, magnesium stearate, pregelatinized corn starch, and titanium dioxide. • BENTYL tablets for oral use contain 20 mg dicyclomine hydrochloride USP. BENTYL 20 mg tablets also contain inactive ingredients: acacia, dibasic calcium phosphate, corn starch, FD&C Blue No. 1, lactose, magnesium stearate, pregelatinized corn starch, and sucrose. • BENTYL syrup for oral use contains 10 mg dicyclomine hydrochloride USP in each 5 mL (1 teaspoonful). BENTYL syrup also contains inactive ingredients: citric acid, D&C Red No. 33, FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6, flavors, glucose, methylparaben, propylene glycol, propylparaben, saccharin sodium, and water. • BENTYL injection is a sterile, pyrogen-free, aqueous solution for intramuscular injection (NOT FOR INTRAVENOUS USE) supplied as an ampoule containing 20 mg/2 mL (10 mg/mL). Each mL contains 10 mg dicyclomine hydrochloride USP in sterile water for injection, made isotonic with sodium chloride. BENTYL (dicyclomine hydrochloride) is [bicyclohexyl]-1 carboxylic acid, 2-(diethylamino) ethyl ester, hydrochloride, with a molecular formula of C19H35NO2•HCl and the following structural formula: structural formulastructural formula O structural formula CH2 CH3 C O CH2 CH2 N structural formula . HCl CH2 CH3 structural formula Molecular weight: 345.95 Dicyclomine hydrochloride occurs as a fine, white, crystalline, practically odorless powder with a bitter taste. It is soluble in water, freely soluble in alcohol and chloroform, and very slightly soluble in ether. Reference ID: 2981284 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 CLINICAL PHARMACOLOGY 12.3 Mechanism of Action Dicyclomine relieves smooth muscle spasm of the gastrointestinal tract. Animal studies indicate that this action is achieved via a dual mechanism: • a specific anticholinergic effect (antimuscarinic) at the acetylcholine-receptor sites with approximately 1/8 the milligram potency of atropine (in vitro, guinea pig ileum); and • a direct effect upon smooth muscle (musculotropic) as evidenced by dicyclomine’s antagonism of bradykinin- and histamine-induced spasms of the isolated guinea pig ileum. Atropine did not affect responses to these two agonists. In vivo studies in cats and dogs showed dicyclomine to be equally potent against acetylcholine (ACh)- or barium chloride (BaCl2)-induced intestinal spasm while atropine was at least 200 times more potent against effects of ACh than BaCl2. Tests for mydriatic effects in mice showed that dicyclomine was approximately 1/500 as potent as atropine; antisialagogue tests in rabbits showed dicyclomine to be 1/300 as potent as atropine. 12.4 Pharmacodynamics BENTYL can inhibit the secretion of saliva and sweat, decrease gastrointestinal secretions and motility, cause drowsiness, dilate the pupils, increase heart rate, and depress motor function 12.5 Pharmacokinetics Absorption and Distribution In man, dicyclomine is rapidly absorbed after oral administration, reaching peak values within 60-90 minutes. Mean volume of distribution for a 20 mg oral dose is approximately 3.65 L/kg suggesting extensive distribution in tissues. Elimination The metabolism of dicyclomine was not studied The principal route of excretion is via the urine (79.5% of the dose). Excretion also occurs in the feces, but to a lesser extent (8.4%). Mean half-life of plasma elimination in one study was determined to be approximately 1.8 hours when plasma concentrations were measured for 9 hours after a single dose. In subsequent studies, plasma concentrations were followed for up to 24 hours after a single dose, showing a secondary phase of elimination with a somewhat longer half-life. 13 NONCLINICAL TOXICOLOGY 13.3 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of dicyclomine. In studies in rats at doses of up to 100 mg/kg/day, dicyclomine produced no deleterious effects on breeding, conception, or parturition. 14 CLINICAL STUDIES In controlled clinical trials involving over 100 patients who received drug, 82% of patients treated for functional bowel/irritable bowel syndrome with dicyclomine hydrochloride at initial doses of 160 mg daily (40 mg four times daily) demonstrated a favorable clinical response compared with 55% treated with placebo (p<0.05). 16 HOW SUPPLIED/STORAGE AND HANDLING BENTYL Capsules 10 mg blue capsules, imprinted BENTYL 10, supplied in bottles of 100. Store at room temperature, preferably below 86°F (30°C). NDC number: 58914-012-10. BENTYL Tablets 20 mg compressed, light blue, round tablets, debossed BENTYL 20, supplied in bottles of 100. To prevent fading, avoid exposure to direct sunlight. Store at room temperature, preferably below 86°F (30°C). NDC 58914-013-10. BENTYL Syrup 10 mg/5 mL pink syrup, supplied in 16 ounce bottles. Store at room temperature, preferably below 86°F (30°C). Protect from excessive heat. NDC 58914-015-16. BENTYL Injection 20 mg/2 mL (10 mg/mL) injection supplied in boxes of five 20 mg/2 mL ampules (10 mg/mL). Store at room temperature, preferably below 86°F (30°C). Protect from freezing. NDC 58914-080-52. 17 PATIENT COUNSELING INFORMATION 17.1 Inadvertent Intravenous Administration BENTYL Injection is for intramuscular administration only. Do not administer by any other route. Inadvertent administration may result in thrombosis or thrombophlebitis, and injection site such as pain, edema, skin color change and even reflex sympathetic dystrophy syndrome [see Adverse Reactions (6.2)]. 17.2 Use in Infants Inform parents and caregivers not to administer BENTYL in infants less than 6 months of age [see Use in Specific Populations (8.4) ]. 17.3 Use in Nursing Mothers Advise lactating women that BENTYL should not be used while human milk feeding their infants [see Use in Specific Populations (8.3,8.4)]. 17.4 Peripheral and Central Nervous System In the presence of a high environmental temperature, heat prostration can occur with BENTYL use (fever and heat stroke due to decreased sweating). If symptoms occur, the drug should be discontinued and a physician contacted. BENTYL may produce drowsiness or blurred vision. The patient should be warned not to engage in activities requiring mental alertness, such as operating a motor vehicle or other machinery or to perform hazardous work while taking BENTYL [see Warnings and Precautions (5.3)]. Manufactured for: Axcan Pharma US, Inc. 22 Inverness Center Parkway Suite 310 Birmingham, AL 35242 USA www.axcan.com BENTYL® is a registered trademark owned by Axcan Pharma Inc., an affiliated company of Axcan Pharma US, Inc. Reference ID: 2981284 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:37.433210	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/008370s032lbl.pdf', 'application_number': 8370, 'submission_type': 'SUPPL ', 'submission_number': 32}
10,704	NDA 08-578/S-016 PRESCRIBING INFORMATION DARAPRIM® (pyrimethamine) 25-mg Scored Tablets DESCRIPTION DARAPRIM (pyrimethamine) is an antiparasitic compound available in tablet form for oral administration. Each scored tablet contains 25 mg pyrimethamine and the inactive ingredients corn and potato starch, lactose, and magnesium stearate. Pyrimethamine, known chemically as 5-(4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine, has the following structural formula: C12H13ClN4 Mol. Wt 248.71 CLINICAL PHARMACOLOGY Pyrimethamine is well absorbed with peak levels occurring between 2 to 6 hours following administration. It is eliminated slowly and has a plasma half-life of approximately 96 hours. Pyrimethamine is 87% bound to human plasma proteins. Microbiology: Pyrimethamine is a folic acid antagonist and the rationale for its therapeutic action is based on the differential requirement between host and parasite for nucleic acid precursors involved in growth. This activity is highly selective against plasmodia and Toxoplasma gondii. Pyrimethamine possesses blood schizonticidal and some tissue schizonticidal activity against malaria parasites of humans. However, the 4-amino-quinoline compounds are more effective against the erythrocytic schizonts. It does not destroy gametocytes, but arrests sporogony in the mosquito. The action of pyrimethamine against Toxoplasma gondii is greatly enhanced when used in conjunction with sulfonamides. This was demonstrated by Eyles and Coleman 1 in the treatment of experimental toxoplasmosis in the mouse. Jacobs et al 2 demonstrated that combination of the 2 drugs effectively prevented the development of severe uveitis in most rabbits following the inoculation of the anterior chamber of the eye with toxoplasma. INDICATIONS AND USAGE Treatment of Toxoplasmosis: DARAPRIM is indicated for the treatment of toxoplasmosis when used conjointly with a sulfonamide, since synergism exists with this combination. Treatment of Acute Malaria: DARAPRIM is also indicated for the treatment of acute malaria. It should not be used alone to treat acute malaria. Fast-acting schizonticides such as chloroquine or quinine are indicated and preferable for the treatment of acute malaria. However, conjoint use of DARAPRIM with a sulfonamide (e.g., sulfadoxine) will initiate transmission control and suppression of susceptible strains of plasmodia. Chemoprophylaxis of Malaria: DARAPRIM is indicated for the chemoprophylaxis of malaria due to susceptible strains of plasmodia. However, resistance to pyrimethamine is prevalent worldwide. It is not suitable as a prophylactic agent for travelers to most areas. CONTRAINDICATIONS Use of DARAPRIM is contraindicated in patients with known hypersensitivity to pyrimethamine or to any component of the formulation. Use of the drug is also contraindicated in patients with documented megaloblastic anemia due to folate deficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08-578/S-016 WARNINGS The dosage of pyrimethamine required for the treatment of toxoplasmosis is 10 to 20 times the recommended antimalaria dosage and approaches the toxic level. If signs of folate deficiency develop (see ADVERSE REACTIONS), reduce the dosage or discontinue the drug according to the response of the patient. Folinic acid (leucovorin) should be administered in a dosage of 5 to 15 mg daily (orally, IV, or IM) until normal hematopoiesis is restored. Data in 2 humans indicate that pyrimethamine may be carcinogenic: a 51-year-old female who developed chronic granulocytic leukemia after taking pyrimethamine for 2 years for toxoplasmosis, 3 and a 56-year-old patient who developed reticulum cell sarcoma after 14 months of pyrimethamine for toxoplasmosis. 4 Pyrimethamine has been reported to produce a significant increase in the number of lung tumors in mice when given intraperitoneally at doses of 25 mg/kg. 5 DARAPRIM should be kept out of the reach of infants and children as they are extremely susceptible to adverse effects from an overdose. Deaths in pediatric patients have been reported after accidental ingestion. PRECAUTIONS General: The recommended dosage for chemoprophylaxis of malaria should not be exceeded. A small “starting” dose for toxoplasmosis is recommended in patients with convulsive disorders to avoid the potential nervous system toxicity of pyrimethamine. DARAPRIM should be used with caution in patients with impaired renal or hepatic function or in patients with possible folate deficiency, such as individuals with malabsorption syndrome, alcoholism, or pregnancy, and those receiving therapy, such as phenytoin, affecting folate levels (see Pregnancy subsection). Information for Patients: Patients should be warned that at the first appearance of a skin rash they should stop use of DARAPRIM and seek medical attention immediately. Patients should also be warned that the appearance of sore throat, pallor, purpura, or glossitis may be early indications of serious disorders which require treatment with DARAPRIM to be stopped and medical treatment to be sought. Women of childbearing potential who are taking DARAPRIM should be warned against becoming pregnant. Patients should be warned to keep DARAPRIM out of the reach of children. Patients should be advised not to exceed recommended doses. Patients should be warned that if anorexia and vomiting occur, they may be minimized by taking the drug with meals. Concurrent administration of folinic acid is strongly recommended when used for the treatment of toxoplasmosis in all patients. Laboratory Tests: In patients receiving high dosage, as for the treatment of toxoplasmosis, semiweekly blood counts, including platelet counts, should be performed. Drug Interactions: Pyrimethamine may be used with sulfonamides, quinine and other antimalarials, and with other antibiotics. However, the concomitant use of other antifolic drugs or agents associated with myelosuppression including sulfonamides or trimethoprim-sulfamethoxazole combinations, proguanil, zidovudine, or cytostatic agents (e.g., methotrexate), while the patient is receiving pyrimethamine, may increase the risk of bone marrow suppression. If signs of folate deficiency develop, pyrimethamine should be discontinued. Folinic acid (leucovorin) should be administered until normal hematopoiesis is restored (see WARNINGS). Mild hepatotoxicity has been reported in some patients when lorazepam and pyrimethamine were administered concomitantly. Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section for information on carcinogenesis. Mutagenesis: Pyrimethamine has been shown to be nonmutagenic in the following in vitro assays: the Ames point mutation assay, the Rec assay, and the E. coli WP2 assay. It was positive in the L5178Y/TK +/- mouse lymphoma assay in the absence of exogenous metabolic activation. 6 Human blood lymphocytes cultured in vitro had structural chromosome aberrations induced by pyrimethamine. In vivo, chromosomes analyzed from the bone marrow of rats dosed with pyrimethamine showed an increased number of structural and numerical aberrations. Pregnancy: Teratogenic Effects: Pregnancy Category C. Pyrimethamine has been shown to be teratogenic in rats when given in oral doses 7 times the human dose for chemoprophylaxis of malaria or 2.5 times the human dose for treatment of toxoplasmosis. At these doses in rats, there was a significant increase in abnormalities such as cleft palate, brachygnathia, oligodactyly, and microphthalmia. Pyrimethamine has also been shown to produce terata such as meningocele in hamsters and cleft palate in miniature pigs when given in oral doses 170 and 5 times the human dose, respectively, for chemoprophylaxis of malaria or for treatment of toxoplasmosis. There are no adequate and well-controlled studies in pregnant women. DARAPRIM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Concurrent administration of folinic acid is strongly recommended when used for the treatment of toxoplasmosis during pregnancy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08-578/S-016 Nursing Mothers: Pyrimethamine is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from pyrimethamine and from concurrent use of a sulfonamide with DARAPRIM for treatment of some patients with toxoplasmosis, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see WARNINGS and PRECAUTIONS: Pregnancy ). Pediatric Use: See DOSAGE AND ADMINISTRATION section. Geriatric Use: Clinical studies of DARAPRIM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS Hypersensitivity reactions, occasionally severe (such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and anaphylaxis), and hyperphenylalaninemia, can occur particularly when pyrimethamine is administered concomitantly with a sulfonamide. Consult the complete prescribing information for the relevant sulfonamide for sulfonamide-associated adverse events. With doses of pyrimethamine used for the treatment of toxoplasmosis, anorexia and vomiting may occur. Vomiting may be minimized by giving the medication with meals; it usually disappears promptly upon reduction of dosage. Doses used in toxoplasmosis may produce megaloblastic anemia, leukopenia, thrombocytopenia, pancytopenia, atrophic glossitis, hematuria, and disorders of cardiac rhythm. Hematologic effects, however, may also occur at low doses in certain individuals (see PRECAUTIONS: General). Pulmonary eosinophilia has been reported rarely. OVERDOSAGE Following the ingestion of 300 mg or more of pyrimethamine, gastrointestinal and/or central nervous system signs may be present, including convulsions. The initial symptoms are usually gastrointestinal and may include abdominal pain, nausea, severe and repeated vomiting, possibly including hematemesis. Central nervous system toxicity may be manifest by initial excitability, generalized and prolonged convulsions which may be followed by respiratory depression, circulatory collapse, and death within a few hours. Neurological symptoms appear rapidly (30 minutes to 2 hours after drug ingestion), suggesting that in gross overdosage pyrimethamine has a direct toxic effect on the central nervous system. The fatal dose is variable, with the smallest reported fatal single dose being 375 mg. There are, however, reports of pediatric patients who have recovered after taking 375 to 625 mg. There is no specific antidote to acute pyrimethamine poisoning. In the event of overdosage, symptomatic and supportive measures should be employed. Gastric lavage is recommended and is effective if carried out very soon after drug ingestion. Parenteral diazepam may be used to control convulsions. Folinic acid should also be administered within 2 hours of drug ingestion to be most effective in counteracting the effects on the hematopoietic system (see WARNINGS). Due to the long half-life of pyrimethamine, daily monitoring of peripheral blood counts is recommended for up to several weeks after the overdose until normal hematologic values are restored. DOSAGE AND ADMINISTRATION For Treatment of Toxoplasmosis: The dosage of DARAPRIM for the treatment of toxoplasmosis must be carefully adjusted so as to provide maximum therapeutic effect and a minimum of side effects. At the dosage required, there is a marked variation in the tolerance to the drug. Young patients may tolerate higher doses than older individuals. Concurrent administration of folinic acid is strongly recommended in all patients. The adult starting dose is 50 to 75 mg of the drug daily, together with 1 to 4 g daily of a sulfonamide of the sulfapyrimidine type, e.g., sulfadoxine. This dosage is ordinarily continued for 1 to 3 weeks, depending on the response of the patient and tolerance to therapy. The dosage may then be reduced to about one half that previously given for each drug and continued for an additional 4 to 5 weeks. The pediatric dosage of DARAPRIM is 1 mg/kg/day divided into 2 equal daily doses; after 2 to 4 days this dose may be reduced to one half and continued for approximately 1 month. The usual pediatric sulfonamide dosage is used in conjunction with DARAPRIM. For Treatment of Acute Malaria: DARAPRIM is NOT recommended alone in the treatment of acute malaria. Fast-acting schizonticides, such as chloroquine or quinine, are indicated for treatment of acute malaria. However, DARAPRIM at a dosage of 25 mg daily for 2 days with a sulfonamide will initiate transmission control and suppression of non-falciparum malaria. DARAPRIM is only recommended for patients infected in areas where susceptible plasmodia exist. Should circumstances arise wherein DARAPRIM must be used alone in semi-immune persons, the adult dosage for acute This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08-578/S-016 malaria is 50 mg for 2 days; children 4 through 10 years old may be given 25 mg daily for 2 days. In any event, clinical cure should be followed by the once-weekly regimen described below for chemoprophylaxis. Regimens which include suppression should be extended through any characteristic periods of early recrudescence and late relapse, i.e., for at least 10 weeks in each case. For Chemoprophylaxis of Malaria: Adults and pediatric patients over 10 years — 25 mg (1 tablet) once weekly Children 4 through 10 years — 12.5 mg (1/2 tablet) once weekly Infants and children under 4 years — 6.25 mg (1/4 tablet) once weekly HOW SUPPLIED White, scored tablets containing 25 mg pyrimethamine, imprinted with “DARAPRIM” and “A3A” in bottles of 100 (NDC 0173-0201-55). Store at 15° to 25°C (59° to 77°F) in a dry place and protect from light. REFERENCES 1. Eyles DE, Coleman N. Synergistic effect of sulfadiazine and Daraprim against experimental toxoplasmosis in the mouse. Antibiot Chemother. 1953;3:483-490. 2. Jacobs L, Melton ML, Kaufman HE. Treatment of experimental ocular toxoplasmosis. Arch Ophthalmol. 1964;71:111- 118. 3. Jim RTS, Elizaga FV. Development of chronic granulocytic leukemia in a patient treated with pyrimethamine. Hawaii Med J. 1977;36:173-176. 4. Sadoff L. Antimalarial drugs and Burkitt’s lymphoma. Lancet. 1973;2:1262-1263. 5. Bahna L. Pyrimethamine. LARC Monogr Eval Carcinog Risk Chem. 1977;13:233-242. 6. Clive D, Johnson KO, Spector JKS, et al. Validation and characterization of the L5178Y/TK +/- mouse lymphoma mutagen assay system. Mut Res. 1979;59:61-108. Manufactured by DSM Pharmaceuticals, Inc. Greenville, NC 27834 for GlaxoSmithKline Research Triangle Park, NC 27709 2003, GlaxoSmithKline. All rights reserved. March 2003 RL-1179 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:37.474069	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/08578slr016_daraprim_lbl.pdf', 'application_number': 8578, 'submission_type': 'SUPPL ', 'submission_number': 16}
10,703	Anectine® (Succinylcholine Chloride Injection, USP) WARNING RISK OF CARDIAC ARREST FROM HYPERKALEMIC RHABDOMYOLYSIS There have been rare reports of acute rhabdomyolysis with hyperkalemia followed by ventricular dysrhythmias, cardiac arrest, and death after the administration of succinylcholine to apparently healthy children who were subsequently found to have undiagnosed skeletal muscle myopathy, most frequently Duchenne's muscular dystrophy. This syndrome often presents as peaked T-waves and sudden cardiac arrest within minutes after the administration of the drug in healthy appearing children (usually, but not exclusively, males, and most frequently 8 years of age or younger). There have also been reports in adolescents. Therefore, when a healthy appearing infant or child develops cardiac arrest soon after administration of succinylcholine not felt to be due to inadequate ventilation, oxygenation, or anesthetic overdose, immediate treatment for hyperkalemia should be instituted. This should include administration of intravenous calcium, bicarbonate, and glucose with insulin, with hyperventilation. Due to the abrupt onset of this syndrome, routine resuscitative measures are likely to be unsuccessful. However, extraordinary and prolonged resuscitative efforts have resulted in successful resuscitation in some reported cases. In addition, in the presence of signs of malignant hyperthermia, appropriate treatment should be instituted concurrently. Since there may be no signs or symptoms to alert the practitioner to which patients are at risk, it is recommended that the use of succinylcholine in children should be reserved for emergency intubation or instances where immediate securing of the airway is necessary, e.g. laryngospasm, difficult airway, full stomach, or for intramuscular use when a suitable vein is inaccessible (see PRECAUTIONS: Pediatric Use and DOSAGE AND ADMINISTRATION). This drug should be used only by individuals familiar with its actions, characteristics, and hazards. DESCRIPTION ANECTINE (succinylcholine chloride) is an ultra short-acting depolarizing-type, skeletal muscle relaxant for intravenous (IV) administration. Reference ID: 2867696 Succinylcholine chloride is a white, odorless, slightly bitter powder and very soluble in water. The drug is unstable in alkaline solutions but relatively stable in acid solutions, depending upon the concentration of the solution and the storage temperature. Solutions of succinylcholine chloride should be stored under refrigeration to preserve potency. ANECTINE Injection is a sterile nonpyrogenic solution for IV injection, containing 20 mg succinylcholine chloride in each mL and made isotonic with sodium chloride. The pH is adjusted to 3.5 with hydrochloric acid. Methylparaben (0.1%) is added as a preservative. The chemical name for succinylcholine chloride is 2,2'-[(1,4-dioxo-1,4 butanediyl)bis(oxy)]bis[N,N,N-trimethylethanaminium] dichloride, and the structural formula is: structural formula CLINICAL PHARMACOLOGY Succinylcholine is a depolarizing skeletal muscle relaxant. As does acetylcholine, it combines with the cholinergic receptors of the motor end plate to produce depolarization. This depolarization may be observed as fasciculations. Subsequent neuromuscular transmission is inhibited so long as adequate concentration of succinylcholine remains at the receptor site. Onset of flaccid paralysis is rapid (less than 1 minute after IV administration), and with single administration lasts approximately 4 to 6 minutes. Succinylcholine is rapidly hydrolyzed by plasma cholinesterase to succinylmonocholine (which possesses clinically insignificant depolarizing muscle relaxant properties) and then more slowly to succinic acid and choline (see PRECAUTIONS). About 10% of the drug is excreted unchanged in the urine. The paralysis following administration of succinylcholine is progressive, with differing sensitivities of different muscles. This initially involves consecutively the levator muscles of the face, muscles of the glottis, and finally, the intercostals and the diaphragm and all other skeletal muscles. Succinylcholine has no direct action on the uterus or other smooth muscle structures. Because it is highly ionized and has low fat solubility, it does not readily cross the placenta. Tachyphylaxis occurs with repeated administration (see PRECAUTIONS). Depending on the dose and duration of succinylcholine administration, the characteristic depolarizing neuromuscular block (Phase I block) may change to a block with characteristics superficially resembling a nondepolarizing block (Phase II block). This may be associated with prolonged respiratory muscle paralysis or weakness in patients who manifest the transition to Phase II block. When this diagnosis is confirmed by peripheral nerve stimulation, it may sometimes be reversed with anticholinesterase drugs such as neostigmine (see PRECAUTIONS). Anticholinesterase drugs may not always be effective. If given before succinylcholine is metabolized by cholinesterase, anticholinesterase drugs may prolong rather than shorten paralysis. Reference ID: 2867696 Succinylcholine has no direct effect on the myocardium. Succinylcholine stimulates both autonomic ganglia and muscarinic receptors which may cause changes in cardiac rhythm, including cardiac arrest. Changes in rhythm, including cardiac arrest, may also result from vagal stimulation, which may occur during surgical procedures, or from hyperkalemia, particularly in children (see PRECAUTIONS: Pediatric Use). These effects are enhanced by halogenated anesthetics. Succinylcholine causes an increase in intraocular pressure immediately after its injection and during the fasciculation phase, and slight increases which may persist after onset of complete paralysis (see WARNINGS). Succinylcholine may cause slight increases in intracranial pressure immediately after its injection and during the fasciculation phase (see PRECAUTIONS). As with other neuromuscular blocking agents, the potential for releasing histamine is present following succinylcholine administration. Signs and symptoms of histamine-mediated release such as flushing, hypotension, and bronchoconstriction are, however, uncommon in normal clinical usage. Succinylcholine has no effect on consciousness, pain threshold, or cerebration. It should be used only with adequate anesthesia (see WARNINGS). INDICATIONS AND USAGE Succinylcholine chloride is indicated as an adjunct to general anesthesia, to facilitate tracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation. CONTRAINDICATIONS Succinylcholine is contraindicated in persons with personal or familial history of malignant hyperthermia, skeletal muscle myopathies, and known hypersensitivity to the drug. It is also contraindicated in patients after the acute phase of injury following major burns, multiple trauma, extensive denervation of skeletal muscle, or upper motor neuron injury, because succinylcholine administered to such individuals may result in severe hyperkalemia which may result in cardiac arrest (see WARNINGS). The risk of hyperkalemia in these patients increases over time and usually peaks at 7 to 10 days after the injury. The risk is dependent on the extent and location of the injury. The precise time of onset and the duration of the risk period are not known. WARNINGS SUCCINYLCHOLINE SHOULD BE USED ONLY BY THOSE SKILLED IN THE MANAGEMENT OF ARTIFICIAL RESPIRATION AND ONLY WHEN FACILITIES ARE INSTANTLY AVAILABLE FOR TRACHEAL INTUBATION AND FOR PROVIDING ADEQUATE VENTILATION OF THE PATIENT, INCLUDING THE ADMINISTRATION OF OXYGEN UNDER POSITIVE PRESSURE AND THE ELIMINATION OF CARBON DIOXIDE. THE CLINICIAN MUST BE PREPARED TO ASSIST OR CONTROL RESPIRATION. TO AVOID DISTRESS TO THE PATIENT, SUCCINYLCHOLINE SHOULD NOT BE ADMINISTERED BEFORE UNCONSCIOUSNESS HAS BEEN INDUCED. IN EMERGENCY SITUATIONS, HOWEVER, IT MAY BE NECESSARY TO ADMINISTER SUCCINYLCHOLINE BEFORE UNCONSCIOUSNESS IS INDUCED. Reference ID: 2867696 SUCCINYLCHOLINE IS METABOLIZED BY PLASMA CHOLINESTERASE AND SHOULD BE USED WITH CAUTION, IF AT ALL, IN PATIENTS KNOWN TO BE OR SUSPECTED OF BEING HOMOZYGOUS FOR THE ATYPICAL PLASMA CHOLINESTERASE GENE. Anaphylaxis Severe anaphylactic reactions to neuromuscular blocking agents, including ANECTINE, have been reported. These reactions have in some cases been life-threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should also be taken in those individuals who have had previous anaphylactic reactions to other neuromuscular blocking agents since cross-reactivity between neuromuscular blocking agents, both depolarizing and non- depolarizing, has been reported in this class of drugs. Hyperkalemia (SEE BOX WARNING.) Succinylcholine should be administered with GREAT CAUTION to patients suffering from electrolyte abnormalities and those who may have massive digitalis toxicity, because in these circumstances succinylcholine may induce serious cardiac arrhythmias or cardiac arrest due to hyperkalemia. GREAT CAUTION should be observed if succinylcholine is administered to patients during the acute phase of injury following major burns, multiple trauma, extensive denervation of skeletal muscle, or upper motor neuron injury (see CONTRAINDICATIONS). The risk of hyperkalemia in these patients increases over time and usually peaks at 7 to 10 days after the injury. The risk is dependent on the extent and location of the injury. The precise time of onset and the duration of the risk period are undetermined. Patients with chronic abdominal infection, subarachnoid hemorrhage, or conditions causing degeneration of central and peripheral nervous systems should receive succinylcholine with GREAT CAUTION because of the potential for developing severe hyperkalemia. Malignant Hyperthermia Succinylcholine administration has been associated with acute onset of malignant hyperthermia, a potentially fatal hypermetabolic state of skeletal muscle. The risk of developing malignant hyperthermia following succinylcholine administration increases with the concomitant administration of volatile anesthetics. Malignant hyperthermia frequently presents as intractable spasm of the jaw muscles (masseter spasm) which may progress to generalized rigidity, increased oxygen demand, tachycardia, tachypnea, and profound hyperpyrexia. Successful outcome depends on recognition of early signs, such as jaw muscle spasm, acidosis, or generalized rigidity to initial administration of succinylcholine for tracheal intubation, or failure of tachycardia to respond to deepening anesthesia. Skin mottling, rising temperature, and coagulopathies may occur later in the course of the hypermetabolic process. Recognition of the syndrome is a signal for discontinuance of anesthesia, attention to increased oxygen consumption, correction of acidosis, support of circulation, assurance of adequate urinary output, and institution of measures to control rising temperature. Intravenous dantrolene sodium is recommended as an adjunct to supportive measures in the management of this problem. Consult literature references and the dantrolene prescribing information for additional information about the management of malignant Reference ID: 2867696 hyperthermic crisis. Continuous monitoring of temperature and expired CO2 is recommended as an aid to early recognition of malignant hyperthermia. Other In both adults and children, the incidence of bradycardia, which may progress to asystole, is higher following a second dose of succinylcholine. The incidence and severity of bradycardia is higher in children than in adults. Pretreatment with anticholinergic agents (e.g., atropine) may reduce the occurrence of bradyarrhythmias. Succinylcholine causes an increase in intraocular pressure. It should not be used in instances in which an increase in intraocular pressure is undesirable (e.g., narrow angle glaucoma, penetrating eye injury) unless the potential benefit of its use outweighs the potential risk. Succinylcholine is acidic (pH = 3.5) and should not be mixed with alkaline solutions having a pH greater than 8.5 (e.g., barbiturate solutions). PRECAUTIONS (SEE BOX WARNING.) General When succinylcholine is given over a prolonged period of time, the characteristic depolarization block of the myoneural junction (Phase I block) may change to a block with characteristics superficially resembling a nondepolarizing block (Phase II block). Prolonged respiratory muscle paralysis or weakness may be observed in patients manifesting this transition to Phase II block. The transition from Phase I to Phase II block has been reported in seven of seven patients studied under halothane anesthesia after an accumulated dose of 2 to 4 mg/kg succinylcholine (administered in repeated, divided doses). The onset of Phase II block coincided with the onset of tachyphylaxis and prolongation of spontaneous recovery. In another study, using balanced anesthesia (N2O/O2/narcotic-thiopental) and succinylcholine infusion, the transition was less abrupt, with great individual variability in the dose of succinylcholine required to produce Phase II block. Of 32 patients studied, 24 developed Phase II block. Tachyphylaxis was not associated with the transition to Phase II block, and 50% of the patients who developed Phase II block experienced prolonged recovery. When Phase II block is suspected in cases of prolonged neuromuscular blockade, positive diagnosis should be made by peripheral nerve stimulation prior to administration of any anticholinesterase drug. Reversal of Phase II block is a medical decision which must be made upon the basis of the individual, clinical pharmacology, and the experience and judgment of the physician. The presence of Phase II block is indicated by fade of responses to successive stimuli (preferably “train-of-four”). The use of an anticholinesterase drug to reverse Phase II block should be accompanied by appropriate doses of an anticholinergic drug to prevent disturbances of cardiac rhythm. After adequate reversal of Phase II block with an anticholinesterase agent, the patient should be continually observed for at least 1 hour for signs of return of muscle relaxation. Reversal should not be attempted unless: (1) a peripheral nerve stimulator is used to determine the presence of Phase II block (since anticholinesterase agents will potentiate succinylcholine- induced Phase I block), and (2) spontaneous recovery of muscle twitch has been observed for at least 20 minutes and has reached a plateau with further recovery proceeding slowly; this delay is to ensure complete hydrolysis of succinylcholine by plasma cholinesterase prior to administration of the anticholinesterase agent. Should the type of block be misdiagnosed, depolarization of the Reference ID: 2867696 type initially induced by succinylcholine (i.e., Phase I block) will be prolonged by an anticholinesterase agent. Succinylcholine should be employed with caution in patients with fractures or muscle spasm because the initial muscle fasciculations may cause additional trauma. Succinylcholine may cause a transient increase in intracranial pressure; however, adequate anesthetic induction prior to administration of succinylcholine will minimize this effect. Succinylcholine may increase intragastric pressure, which could result in regurgitation and possible aspiration of stomach contents. Neuromuscular blockade may be prolonged in patients with hypokalemia or hypocalcemia. Since allergic cross-reactivity has been reported in this class, request information from your patients about previous anaphylactic reactions to other neuromuscular blocking agents. In addition, inform your patients that severe anaphylactic reactions to neuromuscular blocking agents, including ANECTINE have been reported. Reduced Plasma Cholinesterase Activity Succinylcholine should be used carefully in patients with reduced plasma cholinesterase (pseudocholinesterase) activity. The likelihood of prolonged neuromuscular block following administration of succinylcholine must be considered in such patients (see DOSAGE AND ADMINISTRATION). Plasma cholinesterase activity may be diminished in the presence of genetic abnormalities of plasma cholinesterase (e.g., patients heterozygous or homozygous for atypical plasma cholinesterase gene), pregnancy, severe liver or kidney disease, malignant tumors, infections, burns, anemia, decompensated heart disease, peptic ulcer, or myxedema. Plasma cholinesterase activity may also be diminished by chronic administration of oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors, and by irreversible inhibitors of plasma cholinesterase (e.g., organophosphate insecticides, echothiophate, and certain antineoplastic drugs). Patients homozygous for atypical plasma cholinesterase gene (1 in 2500 patients) are extremely sensitive to the neuromuscular blocking effect of succinylcholine. In these patients, a 5- to 10-mg test dose of succinylcholine may be administered to evaluate sensitivity to succinylcholine, or neuromuscular blockade may be produced by the cautious administration of a 1-mg/mL solution of succinylcholine by slow IV infusion. Apnea or prolonged muscle paralysis should be treated with controlled respiration. Drug Interactions Drugs which may enhance the neuromuscular blocking action of succinylcholine include: promazine, oxytocin, aprotinin, certain non-penicillin antibiotics, quinidine, β-adrenergic blockers, procainamide, lidocaine, trimethaphan, lithium carbonate, magnesium salts, quinine, chloroquine, diethylether, isoflurane, desflurane, metoclopramide, and terbutaline. The neuromuscular blocking effect of succinylcholine may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase (see PRECAUTIONS). If other neuromuscular blocking agents are to be used during the same procedure, the possibility of a synergistic or antagonistic effect should be considered. Reference ID: 2867696 Carcinogenesis, Mutagenesis, Impairment of Fertility There have been no long-term studies performed in animals to evaluate carcinogenic potential. Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with succinylcholine chloride. It is also not known whether succinylcholine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Succinylcholine should be given to a pregnant woman only if clearly needed. Nonteratogenic Effects Plasma cholinesterase levels are decreased by approximately 24% during pregnancy and for several days postpartum. Therefore, a higher proportion of patients may be expected to show increased sensitivity (prolonged apnea) to succinylcholine when pregnant than when nonpregnant. Labor and Delivery Succinylcholine is commonly used to provide muscle relaxation during delivery by cesarean section. While small amounts of succinylcholine are known to cross the placental barrier, under normal conditions the quantity of drug that enters fetal circulation after a single dose of 1 mg/kg to the mother should not endanger the fetus. However, since the amount of drug that crosses the placental barrier is dependent on the concentration gradient between the maternal and fetal circulations, residual neuromuscular blockade (apnea and flaccidity) may occur in the neonate after repeated high doses to, or in the presence of atypical plasma cholinesterase in, the mother. Nursing Mothers It is not known whether succinylcholine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised following succinylcholine administration to a nursing woman. Pediatric Use There are rare reports of ventricular dysrhythmias and cardiac arrest secondary to acute rhabdomyolysis with hyperkalemia in apparently healthy children who receive succinylcholine (see BOX WARNING). Many of these children were subsequently found to have a skeletal muscle myopathy such as Duchenne’s muscular dystrophy whose clinical signs were not obvious. The syndrome often presents as sudden cardiac arrest within minutes after the administration of succinylcholine. These children are usually, but not exclusively, males, and most frequently 8 years of age or younger. There have also been reports in adolescents. There may be no signs or symptoms to alert the practitioner to which patients are at risk. A careful history and physical may identify developmental delays suggestive of a myopathy. A preoperative creatine kinase Reference ID: 2867696 could identify some but not all patients at risk. Due to the abrupt onset of this syndrome, routine resuscitative measures are likely to be unsuccessful. Careful monitoring of the electrocardiogram may alert the practitioner to peaked T-waves (an early sign). Administration of IV calcium, bicarbonate, and glucose with insulin, with hyperventilation have resulted in successful resuscitation in some of the reported cases. Extraordinary and prolonged resuscitative efforts have been effective in some cases. In addition, in the presence of signs of malignant hyperthermia, appropriate treatment should be initiated concurrently (see WARNINGS). Since it is difficult to identify which patients are at risk, it is recommended that the use of succinylcholine in children should be reserved for emergency intubation or instances where immediate securing of the airway is necessary, e.g., laryngospasm, difficult airway, full stomach, or for intramuscular use when a suitable vein is inaccessible. As in adults, the incidence of bradycardia in children is higher following the second dose of succinylcholine. The incidence and severity of bradycardia is higher in children than in adults. Pretreatment with anticholinergic agents, e.g., atropine, may reduce the occurrence of bradyarrhythmias. ADVERSE REACTIONS Adverse reactions to succinylcholine consist primarily of an extension of its pharmacological actions. Succinylcholine causes profound muscle relaxation resulting in respiratory depression to the point of apnea; this effect may be prolonged. Hypersensitivity reactions, including anaphylaxis, may occur in rare instances. The following additional adverse reactions have been reported: cardiac arrest, malignant hyperthermia, arrhythmias, bradycardia, tachycardia, hypertension, hypotension, hyperkalemia, prolonged respiratory depression or apnea, increased intraocular pressure, muscle fasciculation, jaw rigidity, postoperative muscle pain, rhabdomyolysis with possible myoglobinuric acute renal failure, excessive salivation, and rash. There have been post-marketing reports of severe allergic reactions (anaphylactic and anaphylactoid reactions) associated with use of neuromuscular blocking agents, including ANECTINE. These reactions, in some cases, have been life-threatening and fatal. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency (see WARNINGS and PRECAUTIONS). OVERDOSAGE Overdosage with succinylcholine may result in neuromuscular block beyond the time needed for surgery and anesthesia. This may be manifested by skeletal muscle weakness, decreased respiratory reserve, low tidal volume, or apnea. The primary treatment is maintenance of a patent airway and respiratory support until recovery of normal respiration is assured. Depending on the dose and duration of succinylcholine administration, the characteristic depolarizing neuromuscular block (Phase I) may change to a block with characteristics superficially resembling a nondepolarizing block (Phase II) (see PRECAUTIONS). DOSAGE AND ADMINISTRATION The dosage of succinylcholine should be individualized and should always be determined by the clinician after careful assessment of the patient (see WARNINGS). Reference ID: 2867696 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are not clear and colorless should not be used. Adults For Short Surgical Procedures The average dose required to produce neuromuscular blockade and to facilitate tracheal intubation is 0.6 mg/kg ANECTINE Injection given intravenously. The optimum dose will vary among individuals and may be from 0.3 to 1.1 mg/kg for adults. Following administration of doses in this range, neuromuscular blockade develops in about 1 minute; maximum blockade may persist for about 2 minutes, after which recovery takes place within 4 to 6 minutes. However, very large doses may result in more prolonged blockade. A 5- to 10-mg test dose may be used to determine the sensitivity of the patient and the individual recovery time (see PRECAUTIONS). For Long Surgical Procedures The dose of succinylcholine administered by infusion depends upon the duration of the surgical procedure and the need for muscle relaxation. The average rate for an adult ranges between 2.5 and 4.3 mg per minute. Solutions containing from 1 to 2 mg per mL succinylcholine have commonly been used for continuous infusion. The more dilute solution (1 mg per mL) is probably preferable from the standpoint of ease of control of the rate of administration of the drug and, hence, of relaxation. This IV solution containing 1 mg per mL may be administered at a rate of 0.5 mg (0.5 mL) to 10 mg (10 mL) per minute to obtain the required amount of relaxation. The amount required per minute will depend upon the individual response as well as the degree of relaxation required. Avoid overburdening the circulation with a large volume of fluid. It is recommended that neuromuscular function be carefully monitored with a peripheral nerve stimulator when using succinylcholine by infusion in order to avoid overdose, detect development of Phase II block, follow its rate of recovery, and assess the effects of reversing agents (see PRECAUTIONS). Intermittent IV injections of succinylcholine may also be used to provide muscle relaxation for long procedures. An IV injection of 0.3 to 1.1 mg/kg may be given initially, followed, at appropriate intervals, by further injections of 0.04 to 0.07 mg/kg to maintain the degree of relaxation required. Pediatrics For emergency tracheal intubation or in instances where immediate securing of the airway is necessary, the IV dose of succinylcholine is 2 mg/kg for infants and small children; for older children and adolescents the dose is 1 mg/kg (see BOX WARNING and PRECAUTIONS: Pediatric Use). Rarely, IV bolus administration of succinylcholine in infants and children may result in malignant ventricular arrhythmias and cardiac arrest secondary to acute rhabdomyolysis with hyperkalemia. In such situations, an underlying myopathy should be suspected. Intravenous bolus administration of succinylcholine in infants or children may result in profound bradycardia or, rarely, asystole. As in adults, the incidence of bradycardia in children is higher Reference ID: 2867696 following a second dose of succinylcholine. The occurrence of bradyarrhythmias may be reduced by pretreatment with atropine (see PRECAUTIONS: Pediatric Use). Intramuscular Use If necessary, succinylcholine may be given intramuscularly to infants, older children, or adults when a suitable vein is inaccessible. A dose of up to 3 to 4 mg/kg may be given, but not more than 150 mg total dose should be administered by this route. The onset of effect of succinylcholine given intramuscularly is usually observed in about 2 to 3 minutes. Compatibility and Admixtures Succinylcholine is acidic (pH 3.5) and should not be mixed with alkaline solutions having a pH greater than 8.5 (e.g., barbiturate solutions). ANECTINE Injection is stable for 24 hours after dilution to a final concentration of 1 to 2 mg/mL in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP. Aseptic techniques should be used to prepare the diluted product. Admixtures of ANECTINE should be prepared for single patient use only. The unused portion of diluted ANECTINE should be discarded. HOW SUPPLIED For immediate injection of single doses for short procedures: ANECTINE (succinylcholine chloride) Injection, 20 mg in each mL. Multiple-dose vials of 10 mL, box of 10 vials (NDC 0781-3009-95). Store in refrigerator at 2° to 8°C (36° to 46°F). The multi-dose vials are stable for up to 14 days at room temperature without significant loss of potency. Manufactured by Strides Arcolab Limited Bangalore – 560 105, India for Sandoz Inc. Princeton, NJ 08540 09-2010 1014768 Reference ID: 2867696	custom-source	2025-02-12T13:43:37.514783	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/008453s027lbl.pdf', 'application_number': 8453, 'submission_type': 'SUPPL ', 'submission_number': 27}
10,702	_______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BENTYL® safely and effectively. See full prescribing information for BENTYL. BENTYL (dicyclomine hydrochloride) capsules, for oral use BENTYL (dicyclomine hydrochloride) tablets, for oral use BENTYL (dicyclomine hydrochloride) injection, for intramuscular use Initial U.S. Approval: 1950 ---------------------------RECENT MAJOR CHANGES-------------------------- Warnings and Precautions, Peripheral and Central Nervous 07/2012 System (5.3) ----------------------------INDICATIONS AND USAGE--------------------------- BENTYL is an antispasmodic and anticholinergic (antimuscarinic) agent indicated for the treatment of functional bowel/irritable bowel syndrome (1) ----------------------DOSAGE AND ADMINISTRATION----------------------- Dosage for BENTYL must be adjusted to individual patient needs (2). If a dose is missed, patients should continue the normal dosing schedule (2). Oral in adults (2.1):  Starting dose: 20 mg four times a day. After a week treatment with the starting dose, the dose may be escalated to 40 mg four times a day, unless side effects limit dosage escalation  Discontinue BENTYL if efficacy not achieved or side effects require doses less than 80 mg per day after two weeks of treatment Intramuscular in adults (2.2):  Intramuscular administration recommended no longer than 1 or 2 days when patients cannot take oral administration  Recommended dose: 10 mg to 20 mg four times a day ---------------------DOSAGE FORMS AND STRENGTHS----------------------  BENTYL capsules 10 mg (3)  BENTYL injection 20 mg/2 mL (10 mg/mL) (3)  BENTYL tablets 20 mg (3) ------------------------------- CONTRAINDICATIONS-----------------------------  Infants less than 6 months of age (4)  Glaucoma (4)  Nursing mothers (4)  Obstructive uropathy (4)  Unstable cardiovascular status in  Obstructive disease of the acute hemorrhage (4) gastrointestinal tract (4)  Myasthenia gravis (4)  Severe ulcerative colitis (4)  Reflux esophagitis (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------  For Intramuscular injection only; should not be administered by any other route. Intravenous injection may result in thrombosis or thrombophlebitis and injection site reactions (5.1)  Cardiovascular conditions: worsening of conditions (5.2)  Peripheral and central nervous system: heat prostration can occur with drug use (fever and heat stroke due to decreased sweating); drug should be discontinued and supportive measures instituted (5.3)  Psychosis and delirium have been reported in patients sensitive to anticholinergic drugs (such as elderly patients and/or in patients with mental illness): signs and symptoms resolve within 12 to 24 hours after discontinuation of BENTYL (5.3)  Myasthenia Gravis: overdose may lead to muscular weakness and paralysis. BENTYL should be given to patients with myasthenia gravis only to reduce adverse muscarinic effects of an anticholinesterase (5.4)  Incomplete intestinal obstruction: diarrhea may be an early symptom especially in patients with ileostomy or colostomy. Treatment with BENTYL would be inappropriate and possibly fatal (5.5)  Salmonella dysenteric patients: due to risk of toxic megacolon (5.6)  Ulcerative colitis: BENTYL should be used with caution in these patients; large doses may suppress intestinal motility or aggravate the serious complications of toxic megacolon (5.7)  Prostatic hypertrophy: BENTYL should be used with caution in these patients; may lead to urinary retention (5.8)  Hepatic and renal disease: should be used with caution (5.9)  Geriatric: use with caution in elderly who may be more susceptible to BENTYL’s adverse events (5.10) ------------------------------ADVERSE REACTIONS------------------------------- The most serious adverse reactions include cardiovascular and central nervous system symptoms. The most common adverse reactions (> 5% of patients) are dizziness, dry mouth, vision blurred, nausea, somnolence, asthenia and nervousness (6) To report SUSPECTED ADVERSE REACTIONS, contact Aptalis Pharma US, Inc. at 1-800-472-2634 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.com ------------------------------DRUG INTERACTIONS------------------------------  Antiglaucoma agents: anticholinergics antagonize antiglaucoma agents and may increase intraoccular pressure (7)  Anticholinergic agents: may affect the gastrointestinal absorption of various drugs; may also increase certain actions or side effects of other anticholinergic drugs (7)  Antacids: interfere with the absorption of anticholinergic agents (7) -----------------------USE IN SPECIFIC POPULATIONS-----------------------  Pregnancy: use only if clearly needed (8.1)  Pediatric Use: Safety and effectiveness not established (8.4)  Hepatic and renal impairment: caution must be taken with patients with significantly impaired hepatic and renal function (8.6) See 17 for PATIENT COUNSELING INFORMATION. Revised: 1/2013 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Oral Dosage and Administration in Adults 2.2 Intramuscular Dosage and Administration in Adults 2.3 Preparation for Intramuscular Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Inadvertent Intravenous Administration 5.2 Cardiovascular Conditions 5.3 Peripheral and Central Nervous System 5.4 Myasthenia Gravis 5.5 Intestinal Obstruction 5.6 Toxic Dilatation of Intestinemegacolon 5.7 Ulcerative Colitis 5.8 Prostatic Hypertrophy 5.9 Hepatic and Renal Disease 5.10 Geriatric Population 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 6.3 Adverse Reactions Reported with Similar Drugs with Anticholinergic/Antispasmodic Action 7 DRUG INTERACTIONS 7.1 Antiglaucoma Agents 7.2 Other Drugs with Anticholinergic Activity 7.3 Other Gastrointestinal Motility Drugs 7.4 Effect of Antacids 7.5 Effect on Absorption of Other Drugs 7.6 Effect on Gastric Acid Secretion 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Inadvertent Intravenous Administration 17.2 Use in Infants 17.3 Use in Nursing Mothers 17.4 Peripheral and Central Nervous System *Sections or subsections omitted from the full prescribing information are not listed Reference ID: 3243661 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE BENTYL® (dicyclomine hydrochloride) is indicated for the treatment of patients with functional bowel/irritable bowel syndrome. 2 DOSAGE AND ADMINISTRATION Dosage must be adjusted to individual patient needs. 2.1 Oral Dosage and Administration in Adults The recommended initial dose is 20 mg four times a day. After one week treatment with the initial dose, the dose may be increased to 40 mg four times a day unless side effects limit dosage escalation. If efficacy is not achieved within 2 weeks or side effects require doses below 80 mg per day, the drug should be discontinued. Documented safety data are not available for doses above 80 mg daily for periods longer than 2 weeks. 2.2 Intramuscular Dosage and Administration in Adults BENTYL Intramuscular Injection must be administered via intramuscular route only. Do not administer by any other route. The recommended intramuscular dose is 10mg to 20 mg four times a day [see Clinical Pharmacology (12)]. The intramuscular injection is to be used only for 1 or 2 days when the patient cannot take oral medication. Intramuscular injection is about twice as bioavailable as oral dosage forms. 2.3 Preparation for Intramuscular Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Aspirate the syringe before injecting to avoid intravascular injection, since thrombosis may occur if the drug is inadvertently injected intravascularly. 3 DOSAGE FORMS AND STRENGTHS  BENTYL 10 mg capsules: blue, imprinted BENTYL 10  BENTYL 20 mg tablets: compressed, light blue, round, debossed BENTYL 20  BENTYL injection 20mg/2ml (10mg/ml) 4 CONTRAINDICATIONS BENTYL is contraindicated in infants less than 6 months of age [see Use in Specific Populations (8.4)], nursing mothers [see Use in Specific Populations (8.3)], and in patients with:  unstable cardiovascular status in acute hemorrhage  myasthenia gravis [see Warnings and Precautions (5.4)]  glaucoma [see Adverse Reactions (6.3) and Drug Interactions (7.1)]  obstructive uropathy [see Warnings and Precautions (5.8)]  obstructive disease of the gastrointestinal tract [see Warnings and Precautions (5.5)]  severe ulcerative colitis [see Warnings and Precautions (5.7)]  reflux esophagitis 5 WARNINGS AND PRECAUTIONS 5.1 Inadvertent Intravenous Administration BENTYL solution is for intramuscular administration only. Do not administer by any other route. Inadvertent intravenous administration may result in thrombosis, thrombophlebitis, and injection site reactions such as pain, edema, skin color change, and reflex sympathetic dystrophy syndrome [see Adverse Reactions (6.2)]. 5.2 Cardiovascular Conditions Dicyclomine hydrochloride needs to be used with caution in conditions characterized by tachyarrhythmia such as thyrotoxicosis, congestive heart failure and in cardiac surgery, where they may further accelerate the heart rate. Investigate any tachycardia before administration of dicyclomine hydrochloride. Care is required in patients with coronary heart disease, as ischemia and infarction may be worsened, and in patients with hypertension [see Adverse Reactions (6.3)]. 5.3 Peripheral and Central Nervous System The peripheral effects of dicyclomine hydrochloride are a consequence of their inhibitory effect on muscarinic receptors of the autonomic nervous system. They include dryness of the mouth with difficulty in swallowing and talking, thirst, reduced bronchial secretions, dilatation of the pupils (mydriasis) with loss of accommodation (cycloplegia) and photophobia, flushing and dryness of the skin, transient bradycardia followed by tachycardia, with palpitations and arrhythmias, and difficulty in micturition, as well as reduction in the tone and motility of the gastrointestinal tract leading to constipation [see Adverse Reactions (6)]. In the presence of high environmental temperature heat prostration can occur with drug use (fever and heat stroke due to decreased sweating). It should also be used cautiously in patients with fever. If symptoms occur, the drug should be discontinued and supportive measures instituted. Because of the inhibitory effect on muscarinic receptors within the autonomic nervous system, caution should be taken in patients with autonomic neuropathy. Central nervous system (CNS) signs and symptoms include confusional state, disorientation, amnesia, hallucinations, dysarthria, ataxia, coma, euphoria, fatigue, insomnia, agitation and mannerisms, and inappropriate affect. Psychosis and delirium have been reported in sensitive individuals (such as elderly patients and/or in patients with mental illness) given anticholinergic drugs. These CNS signs and symptoms usually resolve within 12 to 24 hours after discontinuation of the drug. BENTYL may produce drowsiness, dizziness or blurred vision. The patient should be warned not to engage in activities requiring mental alertness, such as operating a motor vehicle or other machinery or performing hazardous work while taking BENTYL. 5.4 Myasthenia Gravis With overdosage, a curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). It should not be given to patients with myasthenia gravis except to reduce adverse muscarinic effects of an anticholinesterase [see Contraindications (4)]. 5.5 Intestinal Obstruction Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance, treatment with this drug would be inappropriate and possibly harmful [see Contraindications (4)]. Rarely development of Ogilvie’s syndrome (colonic pseudo- obstruction) has been reported. Ogilvie’s syndrome is a clinical disorder with signs, symptoms, and radiographic appearance of an acute large bowel obstruction but with no evidence of distal colonic obstruction 5.6 Toxic Dilatation of Intestinemegacolon Toxic dilatation of intestine and intestinal perforation is possible when anticholinergic agents are administered in patients with Salmonella dysentery. 5.7 Ulcerative Colitis Caution should be taken in patients with ulcerative colitis. Large doses may suppress intestinal motility to the point of producing a paralytic ileus and the use of this drug may precipitate or aggravate the serious complication of toxic megacolon [see Adverse Reactions (6.3)]. BENTYL is contraindicated in patients with severe ulcerative colitis [see Contraindications (4)]. 5.8 Prostatic Hypertrophy BENTYL should be used with caution in patients with known or suspected prostatic enlargement, in whom prostatic enlargement may lead to urinary retention [see Adverse Reactions (6.3)]. 5.9 Hepatic and Renal Disease BENTYL should be used with caution in patients with known hepatic and renal impairment. Reference ID: 3243661 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.10 Geriatric Population Dicyclomine hydrochloride should be used with caution in elderly who may be more susceptible to its adverse effects. 6 ADVERSE REACTIONS The pattern of adverse effects seen with dicylomine is mostly related to its pharmacological actions at muscarinic receptors [see Clinical Pharmacology (12)]. They are a consequence of the inhibitory effect on muscarinic receptors within the autonomic nervous system. These effects are dose-related and are usually reversible when treatment is discontinued. The most serious adverse reactions reported with dicyclomine hydrochloride include cardiovascular and central nervous system symptoms [see Warnings and Precautions (5.2, 5.3)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure in controlled clinical trials involving over 100 patients treated for functional bowel/irritable bowel syndrome with dicyclomine hydrochloride at initial doses of 160 mg daily (40 mg four times a day) In these trials most of the side effects were typically anticholinergic in nature and were reported by 61% of the patients. Table 1 presents adverse reactions (MedDRA 13.0 preferred terms) by decreasing order of frequency in a side-by-side comparison with placebo. Table 1: Adverse reactions experienced in controlled clinical trials with decreasing order of frequency MedDRA Preferred Term Dicyclomine Hydrochloride (40 mg four times a day) % Placebo % Dry Mouth 33 5 Dizziness 40 5 Vision blurred 27 2 Nausea 14 6 Somnolence 9 1 Asthenia 7 1 Nervousness 6 2 Nine percent (9%) of patients were discontinued from BENTYL because of one or more of these side effects (compared with 2% in the placebo group). In 41% of the patients with side effects, side effects disappeared or were tolerated at the 160 mg daily dose without reduction. A dose reduction from 160 mg daily to an average daily dose of 90 mg was required in 46% of the patients with side effects who then continued to experience a favorable clinical response; their side effects either disappeared or were tolerated. 6.2 Postmarketing Experience The following adverse reactions, presented by system organ class in alphabetical order, have been identified during post approval use of BENTYL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.  Cardiac disorders: palpitations, tachyarrhythmias  Eye disorders: cycloplegia, mydriasis, vision blurred  Gastrointestinal disorders: abdominal distension, abdominal pain, constipation, dry mouth, dyspepsia, nausea, vomiting  General disorders and administration site conditions: fatigue, malaise  Immune System Disorders: drug hypersensitivity including face edema, angioedema, anaphylactic shock  Nervous system disorders: dizziness, headache, somnolence, syncope  Psychiatric disorders: As with the other anti-cholinergic drugs, cases of delirium or symptoms of delirium such as amnesia (or transient global amnesia), agitation, confusional state, delusion, disorientation, hallucination (including visual hallucination) as well as mania, mood altered and pseudodementia, have been reported with the use of Dicyclomine. Nervousness and insomnia have also been reported.  Reproductive system and breast disorders: suppressed lactation  Respiratory, thoracic and mediastinal disorders: dyspnoea, nasal congestion  Skin and subcutaneous tissue disorder: dermatitis allergic, erythema, rash Cases of thrombosis, thrombophlebitis and injection site reactions such as local pain, edema, skin color change and even reflex sympathetic dystrophy syndrome have been reported following Inadvertent IV injection of BENTYL. 6.3 Adverse Reactions Reported with Similar Drugs with Anticholinergic/Antispasmodic Action Gastrointestinal: anorexia Central Nervous System: tingling, numbness, dyskinesia, speech disturbance, insomnia Peripheral Nervous System: With overdosage, a curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis) Ophthalmologic: diplopia, increased ocular tension Dermatologic/Allergic: urticaria, itching, and other dermal manifestations Genitourinary: urinary hesitancy, urinary retention in patients with prostatic hypertrophy Cardiovascular: hypertension Respiratory: apnea Other: decreased sweating, sneezing, throat congestion, impotence. With the injectable form, there may be temporary sensation of light-headedness. Some local irritation and focal coagulation necrosis may occur following the intramuscular injection of BENTYL. 7 DRUG INTERACTIONS 7.1 Antiglaucoma Agents Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Use of BENTYL in patients with glaucoma is not recommended [see Contraindications (4)]. 7.2 Other Drugs with Anticholinergic Activity The following agents may increase certain actions or side effects of anticholinergic drugs including BENTYL: amantadine, antiarrhythmic agents of Class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. 7.3 Other Gastrointestinal Motility Drugs Interaction with other gastrointestinal motility drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. 7.4 Effect of Antacids Because antacids may interfere with the absorption of anticholinergic agents including BENTYL, simultaneous use of these drugs should be avoided. 7.5 Effect on Absorption of Other Drugs Anticholinergic agents may affect gastrointestinal absorption of various drugs by affecting on gastrointestinal motility, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentration may result. Reference ID: 3243661 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda s tru ctur al f or m ula 7.6 Effect on Gastric Acid Secretion The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B Adequate and well-controlled studies have not been conducted with BENTYL in pregnant women at the recommended doses of 80 to 160 mg/day. However, epidemiologic studies did not show an increased risk of structural malformations among babies born to women who took products containing dicyclomine hydrochloride at doses up to 40 mg/day during the first trimester of pregnancy. Reproduction studies have been performed in rats and rabbits at doses up to 33 times the maximum recommended human dose based on 160 mg/day (3 mg/kg) and have revealed no evidence of harm to the fetus due to dicyclomine. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers BENTYL is contraindicated in women who are breastfeeding. Dicyclomine hydrochloride is excreted in human milk. Because of the potential for serious adverse reactions in breast-fed infants from BENTYL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother [see Use in Specific Populations (8.4)]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. BENTYL is contraindicated in infants less than 6 months of age [see Contraindications (4)]. There are published cases reporting that the administration of dicyclomine hydrochloride to infants has been followed by serious respiratory symptoms (dyspnea, shortness of breath, breathlessness, respiratory collapse, apnea and asphyxia), seizures, syncope, pulse rate fluctuations, muscular hypotonia, and coma, and death, however; no causal relationship has been established. 8.5 Geriatric Use Clinical studies of BENTYL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range in adults, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Renal Impairment Effects of renal impairment on PK, safety and efficacy of BENTYL have not been studied. BENTYL drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. BENTYL should be administered with caution in patients with renal impairment. 8.7 Hepatic Impairment Effects of renal impairment on PK, safety and efficacy of BENTYL have not been studied. BENTYL should be administered with caution in patients with hepatic impairment. 10 OVERDOSAGE In case of an overdose, patients should contact a physician, poison control center (1-800-222-1222), or emergency room. The signs and symptoms of overdosage include: headache; nausea; vomiting; blurred vision; dilated pupils; hot, dry skin; dizziness; dryness of the mouth; difficulty in swallowing; and CNS stimulation including convulsion. A curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). One reported event included a 37-year-old who reported numbness on the left side, cold fingertips, blurred vision, abdominal and flank pain, decreased appetite, dry mouth, and nervousness following ingestion of 320 mg daily (four 20 mg tablets four times daily). These events resolved after discontinuing the dicyclomine. The acute oral LD50 of the drug is 625 mg/kg in mice. The amount of drug in a single dose that is ordinarily associated with symptoms of overdosage or that is likely to be life- threatening, has not been defined. The maximum human oral dose recorded was 600 mg by mouth in a 10-month-old child and approximately 1500 mg in an adult, each of whom survived. In three of the infants who died following administration of dicyclomine hydrochloride [see Warnings and Precautions (5.1)], the blood concentrations of drug were 200, 220, and 505 ng/mL. It is not known if BENTYL is dialyzable. Treatment should consist of gastric lavage, emetics, and activated charcoal. Sedatives (e.g., short-acting barbiturates, benzodiazepines) may be used for management of overt signs of excitement. If indicated, an appropriate parenteral cholinergic agent may be used as an antidote. 11 DESCRIPTION BENTYL is an antispasmodic and anticholinergic (antimuscarinic) agent available in the following dosage forms:  BENTYL capsules for oral use contain 10 mg dicyclomine hydrochloride USP. BENTYL 10 mg capsules also contain inactive ingredients: calcium sulfate, corn starch, FD&C Blue No. 1, FD&C Red No. 40, gelatin, lactose, magnesium stearate, pregelatinized corn starch, and titanium dioxide.  BENTYL tablets for oral use contain 20 mg dicyclomine hydrochloride USP. BENTYL 20 mg tablets also contain inactive ingredients: acacia, dibasic calcium phosphate, corn starch, FD&C Blue No. 1, lactose, magnesium stearate, pregelatinized corn starch, and sucrose.  BENTYL injection is a sterile, pyrogen-free, aqueous solution for intramuscular injection (NOT FOR INTRAVENOUS USE) supplied as an ampoule containing 20 mg/2 mL (10 mg/mL). Each mL contains 10 mg dicyclomine hydrochloride USP in sterile water for injection, made isotonic with sodium chloride. BENTYL (dicyclomine hydrochloride) is [bicyclohexyl]-1 carboxylic acid, 2-(diethylamino) ethyl ester, hydrochloride, with a molecular formula of C19H35NO2•HCl and the following structural formula: Molecular weight: 345.95 Dicyclomine hydrochloride occurs as a fine, white, crystalline, practically odorless powder with a bitter taste. It is soluble in water, freely soluble in alcohol and chloroform, and very slightly soluble in ether. Reference ID: 3243661 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Dicyclomine relieves smooth muscle spasm of the gastrointestinal tract. Animal studies indicate that this action is achieved via a dual mechanism:  a specific anticholinergic effect (antimuscarinic) at the acetylcholine-receptor sites with approximately 1/8 the milligram potency of atropine (in vitro, guinea pig ileum); and  a direct effect upon smooth muscle (musculotropic) as evidenced by dicyclomine’s antagonism of bradykinin- and histamine-induced spasms of the isolated guinea pig ileum. Atropine did not affect responses to these two agonists. In vivo studies in cats and dogs showed dicyclomine to be equally potent against acetylcholine (ACh)- or barium chloride (BaCl2)-induced intestinal spasm while atropine was at least 200 times more potent against effects of ACh than BaCl2. Tests for mydriatic effects in mice showed that dicyclomine was approximately 1/500 as potent as atropine; antisialagogue tests in rabbits showed dicyclomine to be 1/300 as potent as atropine. 12.2 Pharmacodynamics BENTYL can inhibit the secretion of saliva and sweat, decrease gastrointestinal secretions and motility, cause drowsiness, dilate the pupils, increase heart rate, and depress motor function 12.3 Pharmacokinetics Absorption and Distribution In man, dicyclomine is rapidly absorbed after oral administration, reaching peak values within 60-90 minutes. Mean volume of distribution for a 20 mg oral dose is approximately 3.65 L/kg suggesting extensive distribution in tissues. Elimination The metabolism of dicyclomine was not studied The principal route of excretion is via the urine (79.5% of the dose). Excretion also occurs in the feces, but to a lesser extent (8.4%). Mean half-life of plasma elimination in one study was determined to be approximately 1.8 hours when plasma concentrations were measured for 9 hours after a single dose. In subsequent studies, plasma concentrations were followed for up to 24 hours after a single dose, showing a secondary phase of elimination with a somewhat longer half-life. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of dicyclomine. In studies in rats at doses of up to 100 mg/kg/day, dicyclomine produced no deleterious effects on breeding, conception, or parturition. 14 CLINICAL STUDIES In controlled clinical trials involving over 100 patients who received drug, 82% of patients treated for functional bowel/irritable bowel syndrome with dicyclomine hydrochloride at initial doses of 160 mg daily (40 mg four times daily) demonstrated a favorable clinical response compared with 55% treated with placebo (p<0.05). 16 HOW SUPPLIED/STORAGE AND HANDLING BENTYL Capsules 10 mg blue capsules, imprinted BENTYL 10, supplied in bottles of 100. Store at room temperature, preferably below 86°F (30°C). NDC number: 58914-012-10. BENTYL Tablets 20 mg compressed, light blue, round tablets, debossed BENTYL 20, supplied in bottles of 100. To prevent fading, avoid exposure to direct sunlight. Store at room temperature, preferably below 86°F (30°C). NDC 58914-013-10. BENTYL Injection 20 mg/2 mL (10 mg/mL) injection supplied in boxes of five 20 mg/2 mL ampules (10 mg/mL). Store at room temperature, preferably below 86°F (30°C). Protect from freezing. NDC 58914-080-52. 17 PATIENT COUNSELING INFORMATION 17.1 Inadvertent Intravenous Administration BENTYL Injection is for intramuscular administration only. Do not administer by any other route. Inadvertent administration may result in thrombosis or thrombophlebitis, and injection site such as pain, edema, skin color change and even reflex sympathetic dystrophy syndrome [see Adverse Reactions (6.2)]. 17.2 Use in Infants Inform parents and caregivers not to administer BENTYL in infants less than 6 months of age [see Use in Specific Populations (8.4)]. 17.3 Use in Nursing Mothers Advise lactating women that BENTYL should not be used while breastfeeding their infants [see Use in Specific Populations (8.3,8.4)]. 17.4 Peripheral and Central Nervous System In the presence of a high environmental temperature, heat prostration can occur with BENTYL use (fever and heat stroke due to decreased sweating). If symptoms occur, the drug should be discontinued and a physician contacted. BENTYL may produce drowsiness or blurred vision. The patient should be warned not to engage in activities requiring mental alertness, such as operating a motor vehicle or other machinery or to perform hazardous work while taking BENTYL [see Warnings and Precautions (5.3)]. Manufactured for: Aptalis Pharma US, Inc. 100 Somerset Corporate Boulevard Bridgewater, NJ 08807 USA www.aptalispharma.com BENTYL® is a registered trademark owned by Aptalis Pharma Canada Inc., an affiliated company of Aptalis Pharma US, Inc. Reference ID: 3243661 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:37.575925	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/007409s042,008370s033lbl.pdf', 'application_number': 8370, 'submission_type': 'SUPPL ', 'submission_number': 33}
10,705	Isoniazid Tablets, USP Rx only WARNING Severe and sometimes fatal hepatitis associated with isoniazid therapy has been reported and may occur or may develop even after many months of treatment. The risk of developing hepatitis is age related. Approximate case rates by age are: less than 1 per 1,000 for persons under 20 years of age, 3 per 1,000 for persons in the 20 to 34 year age group, 12 per 1,000 for persons in the 35 to 49 year age group, 23 per 1,000 for persons in the 50 to 64 year age group and 8 per 1,000 for persons over 65 years of age. The risk of hepatitis is increased with daily consumption of alcohol. Precise data to provide a fatality rate for isoniazid-related hepatitis is not available; however, in a U.S. Public Health Service Surveillance Study of 13,838 persons taking isoniazid, there were 8 deaths among 174 cases of hepatitis. Therefore, patients given isoniazid should be carefully monitored and interviewed at monthly intervals. For persons 35 and older, in addition to monthly symptom reviews, hepatic enzymes (specifically, AST and ALT [formerly SGOT and SGPT, respectively]) should be measured prior to starting isoniazid therapy and periodically throughout treatment. Isoniazid-associated hepatitis usually occurs during the first three months of treatment. Usually, enzyme levels return to normal despite continuance of drug, but in some cases progressive liver dysfunction occurs. Other factors associated with an increased risk of hepatitis include daily use of alcohol, chronic liver disease and injection drug use. A recent report suggests an increased risk of fatal hepatitis associated with isoniazid among women, particularly black and Hispanic women. The risk may also be increased during the post partum period. More careful monitoring should be considered in these groups, possibly including more frequent laboratory monitoring. If abnormalities of liver function exceed three to five times the upper limit of normal, discontinuation of isoniazid should be strongly considered. Liver function tests are not a substitute for a clinical evaluation at monthly intervals or for the prompt assessment of signs or symptoms of adverse reactions occurring between regularly scheduled evaluations. Patients should be instructed to immediately report signs or symptoms consistent with liver damage or other adverse effects. These include any of the following: unexplained anorexia, nausea, vomiting, dark urine, icterus, rash, persistent paresthesias of the hands and feet, persistent fatigue, weakness or fever of greater than 3 days duration and/or abdominal tenderness, especially right upper quadrant discomfort. If these symptoms appear or if signs suggestive of hepatic damage are detected, isoniazid should be discontinued promptly, since continued use of the drug in these cases has been reported to cause a more severe form of liver damage. Patients with tuberculosis who have hepatitis attributed to isoniazid should be given appropriate treatment with alternative drugs. If isoniazid must be reinstituted, it should be reinstituted only after symptoms and laboratory abnormalities have cleared. The drug should be restarted in very small and gradually increasing doses and should be withdrawn immediately if there is any indication of recurrent liver involvement. Preventive treatment should be deferred in persons with acute hepatic diseases. DESCRIPTION Isoniazid is an antibacterial available as 100 mg and 300 mg tablets for oral administration. Each tablet also contains as inactive ingredients: colloidal silicon dioxide, lactose monohydrate, pregelatinized starch (corn), povidone and stearic acid. Reference ID: 3957716 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Isoniazid is chemically known as isonicotinyl hydrazine or isonicotinic acid hydrazide. It has a molecular formula of C6H7N3O and a molecular weight of 137.14. It has the following structural formula: structural formula Isoniazid is odorless and occurs as a colorless or white crystalline powder or as white crystals. It is freely soluble in water, sparingly soluble in alcohol and slightly soluble in chloroform and in ether. Isoniazid is slowly affected by exposure to air and light. CLINICAL PHARMACOLOGY Within 1 to 2 hours after oral administration, isoniazid produces peak blood levels which decline to 50 percent or less within 6 hours. It diffuses readily into all body fluids (cerebrospinal, pleural and ascitic fluids), tissues, organs and excreta (saliva, sputum and feces). The drug also passes through the placental barrier and into milk in concentrations comparable to those in the plasma. From 50 to 70 percent of a dose of isoniazid is excreted in the urine in 24 hours. Isoniazid is metabolized primarily by acetylation and dehydrazination. The rate of acetylation is genetically determined. Approximately 50 percent of Blacks and Caucasians are "slow inactivators" and the rest are "rapid inactivators"; the majority of Eskimos and Orientals are "rapid inactivators." The rate of acetylation does not significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood levels of the drug and, thus, to an increase in toxic reactions. Pyridoxine (vitamin B6) deficiency is sometimes observed in adults with high doses of isoniazid and is considered probably due to its competition with pyridoxal phosphate for the enzyme apotryptophanase. Mechanism of Action Isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bactericidal against actively growing intracellular and extracellular Mycobacterium tuberculosis organisms. Resistance Resistance to isoniazid occurs because of mutations in the katG, inhA, kasA and ahpC genes. Resistance in M. tuberculosis develops rapidly when isoniazid monotherapy is administered. Microbiology Two standardized in vitro susceptibility methods are available for testing isoniazid against M. tuberculosis organisms. The agar proportion method (CLSI, M24-A2) utilizes middlebrook 7H10 or 7H11 medium impregnated with isoniazid at two final concentrations, 0.2 mcg/mL and 1.0 mcg/mL and Reference ID: 3957716 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda tubercle bacilli at a 10-2 to 10-4 dilution of 0.5 to 1.0 McFarland turbidity standard.10 MIC99 values are calculated by comparing the quantity of organisms growing in the medium containing drug to the control cultures. Mycobacterial growth in the presence of drug greater than or equal to 1% of the control indicates resistance. The radiometric broth method employs the BACTEC 460 machine to compare the growth index from untreated control cultures to cultures grown in the presence of 0.2 mcg/mL and 1 mcg/mL of isoniazid. Strict adherence to the manufacturer's instructions for sample processing and data interpretation is required for this assay. M. tuberculosis isolates with an MIC99 less than or equal to 0.2 mcg/mL are considered to be susceptible to isoniazid. Susceptibility test results obtained by the two different methods discussed above cannot be compared unless equivalent drug concentrations are evaluated. The clinical relevance of in vitro susceptibility for mycobacterium species other than M. tuberculosis using either the BACTEC or the proportion method has not been determined. INDICATIONS AND USAGE Isoniazid tablets, USP are recommended for all forms of tuberculosis in which organisms are susceptible. However, active tuberculosis must be treated with multiple concomitant anti-tuberculosis medications to prevent the emergence of drug resistance. Single-drug treatment of active tuberculosis with isoniazid or any other medication, is inadequate therapy. Isoniazid tablets, USP are recommended as preventive therapy for the following groups, regardless of age. (Note: the criterion for a positive reaction to a skin test (in millimeters of induration) for each group is given in parenthesis): 1. Persons with human immunodeficiency virus (HIV) infection (greater than or equal to 5 mm) and persons with risk factors for HIV infection whose HIV infection status is unknown but who are suspected of having HIV infection. Preventive therapy may be considered for HIV infected persons who are tuberculin-negative but belong to groups in which the prevalence of tuberculosis infection is high. Candidates for preventive therapy who have HIV infection should have a minimum of 12 months of therapy. 2. Close contacts of persons with newly diagnosed infectious tuberculosis (greater than or equal to 5 mm). In addition, tuberculin-negative (less than 5 mm) children and adolescents who have been close contacts of infectious persons within the past 3 months are candidates for preventive therapy until a repeat tuberculin skin test is done 12 weeks after contact with the infectious source. If the repeat skin test is positive (greater than 5 mm), therapy should be continued. 3. Recent converters, as indicated by a tuberculin skin test (greater than or equal to 10 mm increase within a 2-year period for those less than 35 years old; greater than or equal to 15 mm increase for those greater than or equal to 35 years of age). All infants and children younger than 4 years of age with a greater than 10 mm skin test are included in this category. 4. Persons with abnormal chest radiographs that show fibrotic lesions likely to represent old healed tuberculosis (greater than or equal to 5 mm). Candidates for preventive therapy who have fibrotic Reference ID: 3957716 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda pulmonary lesions consistent with healed tuberculosis or who have pulmonary silicosis should have 12 months of isoniazid or 4 months of isoniazid and rifampin, concomitantly. 5. Intravenous drug users known to be HIV-seronegative (greater than 10 mm). 6. Persons with the following medical conditions that have been reported to increase the risk of tuberculosis (greater than or equal to 10 mm): silicosis; diabetes mellitus; prolonged therapy with adrenocorticosteroids; immunosuppressive therapy; some hematologic and reticuloendothelial diseases, such as leukemia or Hodgkin's disease; end-stage renal disease; clinical situations associated with substantial rapid weight loss or chronic undernutrition (including: intestinal bypass surgery for obesity, the postgastrectomy state [with or without weight loss], chronic peptic ulcer disease, chronic malabsorption syndromes and carcinomas of the oropharynx and upper gastrointestinal tract that prevent adequate nutritional intake). Candidates for preventive therapy who have fibrotic pulmonary lesions consistent with healed tuberculosis or who have pulmonary silicosis should have 12 months of isoniazid or 4 months of isoniazid and rifampin, concomitantly. Additionally, in the absence of any of the above risk factors, persons under the age of 35 with a tuberculin skin test reaction of 10 mm or more are also appropriate candidates for preventive therapy if they are a member of any of the following high-incidence groups: 1. Foreign-born persons from high-prevalence countries who never received BCG vaccine. 2. Medically underserved low-income populations, including high-risk racial or ethnic minority populations, especially blacks, Hispanics and Native Americans. 3. Residents of facilities for long-term care (e.g., correctional institutions, nursing homes and mental institutions). Children who are less than 4 years old are candidates for isoniazid preventive therapy if they have greater than 10 mm induration from a PPD Mantoux tuberculin skin test. Finally, persons under the age of 35 who a) have none of the above risk factors (1 to 6); b) belong to none of the high-incidence groups; and c) have a tuberculin skin test reaction of 15 mm or more, are appropriate candidates for preventive therapy. The risk of hepatitis must be weighed against the risk of tuberculosis in positive tuberculin reactors over the age of 35. However, the use of isoniazid is recommended for those with the additional risk factors listed above (1 to 6) and on an individual basis in situations where there is likelihood of serious consequences to contacts who may become infected. CONTRAINDICATIONS Isoniazid is contraindicated in patients who develop severe hypersensitivity reactions, including drug- induced hepatitis; previous isoniazid-associated hepatic injury; severe adverse reactions to isoniazid such as drug fever, chills, arthritis; and acute liver disease of any etiology. WARNINGS See the boxed warning. Reference ID: 3957716 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General All drugs should be stopped and an evaluation made at the first sign of a hypersensitivity reaction. If isoniazid therapy must be reinstituted, the drug should be given only after symptoms have cleared. The drug should be restarted in very small and gradually increasing doses and should be withdrawn immediately if there is any indication of recurrent hypersensitivity reaction. Use of isoniazid should be carefully monitored in the following: 1. Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of + isoniazid hepatitis. 2. Patients with active chronic liver disease or severe renal dysfunction. 3. Age greater than 35. 4. Concurrent use of any chronically administered medication. 5. History of previous discontinuation of isoniazid. 6. Existence of peripheral neuropathy or conditions predisposing to neuropathy. 7. Pregnancy. 8. Injection drug use. 9. Women belonging to minority groups, particularly in the postpartum period. 10. HIV seropositive patients. Laboratory Tests Because there is a higher frequency of isoniazid associated hepatitis among certain patient groups, including Age greater than 35, daily users of alcohol, chronic liver disease, injection drug use and women belonging to minority groups, particularly in the post-partum period, transaminase measurements should be obtained prior to starting and monthly during preventative therapy or more frequently as needed. If any of the values exceed three to five times the upper limit of normal, isoniazid should be temporarily discontinued and consideration given to restarting therapy. Drug Interactions Food Isoniazid should not be administered with food. Studies have shown that the bioavailability of isoniazid is reduced significantly when administered with food. Tyramine- and histamine-containing foods should be avoided in patients receiving isoniazid. Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (e.g., headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (e.g., skipjack, tuna, other tropical fish). Acetaminophen A report of severe acetaminophen toxicity was reported in a patient receiving Isoniazid. It is believed that the toxicity may have resulted from a previously unrecognized interaction between isoniazid and acetaminophen and a molecular basis for this interaction has been proposed. However, current evidence Reference ID: 3957716 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda suggests that isoniazid does induce P-450IIE1, a mixed-function oxidase enzyme that appears to generate the toxic metabolites, in the liver. Furthermore it has been proposed that isoniazid resulted in induction of P-450IIE1 in the patient's liver which, in turn, resulted in a greater proportion of the ingested acetaminophen being converted to the toxic metabolites. Studies have demonstrated that pretreatment with isoniazid potentiates acetaminophen hepatotoxicity in rats1,2. Carbamazepine Isoniazid is known to slow the metabolism of carbamazepine and increase its serum levels. Carbamazepine levels should be determined prior to concurrent administration with isoniazid, signs and symptoms of carbamazepine toxicity should be monitored closely and appropriate dosage adjustment of the anticonvulsant should be made3 . Ketoconazole Potential interaction of Ketoconazole and Isoniazid may exist. When Ketoconazole is given in combination with isoniazid and rifampin the AUC of ketoconazole is decreased by as much as 88 percent after 5 months of concurrent Isoniazid and Rifampin therapy4 . Phenytoin Isoniazid may increase serum levels of phenytoin. To avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant should be made5,6. Theophylline A recent study has shown that concomitant administration of isoniazid and theophylline may cause elevated plasma levels of theophylline and in some instances a slight decrease in the elimination of isoniazid. Since the therapeutic range of theophylline is narrow, theophylline serum levels should be monitored closely and appropriate dosage adjustments of theophylline should be made7 . Valproate A recent case study has shown a possible increase in the plasma level of valproate when co-administered with isoniazid. Plasma valproate concentration should be monitored when isoniazid and valproate are co administered and appropriate dosage adjustments of valproate should be made5 . Carcinogenesis and Mutagenesis Isoniazid has been shown to induce pulmonary tumors in a number of strains of mice. Isoniazid has not been shown to be carcinogenic in humans. (Note: a diagnosis of mesothelioma in a child with prenatal exposure to isoniazid and no other apparent risk factors has been reported). Isoniazid has been found to be weakly mutagenic in strains TA 100 and TA 1535 of Salmonella typhimurium (Ames assay) without metabolic activation. Reference ID: 3957716 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy Teratogenic Effects Pregnancy Category C Isoniazid has been shown to have an embryocidal effect in rats and rabbits when given orally during pregnancy. Isoniazid was not teratogenic in reproduction studies in mice, rats and rabbits. There are no adequate and well-controlled studies in pregnant women. Isoniazid should be used as a treatment for active tuberculosis during pregnancy because the benefit justifies the potential risk to the fetus. The benefit of preventive therapy also should be weighed against a possible risk to the fetus. Preventive therapy generally should be started after delivery to prevent putting the fetus at risk of exposure; the low levels of isoniazid in breast milk do not threaten the neonate. Since isoniazid is known to cross the placental barrier, neonates of isoniazid treated mothers should be carefully observed for any evidence of adverse effects. Nonteratogenic Effects Since isoniazid is known to cross the placental barrier, neonates of isoniazid-treated mothers should be carefully observed for any evidence of adverse effects. Nursing Mothers The small concentrations of isoniazid in breast milk do not produce toxicity in the nursing newborn; therefore, breast feeding should not be discouraged. However, because levels of isoniazid are so low in breast milk, they can not be relied upon for prophylaxis or therapy of nursing infants. ADVERSE REACTIONS The most frequent reactions are those affecting the nervous system and the liver. Nervous System Reactions Peripheral neuropathy is the most common toxic effect. It is dose-related, occurs most often in the malnourished and in those predisposed to neuritis (e.g., alcoholics and diabetics) and is usually preceded by paresthesias of the feet and hands. The incidence is higher in "slow inactivators". Other neurotoxic effects, which are uncommon with conventional doses, are convulsions, toxic encephalopathy, optic neuritis and atrophy, memory impairment and toxic psychosis. Hepatic Reactions See boxed warning. Elevated serum transaminase (SGOT; SGPT), bilirubinemia, bilirubinuria, jaundice and occasionally severe and sometimes fatal hepatitis. The common prodromal symptoms of hepatitis are anorexia, nausea, vomiting, fatigue, malaise and weakness. Mild hepatic dysfunction, evidenced by mild and transient elevation of serum transaminase levels occurs in 10 to 20 percent of patients taking isoniazid. This abnormality usually appears in the first 1 to 3 months of treatment but can occur at any time during therapy. In most instances, enzyme levels return to normal and generally, there is no necessity to discontinue medication during the period of mild serum transaminase elevation. In occasional Reference ID: 3957716 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda instances, progressive liver damage occurs, with accompanying symptoms. If the SGOT value exceeds three to five times the upper limit of normal, discontinuation of the isoniazid should be strongly considered. The frequency of progressive liver damage increases with age. It is rare in persons under 20, but occurs in up to 2.3 percent of those over 50 years of age. Gastrointestinal Reactions Nausea, vomiting, epigastric distress, and pancreatitis. Hematologic Reactions Agranulocytosis; hemolytic, sideroblastic or aplastic anemia, thrombocytopenia; and eosinophilia. Hypersensitivity Reactions Fever, skin eruptions (morbilliform, maculopapular, purpuric or exfoliative), lymphadenopathy, vasculitis, toxic epidermal necrolysis, and drug reaction with eosinophilia syndrome (DRESS). Metabolic and Endocrine Reactions Pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis and gynecomastia. Miscellaneous Reactions Rheumatic syndrome and systemic lupus erythematosus-like syndrome. OVERDOSAGE Signs and Symptoms Isoniazid overdosage produces signs and symptoms within 30 minutes to 3 hours after ingestion. Nausea, vomiting, dizziness, slurring of speech, blurring of vision and visual hallucinations (including bright colors and strange designs) are among the early manifestations. With marked overdosage, respiratory distress and CNS depression, progressing rapidly from stupor to profound coma, are to be expected, along with severe, intractable seizures. Severe metabolic acidosis, acetonuria and hyperglycemia are typical laboratory findings. Treatment Untreated or inadequately treated cases of gross isoniazid overdosage, 80 mg/kg to 150 mg/kg, can cause neurotoxicity6 and terminate fatally, but good response has been reported in most patients brought under adequate treatment within the first few hours after drug ingestion. For the Asymptomatic Patient Absorption of drugs from the GI tract may be decreased by giving activated charcoal. Gastric emptying should also be employed in the asymptomatic patient. Safeguard the patient's airway when employing these procedures. Patients who acutely ingest greater than 80 mg/kg should be treated with intravenous pyridoxine on a gram per gram basis equal to the isoniazid dose. If an unknown amount of isoniazid is Reference ID: 3957716 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ingested, consider an initial dose of 5 grams of pyridoxine given over 30 to 60 minutes in adults or 80 mg/kg of pyridoxine in children. For the Symptomatic Patient Ensure adequate ventilation, support cardiac output and protect the airway while treating seizures and attempting to limit absorption. If the dose of isoniazid is known, the patient should be treated initially with a slow intravenous bolus of pyridoxine, over 3 to 5 minutes, on a gram per gram basis, equal to the isoniazid dose. If the quantity of isoniazid ingestion is unknown, then consider an initial intravenous bolus of pyridoxine of 5 grams in the adult or 80 mg/kg in the child. If seizures continue, the dosage of pyridoxine may be repeated. It would be rare that more than 10 grams of pyridoxine would need to be given. The maximum safe dose for pyridoxine in isoniazid intoxication is not known. If the patient does not respond to pyridoxine, diazepam may be administered. Phenytoin should be used cautiously, because isoniazid interferes with the metabolism of phenytoin. General Obtain blood samples for immediate determination of gases, electrolytes, BUN, glucose, etc.; type and cross-match blood in preparation for possible hemodialysis. Rapid Control of Metabolic Acidosis Patients with this degree of INH intoxication are likely to have hypoventilation. The administration of sodium bicarbonate under these circumstances can cause exacerbation of hypercarbia. Ventilation must be monitored carefully, by measuring blood carbon dioxide levels and supported mechanically, if there is respiratory insufficiency. Dialysis Both peritoneal and hemodialysis have been used in the management of isoniazid overdosage. These procedures are probably not required if control of seizures and acidosis is achieved with pyridoxine, diazepam and bicarbonate. Along with measures based on initial and repeated determination of blood gases and other laboratory tests as needed, utilize meticulous respiratory and other intensive care to protect against hypoxia, hypotension, aspiration, pneumonitis, etc. DOSAGE AND ADMINISTRATION (See also INDICATIONS AND USAGE) NOTE For preventive therapy of tuberculous infection and treatment of tuberculosis, it is recommended that physicians be familiar with the following publications: (1) the recommendations of the Advisory Council for the Elimination of Tuberculosis, published in the MMWR: vol 42; RR-4, 1993 and (2) Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children, American Journal of Respiratory and Critical Care Medicine: vol 149; 1359-1374, 1994. Reference ID: 3957716 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For Treatment of Tuberculosis Isoniazid is used in conjunction with other effective anti-tuberculous agents. Drug susceptibility testing should be performed on the organisms initially isolated from all patients with newly diagnosed tuberculosis. If the bacilli becomes resistant, therapy must be changed to agents to which the bacilli are susceptible. Usual Oral Dosage (depending on the regimen used): Adults 5 mg/kg up to 300 mg daily in a single dose; or 15 mg/kg up to 900 mg/day, two or three times/week Children 10 mg/kg to 15 mg/kg up to 300 mg daily in a single dose; or 20 mg/kg to 40 mg/kg up to 900 mg/day, two or three times/week Patients with Pulmonary Tuberculosis Without HIV Infection There are 3 regimen options for the initial treatment of tuberculosis in children and adults: Option 1 Daily isoniazid, rifampin and pyrazinamide for 8 weeks followed by 16 weeks of isoniazid and rifampin daily or 2 to 3 times weekly. Ethambutol or streptomycin should be added to the initial regimen until sensitivity to isoniazid and rifampin is demonstrated. The addition of a fourth drug is optional if the relative prevalence of isoniazid-resistant Mycobacterium tuberculosis isolates in the community is less than or equal to four percent. Option 2 Daily isoniazid, rifampin, pyrazinamide and streptomycin or ethambutol for 2 weeks followed by twice weekly administration of the same drugs for 6 weeks, subsequently twice weekly isoniazid and rifampin for 16 weeks. Option 3 Three times weekly with isoniazid, rifampin, pyrazinamide and ethambutol or streptomycin for 6 months. *All regimens given twice weekly or 3 times weekly should be administered by directly observed therapy [see also Directly Observed Therapy (DOT)]. The above treatment guidelines apply only when the disease is caused by organisms that are susceptible to the standard antituberculous agents. Because of the impact of resistance to isoniazid and rifampin on the response to therapy, it is essential that physicians initiating therapy for tuberculosis be familiar with the prevalence of drug resistance in their communities. It is suggested that ethambutol not be used in children whose visual acuity cannot be monitored. Reference ID: 3957716 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients with Pulmonary Tuberculosis and HIV Infection The response of the immunologically impaired host to treatment may not be as satisfactory as that of a person with normal host responsiveness. For this reason, therapeutic decisions for the impaired host must be individualized. Since patients co-infected with HIV may have problems with malabsorption, screening of antimycobacterial drug levels, especially in patients with advanced HIV disease, may be necessary to prevent the emergence of MDRTB. Patients with Extra Pulmonary Tuberculosis The basic principles that underlie the treatment of pulmonary tuberculosis also apply to Extra pulmonary forms of the disease. Although there have not been the same kinds of carefully conducted controlled trials of treatment of Extra pulmonary tuberculosis as for pulmonary disease, increasing clinical experience indicates that a 6 to 9 month short-course regimen is effective. Because of the insufficient data, miliary tuberculosis, bone/joint tuberculosis and tuberculous meningitis in infants and children should receive 12 month therapy. Bacteriologic evaluation of Extra pulmonary tuberculosis may be limited by the relative inaccessibility of the sites of disease. Thus, response to treatment often must be judged on the basis of clinical and radiographic findings. The use of adjunctive therapies such as surgery and corticosteroids is more commonly required in Extra pulmonary tuberculosis than in pulmonary disease. Surgery may be necessary to obtain specimens for diagnosis and to treat such processes as constrictive pericarditis and spinal cord compression from Pott's Disease. Corticosteriods have been shown to be of benefit in preventing cardiac constriction from tuberculous pericarditis and in decreasing the neurologic sequelae of all stages of tuberculosis meningitis, especially when administered early in the course of the disease. Pregnant Women with Tuberculosis The options listed above must be adjusted for the pregnant patient. Streptomycin interferes with in utero development of the ear and may cause congenital deafness. Routine use of pyrazinamide is also not recommended in pregnancy because of inadequate teratogenicity data. The initial treatment regimen should consist of isoniazid and rifampin. Ethambutol should be included unless primary isoniazid resistance is unlikely (isoniazid resistance rate documented to be less than 4%). Treatment of Patients with Multi-Drug Resistant Tuberculosis (MDRTB) Multiple-drug resistant tuberculosis (i.e., resistance to at least isoniazid and rifampin) presents difficult treatment problems. Treatment must be individualized and based on susceptibility studies. In such cases, consultation with an expert in tuberculosis is recommended. Directly Observed Therapy (DOT) A major cause of drug-resistant tuberculosis is patient noncompliance with treatment. The use of DOT can help assure patient compliance with drug therapy. DOT is the observation of the patient by a health care provider or other responsible person as the patient ingests anti-tuberculosis medications. DOT can be achieved with daily, twice weekly or thrice weekly regimens and is recommended for all patients. Reference ID: 3957716 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For Preventative Therapy of Tuberculosis Before isoniazid preventive therapy is initiated, bacteriologically positive or radiographically progressive tuberculosis must be excluded. Appropriate evaluations should be performed if Extra pulmonary tuberculosis is suspected. Adults over 30 kg: 300 mg per day in a single dose. Infants and Children: 10 mg/kg (up to 300 mg daily) in a single dose. In situations where adherence with daily preventative therapy cannot be assured, 20 mg/kg to 30 mg/kg (not to exceed 900 mg) twice weekly under the direct observation of a health care worker at the time of administration8 . Continuous administration of isoniazid for a sufficient period is an essential part of the regimen because relapse rates are higher if chemotherapy is stopped prematurely. In the treatment of tuberculosis, resistant organisms may multiply and the emergence of resistant organisms during the treatment may necessitate a change in the regimen. For following patient compliance: the Potts-Cozart test9, a simple colorimetric6 method of checking for isoniazid in the urine, is a useful tool for assuring patient compliance, which is essential for effective tuberculosis control. Additionally, isoniazid test strips are also available to check patient compliance. Concomitant administration of pyridoxine (B6) is recommended in the malnourished and in those predisposed to neuropathy (e.g., alcoholics and diabetics). HOW SUPPLIED Isoniazid Tablets, USP, for oral administration, are available as following strengths: 100 mg White, round, biconvex, scored on one side and debossed with E over and "4354" below the score and supplied as: Bottles of 30 tablets NDC 0185-4351-30 Bottles of 100 tablets NDC 0185-4351-01 Bottles of 1000 tablets NDC 0185-4351-10 300 mg White, round, biconvex, scored on one side and debossed with E over and "4350" below the score and supplied as: Bottles of 30 tablets NDC 0185-4350-30 Bottles of 100 tablets NDC 0185-4350-01 Bottles of 1000 tablets NDC 0185-4350-10 Reference ID: 3957716 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture and light. References 1. Murphy, R., et al: Annuals of Internal Medicine; 1990: November 15; volume 113: 799-800. 2. Burke, R.F., et al: Res Commun Chem Pathol Pharmacol; 1990: July; vol. 69: 115-118. 3. Fleenor, M. F., et al: Chest (United States) Letter; 1991; June; 99 (6): 1554. 4. Baciewicz, A.M. and Baciewicz, Jr. F.A.: Arch Int Med 1993: September; volume 153: 1970-1971. 5. Jonviller, A.P., et al: European Journal of Clinical Pharmacol (Germany), 1991: 40 (2) p198. 6. American Thoracic Society/Centers for Disease Control: Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children. Amer. J. Respir Crit Care Med.1994;149: p1359-1374. 7. Hoglund P., et al: European Journal of Respir Dis (Denmark) 1987: February; 70 (2) p110-116. 8. Committee on infectious Diseases American Academy of Pediatrics:1994, Red Book: Report of the Committee on Infectious Diseases; 23 edition; p487. 9. Schraufnagel, DE; Testing for Isoniazid; Chest (United States) 1990: August; 98 (2) p314-316. 10. Clinical and Laboratory Standards Institute (CLSI). Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard-Second Edition. CLSI Document M24-A2. Wayne, PA: Clinical and Laboratory Standards Institute, 2011. To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Manufactured for Sandoz Inc. Princeton, NJ 08540 Manufactured by Epic Pharma, LLC Laurelton, NY 11413 OS7323 Rev. July 2016 MF4351REV07/16 MG #15948 Reference ID: 3957716 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:37.744027	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/008678s028lbl.pdf', 'application_number': 8678, 'submission_type': 'SUPPL ', 'submission_number': 28}
10,706	Dilantin-125® (Phenytoin Oral Suspension, USP) (NOT FOR PARENTERAL USE) DESCRIPTION Dilantin (phenytoin) is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-diphenyl-2,4 imidazolidinedione, having the following structural formula: structural formula Each 5 ml of suspension contains 125 mg of phenytoin, USP; alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No. 6. CLINICAL PHARMACOLOGY Phenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures. The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5–7 half-lives) after initiation of therapy with recommended doses of 300 mg/day. When serum level determinations are necessary, they should be obtained at least 5–7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient’s next scheduled dose. Peak levels indicate an individual’s threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. For Dilantin-125 Suspension, peak levels occur 1½–3 hours after administration. Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, congenital enzyme deficiency, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin plasma levels, despite standard doses, presents a difficult clinical Reference ID: 2888819 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high plasma levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more. INDICATIONS AND USAGE Dilantin (phenytoin) is indicated for the control of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures. Phenytoin serum level determinations may be necessary for optimal dosage adjustments (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY sections). CONTRAINDICATIONS Dilantin is contraindicated in those patients with a history of hypersensitivity to phenytoin or other hydantoins. WARNINGS Effects of Abrupt Withdrawal Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When in the judgment of the clinician the need for dosage reduction, discontinuation, or substitution of alternative anticonvulsant medication arises, this should be done gradually. In the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an anticonvulsant not belonging to the hydantoin chemical class. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Dilantin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. Reference ID: 2888819 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients with Relative Risk: Risk Difference: with Events Per Events Per 1000 Incidence of Events in Additional Drug 1000 Patients Patients Drug Patients with Events Patients/Incidence in Per 1000 Patients Placebo Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Dilantin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Lymphadenopathy There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling serum sickness, e.g., fever, rash, and liver involvement. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs. Effects of Alcohol Use on Phenytoin Serum Levels Acute alcoholic intake may increase phenytoin serum levels, while chronic alcoholic use may decrease serum levels. Exacerbation of Porphyria Reference ID: 2888819 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease. Usage in Pregnancy: Clinical: A. Risks to Mother. An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated. B. Risks to the Fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy. C. Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug- induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth. Preclinical: Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits. Skin reactions Dilantin can cause rare, serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs hypersensitivity such as itching, and should seek medical advice from their physician immediately when observing any indicative signs or symptoms. The physician should advise the patient to discontinue treatment if the rash appears (see WARNINGS section regarding drug discontinuation). If the rash is of a milder type (measles-like or scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy, further Dilantin medication is contraindicated. Published literature has suggested that there may be an increased, although still rare, risk of hypersensitivity reactions, including skin rash, SJS, TEN, hepatotoxicity, and Anticonvulsant Hypersensitivity Syndrome in black patients. Reference ID: 2888819 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B1502, an inherited allelic variant of the HLA B gene, in patients using another anticonvulsive drug. Limited evidence suggests that HLA-B1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding use of drugs associated with SJS/TEN, including Dilantin, in HLA-B*1502 positive patients when alternative therapies are otherwise equally available. Anticonvulsant Hypersensitivity Syndrome Anticonvulsant Hypersensitivity Syndrome (AHS) is a rare drug induced, multiorgan syndrome which is potentially fatal and occurs in some patients taking anticonvulsant medication. It is characterized by fever, rash, lymphadenopathy, and other multiorgan pathologies, often hepatic. The mechanism is unknown. The interval between first drug exposure and symptoms is usually 2-4 weeks but has been reported in individuals receiving anticonvulsants for 3 or more months. Although up to 1 in 5 patients on Dilantin may develop cutaneous eruptions, only a small proportion will progress to AHS. Patients at higher risk for developing AHS include black patients, patients who have a family history of or who have experienced this syndrome in the past, and immuno-suppressed patients. The syndrome is more severe in previously sensitized individuals. If a patient is diagnosed with AHS, discontinue the Dilantin and provide appropriate supportive measures. PRECAUTIONS General: The liver is the chief site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity. A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. Phenytoin should be discontinued if a skin rash appears (see WARNINGS section regarding drug discontinuation). If the rash is exfoliative, purpuric, or bullous or if lupus erythematosus, Stevens-Johnson syndrome, or toxic epidermal necrolysis is suspected, use of this drug should not be resumed and alternative therapy should be considered. (See ADVERSE REACTIONS section.) If the rash is of a milder type (measles-like or scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy, further phenytoin medication is contraindicated. Published literature has suggested that there may be an increased, although still rare, risk of hypersensitivity reactions, including skin rash, SJS, TEN, hepatotoxicity, and Anticonvulsant Hypersensitivity Syndrome in black patients. (See WARNINGS section). Phenytoin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, caution should be exercised if using structurally similar (e.g., barbiturates, succinimides, oxazolidinediones and other related compounds) in these same patients. Hyperglycemia, resulting from the drug’s inhibitory effects on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients. Osteomalacia has been associated with phenytoin therapy and is considered to be due to phenytoin’s interference with vitamin D metabolism. Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present, combined drug therapy is needed. Reference ID: 2888819 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended. (See WARNINGS section.) Information for Patients: Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Dilantin. Instruct patients to take Dilantin only as prescribed. Patients taking phenytoin should be advised of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc. Patients should be instructed to use an accurately calibrated measuring device when using this medication to ensure accurate dosing. Patients should also be cautioned on the use of other drugs or alcoholic beverages without first seeking the physician’s advice. Patients should be instructed to call their physician if skin rash develops. The importance of good dental hygiene should be stressed in order to minimize the development of gingival hyperplasia and its complications. Patients, their caregivers, and families should be counseled that AEDs, including Dilantin, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS: Pregnancy section). Laboratory Tests: Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Drug Interactions: There are many drugs which may increase or decrease phenytoin levels or which phenytoin may affect. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected. The most commonly occurring drug interactions are: 1. Drugs which may increase phenytoin serum levels include: acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, cimetidine, diazepam, dicumarol, disulfiram, estrogens, ethosuximide, fluoxetine, H2-antagonists, halothane, isoniazid, methylphenidate, phenothiazines, phenylbutazone, salicylates, succinimides, sulfonamides, ticlopidine, tolbutamide, trazodone. 2. Drugs which may decrease phenytoin levels include: carbamazepine, chronic alcohol abuse, reserpine, and sucralfate. Moban® brand of molindone hydrochloride contains calcium ions which interfere with the absorption of phenytoin. Ingestion times of phenytoin and antacid preparations containing calcium should be staggered in patients with low serum phenytoin levels to prevent absorption problems. 3. Drugs which may either increase or decrease phenytoin serum levels include: phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid, and sodium valproate serum levels is unpredictable. 4. Although not a true drug interaction, tricyclic antidepressants may precipitate seizures in susceptible patients and phenytoin dosage may need to be adjusted. Reference ID: 2888819 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5. Drugs whose efficacy is impaired by phenytoin include: corticosteroids, coumarin anticoagulants, digitoxin, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, theophylline, vitamin D. Drug Enteral Feeding/Nutritional Preparations Interaction: Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients. Drug/Laboratory Test Interactions: Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations. Carcinogenesis: See WARNINGS section for information on carcinogenesis. Pregnancy: Pregnancy Category D; See WARNINGS section. To provide information regarding the effects of in utero exposure to Dilantin, physicians are advised to recommend that pregnant patients taking Dilantin enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Nursing Mothers: Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Pediatric Use: See DOSAGE AND ADMINISTRATION section. ADVERSE REACTIONS Central Nervous System: The most common manifestations encountered with phenytoin therapy are referable to this system and are usually dose-related. These include nystagmus, ataxia, slurred speech, decreased coordination, and mental confusion. Dizziness, insomnia, transient nervousness, motor twitchings, and headaches have also been observed. There have also been rare reports of phenytoin- induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Gastrointestinal System: Nausea, vomiting, constipation, toxic hepatitis and liver damage. Integumentary System: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, lupus erythematosus, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see PRECAUTIONS and WARNINGS section). Hemopoietic System: Hemopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease have been reported (see WARNINGS section). Connective Tissue System: Coarsening of the facial features, enlargement of the lips, gingival hyperplasia, hypertrichosis, and Peyronie’s disease. Reference ID: 2888819 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Immunologic: Anticonvulsant Hypersensitivity Syndrome (AHS)- (which may include, but is not limited to, symptoms such as arthralgias, eosinophilia, fever, liver dysfunction, lymphadenopathy or rash), systemic lupus erythematosus, periarteritis nodosa and immunoglobulin abnormalities (See WARNINGS section). OVERDOSAGE The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL; dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind. DOSAGE AND ADMINISTRATION – (NOT FOR PARENTERAL USE) Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Dilantin® Kapseals® is formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspension and Dilantin Infatabs. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa. General: Dosage should be individualized to provide maximum benefit. In some cases serum blood level determinations may be necessary for optimal dosage adjustments—the clinically effective serum level is usually 10–20 mcg/mL. With recommended dosage, a period of seven to ten days may be required to achieve steady-state blood levels with phenytoin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days. Adult Dose: Patients who have received no previous treatment may be started on one teaspoonful (5 mL) of Dilantin-125 Suspension three times daily, and the dose is then adjusted to suit individual requirements. An increase to five teaspoonfuls daily may be made, if necessary. Pediatric Dose: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day). HOW SUPPLIED N 0071-2214-20—Dilantin-125® Suspension (phenytoin oral suspension, USP), 125 mg phenytoin/5 mL with a maximum alcohol content not greater than 0.6 percent, an orange suspension with an orange-vanilla flavor; available in 8-oz bottles. Store at controlled room temperature 20°–25°C (68°–77°F). [See USP.] Protect from freezing and light. Reference ID: 2888819 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda company logo LAB-0203-6.0 Revised November 2010 9 Reference ID: 2888819 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:37.833467	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/008762s038lbl.pdf', 'application_number': 8762, 'submission_type': 'SUPPL ', 'submission_number': 38}
10,707	NDA 008762 Dilantin-125 (phenytoin) Oral Suspension FDA Approved Labeling Text dated 10/2011 Page 1 of 16 Dilantin-125® (Phenytoin Oral Suspension, USP) (FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE) DESCRIPTION Dilantin (phenytoin) is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-diphenyl-2,4 imidazolidinedione, having the following structural formula: structural formula Each 5 ml of suspension contains 125 mg of phenytoin, USP; alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No. 6. CLINICAL PHARMACOLOGY Mechanism of Action Phenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures. Pharmacokinetics and Drug Metabolism The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5–7 half-lives) after initiation of therapy with recommended doses of 300 mg/day. When serum level determinations are necessary, they should be obtained at least 5–7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient’s next scheduled dose. Peak levels indicate an individual’s threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. For Dilantin-125 Suspension, peak levels occur 1½–3 hours after administration. Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver 1 Reference ID: 3052033 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 008762 Dilantin-125 (phenytoin) Oral Suspension FDA Approved Labeling Text dated 10/2011 Page 2 of 16 disease, variant CYP2C9 and CYP2C19 alleles, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin plasma levels, despite standard doses, presents a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high plasma levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more. Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations. Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION). Gender and Race: Gender and race have no significant impact on phenytoin pharmacokinetics. Pediatrics: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day). INDICATIONS AND USAGE Dilantin (phenytoin) is indicated for the control of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures. Phenytoin serum level determinations may be necessary for optimal dosage adjustments (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY sections). CONTRAINDICATIONS Dilantin is contraindicated in those patients with a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins. Coadministration of Dilantin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors. WARNINGS Effects of Abrupt Withdrawal Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When in the judgment of the clinician the need for dosage reduction, discontinuation, or substitution of alternative anticonvulsant medication arises, this should be done gradually. In the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an anticonvulsant not belonging to the hydantoin chemical class. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Dilantin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be 2 Reference ID: 3052033 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 008762 Dilantin-125 (phenytoin) Oral Suspension FDA Approved Labeling Text dated 10/2011 Page 3 of 16 monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients with Relative Risk: Risk Difference: with Events Per Events Per 1000 Incidence of Events in Additional Drug 1000 Patients Patients Drug Patients with Events Patients/Incidence in Per 1000 Patients Placebo Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Dilantin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. 3 Reference ID: 3052033 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 008762 Dilantin-125 (phenytoin) Oral Suspension FDA Approved Labeling Text dated 10/2011 Page 4 of 16 Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Dilantin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below). Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B1502. The use of HLA-B1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Dilantin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Dilantin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Dilantin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to Dilantin. Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with Dilantin. These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, Dilantin should be immediately discontinued and not readministered. Hematopoietic System Hematopoietic complications, some fatal, have occasionally been reported in association with administration of Dilantin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, 4 Reference ID: 3052033 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 008762 Dilantin-125 (phenytoin) Oral Suspension FDA Approved Labeling Text dated 10/2011 Page 5 of 16 lymphoma, and Hodgkin’s disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs of DRESS. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs. Effects on Vitamin D and Bone The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures. Phenytoin induces hepatic metabolizing enzymes. This may enhance the metabolism of vitamin D and decrease vitamin D levels, which may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia. Consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines. Effects of Alcohol Use on Phenytoin Serum Levels Acute alcoholic intake may increase phenytoin serum levels, while chronic alcoholic use may decrease serum levels. Exacerbation of Porphyria In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease. Usage in Pregnancy: Clinical: Risks to Mother. An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated. Risks to the Fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy. Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth. 5 Reference ID: 3052033 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 008762 Dilantin-125 (phenytoin) Oral Suspension FDA Approved Labeling Text dated 10/2011 Page 6 of 16 Preclinical: Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits. PRECAUTIONS General: The liver is the chief site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity. A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. If early signs of dose-related CNS toxicity develop, plasma levels should be checked immediately. Hyperglycemia, resulting from the drug’s inhibitory effects on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients. Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present, combined drug therapy is needed. Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended. (See WARNINGS section.) Information for Patients: Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Dilantin. Instruct patients to take Dilantin only as prescribed. Patients taking phenytoin should be advised of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc. Patients should be instructed to use an accurately calibrated measuring device when using this medication to ensure accurate dosing. Patients should be made aware of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use. Patients should also be cautioned on the use of other drugs or alcoholic beverages without first seeking the physician’s advice. The importance of good dental hygiene should be stressed in order to minimize the development of gingival hyperplasia and its complications. Patients, their caregivers, and families should be counseled that AEDs, including Dilantin, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. 6 Reference ID: 3052033 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 008762 Dilantin-125 (phenytoin) Oral Suspension FDA Approved Labeling Text dated 10/2011 Page 7 of 16 Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS: Pregnancy section). Laboratory Tests: Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 µg/mL (unbound phenytoin concentrations of 1 to 2 µg/mL). Drug Interactions: Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19, and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected. The most commonly occurring drug interactions are listed below: Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. Drugs that affect phenytoin concentrations: • Drugs, which may increase phenytoin serum levels, include: acute alcohol intake, amiodarone, anti-epileptic agents (felbamate, topiramate, oxcarbazepine), azoles (fluconazole, ketoconazole, itraconazole, voriconazole), chloramphenicol, chlordiazepoxide, cimetidine, diazepam, disulfiram, estrogens, ethosuximide, fluorouracil, fluoxetine, fluvoxamine, H2-antagonists, halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides, ticlopidine, tolbutamide, trazodone, and warfarin. • Drugs, which may decrease phenytoin levels, include: carbamazepine, chronic alcohol abuse, nelfinavir, reserpine, ritonavir, and sucralfate. • Ingestion times of phenytoin and antacid preparations containing calcium should be staggered in patients with low serum phenytoin levels to prevent absorption problems. • Drugs which may either increase or decrease phenytoin serum levels include: phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid, and sodium valproate serum levels is unpredictable. • The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome. Drugs affected by phenytoin: • Drugs that should not be coadministered with phenytoin: Delavirdine • Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, teniposide, theophylline, vitamin D, and warfarin. • Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin. • Phenytoin decreases plasma concentrations of certain HIV antivirals (amprenavir, efavirenz, Kaletra (lopinavir/ritonavir), indinavir, nelfinavir, ritonavir, saquinavir), and anti-epileptic agents (felbamate, topiramate, oxcarbazepine, quetiapine). • The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome. Drug Enteral Feeding/Nutritional Preparations Interaction: Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than 7 Reference ID: 3052033 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 008762 Dilantin-125 (phenytoin) Oral Suspension FDA Approved Labeling Text dated 10/2011 Page 8 of 16 expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients. Drug/Laboratory Test Interactions: Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations. Carcinogenesis: See WARNINGS section for information on carcinogenesis. Pregnancy: Pregnancy Category D; See WARNINGS section. To provide information regarding the effects of in utero exposure to Dilantin, physicians are advised to recommend that pregnant patients taking Dilantin enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Nursing Mothers: Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Pediatric Use: See DOSAGE AND ADMINISTRATION section. Geriatric Use: Phenytoin clearance tends to decrease with increasing age (see CLINICAL PHARMACOLOGY: Special Populations). ADVERSE REACTIONS Body As a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS (see WARNINGS) have been observed. Anaphylaxis has also been reported. There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities. Nervous System: The most common manifestations encountered with phenytoin therapy are referable to this system and are usually dose-related. These include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, insomnia, transient nervousness, motor twitchings, paresthesias, and headaches have also been observed. There have also been rare reports of phenytoin-induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Digestive System: Nausea, vomiting, constipation, enlargement of the lips, gingival hyperplasia, toxic hepatitis and liver damage. Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see WARNINGS section). There have also been reports of hypertrichosis. Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease have been reported (see WARNINGS section). 8 Reference ID: 3052033 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 008762 Dilantin-125 (phenytoin) Oral Suspension FDA Approved Labeling Text dated 10/2011 Page 9 of 16 Special Senses: Altered taste sensation including metallic taste. Urogenital: Peyronie’s disease OVERDOSAGE The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL; dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind. DOSAGE AND ADMINISTRATION FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Dilantin® Kapseals® is formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspension and Dilantin Infatabs. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa. General: Dosage should be individualized to provide maximum benefit. In some cases serum blood level determinations may be necessary for optimal dosage adjustments—the clinically effective serum level is usually 10–20 mcg/mL. With recommended dosage, a period of seven to ten days may be required to achieve steady-state blood levels with phenytoin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days. Adult Dose: Patients who have received no previous treatment may be started on one teaspoonful (5 mL) of Dilantin-125 Suspension three times daily, and the dose is then adjusted to suit individual requirements. An increase to five teaspoonfuls daily may be made, if necessary. Dosing in Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound phenytoin concentrations may be more useful in these patient populations. Elderly Patients: Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required. Pediatric: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day). HOW SUPPLIED 9 Reference ID: 3052033 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 008762 Dilantin-125 (phenytoin) Oral Suspension FDA Approved Labeling Text dated 10/2011 Page 10 of 16 N 0071-2214-20—Dilantin-125® Suspension (phenytoin oral suspension, USP), 125 mg phenytoin/5 mL with a maximum alcohol content not greater than 0.6 percent, an orange suspension with an orange-vanilla flavor; available in 8-oz bottles. Store at controlled room temperature 20°–25°C (68°–77°F). [See USP.] Protect from freezing and company logo LAB-0203-8.0 Revised October 2011 10 Reference ID: 3052033 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 008762 Dilantin-125 (phenytoin) Oral Suspension FDA Approved Labeling Text dated 10/2011 Page 11 of 16 MEDICATION GUIDE DILANTIN-125® (Dī LAN' tĭn-125) (Phenytoin Oral Suspension, USP) Read this Medication Guide before you start taking DILANTIN and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about DILANTIN, ask your healthcare provider or pharmacist. What is the most important information I should know about DILANTIN? Do not stop taking DILANTIN without first talking to your healthcare provider. Stopping DILANTIN suddenly can cause serious problems. DILANTIN can cause serious side effects including: 1. Like other antiepileptic drugs, DILANTIN may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • acting aggressive, being angry, • attempts to commit suicide or violent • new or worse depression • acting on dangerous impulses • new or worse anxiety • an extreme increase activity • feeling agitated or restless and talking (mania) • panic attacks • other unusual changes in • trouble sleeping (insomnia) behavior or mood • new or worse irritability How can I watch for early symptoms of suicidal thoughts and actions? • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. • Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. 11 Reference ID: 3052033 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 008762 Dilantin-125 (phenytoin) Oral Suspension FDA Approved Labeling Text dated 10/2011 Page 12 of 16 Do not stop taking DILANTIN without first talking to a healthcare provider. Stopping DILANTIN suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus). Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. 2. Dilantin may harm your unborn baby. • If you take DILANTIN during pregnancy, your baby is at risk for serious birth defects. • Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors • If you take DILANTIN during pregnancy, your baby is also at risk for bleeding problems right after birth. Your healthcare provider may give you and your baby medicine to prevent this. • All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of DILANTIN. If the decision is made to use DILANTIN, you should use effective birth control (contraception) unless you are planning to become pregnant. • Tell your healthcare provider right away if you become pregnant while taking DILANTIN. You and your healthcare provider should decide if you will take DILANTIN while you are pregnant. • Pregnancy Registry: If you become pregnant while taking DILANTIN, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3. Swollen glands (lymph nodes) 4. Allergic reactions or serious problems which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions. Symptoms can include any of the following: • swelling of your face, eyes, • painful sores in the mouth or lips, or tongue around your eyes • trouble swallowing or • yellowing of your skin or eyes breathing • bruising or bleeding • a skin rash • severe fatigue or weakness • hives • severe muscle pain • fever, swollen glands (lymph • frequent infections or an nodes), or sore throat that do infection that does not go away not go away or come and go • loss of appetite (anorexia) 12 Reference ID: 3052033 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 008762 Dilantin-125 (phenytoin) Oral Suspension FDA Approved Labeling Text dated 10/2011 Page 13 of 16 • nausea or vomiting Call your healthcare provider right away if you have any of the symptoms listed above. What is DILANTIN? DILANTIN is a prescription medicine used to treat tonic-clonic (grand mal), complex partial (psychomotor or temporal lobe) seizures, and to prevent and treat seizures that happen during or after brain surgery. Who should not take DILANTIN? Do not take DILANTIN if you: • are allergic to phenytoin or any of the ingredients in DILANTIN. See the end of this leaflet for a complete list of ingredients in DILANTIN. • have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin). • take delavirdine What should I tell my healthcare provider before taking DILANTIN? Before you take DILANTIN, tell your healthcare provider if you: • Have or had liver disease • Have or had porphyria • Have or had diabetes • Have or have had depression, mood problems, or suicidal thoughts or behavior • Are pregnant or plan to become pregnant. If you become pregnant while taking DILANTIN, the level of DILANTIN in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of DILANTIN. • Are breast feeding or plan to breastfeed. DILANTIN can pass into breast milk. You and your healthcare provider should decide if you will take DILANTIN or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking DILANTIN with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. 13 Reference ID: 3052033 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 008762 Dilantin-125 (phenytoin) Oral Suspension FDA Approved Labeling Text dated 10/2011 Page 14 of 16 How should I take DILANTIN? • Take DILANTIN exactly as prescribed. Your healthcare provider will tell you how much DILANTIN to take. • Your healthcare provider may change your dose. Do not change your dose of DILANTIN without talking to your healthcare provider. • DILANTIN can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking DILANTIN can help prevent this. • If you take too much DILANTIN, call your healthcare provider or local Poison Control Center right away. • Do not stop taking DILANTIN without first talking to your healthcare provider. Stopping DILANTIN suddenly can cause serious problems. What should I avoid while taking DILANTIN? • Do not drink alcohol while you take DILANTIN without first talking to your healthcare provider. Drinking alcohol while taking DILANTIN may change your blood levels of DILANTIN which can cause serious problems. • Do not drive, operate heavy machinery, or do other dangerous activities until you know how DILANTIN affects you. DILANTIN can slow your thinking and motor skills. What are the possible side effects of DILANTIN? See “What is the most important information I should know about DILANTIN?” DILANTIN may cause other serious side effects including: • Softening of your bones (osteopenia, osteoporosis, and osteomalacia). This can cause broken bones. Call your healthcare provider right away, if you have any of the symptoms listed above. The most common side effects of DILANTIN include: • problems with walking and • tremor coordination • headache • slurred speech • nausea • confusion • vomiting • dizziness • constipation • trouble sleeping • rash • nervousness These are not all the possible side effects of DILANTIN. For more information, ask your healthcare provider or pharmacist. 14 Reference ID: 3052033 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 008762 Dilantin-125 (phenytoin) Oral Suspension FDA Approved Labeling Text dated 10/2011 Page 15 of 16 Tell your healthcare provider if you have any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store DILANTIN? • Store DILANTIN-125 Suspension at room temperature between 68°F to 77°F (20°C to 25°C). Protect from light. Do not freeze. Keep DILANTIN and all medicines out of the reach of children. General information about DILANTIN Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DILANTIN for a condition for which it was not prescribed. Do not give DILANTIN to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about DILANTIN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about DILANTIN that was written for healthcare professionals. For more information about DILANTIN, visit http://www.pfizer.com or call 1-800-438-1985. What are the ingredients in DILANTIN-125? Oral Suspension Active ingredient: phenytoin, USP Inactive ingredients: alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No. 6. This Medication Guide has been approved by the U.S. Food and Drug Administration. company logo LAB-0398-3.0 October 2011 15 Reference ID: 3052033 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:37.922948	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/008762s032s039s040s041s043lbl.pdf', 'application_number': 8762, 'submission_type': 'SUPPL ', 'submission_number': 39}
10,709	NDA 010151 Dilantin injection S-038 FDA Approved Labeling Text Jan 2014 Parenteral Dilantin (Phenytoin Sodium Injection, USP) WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION The rate of intravenous Dilantin administration should not exceed 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous Dilantin. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed (see WARNINGS and DOSAGE AND ADMINISTRATION). DESCRIPTION Dilantin (phenytoin sodium injection, USP) is a ready-mixed solution of phenytoin sodium in a vehicle containing 40% propylene glycol and 10% alcohol in water for injection, adjusted to pH 12 with sodium hydroxide. Phenytoin sodium is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is sodium 5,5-diphenyl-2, 4- imidazolidinedione represented by the following structural formula: structural formula CLINICAL PHARMACOLOGY Mechanism of Action Phenytoin is an anticonvulsant which may be useful in the treatment of generalized tonic clonic status epilepticus. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of generalized tonic-clonic seizures. Reference ID: 3440884 NDA 010151 Dilantin injection S-038 FDA Approved Labeling Text Jan 2014 Pharmacokinetics and Drug Metabolism The plasma half-life in man after intravenous administration ranges from 10 to 15 hours. Optimum control without clinical signs of toxicity occurs most often with serum levels between 10 and 20 mcg/mL. Phenytoin is metabolized by the cytochrome P450 enzymes CYP2C9 and CYP2C19. A fall in plasma levels may occur when patients are changed from oral to intramuscular administration. The drop is caused by slower absorption, as compared to oral administration, due to the poor water solubility of phenytoin. Intravenous administration is the preferred route for producing rapid therapeutic serum levels. When intramuscular administration may be required, a sufficient dose must be administered intramuscularly to maintain the plasma level within the therapeutic range. Where oral dosage is resumed following intramuscular usage, the oral dose should be properly adjusted to compensate for the slow, continuing IM absorption to avoid toxic symptoms. Patients stabilized on a daily oral regimen of Dilantin experience a drop in peak blood levels to 50-60 percent of stable levels if crossed over to an equal dose administered intramuscularly. However, the intramuscular depot of poorly soluble material is eventually absorbed, as determined by urinary excretion of 5-(p-hydroxyphenyl)-5 phenylhydantoin (HPPH), the principal metabolite, as well as the total amount of drug eventually appearing in the blood. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. A short-term (one week) study indicates that patients do not experience the expected drop in blood levels when crossed over to the intramuscular route if the Dilantin IM dose is increased by 50 percent over the previously established oral dose. To avoid drug cumulation due to absorption from the muscle depots, it is recommended that for the first week back on oral Dilantin, the dose be reduced to half of the original oral dose (one third of the IM dose). Experience for periods greater than one week is lacking and blood level monitoring is recommended. Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations. Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION). Reference ID: 3440884 NDA 010151 Dilantin injection S-038 FDA Approved Labeling Text Jan 2014 Gender and Race: Gender and race have no significant impact on phenytoin pharmacokinetics. Pediatrics: A loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10 20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1 3 mg/kg/min or 50 mg per minute, whichever is slower. INDICATIONS AND USAGE Parenteral Dilantin is indicated for the control of generalized tonic-clonic status epilepticus, and prevention and treatment of seizures occurring during neurosurgery. Parenteral Dilantin should be used only when oral Dilantin administration is not possible. CONTRAINDICATIONS Phenytoin is contraindicated in patients with a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins. Because of its effect on ventricular automaticity, phenytoin is contraindicated in sinus bradycardia, sino-atrial block, second and third degree A-V block, and patients with Adams-Stokes syndrome. Coadministration of Dilantin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non nucleoside reverse transcriptase inhibitors. WARNINGS Cardiovascular Risk Associated with Rapid Infusion Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, the drug should be administered at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. As non-emergency therapy, Dilantin should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Dilantin. Reduction in rate of administration or discontinuation of dosing may be needed. Reference ID: 3440884 NDA 010151 Dilantin injection S-038 FDA Approved Labeling Text Jan 2014 Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates. Withdrawal Precipitated Seizure, Status Epilepticus Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class. Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Dilantin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below). Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA B1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B1502. The use of HLA-B1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Dilantin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in Reference ID: 3440884 NDA 010151 Dilantin injection S-038 FDA Approved Labeling Text Jan 2014 association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Dilantin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Dilantin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to Dilantin. Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, phenytoin should be immediately discontinued and not re-administered. Hematopoietic System Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling DRESS.In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs. Local Toxicity (including Purple Glove Syndrome) Soft tissue irritation and inflammation has occurred at the site of injection with and without extravasation of intravenous phenytoin. Reference ID: 3440884 NDA 010151 Dilantin injection S-038 FDA Approved Labeling Text Jan 2014 Edema, discoloration and pain distal to the site of injection (described as “purple glove syndrome”) have also been reported following peripheral intravenous phenytoin injection. Soft tissue irritation may vary from slight tenderness to extensive necrosis, and sloughing. The syndrome may not develop for several days after injection. Although resolution of symptoms may be spontaneous, skin necrosis and limb ischemia have occurred and required such interventions as fasciotomies, skin grafting, and, in rare cases, amputation. Because of the risk of local toxicity, intravenous Dilantin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the IV catheter should be tested with a flush of sterile saline. Each injection of parenteral Dilantin should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution. Intramuscular Dilantin administration may cause pain, necrosis, and abscess formation at the injection site (see DOSAGE AND ADMINISTRATION). Alcohol Use Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may decrease serum levels. Exacerbation of Porphyria In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease. Usage in Pregnancy Clinical Risks to Mother An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated. Risks to the Fetus If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin Reference ID: 3440884 NDA 010151 Dilantin injection S-038 FDA Approved Labeling Text Jan 2014 and/or others) during pregnancy is about 10%, or two to three fold that in the general population. However, the relative contribution of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy. Postpartum Period A potentially life-threatening bleeding disorder related to decreased levels of vitamin K- dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth. Preclinical Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits. PRECAUTIONS General The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early toxicity. A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. Hyperglycemia, resulting from the drug's inhibitory effect on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients. Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin is not effective for absence seizures. If tonic-clonicand absence seizures are present, combined drug therapy is needed. Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as "delirium", "psychosis", or "encephalopathy", or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended. (See Warnings) Laboratory Tests Reference ID: 3440884 NDA 010151 Dilantin injection S-038 FDA Approved Labeling Text Jan 2014 Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). Drug Interactions Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected. The most commonly occurring drug interactions are listed below: Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. Drugs that affect phenytoin concentrations: • Drugs that may increase phenytoin serum levels, include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, cimetidine, diazepam, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin. • Drugs that may decrease phenytoin levels, include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, folic acid, fosamprenavir, nelfinavir, reserpine, ritonavir, St. John’s Wort, and vigabatrin. • Drugs that may either increase or decrease phenytoin serum levels include: phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable. • The addition or withdrawal of the agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome. Drugs affected by phenytoin: • Drugs that should not be coadministered with phenytoin: Delavirdine (see CONTRAINDICATIONS). • Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contaceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, tenisposide, theophylline, and Vitamin D. Reference ID: 3440884 NDA 010151 Dilantin injection S-038 FDA Approved Labeling Text Jan 2014 • Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin. • Phenytoin decreases plasma concentrations of active metabolites of albendazole, certain HIV antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic agents (felbamate, topiramate, oxcarbazepine, quetiapine), atorvastatin, cyclosporine, digoxin, fluvastatin, folic acid, mexiletine, nisoldipine, praziquantel, and simvastatin. • Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir. • Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher. • The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome. Drug-Enteral Feeding/Nutritional Preparations Interaction Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients. Drug/Laboratory Test Interactions Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may also cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations following fosphenytoin administration. Carcinogenesis See "Warnings" section for information on carcinogenesis. Pregnancy Pregnancy Category D: See WARNINGS. Nursing Mothers Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Pediatric Use Reference ID: 3440884 NDA 010151 Dilantin injection S-038 FDA Approved Labeling Text Jan 2014 See DOSAGE AND ADMINISTRATION Geriatric Use Phenytoin clearance tends to decrease with increasing age (see CLINICAL PHARMACOLOGY: Special Populations). ADVERSE REACTIONS The most notable signs of toxicity associated with the intravenous use of this drug are cardiovascular collapse and/or central nervous system depression. Hypotension does occur when the drug is administered rapidly by the intravenous route. The rate of administration is very important; it should not exceed 50 mg per minute in adults, and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Body As a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS (see WARNINGS) have been observed. Anaphylaxis has also been reported. There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities. Cardiovascular: Severe cardiovascular events and fatalities have been reported with atrial and ventricular conduction depression and ventricular fibrillation. Severe complications are most commonly encountered in elderly or critically ill patients (see WARNINGS). Nervous System: The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesia, and headaches have also been observed. There have also been rare reports of phenytoin induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Digestive System: Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia. Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see WARNINGS section). There have also been reports of hypertrichosis. Reference ID: 3440884 NDA 010151 Dilantin injection S-038 FDA Approved Labeling Text Jan 2014 Local irritation, inflammation, tenderness, necrosis, and sloughing have been reported with or without extravasation of intravenous phenytoin (see WARNINGS). Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy, including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's Disease have been reported (see Warnings). Special Senses: Altered taste sensation including metallic taste. Urogenital: Peyronie’s disease OVERDOSAGE The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind. DOSAGE AND ADMINISTRATION Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, the drug should be administered at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. Reference ID: 3440884 NDA 010151 Dilantin injection S-038 FDA Approved Labeling Text Jan 2014 As non-emergency therapy, Dilantin should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Dilantin. Reduction in rate of administration or discontinuation of dosing may be needed. Because of the risk of local toxicity, intravenous Dilantin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the IV catheter should be tested with a flush of sterile saline. Each injection of parenteral Dilantin should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution. Dilantin can be given diluted with normal saline. The addition of parenteral Dilantin to dextrose and dextrose-containing solutions should be avoided due to lack of solubility and resultant precipitation. Treatment with Dilantin can be initiated either with a loading dose or an infusion: Loading Dose: A loading dose of parenteral Dilantin should be injected slowly, not exceeding 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Infusion: For infusion administration, parenteral Dilantin should be diluted in normal saline with the final concentration of Dilantin in the solution no less than 5 mg/mL. Administration should commence immediately after the mixture has been prepared and must be completed within 1 to 4 hours (the infusion mixture should not be refrigerated). An in-line filter (0.22-0.55 microns) should be used. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution or container permit. The diluted infusion mixture (Dilantin plus normal saline) should not be refrigerated. If the undiluted parenteral Dilantin is refrigerated or frozen, a precipitate might form: this will dissolve again after the solution is allowed to stand at room temperature. The product is still suitable for use. A faint yellow coloration may develop, however this has no effect on the potency of the solution. Status Epilepticus In adults, a loading dose of 10 to 15 mg/kg should be administered slowly intravenously, at a rate not exceeding 50 mg per minute (this will require approximately 20 minutes in a 70-kg patient). Reference ID: 3440884 NDA 010151 Dilantin injection S-038 FDA Approved Labeling Text Jan 2014 The loading dose should be followed by maintenance doses of 100 mg orally or intravenously every 6-8 hours. In the pediatric population, a loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10-20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. Continuous monitoring of the electrocardiogram and blood pressure is essential. The patient should be observed for signs of respiratory depression. Determination of phenytoin plasma levels is advised when using Dilantin in the management of status epilepticus and in the subsequent establishment of maintenance dosage. Other measures, including concomitant administration of an intravenous benzodiazepine such as diazepam, or an intravenous short-acting barbiturate, will usually be necessary for rapid control of seizures because of the required slow rate of administration of Dilantin. If administration of Parenteral Dilantin does not terminate seizures, the use of other anticonvulsants, intravenous barbiturates, general anesthesia, and other appropriate measures should be considered. Intramuscular administration should not be used in the treatment of status epilepticus because the attainment of peak plasma levels may require up to 24 hours. Nonemergent Loading and Maintenance Dosing Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. In adults, a loading dose of 10 to 15 mg/kg should be administered slowly. The rate of intravenous administration should not exceed 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Slower administration rates are recommended to minimize the cardiovascular adverse reactions. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential. The loading dose should be followed by maintenance doses of oral or intravenous Dilantin every 6-8 hours. Ordinarily, Dilantin should not be given intramuscularly because of the risk of necrosis, abscess formation, and erratic absorption. If intramuscular administration is required, compensating dosage adjustments are necessary to maintain therapeutic plasma levels. An intramuscular dose 50% greater than the oral dose is necessary to maintain these levels. When returned to oral administration, the dose should be reduced by 50% of the original oral dose for one week to prevent excessive plasma levels due to sustained release from intramuscular tissue sites. Reference ID: 3440884 NDA 010151 Dilantin injection S-038 FDA Approved Labeling Text Jan 2014 Monitoring plasma levels would help prevent a fall into the subtherapeutic range. Serum blood level determinations are especially helpful when possible drug interactions are suspected. IV Substitution For Oral Phenytoin Therapy When treatment with oral phenytoin is not possible, IV Dilantin can be substituted for oral phenytoin at the same total daily dose. Dilantin capsules are approximately 90% bioavailable by the oral route. Phenytoin is 100% bioavailable by the IV route. For this reason, plasma phenytoin concentrations may increase modestly when IV phenytoin is substituted for oral phenytoin sodium therapy. The rate of administration for IV Dilantin should be no greater than 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Dilantin® Kapseals® and Dilantin Parenteral are formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspension and Dilantin Infatabs. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa. Dosing in Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound phenytoin concentrations may be more useful in these patient populations. Elderly Patients: Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required. Pediatric: A loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10 20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1 3 mg/kg/min or 50 mg per minute, whichever is slower. HOW SUPPLIED NDC 0071-4488--47 (Steri-Dose® 4488) Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in a 2-mL sterile disposable syringe(22 gauge x 1 ¼ inch needle). Packages of ten syringes. NDC 0071-4488-45 Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in 2-mL Steri-Vials®. Packages of twenty-five. NDC 0071-4475-45 Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in 5-mL Steri-Vials. Packages of twenty-five. Reference ID: 3440884 NDA 010151 Dilantin injection S-038 FDA Approved Labeling Text Jan 2014 Caution- Federal law prohibits dispensing without prescription. Warning- Manufactured with CFC-12, which harms public health and environment by destroying ozone in the upper atmosphere. Rx only company logo LAB-0383-4.1 January 2014 Reference ID: 3440884 NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text January 2014 sNDA 050 Dilantin-125® (Phenytoin Oral Suspension, USP) (FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE) DESCRIPTION Dilantin (phenytoin) is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-diphenyl-2,4 imidazolidinedione, having the following structural formula: structural formula Each 5 ml of suspension contains 125 mg of phenytoin, USP; alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No. 6. CLINICAL PHARMACOLOGY Mechanism of Action Phenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures. Pharmacokinetics and Drug Metabolism The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5–7 half-lives) after initiation of therapy with recommended doses of 300 mg/day. When serum level determinations are necessary, they should be obtained at least 5–7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient’s next scheduled dose. Peak levels indicate an individual’s threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. For Dilantin-125 Suspension, peak levels occur 1½–3 hours after administration. Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low 1 Reference ID: 3440884 NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text January 2014 sNDA 050 levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, variant CYP2C9 and CYP2C19 alleles, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin plasma levels, despite standard doses, presents a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high plasma levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more. Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations. Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION). Gender and Race: Gender and race have no significant impact on phenytoin pharmacokinetics. Pediatrics: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day). INDICATIONS AND USAGE Dilantin (phenytoin) is indicated for the control of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures. Phenytoin serum level determinations may be necessary for optimal dosage adjustments (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY sections). CONTRAINDICATIONS Dilantin is contraindicated in those patients with a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins. Coadministration of Dilantin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors. WARNINGS Effects of Abrupt Withdrawal Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When in the judgment of the clinician the need for dosage reduction, discontinuation, or substitution of alternative anticonvulsant medication arises, this should be done gradually. In the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an anticonvulsant not belonging to the hydantoin chemical class. 2 Reference ID: 3440884 NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text January 2014 sNDA 050 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Dilantin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients with Relative Risk: Risk Difference: with Events Per Events Per 1000 Incidence of Events in Additional Drug 1000 Patients Patients Drug Patients with Events Patients/Incidence in Per 1000 Patients Placebo Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Dilantin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 3 Reference ID: 3440884 NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text January 2014 sNDA 050 Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Dilantin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below). Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B1502. The use of HLA-B1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Dilantin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Dilantin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Dilantin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to Dilantin. Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with Dilantin. These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal 4 Reference ID: 3440884 NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text January 2014 sNDA 050 outcomes. In these patients with acute hepatotoxicity, Dilantin should be immediately discontinued and not readministered. Hematopoietic System Hematopoietic complications, some fatal, have occasionally been reported in association with administration of Dilantin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs of DRESS. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs. Effects on Vitamin D and Bone The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures. Phenytoin induces hepatic metabolizing enzymes. This may enhance the metabolism of vitamin D and decrease vitamin D levels, which may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia. Consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines. Effects of Alcohol Use on Phenytoin Serum Levels Acute alcoholic intake may increase phenytoin serum levels, while chronic alcoholic use may decrease serum levels. Exacerbation of Porphyria In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease. Usage in Pregnancy: Clinical: Risks to Mother. An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated. Risks to the Fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most 5 Reference ID: 3440884 NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text January 2014 sNDA 050 cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy. Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth. Preclinical: Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits. PRECAUTIONS General: The liver is the chief site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity. A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. If early signs of dose-related CNS toxicity develop, plasma levels should be checked immediately. Hyperglycemia, resulting from the drug’s inhibitory effects on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients. Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present, combined drug therapy is needed. Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended. (See WARNINGS section.) Information for Patients: Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Dilantin. Instruct patients to take Dilantin only as prescribed. Patients taking phenytoin should be advised of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc. Patients should be instructed to use an accurately calibrated measuring device when using this medication to ensure accurate dosing. Patients should be made aware of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any 6 Reference ID: 3440884 NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text January 2014 sNDA 050 occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use. Patients should also be cautioned on the use of other drugs or alcoholic beverages without first seeking the physician’s advice. The importance of good dental hygiene should be stressed in order to minimize the development of gingival hyperplasia and its complications. Patients, their caregivers, and families should be counseled that AEDs, including Dilantin, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS: Pregnancy section). Laboratory Tests: Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). Drug Interactions: Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19, and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected. The most commonly occurring drug interactions are listed below: Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. Drugs that affect phenytoin concentrations: • Drugs that may increase phenytoin serum levels, include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, diazepam, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin. • Drugs that may decrease phenytoin levels, include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, folic acid, fosamprenavir, nelfinavir, reserpine, ritonavir, St. John’s Wort, sucralfate and vigabatrin. • Administration of phenytoin with preparations that increase gastric pH (e.g., supplements or antacids containing calcium carbonate, aluminum hydroxide, and magnesium hydroxide) may affect the absorption of phenytoin. In most cases where interactions were seen, the effect is a decrease in phenytoin levels when the drugs are taken at the same time. When possible, phenytoin and these products should not be taken at the same time of day. 7 Reference ID: 3440884 NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text January 2014 sNDA 050 • Drugs that may either increase or decrease phenytoin serum levels include: phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid, and sodium valproate serum levels is unpredictable. • The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome. Drugs affected by phenytoin: • Drugs that should not be coadministered with phenytoin: Delavirdine (see CONTRAINDICATIONS) • Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, teniposide, theophylline, and vitamin D. • Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin. • Phenytoin decreases plasma concentrations of active metabolites of albendazole, certain HIV antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic agents (felbamate, topiramate, oxcarbazepine, quetiapine), atorvastatin, cyclosporine, digoxin, fluvastatin, folic acid, mexiletine, nisoldipine, praziquantel, and simvastatin. • Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir. • Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other nondepolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher. • The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome. Drug Enteral Feeding/Nutritional Preparations Interaction: Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients. Drug/Laboratory Test Interactions: Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations. Carcinogenesis: See WARNINGS section for information on carcinogenesis. Pregnancy: Pregnancy Category D; See WARNINGS section. To provide information regarding the effects of in utero exposure to Dilantin, physicians are advised to recommend that pregnant patients taking Dilantin enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ . 8 Reference ID: 3440884 NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text January 2014 sNDA 050 Nursing Mothers: Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Pediatric Use: See DOSAGE AND ADMINISTRATION section. Geriatric Use: Phenytoin clearance tends to decrease with increasing age (see CLINICAL PHARMACOLOGY: Special Populations). ADVERSE REACTIONS Body As a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS (see WARNINGS) have been observed. Anaphylaxis has also been reported. There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities. Nervous System: The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesias, and headaches have also been observed. There have also been rare reports of phenytoin-induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Digestive System: Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia. Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see WARNINGS section). There have also been reports of hypertrichosis. Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease have been reported (see WARNINGS section). Special Senses: Altered taste sensation including metallic taste. Urogenital: Peyronie’s disease OVERDOSAGE The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL; dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. 9 Reference ID: 3440884 NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text January 2014 sNDA 050 Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind. DOSAGE AND ADMINISTRATION FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Dilantin® Kapseals® is formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspension and Dilantin Infatabs. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa. General: Dosage should be individualized to provide maximum benefit. In some cases serum blood level determinations may be necessary for optimal dosage adjustments—the clinically effective serum level is usually 10–20 mcg/mL. With recommended dosage, a period of seven to ten days may be required to achieve steady-state blood levels with phenytoin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days. Adult Dose: Patients who have received no previous treatment may be started on one teaspoonful (5 mL) of Dilantin-125 Suspension three times daily, and the dose is then adjusted to suit individual requirements. An increase to five teaspoonfuls daily may be made, if necessary. Dosing in Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound phenytoin concentrations may be more useful in these patient populations. Elderly Patients: Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required. Pediatric: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day). HOW SUPPLIED NDC 0071-2214-20—Dilantin-125® Suspension (phenytoin oral suspension, USP), 125 mg phenytoin/5 mL with a maximum alcohol content not greater than 0.6 percent, an orange suspension with an orange-vanilla flavor; available in 8-oz bottles. Store at controlled room temperature 20°–25°C (68°–77°F). [See USP.] Protect from freezing and company logo LAB-0203-11.1 10 Reference ID: 3440884 NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text January 2014 sNDA 050 January 2014 11 Reference ID: 3440884 NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text January 2014 sNDA 050 MEDICATION GUIDE DILANTIN-125® (Dī LAN' tĭn-125) (Phenytoin Oral Suspension, USP) Read this Medication Guide before you start taking DILANTIN and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about DILANTIN, ask your healthcare provider or pharmacist. What is the most important information I should know about DILANTIN? Do not stop taking DILANTIN without first talking to your healthcare provider. Stopping DILANTIN suddenly can cause serious problems. DILANTIN can cause serious side effects including: 1. Like other antiepileptic drugs, DILANTIN may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • acting aggressive, being angry, • attempts to commit suicide or violent • new or worse depression • acting on dangerous impulses • new or worse anxiety • an extreme increase activity • feeling agitated or restless and talking (mania) • panic attacks • other unusual changes in • trouble sleeping (insomnia) behavior or mood • new or worse irritability How can I watch for early symptoms of suicidal thoughts and actions? • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. • Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. 12 Reference ID: 3440884 NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text January 2014 sNDA 050 Do not stop taking DILANTIN without first talking to a healthcare provider. Stopping DILANTIN suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus). Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. 2. Dilantin may harm your unborn baby. • If you take DILANTIN during pregnancy, your baby is at risk for serious birth defects. • Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors • If you take DILANTIN during pregnancy, your baby is also at risk for bleeding problems right after birth. Your healthcare provider may give you and your baby medicine to prevent this. • All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of DILANTIN. If the decision is made to use DILANTIN, you should use effective birth control (contraception) unless you are planning to become pregnant. • Tell your healthcare provider right away if you become pregnant while taking DILANTIN. You and your healthcare provider should decide if you will take DILANTIN while you are pregnant. • Pregnancy Registry: If you become pregnant while taking DILANTIN, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3. Swollen glands (lymph nodes) 4. Allergic reactions or serious problems which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions. Symptoms can include any of the following: • swelling of your face, eyes, • fever, swollen glands (lymph lips, or tongue nodes), or sore throat that do • trouble swallowing or not go away or come and go breathing • painful sores in the mouth or • a skin rash around your eyes • hives • yellowing of your skin or eyes • bruising or bleeding 13 Reference ID: 3440884 NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text January 2014 sNDA 050 • severe fatigue or weakness • loss of appetite (anorexia) • severe muscle pain • nausea or vomiting • frequent infections or an infection that does not go away Call your healthcare provider right away if you have any of the symptoms listed above. What is DILANTIN? DILANTIN is a prescription medicine used to treat tonic-clonic (grand mal), complex partial (psychomotor or temporal lobe) seizures, and to prevent and treat seizures that happen during or after brain surgery. Who should not take DILANTIN? Do not take DILANTIN if you: • are allergic to phenytoin or any of the ingredients in DILANTIN. See the end of this leaflet for a complete list of ingredients in DILANTIN. • have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin). • take delavirdine What should I tell my healthcare provider before taking DILANTIN? Before you take DILANTIN, tell your healthcare provider if you: • Have or had liver disease • Have or had porphyria • Have or had diabetes • Have or have had depression, mood problems, or suicidal thoughts or behavior • Are pregnant or plan to become pregnant. If you become pregnant while taking DILANTIN, the level of DILANTIN in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of DILANTIN. • Are breast feeding or plan to breastfeed. DILANTIN can pass into breast milk. You and your healthcare provider should decide if you will take DILANTIN or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking DILANTIN with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. 14 Reference ID: 3440884 NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text January 2014 sNDA 050 Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take DILANTIN? • Take DILANTIN exactly as prescribed. Your healthcare provider will tell you how much DILANTIN to take. • Your healthcare provider may change your dose. Do not change your dose of DILANTIN without talking to your healthcare provider. • DILANTIN can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking DILANTIN can help prevent this. • If you take too much DILANTIN, call your healthcare provider or local Poison Control Center right away. • Do not stop taking DILANTIN without first talking to your healthcare provider. Stopping DILANTIN suddenly can cause serious problems. What should I avoid while taking DILANTIN? • Do not drink alcohol while you take DILANTIN without first talking to your healthcare provider. Drinking alcohol while taking DILANTIN may change your blood levels of DILANTIN which can cause serious problems. • Do not drive, operate heavy machinery, or do other dangerous activities until you know how DILANTIN affects you. DILANTIN can slow your thinking and motor skills. What are the possible side effects of DILANTIN? See “What is the most important information I should know about DILANTIN?” DILANTIN may cause other serious side effects including: • Softening of your bones (osteopenia, osteoporosis, and osteomalacia). This can cause broken bones. Call your healthcare provider right away, if you have any of the symptoms listed above. The most common side effects of DILANTIN include: • problems with walking and • nervousness coordination • tremor • slurred speech • headache • confusion • nausea • dizziness • vomiting • trouble sleeping • constipation 15 Reference ID: 3440884 NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text January 2014 sNDA 050 • rash These are not all the possible side effects of DILANTIN. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store DILANTIN? • Store DILANTIN-125 Suspension at room temperature between 68°F to 77°F (20°C to 25°C). Protect from light. Do not freeze. Keep DILANTIN and all medicines out of the reach of children. General information about DILANTIN Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DILANTIN for a condition for which it was not prescribed. Do not give DILANTIN to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about DILANTIN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about DILANTIN that was written for healthcare professionals. For more information about DILANTIN, visit http://www.pfizer.com or call 1-800-438-1985. What are the ingredients in DILANTIN-125? Oral Suspension Active ingredient: phenytoin, USP Inactive ingredients: alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No. 6. This Medication Guide has been approved by the U.S. Food and Drug Administration. 16 Reference ID: 3440884 company logo LAB-0398-3.0 January 2014 Reference ID: 3440884	custom-source	2025-02-12T13:43:38.157090	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/008762s050,010151s038lbl.pdf', 'application_number': 8762, 'submission_type': 'SUPPL ', 'submission_number': 50}
10,708	NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 02/2013 Page 1 of 15 Dilantin-125® (Phenytoin Oral Suspension, USP) (FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE) DESCRIPTION Dilantin (phenytoin) is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-diphenyl-2,4 imidazolidinedione, having the following structural formula: structural formula Each 5 ml of suspension contains 125 mg of phenytoin, USP; alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No. 6. CLINICAL PHARMACOLOGY Mechanism of Action Phenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures. Pharmacokinetics and Drug Metabolism The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5–7 half-lives) after initiation of therapy with recommended doses of 300 mg/day. When serum level determinations are necessary, they should be obtained at least 5–7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient’s next scheduled dose. Peak levels indicate an individual’s threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. For Dilantin-125 Suspension, peak levels occur 1½–3 hours after administration. Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, variant CYP2C9 and CYP2C19 alleles, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin plasma levels, despite standard doses, presents a difficult 1 Reference ID: 3258658 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 02/2013 Page 2 of 15 clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high plasma levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more. Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations. Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION). Gender and Race: Gender and race have no significant impact on phenytoin pharmacokinetics. Pediatrics: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day). INDICATIONS AND USAGE Dilantin (phenytoin) is indicated for the control of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures. Phenytoin serum level determinations may be necessary for optimal dosage adjustments (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY sections). CONTRAINDICATIONS Dilantin is contraindicated in those patients with a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins. Coadministration of Dilantin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors. WARNINGS Effects of Abrupt Withdrawal Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When in the judgment of the clinician the need for dosage reduction, discontinuation, or substitution of alternative anticonvulsant medication arises, this should be done gradually. In the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an anticonvulsant not belonging to the hydantoin chemical class. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Dilantin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. 2 Reference ID: 3258658 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 02/2013 Page 3 of 15 Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients with Relative Risk: Risk Difference: with Events Per Events Per 1000 Incidence of Events in Additional Drug 1000 Patients Patients Drug Patients with Events Patients/Incidence in Per 1000 Patients Placebo Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Dilantin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. 3 Reference ID: 3258658 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 02/2013 Page 4 of 15 Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Dilantin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below). Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B1502. The use of HLA-B1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Dilantin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Dilantin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Dilantin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to Dilantin. Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with Dilantin. These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, Dilantin should be immediately discontinued and not readministered. 4 Reference ID: 3258658 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 02/2013 Page 5 of 15 Hematopoietic System Hematopoietic complications, some fatal, have occasionally been reported in association with administration of Dilantin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs of DRESS. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs. Effects on Vitamin D and Bone The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures. Phenytoin induces hepatic metabolizing enzymes. This may enhance the metabolism of vitamin D and decrease vitamin D levels, which may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia. Consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines. Effects of Alcohol Use on Phenytoin Serum Levels Acute alcoholic intake may increase phenytoin serum levels, while chronic alcoholic use may decrease serum levels. Exacerbation of Porphyria In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease. Usage in Pregnancy: Clinical: Risks to Mother. An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated. Risks to the Fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy. 5 Reference ID: 3258658 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 02/2013 Page 6 of 15 Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth. Preclinical: Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits. PRECAUTIONS General: The liver is the chief site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity. A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. If early signs of dose-related CNS toxicity develop, plasma levels should be checked immediately. Hyperglycemia, resulting from the drug’s inhibitory effects on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients. Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present, combined drug therapy is needed. Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended. (See WARNINGS section.) Information for Patients: Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Dilantin. Instruct patients to take Dilantin only as prescribed. Patients taking phenytoin should be advised of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc. Patients should be instructed to use an accurately calibrated measuring device when using this medication to ensure accurate dosing. Patients should be made aware of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use. Patients should also be cautioned on the use of other drugs or alcoholic beverages without first seeking the physician’s advice. The importance of good dental hygiene should be stressed in order to minimize the development of gingival hyperplasia and its complications. 6 Reference ID: 3258658 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 02/2013 Page 7 of 15 Patients, their caregivers, and families should be counseled that AEDs, including Dilantin, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS: Pregnancy section). Laboratory Tests: Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 µg/mL (unbound phenytoin concentrations of 1 to 2 µg/mL). Drug Interactions: Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19, and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected. The most commonly occurring drug interactions are listed below: Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. Drugs that affect phenytoin concentrations: • Drugs that may increase phenytoin serum levels, include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, diazepam, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin. • Drugs that may decrease phenytoin levels, include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, folic acid, fosamprenavir, nelfinavir, reserpine, ritonavir, St. John’s Wort, sucralfate and vigabatrin. • Administration of phenytoin with preparations that increase gastric pH (e.g., supplements or antacids containing calcium carbonate, aluminum hydroxide, and magnesium hydroxide) may affect the absorption of phenytoin. In most cases where interactions were seen, the effect is a decrease in phenytoin levels when the drugs are taken at the same time. When possible, phenytoin and these products should not be taken at the same time of day. • Drugs that may either increase or decrease phenytoin serum levels include: phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid, and sodium valproate serum levels is unpredictable. • The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome. Drugs affected by phenytoin: • Drugs that should not be coadministered with phenytoin: Delavirdine (see CONTRAINDICATIONS) 7 Reference ID: 3258658 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 02/2013 Page 8 of 15 • Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, teniposide, theophylline, and vitamin D. • Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin. • Phenytoin decreases plasma concentrations of certain HIV antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic agents (felbamate, topiramate, oxcarbazepine, quetiapine), atorvastatin, cyclosporine, digoxin, fluvastatin, folic acid, mexiletine, nisoldipine, praziquantel, and simvastatin. • Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir. • Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher. • The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome. Drug Enteral Feeding/Nutritional Preparations Interaction: Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients. Drug/Laboratory Test Interactions: Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations. Carcinogenesis: See WARNINGS section for information on carcinogenesis. Pregnancy: Pregnancy Category D; See WARNINGS section. To provide information regarding the effects of in utero exposure to Dilantin, physicians are advised to recommend that pregnant patients taking Dilantin enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Nursing Mothers: Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Pediatric Use: See DOSAGE AND ADMINISTRATION section. Geriatric Use: Phenytoin clearance tends to decrease with increasing age (see CLINICAL PHARMACOLOGY: Special Populations). ADVERSE REACTIONS Body As a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS (see WARNINGS) have been observed. Anaphylaxis has also been reported. 8 Reference ID: 3258658 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 02/2013 Page 9 of 15 There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities. Nervous System: The most common manifestations encountered with phenytoin therapy are referable to this system and are usually dose-related. These include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, insomnia, transient nervousness, motor twitchings, paresthesias, and headaches have also been observed. There have also been rare reports of phenytoin-induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Digestive System: Nausea, vomiting, constipation, enlargement of the lips, gingival hyperplasia, toxic hepatitis and liver damage. Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see WARNINGS section). There have also been reports of hypertrichosis. Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease have been reported (see WARNINGS section). Special Senses: Altered taste sensation including metallic taste. Urogenital: Peyronie’s disease OVERDOSAGE The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL; dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind. DOSAGE AND ADMINISTRATION FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Dilantin® Kapseals® is formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspension and Dilantin Infatabs. Because there is 9 Reference ID: 3258658 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 02/2013 Page 10 of 15 approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa. General: Dosage should be individualized to provide maximum benefit. In some cases serum blood level determinations may be necessary for optimal dosage adjustments—the clinically effective serum level is usually 10–20 mcg/mL. With recommended dosage, a period of seven to ten days may be required to achieve steady-state blood levels with phenytoin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days. Adult Dose: Patients who have received no previous treatment may be started on one teaspoonful (5 mL) of Dilantin-125 Suspension three times daily, and the dose is then adjusted to suit individual requirements. An increase to five teaspoonfuls daily may be made, if necessary. Dosing in Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound phenytoin concentrations may be more useful in these patient populations. Elderly Patients: Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required. Pediatric: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day). HOW SUPPLIED N 0071-2214-20—Dilantin-125® Suspension (phenytoin oral suspension, USP), 125 mg phenytoin/5 mL with a maximum alcohol content not greater than 0.6 percent, an orange suspension with an orange-vanilla flavor; available in 8-oz bottles. Store at controlled room temperature 20°–25°C (68°–77°F). [See USP.] Protect from freezing and company logo LAB-0203-8.1 Revised February 2013 10 Reference ID: 3258658 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 02/2013 Page 11 of 15 MEDICATION GUIDE DILANTIN-125® (Dī LAN' tĭn-125) (Phenytoin Oral Suspension, USP) Read this Medication Guide before you start taking DILANTIN and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about DILANTIN, ask your healthcare provider or pharmacist. What is the most important information I should know about DILANTIN? Do not stop taking DILANTIN without first talking to your healthcare provider. Stopping DILANTIN suddenly can cause serious problems. DILANTIN can cause serious side effects including: 1. Like other antiepileptic drugs, DILANTIN may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • acting aggressive, being angry, • attempts to commit suicide or violent • new or worse depression • acting on dangerous impulses • new or worse anxiety • an extreme increase activity • feeling agitated or restless and talking (mania) • panic attacks • other unusual changes in • trouble sleeping (insomnia) behavior or mood • new or worse irritability How can I watch for early symptoms of suicidal thoughts and actions? • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. • Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. 11 Reference ID: 3258658 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 02/2013 Page 12 of 15 Do not stop taking DILANTIN without first talking to a healthcare provider. Stopping DILANTIN suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus). Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. 2. Dilantin may harm your unborn baby. • If you take DILANTIN during pregnancy, your baby is at risk for serious birth defects. • Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors • If you take DILANTIN during pregnancy, your baby is also at risk for bleeding problems right after birth. Your healthcare provider may give you and your baby medicine to prevent this. • All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of DILANTIN. If the decision is made to use DILANTIN, you should use effective birth control (contraception) unless you are planning to become pregnant. • Tell your healthcare provider right away if you become pregnant while taking DILANTIN. You and your healthcare provider should decide if you will take DILANTIN while you are pregnant. • Pregnancy Registry: If you become pregnant while taking DILANTIN, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3. Swollen glands (lymph nodes) 4. Allergic reactions or serious problems which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions. Symptoms can include any of the following: • swelling of your face, eyes, lips, or tongue • trouble swallowing or breathing • a skin rash • hives • fever, swollen glands (lymph nodes), or sore throat that do not go away or come and go 12 Reference ID: 3258658 • painful sores in the mouth or around your eyes • yellowing of your skin or eyes • bruising or bleeding • severe fatigue or weakness • severe muscle pain • frequent infections or an infection that does not go away • loss of appetite (anorexia) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 02/2013 Page 13 of 15 • nausea or vomiting Call your healthcare provider right away if you have any of the symptoms listed above. What is DILANTIN? DILANTIN is a prescription medicine used to treat tonic-clonic (grand mal), complex partial (psychomotor or temporal lobe) seizures, and to prevent and treat seizures that happen during or after brain surgery. Who should not take DILANTIN? Do not take DILANTIN if you: • are allergic to phenytoin or any of the ingredients in DILANTIN. See the end of this leaflet for a complete list of ingredients in DILANTIN. • have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin). • take delavirdine What should I tell my healthcare provider before taking DILANTIN? Before you take DILANTIN, tell your healthcare provider if you: • Have or had liver disease • Have or had porphyria • Have or had diabetes • Have or have had depression, mood problems, or suicidal thoughts or behavior • Are pregnant or plan to become pregnant. If you become pregnant while taking DILANTIN, the level of DILANTIN in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of DILANTIN. • Are breast feeding or plan to breastfeed. DILANTIN can pass into breast milk. You and your healthcare provider should decide if you will take DILANTIN or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking DILANTIN with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. 13 Reference ID: 3258658 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 02/2013 Page 14 of 15 How should I take DILANTIN? • Take DILANTIN exactly as prescribed. Your healthcare provider will tell you how much DILANTIN to take. • Your healthcare provider may change your dose. Do not change your dose of DILANTIN without talking to your healthcare provider. • DILANTIN can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking DILANTIN can help prevent this. • If you take too much DILANTIN, call your healthcare provider or local Poison Control Center right away. • Do not stop taking DILANTIN without first talking to your healthcare provider. Stopping DILANTIN suddenly can cause serious problems. What should I avoid while taking DILANTIN? • Do not drink alcohol while you take DILANTIN without first talking to your healthcare provider. Drinking alcohol while taking DILANTIN may change your blood levels of DILANTIN which can cause serious problems. • Do not drive, operate heavy machinery, or do other dangerous activities until you know how DILANTIN affects you. DILANTIN can slow your thinking and motor skills. What are the possible side effects of DILANTIN? See “What is the most important information I should know about DILANTIN?” DILANTIN may cause other serious side effects including: • Softening of your bones (osteopenia, osteoporosis, and osteomalacia). This can cause broken bones. Call your healthcare provider right away, if you have any of the symptoms listed above. The most common side effects of DILANTIN include: • problems with walking and • tremor coordination • headache • slurred speech • nausea • confusion • vomiting • dizziness • constipation • trouble sleeping • rash • nervousness These are not all the possible side effects of DILANTIN. For more information, ask your healthcare provider or pharmacist. 14 Reference ID: 3258658 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tell your healthcare provider if you have any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store DILANTIN? • Store DILANTIN-125 Suspension at room temperature between 68°F to 77°F (20°C to 25°C). Protect from light. Do not freeze. Keep DILANTIN and all medicines out of the reach of children. General information about DILANTIN Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DILANTIN for a condition for which it was not prescribed. Do not give DILANTIN to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about DILANTIN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about DILANTIN that was written for healthcare professionals. For more information about DILANTIN, visit http://www.pfizer.com or call 1-800-438-1985. What are the ingredients in DILANTIN-125? Oral Suspension Active ingredient: phenytoin, USP Inactive ingredients: alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No. 6. This Medication Guide has been approved by the U.S. Food and Drug Administration. company logo LAB-0398-3.0 February 2013 Reference ID: 3258658 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:38.225342	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/008762s047lbl.pdf', 'application_number': 8762, 'submission_type': 'SUPPL ', 'submission_number': 47}
10,711	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use M.V.I.-12TM Pharmacy Bulk Package (Multi-Vitamin Infusion without vitamin K) safely and effectively. See full prescribing information for M.V.I.-12TM Pharmacy Bulk Package (Multi-Vitamin Infusion without vitamin K). M.V.I.-12TM Pharmacy Bulk Package (Multi-Vitamin Infusion without vitamin K) dilution for intravenous infusion only. Initial U.S. Approval: 1953 __________________ RECENT MAJOR CHANGES ________________ Dosage and Administration, (2.1) (2.3) (2.4) 06/2012 Warnings and Precautions (5.1) (5.2) (5.3) (5.4) (5.5) (5.6) (5.7) (5.8) 06/2012 ------------------------------------------------ INDICATIONS AND USAGE -------------------------------------- M.V.I.-12TM Pharmacy Bulk Package is indicated for prevention of vitamin deficiency in adults and children aged 11 years and above who are on warfarin anticoagulant therapy receiving home parenteral nutrition. (1) ----------------------------------------DOSAGE AND ADMINISTRATION ------------------------------- • M.V.I.–12TM is ready for immediate use in adults and children aged 11 years and above when added to intravenous infusion fluids. (2) • M.V.I.–12TM SHOULD BE ASEPTICALLY TRANSFERRED TO THE INFUSION FLUID. (2.3) ----------------------------------- DOSAGE FORMS AND STRENGTHS ------------------------------- M.V.I.–12TM Pharmacy Bulk Package is a sterile product consisting of two vials labeled Vial 1 (50 mL) and Vial 2 (50 mL). The mixed solution (100 mL) will provide ten 10 mL single doses (3). --------------------------------------------------CONTRAINDICATIONS -------------------------------------------- Hypersensitivity to any of the vitamins in this product or an existing hypervitaminosis. (4) ------------------------------------------ WARNINGS AND PRECAUTIONS ------------------------------- • This product contains aluminum that may be toxic. (5.1) • Studies have shown that vitamin A may adhere to plastic, resulting in inadequate vitamin A administration in the doses recommended with M.V.I.–12TM. (5.2) • M.V.I.–12TM may not correct long standing specific vitamin deficiencies. The administration of additional doses may be required. (5.3) • Allergic reactions such as urticaria, periorbital and digital edema, have been reported following intravenous administration of thiamine. (5.4) • Hypervitaminosis A has been reported in patients with renal failure receiving 1.5 mg/day retinol and in patients with liver disease. (5.5) • Do not administer M.V.I.–12TM to patients with suspected or diagnosed megaloblastic anemia prior to the blood sampling for the detection of the folic acid and cyanocobalamin deficiencies. (5.6) • Blood vitamin concentration should be periodically monitored to determine if vitamin deficiencies or excesses are developing. (5.7) • Ascorbic acid in the urine may cause negative urine glucose determination. (5.8) ---------------------------------------------------ADVERSE REACTIONS -------------------------------------------- There have been rare reports of the following types of reactions: • Allergic — anaphylactoid reactions following large intravenous doses of thiamine, urticaria, periorbital and digital edema (6) • Dermatologic — rash, erythema, pruritus (6) • CNS — headache, dizziness, agitation, anxiety (6) • Ophthalmic — diplopia (6) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or contact by e-mail at ProductComplaintsPP@hospira.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------------------------------------- DRUG INTERACTIONS ------------------------------------------ A number of interactions between vitamins and drugs have been reported. The following are examples of these interactions: Physical Incompatibilities: • Acetazolamide (2.4) • Intravenous chlorothiazide sodium (2.4) • Aminophylline (2.4) • Ampicillin (2.4) • Moderately alkaline solutions (2.4) • Tetracycline HCl (2.4) • Calcium salts such as calcium gluconate (2.4) • Vitamin K bisulfite or sodium bisulfite (2.4) • Thiamine, riboflavin, pyridoxine, niacinamide, and ascorbic acid have been reported to decrease the antibiotic activity of erythromycin, kanamycin, streptomycin, doxycycline, and lincomycin. (7.1) • Bleomycin (7.1) Clinical Interactions: • Phenytoin (7.1) • Levodopa (7.1) • Chloramphenicol (7.2) ---------------------------------------- USE IN SPECIFIC POPULATIONS -------------------------------- • Pregnant and Nursing Mothers: Pregnant women should follow the U.S. Recommended Daily Allowances for their condition, because their vitamin requirements may exceed those of nonpregnant women. (8.1, 8.3) • Pediatric Use: Safety and effectiveness in children below the age of 11 years have not been established. (8.4) • Monitor calcium and phosphorus levels in patients with renal impairment. (8.6) • Monitor vitamin A level in patients with liver disease, high alcohol consumption. (8.7) See 17 for PATIENT COUNSELING INFORMATION Revised: 06/2012 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Starting Dose, Dose Range and Route of Administration 2.2 Monitoring 2.3 Instructions for Intravenous Administration 2.4 Drug Incompatibilities 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Aluminum Toxicity 5.2 Adherence of Vitamin A to Plastic 5.3 Intravenous Fat Emulsions 5.4 Allergic Reactions to Thiamine 5.5 Hypervitaminosis A 5.6 Blood Sampling of Megaloblastic Anemia Patients 5.7 Monitor Blood Vitamin Concentrations 5.8 Interference with Urine Glucose Testing 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 7.1 Clinical Interactions Affecting Drug Levels 7.2 Clinical Interactions Affecting Vitamin Levels 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.6 Patients with Renal Impairment 8.7 Patients with Liver Impairment 10 OVERDOSAGE 11 DESCRIPTION 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed Reference ID: 3144235 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE M.V.I.-12TM Pharmacy Bulk Package (Multi-Vitamin Infusion without vitamin K) is indicated for the prevention of vitamin deficiency in adults and children aged 11 years and above on warfarin anticoagulant therapy receiving parenteral nutrition. The physician should not await the development of clinical signs of vitamin deficiency before initiating vitamin therapy. 2 DOSAGE AND ADMINISTRATION  M.V.I.–12TM is ready for immediate intravenous use in adults and children aged 11 years and above when added to intravenous infusion fluids. Do not administer M.V.I.–12TM as a direct, undiluted intravenous injection as it may cause dizziness, faintness, and tissue irritation. 2.1 Starting Dose, Dose Range and Route of Administration The starting dose is one 10 mL daily dose added directly to an intravenous fluid. Patients with multiple vitamin deficiencies or with increased vitamin requirements may need multiple daily dosages as indicated. Some patients do not maintain adequate levels of certain vitamins when this formulation in recommended amounts is the only source of vitamins. 2.2 Monitoring Blood vitamin concentrations should be monitored to ensure maintenance of adequate levels, particularly in patients receiving parenteral multivitamins as the only source of vitamins for long periods of time. 2.3 Instructions for Intravenous Administration The solution must be prepared prior to intravenous administration.  Aseptically transfer the contents of the 50 mL Vial 1 into 50 mL Vial 2. The mixed solution will provide ten 10 mL single doses. Once closure system has been compromised, withdrawal of container contents should be completed within 4 hours. Mixed solution may be stored for up to 4 hours refrigerated. Discard unused portion.  Do not administer M.V.I.–12TM as a direct, undiluted intravenous injection as it may cause dizziness, faintness, and tissue irritation.  Utlizing a suitable sterile automated compounding device or dispensing pin for accuracy, aseptically transfer each 10 mL dose into a plastic or glass bottle containing at least 500 – 1000 mL intravenous total parenteral nutrition solution containing dextrose or saline. Discard unused portions. This infusion solution may be stored up to 24 hours refrigerated.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Handling of MVI-12 solution, including preparation of the Pharmacy Bulk Pack, should be restricted to a suitable work area, such as a laminar flow hood. wEN-3073 Page 2 of 7 Reference ID: 3144235 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2.4 Drug Incompatibilities  M.V.I.–12TM (Multi-Vitamin Infusion without vitamin K) is not physically compatible with moderately alkaline solutions such as a sodium bicarbonate solution and other alkaline drugs such as acetazolamide sodium, aminophylline, ampicillin sodium, and chlorothiazide sodium..  Folic acid is unstable in the presence of calcium salts such as calcium gluconate.  Vitamin A and thiamine in M.V.I.–12TM may react with bisulfite solutions such as sodium bisulfite or vitamin K bisulfate. Patients should be monitored for vitamin A and thiamine deficiencies.  Consult appropriate references for listings of physical and chemical compatibility of solutions and drugs with the vitamin infusion. In such circumstances, admixture or Y-site administration with vitamin solutions should be avoided. 3 DOSAGE FORMS AND STRENGTHS M.V.I.–12TM Pharmacy Bulk Package is a sterile product consisting of two vials labeled Vial 1 (50 mL) and Vial 2 (50 mL). The mixed solution (100 mL) will provide ten 10 mL single doses [see Description (11)]. 4 CONTRAINDICATIONS M.V.I.–12TM is contraindicated in patients who have a history of hypersensitivity to any of the vitamins in this product or existing hypervitaminosis due to any vitamins contained in this formulation. 5 WARNINGS AND PRECAUTIONS 5.1 Aluminum Toxicity MVI-12TM contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 microgram per kg per day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration. 5.2 Adherence of Vitamin A to Plastic Studies have shown that vitamin A, which is found in MVI-12TM, may adhere to polyvinyl chloride (PVC) plastic, resulting in lower vitamin A concentrations in the administered M.V.I.–12TM doses. Therefore, blood vitamin concentrations should be periodically monitored and the administration of additional therapeutic doses of Vitamin A may be required. [see Warnings and Precautions (5.7)] 5.3 Intravenous Fat Emulsions Do not add M.V.I.–12TM directly to intravenous fat emulsions. 5.4 Allergic Reactions to Thiamine Allergic reactions such as urticaria, periorbital and digital edema, have been reported following intravenous administration of thiamine, which is found in M.V.I.-12TM. There have been rare reports of anaphylactoid reactions following intravenous doses of thiamine. No fatal anaphylactoid reactions associated with M.V.I.–12TM have been reported. wEN-3073 Page 3 of 7 Reference ID: 3144235 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.5 Hypervitaminosis A Hypervitaminosis A, manifested by nausea ,vomiting, headache, dizziness, blurred vision, has been reported in patients with renal failure receiving 1.5 mg/day retinol and in patients with liver disease. Therefore, supplementation of renal failure patients and patients with liver diseases with vitamin A, an ingredient found in M.V.I.-12TM, should be undertaken with caution [see Use in Specific Populations (8.6 and 8.7)]. 5.6 Blood Sampling of Megaloblastic Anemia Patients Do not administer M.V.I.–12TM to patients with suspected or diagnosed megaloblastic anemia prior to blood sampling for the detection of the folic acid and cyanocobalamin deficiencies. The folic acid and the cyanocobalamin in the M.V.I.–12TM solution can mask serum deficits of folic acid and cyanocobalamin in these patients. 5.7 Monitor Blood Vitamin Concentrations In patients receiving parenteral multivitamins such as with MVI-12TM, blood vitamin concentrations should be periodically monitored to determine if vitamin deficiencies or excesses are developing. M.V.I.–12TM may not correct long-standing specific vitamin deficiencies. The administration of additional therapeutic doses of specific vitamins may be required [see Dosage and Administration (2.2)]. 5.8 Interference with Urine Glucose Testing MVI-12TM contains vitamin C which is also known as ascorbic acid. Ascorbic acid in the urine may cause false negative urine glucose determinations. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other section of the labeling.  Allergic and anaphylactoid reactions following intravenous administration of thiamine [see Warnings and Precautions (5.4)].  Hypervitaminosis A [see Warnings and Precautions (5.5)]. Other adverse reactions: Dermatologic: rash, erythema, pruritus CNS: headache, dizziness, agitation, anxiety Ophthalmic: diplopia 7 DRUG INTERACTIONS A number of drug interactions between vitamins and other drugs have been reported. Consult appropriate references for additional specific vitamin-drug interactions. The following are examples of these types of interactions: 7.1 Clinical Interactions Affecting Drug Levels Folic acid Phenytoin metabolism may be increased by folic acid. Low serum concentration of phenytoin may result in increased seizure frequency. Patient's response to methotrexate therapy may be decreased by folic acid. wEN-3073 Page 4 of 7 Reference ID: 3144235 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pyridoxine The metabolism of levodopa may be increased and its efficacy may be decreased by pyridoxine. Antibiotics Antibiotic activity of erythromycin, kanamycin, streptomycin, doxycycline, and lincomycin is decreased by thiamine, riboflavin, pyridoxine, niacinamide, and ascorbic acid. Bleomycin is inactivated in vitro by ascorbic acid and riboflavin. 7.2 Clinical Interactions Affecting Vitamin Levels Hydralazine, Isoniazid Pyridoxine requirements may be increased by concomitant administration of hydralazine or isoniazid. Chloramphenicol In patients with pernicious anemia, the hematologic response to vitamin B12 therapy may be inhibited by concomitant administration of chloramphenicol. Phenytoin Serum folic acid concentrations may be decreased by phenytoin and, therefore it should be avoided in pregnancy. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy M.V.I.-12TM has not been studied in pregnant women. Pregnant women should follow the U.S. Recommended Daily Allowances for their condition, because their vitamin requirements may be different than nonpregnant women. 8.3 Nursing Mothers M.V.I.-12TM has not been studied in lactating women. Lactating women should follow the U.S. Recommended Daily Allowances for their condition, because their vitamin requirements may be different than a nonlactating woman. Caution should be exercised when M.V.I.–12TM Pharmacy Bulk Package is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of M.V.I.-12™ in children below the age of 11 years have not been established. 8.6 Patients with Renal Impairment M.V.I.-12TM has not been studied in patients with renal impairment. Monitor renal function, calcium, phosphorus and vitamin A levels in patients with renal impairment [see Warning and Precautions (5.1, 5.5)]. 8.7 Patients with Liver Impairment M.V.I.-12TM has not been studied in patients with liver impairments. Monitor vitamin A level in patients with liver disease, high alcohol consumption [see Warning and Precautions (5.5)]. 10 OVERDOSAGE There is no clinical experience with M.V.I.-12 TM overdosage. Signs and symptoms of acute or chronic overdosage may be those of individual M.V.I.-12 TM component toxicity. wEN-3073 Page 5 of 7 Reference ID: 3144235 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 DESCRIPTION M.V.I.–12TM Pharmacy Bulk Package: A sterile product consisting of two Type 1, amber glass vials labeled Vial 1 (50 mL) and Vial 2 (50 mL). The mixed solution will provide ten single doses of 10 mL each. ADULT FORMULATION (INTENDED FOR AGES 11 AND OLDER) Vial 1* Ingredient Amount per Unit Dose Fat Soluble Vitamins** Vitamin A (retinol) 1 mg (3,300 USP units) Vitamin D (ergocalciferol) 5 mcg (200 USP units) Vitamin E (dl-alpha-tocopheryl acetate) 10 mg (10 USP units) Water Soluble Vitamins Vitamin C (ascorbic acid) 200 mg Niacinamide 40 mg Vitamin B2 (as riboflavin 5-phosphate sodium) 3.6 mg Vitamin B1(thiamine) 6 mg Vitamin B6 (pyridoxine HCl) 6 mg Dexpanthenol (d-pantothenyl alcohol) 15 mg * With 30% propylene glycol and 2% gentisic acid ethanolamide as stabilizers and preservatives; sodium hydroxide for pH adjustment; 1.6% polysorbate 80; 0.028% polysorbate 20; 0.002% butylated hydroxytoluene; 0.0005% butylated hydroxyanisole. ** Fat-soluble vitamins A, D, and E are water solubilized with polysorbate 80. Vial 2* Biotin 60 mcg Folic acid 600 mcg Vitamin B12 (cyanocobalamin) 5 mcg * With 30% propylene glycol; and citric acid, sodium citrate, and sodium hydroxide for pH adjustment. “Aqueous” multivitamin formula for intravenous infusion: M.V.I.–12TM (Multi-Vitamin Infusion without vitamin K) makes available a combination of important fat-soluble and water-soluble vitamins in an aqueous solution, formulated specially for incorporation into intravenous infusions. Through special processing techniques, the liposoluble vitamins A, D, and E have been solubilized in an aqueous medium with polysorbate 80, permitting intravenous administration of these vitamins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity and fertility studies were not performed. 16 HOW SUPPLIED/STORAGE AND HANDLING M.V.I.-12TM PHARMACY BULK PACKAGE NDC 61703-423-83 2 Boxes of 10 vials, 50 mL each (5 Vial 1 and 5 Vial 2). Mix contents of Vial 1 and Vial 2 to provide ten 10 mL single doses. wEN-3073 Page 6 of 7 Reference ID: 3144235 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Minimize the exposure of M.V.I.–12TM to the light, because vitamins A , D and riboflavin are light sensitive. Store at 2-8°C (36-46°F). 17 PATIENT COUNSELING INFORMATION  Instruct patient that M.V.I.-12TM is indicated for the prevention of vitamin deficiency in patients on warfarin anticoagulant therapy receiving parenteral nutrition.  M.V.I.–12TM is contraindicated in patients who have a history of hypersensitivity to any of the vitamins in this product or existing hypervitaminosis due to any vitamins contained in this formulation. Obtain detailed allergy and concomitant drug information from the patient, as well as if they have any kidney or liver impairment and if they are pregnant, prior to M.V.I.-12TM administration.  Tell patients to watch for signs of allergic reactions such as urticaria, periorbital and digital edema, which have been reported following intravenous administration of thiamine.  Instruct patients with renal impairment to immediately report signs of hypervitaminosis A, manifested by nausea, vomiting, headache, dizziness, blurred vision, which has been reported in patients with renal failure receiving 1.5 mg/day retinol and in patients with liver disease.  Instruct patients to report other adverse reactions such as rash, erythema, pruritus, headache, dizziness, agitation, anxiety, and diplopia.  Explain the significance of periodic monitoring of blood vitamin concentrations to determine if vitamin deficiencies or excesses are developing and the need to monitor renal function, calcium, phosphorus, aluminum and vitamin A levels in patients with renal impairment. Printed in USA EN-3073 Manufactured by Hospira, Inc., Lake Forest, IL 60045 USA company logo wEN-3073 Page 7 of 7 Reference ID: 3144235 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:38.277469	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/008809s065lbl.pdf', 'application_number': 8809, 'submission_type': 'SUPPL ', 'submission_number': 65}
10,710	NDA 8-809/S-054 Page 4 M.V.I. – 12 ® (Multi-Vitamin Infusion without vitamin K) For dilution in intravenous infusions only. only M.V.I. - 12® UNIT VIAL multi-vitamin infusion without vitamin K DESCRIPTION M.V.I. - 12® UNIT VIAL is a sterile product in a two-chambered single-dose vial which must be mixed just prior to use. ADULT FORMULATION (INTENDED FOR AGES 11 AND OLDER) LOWER CHAMBER OF UNIT VIAL* Ingredient Amount per Unit Dose Fat Soluble Vitamins** Vitamin A (retinol) 1 mga Vitamin D (ergocalciferol) 5 µgb Vitamin E (dl-alpha-tocopheryl acetate) 10 mgc Water Soluble Vitamins Vitamin C (ascorbic acid) 200 mg Niacinamide 40 mg Vitamin B2 (as riboflavin 5-phosphate sodium) 3.6 mg Vitamin B1 (thiamine) 6 mg Vitamin B6 (pyridoxine HCl) 6 mg Dexpanthenol (d-pantothenyl alcohol) 15 mg WITH 30% PROPYLENE GLYCOL AND 2% GENTISIC ACID ETHANOLAMIDE AS STABILIZERS AND PRESERVATIVES; SODIUM HYDROXIDE FOR PH ADJUSTMENT; 1.6% POLYSORBATE 80; 0.028% POLYSORBATE 20; 0.002% BUTYLATED HYDROXYTOLUENE; 0.0005% BUTYLATED HYDROXYANISOLE. Fat-soluble vitamins A, D, and E are water solubilized with polysorbate 80. (a) 1 mg vitamin A equals 3,300 USP units. (b) 5 µg ergocalciferol equals 200 USP units. (c) 10 mg vitamin E equals 10 USP units. Upper Chamber of Unit Vial Biotin 60 µg Folic acid 600 µg Vitamin B12 (cyanocobalamin) 5 µg WITH 30% PROPYLENE GLYCOL; AND CITRIC ACID, SODIUM CITRATE, AND SODIUM HYDROXIDE FOR PH ADJUSTMENT. “Aqueous” multivitamin formula for intravenous infusion: M.V.I – 12 ® (Multi-Vitamin Infusion without vitamin K) makes available a combination of important fat-soluble and water-soluble vitamins in an aqueous solution, formulated specially for incorporation into intravenous infusions. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-809/S-054 Page 5 Through special processing techniques, the liposoluble vitamins A, D, and E have been solubilized in an aqueous medium with polysorbate 80, permitting intravenous administration of these vitamins. INDICATIONS AND USAGE This formulation is indicated for the prevention of vitamin deficiency and thromboembolic complications in people receiving home parenteral nutrition who also receive warfarin-type anticoagulant therapy. The physician should not await the development of clinical signs of vitamin deficiency before initiating vitamin therapy. Patients with multiple vitamin deficiencies or with markedly increased requirements may be given multiples of the daily dosage for two or more days as indicated by the clinical status. Clinical testing indicates that some patients do not maintain adequate levels of certain vitamins when this formulation in recommended amounts is the sole source of vitamins. CONTRAINDICATIONS Known hypersensitivity to any of the vitamins in this product or a pre-existing hypervitaminosis. Allergic reaction has been known to occur following intravenous administration of thiamine. This formulation is contraindicated prior to blood sampling for detection of megaloblastic anemia, as the folic acid and the cyanocobalamin in the vitamin solution can mask serum deficits. WARNINGS WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 µg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration. PRECAUTIONS Studies have shown that vitamin A may adhere to plastic, resulting in inadequate vitamin A administration in the doses recommended with M.V.I. – 12 ®. Where long-standing specific vitamin deficiencies exist, it may be necessary to add therapeutic amounts of specific vitamins to supplement the maintenance vitamins provided in M.V.I. – 12 ®. In patients receiving parenteral multivitamins, blood vitamin concentrations should be periodically monitored to determine if vitamin deficiencies or excesses are developing. M.V.I. – 12 ® SHOULD BE ASEPTICALLY TRANSFERRED TO THE INFUSION FLUID. Drug-Drug Interactions: Physical Incompatibilities: M.V.I. – 12 ® (Multi-Vitamin Infusion without vitamin K) is not physically compatible with DIAMOX® (acetazolamide) 500 mg, DIURIL® Intravenous Sodium (chlorothiazide sodium) 500 mg, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-809/S-054 Page 6 or aminophylline 125 mg, ampicillin 500 mg or moderately alkaline solutions. ACHROMYCIN® (tetracycline HCl) 500 mg may not be physically compatible with M.V.I.-12®. It has been reported that folic acid is unstable in the presence of calcium salts such as calcium gluconate. Some of the vitamins in M.V.I –12 ® may react with vitamin K bisulfite. Direct addition of M.V.I. – 12 ® to intravenous fat emulsions is not recommended. Consult appropriate references for listings of physical compatibility of solutions and drugs with the vitamin infusion. In such circumstances, admixture or Y-site administration with vitamin solutions should be avoided. Several vitamins have been reported to decrease the activity of certain antibiotics. Thiamine, riboflavin, pyridoxine, niacinamide, and ascorbic acid have been reported to decrease the antibiotic activity of erythromycin, kanamycin, streptomycin, doxycycline, and lincomycin. Bleomycin is inactivated in vitro by ascorbic acid and riboflavin. Some of the vitamins in M.V.I. – 12 ® may react with vitamin K bisulfite or sodium bisulfite; if bisulfite solutions are necessary, patients should be monitored for vitamin A and thiamine deficiencies. Clinical Interactions: A number of interactions between vitamins and drugs have been reported which may affect the metabolism of either agent. The following are examples of these types of interactions. Folic acid may lower the serum concentration of phenytoin resulting in increased seizure frequency. Conversely, phenytoin may decrease serum folic acid concentrations and, therefore, should be avoided in pregnancy. Folic acid may decrease the patient's response to methotrexate therapy. Pyridoxine may decrease the efficacy of levodopa by increasing its metabolism. Concomitant administration of hydralazine or isoniazid may increase pyridoxine requirements. In patients with pernicious anemia, the hematologic response to vitamin B12 therapy may be inhibited by concomitant administration of chloramphenicol. Consult appropriate references for additional specific vitamin-drug interactions. Drug-Laboratory Test Interactions ASCORBIC ACID IN THE URINE MAY CAUSE FALSE NEGATIVE URINE GLUCOSE DETERMINATIONS. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenicity studies have not been performed. PREGNANCY: Pregnant women should follow the U.S. Recommended Daily Allowances for their condition, because their vitamin requirements may exceed those of nonpregnant women. Nursing Mothers: Lactating women should follow the U.S. Recommended Daily Allowances for their condition, because their vitamin requirements may exceed those of nonlactating women. Pediatric Use: Safety and effectiveness in children below the age of 11 years have not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-809/S-054 Page 7 ADVERSE REACTIONS There have been rare reports of anaphylactoid reactions following large intravenous doses of thiamine. The risk, however, is negligible if thiamine is co-administered with other vitamins in the B group. There have been no reports of fatal anaphylactoid reactions associated with M.V.I. – 12 ®. There have been rare reports of the following types of reactions: Dermatologic — rash, erythema, pruritus CNS — headache, dizziness, agitation, anxiety Ophthalmic — diplopia Allergic — urticaria, periorbital and digital edema OVERDOSAGE The possibility of hypervitaminosis A or D should be borne in mind. Clinical manifestations of hypervitaminosis A have been reported in patients with renal failure receiving 1.5 mg/day retinol. Therefore, vitamin A supplementation of renal failure patients should be undertaken with caution. DOSAGE AND ADMINISTRATION M.V.I.–12® is ready for immediate use in adults and children aged 11 years and above when added to intravenous infusion fluids. Directions for UNIT VIAL: Remove the protective plastic cap, turn the plunger-stopper 90° and press down firmly to force liquid in the upper chamber and the center seal into the lower compartment. Gently agitate to mix solution. Sterilize the rubber stopper in the usual manner and insert needle squarely through the center of the plunger-stopper until tip is just visible. Vial should be mixed just prior to use. Invert vial and withdraw a 10mL dose in the usual manner. The mixed solution is ready for dilution in not less than 500 mL of infusion solution. M.V.I.–12® should not be given as a direct, undiluted intravenous injection as it may give rise to dizziness, faintness, and possible tissue irritation. The withdrawal of container contents should be accomplished without delay. The solution should be used within 4 hours after dilution. USE OF THIS PRODUCT IS RESTRICTED TO A SUITABLE WORK AREA, SUCH AS A LAMINAR FLOW HOOD. FOR INTRAVENOUS FEEDING, ONE DAILY DOSE OF M.V.I.–12® (10 ML) ADDED DIRECTLY TO NOT LESS THAN 500 ML, PREFERABLY 1,000 ML, OF INTRAVENOUS DEXTROSE, SALINE OR SIMILAR INFUSION SOLUTIONS. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. After M.V.I.–12® is diluted in an intravenous infusion, the resulting solution is ready for immediate use. Some of the vitamins in this product, particularly A and D and riboflavin, are light sensitive, and exposure to light should be minimized. Store at 2–8°C (36-46°F). HOW SUPPLIED M.V.I.-12® UNIT VIAL — NDC 61703-423-81 Boxes of 10 two-chambered 10 mL vials. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-809/S-054 Page 8 Manufactured by: AstraZeneca LP, Westborough, MA 01581 Sterilized and Filled by: Enzon Pharmaceuticals Indianapolis, IN 46268 Manufactured for: Mayne Pharma (USA) Inc. Paramus, NJ 07652 Rev. 08-2004 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-809/S-054 Page 9 M.V.I. – 12® (Multi-Vitamin Infusion without vitamin K) For dilution in intravenous infusions only. only This package insert contains information for both the Pharmacy Bulk Package and the single dose vial. DESCRIPTION M.V.I.–12® is available as a sterile product consisting of two vials, labeled Vial 1 (50 mL) and Vial 2 (50 mL Fill) to provide ten 10 mL single doses. Single Dose Vial: A sterile product consisting of two vials labeled Vial 1 (5 mL) and Vial 2 (5 mL). Both vials to be used for a single 10 mL dose. ADULT FORMULATION (INTENDED FOR AGES 11 AND OLDER) VIAL 1 Ingredient Amount per Unit Dose Fat Soluble Vitamins** Vitamin A (retinol) 1 mga Vitamin D (ergocalciferol) 5 µgb Vitamin E (dl-alpha-tocopheryl acetate) 10 mgc Water Soluble Vitamins Vitamin C (ascorbic acid) 200 mg Niacinamide 40 mg Vitamin B2 (as riboflavin 5-phosphate sodium) 3.6 mg Vitamin B1 (thiamine) 6 mg Vitamin B6 (pyridoxine HCl) 6 mg Dexpanthenol (d-pantothenyl alcohol) 15 mg WITH 30% PROPYLENE GLYCOL AND 2% GENTISIC ACID ETHANOLAMIDE AS STABILIZERS AND PRESERVATIVES; SODIUM HYDROXIDE FOR PH ADJUSTMENT; 1.6% POLYSORBATE 80; 0.028% POLYSORBATE 20; 0.002% BUTYLATED HYDROXYTOLUENE; 0.0005% BUTYLATED HYDROXYANISOLE. Fat-soluble vitamins A, D, and E are water solubilized with polysorbate 80. (d) 1 mg vitamin A equals 3,300 USP units. (e) 5 µg ergocalciferol equals 200 USP units. (c) 10 mg vitamin E equals 10 USP units. Vial 2 Biotin 60 µg Folic acid 600 µg Vitamin B12 (cyanocobalamin) 5 µg *WITH 30% PROPYLENE GLYCOL; AND CITRIC ACID, SODIUM CITRATE, AND SODIUM HYDROXIDE FOR PH ADJUSTMENT. “Aqueous” multivitamin formula for intravenous infusion: M.V.I.–12® (Multi-Vitamin Infusion without vitamin K) makes available a combination of important fat-soluble and water-soluble vitamins in an aqueous solution, formulated specially for incorporation into intravenous infusions. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-809/S-054 Page 10 Through special processing techniques, the liposoluble vitamins A, D, and E have been solubilized in an aqueous medium with polysorbate 80, permitting intravenous administration of these vitamins. INDICATIONS AND USAGE This formulation is indicated for the prevention of vitamin deficiency and thromboembolic complications in people receiving home parenteral nutrition who also receive warfarin-type anticoagulant therapy. The physician should not await the development of clinical signs of vitamin deficiency before initiating vitamin therapy. Patients with multiple vitamin deficiencies or with markedly increased requirements may be given multiples of the daily dosage for two or more days as indicated by the clinical status. Clinical testing indicates that some patients do not maintain adequate levels of certain vitamins when this formulation in recommended amounts is the sole source of vitamins. CONTRAINDICATIONS Known hypersensitivity to any of the vitamins in this product or a pre-existing hypervitaminosis. Allergic reaction has been known to occur following intravenous administration of thiamine. This formulation is contraindicated prior to blood sampling for detection of megaloblastic anemia, as the folic acid and the cyanocobalamin in the vitamin solution can mask serum deficits. WARNINGS WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 µg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration. PRECAUTIONS Studies have shown that vitamin A may adhere to plastic, resulting in inadequate vitamin A administration in the doses recommended with M.V.I.–12®. Where long-standing specific vitamin deficiencies exist, it may be necessary to add therapeutic amounts of specific vitamins to supplement the maintenance vitamins provided in M.V.I. – 12 ®. In patients receiving parenteral multivitamins, blood vitamin concentrations should be periodically monitored to determine if vitamin deficiencies or excesses are developing. M.V.I.–12® SHOULD BE ASEPTICALLY TRANSFERRED TO THE INFUSION FLUID. Drug-Drug Interactions: Physical Incompatibilities: M.V.I.–12® (Multi-Vitamin Infusion without vitamin K) is not physically compatible with DIAMOX® (acetazolamide) 500 mg, DIURIL® Intravenous Sodium (chlorothiazide sodium) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-809/S-054 Page 11 500 mg, or aminophylline 125 mg, ampicillin 500 mg or moderately alkaline solutions. ACHROMYCIN® (tetracycline HCl) 500 mg may not be physically compatible with M.V.I.-12®. It has been reported that folic acid is unstable in the presence of calcium salts such as calcium gluconate. Some of the vitamins in M.V.I–12® may react with vitamin K bisulfite. Direct addition of M.V.I.–12® to intravenous fat emulsions is not recommended. Consult appropriate references for listings of physical compatibility of solutions and drugs with the vitamin infusion. In such circumstances, admixture or Y-site administration with vitamin solutions should be avoided. Several vitamins have been reported to decrease the activity of certain antibiotics. Thiamine, riboflavin, pyridoxine, niacinamide, and ascorbic acid have been reported to decrease the antibiotic activity of erythromycin, kanamycin, streptomycin, doxycycline, and lincomycin. Bleomycin is inactivated in vitro by ascorbic acid and riboflavin. Some of the vitamins in M.V.I.–12® may react with vitamin K bisulfite or sodium bisulfite; if bisulfite solutions are necessary, patients should be monitored for vitamin A and thiamine deficiencies. Clinical Interactions: A number of interactions between vitamins and drugs have been reported which may affect the metabolism of either agent. The following are examples of these types of interactions. Folic acid may lower the serum concentration of phenytoin resulting in increased seizure frequency. Conversely, phenytoin may decrease serum folic acid concentrations and, therefore, should be avoided in pregnancy. Folic acid may decrease the patient's response to methotrexate therapy. Pyridoxine may decrease the efficacy of levodopa by increasing its metabolism. Concomitant administration of hydralazine or isoniazid may increase pyridoxine requirements. In patients with pernicious anemia, the hematologic response to vitamin B12 therapy may be inhibited by concomitant administration of chloramphenicol. Consult appropriate references for additional specific vitamin-drug interactions. Drug-Laboratory Test Interactions ASCORBIC ACID IN THE URINE MAY CAUSE FALSE NEGATIVE URINE GLUCOSE DETERMINATIONS. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenicity studies have not been performed. PREGNANCY: Pregnant women should follow the U.S. Recommended Daily Allowances for their condition, because their vitamin requirements may exceed those of nonpregnant women. Nursing Mothers: Lactating women should follow the U.S. Recommended Daily Allowances for their condition, because their vitamin requirements may exceed those of nonlactating women. Pediatric Use: Safety and effectiveness in children below the age of 11 years have not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-809/S-054 Page 12 ADVERSE REACTIONS There have been rare reports of anaphylactoid reactions following large intravenous doses of thiamine. The risk, however, is negligible if thiamine is co-administered with other vitamins in the B group. There have been no reports of fatal anaphylactoid reactions associated with M.V.I.–12®. There have been rare reports of the following types of reactions: Dermatologic — rash, erythema, pruritus CNS — headache, dizziness, agitation, anxiety Ophthalmic — diplopia Allergic — urticaria, periorbital and digital edema OVERDOSAGE The possibility of hypervitaminosis A or D should be borne in mind. Clinical manifestations of hypervitaminosis A have been reported in patients with renal failure receiving 1.5 mg/day retinol. Therefore, vitamin A supplementation of renal failure patients should be undertaken with caution. DOSAGE AND ADMINISTRATION M.V.I.–12® is ready for immediate use in adults and children aged 11 years and above when added to intravenous infusion fluids. Directions for Pharmacy Bulk Package: Transfer the contents of Vial 1 into Vial 2. The mixed solution will provide ten 10 mL single doses. Each 10 mL single dose is ready for dilution in not less than 500 mL of infusion fluid. Utilize a suitable sterile transfer device or dispensing set, which allows measured distribution of the contents. Directions for Single Dose Vial: Dilute the contents of Vial 1 (5 mL) and the contents of Vial 2 (5 mL) in not less than 500 mL of infusion fluid, both vials to be used for a single dose. The vial 1 and vial 2 container closures may be penetrated only one time, utilizing a suitable sterile transfer device or dispensing set, which allows measured distribution of the contents. The withdrawal of container contents should be accomplished without delay. The solution should be used within 4 hours after dilution. USE OF THIS PRODUCT IS RESTRICTED TO A SUITABLE WORK AREA, SUCH AS A LAMINAR FLOW HOOD. M.V.I.–12® should not be given as a direct, undiluted intravenous injection as it may give rise to dizziness, faintness, and possible tissue irritation. FOR INTRAVENOUS FEEDING, ONE DAILY DOSE OF M.V.I.–12® (10 ML) ADDED DIRECTLY TO NOT LESS THAN 500 ML, PREFERABLY 1,000 ML, OF INTRAVENOUS DEXTROSE, SALINE OR SIMILAR INFUSION SOLUTIONS. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. After M.V.I.–12® is diluted in an intravenous infusion, the resulting solution is ready for immediate use. Some of the vitamins in this product, particularly A and D and riboflavin, are light sensitive, and exposure to light should be minimized. Store at 2–8°C (36-46°F). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-809/S-054 Page 13 HOW SUPPLIED M.V.I.-12® — NDC 61703-423-82 Boxes of 10 single doses and cartons of 100 single doses. Each box contains two vials— Vial 1 (5 mL) and Vial 2 (5 mL), both vials to be used for a single dose. M.V.I.-12® PHARMACY BULK PACKAGE — NDC 61703-423-83 Boxes of 20 vials, 50 mL each (10 Vial 1 and 10 Vial 2). Mix contents of Vial 1 and Vial 2 to provide ten single doses. Manufactured for: Mayne Pharma (USA) Inc. Paramus, NJ 07650 By: AstraZeneca LP Westborough, MA 808604-00 Rev. 08-2004 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:38.300778	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/08809s054lbl.pdf', 'application_number': 8809, 'submission_type': 'SUPPL ', 'submission_number': 54}
10,712	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use M.V.I.-12™ M.V.I.-12™ Unit Vial (Multi-Vitamin Infusion without vitamin K) for dilution in intravenous infusions only. Unit Vial (Multi-Vitamin Infusion without vitamin K) safely and effectively. See full prescribing information for M.V.I.-12™ Unit Vial (Multi-Vitamin Infusion without vitamin K). Initial U.S. Approval: 1953 ------------------------------------------------ RECENT MAJOR CHANGES ------------------------------------- Dosage and Administration (2.1) (2.3) (2.4) 03/2013 Warnings and Precautions (5) 03/2013 ------------------------------------------------ INDICATIONS AND USAGE --------------------------------------- M.V.I.-12™ Unit Vial, is indicated for the prevention of vitamin deficiency in adults and children aged 11 years and above who are on warfarin anticoagulant therapy receiving home parenteral nutrition. (1) ---------------------------------------- DOSAGE AND ADMINISTRATION -------------------------------- M.V.I.–12™ is ready for immediate use in adults and children aged 11 years and above when added to intravenous infusion fluids. (2) A number of the physical incompatibilities between M.V.I.–12™ infusion and drugs have been reported. The following are examples of these interactions (2.4): • Acetazolamide • Intravenous chlorothiazide sodium • Aminophylline • Ampicillin • Moderately alkaline solutions • Calcium salts such as calcium gluconate • Vitamin K bisulfite or sodium bisulfite ----------------------------------- DOSAGE FORMS AND STRENGTHS -------------------------------- M.V.I.–12™ Unit Vial is a sterile product in a two-chambered single-dose 10 mL vial which must be mixed just prior to use. (3) ---------------------------------------------------- CONTRAINDICATIONS ------------------------------------------- Hypersensitivity to any of the vitamins in this product or an existing hypervitaminosis. (4) ------------------------------------------ WARNINGS AND PRECAUTIONS -------------------------------- • This product contains aluminum that may be toxic. (5.1) • Studies have shown that vitamin A may adhere to plastic, resulting in inadequate vitamin A administration in the doses recommended with M.V.I.–12™. (5.2) • Do not add M.V.I.–12™ directly to intravenous fat emulsions. (5.3) • Allergic reactions such as urticaria, periorbital and digital edema, have been reported following intravenous administration of thiamine. (5.4) • Hypervitaminosis A has been reported in patients with renal failure receiving 1.5 mg/day retinol and in patients with liver disease. (5.5) • Do not administer M.V.I.–12™ to patients with suspected or diagnosed megaloblastic anemia prior to the blood sampling for the detection of the folic acid and cyanocobalamin deficiencies. (5.6) • Blood vitamin concentration should be periodically monitored to determine if vitamin deficiencies or excesses are developing. (5.7) • Ascorbic acid in the urine may cause negative urine glucose determination. (5.8) --------------------------------------------------- ADVERSE REACTIONS --------------------------------------------- There have been rare reports of the following types of reactions(6): • Allergic — anaphylactoid reactions following large intravenous doses of thiamine, urticaria, periorbital and digital edema • Dermatologic — rash, erythema, pruritus • CNS — headache, dizziness, agitation, anxiety • Ophthalmic — diplopia To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------------------------------------- DRUG INTERACTIONS ------------------------------------------- A number of interactions between vitamins and drugs have been reported. The following are examples of these interactions: Physical Incompatibilities • Thiamine, riboflavin, pyridoxine, niacinamide, and ascorbic acid have been reported to decrease the antibiotic activity of erythromycin, kanamycin, streptomycin, doxycycline, and lincomycin. (7.1): • Bleomycin Clinical Interactions • Phenytoin (7.1) : • Levodopa (7.1) • Chloramphenicol (7.2) ---------------------------------------- USE IN SPECIFIC POPULATIONS --------------------------------- • Pregnant and Nursing Mothers: Pregnant women should follow the U.S. Recommended Daily Allowances for their condition, because their vitamin requirements may exceed those of nonpregnant women. (8.1, 8.3) • Pediatric Use: Safety and effectiveness in children below the age of 11 years have not been established. (8.4) • Monitor calcium and phosphorus levels in patients with renal impairment. (8.6) • Monitor vitamin A level in patients with liver disease, high alcohol consumption. (8.7) See 17 for PATIENT COUNSELING INFORMATION Revised: 03/2013 _______________________________________________________________________________________________________________________________________ Reference ID: 3282431 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Starting Dose, Dose Range and Route of Administration 2.2 Monitoring 2.3 Instructions for Intravenous Administration 2.4 Drug Incompatibilities 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Aluminum Toxicity 5.2 Adherence of Vitamin A to Plastic 5.3 Intravenous Fat Emulsions 5.4 Allergic Reactions to Thiamine 5.5 Hypervitaminosis A 5.6 Blood Sampling of Megaloblastic Anemia Patients 5.7 Monitor Blood Vitamin Concentrations 5.8 Interference with Urine Glucose Testing 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 7.1 Clinical Interactions Affecting Drug Levels 7.2 Clinical Interactions Affecting Vitamin Levels 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.6 Patients with Renal Impairment 8.7 Patients with Liver Impairment 10 OVERDOSAGE 11 DESCRIPTION 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed _______________________________________________________________________________________________________________________________________ Reference ID: 3282431 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda wEN-3087v02 Page 3 of 8 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE M.V.I.-12™ Unit Vial (Multi-Vitamin Infusion without vitamin K) is indicated for the prevention of vitamin deficiency in adults and children aged 11 years and above on warfarin anticoagulant therapy receiving parenteral nutrition. The physician should not await the development of clinical signs of vitamin deficiency before initiating vitamin therapy. 2 DOSAGE AND ADMINISTRATION M.V.I.–12™ is ready for immediate intravenous use in adults and children aged 11 years and above when added to intravenous infusion fluids. Do not administer M.V.I.-12™ as a direct, undiluted intravenous injection as it may cause dizziness, faintness, and tissue irritation. 2.1 Starting Dose, Dose Range and Route of Administration The starting dose is one 10 mL daily dose added directly to an intravenous fluid. Patients with multiple vitamin deficiencies or with markedly increased requirements may need multiple daily dosages as indicated. Some patients do not maintain adequate levels of certain vitamins when this formulation in recommended amounts is the only source of vitamins. 2.2 Monitoring Blood vitamin concentrations should be monitored to ensure maintenance of adequate levels, particularly in patients receiving parenteral multivitamins as the only source of vitamins for long periods of time. 2.3 Instructions for Intravenous Administration The solution must be prepared prior to intravenous administration. • Remove the protective plastic cap, turn the plunger-stopper 90° and press down firmly to force liquid in the upper chamber and the center seal into the lower compartment. Gently agitate to mix solution. Disinfect the rubber stopper in the usual manner before inserting needle squarely through the center of the plunger-stopper until tip is just visible. Vial should be mixed just prior to use. Invert vial and withdraw a 10 mL dose in the usual manner. • Do not administer M.V.I.–12™ • Aseptically transfer each sterile 10 mL dose into a plastic or glass container containing at least 500-1000 mL of intravenous dextrose or saline. as a direct, undiluted intravenous injection as it may cause dizziness, faintness, and possible tissue irritation. • Withdraw container contents without delay. • After M.V.I.–12™ is diluted in an intravenous fluid, the resulting solution is ready for immediate use. Use the prepared solution within 4 hours after dilution. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. • Handling of M.V.I-12 solution should be performed in a suitable work area, such as a laminar flow hood. Reference ID: 3282431 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda wEN-3087v02 Page 4 of 8 2.4 Drug Incompatibilities • M.V.I.–12™ (Multi-Vitamin Infusion without vitamin K) is not physically compatible with moderately alkaline solutions such as a sodium bicarbonate solution and other alkaline drugs such as acetazolamide sodium, aminophylline, ampicillin sodium, and chlorothiazide sodium. • Folic acid is unstable in the presence of calcium salts such as calcium gluconate. • Vitamin A and thiamine in M.V.I.–12™ may react with bisulfite solutions such as sodium bisulfite or vitamin K bisulfate. Patients should be monitored for vitamin A and thiamine deficiencies. • Consult appropriate references for listings of physical and chemical compatibility of solutions and drugs with the vitamin infusion. In such circumstances, admixture or Y-site administration with vitamin solutions should be avoided. 3 DOSAGE FORMS AND STRENGTHS M.V.I.–12™ Unit Vial is a sterile product in a two-chambered single-dose 10 mL vial which must be mixed just prior to use [see Description (11)]. 4 CONTRAINDICATIONS M.V.I.–12™ is contraindicated in patients who have a history of hypersensitivity to any of the vitamins in this product or existing hypervitaminosis due to any vitamins contained in this formulation. 5 WARNINGS AND PRECAUTIONS 5.1 Aluminum Toxicity M.V.I.-12™ contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration. 5.2 Adherence of Vitamin A to Plastic Studies have shown that vitamin A, which is found in M.V.I.-12™, 5.3 Intravenous Fat Emulsions may adhere to polyvinyl chloride (PVC) plastic, resulting in lower vitamin A concentrations in the administered M.V.I.-12™ doses. Therefore, blood vitamin concentrations should be periodically monitored and the administration of additional therapeutic doses of Vitamin A may be required [see Warnings and Precautions (5.7)]. Do not add M.V.I.–12™ directly to intravenous fat emulsions. 5.4 Allergic Reactions to Thiamine Allergic reactions such as urticaria, periorbital and digital edema, have been reported following intravenous administration of thiamine, which is found in M.V.I.-12™. There have been rare reports of anaphylactoid reactions following large intravenous doses of thiamine. No fatal anaphylactoid reactions associated with M.V.I.–12™ have been reported. Reference ID: 3282431 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda wEN-3087v02 Page 5 of 8 5.5 Hypervitaminosis A Hypervitaminosis A, manifested by nausea, vomiting, headache, dizziness, blurred vision, has been reported in patients with renal failure receiving 1.5 mg/day retinol and in patients with liver disease. Therefore, supplementation of renal failure patients and patients with liver diseases with vitamin A, an ingredient found in M.V.I.-12™, should be undertaken with caution [see Use in Specific Populations (8.6, 8.7)]. 5.6 Blood Sampling of Megaloblastic Anemia Patients Do not administer M.V.I.–12™ to patients with suspected or diagnosed megaloblastic anemia prior to blood sampling for the detection of the folic acid and cyanocobalamin deficiencies. The folic acid and the cyanocobalamin in the M.V.I.–12™ solution can mask serum deficits of folic acid and cyanocobalamin in these patients. 5.7 Monitor Blood Vitamin Concentrations In patients receiving parenteral multivitamins, such as with M.V.I.-12™, blood vitamin concentrations should be periodically monitored to determine if vitamin deficiencies or excesses are developing. M.V.I.–12™ may not correct long-standing specific vitamin deficiencies. The administration of additional therapeutic doses of specific vitamins may be required [see Dosage and Administration (2.2)]. 5.8 Interference with Urine Glucose Testing M.V.I-12™ contains Vitamin C, which is also known as ascorbic acid. Ascorbic acid in the urine may cause false negative urine glucose determinations. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Allergic and anaphylactoid reactions following intravenous administration of thiamine [see Warnings and Precautions (5.4)]. • Hypervitaminosis A [see Warnings and Precautions (5.5)]. Other adverse reactions: Dermatologic: rash, erythema, pruritus CNS: headache: dizziness, agitation, anxiety Ophthalmic: diplopia 7 DRUG INTERACTIONS A number of drug interactions between vitamins and other drugs have been reported. Consult appropriate references for additional specific vitamin-drug interactions. The following are examples of these types of interactions: 7.1 Clinical Interactions Affecting Drug Levels Folic acid Phenytoin metabolism may be increased by folic acid. Low serum concentration of phenytoin may result in increased seizure frequency. Patient's response to methotrexate therapy may be decreased by folic acid. Reference ID: 3282431 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda wEN-3087v02 Page 6 of 8 Pyridoxine The metabolism of levodopa may be increased and its efficacy may be decreased by pyridoxine. Antibiotics Antibiotic activity of erythromycin, kanamycin, streptomycin, doxycycline, and lincomycin is decreased by thiamine, riboflavin, pyridoxine, niacinamide, and ascorbic acid. Bleomycin is inactivated in vitro by ascorbic acid and riboflavin. 7.2 Clinical Interactions Affecting Vitamin Levels Hydralazine, Isoniazid Pyridoxine requirements may be increased by concomitant administration of hydralazine or isoniazid. Chloramphenicol In patients with pernicious anemia, the hematologic response to vitamin B12 therapy may be inhibited by concomitant administration of chloramphenicol. Phenytoin Serum folic acid concentrations may be decreased by phenytoin and, therefore it should be avoided in pregnancy. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy M.V.I.-12™ has not been studied in pregnant women. Pregnant women should follow the U.S. Recommended Daily Allowances for their condition, because their vitamin requirements may be different than those of nonpregnant women. 8.3 Nursing Mothers M.V.I.-12™ has not been studied in lactating women. Lactating women should follow the U.S. Recommended Daily Allowances for their condition, because their vitamin requirements may be different than a nonlactating women. Caution should be exercised when M.V.I.-12™ Unit Vial is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of M.V.I.-12™ in children below the age of 11 years have not been established. 8.6 Patients with Renal Impairment M.V.I.-12™ has not been studied in patients with renal impairment. Monitor renal function, calcium, phosphorus and vitamin A levels in patients with renal impairment [see Warnings and Precautions (5.1, 5.5)]. 8.7 Patients with Liver Impairment M.V.I.-12™ has not been studied in patients with liver impairment. Monitor vitamin A level in patients with liver disease, high alcohol consumption [see Warnings and Precautions (5.5)]. Reference ID: 3282431 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda wEN-3087v02 Page 7 of 8 10 OVERDOSAGE There is no clinical experience with M.V.I.-12™ overdosage. Signs and symptoms of acute or chronic overdosage may be those of individual M.V.I.-12™ component toxicity. 11 DESCRIPTION M.V.I.–12™ Unit Vial: A sterile product in a two-chambered single-dose Type I amber glass, vial, 10 mL, which must be mixed just prior to use. LOWER CHAMBER OF UNIT VIAL* Ingredient Amount per Unit Dose Fat Soluble Vitamins** Vitamin A (retinol) 1 mg Vitamin D (ergocalciferol) (3,300 USP units) 5 mcg (200 USP units) Vitamin E (dl-alpha-tocopheryl acetate) 10 mg (10 USP units) Water Soluble Vitamins Vitamin C (ascorbic acid) 200 mg Niacinamide 40 mg Vitamin B2 3.6 mg (as riboflavin 5-phosphate sodium) Vitamin B1 6 mg (thiamine) Vitamin B6 6 mg (pyridoxine HCl) Dexpanthenol (d-pantothenyl alcohol) 15 mg * With 30% propylene glycol and 2% gentisic acid ethanolamide as stabilizers and preservatives; sodium hydroxide for pH adjustment; 1.6% polysorbate 80; 0.028% polysorbate 20; 0.002% butylated hydroxytoluene; 0.0005% butylated hydroxyanisole. ** Fat-soluble vitamins A, D, and E are water solubilized with polysorbate 80. UPPER CHAMBER OF UNIT VIAL* Biotin 60 mcg Folic acid 600 mcg Vitamin B12 5 mcg (cyanocobalamin) * With 30% propylene glycol and citric acid, sodium citrate, and sodium hydroxide for pH adjustment. “Aqueous” multivitamin formula for intravenous infusion: M.V.I.–12™ (Multi-Vitamin Infusion without vitamin K) makes available a combination of important fat-soluble and water-soluble vitamins in an aqueous solution, formulated specially for incorporation into intravenous infusions. Through special processing techniques, the liposoluble vitamins A, D, and E have been solubilized in an aqueous medium with polysorbate 80, permitting intravenous administration of these vitamins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity and fertility studies were not performed. Reference ID: 3282431 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda wEN-3087v02 Page 8 of 8 16 HOW SUPPLIED/STORAGE AND HANDLING M.V.I. – 12™ UNIT VIAL NDC 61703-423-11 Boxes of 25 two-chambered 10 mL vials. Minimize the exposure of M.V.I.–12™ to the light, because vitamins A, D and riboflavin are light sensitive. Store at 2-8°C (36-46°F). 17 PATIENT COUNSELING INFORMATION • Instruct patient that M.V.I.-12™ is indicated for the prevention of vitamin deficiency in patients on warfarin anticoagulant therapy receiving parenteral nutrition. • M.V.I.–12™ is contraindicated in patients who have a history of hypersensitivity to any of the vitamins in this product or existing hypervitaminosis due to any vitamins contained in this formulation. Obtain detailed allergy and concomitant drug information from the patient, as well as if they have any kidney or liver disorders and if they are pregnant, prior to M.V.I.-12™ administration. • Tell patients to watch for signs of allergic reactions such as urticaria, periorbital and digital edema, which have been reported following intravenous administration of thiamine. • Instruct patients with renal impairment to immediately report signs of Hypervitaminosis A, manifested by nausea, vomiting, headache, dizziness, blurred vision, which has been reported in patients with renal failure receiving 1.5 mg/day retinol and in patients with liver disease. • Instruct patients to report other adverse reactions such as rash, erythema, pruritus, headache, dizziness, agitation, anxiety, and diplopia. • Explain the significance of periodic monitoring of blood vitamin concentrations to determine if vitamin deficiencies or excesses are developing. Monitor renal function, calcium, phosphorus, aluminum and vitamin A levels in patients with renal impairment. EN-3087 Manufactured by Hospira, Inc., Lake Forest, IL 60045 USA Reference ID: 3282431 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:38.454005	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/008809s066lbl.pdf', 'application_number': 8809, 'submission_type': 'SUPPL ', 'submission_number': 66}
10,714	NDA 9-000/S-022/S-023 Package Insert Page 1 T2001-27 89000402 CAFERGOT® (ergotamine tartrate and caffeine) SUPPOSITORIES, USP Rx only WARNING Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of CAFERGOT® with potent CYP 3A4 inhibitors including protease inhibitors and macrolide antibiotics. Because CYP 3A4 inhibition elevates the serum levels of CAFERGOT®, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased. Hence, concomitant use of these medications is contraindicated. (See also CONTRAINDICATIONS and WARNINGS section) DESCRIPTION CAFERGOT® (ergotamine tartrate and caffeine) Suppository ergotamine tartrate USP.............. 2 mg caffeine USP ............................... 100 mg Inactive Ingredients: cocoa butter NF and tartaric acid NF. CAFERGOT® (ergotamine tartrate and caffeine) suppositories are sealed in foil to afford protection from cocoa butter leakage. If an unavoidable period of exposure to heat softens the suppository, it should be chilled in ice-cold water to solidify it before removing the foil. CLINICAL PHARMACOLOGY Ergotamine is an alpha adrenergic blocking agent with a direct stimulating effect on the smooth muscle of peripheral and cranial blood vessels and produces depression of central vasomotor centers. The compound also has the properties of serotonin antagonism. In comparison to hydrogenated ergotamine, the adrenergic blocking actions are less pronounced and vasoconstrictive actions are greater. Caffeine, also a cranial vasoconstrictor, is added to further enhance the vasoconstrictive effect without the necessity of increasing ergotamine dosage. Many migraine patients experience excessive nausea and vomiting during attacks, making it impossible for them to retain any oral medication. In such cases, therefore, the only practical means of medication is through the rectal route where medication may reach the cranial vessels directly, evading the splanchnic vasculature and the liver. NDA 9-000/S-022/S-023 Package Insert Page 2 Pharmacokinetics: Interactions Pharmacokinetic interactions (increased blood levels of ergotamine) have been reported in patients treated orally with ergotamine and macrolide antibiotics (e.g., troleandomycin, clarithromycin, erythromycin), and in patients treated orally with ergotamine and protease inhibitors (e.g. ritonavir) presumably due to inhibition of cytochrome P450 3A metabolism of ergotamine (See CONTRAINDICATIONS). Ergotamine has also been shown to be an inhibitor of cytochrome P450 3A catalyzed reactions. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. INDICATIONS AND USAGE CAFERGOT® (ergotamine tartrate and caffeine) Indicated as therapy to abort or prevent vascular headache, e.g., migraine, migraine variants or so-called “histaminic cephalalgia’’. CONTRAINDICATIONS Coadministration of ergotamine with potent CYP 3A4 inhibitors (ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, and troleandomycin) has been associated with acute ergot toxicity (ergotism) characterized by vasospasm and ischemia of the extremities (see PRECAUTIONS: Drug Interactions), with some cases resulting in amputation. There have been rare reports of cerebral ischemia in patients on protease inhibitor therapy when CAFERGOT® (ergotamine tartrate and caffeine) was coadministered, at least one resulting in death. Because of the increased risk for ergotism and other serious vasospastic adverse events, ergotamine use is contraindicated with these drugs and other potent inhibitors of CYP 3A4 (e.g., ketoconazole, itraconazole) (see WARNINGS: CYP 3A4 Inhibitors). CAFERGOT® (ergotamine tartrate and caffeine) may cause fetal harm when administered to pregnant women. CAFERGOT® (ergotamine tartrate and caffeine) is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this product, the patient should be apprised of the potential hazard to the fetus. Peripheral vascular disease, coronary heart disease, hypertension, impaired hepatic or renal function and sepsis. Hypersensitivity to any of the components. WARNINGS CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) Coadministration of ergotamine with potent CYP 3A4 inhibitors such as protease inhibitors or macrolide antibiotics has been associated with serious adverse events; for this reason, these drug should not be given concomitantly with ergotamine (See CONTRAINDICATIONS). While these reactions have not been reported with less potent CYP 3A4 inhibitors, there is a potential risk for serious toxicity including vasospasm when these drugs are used with ergotamine. Examples of less potent CYP 3A4 inhibitors include: saquinavir, nefazodone, fluconazole, fluoxetine, grapefruit juice, fluvoxamine, zileuton, metronidazole, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP3A4 of other agents being considered for concomitant use with ergotamine. NDA 9-000/S-022/S-023 Package Insert Page 3 Fibrotic Complications There have been a few reports of patients on CAFERGOT® (ergotamine tartrate and caffeine) therapy developing retroperitoneal and/or pleuropulmonary fibrosis. There have also been rare reports of fibrotic thickening of the aortic, mitral, tricuspid, and/or pulmonary valves with long-term continuous use of CAFERGOT® (ergotamine tartrate and caffeine). CAFERGOT® (ergotamine tartrate) suppositories should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION). PRECAUTIONS General Although signs and symptoms of ergotism rarely develop even after long term intermittent use of the rectally administered drug, care should be exercised to remain within the limits of recommended dosage. Ergotism is manifested by intense arterial vasoconstriction, producing signs and symptoms of peripheral vascular ischemia. Ergotamine induces vasoconstriction by a direct action on vascular smooth muscle. In chronic intoxication with ergot derivatives, headache, intermittent claudication, muscle pains, numbness, coldness and pallor of the digits may occur. If the condition is allowed to progress untreated, gangrene can result. While most cases of ergotism associated with ergotamine treatment result from frank overdosage, some cases have involved apparent hypersensitivity. There are few reports of ergotism among patients taking doses within the recommended limits or for brief periods of time. In rare instances, patients, particularly those who have used the medication indiscriminately over long periods of time, may display withdrawal symptoms consisting of rebound headache upon discontinuation of the drug. Rare cases of a solitary rectal or anal ulcer have occurred from abuse of ergotamine suppositories usually in higher than recommended doses or with continual use at the recommended dose for many years. Spontaneous healing occurs within usually 4-8 weeks after drug withdrawal. Information for Patients Patients should be advised that one suppository of CAFERGOT® (ergotamine tartrate and caffeine) should be taken at the first sign of a migraine headache. No more than 2 suppositories should be taken for any single migraine attack. No more than 5 suppositories should be taken during any 7-day period. Administration of CAFERGOT® (ergotamine tartrate and caffeine) suppositories should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION). CAFERGOT® (ergotamine tartrate and caffeine) should be used only for migraine headaches. It is not effective for other types of headaches and it lacks analgesic properties. Patients should be advised to report to the physician immediately any of the following: numbness or tingling in the fingers and toes, muscle pain in the arms and legs, weakness in the legs, pain in the chest or temporary speeding or slowing of the heart rate, swelling or itching. Drug Interactions CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) See CONTRAINDICATIONS and WARNINGS. NDA 9-000/S-022/S-023 Package Insert Page 4 CAFERGOT® (ergotamine tartrate and caffeine) should not be administered with other vasoconstrictors. Use with sympathomimetics (pressor agents) may cause extreme elevation of blood pressure. The beta-blocker Inderal (propranolol) has been reported to potentiate the vasoconstrictive action of CAFERGOT® (ergotamine tartrate and caffeine) by blocking the vasodilating property of epinephrine. Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy. The blood levels of ergotamine-containing drugs are reported to be elevated by the concomitant administration of macrolide antibiotics and vasospastic reactions have been reported with therapeutic doses of the ergotamine-containing drugs when coadministered with these antibiotics. Pregnancy Teratogenic Effects Pregnancy Category X: There are no studies on the placental transfer or teratogenicity of the combined products of CAFERGOT® (ergotamine tartrate and caffeine). Caffeine is known to cross the placenta and has been shown to be teratogenic in animals. Ergotamine crosses the placenta in small amounts, although it does not appear to be embryotoxic in this quantity. However, prolonged vasoconstriction of the uterine vessels and/or increased myometrial tone leading to reduced myometrial and placental blood flow may have contributed to fetal growth retardation observed in animals. (See CONTRAINDICATIONS) Nonteratogenic Effects CAFERGOT® (ergotamine tartrate and caffeine) is contraindicated in pregnancy due to the oxytocic effects of ergotamine. (See CONTRAINDICATIONS) Labor and Delivery CAFERGOT® (ergotamine tartrate and caffeine) is contraindicated in labor and delivery due to its oxytocic effect which is maximal in the third trimester. (See CONTRAINDICATIONS) Nursing Mothers Ergot drugs are known to inhibit prolactin but there are no reports of decreased lactation with CAFERGOT ® (ergotamine tartrate and caffeine). Ergotamine is excreted in breast milk and may cause symptoms of vomiting, diarrhea, weak pulse and unstable blood pressure in nursing infants. Because of the potential for serious adverse reactions in nursing infants from CAFERGOT® (ergotamine tartrate and caffeine), a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. ADVERSE REACTIONS Cardiovascular: Vasoconstrictive complications of a serious nature may occur at times. These include ischemia, cyanosis, absence of pulse, cold extremities, gangrene, precordial distress and pain, EKG changes and muscle pains. Although these effects occur most commonly with long-term therapy at NDA 9-000/S-022/S-023 Package Insert Page 5 relatively high doses, they have also been reported with short-term or normal doses. Other cardiovascular adverse effects include transient tachycardia or bradycardia and hypertension. Gastrointestinal: Nausea and vomiting; rectal or anal ulcer (from overuse of suppositories). Neurological: paresthesias, numbness, weakness, and vertigo. Allergic: Localized edema and itching. Fibrotic Complications: (see WARNINGS). DRUG ABUSE AND DEPENDENCE There have been reports of drug abuse and psychological dependence in patients on CAFERGOT® (ergotamine tartrate and caffeine) therapy. Due to the chronicity of vascular headaches, it is imperative that patients be advised not to exceed recommended dosages with long-term use to avoid ergotism. (See PRECAUTIONS) OVERDOSAGE The toxic effects of an acute overdosage of CAFERGOT® (ergotamine tartrate and caffeine) are due primarily to the ergotamine component. The amount of caffeine is such that its toxic effects will be overshadowed by those of ergotamine. Symptoms include vomiting, numbness, tingling, pain and cyanosis of the extremities associated with diminished or absent peripheral pulses; hypertension or hypotension; drowsiness, stupor, coma, convulsions and shock. A case has been reported of reversible bilateral papillitis with ring scotomata in a patient who received five times the recommended daily adult dose over a period of 14 days. Treatment consists of removal of the offending drug by enema. Maintenance of adequate pulmonary ventilation, correction of hypotension, and control of convulsions and blood pressure are important considerations. Treatment of peripheral vasospasm should consist of warmth, but not heat, and protection of the ischemic limbs. Vasodilators may be beneficial but caution must be exercised to avoid aggravating an already existent hypotension. DOSAGE AND ADMINISTRATION Procedure For best results, dosage should start at the first sign of an attack. RECTALLY One suppository at start of attack; second suppository after 1 hour, if needed for full relief . 1 hr . Early Administration Gives Maximum Effectiveness NDA 9-000/S-022/S-023 Package Insert Page 6 Maximum Adult Dosage Rectally Two suppositories is the maximum dose for an individual attack. Total weekly dosage should not exceed 5 suppositories. CAFERGOT® (ergotamine tartrate and caffeine) suppositories should not be used for chronic daily administration. In carefully selected patients, with due consideration of maximum dosage recommendations, administration of the drug at bedtime may be an appropriate short-term preventive measure. HOW SUPPLIED CAFERGOT® (ergotamine tartrate and caffeine) Suppositories, USP Yellowish-white bullet-shaped, cocoa butter base suppositories wrapped in silver colored foil with NOVARTIS CAFERGOT® SUPPOSITORY 78-33 NOVARTIS’’ printed in fuchsia. Boxes of 12 (NDC 0078-0033-02). Store and Dispense Below 77°F (25°C); tight container (sealed foil). Protect from moisture. Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Russell Katz 6/4/02 09:16:17 AM	custom-source	2025-02-12T13:43:38.653464	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/9000s22s23lbl.pdf', 'application_number': 9000, 'submission_type': 'SUPPL ', 'submission_number': 22}
10,713	NDA 8-816/S-032 Page 3 721838- XYLOCAINE 2% JELLY (lidocaine hydrochloride) DESCRIPTION Xylocaine (lidocaine HCl) 2% Jelly is a sterile aqueous product that contains a local anesthetic agent and is administered topically. (See INDICATIONS for specific uses.) Xylocaine 2% Jelly contains lidocaine HCl which is chemically designated as acetamide, 2- (diethyl-amino)-N-(2,6-dimethylphenyl)-, monohydrochloride and has the following structural formula: Xylocaine 2% Jelly also contains hypromellose, and the resulting mixture maximizes contact with mucosa and provides lubrication for instrumentation. The unused portion should be discarded after initial use. Composition of Xylocaine 2% Jelly 30 mL and 5 mL tubes: Each mL contains 20 mg of lidocaine HCl. The formulation also contains methylparaben, propylparaben, hypromellose, and sodium hydroxide and/or hydrochloric acid to adjust pH to 6.0–7.0. CLINICAL PHARMACOLOGY Mechanism of Action Lidocaine stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action. Onset of Action The onset of action is 3–5 minutes. It is ineffective when applied to intact skin. Hemodynamics Excessive blood levels may cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. These changes may be attributable to a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-816/S-032 Page 4 Pharmacokinetics and Metabolism Lidocaine may be absorbed following topical administration to mucous membranes, its rate and extent of absorption depending upon concentration and total dose administered, the specific site of application, and duration of exposure. In general, the rate of absorption of local anesthetic agents following topical application occurs most rapidly after intratracheal administration. Lidocaine is also well-absorbed from the gastrointestinal tract, but little intact drug may appear in the circulation because of biotransformation in the liver. Lidocaine is metabolized rapidly by the liver, and metabolites and unchanged drug are excreted by the kidneys. Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation. N-dealkylation, a major pathway of biotransformation, yields the metabolites monoethylglycinexylidide and glycinexylidide. The pharmacological/toxicological actions of these metabolites are similar to, but less potent than, those of lidocaine. Approximately 90% of lidocaine administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged. The primary metabolite in urine is a conjugate of 4-hydroxy-2,6-dimethylaniline. The plasma binding of lidocaine is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At concentrations of 1 to 4 µg of free base per mL, 60 to 80 percent of lidocaine is protein bound. Binding is also dependent on the plasma concentration of the alpha-l-acid glycoprotein. Lidocaine crosses the blood-brain and placental barriers, presumably by passive diffusion. Studies of lidocaine metabolism following intravenous bolus injections have shown that the elimination half-life of this agent is typically 1.5 to 2.0 hours. Because of the rapid rate at which lidocaine is metabolized, any condition that affects liver function may alter lidocaine kinetics. The half-life may be prolonged twofold or more in patients with liver dysfunction. Renal dysfunction does not affect lidocaine kinetics but may increase the accumulation of metabolites. Factors such as acidosis and the use of CNS stimulants and depressants affect the CNS levels of lidocaine required to produce overt systemic effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6.0 µg free base per mL. In the rhesus monkey arterial blood levels of 18-21 µg/mL have been shown to be threshold for convulsive activity. INDICATIONS AND USAGE Xylocaine (lidocaine HCl) 2% Jelly is indicated for prevention and control of pain in procedures involving the male and female urethra, for topical treatment of painful urethritis, and as an anesthetic lubricant for endotracheal intubation (oral and nasal). CONTRAINDICATIONS Lidocaine is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type or to other components of Xylocaine 2% Jelly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-816/S-032 Page 5 WARNINGS EXCESSIVE DOSAGE, OR SHORT INTERVALS BETWEEN DOSES, CAN RESULT IN HIGH PLASMA LEVELS AND SERIOUS ADVERSE EFFECTS. PATIENTS SHOULD BE INSTRUCTED TO STRICTLY ADHERE TO THE RECOMMENDED DOSAGE AND ADMINISTRATION GUIDELINES AS SET FORTH IN THIS PACKAGE INSERT. THE MANAGEMENT OF SERIOUS ADVERSE REACTIONS MAY REQUIRE THE USE OF RESUSCITATIVE EQUIPMENT, OXYGEN, AND OTHER RESUSCITATIVE DRUGS. Xylocaine 2% Jelly should be used with extreme caution in the presence of sepsis or severely traumatized mucosa in the area of application, since under such conditions there is the potential for rapid systemic absorption. When used for endotracheal tube lubrication care should be taken to avoid introducing the product into the lumen of the tube. Do not use the jelly to lubricate the endotracheal stylettes. If allowed into the inner lumen, the jelly may dry on the inner surface leaving a residue which tends to clump with flexion, narrowing the lumen. There have been rare reports in which this residue has caused the lumen to occlude. (See also ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION.) PRECAUTIONS General: The safety and effectiveness of lidocaine depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. (See WARNINGS and ADVERSE REACTIONS.) The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. Repeated doses of lidocaine may cause significant increases in blood levels with each repeated dose because of slow accumulation of the drug or its metabolites. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their age and physical status. Lidocaine should also be used with caution in patients with severe shock or heart block. Xylocaine 2% Jelly should be used with caution in patients with known drug sensitivities. Patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to lidocaine. Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Since it is not known whether amide-type local anesthetics may trigger this reaction and since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for management should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene (consult dantrolene sodium intravenous package insert before using). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-816/S-032 Page 6 Information for Patients: When topical anesthetics are used in the mouth, the patient should be aware that the production of topical anesthesia may impair swallowing and thus enhance the danger of aspiration. For this reason, food should not be ingested for 60 minutes following use of local anesthetic preparations in the mouth or throat area. This is particularly important in children because of their frequency of eating. Numbness of the tongue or buccal mucosa may enhance the danger of unintentional biting trauma. Food and chewing gum should not be taken while the mouth or throat area is anesthetized. Carcinogenesis – Long-term studies in animals have not been performed to evaluate the carcinogenic potential of lidocaine. Mutagenesis – The mutagenic potential of lidocaine has been tested in the Ames Salmonella reverse mutation assay, an in vitro chromosome aberrations assay in human lymphocytes and in an in vivo mouse micronucleus assay. There was no indication of any mutagenic effect in these studies. Impairment of Fertility: The effect of lidocaine on fertility was examined in the rat model. Administration of 30 mg/kg, s.c. (180 mg/m2 ) to the mating pair did not produce alterations in fertility or general reproductive performance of rats. There are no studies that examine the effect of lidocaine on sperm parameters. There was no evidence of altered fertility. Use in Pregnancy: Teratogenic Effects: Pregnancy Category B Reproduction studies for lidocaine have been performed in both rats and rabbits. There was no evidence of harm to the fetus at subcutaneous doses of up to 50 mg/kg lidocaine (300 mg/m2 on a body surface area basis) in the rat model. In the rabbit model, there was no evidence of harm to the fetus at a dose of 5 mg/kg, s.c. (60 mg/m2 on a body surface area basis). Treatment of rabbits with 25 mg/kg (300 mg/m2) produced evidence of maternal toxicity and evidence of delayed fetal development, including a non-significant decrease in fetal weight (7%) and an increase in minor skeletal anomalies (skull and sternebral defect, reduced ossification of the phalanges). The effect of lidocaine on post-natal development was examined in rats by treating pregnant female rats daily subcutaneously at doses of 2, 10, and 50 mg/kg (12, 60, and 300 mg/m2) from day 15 of pregnancy and up to 20 days post partum. No signs of adverse effects were seen either in dams or in the pups up to and including the dose of 10 mg/kg (60 mg/m2); however, the number of surviving pups was reduced at 50 mg/kg (300 mg/m2), both at birth and the duration of lactation period, the effect most likely being secondary to maternal toxicity. No other effects on litter size, litter weight, abnormalities in the pups and physical developments of the pups were seen in this study. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-816/S-032 Page 7 A second study examined the effects of lidocaine on post-natal development in the rat that included assessment of the pups from weaning to sexual maturity. Rats were treated for 8 months with 10 or 30 mg/kg, s.c. lidocaine (60 mg/m2 and 180mg/m2 on a body surface area basis, respectively). This time period encompassed 3 mating periods. There was no evidence of altered post-natal development in any offspring; however, both doses of lidocaine significantly reduced the average number of pups per litter surviving until weaning of offspring from the first 2 mating period. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery: Lidocaine is not contraindicated in labor and delivery. Should Xylocaine 2% Jelly be used concomitantly with other products containing lidocaine, the total dose contributed by all formulations must be kept in mind. Nursing Mothers: Lidocaine is secreted in human milk. The clinical significance of this observation is unknown. Caution should be exercised when lidocaine is administered to a nursing woman. Pediatric Use: Although, the safety and effectiveness of Xylocaine 2% Jelly in pediatric patients have not been established, a study of 19 premature neonates (gestational age <33 weeks) found no correlation between the plasma concentration of lidocaine or monoethylglycinexylidide and infant body weight when moderate amounts of lidocaine (i.e. 0.3 mL/kg of lidocaine gel 20 mg/ml) were used for lubricating both intranasal and endotracheal tubes. No neonate had plasma levels of lidocaine above 750 mcg/L. Dosages in children should be reduced, commensurate with age, body weight, and physical condition. (See DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS Adverse experiences following the administration of lidocaine are similar in nature to those observed with other amide local anesthetic agents. These adverse experiences are, in general, dose-related and may result from high plasma levels caused by excessive dosage or rapid absorption, or may result from a hypersensitivity, idiosyncrasy, or diminished tolerance on the part of the patient. Serious adverse experiences are generally systemic in nature. The following types are those most commonly reported: There have been rare reports of endotracheal tube occlusion associated with the presence of dried jelly residue in the inner lumen of the tube. (See also WARNINGS and DOSAGE AND ADMINISTRATION.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-816/S-032 Page 8 Central Nervous System: CNS manifestations are excitatory and/or depressant and may be characterized by lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression, and arrest. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest. Drowsiness following the administration of lidocaine is usually an early sign of a high blood level of the drug and may occur as a consequence of rapid absorption. Cardiovascular System: Cardiovascular manifestations are usually depressant and are characterized by bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac arrest. Allergic: Allergic reactions are characterized by cutaneous lesions, urticaria, edema, or anaphylactoid reactions. Allergic reactions may occur as a result of sensitivity either to the local anesthetic agent or to other components in the formulation. Allergic reactions as a result of sensitivity to lidocaine are extremely rare and, if they occur, should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value. OVERDOSAGE Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics. (See ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS.) Management of Local Anesthetic Emergencies: The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic administration. At the first sign of change, oxygen should be administered. The first step in the management of convulsions consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to use of local anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor as directed by the clinical situation (e.g., ephedrine). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-816/S-032 Page 9 If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias, and cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Dialysis is of negligible value in the treatment of acute overdosage with lidocaine. The oral LD50 of lidocaine HCl in non-fasted female rats is 459 (346-773) mg/kg (as the salt) and 214 (159-324) mg/kg (as the salt) in fasted female rats. DOSAGE AND ADMINISTRATION When Xylocaine 2% Jelly is used concomitantly with other products containing lidocaine, the total dose contributed by all formulations must be kept in mind. The dosage varies and depends upon the area to be anesthetized, vascularity of the tissues, individual tolerance, and the technique of anesthesia. The lowest dosage needed to provide effective anesthesia should be administered. Dosages should be reduced for children and for elderly and debilitated patients. Although the incidence of adverse effects with Xylocaine 2% Jelly is quite low, caution should be exercised, particularly when employing large amounts, since the incidence of adverse effects is directly proportional to the total dose of local anesthetic agent administered. For Surface Anesthesia of the Male Adult Urethra: When using Xylocaine 2% Jelly 30 mL tubes, sterilize the plastic cone for 5 minutes in boiling water, cool, and attach to the tube. The cone may be gas sterilized or cold sterilized, as preferred. Slowly instill approximately 15 mL (300 mg of lidocaine HCl) into the urethra or until the patient has a feeling of tension. A penile clamp is then applied for several minutes at the corona. An additional dose of not more than 15 mL (300 mg) can be instilled for adequate anesthesia. Prior to sounding or cystoscopy, a penile clamp should be applied for 5 to 10 minutes to obtain adequate anesthesia. A total dose of 30 mL (600 mg) is usually required to fill and dilate the male urethra. Prior to catheterization, smaller volumes of 5-10 mL (100-200 mg) are usually adequate for lubrication. For Surface Anesthesia of the Female Adult Urethra: When using Xylocaine 2% Jelly 30 mL tubes, sterilize the plastic cone for 5 minutes in boiling water, cool, and attach to the tube. The cone may be gas sterilized or cold sterilized, as preferred. Slowly instill 3–5 mL (60–100 mg of lidocaine HCl) of the jelly into the urethra. If desired, some jelly may be deposited on a cotton swab and introduced into the urethra. In order to obtain adequate anesthesia, several minutes should be allowed prior to performing urological procedures. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 8-816/S-032 Page 10 Lubrication for Endotracheal Intubation: Apply a moderate amount of jelly to the external surface of the endotracheal tube shortly before use. Care should be taken to avoid introducing the product into the lumen of the tube. Do not use the jelly to lubricate endotracheal stylettes. See WARNINGS and ADVERSE REACTIONS concerning rare reports of inner lumen occlusion. It is also recommended that use of endotracheal tubes with dried jelly on the external surface be avoided for lack of lubricating effect. MAXIMUM DOSAGE No more than 600 mg of lidocaine HCl should be given in any 12 hour period. Children: It is difficult to recommend a maximum dose of any drug for children since this varies as a function of age and weight. For children less than ten years who have a normal lean body mass and a normal lean body development, the maximum dose may be determined by the application of one of the standard pediatric drug formulas (e.g., Clark’s rule). For example, in a child of five years weighing 50 lbs, the dose of lidocaine hydrochloride should not exceed 75-100 mg when calculated according to Clark’s rule. In any case, the maximum amount of Xylocaine administered should not exceed 4.5 mg/kg (2.0 mg/lb) of body weight. HOW SUPPLIED Xylocaine (lidocaine HCl) 2% Jelly is supplied in the listed dosage forms. NDC 0186-0330-01 30 mL aluminum tube Box of 1 A detachable applicator cone and a key for expressing the contents are included. NDC 0186-0330-36 5 mL plastic tube Box of 10 Storage: Store at controlled room temperature 20–25°C (68–77°F) [see USP]. All trademarks are the property of the AstraZeneca group ©AstraZeneca 2004 AstraZeneca LP, Wilmington, DE 19850 721838- Rev XX/XX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:38.717933	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/08816s032lbl.pdf', 'application_number': 8816, 'submission_type': 'SUPPL ', 'submission_number': 32}
10,716	PURINETHOL® (mercaptopurine) 50-mg Scored Tablets CAUTION PURINETHOL (mercaptopurine) is a potent drug. It should not be used unless a diagnosis of acute lymphatic leukemia has been adequately established and the responsible physician is experienced with the risks of PURINETHOL and knowledgeable in assessing response to chemotherapy. DESCRIPTION PURINETHOL (mercaptopurine) was synthesized and developed by Hitchings, Elion, and associates at the Wellcome Research Laboratories. Mercaptopurine, known chemically as 1,7-dihydro-6H-purine-6-thione monohydrate, is an analogue of the purine bases adenine and hypoxanthine. Its structural formula is: structural formula PURINETHOL is available in tablet form for oral administration. Each scored tablet contains 50 mg mercaptopurine and the inactive ingredients corn and potato starch, lactose, magnesium stearate, and stearic acid. CLINICAL PHARMACOLOGY Mechanism of Action Mercaptopurine (6-MP) competes with hypoxanthine and guanine for the enzyme hypoxanthine- guanine phosphoribosyltransferase (HGPRTase) and is itself converted to thioinosinic acid (TIMP). This intracellular nucleotide inhibits several reactions involving inosinic acid (IMP), including the conversion of IMP to xanthylic acid (XMP) and the conversion of IMP to adenylic acid (AMP) via adenylosuccinate (SAMP). In addition, 6-methylthioinosinate (MTIMP) is formed by the methylation of TIMP. Both TIMP and MTIMP have been reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. Experiments indicate that radiolabeled mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine. Some mercaptopurine is converted to nucleotide derivatives of 6-thioguanine (6-TG) by the sequential actions of inosinate (IMP) dehydrogenase and xanthylate (XMP) aminase, converting TIMP to thioguanylic acid (TGMP). Reference ID: 2953022 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Animal tumors that are resistant to mercaptopurine often have lost the ability to convert mercaptopurine to TIMP. However, it is clear that resistance to mercaptopurine may be acquired by other means as well, particularly in human leukemias. It is not known exactly which of any one or more of the biochemical effects of mercaptopurine and its metabolites are directly or predominantly responsible for cell death. Pharmacokinetics Clinical studies have shown that the absorption of an oral dose of mercaptopurine in humans is incomplete and variable, averaging approximately 50% of the administered dose. The factors influencing absorption are unknown. Intravenous administration of an investigational preparation of mercaptopurine revealed a plasma half-disappearance time of 21 minutes in pediatric patients and 47 minutes in adults. The volume of distribution usually exceeded that of the total body water. Following the oral administration of 35S-6-mercaptopurine in one subject, a total of 46% of the dose could be accounted for in the urine (as parent drug and metabolites) in the first 24 hours. There is negligible entry of mercaptopurine into cerebrospinal fluid. Plasma protein binding averages 19% over the concentration range 10 to 50 mcg/mL (a concentration only achieved by intravenous administration of mercaptopurine at doses exceeding 5 to 10 mg/kg). A reduction in mercaptopurine dosage is required if patients are receiving both mercaptopurine and allopurinol (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Metabolism and Genetic Polymorphism Variability in mercaptopurine metabolism is one of the major causes of interindividual differences in systemic exposure to the drug and its active metabolites. Mercaptopurine activation occurs via hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and several enzymes to form 6-thioguanine nucleotides (6-TGNs). The cytotoxicity of mercaptopurine is due, in part, to the incorporation of 6-TGN into DNA. Mercaptopurine is inactivated via two major pathways. One is thiol methylation, which is catalyzed by the polymorphic enzyme thiopurine S methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP. TPMT activity is highly variable in patients because of a genetic polymorphism in the TPMT gene. For Caucasians and African Americans, approximately 0.3% (1:300) of patients have two non-functional alleles (homozygous-deficient) of the TPMT gene and have little or no detectable enzyme activity. Approximately 10% of patients have one TPMT non-functional allele (heterozygous) leading to low or intermediate TPMT activity and 90% of individuals have normal TPMT activity with two functional alleles. Homozygous-deficient patients (two non-functional alleles), if given usual doses of mercaptopurine, accumulate excessive cellular concentrations of active thioguanine nucleotides predisposing them to PURINETHOL toxicity (see WARNINGS and PRECAUTIONS). Heterozygous patients with low or intermediate TPMT activity accumulate higher concentrations of active thioguanine nucleotides than people with normal TPMT activity and are more likely to experience mercaptopurine toxicity (see WARNINGS and PRECAUTIONS). TPMT genotyping or phenotyping (red blood cell TPMT activity) can identify patients who are homozygous deficient or have low or intermediate TPMT activity (see WARNINGS, PRECAUTIONS, Laboratory Tests, and DOSAGE AND ADMINISTRATION sections). Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (XO) and forms 6-thiouric acid. Xanthine oxidase is inhibited by ZYLOPRIM® (allopurinol). Concomitant Reference ID: 2953022 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda use of allopurinol with mercaptopurine decreases the catabolism of mercaptopurine and its active metabolites leading to mercaptopurine toxicity. A reduction in mercaptopurine dosage is therefore required if patients are receiving both mercaptopurine and allopurinol (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). After oral administration of 35S-6-mercaptopurine, urine contains intact mercaptopurine, thiouric acid (formed by direct oxidation by xanthine oxidase, probably via 6-mercapto-8-hydroxypurine), and a number of 6-methylated thiopurines. INDICATIONS AND USAGE PURINETHOL (mercaptopurine) is indicated for maintenance therapy of acute lymphatic (lymphocytic, lymphoblastic) leukemia as part of a combination regimen. The response to this agent depends upon the particular subclassification of acute lymphatic leukemia and the age of the patient (pediatric or adult). PURINETHOL is not effective for prophylaxis or treatment of central nervous system leukemia. PURINETHOL is not effective in acute myelogenous leukemia, chronic lymphatic leukemia, the lymphomas (including Hodgkins Disease), or solid tumors. CONTRAINDICATIONS PURINETHOL should not be used in patients whose disease has demonstrated prior resistance to this drug. In animals and humans, there is usually complete cross-resistance between mercaptopurine and thioguanine. PURINETHOL should not be used in patients who have a hypersensitivity to mercaptopurine or any component of the formulation. WARNINGS Mercaptopurine is mutagenic in animals and humans, carcinogenic in animals, and may increase the patient's risk of neoplasia. Cases of hepatosplenic T-cell lymphoma have been reported in patients treated with mercaptopurine for inflammatory bowel disease. The safety and efficacy of mercaptopurine in patients with inflammatory bowel disease have not been established. Bone Marrow Toxicity The most consistent, dose-related toxicity is bone marrow suppression. This may be manifest by anemia, leukopenia, thrombocytopenia, or any combination of these. Any of these findings may also reflect progression of the underlying disease. In many patients with severe depression of the formed elements of the blood due to PURINETHOL, the bone marrow appears hypoplastic on aspiration or biopsy, whereas in other cases it may appear normocellular. The qualitative changes in the erythroid elements toward the megaloblastic series, characteristically seen with the folic acid antagonists and some other antimetabolites, are not seen with this drug. Life-threatening infections and bleeding have been observed as a consequence of mercaptopurine-induced granulocytopenia and thrombocytopenia. Since mercaptopurine may have a delayed effect, it is important to withdraw the medication temporarily at the first sign of an unexpected abnormally large fall in any of the formed elements of the blood, if not attributable to another drug or disease process. Reference ID: 2953022 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Individuals who are homozygous for an inherited defect in the TPMT (thiopurine-S methyltransferase) gene are unusually sensitive to the myelosuppressive effects of mercaptopurine and prone to developing rapid bone marrow suppression following the initiation of treatment. Laboratory tests are available, both genotypic and phenotypic, to determine the TPMT status. Substantial dose reductions are generally required for homozygous-TPMT deficiency patients (two non-functional alleles) to avoid the development of life threatening bone marrow suppression. Although heterozygous patients with intermediate TPMT activity may have increased mercaptopurine toxicity, this is variable, and the majority of patients tolerate normal doses of PURINETHOL. If a patient has clinical or laboratory evidence of severe toxicity, particularly myelosuppression, TPMT testing should be considered. In patients who exhibit excessive myelosuppression due to 6-mercaptopurine, it may be possible to adjust the mercaptopurine dose and administer the usual dosage of other myelosuppressive chemotherapy as required for treatment (see DOSAGE AND ADMINISTRATION). Bone marrow toxicity may be more profound in patients treated with concomitant allopurinol (see PRECAUTIONS, Drug Interactions and DOSAGE AND ADMINISTRATION). This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine, or sulphasalazine. Hepatotoxicity Mercaptopurine is hepatotoxic in animals and humans. A small number of deaths have been reported that may have been attributed to hepatic necrosis due to administration of mercaptopurine. Hepatic injury can occur with any dosage, but seems to occur with more frequency when doses of 2.5 mg/kg/day are exceeded. The histologic pattern of mercaptopurine hepatotoxicity includes features of both intrahepatic cholestasis and parenchymal cell necrosis, either of which may predominate. It is not clear how much of the hepatic damage is due to direct toxicity from the drug and how much may be due to a hypersensitivity reaction. In some patients jaundice has cleared following withdrawal of mercaptopurine and reappeared with its reintroduction. Published reports have cited widely varying incidences of overt hepatotoxicity. In a large series of patients with various neoplastic diseases, mercaptopurine was administered orally in doses ranging from 2.5 mg/kg to 5.0 mg/kg without evidence of hepatotoxicity. It was noted by the authors that no definite clinical evidence of liver damage could be ascribed to the drug, although an occasional case of serum hepatitis did occur in patients receiving 6-MP who previously had transfusions. In reports of smaller cohorts of adult and pediatric leukemic patients, the incidence of hepatotoxicity ranged from 0% to 6%. In an isolated report by Einhorn and Davidsohn, jaundice was observed more frequently (40%), especially when doses exceeded 2.5 mg/kg. Usually, clinically detectable jaundice appears early in the course of treatment (1 to 2 months). However, jaundice has been reported as early as 1 week and as late as 8 years after the start of treatment with mercaptopurine. The hepatotoxicity has been associated in some cases with anorexia, diarrhea, jaundice and ascites. Hepatic encephalopathy has occurred. Monitoring of serum transaminase levels, alkaline phosphatase, and bilirubin levels may allow early detection of hepatotoxicity. It is advisable to monitor these liver function tests at weekly intervals when first beginning therapy and at monthly intervals thereafter. Liver function tests may be advisable more frequently in patients who are receiving mercaptopurine with other hepatotoxic drugs or with known pre-existing liver disease. The onset of clinical jaundice, hepatomegaly, or anorexia with tenderness in the right hypochondrium are immediate indications for withholding mercaptopurine until the exact etiology can be identified. Likewise, any evidence Reference ID: 2953022 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda of deterioration in liver function studies, toxic hepatitis, or biliary stasis should prompt discontinuation of the drug and a search for an etiology of the hepatotoxicity. The concomitant administration of mercaptopurine with other hepatotoxic agents requires especially careful clinical and biochemical monitoring of hepatic function. Combination therapy involving mercaptopurine with other drugs not felt to be hepatotoxic should nevertheless be approached with caution. The combination of mercaptopurine with doxorubicin was reported to be hepatotoxic in 19 of 20 patients undergoing remission-induction therapy for leukemia resistant to previous therapy. Immunosuppression Mercaptopurine recipients may manifest decreased cellular hypersensitivities and decreased allograft rejection. Induction of immunity to infectious agents or vaccines will be subnormal in these patients; the degree of immunosuppression will depend on antigen dose and temporal relationship to drug. This immunosuppressive effect should be carefully considered with regard to intercurrent infections and risk of subsequent neoplasia. Pregnancy Pregnancy Category D Mercaptopurine can cause fetal harm when administered to a pregnant woman. Women receiving mercaptopurine in the first trimester of pregnancy have an increased incidence of abortion; the risk of malformation in offspring surviving first trimester exposure is not accurately known. In a series of 28 women receiving mercaptopurine after the first trimester of pregnancy, 3 mothers died undelivered, 1 delivered a stillborn child, and 1 aborted; there were no cases of macroscopically abnormal fetuses. Since such experience cannot exclude the possibility of fetal damage, mercaptopurine should be used during pregnancy only if the benefit clearly justifies the possible risk to the fetus, and particular caution should be given to the use of mercaptopurine in the first trimester of pregnancy. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. PRECAUTIONS General The safe and effective use of PURINETHOL demands close monitoring of the CBC and patient clinical status. After selection of an initial dosage schedule, therapy will frequently need to be modified depending upon the patient’s response and manifestations of toxicity. It is probably advisable to start with lower dosages in patients with impaired renal function, due to slower elimination of the drug and metabolites and a greater cumulative effect. Information for Patients Reference ID: 2953022 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients should be informed that the major toxicities of PURINETHOL are related to myelosuppression, hepatotoxicity, and gastrointestinal toxicity. Patients should never be allowed to take the drug without medical supervision and should be advised to consult their physician if they experience fever, sore throat, jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia. Women of childbearing potential should be advised to avoid becoming pregnant. Laboratory Tests (Also see WARNINGS, Bone Marrow Toxicity) It is recommended that evaluation of the hemoglobin or hematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained weekly while the patient is on therapy with PURINETHOL. Bone marrow examination may also be useful for the evaluation of marrow status. The decision to increase, decrease, continue, or discontinue a given dosage of PURINETHOL must be based upon the degree of severity and rapidity with which changes are occurring. In many instances, particularly during the induction phase of acute leukemia, complete blood counts will need to be done more frequently than once weekly in order to evaluate the effect of the therapy. If a patient has clinical or laboratory evidence of severe bone marrow toxicity, particularly myelosuppression, TPMT testing should be considered. TPMT Testing Genotypic and phenotypic testing of TPMT status are available. Genotypic testing can determine the allelic pattern of a patient. Currently, 3 alleles—TPMT2, TPMT3A and TPMT*3C— account for about 95% of individuals with reduced levels of TPMT activity. Individuals homozygous for these alleles are TPMT deficient and those heterozygous for these alleles have variable TPMT (low or intermediate) activity. Phenotypic testing determines the level of thiopurine nucleotides or TPMT activity in erythrocytes and can also be informative. Caution must be used with phenotyping since some coadministered drugs can influence measurement of TPMT activity in blood, and recent blood transfusions will misrepresent a patient’s actual TPMT activity. Drug Interactions When allopurinol and mercaptopurine are administered concomitantly, the dose of mercaptopurine must be reduced to one third to one quarter of the usual dose to avoid severe toxicity. There is usually complete cross-resistance between mercaptopurine and thioguanine. The dosage of mercaptopurine may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression. Enhanced marrow suppression has been noted in some patients also receiving trimethoprim-sulfamethoxazole. Inhibition of the anticoagulant effect of warfarin, when given with mercaptopurine, has been reported. As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent mercaptopurine therapy (see WARNINGS). Carcinogenesis, Mutagenesis, Impairment of Fertility Reference ID: 2953022 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Mercaptopurine causes chromosomal aberrations in animals and humans and induces dominant- lethal mutations in male mice. In mice, surviving female offspring of mothers who received chronic low doses of mercaptopurine during pregnancy were found sterile, or if they became pregnant, had smaller litters and more dead fetuses as compared to control animals. Carcinogenic potential exists in humans, but the extent of the risk is unknown. The effect of mercaptopurine on human fertility is unknown for either males or females. Pregnancy Teratogenic Effects Pregnancy category D See WARNINGS section. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from mercaptopurine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use See DOSAGE AND ADMINISTRATION section. Geriatric Use Clinical studies of PURINETHOL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS The principal and potentially serious toxic effects of PURINETHOL are bone marrow toxicity and hepatotoxicity (see WARNINGS and PRECAUTIONS). Hematologic The most frequent adverse reaction to PURINETHOL is myelosuppression. The induction of complete remission of acute lymphatic leukemia frequently is associated with marrow hypoplasia. Patients without TPMT enzyme activity (homozygous-deficient) are particularly susceptible to hematologic toxicity, and some patients with low or intermediate TPMT enzyme activity are more susceptible to hematologic toxicity than patients with normal TPMT activity (see Reference ID: 2953022 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS, Bone Marrow Toxicity), although the latter can also experience severe toxicity. Maintenance of remission generally involves multiple-drug regimens whose component agents cause myelosuppression. Anemia, leukopenia, and thrombocytopenia are frequently observed. Dosages and also schedules are adjusted to prevent life-threatening cytopenias. Renal Hyperuricemia and/or hyperuricosuria may occur in patients receiving PURINETHOL as a consequence of rapid cell lysis accompanying the antineoplastic effect. Renal adverse effects can be minimized by increased hydration, urine alkalinization, and the prophylactic administration of a xanthine oxidase inhibitor such as allopurinol. The dosage of PURINETHOL should be reduced to one third to one quarter of the usual dose if allopurinol is given concurrently. Gastrointestinal Intestinal ulceration has been reported. Nausea, vomiting, and anorexia are uncommon during initial administration, but may increase with continued administration. Mild diarrhea and sprue- like symptoms have been noted occasionally, but it is difficult at present to attribute these to the medication. Oral lesions are rarely seen, and when they occur they resemble thrush rather than antifolic ulcerations. Miscellaneous The administration of PURINETHOL has been associated with skin rashes and hyperpigmentation. Alopecia has been reported. Drug fever has been very rarely reported with PURINETHOL. Before attributing fever to PURINETHOL, every attempt should be made to exclude more common causes of pyrexia, such as sepsis, in patients with acute leukemia. Oligospermia has been reported. OVERDOSAGE Signs and symptoms of overdosage may be immediate (anorexia, nausea, vomiting, and diarrhea); or delayed (myelosuppression, liver dysfunction, and gastroenteritis). Dialysis cannot be expected to clear mercaptopurine. Hemodialysis is thought to be of marginal use due to the rapid intracellular incorporation of mercaptopurine into active metabolites with long persistence. The oral LD50 of mercaptopurine was determined to be 480 mg/kg in the mouse and 425 mg/kg in the rat. There is no known pharmacologic antagonist of mercaptopurine. The drug should be discontinued immediately if unintended toxicity occurs during treatment. If a patient is seen immediately following an accidental overdosage of the drug, it may be useful to induce emesis. DOSAGE AND ADMINISTRATION Maintenance Therapy Reference ID: 2953022 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Once a complete hematologic remission is obtained, maintenance therapy is considered essential. Maintenance doses will vary from patient to patient. The usual daily maintenance dose of PURINETHOL is 1.5 to 2.5 mg/kg/day as a single dose. It is to be emphasized that in pediatric patients with acute lymphatic leukemia in remission, superior results have been obtained when PURINETHOL has been combined with other agents (most frequently with methotrexate) for remission maintenance. PURINETHOL should rarely be relied upon as a single agent for the maintenance of remissions induced in acute leukemia. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Dosage with Concomitant Allopurinol When allopurinol and mercaptopurine are administered concomitantly, the dose of mercaptopurine must be reduced to one third to one quarter of the usual dose to avoid severe toxicity. Dosage in TPMT-deficient Patients Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe PURINETHOL toxicity from conventional doses of mercaptopurine and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established. (See CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS sections.) Most patients with heterozygous TPMT deficiency tolerated recommended PURINETHOL doses, but some require dose reduction. Genotypic and phenotypic testing of TPMT status are available. (See CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS sections.) Dosage in Renal and Hepatic Impairment It is probably advisable to start with lower dosages in patients with impaired renal function, due to slower elimination of the drug and metabolites and a greater cumulative effect. Consideration should be given to reducing the dosage in patients with impaired hepatic function. HOW SUPPLIED Pale yellow to buff, scored tablets containing 50 mg mercaptopurine, imprinted with “PURINETHOL” and “04A”; bottles of 60 (NDC 57844-522-06). Store at 15° to 25°C (59° to 77°F) in a dry place. REFERENCES 1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society;1999:32-41. 2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety; Clinical Center Pharmacy Department and Cancer Nursing Services, Reference ID: 2953022 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda National Institutes of Health; 1992. US Dept of Health and Human Services. Public Health Service publication NIH 92-2621. 3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1591. 4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. 5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428. 6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Cancer J for Clinicians. 1983;33:258-263. 7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049. 8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) Am J Health-Syst Pharm. 1996;53:1669-1685. Manufactured for: GATE PHARMACEUTICALS div. of Teva Pharmaceuticals USA Sellersville, PA 18960 Manufactured by: DSM Pharmaceuticals, Inc. Greenville, NC 27834 Rev. F 4/2011 Reference ID: 2953022 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:38.750858	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/009053s032lbl.pdf', 'application_number': 9053, 'submission_type': 'SUPPL ', 'submission_number': 32}
10,715	PRESCRIBING INFORMATION 522 INETHOL® captopurine) g Scored Tablets HOL (mercaptopurine) is a potent drug. It should not be used unless a diagnosis of sible physician is of purinethol and knowledgeable in assessing response to PURINETHOL (mercaptopurine) was synthesized and developed by Hitchings, Elion, and associates ptopurine, known chemically as 1,7-dihydro-6H-purine-6-thione monohydrate, is an analogue and hypoxanthine. Its structural formula is: PURINETHOL is available in tablet form for oral administration. Each scored tablet contains 50 mg sium stearate, and poxanthine-guanine cid (TIMP). This intracellular nucleotide inhibits several reactions involving inosinic acid (IMP), including the lic acid (AMP) via y the methylation of IMP have been reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. Experiments indicate that radiolabeled mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine. Some mercaptopurine is converted to nucleotide derivatives of 6-thioguanine (6- TG) by the sequential actions of inosinate (IMP) dehydrogenase and xanthylate (XMP) aminase, converting TIMP to thioguanylic acid (TGMP). Animal tumors that are resistant to mercaptopurine often have lost the ability to convert mercaptopurine to TIMP. However, it is clear that resistance to mercaptopurine may be acquired by other means as well, particularly in human leukemias. PUR (mer 50-m CAUTION PURINET acute lymphatic leukemia has been adequately established and the respon experienced with the risks chemotherapy. DESCRIPTION at the Wellcome Research Laboratories. Merca of the purine bases adenine mercaptopurine and the inactive ingredients corn and potato starch, lactose, magne stearic acid. CLINICAL PHARMACOLOGY Mechanism of action Mercaptopurine (6-MP) competes with hypoxanthine and guanine for the enzyme hy phosphoribosyltransferase (HGPRTase) and is itself converted to thioinosinic a conversion of IMP to xanthylic acid (XMP) and the conversion of IMP to adeny adenylosuccinate (SAMP). In addition, 6-methylthioinosinate (MTIMP) is formed b TIMP. Both TIMP and MT 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda It is not known exactly which of any one or more of the biochemical effects of mercaptopurine and its e directly or predominantly responsible for cell death. urine in humans is dose. The factors onal preparation of ric patients and 47 ually exceeded that of the total body water. of 46% of the dose first 24 hours. There is es 19% over the concentration range 10 to 50 mcg/mL (a concentration only achieved by intravenous administration of mercaptopurine at doses exceeding 5 to 10 mg/kg). ercaptopurine and dual differences in tivation occurs via form 6-thioguanine incorporation of 6- methylation, which form the inactive use of a genetic ately 0.3% (1:300) e and have little or on-functional allele iduals have normal omozygous-deficient patients (two non-functional alleles), ntrations of active WARNINGS and accumulate higher tivity and are more UTIONS). TPMT genotyping or phenotyping (red blood cell TPMT activity) can identify patients who are homozygous deficient or have low or intermediate TPMT activity (see WARNINGS, PRECAUTIONS: Laboratory Tests, and DOSAGE and ADMINISTRATION sections). Another inactivation pathway is oxidation, which is catalyzed by Xanthine oxidase (XO) and forms 6- thiouric acid. Xanthine oxidase is inhibited by ZYLOPRIM® (allopurinol). Concomitant use of allopurinol with mercaptopurine decreases the catabolism of mercaptopurine and its active metabolites leading to mercaptopurine toxicity. A reduction in mercaptopurine dosage is therefore required if patients are receiving both mercaptopurine and allopurinol(see PRECAUTIONS and DOSAGE AND ADMINISTRATION). metabolites ar Pharmacokinetics Clinical studies have shown that the absorption of an oral dose of mercaptop incomplete and variable, averaging approximately 50% of the administered influencing absorption are unknown. Intravenous administration of an investigati mercaptopurine revealed a plasma half-disappearance time of 21 minutes in pediat minutes in adults. The volume of distribution us Following the oral administration of 35S-6-mercaptopurine in one subject, a total could be accounted for in the urine (as parent drug and metabolites) in the negligible entry of mercaptopurine into cerebrospinal fluid. Plasma protein binding averag A reduction in mercaptopurine dosage is required if patients are receiving both m allopurinol (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Metabolism and Genetic Polymorphism Variability in mercaptopurine metabolism is one of the major causes of interindivi systemic exposure to the drug and its active metabolites. Mercaptopurine ac hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and several enzymes to nucleotides (6-TGNs). The cytotoxicity of mercaptopurine is due, in part, to the TGN into DNA. Mercaptopurine is inactivated via two major pathways. One is thiol is catalyzed by the polymorphic enzyme thiopurine S-methyltransferase (TPMT), to metabolite methyl-6-MP. TPMT activity is highly variable in patients beca polymorphism in the TPMT gene. For Caucasians and African Americans, approxim of patients have two non-functional alleles (homozygous-deficient) of the TPMT gen no detectable enzyme activity. Approximately 10% of patients have one TPMT n (heterozygous) leading to low or intermediate TPMT activity and 90% of indiv TPMT activity with two functional alleles. H if given usual doses of mercaptopurine, accumulate excessive cellular conce thioguanine nucleotides predisposing them to PURINETHOL toxicity (see PRECAUTIONS). Heterozygous patients with low or intermediate TPMT activity concentrations of active thioguanine nucleotides than people with normal TPMT ac likely to experience mercaptopurine toxicity (see WARNINGS and PRECA 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda After oral administration of 35S-6-mercaptopurine, urine contains intact mercaptop (formed by direct oxidation urine, thiouric acid by xanthine oxidase, probably via 6-mercapto-8-hydroxypurine), and a hiopurines. acute lymphatic lymphoblastic) leukemia as part of a combination regimen.. The response to this agent and the age of the patient effective for prophylaxis or treatment of central nervous system leukemia. PURINETHOL is not effective in acute myelogenous leukemia, chronic lymphatic leukemia, the AINDICATIONS d not be used in patients whose disease has demonstrated prior resistance to this imals and humans, there is usually complete cross-resistance between mercaptopurine and rcaptopurine or any suppression. This ese. Any of these h severe depression , the bone marrow appears hypoplastic on ative changes in the lic acid antagonists ctions and bleeding ulocytopenia and nt to withdraw the any of the formed -methyltransferase) prone to developing on of treatment. Laboratory tests are available, both genotypic and phenotypic, to determine the TPMT status. Substantial dose reductions are generally required for homozygous-TPMT deficiency patients (two non functional alleles) to avoid the development of life threatening bone marrow suppression. Although heterozygous patients with number of 6-methylated t INDICATIONS AND USAGE PURINETHOL (mercaptopurine) is indicated for maintenance therapy of (lymphocytic, depends upon the particular subclassification of acute lymphatic leukemia (pediatric or adult). PURINETHOL is not lymphomas (including Hodgkins Disease), or solid tumors. CONTR PURINETHOL shoul drug. In an thioguanine. PURINETHOL should not be used in patients who have a hypersensitivity to me component of the formulation. WARNINGS Bone Marrow Toxicity: The most consistent, dose-related toxicity is bone marrow may be manifest by anemia, leukopenia , thrombocytopenia, or any combination of th findings may also reflect progression of the underlying disease. In many patients wit of the formed elements of the blood due to PURINETHOL aspiration or biopsy, whereas in other cases it may appear normocellular. The qualit erythroid elements toward the megaloblastic series, characteristically seen with the fo and some other antimetabolites, are not seen with this drug. Life-threatening infe have been observed as a consequence of mercaptopurine-induced gran thrombocytopenia. Since mercaptopurine may have a delayed effect, it is importa medication temporarily at the first sign of an unexpected abnormally large fall in elements of the blood, if not attributable to another drug or disease process. Individuals who are homozygous for an inherited defect in the TPMT (thiopurine-S gene are unusually sensitive to the myelosuppressive effects of mercaptopurine and rapid bone marrow suppression following the initiati intermediate TPMT activity may have increased mercaptopurine toxicity, this is variable, and the majority of patients tolerate normal doses of PURINETHOL. If a patient has clinical or laboratory evidence of severe toxicity, particularly myelosuppression, TPMT testing should be considered. In patients who exhibit excessive myelosuppression due to 6-mercaptopurine, it may be possible to adjust the mercaptopurine dose and administer the usual dosage of other myelosuppressive chemotherapy as required for treatment (see DOSAGE AND ADMINITRATION). 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Bone marrow toxicity may be more profound in patients treated with concomit PRECAUTIONS: Drug Interactions and DOSAGE AND ADMONISTRATION). Th ant allopurinol (see is problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine, or ber of deaths have of mercaptopurine. when doses of 2.5 ncludes features of al cell necrosis, either of which may predominate. It is not much may be due ing withdrawal of In a large series of doses ranging from ors that no definite ional case of serum reports of smaller city ranged from 0% to 6%. In an isolated report by Einhorn and Davidsohn, jaundice was observed more frequently (40%), appears early in the s 1 week and as late been associated in occurred. els may allow early f hepatotoxicity. It is advisable to monitor these liver function tests at weekly intervals when ore gs or with known with tenderness in ction studies, toxic r an etiology of the ptopurine with other hepatotoxic agents requires especially careful clinical and biochemical monitoring of hepatic function. Combination therapy involving mercaptopurine with other drugs not felt to be hepatotoxic should nevertheless be approached with caution. The combination of mercaptopurine with doxorubicin was reported to be hepatotoxic in 19 of 20 patients undergoing remission-induction therapy for leukemia resistant to previous therapy. Immunosuppression: Mercaptopurine recipients may manifest decreased cellular hypersensitivities and decreased allograft rejection. Induction of immunity to infectious agents or vaccines will be subnormal in these patients; the degree of immunosuppression will depend on antigen dose and temporal relationship to drug. This immunosuppressive effect should be carefully considered with regard to intercurrent infections and risk of subsequent neoplasia. sulphasalazine. Hepatotoxicity: Mercaptopurine is hepatotoxic in animals and humans. A small num been reported that may have been attributed to hepatic necrosis due to administration Hepatic injury can occur with any dosage, but seems to occur with more frequency mg/kg/day are exceeded. The histologic pattern of mercaptopurine hepatotoxicity i both intrahepatic cholestasis and parenchym clear how much of the hepatic damage is due to direct toxicity from the drug and how to a hypersensitivity reaction. In some patients jaundice has cleared follow mercaptopurine and reappeared with its reintroduction. Published reports have cited widely varying incidences of overt hepatotoxicity. patients with various neoplastic diseases, mercaptopurine was administered orally in 2.5 mg/kg to 5.0 mg/kg without evidence of hepatotoxicity. It was noted by the auth clinical evidence of liver damage could be ascribed to the drug, although an occas hepatitis did occur in patients receiving 6-MP who previously had transfusions. In cohorts of adult and pediatric leukemic patients, the incidence of hepatotoxi especially when doses exceeded 2.5 mg/kg. Usually, clinically detectable jaundice course of treatment (1 to 2 months). However, jaundice has been reported as early a as 8 years after the start of treatment with mercaptopurine. The hepatotoxicity has some cases with anorexia, diarrhea,jaundice and ascites. Hepatic encephalopathy has Monitoring of serum transaminase levels, alkaline phosphatase, and bilirubin lev detection o first beginning therapy and at monthly intervals thereafter. Liver function tests may be advisable m frequently in patients who are receiving mercaptopurine with other hepatotoxic dru pre-existing liver disease. The onset of clinical jaundice, hepatomegaly, or anorexia the right hypochondrium are immediate indications for withholding mercaptopurine until the exact etiology can be identified. Likewise, any evidence of deterioration in liver fun hepatitis, or biliary stasis should prompt discontinuation of the drug and a search fo hepatotoxicity. The concomitant administration of merca 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy: Pregnancy Category D. Mercaptopurine can cause fetal harm when pregnant woman. Women receiving mercaptopurine in the first trimester of pregnanc incidence of abortion; the risk of malformation in offspring surviving first trimes accurately known. In a series of 28 women receiving mercaptopurine after the pregnancy, 3 mothers died undelivered, 1 delivered a stillborn child, and 1 aborted; t of macroscopically abnormal fetuses. Since such experience cannot exclude the damage, mercapt administered to a y have an increased ter exposure is not first trimester of here were no cases possibility of fetal opurine should be used during pregnancy only if the benefit clearly justifies the topurine in the first e are no adequate and well-controlled studies in pregnant women. If this drug is used during if the patient becomes pregnant while taking the drug, the patient should be apprised of the to avoid becoming The safe and effective use of PURINETHOL demands close monitoring of the CBC and probably advisable r elimination of the PURINETHOL are ts should never be lt their physician if tion, bleeding from ould be advised to t and differential count, and quantitative nt be obtained weekly while the patient is on therapy with PURINETHOL. Bone marrow increase, decrease, degree of severity uring the induction y than once weekly ence of severe bone Genotypic and phenotypic testing of TPMT status are available. Genotypic testing can determine the allelic pattern of a patient. Currently, 3 alleles-- TPMT2, TPMT3A and TPMT*3C—account for about 95% of individuals with reduced levels of TPMT activity. Individuals homozygous for these alleles are TPMT deficient and those heterozygous for these alleles have variable TPMT (low or intermediate) activity. Phenotypic testing determines the level of thiopurine nucleotides or TPMT activity in erythrocytes and can also be informative. Caution must be used with phenotyping since some co-administered drugs can influence measurement of TPMT activity in blood, and recent blood transfusions will misrepresent a patient’s actual TPMT activity possible risk to the fetus, and particular caution should be given to the use of mercap trimester of pregnancy. Ther pregnancy or potential hazard to the fetus. Women of childbearing potential should be advised pregnant. PRECAUTIONS General: patient clinical status. After selection of an initial dosage schedule, therapy will frequently need to be modified depending upon the patient’s response and manifestations of toxicity. It is to start with lower dosages in patients with impaired renal function, due to slowe drug and metabolites and a greater cumulative effect. Information for Patients: Patients should be informed that the major toxicities of related to myelosuppression, hepatotoxicity, and gastrointestinal toxicity. Patien allowed to take the drug without medical supervision and should be advised to consu they experience fever, sore throat, jaundice, nausea, vomiting, signs of local infec any site, or symptoms suggestive of anemia. Women of childbearing potential sh avoid becoming pregnant. Laboratory Tests: (Also see WARNINGS, Bone Marrow Toxicity) It is recommended that evaluation of the hemoglobin or hematocrit, total white blood cell coun platelet cou examination may also be useful for the evaluation of marrow status. The decision to continue, or discontinue a given dosage of PURINETHOL must be based upon the and rapidity with which changes are occurring. In many instances, particularly d phase of acute leukemia, complete blood counts will need to be done more frequentl in order to evaluate the effect of the therapy. If a patient has clinical or laboratory evid marrow toxicity, particularly myelosuppression, TPMT testing should be considered. TPMT Testing 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions: When allopurinol and mercaptopurine are administered concomitantly, the dose of l dose to avoid severe toxicity. e. d when this agent is combined with other drugs ppression has been has been reported. e, mesalazine, or aution to patients uses chromosomal ions in animals and humans and induces dominant-lethal mutations in male mice. In mice, ses of mercaptopurine during ore dead fetuses as xtent of the risk is ales. y D. See WARNINGS section. ecause many drugs s in nursing infants r to discontinue the Pediatric Use: See DOSAGE AND ADMINISTRATION section. cal studies of PURINETHOL did not include sufficient numbers of subjects aged cts. Other reported ces in responses between the elderly and younger patients. the low end of the ac function, and of arrow toxicity and NGS and PRECAUTIONS). Hematologic: The most frequent adverse reaction to PURINETHOL is myelosuppression. The induction of complete remission of acute lymphatic leukemia frequently is associated with marrow hypoplasia. Patients without TPMT enzyme activity (homozygous-deficient) are particularly susceptible to hematologic toxicity, and some patients with low or intermediate TPMT enzyme activity are more susceptible to hematologic toxicity than patients with normal TPMT activity (See Warnings: Bone Marrow Toxicity),although the latter can also experience severe toxicity. Maintenance of remission generally involves multiple-drug regimens whose component agents cause myelosuppression. Anemia, leukopenia, and thrombocytopenia are frequently observed. Dosages and also schedules are adjusted to prevent life-threatening cytopenias. mercaptopurine must be reduced to one third to one quarter of the usua There is usually complete cross-resistance between mercaptopurine and thioguanin The dosage of mercaptopurine may need to be reduce whose primary or secondary toxicity is myelosuppression. Enhanced marrow su noted in some patients also receiving trimethoprim-sulfamethoxazole. Inhibition of the anticoagulant effect of warfarin, when given with mercaptopurine, As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazin sulphasalazine) inhibit the TPMT enzyme, they should be administered with c receiving concurrent mercaptopurine therapy (see WARNINGS). Carcinogenesis, Mutagenesis, Impairment of Fertility: Mercaptopurine ca aberrat surviving female offspring of mothers who received chronic low do pregnancy were found sterile, or if they became pregnant, had smaller litters and m compared to control animals. Carcinogenic potential exists in humans, but the e unknown. The effect of mercaptopurine on human fertility is unknown for either males or fem Pregnancy: Teratogenic Effects: Pregnancy Categor Nursing Mothers: It is not known whether this drug is excreted in human milk. B are excreted in human milk, and because of the potential for serious adverse reaction from mercaptopurine, a decision should be made whether to discontinue nursing o drug, taking into account the importance of the drug to the mother. Geriatric Use: Clini 65 and over to determine whether they respond differently from younger subje clinical experience has not identified differen In general, dose selection for an elderly patient should be cautious, usually starting at dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardi concomitant disease or other drug therapy. ADVERSE REACTIONS The principal and potentially serious toxic effects of PURINETHOL are bone m hepatotoxicity (see WARNI 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Renal: Hyperuricemia and/or hyperuricosuria may occur in patients receiving P consequence of rapid cell lysis accompanying the antineoplastic effect. Renal adv minimized by increased hydration, urine alkalinization URINETHOL as a erse effects can be , and the prophylactic administration of a be reduced to one and anorexia are ng initial administration, but may increase with continued administration. Mild diarrhea o attribute these to ly seen, and when they occur they resemble thrush rather than h skin rashes and as been reported. r has been very rarely reported with PURINETHOL. Before attributing fever to of pyrexia, such as g, and diarrhea); or be expected to clear marginal use due to the rapid intracellular ne into active metabolites with long persistence. The oral LD50 of mercaptopurine was determined to be 480 mg/kg in the mouse and 425 mg/kg in the rat. ld be discontinued diately following an tenance therapy is atient to patient. The usual daily maintenance phasized that in pediatric een obtained when s been combined with other agents (most frequently with methotrexate) for remission maintenance. PURINETHOL should rarely be relied upon as a single agent for the maintenance of Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Dosage with concomitant Allopurinol: When allopurinol and mercaptopurine are administered concomitantly, the dose of mercaptopurine must be reduced to one third to one quarter of the usual dose to avoid severe toxicity. Dosage in TPMT-deficient Patients: Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe PURINETHOL toxicity from conventional doses of xanthine oxidase inhibitor such as allopurinol. The dosage of PURINETHOL should third to one quarter of the usual dose if allopurinol is given concurrently. Gastrointestinal: Intestinal ulceration has been reported. Nausea, vomiting, uncommon duri and sprue-like symptoms have been noted occasionally, but it is difficult at present t the medication. Oral lesions are rare antifolic ulcerations. Miscellaneous:,The administration of PURINETHOL has been associated wit hyperpigmentation. Alopecia h Drug feve PURINETHOL, every attempt should be made to exclude more common causes sepsis, in patients with acute leukemia. Oligospermia has been reported. OVERDOSAGE Signs and symptoms of overdosage may be immediate ( anorexia, nausea, vomitin delayed (myelosuppression, liver dysfunction, and gastroenteritis).. Dialysis cannot mercaptopurine. Hemodialysis is thought to be of incorporation of mercaptopuri There is no known pharmacologic antagonist of mercaptopurine. The drug shou immediately if unintended toxicity occurs during treatment. If a patient is seen imme accidental overdosage of the drug, it may be useful to induce emesis. DOSAGE AND ADMINISTRATION Maintenance Therapy: Once a complete hematologic remission is obtained, main considered essential. Maintenance doses will vary from p dose of PURINETHOL is 1.5 to 2.5 mg/kg/day as a single dose. It is to be em patients with acute lymphatic leukemia in remission, superior results have b PURINETHOL ha remissions induced in acute leukemia. 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda mercaptopurine and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established. (see CLINICAL PHARMACOLOGY, mmended PURINETHOL doses, but some require dose reduction. Genotypic and phenotypic testing of TPMT status are available. (See CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS sections). d Hepatic Impairment: It is probably advisable to start with lower dosages in patients with impaired renal function, due to slower elimination of the drug and metabolites and a tive effect. Consideration should be given to reducing the dosage in patients with LIED P , imprinted with “PU 22-07) and 250 (NDC 57844-522-52). S RE 1. mmittee. Cancer Chemotherapy Guidelines and Recommendations for . Washington, DC: Nursing Services, ces. Public Health 21. 3. lines for handling parenteral antineoplastics. JAMA. 4. ecommendations for handling cytotoxic y Commission on macy and Allied Health Sciences, 179 5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of nts. Med J Australia. 1983;1:426-428. Mass T. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Cancer J for Clinicians. 1983;33:258-263. 7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049. 8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) Am J Health-Syst Pharm. 1996;53:1669-1685. Manufactured for: GATE PHARMACEUTICALS div. of Teva Pharmaceuticals USA WARNINGS and PRECAUTIONS sections.) Most patients with heterozygous TPMT deficiency tolerated reco Dosage in Renal an greater cumula impaired hepatic function. HOW SUPP ale yellow to buff, scored tablets containing 50 mg mercaptopurine RINETHOL” and “04A”; bottles of 25 (NDC 57844-5 tore at 15° to 25°C (59° to 77°F) in a dry place. FERENCES ONS Clinical Practice Co Practice. Pittsburgh, PA: Oncology Nursing Society;1999:32-41. 2. Recommendations for the safe handling of parenteral antineoplastic drugs Division of Safety; Clinical Center Pharmacy Department and Cancer National Institutes of Health; 1992. US Dept of Health and Human Servi Service publication NIH 92-26 AMA Council on Scientific Affairs. Guide 1985;253:1590-1591. National Study Commission on Cytotoxic Exposure. R agents. 1987. Available from Louis P. Jeffrey, Chairman, National Stud Cytotoxic Exposure. Massachusetts College of Phar Longwood Avenue, Boston, MA 02115. antineoplastic age 6. Jones RB, Frank R, 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Manufactured by DSM Pharmaceuticals, Inc. Greenville, NC 27834 Rev. A 8/2003 Sellersville, PA 18960 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:38.780223	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/09053s024lbl.pdf', 'application_number': 9053, 'submission_type': 'SUPPL ', 'submission_number': 24}
10,717	NDA 6-927/S-030 NDA 9-112/S-021 Page 3 Rx only Eurax (crotamiton USP) Lotion/Cream FOR TOPICAL USE ONLY NOT FOR OPHTHALMIIC, ORAL, OR INTRAVAGINAL USE DESCRIPTION Eurax (crotamiton USP) is a scabicidal and antipruritic agent available as a cream or lotion for topical use only. Eurax provides 10% (w/w) of the synthetic, crotamiton USP, in a vanishing-cream or emollient-lotion base containing: water, petrolatum, propylene glycol, steareth-2, cetyl alcohol, dimethicone, laureth-23, fragrance, magnesium aluminum silicate, carbomer-934, sodium hydroxide, diazolidinylurea, methylchloroisothiazolinone, methylisothiazolinone and magnesium nitrate. In addition, the cream contains glyceryl stearate. Crotamiton is N-ethyl-N-(o-methylphenyl) -2- butenamide and its structural formula is: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 6-927/S-030 NDA 9-112/S-021 Page 4 Crotamiton USP is a colorless to slightly yellowish oil, having a faint amine-like odor. It is miscible with alcohol and with methanol. Crotamiton is a mixture of the cis and trans isomers. Its molecular weight is 203.28. CLINICAL PHARMACOLOGY Eurax has scabicidal and antipruritic actions. The mechanisms of these actions are not known. The pharmacokinetics of crotamiton and its degree of systemic absorption following topical application have not been determined. INDICATIONS AND USAGE For eradication of scabies (Sarcoptes scabiei) and for symptomatic treatment of pruritic skin. CONTRAINDICATIONS Eurax should not be applied topically to patients who develop a sensitivity or are allergic to it or who manifest a primary irritation response to topical medications. WARNINGS If severe irritation or sensitization develops, treatment with this product should be discontinued and appropriate therapy instituted. PRECAUTIONS General Eurax should not be applied in the eyes or mouth because it may cause irritation. It should not be applied to acutely inflamed skin or raw or weeping surfaces until the acute inflammation has subsided. lnformation for Patients See DIRECTIONS FOR PATIENTS WITH SCABIES. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 6-927/S-030 NDA 9-112/S-021 Page 5 Drug interactions None known. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies in animals have not been conducted. Pregnancy (Category C) Animal reproduction studies have not been conducted with Eurax. It is also not known whether Eurax can cause fetal harm when applied topically to a pregnant woman or can affect reproduction capacity. Eurax should be given to a pregnant woman only if clearly needed. Pediatric Use Safety and effectiveness in children have not been established. Geriatric Use Clinical studies with Eurax (crotamiton USP) Lotion/Cream did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS Primary irritation reactions, such as dermatitis, pruritus, and rash, and allergic sensitivity reactions have been reported in a few patients. OVERDOSAGE There is no specific information on the effect of overtreatment with repeated topical applications in humans. A death was reported but cause was not confirmed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 6-927/S-030 NDA 9-112/S-021 Page 6 Accidental oral ingestion may be accompanied by burning sensation in the mouth, irritation of the buccal, esophageal and gastric mucosa, nausea, vomiting, abdominal pain. If accidental ingestion occurs, call your Poison Control Center. DOSAGE AND ADMINISTRATION In Scabies: Thoroughly massage into the skin of the whole body from the chin down, paying particular attention to all folds and creases. A second application is advisable 24 hours later. Clothing and bed linen should be changed the next morning. A cleansing bath should be taken 48 hours after the last application. In Pruritus: Massage gently into affected areas until medication is completely absorbed. Repeat as needed. LOTION: Shake well before using. DIRECTIONS FOR PATIENTS WITH SCABIES: 1. Take a routine bath or shower. Thoroughly massage Eurax cream or lotion into the skin from the chin to the toes including folds and creases. 2. Put Eurax cream or lotion under fingernails after trimming the fingernails short, because scabies are very likely to remain there. A toothbrush can be used to apply the Eurax cream or lotion under the fingernails. Immediately after use, the toothbrush should be wrapped in paper and thrown away. Use of the same brush in the mouth could lead to poisoning. 3. A second application is advisable 24 hours later. 4. This 60 gram tube or bottle is sufficient for two applications. 5. Clothing and bed linen should be changed the next day. Contaminated clothing and bed linen may be dry-cleaned, or washed in the hot cycle of the washing machine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 6-927/S-030 NDA 9-112/S-021 Page 7 6. A cleansing bath should be taken 48 hours after the last application. HOW SUPPLIED Eurax (crotamiton USP) Cream: 60g tubes (NDC 0072-2103-60; NSN 6505-00-116-0200). Lotion: 60g (2 oz.) bottles (NDC 0072-2203-60, NSN 6505-01-153- 4423). 454g (16 oz.) bottles (NDC 0072-2203-16). SHAKE WELL before using. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 6-927/S-030 NDA 9-112/S-021 Page 8 Store at room temperature. Keep out of reach of children. Westwood-Squibb Pharmaceuticals, Inc. A Bristol-Myers Squibb Company Princeton, NJ 08543 USA Insert code TBD Revised TBD This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:38.870256	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/06927slr030,09112slr021_eurax_lbl.pdf', 'application_number': 9112, 'submission_type': 'SUPPL ', 'submission_number': 21}
10,719	structural formula ________________________________________________________________ Mysoline® (primidone, USP) Anticonvulsant Rx only DESCRIPTION Chemical name: 5-ethyldihydro-5-phenyl-4,6 (1H, 5H)-pyrimidinedione. Structural formula: C12H14N2O2 M.W.218.25 Mysoline* (primidone) is a white, crystalline, highly stable substance, M.P. 279 284°C. It is poorly soluble in water (60 mg per 100 mL at 37°C) and in most organic solvents. It possesses no acidic properties, in contrast to its barbiturate analog. Mysoline 50 mg and 250 mg tablets contain the following inactive ingredients: Microcrystalline Cellulose, NF; Lactose, USP; Methylcellulose, USP; Sodium Starch Glycolate, NF; Talc, USP; Sodium Lauryl Sulfate, NF; Magnesium Stearate, NF; Water, USP, Purified. Mysoline 250 mg tablets also contain Yellow Iron Oxide, NF. * Registered trademark of Valeant Pharmaceuticals North America. ACTIONS Mysoline raises electro- or chemoshock seizure thresholds or alters seizure patterns in experimental animals. The mechanism(s) of primidone’s antiepileptic action is not known. Primidone per se has anticonvulsant activity as do its two metabolites, phenobarbital and phenylethylmalonamide (PEMA). In addition to its anticonvulsant activity, PEMA potentiates the anticonvulsant activity of phenobarbital in experimental animals. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE Mysoline, used alone or concomitantly with other anticonvulsants, is indicated in the control of grand mal, psychomotor, and focal epileptic seizures. It may control grand mal seizures refractory to other anticonvulsant therapy. CONTRAINDICATIONS Primidone is contraindicated in: 1) patients with porphyria and 2) patients who are hypersensitive to phenobarbital (see ACTIONS). WARNINGS The abrupt withdrawal of antiepileptic medication may precipitate status epilepticus. The therapeutic efficacy of a dosage regimen takes several weeks before it can be assessed. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Mysoline, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Drug Patients Relative Risk: Risk Patients with with Events Incidence Difference: Events Per Per 1000 of Events in Additional 1000 Patients Patients Drug Patients/ Drug Patients Incidence with Events in Placebo Per 1000 Patients Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Mysoline or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Usage in Pregnancy To provide information regarding the effects of in utero exposure to Mysoline, physicians are advised to recommend that pregnant patients taking Mysoline enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. The effects of Mysoline in human pregnancy and nursing infants are unknown. Recent reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to diphenylhydantoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs. The reports suggesting an elevated incidence of birth defects in children of drugtreated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors leading to birth defects, e.g., genetic factors or the epileptic condition itself, may be more important than drug therapy. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorders are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of childbearing potential. Neonatal hemorrhage, with a coagulation defect resembling vitamin K deficiency, has been described in newborns whose mothers were taking primidone and other anticonvulsants. Pregnant women under anticonvulsant therapy should receive prophylactic vitamin K1 therapy for one month prior to, and during, delivery. PRECAUTIONS The total daily dosage should not exceed 2 g. Since Mysoline therapy generally extends over prolonged periods, a complete blood count and a sequential multiple analysis-12 (SMA-12) test should be made every six months. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In Nursing Mothers There is evidence in mothers treated with primidone, the drug appears in the milk in substantial quantities. Since tests for the presence of primidone in biological fluids are too complex to be carried out in the average clinical laboratory, it is suggested that the presence of undue somnolence and drowsiness in nursing newborns of Mysoline-treated mothers be taken as an indication that nursing should be discontinued. Information for Patients Suicidal Thinking and Behavior - Patients, their caregivers, and families should be counseled that AEDs, including Mysoline, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see Usage in Pregnancy section). Please refer to the Mysoline Medication Guide provided with the product for more information. ADVERSE REACTIONS The most frequently occurring early side effects are ataxia and vertigo. These tend to disappear with continued therapy, or with reduction of initial dosage. Occasionally, the following have been reported: nausea, anorexia, vomiting, fatigue, hyperirritability, emotional disturbances, sexual impotency, diplopia, nystagmus, drowsiness, and morbilliform skin eruptions. Granulocytopenia, agranulocytosis, and red-cell hypoplasia and aplasia, have been reported rarely. These and, occasionally, other persistant or severe side effects may necessitate withdrawal of the drug. Megaloblastic anemia may occur as a rare idiosyncrasy to Mysoline and to other anticonvulsants. The anemia responds to folic acid without necessity of discontinuing medication. DOSAGE AND ADMINISTRATION This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adult Dosage Patients 8 years of age and older who have received no previous treatment may be started on Mysoline according to the following regimen using either 50 mg or scored 250 mg Mysoline tablets: Days 1 to 3: 100 to 125 mg at bedtime. Days 4 to 6: 100 to 125 mg b.i.d. Days 7 to 9: 100 to 125 mg t.i.d. Day 10 to maintenance: 250 mg t.i.d. For most adults and children 8 years of age and over, the usual maintenance dosage is three to four 250 mg Mysoline tablets in divided doses (250 mg t.i.d. or q.i.d.). If required, an increase to five or six 250 mg tablets daily may be made but daily doses should not exceed 500 mg q.i.d. INITIAL: ADULTS AND CHILDREN OVER 8 KEY: • = 50 mg tablet；● = 250 mg tablet DAY 1 2 3 4 5 6 AM •• •• •• NOON PM •• •• •• •• •• •• DAY 7 8 9 10 11 12 AM NOON •• •• •• •• •• •• ● ● Adjust to Maintenance PM •• •• •• ● Dosage should be individualized to provide maximum benefit. In some cases, serum blood level determinations of primidone may be necessary for optimal dosage adjustment. The clinically effective serum level for primidone is between 5 to 12 μg/mL. In Patients Already Receiving Other Anticonvulsants Mysoline should be started at 100 to 125 mg at bedtime and gradually increased to maintenance level as the other drug is gradually decreased. This regimen should be continued until satisfactory dosage level is achieved for the combination, or the other medication is completely withdrawn. When therapy with Mysoline alone is the objective, the transition from concomitant therapy should not be completed in less than two weeks. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Dosage For children under 8 years of age, the following regimen may be used: Days 1 to 3: 50 mg at bedtime. Days 4 to 6: 50 mg b.i.d. Days 7 to 9: 100 mg b.i.d. Day 10 to maintenance: 125 mg t.i.d. to 250 mg t.i.d. For children under 8 years of age, the usual maintenance dosage is 125 to 250 mg three times daily or, 10 to 25 mg/kg/day in divided doses. HOW SUPPLIED Mysoline Tablets Each square-shaped, scored, yellow tablet, identified by “MYSOLINE 250” and an embossed M, contains 250 mg of primidone, in bottles of 100 (NDC 66490 691-10) Each square-shaped, scored, white tablet, identified by “MYSOLINE 50” and an embossed M, contains 50 mg of primidone, in bottles of 100 (NDC 66490-690 10) The appearance of these tablets is a trademark of Valeant Pharmaceuticals North America. Store at 20°C-25°C (68°F-77°F). [See USP controlled room temperature]. Dispense in a tight, light-resistant container with a child-resistant closure. Manufacture by: Piramal Healthcare Ltd. Plot No. 67-70, Sector - 2, Pithampur, 454775, Dist. Dhar, Madhya Pradesh, INDIA Distributed by: Valeant Pharmaceuticals North America One Enterprise Aliso Viejo, CA 92656 U.S.A. Part No. EM 10142/a Rev. 05/09 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:38.962556	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/009170s035lbl.pdf', 'application_number': 9170, 'submission_type': 'SUPPL ', 'submission_number': 35}
10,720	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LIPIODOL safely and effectively. See full prescribing information for LIPIODOL. LIPIODOL® (Ethiodized Oil) Injection Initial U.S. Approval: 1954 WARNING: FOR INTRALYMPHATIC, INTRAUTERINE AND SELECTIVE HEPATIC INTRA-ARTERIAL USE ONLY See Full Prescribing Information for complete Boxed Warning Pulmonary and cerebral embolism can result from inadvertent intravascular injection or intravasation of Lipiodol. Inject Lipiodol slowly with radiologic monitoring; do not exceed recommended dose (5.1). _______________RECENT MAJOR CHANGES______________ Indications and Usage (1) 4/2014 Dosage and Administration, Dosage Guidelines (2.1) 4/2014 Contraindications (4) 4/2014 Warnings and Precautions (5) 4/2014 ---------------------- INDICATIONS AND USAGE --------------------- Lipiodol is an oil-based radiopaque contrast agent indicated for: • hysterosalpingography in adults • lymphography in adult and pediatric patients • selective hepatic intra-arterial use for imaging tumors in adults with known hepatocellular carcinoma (HCC) (1) ------------------ DOSAGE AND ADMINISTRATION --------------- Use a glass syringe to draw and inject Lipiodol. (2) • Hysterosalpingography Inject increments of 2 mL of Lipiodol into the endometrial cavity until tubal patency is determined; stop the injection if the patient develops excessive discomfort. Inject with radiologic monitoring. • Lymphography Inject Lipiodol into a lymphatic vessel with radiologic monitoring. Adults: • unilateral lymphography of the upper extremities: 2 to 4 mL unilateral lymphography of the lower extremities: 6 to 8 mL • penile lymphography: 2 to 3 mL • cervical lymphography:1 to 2 mL Pediatric patients: • Inject a minimum of 1 mL to a maximum of 6 mL according to the anatomical area to be visualized. Do not exceed 0.25 mL/kg. • Selective Hepatic Intra-arterial Use Inject 1.5 to 15 mL of Lipiodol slowly under continuous radiologic monitoring. Do not exceed 20mL total dosage. ------------------ DOSAGE FORMS AND STRENGTHS ------------ Each mL of Lipiodol contains 480 mg Iodine organically combined with ethyl esters of fatty acids of poppy seed oil. (3) ------------------------- CONTRAINDICATIONS ----------------------- Hypersensitivity to Lipiodol, hyperthyroidism, traumatic injuries, recent hemorrhage or bleeding. (4) • Lipiodol Hysterosalpingography is contraindicated in: pregnancy, acute pelvic inflammatory disease, marked cervical erosion, endocervicitis and intrauterine bleeding, in the immediate pre-or postmenstrual phase, or within 30 days of curettage or conization • Lipiodol Lymphography is contraindicated in: right to left cardiac shunt, advanced pulmonary disease, tissue trauma or hemorrhage, advanced neoplastic disease with expected lymphatic obstruction, previous surgery interrupting the lymphatic system, or radiation therapy to the examined area. • Lipiodol Selective Hepatic Intra-arterial Injection is contraindicated in: the presence of dilated bile ducts unless external biliary drainage was performed before injection. ----------------- WARNINGS AND PRECAUTIONS ---------------- • Pulmonary and cerebral embolism: avoid use in patients with severely impaired lung function, cardiorespiratory failure or right-sided cardiac overload (5.1) • Hypersensitivity reactions: avoid use in patients with a history of sensitivity to other iodinated contrast agents, bronchial asthma or allergic disorders because of an increased risk of a hypersensitivity reaction to Lipiodol. (5.2) • Exacerbation of chronic liver disease (5.3) • Thyroid dysfunction (5.4) ------------------------ ADVERSE REACTIONS ----------------------- Adverse reactions caused by Lipiodol include hypersensitivity reactions, pulmonary embolism, pulmonary dysfunction, exacerbation of liver disease, procedural complications, abdominal pain, fever, nausea, vomiting, and thyroid dysfunction. (6.2) To report SUSPECTED ADVERSE REACTIONS, contact GUERBET LLC at 1-877-729-6679 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch Revised: 04/2014 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Guidelines 2.2 Drug Handling 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Pulmonary and Cerebral Embolism 5.2 Hypersensitivity Reactions 5.3 Exacerbation of Chronic Liver Disease 5.4 Thyroid Dysfunction 6 ADVERSE REACTIONS 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Interference with Iodine-Based Diagnostic Tests and Iodine-Based Radiotherapy 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Nursing Mothers 8.3 Pediatric Use 8.4 Geriatric Use 8.5 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3484171 Page 1 of 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ______________________________________________________________________________________________________________ FULL PRESCRIBING INFORMATION WARNING: FOR INTRALYMPHATIC, INTRAUTERINE AND SELECTIVE HEPATIC INTRA-ARTERIAL USE ONLY Pulmonary and cerebral embolism can result from inadvertent intravascular injection or intravasation of Lipiodol. Inject Lipiodol slowly with radiologic monitoring; do not exceed recommended dose (5.1). 1 INDICATIONS AND USAGE Lipiodol is an oil-based radio-opaque contrast agent indicated for: • hysterosalpingography in adults • lymphography in adult and pediatric patients • selective hepatic intra-arterial use for imaging tumors in adults with known hepatocellular carcinoma (HCC). 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Guidelines Draw Lipiodol into a glass syringe. Use the smallest possible amount of Lipiodol according to the anatomical area to be visualized. Hysterosalpingography Using aseptic technique inject Lipiodol into the endometrial cavity with fluoroscopic control. Inject increments of 2 mL of Lipiodol until tubal patency is determined; stop the injection if patient develops excessive discomfort. Re-image after 24 hours to establish whether Lipiodol has entered the peritoneal cavity. Before using Lipiodol exclude the presence of these conditions: pregnancy, uterine bleeding and endocervicitis, acute pelvic inflammatory disease, the immediate pre-or postmenstrual phase or within 30 days of curettage or conization. Lymphography Inject Lipiodol into a lymphatic vessel under radiologic guidance to prevent inadvertent venous administration or intravasation. Adults: • unilateral lymphography of the upper extremities 2 to 4 mL • unilateral lymphography of the lower extremities 6 to 8 mL • penile lymphography 2 to 3 mL • cervical lymphography 1 to 2 mL Pediatric patients: • Inject a minimum of 1 mL to a maximum of 6 mL according to the anatomical area to be visualized. Do not exceed 0.25 mL/kg. The following method is recommended for lymphography of the upper or lower extremities. Start the injection of Lipiodol into a lymphatic channel at a rate not to exceed 0.2 mL per minute. Inject the total dose of Lipiodol in no less than 1.25 hours. Use frequent radiologic monitoring to determine the appropriate injection rate and to follow the progress of Lipiodol within the lymphatics. Interrupt the injection if the patient experiences pain. Terminate the injection if lymphatic blockage is present to minimize introduction of Lipiodol into the venous circulation via lymphovenous channels. Terminate the injection as soon as Lipiodol is radiographically evident in the thoracic duct to minimize entry of Lipiodol into the subclavian vein and pulmonary embolization. Obtain immediate post-injection images. Re-image at 24 or 48 hours to evaluate nodal architecture. Selective Hepatic Intra-arterial Injection Determine the dose depending on the tumor size, local blood flow in the liver and in the tumor(s). • Inject from 1.5 to 15 mL slowly under continuous radiologic monitoring. Stop the injection when stagnation or reflux is evident. Limit the dose to only the quantity required for adequate visualization. The total dose of Lipiodol administered should not exceed 20 mL. 2.2 Drug Handling Inspect Lipiodol visually for particulate matter and discoloration before administration. Do not use the solution if particulate matter is present or if the container appears damaged. Lipiodol is a clear, pale yellow to amber colored oil; do not use if the color has darkened. Draw Lipiodol into a glass syringe and use promptly. Discard any unused portion of Lipiodol. Page 2 of 6 Reference ID: 3484171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 DOSAGE FORMS AND STRENGTHS Each milliliter of Lipiodol contains 480 mg/mL of Iodine organically combined with ethyl esters of fatty acids of poppy seed oil. 4 CONTRAINDICATIONS Lipiodol is contraindicated in patients with hypersensitivity to Lipiodol, hyperthyroidism, traumatic injuries, recent hemorrhage or bleeding. Hysterosalpingography Lipiodol hysterosalpingography is contraindicated in pregnancy, acute pelvic inflammatory disease, marked cervical erosion, endocervicitis and intrauterine bleeding, in the immediate pre-or postmenstrual phase, or within 30 days of curettage or conization. Lymphography Lipiodol Lymphography is contraindicated in patients with a right to left cardiac shunt, advanced pulmonary disease, tissue trauma or hemorrhage advanced neoplastic disease with expected lymphatic obstruction, previous surgery interrupting the lymphatic system, radiation therapy to the examined area. Selective Hepatic Intra-arterial Use Patients with HCC Lipiodol use is contraindicated in areas of the liver where the bile ducts are dilated unless external biliary drainage was performed before injection. 5 WARNINGS AND PRECAUTIONS 5.1 Pulmonary and Cerebral Embolism Pulmonary embolism may occur immediately or after a few hours to days from inadvertent systemic vascular injection or intravasation of Lipiodol and cause decreased pulmonary diffusing capacity and pulmonary blood flow, pulmonary infarction, acute respiratory distress syndrome and fatalities. Embolization of Lipiodol to brain and other major organs may occur. Avoid use of Lipiodol in patients with severely impaired lung function, cardiorespiratory failure, or right–sided cardiac overload. Perform radiological monitoring during the Lipiodol injection. Do not exceed the recommended maximum dose and rate of injection of Lipiodol. During lymphography to minimize the risk of pulmonary embolism obtain radiographic confirmation of intralymphatic (rather than venous) injection, and terminate the procedure when Lipiodol becomes visible in the thoracic duct or lymphatic obstruction is observed. 5.2 Hypersensitivity Reactions Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred following Lipiodol administration. Avoid use in patients with a history of sensitivity to other iodinated contrast agents, bronchial asthma or allergic disorders because of an increased risk of a hypersensitivity reaction to Lipiodol. Administer Lipiodol only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation; ensure continuous medical monitoring and maintain an intravenous access line. Most hypersensitivity reactions to Lipiodol occur within half an hour after administration. Delayed reactions can occur up to several days after administration. Observe patients for signs and symptoms of hypersensitivity reactions during and for at least 30 minutes following Lipiodol administration. 5.3 Exacerbation of Chronic Liver Disease Lipiodol hepatic intra-arterial administration can exacerbate the following conditions: portal hypertension and cause variceal bleeds due to obstruction of the intrahepatic portal channels by opening a pre-sinusoidal anastomosis; hepatic ischemia and cause liver enzyme elevations, fever and abdominal pain; hepatic failure and cause ascites and encephalopathy. Hepatic vein thrombosis, irreversible liver insufficiency and fatalities have been reported. Procedural risks include vascular complications and infections. 5.4 Thyroid Dysfunction Iodinated contrast media can affect thyroid function because of the free iodine content and can cause hyperthyroidism or hypothyroidism in predisposed patients. Patients at risk are those with latent hyperthyroidism and those with Hashimoto thyroiditis, or history of thyroid irradiation. As Lipiodol may remain in the body for several months, thyroid diagnostic results can be affected for up to two years after lymphography Page 3 of 6 Reference ID: 3484171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 ADVERSE REACTIONS 6.2 Postmarketing Experience The following adverse reactions (Table 1) have been identified during post approval use of Lipiodol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions are described in more detail in other sections of the prescribing information: Pulmonary and cerebral embolism [see Warnings and Precautions (5.1)] Hypersensitivity reactions [see Warnings and Precautions (5.2)] Exacerbation of chronic liver disease [see Warnings and Precautions (5.3)] Table 1: Adverse Reactions in the Postmarketing Experience System Organ Class Adverse Reaction Endocrine disorders hypothyroidism, hyperthyroidism, thyroiditis Eye disorders retinal vein thrombosis Gastrointestinal disorders nausea, vomiting, diarrhea General disorders and administration site conditions fever, pain, granuloma Hepatobiliary disorders hepatic vein thrombosis Immune system disorders hypersensitivity, anaphylactic reaction, anaphylactoid reaction Nervous system disorders cerebral embolism Respiratory, thoracic and mediastinal disorders pulmonary embolism, dyspnea, cough, acute respiratory distress syndrome Urinary system disorders renal insufficiency Hysterosalpingography Abdominal pain, foreign body reactions, exacerbation of pelvic inflammatory disease. Lymphography Cardiovascular collapse, lymphangitis, thrombophlebitis, edema or exacerbation of preexisting lymphedema, dyspnea and cough, fever, iodism (headache, soreness of mouth and pharynx, coryza and skin rash), allergic dermatitis, lipogranuloma, delayed healing at the site of incision. Selective Hepatic Intra-arterial Injection Fever, abdominal pain, nausea, and vomiting are the most common reactions; other reactions include hepatic ischemia, liver enzymes abnormalities, transitory decrease in liver function, liver decompensation and renal insufficiency. Procedural risks include vascular complications and infections. 7 DRUG INTERACTIONS 7.1 Interference with Iodine-Based Diagnostic Tests and Iodine-Based Radiotherapy Following Lipiodol administration, ethiodized oil remains in the body for several months, and may interfere with thyroid function testing for up to two years. Ethiodized oil interferes with radioactive iodine uptake by thyroid tissue for several weeks to months and may impair visualization of thyroid scintigraphy and reduce effectiveness of iodine 131 treatment. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of Lipiodol effects in pregnant women. Use Lipiodol during pregnancy only if clearly needed. Human Data It is not known whether Lipiodol can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. The use of Lipiodol during pregnancy causes iodine transfer which may interfere with the thyroid function of the fetus and result in brain damage and permanent hypothyroidism. Institute thyroid function testing and careful medical monitoring of the neonate exposed to Page 4 of 6 Reference ID: 3484171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lipiodol in utero. Animal Data Animal reproduction studies have not been conducted using the indicated routes of administration of Lipiodol. Lipiodol was not embryotoxic or teratogenic in rats after oral administration of up to 110 mg Iodine/kg each day between gestation days 6 to 17, or in rabbits after 4-5 intermittent (once every three days) oral administrations of 12.5 mg Iodine/kg between gestation days 6 to 18. 8.2 Nursing Mothers No nonclinical lactation studies of Lipiodol have been reported. Lipiodol is excreted in human milk. Avoid use of Lipiodol in a nursing woman because of risk of hypothyroidism in nursing infants. If breastfeeding is continued the neonate’s thyroid function should be monitored. 8.3 Pediatric Use For lymphography use a dose of minimum of 1 mL to a maximum of 6 mL according to the anatomical area to be visualized. Do not exceed 0.25 mL/kg. Administer the smallest possible amount of Lipiodol according to the anatomical area to be visualized. 8.4 Geriatric Use There are no studies conducted in geriatric patients. 8.5 Renal Impairment Prior to an intra-arterial administration of Lipiodol screen all patients for renal dysfunction by obtaining history and/or laboratory tests. Consider follow-up renal function assessments for patients with a history of renal dysfunction. 10 OVERDOSAGE Overdose may lead to respiratory, cardiac or cerebral complications, which can potentially be fatal. Microembolisms to multiple organs may occur more frequently after overdose. Promptly initiate symptomatic treatment and support of vital functions. 11 DESCRIPTION Lipiodol, ethiodized oil injection, is a sterile injectable radio-opaque agent. Each milliliter contains 480 mg of Iodine organically combined with ethyl esters of fatty acids of poppy seed oil. The precise structure of Lipiodol is unknown. Lipiodol is a sterile, clear, pale yellow to amber colored oil. Lipiodol has a viscosity of 34 – 70 mPa·s at 20°C, and a density of 1.28 g/cm3 at 20°C. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ethiodized oil is an iodinated poppy seed oil based contrast agent. 12.3 Pharmacokinetics Following intra-arterial administration of Lipiodol, ethiodized oil retained in normal hepatic parenchyma is phagocytized by the Kupffer cells of the liver and washed out via the hepatic lymphatic system in about 2 to 4 weeks. In HCC, retention in the liver tumor is prolonged, allowing re-imaging of the tumor for four weeks or longer. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate carcinogenic potential, or whether Lipiodol can affect fertility in males or females. Lipiodol did not demonstrate mutagenic potential in bacterial reverse mutation assays (in vitro), in a chromosomal aberration test in the mouse lymphoma assay (in vitro), and was negative in an in vivo micronucleus test in rats after intravenous injection of 479 mg I/kg. Page 5 of 6 Reference ID: 3484171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 HOW SUPPLIED/STORAGE AND HANDLING Lipiodol is supplied in a box of one 10 mL ampoule, NDC 67684-1901-1. Store at controlled room temperature 15°-30°C (59°-86°F) [see USP, Controlled Room Temperature (CRT)]. Protect from light. Remove from carton only upon use. Rx Only company logo Guerbet LLC 120 W. 7th Street, Suite 108 Bloomington, IN 47404, USA For further information or ordering, call 1-877-729-6679 Manufactured for Guerbet LLC by: Jubilant HollisterStier General Partnership 16751 Trans-Canada Highway Kirkland, Quebec, Canada H9H 4J4 Revised 04/2014 Page 6 of 6 Reference ID: 3484171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:39.063948	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/009190s024lbl.pdf', 'application_number': 9190, 'submission_type': 'SUPPL ', 'submission_number': 24}
10,718	Rx Only Delatestryl® (Testosterone Enanthate Injection, USP) Multiple Dose Vial company logo DESCRIPTION DELATESTRYL® (Testosterone Enanthate Injection, USP) provides testosterone enanthate, a derivative of the primary endogenous androgen testosterone, for intramuscular administration. In their active form, androgens have a 17-beta-hydroxy group. Esterification of the 17-beta-hydroxy group increases the duration of action of testosterone; hydrolysis to free testosterone occurs in vivo. Each mL of sterile, colorless to pale yellow solution provides 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol (chloral derivative) as a preservative. Testosterone enanthate is designated chemically as androst-4-en-3-one, 17-[(1-oxoheptyl)-oxy]-, (17β)-. Structural formula: structural formula CLINICAL PHARMACOLOGY Endogenous androgens are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include growth and maturation of prostate, seminal vesicles, penis, and scrotum; development of male hair distribution, such as beard, pubic, chest, and axillary hair; laryngeal enlargement; vocal chord thickening; alterations in body musculature; and fat distribution. Androgens also cause retention of nitrogen, sodium, potassium, and phosphorus, and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein. Androgens are responsible for the growth spurt of adolescence and for the eventual termination of linear growth which is brought about by fusion of the epiphyseal growth centers. In children, exogenous androgens accelerate linear growth rates but may cause a disproportionate advancement in bone maturation. Use over long periods may result in fusion of the epiphyseal Reference ID: 3528032 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda growth centers and termination of the growth process. Androgens have been reported to stimulate the production of red blood cells by enhancing the production of erythropoietic stimulating factor. During exogenous administration of androgens, endogenous testosterone release is inhibited through feedback inhibition of pituitary luteinizing hormone (LH). At large doses of exogenous androgens, spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle stimulating hormone (FSH). There is a lack of substantial evidence that androgens are effective in fractures, surgery, convalescence, and functional uterine bleeding. PHARMACOKINETICS Testosterone esters are less polar than free testosterone. Testosterone esters in oil injected intramuscularly are absorbed slowly from the lipid phase; thus testosterone enanthate can be given at intervals of two to four weeks. Testosterone in plasma is 98 percent bound to a specific testosterone-estradiol binding globulin, and about two percent is free. Generally, the amount of this sex-hormone binding globulin (SHBG) in the plasma will determine the distribution of testosterone between free and bound forms, and the free testosterone concentration will determine its half-life. About 90 percent of a dose of testosterone is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about six percent of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. Testosterone is metabolized to various 17-keto steroids through two different pathways. There are considerable variations of the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes. In responsive tissues, the activity of testosterone appears to depend on reduction to dihydrotestosterone (DHT), which binds to cytosol receptor proteins. The steroid-receptor complex is transported to the nucleus where it initiates transcription events and cellular changes related to androgen action. INDICATIONS AND USAGE Males DELATESTRYL® (Testosterone Enanthate Injection, USP) is indicated for replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone. Primary hypogonadism (congenital or acquired) – Testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, or orchidectomy. Hypogonadotropic hypogonadism (congenital or acquired) – Idiopathic gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation. (Appropriate adrenal cortical and thyroid hormone replacement therapy are still necessary, however, and are actually of primary importance.) Reference ID: 3528032 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If the above conditions occur prior to puberty, androgen replacement therapy will be needed during the adolescent years for development of secondary sexual characteristics. Prolonged androgen treatment will be required to maintain sexual characteristics in these and other males who develop testosterone deficiency after puberty. Delayed puberty – DELATESTRYL® (Testosterone Enanthate Injection, USP) may be used to stimulate puberty in carefully selected males with clearly delayed puberty. These patients usually have a familial pattern of delayed puberty that is not secondary to a pathological disorder; puberty is expected to occur spontaneously at a relatively late date. Brief treatment with conservative doses may occasionally be justified in these patients if they do not respond to psychological support. The potential adverse effect on bone maturation should be discussed with the patient and parents prior to androgen administration. An X-ray of the hand and wrist to determine bone age should be obtained every six months to assess the effect of treatment on the epiphyseal centers (see WARNINGS). Females Metastatic mammary cancer – DELATESTRYL® (Testosterone Enanthate Injection, USP) may be used secondarily in women with advancing inoperable metastatic (skeletal) mammary cancer who are one to five years postmenopausal. Primary goals of therapy in these women include ablation of the ovaries. Other methods of counteracting estrogen activity are adrenalectomy, hypophysectomy, and/or antiestrogen therapy. This treatment has also been used in premenopausal women with breast cancer who have benefited from oophorectomy and are considered to have a hormone-responsive tumor. Judgment concerning androgen therapy should be made by an oncologist with expertise in this field. CONTRAINDICATIONS Androgens are contraindicated in men with carcinomas of the breast or with known or suspected carcinomas of the prostate and in women who are or may become pregnant. When administered to pregnant women, androgens cause virilization of the external genitalia of the female fetus. This virilization includes clitoromegaly, abnormal vaginal development, and fusion of genital folds to form a scrotal-like structure. The degree of masculinization is related to the amount of drug given and the age of the fetus and is most likely to occur in the female fetus when the drugs are given in the first trimester. If the patient becomes pregnant while taking androgens, she should be apprised of the potential hazard to the fetus. This preparation is also contraindicated in patients with a history of hypersensitivity to any of its components. WARNINGS In patients with breast cancer and in immobilized patients, androgen therapy may cause hypercalcemia by stimulating osteolysis. In patients with cancer, hypercalcemia may indicate progression of bony metastasis. If hypercalcemia occurs, the drug should be discontinued and appropriate measures instituted. Reference ID: 3528032 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Prolonged use of high doses of androgens has been associated with the development of peliosis hepatis and hepatic neoplasms including hepatocellular carcinoma (see PRECAUTIONS, Carcinogenesis). Peliosis hepatis can be a life-threatening or fatal complication. If cholestatic hepatitis with jaundice appears or if liver function tests become abnormal, the androgen should be discontinued and the etiology should be determined. Drug-induced jaundice is reversible when the medication is discontinued. Geriatric patients treated with androgens may be at an increased risk for the development of prostatic hypertrophy and prostatic carcinoma. There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products, such as DELATESTRYL® . Evaluate patients who report symptoms of pain, edema, warmth and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If a venous thromboembolic event is suspected, discontinue treatment with DELATESTRYL® and initiate appropriate workup and management. Due to sodium and water retention, edema with or without congestive heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required. If the administration of testosterone enanthate is restarted, a lower dose should be used. Gynecomastia frequently develops and occasionally persists in patients being treated for hypogonadism. Androgen therapy should be used cautiously in healthy males with delayed puberty. The effect on bone maturation should be monitored by assessing bone age of the wrist and hand every six months. In children, androgen treatment may accelerate bone maturation without producing compensatory gain in linear growth. This adverse effect may result in compromised adult stature. The younger the child the greater the risk of compromising final mature height. PRECAUTIONS General Women should be observed for signs of virilization (deepening of the voice, hirsutism, acne, clitoromegaly, and menstrual irregularities). Discontinuation of drug therapy at the time of evidence of mild virilism is necessary to prevent irreversible virilization. Such virilization is usual following androgen use at high doses and is not prevented by concomitant use of estrogens. A decision may be made by the patient and the physician that some virilization will be tolerated during treatment for breast carcinoma. Because androgens may alter serum cholesterol concentration, caution should be used when administering these drugs to patients with a history of myocardial infarction or coronary artery disease. Serial determinations of serum cholesterol should be made and therapy adjusted accordingly. A causal relationship between myocardial infarction and hypercholesterolemia has not been established. Reference ID: 3528032 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Information for Patients Male adolescent patients receiving androgens for delayed puberty should have bone development checked every six months. The physician should instruct patients to report any of the following side effects of androgens: Adult or adolescent males – too frequent or persistent erections of the penis. Women – hoarseness, acne, changes in menstrual periods, or more facial hair. All patients – any nausea, vomiting, changes in skin color, or ankle swelling. Geriatric Use Clinical studies of DELATESTRYL did not include sufficient numbers of subjects, aged 65 and older, to determine whether they respond differently from younger subjects. Testosterone replacement is not indicated in geriatric patients who have age-related hypogonadism only (“andropause”), because there is insufficient safety and efficacy information to support such use. Current studies do not assess whether testosterone use increases risks of prostate cancer, prostate hyperplasia, and cardiovascular disease in the geriatric population. Intramuscular Administration When properly given, injections of DELATESTRYL are well tolerated. Care should be taken to slowly inject the preparation deeply into the gluteal muscle, being sure to follow the usual precautions for intramuscular administration, such as the avoidance of intravascular injection. There have been rare postmarketing reports of transient reactions involving urge to cough, coughing fits, and respiratory distress immediately after the injection of DELATESTRYL, an oil-based depot preparation (see DOSAGE AND ADMINISTRATION). Laboratory Tests Women with disseminated breast carcinoma should have frequent determination of urine and serum calcium levels during the course of androgen therapy (see WARNINGS). Periodic (every six months) X-ray examinations of bone age should be made during treatment of pre-pubertal males to determine the rate of bone maturation and the effects of androgen therapy on the epiphyseal centers. Hemoglobin and hematocrit should be checked periodically for polycythemia in patients who are receiving high doses of androgens. Drug Interactions When administered concurrently, the following drugs may interact with androgens: Anticoagulants, oral – C-17 substituted derivatives of testosterone, such as methandrostenolone, have been reported to decrease the anticoagulant requirement. Patients receiving oral anticoagulant therapy require close monitoring especially when androgens are started or stopped. Reference ID: 3528032 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Antidiabetic drugs and insulin – In diabetic patients, the metabolic effects of androgens may decrease blood glucose and insulin requirements. ACTH and corticosteroids – Enhanced tendency toward edema. Use caution when giving these drugs together, especially in patients with hepatic or cardiac disease. Oxyphenbutazone – Elevated serum levels of oxyphenbutazone may result. Drug/Laboratory Test Interferences Androgens may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction. Carcinogenesis Testosterone has been tested by subcutaneous injection and implantation in mice and rats. The implant induced cervical-uterine tumors in mice, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats. There are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumors in all cases. Geriatric patients treated with androgens may be at an increased risk for the development of prostatic hypertrophy and prostatic carcinoma. Pregnancy: Teratogenic Effects Category X (see CONTRAINDICATIONS). Nursing Mothers It is not known whether androgens are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from androgens, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Androgen therapy should be used very cautiously in pediatric patients and only by specialists who are aware of the adverse effects on bone maturation. Skeletal maturation must be monitored every six months by an X-ray of the hand and wrist (see INDICATIONS AND USAGE, and WARNINGS). ADVERSE REACTIONS Endocrine and Urogenital, Female – The most common side effects of androgen therapy are amenorrhea and other menstrual irregularities, inhibition of gonadotropin secretion, and Reference ID: 3528032 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda virilization, including deepening of the voice and clitoral enlargement. The latter usually is not reversible after androgens are discontinued. When administered to a pregnant woman, androgens cause virilization of the external genitalia of the female fetus. Male – Gynecomastia, and excessive frequency and duration of penile erections. Oligospermia may occur at high dosages (see CLINICAL PHARMACOLOGY). Skin and Appendages – Hirsutism, male pattern baldness, and acne. Fluid and Electrolyte Disturbances – Retention of sodium, chloride, water, potassium, calcium (see WARNINGS), and inorganic phosphates. Gastrointestinal – Nausea, cholestatic jaundice, alterations in liver function tests; rarely, hepatocellular neoplasms, peliosis hepatis (see WARNINGS). Hematologic – Suppression of clotting factors II, V, VII, and X; bleeding in patients on concomitant anticoagulant therapy; polycythemia. Nervous System – Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia. Metabolic – Increased serum cholesterol. Vascular Disorders – venous thromboembolism Miscellaneous – Rarely, anaphylactoid reactions; inflammation and pain at injection site. DRUG ABUSE AND DEPENDENCE DELATESTRYL® (Testosterone Enanthate Injection, USP) is classified as a controlled substance under the Anabolic Steroids Control Act of 1990 and has been assigned to Schedule III. OVERDOSAGE There have been no reports of acute overdosage with androgens. DOSAGE AND ADMINISTRATION Dosage and duration of therapy with DELATESTRYL® (Testosterone Enanthate Injection, USP) will depend on age, sex, diagnosis, patient’s response to treatment, and appearance of adverse effects. When properly given, injections of DELATESTRYL are well tolerated. Care should be taken to slowly inject the preparation deeply into the gluteal muscle, being sure to follow the usual precautions for intramuscular administration, such as the avoidance of intravascular injection (see PRECAUTIONS). In general, total doses above 400 mg per month are not required because of the prolonged action of the preparation. Injections more frequently than every two weeks are rarely indicated. NOTE: Use of a wet needle or wet syringe may cause the solution to become cloudy; however this does Reference ID: 3528032 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda not affect the potency of the material. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. DELATESTRYL is a clear, colorless to pale yellow solution. Male hypogonadism: As replacement therapy, i.e., for eunuchism, the suggested dosage is 50 to 400 mg every 2 to 4 weeks. In males with delayed puberty: Various dosage regimens have been used; some call for lower dosages initially with gradual increases as puberty progresses, with or without a decrease to maintenance levels. Other regimens call for higher dosage to induce pubertal changes and lower dosage for maintenance after puberty. The chronological and skeletal ages must be taken into consideration, both in determining the initial dose and in adjusting the dose. Dosage is within the range of 50 to 200 mg every 2 to 4 weeks for a limited duration, for example, 4 to 6 months. X- rays should be taken at appropriate intervals to determine the amount of bone maturation and skeletal development (see INDICATIONS AND USAGE, and WARNINGS). Palliation of inoperable mammary cancer in women: A dosage of 200 to 400 mg every 2 to 4 weeks is recommended. Women with metastatic breast carcinoma must be followed closely because androgen therapy occasionally appears to accelerate the disease. HOW SUPPLIED DELATESTRYL® (Testosterone Enanthate Injection, USP) is available in 5 mL (200 mg/mL) multiple dose vials. STORAGE DELATESTRYL® (Testosterone Enanthate Injection, USP) should be stored at room temperature. Warming and rotating the vial between the palms of the hands will redissolve any crystals that may have formed during storage at low temperatures. For Prescription Use Only Manufactured for: Endo Pharmaceuticals Solutions Inc. Malvern, PA 19355 Medical Inquiries: 1-800-462-3636 Revised: 06/2014 Reference ID: 3528032 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:39.102570	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/009165s032lbl.pdf', 'application_number': 9165, 'submission_type': 'SUPPL ', 'submission_number': 32}
10,721	1 COUMADIN TABLETS Anticoagulant (Warfarin Sodium Tablets, USP) Crystalline COUMADIN FOR INJECTION (Warfarin Sodium for Injection, USP) WARNING: BLEEDING RISK Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur during the starting period and with a higher dose (resulting in a higher INR). Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age ≥65, highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs (see PRECAUTIONS), and long duration of warfarin therapy. Regular monitoring of INR should be performed on all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy. Patients should be instructed about prevention measures to minimize risk of bleeding and to report immediately to physicians signs and symptoms of bleeding (see PRECAUTIONS: Information for Patients). DESCRIPTION COUMADIN (crystalline warfarin sodium) is an anticoagulant which acts by inhibiting vitamin K-dependent coagulation factors. Chemically, it is 3-(α-acetonylbenzyl)-4- hydroxycoumarin and is a racemic mixture of the R- and S-enantiomers. Crystalline warfarin sodium is an isopropanol clathrate. The crystallization of warfarin sodium virtually eliminates trace impurities present in amorphous warfarin. Its empirical formula is C19H15NaO4, and its structural formula may be represented by the following: O ONa O C H CH2COCH3 Rx only Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Crystalline warfarin sodium occurs as a white, odorless, crystalline powder, is discolored by light and is very soluble in water; freely soluble in alcohol; very slightly soluble in chloroform and in ether. COUMADIN Tablets for oral use also contain: All strengths: Lactose, starch and magnesium stearate 1 mg: D&C Red No. 6 Barium Lake 2 mg: FD&C Blue No. 2 Aluminum Lake and FD&C Red No. 40 Aluminum Lake 2-1/2 mg: D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake 3 mg: FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake and FD&C Red No. 40 Aluminum Lake 4 mg: FD&C Blue No. 1 Aluminum Lake 5 mg: FD&C Yellow No. 6 Aluminum Lake 6 mg: FD&C Yellow No. 6 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake 7-1/2 mg: D&C Yellow No. 10 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake 10 mg: Dye Free COUMADIN for Injection is supplied as a sterile, lyophilized powder, which, after reconstitution with 2.7 mL sterile Water for Injection, contains: Warfarin Sodium 2 mg/mL Sodium Phosphate, Dibasic, Heptahydrate 4.98 mg/mL Sodium Phosphate, Monobasic, Monohydrate 0.194 mg/mL Sodium Chloride 0.1 mg/mL Mannitol 38.0 mg/mL Sodium Hydroxide, as needed for pH adjustment to 8.1 to 8.3 CLINICAL PHARMACOLOGY COUMADIN and other coumarin anticoagulants act by inhibiting the synthesis of vitamin K dependent clotting factors, which include Factors II, VII, IX and X, and the anticoagulant proteins C and S. Half-lives of these clotting factors are as follows: Factor II - 60 hours, VII - 4-6 hours, IX - 24 hours, and X - 48-72 hours. The half-lives of proteins C and S are approximately 8 hours and 30 hours, respectively. The resultant in vivo effect is a sequential depression of Factor VII, Protein C, Factor IX, Protein S, and Factor X and II activities. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K dependent clotting factors. The vitamin promotes the Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 biosynthesis of γ-carboxyglutamic acid residues in the proteins which are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the regeneration of vitamin K1 epoxide. The degree of depression is dependent upon the dosage administered. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K dependent clotting factor made by the liver by approximately 30% to 50%. An anticoagulation effect generally occurs within 24 hours after drug administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of COUMADIN may become more pronounced as effects of daily maintenance doses overlap. Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae. Pharmacokinetics COUMADIN is a racemic mixture of the R- and S-enantiomers. The S-enantiomer exhibits 2-5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance. Absorption COUMADIN is essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hours. Distribution There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses of warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 liter/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Using a one compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the racemate. Concentrations in fetal plasma approach the maternal values, but warfarin has not been found in human milk (see WARNINGS: Lactation). Approximately 99% of the drug is bound to plasma proteins. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Metabolism The elimination of warfarin is almost entirely by metabolism. COUMADIN is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols). The warfarin alcohols have minimal anticoagulant activity. The metabolites are principally excreted into the urine; and to a lesser extent into the bile. The metabolites of warfarin that have been identified include dehydrowarfarin, two diastereoisomer alcohols, 4'-, 6-, 7-, 8- and 10-hydroxywarfarin. The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin. Excretion The terminal half-life of warfarin after a single dose is approximately one week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites. Elderly Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin. The cause of the increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown. This increased anticoagulant effect from warfarin may be due to a combination of pharmacokinetic and pharmacodynamic factors. Racemic warfarin clearance may be unchanged or reduced with increasing age. Limited information suggests there is no difference in the clearance of S-warfarin in the elderly versus young subjects. However, there may be a slight decrease in the clearance of R-warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation. Asians Asian patients may require lower initiation and maintenance doses of warfarin. One non- controlled study conducted in 151 Chinese outpatients reported a mean daily warfarin Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 requirement of 3.3±1.4 mg to achieve an INR of 2 to 2.5. These patients were stabilized on warfarin for various indications. Patient age was the most important determinant of warfarin requirement in Chinese patients with a progressively lower warfarin requirement with increasing age. Renal Dysfunction Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal failure. Hepatic Dysfunction Hepatic dysfunction can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin. The administration of COUMADIN via the intravenous (IV) route should provide the patient with the same concentration of an equal oral dose, but maximum plasma concentration will be reached earlier. However, the full anticoagulant effect of a dose of warfarin may not be achieved until 72-96 hours after dosing, indicating that the administration of IV COUMADIN should not provide any increased biological effect or earlier onset of action. CLINICAL TRIALS Atrial Fibrillation (AF) In five prospective randomized controlled clinical trials involving 3711 patients with non-rheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (See Table 1). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%) which stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6 to 2.7% (See Table 1). Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2.0-4.5) or low INR (1.4-3.0). There was a significant reduction in minor bleeds at the low INR. Similar data from clinical studies in valvular atrial fibrillation patients are not available. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Table 1: Clinical Studies Of Warfarin In Non-Rheumatic AF Patients* N Thromboembolism % Major Bleeding Study Warfarin- Treated Patients Control Patients PT Ratio INR % Risk Reduction p-value Warfarin- Treated Patients Control Patients AFASAK 335 336 1.5-2.0 2.8-4.2 60 0.027 0.6 0.0 SPAF 210 211 1.3-1.8 2.0-4.5 67 0.01 1.9 1.9 BAATAF 212 208 1.2-1.5 1.5-2.7 86 <0.05 0.9 0.5 CAFA 187 191 1.3-1.6 2.0-3.0 45 0.25 2.7 0.5 SPINAF 260 265 1.2-1.5 1.4-2.8 79 0.001 2.3 1.5 All study results of warfarin vs. control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhage and transient ischemic attacks. Myocardial Infarction WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8. [But note that a lower INR was achieved and increased bleeding was associated with INR’s above 4.0; (see DOSAGE AND ADMINISTRATION)]. The primary endpoint was a combination of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in the following table: Table 2: Event Warfarin (N=607) Placebo (N=607) RR (95% CI) % Risk Reduction (p-value) Total Patient Years of Follow-up 2018 1944 Total Mortality 94 (4.7/100 py) 123 (6.3/100 py) 0.76 (0.60, 0.97) 24 (p=0.030) Vascular Death 82 (4.1/100 py) 105 (5.4/100 py) 0.78 (0.60, 1.02) 22 (p=0.068) Recurrent MI 82 (4.1/100 py) 124 (6.4/100 py) 0.66 (0.51, 0.85) 34 (p=0.001) Cerebrovascular Event 20 (1.0/100 py) 44 (2.3/100 py) 0.46 (0.28, 0.75) 54 (p=0.002) RR=Relative risk; Risk reduction=(I - RR); CI=Confidence interval; MI=Myocardial infarction; py=patient years WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label randomized study of 3630 patients hospitalized for acute myocardial infarction treated with warfarin target INR 2.8 to 4.2, aspirin 160 mg/day, or warfarin target INR 2.0 to 2.5 plus aspirin Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Bristol-Myers Squibb Company 75 mg/day prior to hospital discharge. There were approximately four times as many major bleeding episodes in the two groups receiving warfarin than in the group receiving aspirin alone. Major bleeding episodes were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group. The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke. The mean duration of observation was approximately 4 years. The results for WARIS II are provided in the following table1: Table 3: WARIS II - Distribution of Separate Events According to Treatment Group Event Aspirin (N=1206) Warfarin (N=1216) Aspirin plus Warfarin (N=1208) Rate Ratio (95% CI) p-value No. of Events Reinfarction 117 90 69 0.56 (0.41-0.78)a 0.74 (0.55-0.98)b <0.001 0.03 Thromboembolic stroke 32 17 17 0.52 (0.28-0.98)a 0.52 (0.28-0.97)b 0.03 0.03 Major Bleedingc 8 33 28 3.35a (ND) 4.00b (ND) ND ND Minor Bleedingd 39 103 133 3.21a (ND) 2.55b (ND) ND ND Death 92 96 95 0.82 * CI denotes confidence interval. a The rate ratio is for aspirin plus warfarin as compared with aspirin. b The rate ratio is for warfarin as compared with aspirin. C Major bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention. d Minor bleeding episodes were defined as non-cerebral hemorrhage not necessitating surgical intervention of blood transfusion. ND =not determined. Mechanical and Bioprosthetic Heart Valves In a prospective, randomized, open label, positive-controlled study2 in 254 patients, the thromboembolic-free interval was found to be significantly greater in patients with mechanical prosthetic heart valves treated with warfarin alone compared with dipyridamole-aspirin (p<0.005) and pentoxifylline-aspirin (p<0.05) treated patients. Rates of thromboembolic events in these groups were 2.2, 8.6, and 7.9/100 patient years, respectively. Major bleeding rates were 2.5, 0.0, and 0.9/100 patient years, respectively. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 In a prospective, open label, clinical trial comparing moderate (INR 2.65) vs. high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events/100 patient years, respectively). Major bleeding was more common in the high intensity group (2.1 events/100 patient years) vs. 0.95 events/100 patient years in the moderate intensity group.3 In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2.0-2.25 vs. INR 2.5-4.0) for a three-month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs. 1.9%, respectively and minor embolic events 10.8% vs. 10.2%, respectively). Major bleeding complications were more frequent with the higher intensity (major hemorrhages 4.6%) vs. none in the lower intensity.4 INDICATIONS AND USAGE COUMADIN is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, and pulmonary embolism. COUMADIN is indicated for the prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement. COUMADIN is indicated to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction. CONTRAINDICATIONS Anticoagulation is contraindicated in any localized or general physical condition or personal circumstance in which the hazard of hemorrhage might be greater than the potential clinical benefits of anticoagulation, such as: Pregnancy COUMADIN is contraindicated in women who are or may become pregnant because the drug passes through the placental barrier and may cause fatal hemorrhage to the fetus in utero. Furthermore, there have been reports of birth malformations in children born to mothers who have been treated with warfarin during pregnancy. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Embryopathy characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) has been reported in pregnant women exposed to warfarin during the first trimester. Central nervous system abnormalities also have been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, and midline cerebellar atrophy. Ventral midline dysplasia, characterized by optic atrophy, and eye abnormalities have been observed. Mental retardation, blindness, and other central nervous system abnormalities have been reported in association with second and third trimester exposure. Although rare, teratogenic reports following in utero exposure to warfarin include urinary tract anomalies such as single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, hydrocephalus, cardiac defects and congenital heart disease, polydactyly, deformities of toes, diaphragmatic hernia, corneal leukoma, cleft palate, cleft lip, schizencephaly, and microcephaly. Spontaneous abortion and stillbirth are known to occur and a higher risk of fetal mortality is associated with the use of warfarin. Low birth weight and growth retardation have also been reported. Women of childbearing potential who are candidates for anticoagulant therapy should be carefully evaluated and the indications critically reviewed with the patient. If the patient becomes pregnant while taking this drug, she should be apprised of the potential risks to the fetus, and the possibility of termination of the pregnancy should be discussed in light of those risks. Hemorrhagic tendencies or blood dyscrasias. Recent or contemplated surgery of: (1) central nervous system; (2) eye; (3) traumatic surgery resulting in large open surfaces. Bleeding tendencies associated with active ulceration or overt bleeding of: (1) gastrointestinal, genitourinary or respiratory tracts; (2) cerebrovascular hemorrhage; (3) aneurysms-cerebral, dissecting aorta; (4) pericarditis and pericardial effusions; (5) bacterial endocarditis. Threatened abortion, eclampsia and preeclampsia. Inadequate laboratory facilities. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 Unsupervised patients with senility, alcoholism, or psychosis or other lack of patient cooperation. Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding. Miscellaneous: major regional, lumbar block anesthesia, malignant hypertension and known hypersensitivity to warfarin or to any other components of this product. WARNINGS The most serious risks associated with anticoagulant therapy with warfarin sodium are hemorrhage in any tissue or organ5 (see BLACK BOX WARNING) and, less frequently (<0.1%), necrosis and/or gangrene of skin and other tissues. Hemorrhage and necrosis have in some cases been reported to result in death or permanent disability. Necrosis appears to be associated with local thrombosis and usually appears within a few days of the start of anticoagulant therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast or penis has been reported. Careful diagnosis is required to determine whether necrosis is caused by an underlying disease. Warfarin therapy should be discontinued when warfarin is suspected to be the cause of developing necrosis and heparin therapy may be considered for anticoagulation. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. See below for information on predisposing conditions. These and other risks associated with anticoagulant therapy must be weighed against the risk of thrombosis or embolization in untreated cases. It cannot be emphasized too strongly that treatment of each patient is a highly individualized matter. COUMADIN (Warfarin Sodium), a narrow therapeutic range (index) drug, may be affected by factors such as other drugs and dietary vitamin K. Dosage should be controlled by periodic determinations of prothrombin time (PT)/International Normalized Ratio (INR) or other suitable coagulation tests. Determinations of whole blood clotting and bleeding times are not effective measures for control of therapy. Heparin prolongs the one-stage PT. When heparin and COUMADIN are administered concomitantly, refer below to CONVERSION FROM HEPARIN THERAPY for recommendations. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Caution should be observed when COUMADIN is administered in any situation or in the presence of any predisposing condition where added risk of hemorrhage, necrosis, and/or gangrene is present. Anticoagulation therapy with COUMADIN may enhance the release of atheromatous plaque emboli, thereby increasing the risk of complications from systemic cholesterol microembolization, including the “purple toes syndrome.” Discontinuation of COUMADIN therapy is recommended when such phenomena are observed. Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms including purple toes syndrome, livedo reticularis, rash, gangrene, abrupt and intense pain in the leg, foot, or toes, foot ulcers, myalgia, penile gangrene, abdominal pain, flank or back pain, hematuria, renal insufficiency, hypertension, cerebral ischemia, spinal cord infarction, pancreatitis, symptoms simulating polyarteritis, or any other sequelae of vascular compromise due to embolic occlusion. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. Purple toes syndrome is a complication of oral anticoagulation characterized by a dark, purplish or mottled color of the toes, usually occurring between 3-10 weeks, or later, after the initiation of therapy with warfarin or related compounds. Major features of this syndrome include purple color of plantar surfaces and sides of the toes that blanches on moderate pressure and fades with elevation of the legs; pain and tenderness of the toes; waxing and waning of the color over time. While the purple toes syndrome is reported to be reversible, some cases progress to gangrene or necrosis which may require debridement of the affected area, or may lead to amputation. Heparin-induced thrombocytopenia: COUMADIN should be used with caution in patients with heparin-induced thrombocytopenia and deep venous thrombosis. Cases of venous limb ischemia, necrosis, and gangrene have occurred in patients with heparin- induced thrombocytopenia and deep venous thrombosis when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients sequelae have included amputation of the involved area and/or death.6 A severe elevation (>50 seconds) in activated partial thromboplastin time (aPTT) with a PT/INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 The decision to administer anticoagulants in the following conditions must be based upon clinical judgment in which the risks of anticoagulant therapy are weighed against the benefits: Lactation: Based on very limited published data, warfarin has not been detected in the breast milk of mothers treated with warfarin. The same limited published data reports that some breast-fed infants, whose mothers were treated with warfarin, had prolonged prothrombin times, although not as prolonged as those of the mothers. The decision to breast-feed should be undertaken only after careful consideration of the available alternatives. Women who are breast-feeding and anticoagulated with warfarin should be very carefully monitored so that recommended PT/INR values are not exceeded. It is prudent to perform coagulation tests and to evaluate vitamin K status in infants at risk for bleeding tendencies before advising women taking warfarin to breast-feed. Effects in premature infants have not been evaluated. Severe to moderate hepatic or renal insufficiency. Infectious diseases or disturbances of intestinal flora: sprue, antibiotic therapy. Trauma which may result in internal bleeding. Surgery or trauma resulting in large exposed raw surfaces. Indwelling catheters. Severe to moderate hypertension. Known or suspected deficiency in protein C mediated anticoagulant response: Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. Not all patients with these conditions develop necrosis, and tissue necrosis occurs in patients without these deficiencies. Inherited resistance to activated protein C has been described in many patients with venous thromboembolic disorders but has not yet been evaluated as a risk factor for tissue necrosis. The risk associated with these conditions, both for recurrent thrombosis and for adverse reactions, is difficult to evaluate since it does not appear to be the same for everyone. Decisions about testing and therapy must be made on an individual basis. It has been reported that concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with COUMADIN may minimize the incidence of tissue necrosis. Warfarin therapy should be discontinued when warfarin is Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 suspected to be the cause of developing necrosis and heparin therapy may be considered for anticoagulation. Miscellaneous: polycythemia vera, vasculitis, and severe diabetes. Minor and severe allergic/hypersensitivity reactions and anaphylactic reactions have been reported. In patients with acquired or inherited warfarin resistance, decreased therapeutic responses to COUMADIN have been reported. Exaggerated therapeutic responses have been reported in other patients. Patients with congestive heart failure may exhibit greater than expected PT/INR response to COUMADIN, thereby requiring more frequent laboratory monitoring, and reduced doses of COUMADIN. Concomitant use of anticoagulants with streptokinase or urokinase is not recommended and may be hazardous. (Please note recommendations accompanying these preparations.) PRECAUTIONS Periodic determination of PT/INR or other suitable coagulation test is essential. (See DOSAGE AND ADMINISTRATION: LABORATORY CONTROL.) Drug-Drug and Drug-Disease Interactions Numerous factors, alone or in combination, including changes in diet and medications, including botanicals, may influence response of the patient to anticoagulants. It is generally good practice to monitor the patient’s response with additional PT/INR determinations in the period immediately after discharge from the hospital, and whenever other medications, including botanicals, are initiated, discontinued or taken irregularly. The following factors are listed for reference; however, other factors may also affect the anticoagulant response. Drugs may interact with COUMADIN through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with COUMADIN are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and altered physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with COUMADIN are mainly enzyme induction, enzyme Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism. The following factors, alone or in combination, may be responsible for INCREASED PT/INR response: ENDOGENOUS FACTORS: blood dyscrasias - see CONTRAINDICATIONS cancer collagen vascular disease congestive heart failure diarrhea elevated temperature hepatic disorders infectious hepatitis jaundice hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency EXOGENOUS FACTORS: Potential drug interactions with COUMADIN are listed below by drug class and by specific drugs. Classes of Drugs 5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors† Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins† Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 Specific Drugs Reported acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate COUMADIN overdose cyclophosphamide† danazol dextran dextrothyroxine diazoxide diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemfibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/sulfamethoxazole urokinase valdecoxib valproate vitamin E zafirlukast zileuton also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 The following factors, alone or in combination, may be responsible for DECREASED PT/INR response: ENDOGENOUS FACTORS: edema hereditary coumarin resistance hyperlipemia hypothyroidism nephrotic syndrome EXOGENOUS FACTORS: Potential drug interactions with COUMADIN (Warfarin Sodium) are listed below by drug class and by specific drugs. Classes of Drugs Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics† Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins† Specific Drugs Reported alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone cholestyramine† clozapine corticotropin cortisone COUMADIN underdosage cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate 6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 Because a patient may be exposed to a combination of the above factors, the net effect of COUMADIN on PT/INR response may be unpredictable. More frequent PT/INR monitoring is therefore advisable. Medications of unknown interaction with coumarins are best regarded with caution. When these medications are started or stopped, more frequent PT/INR monitoring is advisable. It has been reported that concomitant administration of warfarin and ticlopidine may be associated with cholestatic hepatitis. Botanical (Herbal) Medicines Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN. Few adequate, well-controlled studies exist evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and COUMADIN. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation. It is good practice to monitor the patient’s response with additional PT/INR determinations when initiating or discontinuing botanicals. Specific botanicals reported to affect COUMADIN therapy include the following: • Bromelains, danshen, dong quai (Angelica sinensis), garlic, Ginkgo biloba, ginseng, and cranberry products are associated most often with an INCREASE in the effects of COUMADIN. • Coenzyme Q10 (ubidecarenone) and St. John’s wort are associated most often with a DECREASE in the effects of COUMADIN. Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of COUMADIN. Conversely, other botanicals may have coagulant properties when taken alone or may decrease the effects of COUMADIN. Some botanicals that may affect coagulation are listed below for reference; however, this list should not be considered all-inclusive. Many botanicals have several common names and scientific names. The most widely recognized common botanical names are listed. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 Botanicals that contain coumarins with potential anticoagulant effects: Alfalfa Angelica (Dong Quai) Aniseed Arnica Asa Foetida Bogbean1 Boldo Buchu Capsicum2 Cassia3 Celery Chamomile (German and Roman) Dandelion3 Fenugreek Horse Chestnut Horseradish Licorice3 Meadowsweet1 Nettle Parsley Passion Flower Prickly Ash (Northern) Quassia Red Clover Sweet Clover Sweet Woodruff Tonka Beans Wild Carrot Wild Lettuce Miscellaneous botanicals with anticoagulant properties: Bladder Wrack (Fucus) Pau d’arco Botanicals that contain salicylate and/or have antiplatelet properties: Agrimony4 Aloe Gel Aspen Black Cohosh Black Haw Bogbean1 Cassia3 Clove Dandelion3 Feverfew Garlic5 German Sarsaparilla Ginger Ginkgo Biloba Ginseng (Panax)5 Licorice3 Meadowsweet1 Onion5 Policosanol Poplar Senega Tamarind Willow Wintergreen Botanicals with fibrinolytic properties: Bromelains Capsicum2 Garlic5 Ginseng (Panax)5 Inositol Nicotinate Onion 5 Botanicals with coagulant properties: Agrimony4 Goldenseal Mistletoe Yarrow 1Contains coumarins and salicylate. 2Contains coumarins and has fibrinolytic properties. 3Contains coumarins and has antiplatelet properties. 4Contains salicylate and has coagulant properties. 5Has antiplatelet and fibrinolytic properties. Effect on Other Drugs Coumarins may also affect the action of other drugs. Hypoglycemic agents (chlorpropamide and tolbutamide) and anticonvulsants (phenytoin and phenobarbital) may accumulate in the body as a result of interference with either their metabolism or excretion. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 Special Risk Patients COUMADIN is a narrow therapeutic range (index) drug, and caution should be observed when warfarin sodium is administered to certain patients such as the elderly or debilitated or when administered in any situation or physical condition where added risk of hemorrhage is present. Intramuscular (I.M.) injections of concomitant medications should be confined to the upper extremities which permits easy access for manual compression, inspections for bleeding and use of pressure bandages. Caution should be observed when COUMADIN (or warfarin) is administered concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to be certain that no change in anticoagulation dosage is required. In addition to specific drug interactions that might affect PT/INR, NSAIDs, including aspirin, can inhibit platelet aggregation, and can cause gastrointestinal bleeding, peptic ulceration and/or perforation. Acquired or inherited warfarin resistance should be suspected if large daily doses of COUMADIN are required to maintain a patient’s PT/INR within a normal therapeutic range. Information for Patients The objective of anticoagulant therapy is to decrease the clotting ability of the blood so that thrombosis is prevented, while avoiding spontaneous bleeding. Effective therapeutic levels with minimal complications are in part dependent upon cooperative and well- instructed patients who communicate effectively with their physician. Patients should be advised: Strict adherence to prescribed dosage schedule is necessary. Do not take or discontinue any other medication, including salicylates (e.g., aspirin and topical analgesics), other over-the-counter medications, and botanical (herbal) products (e.g., bromelains, coenzyme Q10, danshen, dong quai, garlic, Ginkgo biloba, ginseng, and St. John’s wort) except on advice of the physician. Avoid alcohol consumption. Do not take COUMADIN during pregnancy and do not become pregnant while taking it (see CONTRAINDICATIONS). Avoid any activity or sport that may result in traumatic injury. Prothrombin time tests and regular visits to physician or clinic are needed to monitor therapy. Carry identification stating that COUMADIN is being taken. If the prescribed dose of COUMADIN is forgotten, notify the physician immediately. Take the dose as soon as possible on the same day but do not take a double dose of COUMADIN Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 the next day to make up for missed doses. The amount of vitamin K in food may affect therapy with COUMADIN. Eat a normal, balanced diet maintaining a consistent amount of vitamin K. Avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables. You should also avoid intake of cranberry juice or any other cranberry products. Notify your healthcare provider if any of these products are part of your normal diet. Contact physician to report any illness, such as diarrhea, infection or fever. Notify physician immediately if any unusual bleeding or symptoms occur. Signs and symptoms of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness. If therapy with COUMADIN is discontinued, patients should be cautioned that the anticoagulant effects of COUMADIN may persist for about 2 to 5 days. Patients should be informed that all warfarin sodium, USP, products represent the same medication, and should not be taken concomitantly, as overdosage may result. A Medication Guide7 should be available to patients when their prescriptions for warfarin sodium are issued. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity and mutagenicity studies have not been performed with COUMADIN. The reproductive effects of COUMADIN have not been evaluated. Use in Pregnancy Pregnancy Category X - See CONTRAINDICATIONS. Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 have not been established, in randomized, controlled clinical trials. However, the use of COUMADIN in pediatric patients is well-documented for the prevention and treatment of thromboembolic events. Difficulty achieving and maintaining therapeutic PT/INR ranges in the pediatric patient has been reported. More frequent PT/INR determinations are recommended because of possible changing warfarin requirements. Geriatric Use Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin (see CLINICAL PHARMACOLOGY). COUMADIN is contraindicated in any unsupervised patient with senility. Caution should be observed with administration of warfarin sodium to elderly patients in any situation or physical Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 condition where added risk of hemorrhage is present. Lower initiation and maintenance doses of COUMADIN are recommended for elderly patients (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Potential adverse reactions to COUMADIN may include: • Fatal or nonfatal hemorrhage from any tissue or organ. This is a consequence of the anticoagulant effect. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Hemorrhagic complications may present as paralysis; paresthesia; headache, chest, abdomen, joint, muscle or other pain; dizziness; shortness of breath, difficult breathing or swallowing; unexplained swelling; weakness; hypotension; or unexplained shock. Therefore, the possibility of hemorrhage should be considered in evaluating the condition of any anticoagulated patient with complaints which do not indicate an obvious diagnosis. Bleeding during anticoagulant therapy does not always correlate with PT/INR. (See OVERDOSAGE: Treatment.) • Bleeding which occurs when the PT/INR is within the therapeutic range warrants diagnostic investigation since it may unmask a previously unsuspected lesion, e.g., tumor, ulcer, etc. • Necrosis of skin and other tissues. (See WARNINGS.) • Adverse reactions reported infrequently include: hypersensitivity/allergic reactions, systemic cholesterol microembolization, purple toes syndrome, hepatitis, cholestatic hepatic injury, jaundice, elevated liver enzymes, hypotension, vasculitis, edema, anemia, pallor, fever, rash, dermatitis, including bullous eruptions, urticaria, angina syndrome, chest pain, abdominal pain including cramping, flatulence/bloating, fatigue, lethargy, malaise, asthenia, nausea, vomiting, diarrhea, pain, headache, dizziness, loss of consciousness, syncope, coma, taste perversion, pruritus, alopecia, cold intolerance, and paresthesia including feeling cold and chills. Rare events of tracheal or tracheobronchial calcification have been reported in association with long-term warfarin therapy. The clinical significance of this event is unknown. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 Priapism has been associated with anticoagulant administration, however, a causal relationship has not been established. OVERDOSAGE Signs and Symptoms Suspected or overt abnormal bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries) are early manifestations of anticoagulation beyond a safe and satisfactory level. Treatment Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing COUMADIN therapy and if necessary, by administration of oral or parenteral vitamin K1. (Please see recommendations accompanying vitamin K1 preparations prior to use.)8,9 Such use of vitamin K1 reduces response to subsequent COUMADIN therapy. Patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged PT/INR. Resumption of COUMADIN administration reverses the effect of vitamin K, and a therapeutic PT/INR can again be obtained by careful dosage adjustment. If rapid anticoagulation is indicated, heparin may be preferable for initial therapy. If minor bleeding progresses to major bleeding, give 5 to 25 mg (rarely up to 50 mg) parenteral vitamin K1. In emergency situations of severe hemorrhage, clotting factors can be returned to normal by administering 200 to 500 mL of fresh whole blood or fresh frozen plasma, or by giving commercial Factor IX complex. A risk of hepatitis and other viral diseases is associated with the use of these blood products; Factor IX complex is also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to COUMADIN (Warfarin Sodium) overdosage. Purified Factor IX preparations should not be used because they cannot increase the levels of prothrombin, Factor VII and Factor X which are also depressed along with the levels of Factor IX as a result of COUMADIN treatment. Packed red blood cells may also be given if significant blood loss has occurred. Infusions of blood or plasma should be monitored carefully to avoid precipitating pulmonary edema in elderly patients or patients with heart disease. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 DOSAGE AND ADMINISTRATION The dosage and administration of COUMADIN must be individualized for each patient according to the particular patient’s PT/INR response to the drug. The dosage should be adjusted based upon the patient’s PT/INR.8,9,10,11,12 The best available information supports the following recommendations for dosing of COUMADIN. Venous Thromboembolism (including deep venous thrombosis [DVT] and pulmonary embolism [PE]) For patients with a first episode of DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with a first episode of idiopathic DVT or PE, warfarin is recommended for at least 6 to 12 months. For patients with two or more episodes of documented DVT or PE, indefinite treatment with warfarin is suggested. For patients with a first episode of DVT or PE who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions, treatment for 12 months is recommended and indefinite therapy is suggested. For patients with a first episode of DVT or PE who have documented deficiency of antithrombin, deficiency of Protein C or Protein S, or the Factor V Leiden or prothrombin 20210 gene mutation, homocystinemia, or high Factor VIII levels (>90th percentile of normal), treatment for 6 to 12 months is recommended and indefinite therapy is suggested for idiopathic thrombosis. The risk-benefit should be reassessed periodically in patients who receive indefinite anticoagulant treatment.5,13 The dose of warfarin should be adjusted to maintain a target INR of 2.5 (INR range, 2.0 to 3.0) for all treatment durations. These recommendations are supported by the 7th ACCP guidelines.8,10,14,15 Atrial Fibrillation Five recent clinical trials evaluated the effects of warfarin in patients with non-valvular atrial fibrillation (AF). Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2.0-4.5) or low INR (1.4-3.0). There was a significant reduction in minor bleeds at the low INR. There are no adequate and well-controlled studies in populations with atrial fibrillation and valvular heart disease. Similar data from clinical studies in valvular atrial fibrillation patients are not available. The trials in non-valvular atrial fibrillation support the American College of Chest Physicians’ (7th ACCP) recommendation that an INR of 2.0-3.0 be used for warfarin therapy in appropriate AF patients.10 Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 Oral anticoagulation therapy with warfarin is recommended in patients with persistent or paroxysmal AF (PAF) (intermittent AF) at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, age >75 years, moderately or severely impaired left ventricular systolic function and/or congestive heart failure, history of hypertension, or diabetes mellitus). In patients with persistent AF or PAF, age 65 to 75 years, in the absence of other risk factors, but who are at intermediate risk of stroke, antithrombotic therapy with either oral warfarin or aspirin, 325 mg/day, is recommended. For patients with AF and mitral stenosis, anticoagulation with oral warfarin is recommended (7th ACCP). For patients with AF and prosthetic heart valves, anticoagulation with oral warfarin should be used; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.10 Post-Myocardial Infarction The results of the WARIS II study and 7th ACCP guidelines suggest that in most healthcare settings, moderate- and low-risk patients with a myocardial infarction should be treated with aspirin alone over oral vitamin-K antagonist (VKA) therapy plus aspirin. In healthcare settings in which meticulous INR monitoring is standard and routinely accessible, for both high- and low-risk patients after myocardial infarction (MI), long- term (up to 4 years) high-intensity oral warfarin (target INR, 3.5; range, 3.0 to 4.0) without concomitant aspirin or moderate-intensity oral warfarin (target INR, 2.5; range, 2.0 to 3.0) with aspirin is recommended. For high-risk patients with MI, including those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on echocardiography, and those with a history of a thromboembolic event, therapy with combined moderate-intensity (INR, 2.0 to 3.0) oral warfarin plus low- dose aspirin (≤100 mg/day) for 3 months after the MI is suggested.16 Mechanical and Bioprosthetic Heart Valves For all patients with mechanical prosthetic heart valves, warfarin is recommended. For patients with a St. Jude Medical (St. Paul, MN) bileaflet valve in the aortic position, a target INR of 2.5 (range, 2.0 to 3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, the 7th ACCP recommends a target INR of 3.0 (range, 2.5 to 3.5). For patients with caged ball or caged disk valves, a target INR of 3.0 (range, 2.5 to 3.5) in combination with aspirin, 75 to 100 mg/day is recommended. For patients with bioprosthetic valves, warfarin therapy with a target INR Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 of 2.5 (range, 2.0 to 3.0) is recommended for valves in the mitral position and is suggested for valves in the aortic position for the first 3 months after valve insertion.8 Recurrent Systemic Embolism and Other Indications Oral anticoagulation therapy has not been evaluated by properly designed clinical trials in patients with valvular disease associated with atrial fibrillation, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. A moderate dose regimen (INR 2.0 to 3.0) is recommended for these patients.10 An INR of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding. Initial Dosage The dosing of COUMADIN must be individualized according to patient’s sensitivity to the drug as indicated by the PT/INR. Use of a large loading dose may increase the incidence of hemorrhagic and other complications, does not offer more rapid protection against thrombi formation, and is not recommended. Lower initiation and maintenance doses are recommended for elderly and/or debilitated patients and patients with potential to exhibit greater than expected PT/INR response to COUMADIN (see PRECAUTIONS). Based on limited data, Asian patients may also require lower initiation and maintenance doses of COUMADIN (see CLINICAL PHARMA- COLOGY). It is recommended that COUMADIN therapy be initiated with a dose of 2 to 5 mg per day with dosage adjustments based on the results of PT/INR determinations.10,11 Maintenance Most patients are satisfactorily maintained at a dose of 2 to 10 mg daily. Flexibility of dosage is provided by breaking scored tablets in half. The individual dose and interval should be gauged by the patient’s prothrombin response. Duration of Therapy The duration of therapy in each patient should be individualized. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed.7,8,10,11,14,15 Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 Missed Dose The anticoagulant effect of COUMADIN persists beyond 24 hours. If the patient forgets to take the prescribed dose of COUMADIN at the scheduled time, the dose should be taken as soon as possible on the same day. The patient should not take the missed dose by doubling the daily dose to make up for missed doses, but should refer back to his or her physician. Intravenous Route of Administration COUMADIN for Injection provides an alternate administration route for patients who cannot receive oral drugs. The IV dosages would be the same as those that would be used orally if the patient could take the drug by the oral route. COUMADIN for Injection should be administered as a slow bolus injection over 1 to 2 minutes into a peripheral vein. It is not recommended for intramuscular administration. The vial should be reconstituted with 2.7 mL of sterile Water for Injection and inspected for particulate matter and discoloration immediately prior to use. Do not use if either particulate matter and/or discoloration is noted. After reconstitution, COUMADIN for Injection is chemically and physically stable for 4 hours at room temperature. It does not contain any antimicrobial preservative and, thus, care must be taken to assure the sterility of the prepared solution. The vial is not recommended for multiple use and unused solution should be discarded. LABORATORY CONTROL The PT reflects the depression of vitamin K dependent Factors VII, X and II. A system of standardizing the PT in oral anticoagulant control was introduced by the World Health Organization in 1983. It is based upon the determination of an International Normalized Ratio (INR) which provides a common basis for communication of PT results and interpretations of therapeutic ranges.17 The PT should be determined daily after the administration of the initial dose until PT/INR results stabilize in the therapeutic range. Intervals between subsequent PT/INR determinations should be based upon the physician’s judgment of the patient’s reliability and response to COUMADIN in order to maintain the individual within the therapeutic range. Acceptable intervals for PT/INR determinations are normally within the range of one to four weeks after a stable dosage has been determined. To ensure adequate control, it is recommended that additional PT tests be done when other warfarin products are interchanged with warfarin sodium tablets, USP, as well as whenever other medications are initiated, discontinued, or taken irregularly (see PRECAUTIONS). Safety and efficacy of warfarin therapy can be improved by increasing the quality of laboratory control. Reports suggest that in usual care monitoring, Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 patients are in therapeutic range only 33%-64% of the time. Time in therapeutic range is significantly greater (56%-93%) in patients managed by anticoagulation clinics, among self-testing and self-monitoring patients, and in patients managed with the help of computer programs.18 Self-testing patients had fewer bleeding events than patients in usual care.18 TREATMENT DURING DENTISTRY AND SURGERY The management of patients who undergo dental and surgical procedures requires close liaison between attending physicians, surgeons and dentists.8,12 PT/INR determination is recommended just prior to any dental or surgical procedure. In patients undergoing minimal invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of COUMADIN to maintain the PT/INR at the low end of the therapeutic range may safely allow for continued anticoagulation. The operative site should be sufficiently limited and accessible to permit the effective use of local procedures for hemostasis. Under these conditions, dental and minor surgical procedures may be performed without undue risk of hemorrhage. Some dental or surgical procedures may necessitate the interruption of COUMADIN therapy. When discontinuing COUMADIN even for a short period of time, the benefits and risks should be strongly considered. CONVERSION FROM HEPARIN THERAPY Since the anticoagulant effect of COUMADIN is delayed, heparin is preferred initially for rapid anticoagulation. Conversion to COUMADIN may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure continuous anticoagulation, it is advisable to continue full dose heparin therapy and that COUMADIN therapy be overlapped with heparin for 4 to 5 days, until COUMADIN has produced the desired therapeutic response as determined by PT/INR. When COUMADIN has produced the desired PT/INR or prothrombin activity, heparin may be discontinued. COUMADIN may increase the aPTT test, even in the absence of heparin. During initial therapy with COUMADIN, the interference with heparin anticoagulation is of minimal clinical significance. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28 As heparin may affect the PT/INR, patients receiving both heparin and COUMADIN should have blood for PT/INR determination drawn at least: • 5 hours after the last IV bolus dose of heparin, or • 4 hours after cessation of a continuous IV infusion of heparin, or • 24 hours after the last subcutaneous heparin injection. HOW SUPPLIED Tablets For oral use, single scored with one face imprinted numerically with 1, 2, 2-1/2, 3, 4, 5, 6, 7-1/2 or 10 superimposed and inscribed with “COUMADIN” and with the opposite face plain. COUMADIN is available in bottles and Hospital Unit-Dose Blister Packages with potencies and colors as follows: 100’s 1000’s Hospital Unit-Dose Blister Package of 100 1 mg pink NDC 0056-0169-70 NDC 0056-0169-90 NDC 0056-0169-75 2 mg lavender NDC 0056-0170-70 NDC 0056-0170-90 NDC 0056-0170-75 2-1/2 mg green NDC 0056-0176-70 NDC 0056-0176-90 NDC 0056-0176-75 3 mg tan NDC 0056-0188-70 NDC 0056-0188-90 NDC 0056-0188-75 4 mg blue NDC 0056-0168-70 NDC 0056-0168-90 5 mg peach NDC 0056-0172-70 NDC 0056-0172-90 NDC 0056-0172-75 6 mg teal NDC 0056-0189-70 NDC 0056-0189-90 NDC 0056-0189-75 7-1/2 mg yellow NDC 0056-0173-70 10 mg white (Dye Free) NDC 0056-0174-70 Protect from light. Store at controlled room temperature (59°-86°F, 15°-30°C). Dispense in a tight, light-resistant container as defined in the USP. Hospital Unit-Dose Blister Packages are to be stored in carton until contents have been used. Injection Available for intravenous use only. Not recommended for intramuscular administration. Reconstitute with 2.7 mL of sterile Water for Injection to yield 2 mg/mL. Net contents 5.4 mg lyophilized powder. Maximum yield 2.5 mL. 5 mg vial (box of 6) NDC 0590-0324-35 Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 29 Protect from light. Keep vial in box until used. Store at controlled room temperature (59°-86°F, 15°-30°C). After reconstitution, store at controlled room temperature (59°-86°F, 15°-30°C) and use within 4 hours. Do not refrigerate. Discard any unused solution. REFERENCES 1. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347:969-974. 2. Mok CK, Boey J, Wang R, et al. Warfarin versus dipyridamole-aspirin and pentoxifylline-aspirin for prevention of prosthetic valve thromboembolism: a prospective randomized clinical trial. Circ. 1985;72:1059-1063. 3. Saour JN, Sieck JO, Mamo LA, Gallus AS. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med. 1990;322:428-432. 4. Turpie AG, Hirsh J, Gunstensen J, Nelson H, Gent M. Randomized comparison to two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet. 1988;331:1242-1245. 5. Büller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:401S-428S. 6. Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MG, Russett JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med. 1997;127:804-812. 7. COUMADIN Medication Guide. Princeton, NJ: Bristol-Myers Squibb Company; 2006. 8. Salem DN, Stein PD, Al-Ahmad A, et al. Antithrombotic therapy in valvular heart disease–native and prosthetic. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:457S-482S. 9. American Geriatrics Society Clinical Practice Guidelines. The use of oral anticoagulants (warfarin) in older people. J Amer Geriatr Soc. 2000;48:224-227. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 30 10. Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic therapy in atrial fibrillation. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:429S-456S. 11. Jaffer AK, Bragg L. Practical tips for warfarin dosing and monitoring. Cleveland Clinic J Med. 2003;70:361-371. 12. Jaffer AK, Brotman DJ, Chukwumerije N. When patients on warfarin need surgery. Cleveland Clinic J Med. 2003;70:973-984. 13. Kearon C, Ginsberg JS, Kovacs MJ, et al, for the Extended Low-Intensity Anticoagulation for Thrombo-Embolism Investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003;349:631-639. 14. Schulman S, Granqvist S, Holmström M, et al, and the Duration of Anticoagulation Trial Study Group. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med. 1997;336:393-398. 15. Ridker PM, Goldhaber SZ, Danielson E, et al, for the PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003;348:1425-1434. 16. Harrington RA, Becker RC, Ezekowitz M, et al. Antithrombotic therapy for coronary artery disease. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:513S-548S. 17. Ansell J, Hirsh J, Pollen L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:204S-233S. 18. Heneghan C, Alonso-Coello P, Garcia-Alamino JM, Perera R, Meats E, Glasziou P. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet. 2006;367:404-411. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 31 Distributed by: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA COUMADIN and the color and configuration of COUMADIN tablets are trademarks of Bristol-Myers Squibb Pharma Company. Copyright  Bristol-Myers Squibb Company 2006 Printed in USA 1205733 1205735 Revised April 2006 MEDICATION GUIDE COUMADIN (COU-ma-din) Tablets (Warfarin Sodium Tablets, USP) Crystalline Read this Medication Guide before you start taking COUMADIN (Warfarin Sodium) and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about COUMADIN when you start taking it and at regular checkups. What is the most important information I should know about COUMADIN? • Take your COUMADIN exactly as prescribed to lower the chance of blood clots forming in your body. (See “What is COUMADIN?”). • COUMADIN is very important for your health, but it can cause serious and life- threatening bleeding problems. To benefit from COUMADIN and also lower your chance for bleeding problems, you must: • Get your regular blood test to check for your response to COUMADIN. This blood test is called a PT/INR test. The PT/INR test checks to see how fast your blood clots. Your healthcare provider will decide what PT/INR numbers are best for you. Your dose of COUMADIN will be adjusted to keep your PT/INR in a target range for you. • Call your healthcare provider right away if you get any of the following signs or symptoms of bleeding problems: • pain, swelling or discomfort • headaches, dizziness, or weakness • unusual bruising (bruises that develop without known cause or grow in size) Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 32 • nose bleeds • bleeding gums • bleeding from cuts takes a long time to stop • menstrual bleeding or vaginal bleeding that is heavier than normal • pink or brown urine • red or black stools • coughing up blood • vomiting blood or material that looks like coffee grounds • Many other medicines, including prescription and non-prescription medicines, vitamins and herbal supplements can interact with COUMADIN and: • affect the dose you need, or • increase COUMADIN side effects. Tell your healthcare provider about all the medicines you take. Do not stop medicines or take anything new unless you have talked to your healthcare provider. Keep a list of your medicines with you at all times to show your healthcare provider and pharmacist. • Do not take other medicines that contain warfarin. Warfarin is the active ingredient in COUMADIN. • Some foods can interact with COUMADIN and affect your treatment and dose. • Eat a normal, balanced diet. Talk to your doctor before you make any diet changes. Do not eat large amounts of leafy green vegetables. Leafy green vegetables contain Vitamin K. Certain vegetable oils also contain large amounts of Vitamin K. Too much Vitamin K can lower the effect of COUMADIN. • Avoid drinking cranberry juice or eating cranberry products. • Avoid drinking alcohol. • Always tell all of your healthcare providers that you take COUMADIN. • Wear or carry information that you take COUMADIN. What is COUMADIN? COUMADIN is an anticoagulant medicine. It is used to lower the chance of blood clots forming in your body. Blood clots can cause a stroke, heart attack, or other serious conditions such as blood clots in the legs or lungs. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 33 Who should not take COUMADIN? Do not take COUMADIN if: • your chance of having bleeding problems is higher than the possible benefit of treatment. Your healthcare provider will decide if COUMADIN is right for you. Talk to your healthcare provider about all of your health conditions. • you are pregnant or plan to become pregnant. COUMADIN can cause death or birth defects to an unborn baby. Use effective birth control if you can get pregnant. • you are allergic to warfarin or to anything else in COUMADIN. What should I tell my healthcare provider before starting COUMADIN? Tell your healthcare provider about all of your health conditions, including if you: • have bleeding problems • fall often • have liver or kidney problems • have high blood pressure • have a heart problem called congestive heart failure • have diabetes • drink alcohol or have problems with alcohol abuse. Alcohol can affect your COUMADIN dose and should be avoided. • are pregnant or planning to become pregnant. See “Who should not take COUMADIN?” • are breastfeeding. COUMADIN may increase bleeding in your baby. Talk to your doctor about the best way to feed your baby. If you choose to breastfeed while taking COUMADIN, both you and your baby should be carefully monitored for bleeding problems. Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. See “What is the most important information I should know about COUMADIN?” How should I take COUMADIN? • Take COUMADIN exactly as prescribed. Your healthcare provider will adjust your dose from time to time depending on your response to COUMADIN. • You must have regular blood tests and visits with your healthcare provider to monitor your condition. • Take COUMADIN at the same time every day. You can take COUMADIN either with food or on an empty stomach. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 34 • If you miss a dose of COUMADIN, call your healthcare provider. Take the dose as soon as possible on the same day. Do not take a double dose of COUMADIN the next day to make up for a missed dose. • Call your healthcare provider right away if you take too much COUMADIN. • Call your healthcare provider if you are sick with diarrhea, an infection, or have a fever. • Tell your healthcare provider about any planned surgeries, medical or dental procedures. Your COUMADIN may have to be stopped for a short time or you may need your dose adjusted. • Call your healthcare provider right away if you fall or injure yourself, especially if you hit your head. Your healthcare provider may need to check you. What should I avoid while taking COUMADIN? • Do not start, stop, or change any medicine without talking with your healthcare provider. • Do not make changes in your diet, such as eating large amounts of green, leafy vegetables. • Do not change your weight by dieting, without first checking with your healthcare provider. • Avoid drinking alcohol. • Do not do any activity or sport that may cause a serious injury. What are the possible side effects of COUMADIN? • COUMADIN is very important for your health, but it can cause serious and life- threatening bleeding problems. See “What is the most important information I should know about COUMADIN?” • Serious side effects of COUMADIN also include: • death of skin tissue (skin necrosis or gangrene). This can happen soon after starting COUMADIN. It happens because blood clots form and block blood flow to an area of your body. Call your healthcare provider right away if you have pain, color, or temperature change to any area of your body. You may need medical care right away to prevent death or loss (amputation) of your affected body part. • “purple toes syndrome.” Call your healthcare provider right away if you have pain in your toes and they look purple in color or dark in color. Other side effects with COUMADIN include allergic reactions, liver problems, low blood pressure, swelling, low red blood cells, paleness, fever, and rash. Call your healthcare provider if you have any side effect that bothers you. Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 35 These are not all of the side effects of COUMADIN. For more information, ask your healthcare provider or pharmacist. How should I store COUMADIN? • Store COUMADIN at room temperature between 59° and 86° F. Protect from light. • Keep COUMADIN and all medicines out of the reach of children. General Information about COUMADIN Medicines are sometimes prescribed for purposes not mentioned in a Medication Guide. Do not use COUMADIN for a condition for which it was not prescribed. Do not give COUMADIN to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about COUMADIN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about COUMADIN that was written for healthcare professionals. If you would like more information, call 1-800-321-1335. Rx only COUMADIN is distributed by: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA COUMADIN is a registered trademark of Bristol-Myers Squibb Pharma Company. COUMADIN (Warfarin Sodium), the COUMADIN color logo, COLORS OF COUMADIN, and the color and configuration of COUMADIN tablets are trademarks of Bristol-Myers Squibb Pharma Company. **The brands listed (other than COUMADIN) are registered trademarks of their respective owners and are not trademarks of Bristol-Myers Squibb Company. This Medication Guide has been approved by the U.S. Food and Drug Administration. 1205733 1205735 April 2006 Bristol-Myers Squibb Company Approved 2.0 Item 2 proposed.pdf This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:39.418218	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/009218s102lbl.pdf', 'application_number': 9218, 'submission_type': 'SUPPL ', 'submission_number': 102}
10,722	COUMADIN® TABLETS (Warfarin Sodium Tablets, USP) Crystalline COUMADIN® FOR INJECTION (Warfarin Sodium for Injection, USP) Anticoagulant WARNING: BLEEDING RISK Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur during the starting period and with a higher dose (resulting in a higher INR). Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age ≥65, highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs (see PRECAUTIONS), and long duration of warfarin therapy. Regular monitoring of INR should be performed on all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy. Patients should be instructed about prevention measures to minimize risk of bleeding and to report immediately to physicians signs and symptoms of bleeding (see PRECAUTIONS: Information for Patients). DESCRIPTION COUMADIN (crystalline warfarin sodium) is an anticoagulant which acts by inhibiting vitamin K-dependent coagulation factors. Chemically, it is 3-(α-acetonylbenzyl)-4-hydroxycoumarin and is a racemic mixture of the R- and S-enantiomers. Crystalline warfarin sodium is an isopropanol clathrate. The crystallization of warfarin sodium virtually eliminates trace impurities present in amorphous warfarin. Its empirical formula is C19H15NaO4, and its structural formula may be represented by the following: Structural Formula 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Crystalline warfarin sodium occurs as a white, odorless, crystalline powder, is discolored by light and is very soluble in water; freely soluble in alcohol; very slightly soluble in chloroform and in ether. COUMADIN Tablets for oral use also contain: All strengths: Lactose, starch and magnesium stearate 1 mg: D&C Red No. 6 Barium Lake 2 mg: FD&C Blue No. 2 Aluminum Lake and FD&C Red No. 40 Aluminum Lake 2-1/2 mg: D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake 3 mg: FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake and FD&C Red No. 40 Aluminum Lake 4 mg: FD&C Blue No. 1 Aluminum Lake 5 mg: FD&C Yellow No. 6 Aluminum Lake 6 mg: FD&C Yellow No. 6 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake 7-1/2 mg: D&C Yellow No. 10 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake 10 mg: Dye Free COUMADIN for Injection is supplied as a sterile, lyophilized powder, which, after reconstitution with 2.7 mL sterile Water for Injection, contains: Warfarin Sodium 2 mg/mL Sodium Phosphate, Dibasic, Heptahydrate 4.98 mg/mL Sodium Phosphate, Monobasic, Monohydrate 0.194 mg/mL Sodium Chloride 0.1 mg/mL Mannitol 38.0 mg/mL Sodium Hydroxide, as needed for pH adjustment to 8.1 to 8.3 CLINICAL PHARMACOLOGY COUMADIN and other coumarin anticoagulants act by inhibiting the synthesis of vitamin K dependent clotting factors, which include Factors II, VII, IX and X, and the anticoagulant proteins C and S. Half-lives of these clotting factors are as follows: Factor II - 60 hours, VII - 4 to 6 hours, IX - 24 hours, and X - 48 to 72 hours. The half-lives of proteins C and S are approximately 8 hours and 30 hours, respectively. The resultant in vivo effect is a sequential depression of Factor VII, Protein C, Factor IX, Protein S, and Factor X and II activities. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K dependent 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda clotting factors. The vitamin promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins which are essential for biological activity. Mechanism of Action Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of the vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K1 epoxide. The degree of depression is dependent upon the dosage administered and, in part, by the patient’s VKORC1 genotype. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K dependent clotting factor made by the liver by approximately 30% to 50%. An anticoagulation effect generally occurs within 24 hours after drug administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of COUMADIN may become more pronounced as effects of daily maintenance doses overlap. Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae. Pharmacokinetics COUMADIN is a racemic mixture of the R- and S-enantiomers. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance. Absorption COUMADIN is essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hours. Distribution There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses of warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 liter/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Using a one compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the racemate. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Concentrations in fetal plasma approach the maternal values, but warfarin has not been found in human milk (see WARNINGS: Lactation). Approximately 99% of the drug is bound to plasma proteins. Metabolism The elimination of warfarin is almost entirely by metabolism. COUMADIN is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols). The warfarin alcohols have minimal anticoagulant activity. The metabolites are principally excreted into the urine; and to a lesser extent into the bile. The metabolites of warfarin that have been identified include dehydrowarfarin, two diastereoisomer alcohols, 4′-, 6-, 7-, 8- and 10-hydroxywarfarin. The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin. The S-enantiomer of warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphic enzyme. The variant alleles CYP2C92 and CYP2C93 result in decreased in vitro CYP2C9 enzymatic 7-hydroxylation of S-warfarin. The frequencies of these alleles in Caucasians are approximately 11% and 7% for CYP2C92 and CYP2C93, respectively.1 Patients with one or more of these variant CYP2C9 alleles have decreased S-warfarin clearance (Table 1).2 Table 1: Relationship Between S-Warfarin Clearance and CYP2C9 Genotype in Caucasian Patients CYP2C9 Genotype N S-Warfarin Clearance/Lean Body Weight (mL/min/kg) Mean (SD)a 1/1 118 0.065 (0.025)b 1/2 or 1/3 59 0.041 (0.021)b 2/2, 2/3, or 3/3 11 0.020 (0.011)b Total 188 a SD=Standard deviation. b p<0.001. Pairwise comparisons indicated significant differences among all 3 genotypes. Other CYP2C9 alleles associated with reduced enzymatic activity occur at lower frequencies, including 5, 6, and 11 alleles in populations of African ancestry and 5, 9, and 11 alleles in Caucasians. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Excretion The terminal half-life of warfarin after a single dose is approximately 1 week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites. Pharmacogenomics A meta-analysis of 9 qualified studies including 2775 patients (99% Caucasian) was performed to examine the clinical outcomes associated with CYP2C9 gene variants in warfarin-treated patients.3 In this meta-analysis, 3 studies assessed bleeding risks and 8 studies assessed daily dose requirements. The analysis suggested an increased bleeding risk for patients carrying either the CYP2C92 or CYP2C93 alleles. Patients carrying at least one copy of the CYP2C92 allele required a mean daily warfarin dose that was 17% less than the mean daily dose for patients homozygous for the CYP2C91 allele. For patients carrying at least one copy of the CYP2C93 allele, the mean daily warfarin dose was 37% less than the mean daily dose for patients homozygous for the CYP2C91 allele. In an observational study, the risk of achieving INR >3 during the first 3 weeks of warfarin therapy was determined in 219 Swedish patients retrospectively grouped by CYP2C9 genotype. The relative risk of overanticoagulation as measured by INR >3 during the first 2 weeks of therapy was approximately doubled for those patients classified as 2 or 3 compared to patients who were homozygous for the 1 allele.4 Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle, through inhibition of vitamin K epoxide reductase (VKOR), a multiprotein enzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene (especially the –1639G>A allele) have been associated with lower dose requirements for warfarin. In 201 Caucasian patients treated with stable warfarin doses, genetic variations in the VKORC1 gene were associated with lower warfarin doses. In this study, about 30% of the variance in warfarin dose could be attributed to variations in the VKORC1 gene alone; about 40% of the variance in warfarin dose could be attributed to variations in VKORC1 and CYP2C9 genes combined.5 About 55% of the variability in warfarin dose could be explained by the combination of VKORC1 and CYP2C9 genotypes, age, height, body weight, interacting drugs, and indication 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda for warfarin therapy in Caucasian patients.5 Similar observations have been reported in Asian patients.6,7 Elderly Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin. The cause of the increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown. This increased anticoagulant effect from warfarin may be due to a combination of pharmacokinetic and pharmacodynamic factors. Racemic warfarin clearance may be unchanged or reduced with increasing age. Limited information suggests there is no difference in the clearance of S-warfarin in the elderly versus young subjects. However, there may be a slight decrease in the clearance of R-warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation. Asians Asian patients may require lower initiation and maintenance doses of warfarin. One non- controlled study conducted in 151 Chinese outpatients reported a mean daily warfarin requirement of 3.3±1.4 mg to achieve an INR of 2 to 2.5. These patients were stabilized on warfarin for various indications. Patient age was the most important determinant of warfarin requirement in Chinese patients with a progressively lower warfarin requirement with increasing age. Renal Dysfunction Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal failure. Hepatic Dysfunction Hepatic dysfunction can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin. The administration of COUMADIN via the intravenous (IV) route should provide the patient with the same concentration of an equal oral dose, but maximum plasma concentration will be reached earlier. However, the full anticoagulant effect of a dose of warfarin may not be achieved until 72 to 96 hours after dosing, indicating that the administration of IV COUMADIN should not provide any increased biological effect or earlier onset of action. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL TRIALS Atrial Fibrillation (AF) In five prospective randomized controlled clinical trials involving 3711 patients with non- rheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (see Table 2). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%) which stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6% to 2.7% (see Table 2). Meta- analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2.0-4.5) or low INR (1.4-3.0). There was a significant reduction in minor bleeds at the low INR. Similar data from clinical studies in valvular atrial fibrillation patients are not available. Table 2: Clinical Studies of Warfarin in Non-Rheumatic AF Patients N Thromboembolism % Major Bleeding Warfarin- Warfarin- Treated Control % Risk Treated Control Study Patients Patients PT Ratio INR Reduction p-value Patients Patients AFASAK 335 336 1.5-2.0 2.8-4.2 60 0.027 0.6 0.0 SPAF 210 211 1.3-1.8 2.0-4.5 67 0.01 1.9 1.9 BAATAF 212 208 1.2-1.5 1.5-2.7 86 <0.05 0.9 0.5 CAFA 187 191 1.3-1.6 2.0-3.0 45 0.25 2.7 0.5 SPINAF 260 265 1.2-1.5 1.4-2.8 79 0.001 2.3 1.5 All study results of warfarin vs. control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhagic stroke and transient ischemic attacks. Myocardial Infarction WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8. [But note that a lower INR was achieved and increased bleeding was associated with INRs above 4.0; (see DOSAGE AND ADMINISTRATION).] The primary endpoint was a combination of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in the following table: 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 3 % Risk Warfarin Placebo RR Reduction Event (N=607) (N=607) (95% CI) (p-value) Total Patient Years of Follow-up 2018 1944 Total Mortality Vascular Death 94 (4.7/100 py) 82 (4.1/100 py) 123 (6.3/100 py) 105 (5.4/100 py) 0.76 (0.60, 0.97) 0.78 (0.60, 1.02) 24 (p=0.030) 22 (p=0.068) Recurrent MI 82 (4.1/100 py) 124 (6.4/100 py) 0.66 (0.51, 0.85) 34 (p=0.001) Cerebrovascular Event 20 (1.0/100 py) 44 (2.3/100 py) 0.46 (0.28, 0.75) 54 (p=0.002) RR=Relative risk; Risk reduction=(1 - RR); CI=Confidence interval; MI=Myocardial infarction; py=patient years WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label, randomized study of 3630 patients hospitalized for acute myocardial infarction treated with warfarin target INR 2.8 to 4.2, aspirin 160 mg/day, or warfarin target INR 2.0 to 2.5 plus aspirin 75 mg/day prior to hospital discharge. There were approximately four times as many major bleeding episodes in the two groups receiving warfarin than in the group receiving aspirin alone. Major bleeding episodes were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group. The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke. The mean duration of observation was approximately 4 years. The results for WARIS II are provided in the following table.8 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 4: WARIS II - Distribution of Separate Events According to Treatment Group Aspirin plus Aspirin Warfarin Warfarin Rate Ratio Event (N=1206) (N=1216) (N=1208) (95% CI) p-value No. of Events Reinfarction 117 90 69 0.56 (0.41-0.78)a <0.001 0.74 (0.55-0.98)b 0.03 Thromboembolic 32 17 17 0.52 (0.28-0.98)a 0.03 Stroke 0.52 (0.28-0.97)b 0.03 Major Bleedingc 8 33 28 3.35a (ND) ND 4.00b (ND) ND Minor Bleedingd 39 103 133 3.21a (ND) ND 2.55b (ND) ND Death 92 96 95 0.82 * CI denotes confidence interval. a The rate ratio is for aspirin plus warfarin as compared with aspirin. b The rate ratio is for warfarin as compared with aspirin. c Major bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion. d Minor bleeding episodes were defined as non-cerebral hemorrhage not necessitating surgical intervention or blood transfusion. ND=not determined Mechanical and Bioprosthetic Heart Valves In a prospective, randomized, open-label, positive-controlled study9 in 254 patients, the thromboembolic-free interval was found to be significantly greater in patients with mechanical prosthetic heart valves treated with warfarin alone compared with dipyridamole-aspirin (p<0.005) and pentoxifylline-aspirin (p<0.05) treated patients. Rates of thromboembolic events in these groups were 2.2, 8.6, and 7.9/100 patient years, respectively. Major bleeding rates were 2.5, 0.0, and 0.9/100 patient years, respectively. In a prospective, open label, clinical trial comparing moderate (INR 2.65) vs. high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events/100 patient years, respectively). Major bleeding was more common in the high intensity group (2.1 events/100 patient years) vs. 0.95 events/100 patient years in the moderate intensity 10 group. In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2.0 2.25 vs. INR 2.5-4.0) for a three-month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs. 1.9%, respectively, and minor embolic events 10.8% vs. 10.2%, respectively). Major 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda bleeding complications were more frequent with the higher intensity (major hemorrhages 4.6%) vs. none in the lower intensity.11 INDICATIONS AND USAGE COUMADIN is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, and pulmonary embolism. COUMADIN is indicated for the prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement. COUMADIN is indicated to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction. CONTRAINDICATIONS Anticoagulation is contraindicated in any localized or general physical condition or personal circumstance in which the hazard of hemorrhage might be greater than the potential clinical benefits of anticoagulation, such as: Pregnancy COUMADIN is contraindicated in women who are or may become pregnant because the drug passes through the placental barrier and may cause fatal hemorrhage to the fetus in utero. Furthermore, there have been reports of birth malformations in children born to mothers who have been treated with warfarin during pregnancy. Embryopathy characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) has been reported in pregnant women exposed to warfarin during the first trimester. Central nervous system abnormalities also have been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, and midline cerebellar atrophy. Ventral midline dysplasia, characterized by optic atrophy, and eye abnormalities have been observed. Mental retardation, blindness, and other central nervous system abnormalities have been reported in association with second and third trimester exposure. Although rare, teratogenic reports following in utero exposure to warfarin include urinary tract anomalies such as single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, hydrocephalus, cardiac defects and congenital heart disease, polydactyly, deformities of toes, diaphragmatic hernia, corneal leukoma, cleft palate, cleft lip, schizencephaly, and microcephaly. 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Spontaneous abortion and stillbirth are known to occur and a higher risk of fetal mortality is associated with the use of warfarin. Low birth weight and growth retardation have also been reported. Women of childbearing potential who are candidates for anticoagulant therapy should be carefully evaluated and the indications critically reviewed with the patient. If the patient becomes pregnant while taking this drug, she should be apprised of the potential risks to the fetus, and the possibility of termination of the pregnancy should be discussed in light of those risks. Hemorrhagic tendencies or blood dyscrasias. Recent or contemplated surgery of: (1) central nervous system; (2) eye; (3) traumatic surgery resulting in large open surfaces. Bleeding tendencies associated with active ulceration or overt bleeding of: (1) gastrointestinal, genitourinary or respiratory tracts; (2) cerebrovascular hemorrhage; (3) aneurysms-cerebral, dissecting aorta; (4) pericarditis and pericardial effusions; (5) bacterial endocarditis. Threatened abortion, eclampsia and preeclampsia. Inadequate laboratory facilities. Unsupervised patients with senility, alcoholism, or psychosis or other lack of patient cooperation. Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding. Miscellaneous: major regional, lumbar block anesthesia, malignant hypertension and known hypersensitivity to warfarin or to any other components of this product. WARNINGS The most serious risks associated with anticoagulant therapy with warfarin sodium are hemorrhage in any tissue or organ12 (see BLACK BOX WARNING) and, less frequently (<0.1%), necrosis and/or gangrene of skin and other tissues. Hemorrhage and necrosis have in some cases been reported to result in death or permanent disability. Necrosis appears to be associated with local thrombosis and usually appears within a few days of the start of anticoagulant therapy. In severe cases of necrosis, treatment through debridement or 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda amputation of the affected tissue, limb, breast or penis has been reported. Careful diagnosis is required to determine whether necrosis is caused by an underlying disease. Warfarin therapy should be discontinued when warfarin is suspected to be the cause of developing necrosis and heparin therapy may be considered for anticoagulation. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. See below for information on predisposing conditions. These and other risks associated with anticoagulant therapy must be weighed against the risk of thrombosis or embolization in untreated cases. It cannot be emphasized too strongly that treatment of each patient is a highly individualized matter. COUMADIN (Warfarin Sodium), a narrow therapeutic range (index) drug, may be affected by factors such as other drugs and dietary vitamin K. Dosage should be controlled by periodic determinations of prothrombin time (PT)/International Normalized Ratio (INR). Determinations of whole blood clotting and bleeding times are not effective measures for control of therapy. Heparin prolongs the one-stage PT. When heparin and COUMADIN are administered concomitantly, refer below to Conversion From Heparin Therapy for recommendations. Increased caution should be observed when COUMADIN is administered in the presence of any predisposing condition where added risk of hemorrhage, necrosis, and/or gangrene is present. Anticoagulation therapy with COUMADIN may enhance the release of atheromatous plaque emboli, thereby increasing the risk of complications from systemic cholesterol microembolization, including the “purple toes syndrome.” Discontinuation of COUMADIN therapy is recommended when such phenomena are observed. Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms including purple toes syndrome, livedo reticularis, rash, gangrene, abrupt and intense pain in the leg, foot, or toes, foot ulcers, myalgia, penile gangrene, abdominal pain, flank or back pain, hematuria, renal insufficiency, hypertension, cerebral ischemia, spinal cord infarction, pancreatitis, symptoms simulating polyarteritis, or any other sequelae of vascular compromise due to embolic occlusion. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. Purple toes syndrome is a complication of oral anticoagulation characterized by a dark, purplish or mottled color of the toes, usually occurring between 3 to 10 weeks, or later, after the initiation of therapy with warfarin or related compounds. Major features of this syndrome include purple color of plantar surfaces and sides of the toes that blanches on moderate pressure 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and fades with elevation of the legs; pain and tenderness of the toes; waxing and waning of the color over time. While the purple toes syndrome is reported to be reversible, some cases progress to gangrene or necrosis which may require debridement of the affected area, or may lead to amputation. COUMADIN should be used with caution in patients with heparin-induced thrombocytopenia and deep venous thrombosis. Cases of venous limb ischemia, necrosis, and gangrene have occurred in patients with heparin-induced thrombocytopenia and deep venous thrombosis when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients sequelae have included amputation of the involved area and/or death.13 The decision to administer anticoagulants in the following conditions must be based upon clinical judgment in which the risks of anticoagulant therapy are weighed against the benefits: Lactation: Based on very limited published data, warfarin has not been detected in the breast milk of mothers treated with warfarin. The same limited published data report that some breast- fed infants, whose mothers were treated with warfarin, had prolonged prothrombin times, although not as prolonged as those of the mothers. The decision to breast-feed should be undertaken only after careful consideration of the available alternatives. Women who are breast-feeding and anticoagulated with warfarin should be very carefully monitored so that recommended PT/INR values are not exceeded. It is prudent to perform coagulation tests and to evaluate vitamin K status in infants before advising women taking warfarin to breast-feed. Effects in premature infants have not been evaluated. Severe to moderate hepatic or renal insufficiency. Infectious diseases or disturbances of intestinal flora: sprue, antibiotic therapy. Trauma which may result in internal bleeding. Surgery or trauma resulting in large exposed raw surfaces. Indwelling catheters. Severe to moderate hypertension. Known or suspected deficiency in protein C mediated anticoagulant response: Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. Not all patients with these conditions develop necrosis, and tissue necrosis occurs in patients without these deficiencies. Inherited resistance 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda to activated protein C has been described in many patients with venous thromboembolic disorders but has not yet been evaluated as a risk factor for tissue necrosis. The risk associated with these conditions, both for recurrent thrombosis and for adverse reactions, is difficult to evaluate since it does not appear to be the same for everyone. Decisions about testing and therapy must be made on an individual basis. It has been reported that concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with COUMADIN may minimize the incidence of tissue necrosis. Warfarin therapy should be discontinued when warfarin is suspected to be the cause of developing necrosis, and heparin therapy may be considered for anticoagulation. Miscellaneous: polycythemia vera, vasculitis, and severe diabetes. PRECAUTIONS Periodic determination of PT/INR is essential. (See DOSAGE AND ADMINISTRATION: Laboratory Control.) Numerous factors, alone or in combination including changes in diet, medications, botanicals, and genetic variations in the CYP2C9 and VKORC1 enzymes (see CLINICAL PHARMACOLOGY: Pharmacogenomics) may influence the response of the patient to warfarin. Drug-Drug and Drug-Disease Interactions It is generally good practice to monitor the patient’s response with additional PT/INR determinations in the period immediately after discharge from the hospital, and whenever other medications, including botanicals, are initiated, discontinued or taken irregularly. The following factors are listed for reference; however, other factors may also affect the anticoagulant response. Drugs may interact with COUMADIN through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with COUMADIN are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and altered physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with COUMADIN are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism. The following factors, alone or in combination, may be responsible for INCREASED PT/INR response: 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ENDOGENOUS FACTORS: blood dyscrasias diarrhea hyperthyroidism see CONTRAINDICATIONS elevated temperature poor nutritional state cancer hepatic disorders steatorrhea collagen vascular disease infectious hepatitis vitamin K deficiency congestive heart failure jaundice EXOGENOUS FACTORS: Potential drug interactions with COUMADIN are listed below by drug class and by specific drugs. Classes of Drugs 5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors† Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti-Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins† 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Specific Drugs Reported acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate COUMADIN overdose cyclophosphamide† danazol dextran dextrothyroxine diazoxide diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemfibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/sulfamethoxazole urokinase valdecoxib valproate vitamin E zafirlukast zileuton also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The following factors, alone or in combination, may be responsible for DECREASED PT/INR response: ENDOGENOUS FACTORS: edema hypothyroidism hereditary coumarin resistance nephrotic syndrome hyperlipemia EXOGENOUS FACTORS: Potential drug interactions with COUMADIN (Warfarin Sodium) are listed below by drug class and by specific drugs. Classes of Drugs Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics† Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins† Specific Drugs Reported alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone cholestyramine† clozapine corticotropin cortisone COUMADIN underdosage cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate 6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Because a patient may be exposed to a combination of the above factors, the net effect of COUMADIN on PT/INR response may be unpredictable. More frequent PT/INR monitoring is therefore advisable. Medications of unknown interaction with coumarins are best regarded with caution. When these medications are started or stopped, more frequent PT/INR monitoring is advisable. It has been reported that concomitant administration of warfarin and ticlopidine may be associated with cholestatic hepatitis. Botanical (Herbal) Medicines Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN. Few adequate, well-controlled studies exist evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and COUMADIN. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation. It is good practice to monitor the patient’s response with additional PT/INR determinations when initiating or discontinuing botanicals. Specific botanicals reported to affect COUMADIN therapy include the following: • Bromelains, danshen, dong quai (Angelica sinensis), garlic, Ginkgo biloba, ginseng, and cranberry products are associated most often with an INCREASE in the effects of COUMADIN. • Coenzyme Q10 (ubidecarenone) and St. John’s wort are associated most often with a DECREASE in the effects of COUMADIN. Some botanicals may cause bleeding events when taken alone (eg, garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of COUMADIN. Conversely, other botanicals may have coagulant properties when taken alone or may decrease the effects of COUMADIN. Some botanicals that may affect coagulation are listed below for reference; however, this list should not be considered all-inclusive. Many botanicals have several common names and scientific names. The most widely recognized common botanical names are listed. 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Botanicals that contain coumarins with potential anticoagulant effects: Agrimony1 Celery Passion Flower Alfalfa Chamomile (German and Roman) Prickly Ash (Northern) Angelica (Dong Quai) Dandelion4 Quassia Aniseed Fenugreek Red Clover Arnica Horse Chestnut Sweet Clover Asafoetida Horseradish Sweet Woodruff Bogbean2 Licorice4 Tonka Beans Boldo Meadowsweet2 Wild Carrot Buchu Nettle Wild Lettuce Capsicum3 Parsley Cassia4 Miscellaneous botanicals with anticoagulant properties: Bladder Wrack (Fucus) Pau d’arco Botanicals that contain salicylate and/or have antiplatelet properties: Agrimony1 Dandelion4 Meadowsweet2 Aloe Gel Feverfew Onion5 Aspen Garlic5 Policosanol Black Cohosh German Sarsaparilla Poplar Black Haw Ginger Senega Bogbean2 Ginkgo Biloba Tamarind Cassia4 Ginseng (Panax)5 Willow Clove Licorice4 Wintergreen Botanicals with fibrinolytic properties: Bromelains Garlic5 Inositol Nicotinate Capsicum3 Ginseng (Panax)5 Onion5 Botanicals with coagulant properties: Agrimony1 Goldenseal Mistletoe Yarrow 1Contains coumarins, has antiplatelet properties, and may have coagulant properties due to possible vitamin K content. 2Contains coumarins and salicylate. 3Contains coumarins and has fibrinolytic properties. 4Contains coumarins and has antiplatelet properties. 5Has antiplatelet and fibrinolytic properties. Effect on Other Drugs Coumarins may also affect the action of other drugs. Hypoglycemic agents (chlorpropamide and tolbutamide) and anticonvulsants (phenytoin and phenobarbital) may accumulate in the body as a result of interference with either their metabolism or excretion. 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Considerations for Increased Bleeding Risk COUMADIN is a narrow therapeutic range (index) drug, and additional caution should be observed when warfarin sodium is administered to certain patients. Reported risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age ≥65, highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs (see PRECAUTIONS), and long duration of warfarin therapy. Identification of risk factors for bleeding and certain genetic variations in CYP2C9 and VKORC1 in a patient may increase the need for more frequent INR monitoring and the use of lower warfarin doses (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Metabolism and DOSAGE AND ADMINISTRATION). Bleeding is more likely to occur during the starting period and with a higher dose of COUMADIN (resulting in a higher INR). Intramuscular (IM) injections of concomitant medications should be confined to the upper extremities which permits easy access for manual compression, inspections for bleeding and use of pressure bandages. Caution should be observed when COUMADIN (or warfarin) is administered concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to be certain that no change in anticoagulation dosage is required. In addition to specific drug interactions that might affect PT/INR, NSAIDs, including aspirin, can inhibit platelet aggregation, and can cause gastrointestinal bleeding, peptic ulceration and/or perforation. Information for Patients The objective of anticoagulant therapy is to decrease the clotting ability of the blood so that thrombosis is prevented, while avoiding spontaneous bleeding. Effective therapeutic levels with minimal complications are in part dependent upon cooperative and well-instructed patients who communicate effectively with their physician. Patients should be advised: Strict adherence to prescribed dosage schedule is necessary. Do not take or discontinue any other medication, including salicylates (eg, aspirin and topical analgesics), other over-the-counter medications, and botanical (herbal) products except on advice of the physician. Avoid alcohol consumption. Do not take COUMADIN during pregnancy and do not become pregnant while taking it (see CONTRAINDICATIONS). Avoid any activity or sport that may result in traumatic injury. Prothrombin time tests and regular visits to physician or clinic are needed to monitor therapy. Carry identification stating that COUMADIN is being taken. If the prescribed dose of COUMADIN is forgotten, notify the physician immediately. Take the dose as soon as possible on the same day but do not take a double dose of COUMADIN the next day to make up for 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda missed doses. The amount of vitamin K in food may affect therapy with COUMADIN. Eat a normal, balanced diet maintaining a consistent amount of vitamin K. Avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables. You should also avoid intake of cranberry juice or any other cranberry products. Notify your healthcare provider if any of these products are part of your normal diet. Contact physician to report any illness, such as diarrhea, infection or fever. Notify physician immediately if any unusual bleeding or symptoms occur. Signs and symptoms of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness. If therapy with COUMADIN is discontinued, patients should be cautioned that the anticoagulant effects of COUMADIN may persist for about 2 to 5 days. Patients should be informed that all warfarin sodium, USP, products represent the same medication, and should not be taken concomitantly, as overdosage may result. A Medication Guide14 should be available to patients when their prescriptions for warfarin sodium are issued. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity and mutagenicity studies have not been performed with COUMADIN. The reproductive effects of COUMADIN have not been evaluated. The use of warfarin during pregnancy has been associated with the development of fetal malformations in humans (see CONTRAINDICATIONS). Use in Pregnancy Pregnancy Category X See CONTRAINDICATIONS. Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 have not been established in randomized, controlled clinical trials. However, the use of COUMADIN in pediatric patients is well-documented for the prevention and treatment of thromboembolic events. Difficulty achieving and maintaining therapeutic PT/INR ranges in the pediatric patient has been reported. More frequent PT/INR determinations are recommended because of possible changing warfarin requirements. 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Geriatric Use Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin (see CLINICAL PHARMACOLOGY). COUMADIN is contraindicated in any unsupervised patient with senility. Caution should be observed with administration of warfarin sodium to elderly patients in any situation or physical condition where added risk of hemorrhage is present. Lower initiation and maintenance doses of COUMADIN are recommended for elderly patients (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Potential adverse reactions to COUMADIN may include: • Fatal or nonfatal hemorrhage from any tissue or organ. This is a consequence of the anticoagulant effect. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Hemorrhagic complications may present as paralysis; paresthesia; headache, chest, abdomen, joint, muscle or other pain; dizziness; shortness of breath, difficult breathing or swallowing; unexplained swelling; weakness; hypotension; or unexplained shock. Therefore, the possibility of hemorrhage should be considered in evaluating the condition of any anticoagulated patient with complaints which do not indicate an obvious diagnosis. Bleeding during anticoagulant therapy does not always correlate with PT/INR. (See OVERDOSAGE: Treatment.) • Bleeding which occurs when the PT/INR is within the therapeutic range warrants diagnostic investigation since it may unmask a previously unsuspected lesion, eg, tumor, ulcer, etc. • Necrosis of skin and other tissues. (See WARNINGS.) • Adverse reactions reported infrequently include: hypersensitivity/allergic reactions, including anaphylactic reactions, systemic cholesterol microembolization, purple toes syndrome, hepatitis, cholestatic hepatic injury, jaundice, elevated liver enzymes, hypotension, vasculitis, edema, anemia, pallor, fever, rash, dermatitis, including bullous eruptions, urticaria, angina syndrome, chest pain, abdominal pain including cramping, flatulence/bloating, fatigue, lethargy, malaise, asthenia, nausea, vomiting, diarrhea, pain, headache, dizziness, loss of consciousness, syncope, coma, taste perversion, pruritus, alopecia, cold intolerance, and paresthesia including feeling cold and chills. 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rare events of tracheal or tracheobronchial calcification have been reported in association with long-term warfarin therapy. The clinical significance of this event is unknown. Priapism has been associated with anticoagulant administration; however, a causal relationship has not been established. OVERDOSAGE Signs and Symptoms Suspected or overt abnormal bleeding (eg, appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries) are early manifestations of anticoagulation beyond a safe and satisfactory level. Treatment Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing COUMADIN therapy and if necessary, by administration of oral or parenteral vitamin K1. (Please see recommendations accompanying vitamin K1 preparations prior to use.)15,16 Such use of vitamin K1 reduces response to subsequent COUMADIN therapy. Patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged PT/INR. Resumption of COUMADIN administration reverses the effect of vitamin K, and a therapeutic PT/INR can again be obtained by careful dosage adjustment. If rapid anticoagulation is indicated, heparin may be preferable for initial therapy. If minor bleeding progresses to major bleeding, give 5 to 25 mg (rarely up to 50 mg) parenteral vitamin K1. In emergency situations of severe hemorrhage, clotting factors can be returned to normal by administering 200 to 500 mL of fresh whole blood or fresh frozen plasma, or by giving commercial Factor IX complex. A risk of hepatitis and other viral diseases is associated with the use of these blood products; Factor IX complex is also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to COUMADIN (Warfarin Sodium) overdosage. Purified Factor IX preparations should not be used because they cannot increase the levels of prothrombin, Factor VII and Factor X which are also depressed along with the levels of Factor IX as a result of COUMADIN treatment. Packed red blood cells may also be given if 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda significant blood loss has occurred. Infusions of blood or plasma should be monitored carefully to avoid precipitating pulmonary edema in elderly patients or patients with heart disease. DOSAGE AND ADMINISTRATION The dosage and administration of COUMADIN must be individualized for each patient according to the particular patient’s PT/INR response to the drug. The dosage should be adjusted based upon the patient’s PT/INR.15,16,17,18,19 The best available information supports the following recommendations for dosing of COUMADIN. Venous Thromboembolism (including deep venous thrombosis [DVT] and pulmonary embolism [PE]) For patients with a first episode of DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with a first episode of idiopathic DVT or PE, warfarin is recommended for at least 6 to 12 months. For patients with two or more episodes of documented DVT or PE, indefinite treatment with warfarin is suggested. For patients with a first episode of DVT or PE who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions, treatment for 12 months is recommended and indefinite therapy is suggested. For patients with a first episode of DVT or PE who have documented deficiency of antithrombin, deficiency of Protein C or Protein S, or the Factor V Leiden or prothrombin 20210 gene mutation, homocystinemia, or high Factor VIII levels (>90th percentile of normal), treatment for 6 to 12 months is recommended and indefinite therapy is suggested for idiopathic thrombosis. The risk-benefit should be reassessed periodically in patients who receive indefinite anticoagulant treatment.12,20 The dose of warfarin should be adjusted to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. These recommendations are supported by the American College of Chest Physicians’ (7th ACCP) guidelines.15,17,21,22 Atrial Fibrillation Five clinical trials evaluated the effects of warfarin in patients with non-valvular atrial fibrillation (AF). Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2.0-4.5) or low INR (1.4-3.0). There was a significant reduction in minor bleeds at the low INR. There are no adequate and well-controlled studies in populations with atrial fibrillation and valvular heart disease. Similar data from clinical studies in valvular atrial fibrillation patients are not available. The trials in non-valvular atrial fibrillation support the 7th ACCP 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda recommendation that an INR of 2.0 to 3.0 be used for warfarin therapy in appropriate AF patients.17 Oral anticoagulation therapy with warfarin is recommended in patients with persistent or paroxysmal AF (PAF) (intermittent AF) at high risk of stroke (ie, having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, age >75 years, moderately or severely impaired left ventricular systolic function and/or congestive heart failure, history of hypertension, or diabetes mellitus). In patients with persistent AF or PAF, age 65 to 75 years, in the absence of other risk factors, but who are at intermediate risk of stroke, antithrombotic therapy with either oral warfarin or aspirin, 325 mg/day, is recommended. For patients with AF and mitral stenosis, anticoagulation with oral warfarin is recommended (7th ACCP). For patients with AF and prosthetic heart valves, anticoagulation with oral warfarin should be used; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.17 Post-Myocardial Infarction The results of the WARIS II study and 7th ACCP guidelines suggest that in most healthcare settings, moderate- and low-risk patients with a myocardial infarction should be treated with aspirin alone over oral vitamin-K antagonist (VKA) therapy plus aspirin. In healthcare settings in which meticulous INR monitoring is standard and routinely accessible, for both high- and low-risk patients after myocardial infarction (MI), long-term (up to 4 years) high-intensity oral warfarin (target INR, 3.5; range, 3.0-4.0) without concomitant aspirin or moderate-intensity oral warfarin (target INR, 2.5; range, 2.0-3.0) with aspirin is recommended. For high-risk patients with MI, including those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on echocardiography, and those with a history of a thromboembolic event, therapy with combined moderate-intensity (INR, 2.0-3.0) oral warfarin plus low-dose aspirin (≤100 mg/day) for 3 months after the MI is suggested.23 Mechanical and Bioprosthetic Heart Valves For all patients with mechanical prosthetic heart valves, warfarin is recommended. For patients with a St. Jude Medical (St. Paul, MN) bileaflet valve in the aortic position, a target INR of 2.5 (range, 2.0-3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, the 7th ACCP recommends a target INR of 3.0 (range, 2.5-3.5). For patients with caged ball or caged disk valves, a target INR of 3.0 (range, 2.5-3.5) in combination with aspirin, 75 to 100 mg/day is recommended. For patients with bioprosthetic valves, warfarin therapy with a target INR of 2.5 (range, 2.0-3.0) is recommended for valves in 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the mitral position and is suggested for valves in the aortic position for the first 3 months after valve insertion.15 Recurrent Systemic Embolism and Other Indications Oral anticoagulation therapy has not been evaluated by properly designed clinical trials in patients with valvular disease associated with atrial fibrillation, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. A moderate dose regimen (INR 2.0-3.0) is recommended for these patients.17 An INR of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding. Initial Dosage The dose of COUMADIN must be individualized by monitoring the PT/INR. Not all factors causing warfarin dose variability are known. The maintenance dose needed to achieve a target PT/INR is influenced by: · Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities and · Genetic factors (CYP2C9 and VKORC1 genotypes). Select the starting dose based on the expected maintenance dose, taking into account the above factors. Routine use of loading doses is not recommended as this may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation. If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg per day. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initiation doses for elderly and/or debilitated patients. (See CLINICAL PHARMACOLOGY and PRECAUTIONS). The patient’s CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose. Table 5 describes the range of stable maintenance doses observed in multiple patients having different combinations of CYP2C9 and VKORC1 gene variants. Consider these ranges in choosing the initial dose. 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In all patients, subsequent dosage adjustments must be made based on the results of PT/INR determinations.17, 18 Table 5: Range of Expected Therapeutic Warfarin Doses Based on CYP2C9 and VKORC1 Genotypes† VKORC1 CYP2C9 1/1 1/2 1/3 2/2 2/3 3/3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg †Ranges are derived from multiple published clinical studies. Other clinical factors (e.g., age, race, body weight, sex, concomitant medications, and comorbidities) are generally accounted for along with genotype in the ranges expressed in the Table. VKORC1 –1639 GÆA (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin dose. Patients with CYP2C9 1/3, 2/2, 2/3 and 3/3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen. Maintenance Most patients are satisfactorily maintained at a dose of 2 to 10 mg daily. Flexibility of dosage is provided by breaking scored tablets in half. The individual dose and interval should be gauged by the patient’s prothrombin response. Acquired or inherited warfarin resistance is rare, but should be suspected if large daily doses of COUMADIN are required to maintain a patient’s PT/INR within a normal therapeutic range. Lower maintenance doses are recommended for elderly and/or debilitated patients and patients with a potential to exhibit greater than expected PT/INR response to COUMADIN (see PRECAUTIONS). Duration of Therapy The duration of therapy in each patient should be individualized. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed.14,15,17,18,21,22 Missed Dose The anticoagulant effect of COUMADIN persists beyond 24 hours. If the patient forgets to take the prescribed dose of COUMADIN at the scheduled time, the dose should be taken as soon as possible on the same day. The patient should not take the missed dose by doubling the daily dose to make up for missed doses, but should refer back to his or her physician. 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Intravenous Route of Administration COUMADIN for Injection provides an alternate administration route for patients who cannot receive oral drugs. The IV dosages would be the same as those that would be used orally if the patient could take the drug by the oral route. COUMADIN for Injection should be administered as a slow bolus injection over 1 to 2 minutes into a peripheral vein. It is not recommended for intramuscular administration. The vial should be reconstituted with 2.7 mL of sterile Water for Injection and inspected for particulate matter and discoloration immediately prior to use. Do not use if either particulate matter and/or discoloration is noted. After reconstitution, COUMADIN for Injection is chemically and physically stable for 4 hours at room temperature. It does not contain any antimicrobial preservative and, thus, care must be taken to assure the sterility of the prepared solution. The vial is not recommended for multiple use and unused solution should be discarded. Laboratory Control The PT reflects the depression of vitamin K dependent Factors VII, X and II. A system of standardizing the PT in oral anticoagulant control was introduced by the World Health Organization in 1983. It is based upon the determination of an International Normalized Ratio (INR) which provides a common basis for communication of PT results and interpretations of therapeutic ranges.24 The PT should be determined daily after the administration of the initial dose until PT/INR results stabilize in the therapeutic range. Intervals between subsequent PT/INR determinations should be based upon the physician’s judgment of the patient’s reliability and response to COUMADIN in order to maintain the individual within the therapeutic range. Acceptable intervals for PT/INR determinations are normally within the range of 1 to 4 weeks after a stable dosage has been determined. To ensure adequate control, it is recommended that additional PT tests be done when other warfarin products are interchanged with warfarin sodium tablets, USP, as well as whenever other medications are initiated, discontinued, or taken irregularly (see PRECAUTIONS). Safety and efficacy of warfarin therapy can be improved by increasing the quality of laboratory control. Reports suggest that in usual care monitoring, patients are in therapeutic range only 33% to 64% of the time. Time in therapeutic range is significantly greater (56%-93%) in patients managed by anticoagulation clinics, among self-testing and self- monitoring patients, and in patients managed with the help of computer programs.25 Self- testing patients had fewer bleeding events than patients in usual care.25 28 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Treatment During Dentistry and Surgery The management of patients who undergo dental and surgical procedures requires close liaison between attending physicians, surgeons, and dentists.15,19 PT/INR determination is recommended just prior to any dental or surgical procedure. In patients undergoing minimal invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of COUMADIN to maintain the PT/INR at the low end of the therapeutic range may safely allow for continued anticoagulation. The operative site should be sufficiently limited and accessible to permit the effective use of local procedures for hemostasis. Under these conditions, dental and minor surgical procedures may be performed without undue risk of hemorrhage. Some dental or surgical procedures may necessitate the interruption of COUMADIN therapy. When discontinuing COUMADIN even for a short period of time, the benefits and risks should be strongly considered. Conversion From Heparin Therapy Since the anticoagulant effect of COUMADIN is delayed, heparin is preferred initially for rapid anticoagulation. Conversion to COUMADIN may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure continuous anticoagulation, it is advisable to continue full dose heparin therapy and that COUMADIN therapy be overlapped with heparin for 4 to 5 days, until COUMADIN has produced the desired therapeutic response as determined by PT/INR. When COUMADIN has produced the desired PT/INR or prothrombin activity, heparin may be discontinued. COUMADIN may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin. A severe elevation (>50 seconds) in activated partial thromboplastin time (aPTT) with a PT/INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage. During initial therapy with COUMADIN, the interference with heparin anticoagulation is of minimal clinical significance. As heparin may affect the PT/INR, patients receiving both heparin and COUMADIN should have blood for PT/INR determination drawn at least: • 5 hours after the last IV bolus dose of heparin, or • 4 hours after cessation of a continuous IV infusion of heparin, or • 24 hours after the last subcutaneous heparin injection. 29 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED Tablets For oral use, single scored with one face imprinted numerically with 1, 2, 2-1/2, 3, 4, 5, 6, 7-1/2 or 10 superimposed and inscribed with “COUMADIN” and with the opposite face plain. COUMADIN is available in bottles and Hospital Unit-Dose Blister Packages with potencies and colors as follows: Hospital Unit-Dose 100’s 1000’s Blister Package of 100 1 mg pink NDC 0056-0169-70 NDC 0056-0169-90 NDC 0056-0169-75 2 mg lavender NDC 0056-0170-70 NDC 0056-0170-90 NDC 0056-0170-75 2-1/2 mg green NDC 0056-0176-70 NDC 0056-0176-90 NDC 0056-0176-75 3 mg tan NDC 0056-0188-70 NDC 0056-0188-90 NDC 0056-0188-75 4 mg blue NDC 0056-0168-70 NDC 0056-0168-90 NDC 0056-0168-75 5 mg peach NDC 0056-0172-70 NDC 0056-0172-90 NDC 0056-0172-75 6 mg teal NDC 0056-0189-70 NDC 0056-0189-90 NDC 0056-0189-75 7-1/2 mg yellow NDC 0056-0173-70 NDC 0056-0173-75 10 mg white (Dye Free) NDC 0056-0174-70 NDC 0056-0174-75 Protect from light. Store at controlled room temperature (59°-86°F, 15°-30°C). Dispense in a tight, light-resistant container as defined in the USP. Hospital Unit-Dose Blister Packages are to be stored in carton until contents have been used. Injection Available for intravenous use only. Not recommended for intramuscular administration. Reconstitute with 2.7 mL of sterile Water for Injection to yield 2 mg/mL. Net contents 5.4 mg lyophilized powder. Maximum yield 2.5 mL. 5 mg vial (box of 6) NDC 0590-0324-35 Protect from light. Keep vial in box until used. Store at controlled room temperature (59°-86°F, 15°-30°C). After reconstitution, store at controlled room temperature (59°-86°F, 15°-30°C) and use within 4 hours. Do not refrigerate. Discard any unused solution. 30 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda REFERENCES 1. Yasar U, Eliasson E, Dahl M, Johansson I, Ingelman-Sundberg M, Sjoqvist F. Validation of methods for CYP2C9 genotyping: Frequencies of mutant alleles in Swedish population. Biochem Biophys Res Comm. 1999;254:628-631. 2. Herman D, Locatelli I, Grabnar I, et al. Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose. Pharmacogenomics J. 2005;5:193-202. 3. Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: A HuGEnet ™ systemic review and meta-analysis. Genet Med. 2005;7:97-104. 4. Lindh JD, Lundgren S, Holm L, Alfredsson L, Rane A. Several-fold increase in risk of overanticoagulation by CYP2C9 mutations. Clin Pharmacol Ther. 2005;78:540 550. 5. Wadelius M, Chen LY, Downes K, et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J. 2005;5:262 270. 6. Veenstra DL, You JHS, Rieder MJ, et al. Association of Vitamin K epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population. Pharmacogenet Genomics. 2005;15:687-691. 7. Takahashi H, Wilkinson GR, Nutescu EA, et al. Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance doses of warfarin in Japanese, Caucasians and African Americans. Pharmacogenet Genomics. 2006;16:101-110. 8. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347:969-974. 9. Mok CK, Boey J, Wang R, et al. Warfarin versus dipyridamole-aspirin and pentoxifylline-aspirin for prevention of prosthetic valve thromboembolism: a prospective randomized clinical trial. Circ. 1985;72:1059-1063. 10. Saour JN, Sieck JO, Mamo LA, Gallus AS. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med. 1990;322:428 432. 11. Turpie AG, Hirsh J, Gunstensen J, Nelson H, Gent M. Randomized comparison to two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet. 1988;331:1242-1245. 31 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12. Büller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:401S-428S. 13. Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MG, Russett JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med. 1997;127:804-812. 14. COUMADIN Medication Guide. Princeton, NJ: Bristol-Myers Squibb Company; 20XX. 15. Salem DN, Stein PD, Al-Ahmad A, et al. Antithrombotic therapy in valvular heart disease–native and prosthetic. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:457S-482S. 16. American Geriatrics Society Clinical Practice Guidelines. The use of oral anticoagulants (warfarin) in older people. J Amer Geriatr Soc. 2000;48:224-227. 17. Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic therapy in atrial fibrillation. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:429S-456S. 18. Jaffer AK, Bragg L. Practical tips for warfarin dosing and monitoring. Cleveland Clinic J Med. 2003;70:361-371. 19. Jaffer AK, Brotman DJ, Chukwumerije N. When patients on warfarin need surgery. Cleveland Clinic J Med. 2003;70:973-984. 20. Kearon C, Ginsberg JS, Kovacs MJ, et al, for the Extended Low-Intensity Anticoagulation for Thrombo-Embolism Investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003;349:631-639. 21. Schulman S, Granqvist S, Holmström M, et al, and the Duration of Anticoagulation Trial Study Group. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med. 1997;336:393-398. 22. Ridker PM, Goldhaber SZ, Danielson E, et al, for the PREVENT Investigators. Long- term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003;348:1425-1434. 23. Harrington RA, Becker RC, Ezekowitz M, et al. Antithrombotic therapy for coronary artery disease. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:513S-548S. 24. Ansell J, Hirsh J, Pollen L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:204S-233S. 32 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25. Heneghan C, Alonso-Coello P, Garcia-Alamino JM, Perera R, Meats E, Glasziou P. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet. 2006;367:404-411. Distributed by: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA COUMADIN® and the color and configuration of COUMADIN tablets are trademarks of Bristol-Myers Squibb Pharma Company. Copyright © Bristol-Myers Squibb Company 20XX Printed in USA TBD Rev TBD 33 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE COUMADIN® (COU-ma-din) Tablets (Warfarin Sodium Tablets, USP) Crystalline Read this Medication Guide before you start taking COUMADIN (Warfarin Sodium) and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about COUMADIN when you start taking it and at regular checkups. What is the most important information I should know about COUMADIN? • Take your COUMADIN exactly as prescribed to lower the chance of blood clots forming in your body. (See “What is COUMADIN?”) • COUMADIN is very important for your health, but it can cause serious and life- threatening bleeding problems. To benefit from COUMADIN and also lower your chance for bleeding problems, you must: • Get your regular blood test to check for your response to COUMADIN. This blood test is called a PT/INR test. The PT/INR test checks to see how fast your blood clots. Your healthcare provider will decide what PT/INR numbers are best for you. Your dose of COUMADIN will be adjusted to keep your PT/INR in a target range for you. • Call your healthcare provider right away if you get any of the following signs or symptoms of bleeding problems: • pain, swelling, or discomfort • headaches, dizziness, or weakness • unusual bruising (bruises that develop without known cause or grow in size) • nosebleeds • bleeding gums • bleeding from cuts takes a long time to stop • menstrual bleeding or vaginal bleeding that is heavier than normal • pink or brown urine • red or black stools • coughing up blood 34 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • vomiting blood or material that looks like coffee grounds • Many other medicines, including prescription and non-prescription medicines, vitamins and herbal supplements can interact with COUMADIN and: • affect the dose you need, or • increase COUMADIN side effects. Tell your healthcare provider about all the medicines, vitamins, and herbal supplements you take. Do not stop medicines or take anything new unless you have talked to your healthcare provider. Keep a list of your medicines with you at all times to show your healthcare provider and pharmacist. • Do not take other medicines that contain warfarin. Warfarin is the active ingredient in COUMADIN. • Some foods can interact with COUMADIN and affect your treatment and dose. • Eat a normal, balanced diet. Talk to your doctor before you make any diet changes. Do not eat large amounts of leafy green vegetables. Leafy green vegetables contain vitamin K. Certain vegetable oils also contain large amounts of vitamin K. Too much vitamin K can lower the effect of COUMADIN. • Avoid drinking cranberry juice or eating cranberry products. • Avoid drinking alcohol. • Always tell all of your healthcare providers that you take COUMADIN. • Wear or carry information that you take COUMADIN. What is COUMADIN? COUMADIN is an anticoagulant medicine. It is used to lower the chance of blood clots forming in your body. Blood clots can cause a stroke, heart attack, or other serious conditions such as blood clots in the legs or lungs. Who should not take COUMADIN? Do not take COUMADIN if: • your chance of having bleeding problems is higher than the possible benefit of treatment. Your healthcare provider will decide if COUMADIN is right for you. Talk to your healthcare provider about all of your health conditions. 35 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • you are pregnant or plan to become pregnant. COUMADIN can cause death or birth defects to an unborn baby. Use effective birth control if you can get pregnant. • you are allergic to warfarin or to anything else in COUMADIN. What should I tell my healthcare provider before starting COUMADIN? Tell your healthcare provider about all of your health conditions, including if you: • have bleeding problems • fall often • have liver or kidney problems • have high blood pressure • have a heart problem called congestive heart failure • have diabetes • drink alcohol or have problems with alcohol abuse. Alcohol can affect your COUMADIN dose and should be avoided. • are pregnant or planning to become pregnant. See “Who should not take COUMADIN?” • are breast-feeding. COUMADIN may increase bleeding in your baby. Talk to your doctor about the best way to feed your baby. If you choose to breast-feed while taking COUMADIN, both you and your baby should be carefully monitored for bleeding problems. Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. See “What is the most important information I should know about COUMADIN?” How should I take COUMADIN? • Take COUMADIN exactly as prescribed. Your healthcare provider will adjust your dose from time to time depending on your response to COUMADIN. • You must have regular blood tests and visits with your healthcare provider to monitor your condition. • Take COUMADIN at the same time every day. You can take COUMADIN either with food or on an empty stomach. 36 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • If you miss a dose of COUMADIN, call your healthcare provider. Take the dose as soon as possible on the same day. Do not take a double dose of COUMADIN the next day to make up for a missed dose. • Call your healthcare provider right away if you take too much COUMADIN. • Call your healthcare provider if you are sick with diarrhea, an infection, or have a fever. • Tell your healthcare provider about any planned surgeries, medical or dental procedures. Your COUMADIN may have to be stopped for a short time or you may need your dose adjusted. • Call your healthcare provider right away if you fall or injure yourself, especially if you hit your head. Your healthcare provider may need to check you. What should I avoid while taking COUMADIN? • Do not start, stop, or change any medicine without talking with your healthcare provider. • Do not make changes in your diet, such as eating large amounts of green, leafy vegetables. • Do not change your weight by dieting, without first checking with your healthcare provider. • Avoid drinking alcohol. • Do not do any activity or sport that may cause a serious injury. What are the possible side effects of COUMADIN? • COUMADIN is very important for your health, but it can cause serious and life- threatening bleeding problems. See “What is the most important information I should know about COUMADIN?” • Serious side effects of COUMADIN also include: • death of skin tissue (skin necrosis or gangrene). This can happen soon after starting COUMADIN. It happens because blood clots form and block blood flow to an area of your body. Call your healthcare provider right away if you have pain, color, or temperature change to any area of your body. You may need medical care right away to prevent death or loss (amputation) of your affected body part. • “purple toes syndrome.” Call your healthcare provider right away if you have pain in your toes and they look purple in color or dark in color. 37 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Other side effects with COUMADIN include allergic reactions, liver problems, low blood pressure, swelling, low red blood cells, paleness, fever, and rash. Call your healthcare provider if you have any side effect that bothers you. These are not all of the side effects of COUMADIN. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store COUMADIN? • Store COUMADIN at room temperature between 59° and 86°F. Protect from light. • Keep COUMADIN and all medicines out of the reach of children. General Information about COUMADIN Medicines are sometimes prescribed for purposes not mentioned in a Medication Guide. Do not use COUMADIN for a condition for which it was not prescribed. Do not give COUMADIN to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about COUMADIN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about COUMADIN that was written for healthcare professionals. If you would like more information, call 1-800-321-1335 and also speak with your health care provider. Rx only COUMADIN is distributed by: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA COUMADIN® is a registered trademark of Bristol-Myers Squibb Pharma Company. COUMADIN (Warfarin Sodium), the COUMADIN color logo, COLORS OF COUMADIN, and the color and configuration of COUMADIN tablets are trademarks of Bristol-Myers Squibb Pharma Company. 38 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda **The brands listed (other than COUMADIN®) are registered trademarks of their respective owners and are not trademarks of Bristol-Myers Squibb Company. This Medication Guide has been approved by the U.S. Food and Drug Administration. TBD Rev TBD 39 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:39.419824	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/009218s108lbl.pdf', 'application_number': 9218, 'submission_type': 'SUPPL ', 'submission_number': 108}
10,724	NDA 09-321; CHOLOGRAFIN® MEGLUMINE (Iodipamide Meglumine Injection USP 52%) CHOLOGRAFIN _PI_(Patheon-CL64903) CLEAN_Rev June-2015 company logo Bracco Diagnostics CL64903 - 000000 CHOLOGRAFIN® MEGLUMINE Iodipamide Meglumine Injection USP 52% NOT FOR INTRATHECAL USE FOR INTRAVENOUS USE ONLY DESCRIPTION Cholografin Meglumine (lodipamide Meglumine Injection 52%) is a radiopaque contrast agent for rapid intravenous cholangiography and cholecystography supplied as a sterile, aqueous solution. Each mL provides 520 mg iodipamide meglumine; at manufacture, 3.2 mg sodium citrate buffer and 0.4 mg edetate disodium sequestering agent are added per mL. The pH has been adjusted between 6.5 and 7.7 with meglumine and iodipamide. Each mL of solution also contains approximately 0.91 mg (0.039 mEq) sodium [18.2 mg/20 mL] and 257 mg organically bound iodine (5.2 g/20 mL). At the time of manufacture, the air in the container is replaced by nitrogen. The appearance of the solution may vary from essentially colorless to light amber. Solutions which have become substantially darker, however, should not be used. CLINICAL PHARMACOLOGY Following intravenous administration of Cholografin Meglumine, iodipamide is carried to the liver where it is rapidly secreted. The contrast medium appears in the bile within 10 to 15 minutes after injection, thus permitting visualization of the hepatic and common bile ducts, even in cholecystectomized patients. The biliary ducts are readily visualized within about 25 minutes after administration, except in patients with impaired liver function. The gallbladder begins to fill within an hour after injection; maximum filling is reached after two to two and one-half hours. The contrast medium is finally eliminated in the feces without passing through the enterohepatic circulation, except for approximately 10 percent of the intravenously administered dose which is excreted through the kidneys. The LD50 for intravenous administration of a 52% iodipamide meglumine solution in mice is 6.2 ± 0.3 mL/kg (equivalent to 3224 ± 156 mg iodipamide meglumine/kg). INDICATIONS AND USAGE Cholografin Meglumine is indicated for intravenous cholangiography and cholecystography as follows: (a) visualization of the gallbladder and biliary ducts in the differential diagnosis of acute abdominal conditions, (b) visualization of the biliary ducts, especially in patients with symptoms after cholecystectomy, and (c) visualization of the gallbladder in patients unable to take oral contrast media or to absorb contrast media from the gastrointestinal tract. Reference ID: 3788307 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS Cholografin is contraindicated for use in intrathecal procedures. lodipamide meglumine is contraindicated in patients with a hypersensitivity to salts of iodipamide or who exhibit sensitivity reactions to the test dose. It is also contraindicated in patients with concomitant severe impairment of renal and liver function. WARNINGS Severe Adverse Events–Inadvertent Intrathecal Administration Serious adverse reactions have been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use. These serious adverse reactions include: death,convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. Special attention must be given to insure that this drug product is not inadvertently administered intrathecally. The possibility exists for inadvertent administration into the intrathecal space during epidural administrations. Therefore, epidural administration procedures, such as pain management catheter placement, should not be performed with use of this product. General Administration of radiopaque materials to patients known or suspected to have pheochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the possible benefits of such procedures outweigh the considered risks, the procedures may be performed; however, the amount of radiopaque medium injected should be kept to an absolute minimum. The blood pressure should be assessed throughout the procedure and measures for treatment of a hypertensive crisis should be available. Contrast media have been shown to promote the phenomenon of sickling in individuals who are homozygous for sickle cell disease when the material is injected intravenously or intra-arterially. Since iodine-containing contrast agents may alter the results of thyroid function tests, such tests, if indicated, should be performed prior to the administration of this preparation. A history of sensitivity to iodine per se or to other contrast agents is not an absolute contraindication to the use of iodipamide meglumine, but calls for extreme caution in administration. PRECAUTIONS Diagnostic procedures which involve the use of radiopaque contrast agents should be carried out under the direction of personnel with the prerequisite training and with a thorough knowledge of the particular procedure to be performed. Appropriate facilities should be available for coping with situations which may arise as a result of the procedure, as well as for emergency treatment of severe reactions to the contrast agent itself. After intravascular administration of a radiopaque agent, competent personnel and emergency facilities should be available for at least 30 to 60 minutes, since severe delayed reactions have been known to occur. Reference ID: 3788307 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda These severe, life-threatening reactions suggest hypersensitivity to the radiopaque agent, which has prompted the use of several pretesting methods, none of which can be relied upon to predict severe reactions. Many authorities question the value of any pretest. A history of bronchial asthma or allergy, a family history of allergy, or a previous reaction to a contrast agent warrant special attention. Such a history, by suggesting histamine sensitivity and a consequent proneness to reactions, may be more accurate than pretesting in predicting the likelihood of a reaction, although not necessarily the severity or type of reaction in the individual case. The sensitivity test most often performed is the slow injection of 0.5 to 1.0 mL of the radiopaque medium, administered intravenously, prior to injection of the full diagnostic dose. It should be noted that the absence of a reaction to the test dose does not preclude the possibility of a reaction to the full diagnostic dose. If the test dose causes an untoward response of any kind, the necessity for continuing with the examination should be carefully reevaluated and, if it is deemed essential, the examination should be conducted with all possible caution. In rare instances reactions to the test dose itself may be extremely severe; therefore, close observation of the patient, and facilities for emergency treatment, appear indicated. Caution should be exercised with the use of radiopaque media in severely debilitated patients and in those with marked hypertension. The possibility of thrombosis should be borne in mind when intravenous techniques are employed. Contrast agents may interfere with some chemical determinations made on urine specimens; therefore, urine should be collected before administration of the contrast media or two or more days afterwards. Some clinicians feel it may be advisable to have a continuous intravenous infusion running prior to and during administration of the drug. The admixture of Benadryl® (Diphenhydramine Hydrochloride Injection) with Cholografin Meglumine (lodipamide Meglumine Injection USP 52%) may cause a precipitate which may form in the syringe or tubing. If antihistamines are administered concomitantly, they should not be mixed with the contrast agent but administered at another site. Usage in Pregnancy The safety of iodipamide meglumine for use during pregnancy has not been established; therefore, it should be used in pregnant patients, only when, in the judgment of the physician, its use is deemed essential to the welfare of the patient. ADVERSE REACTIONS Local reactions at the site of injection are not observed, unless excessive amounts are extravasated during injection. After too rapid administration, mild transient symptoms such as restlessness, sensations of warmth, sneezing, perspiration, salivation, flushing, pressure in the upper abdomen, dizziness, nausea, vomiting, chills, fever, headache, pallor and tremors may occur. These symptoms disappear when the injection has been completed. Rarely, swollen eyelids, laryngospasm, respiratory difficulties, hypotension, cardiac reactions and cyanosis have been reported. Hypersensitivity reactions may occur. In rare instances, despite the most careful sensitivity testing, anaphylactoid reactions may occur. Renal function tests may be altered and renal failure may occur. Reference ID: 3788307 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Thyroid function tests indicative of hypothyroidism or transient thyroid suppression have been uncommonly reported following iodinated contrast media administration to adult and pediatric patients, including infants. Some patients were treated for hypothyroidism. DOSAGE AND ADMINISTRATION Cholografin Meglumine (lodipamide Meglumine Injection USP 52%) is for intravenous use only. Directions For Use Preparation of the Patient: For best results, the usual preliminary measures for cholecystography are recommended, particularly in cholecystectomized patients, i.e., a low residue diet on the day before examination and administration of castor oil the night before or neostigmine at the time of examination to dispel excess intestinal gas. Cholecystography is preferably carried out in the morning with the patient fasting. Dose: The usual adult dose is 20 mL. For infants and children, the suggested dose is 0.3 to 0.6 mL/kg of body weight; the dosage for infants and children should not exceed 20 mL. Note: The dose should not be repeated for 24 hours. Administration: After warming to body temperature, Cholografin Meglumine should be given by slow intravenous injection, following the usual precautions of intravenous administration. It is important that the preparation be injected slowly over a period of 10 minutes. Use of a narrow bore hypodermic needle will ensure a slow rate of injection. During the injection, the patient should be watched for untoward reactions such as a feeling of warmth, flushing and occasionally nausea. Nausea indicates that the injection rate is too rapid. Radiography: A scout film should be exposed routinely before the intravenous injection is made. Position of the Patient: With the patient prone and the right side elevated, radiographs are made in the posterior-anterior projection. Some radiologists prefer the supine position with the left side elevated. Serial 10-minute exposures should be started 10 minutes after the injection is made and continued until optimal visualization of the biliary ducts is obtained. Wet films should be examined immediately by the radiologist. In some cases a 15-degree rotation or the upright position may prove helpful. Depending on the situation revealed by the roentgenograms in which the duct is first seen, the position of the subject should be changed to displace the shadow of the common bile duct from that of the spine. Tomography is a useful technique for enhancing bile duct visualization after administration of the radiopaque medium. Examination of the gallbladder should be started about two hours after administration. The standard positions in routine examination of the gallbladder should be used unless otherwise indicated. There is no need for the patient to remain quiet awaiting the time for the gallbladder film to be exposed. Moderate activity on the part of the patient will, in most cases, preclude “stratification” of the contrast agent in the gallbladder. If the contrast medium should stratify in the gallbladder, decubitus as well as upright films should be obtained. Additional exposures may be made after the ingestion of a fatty meal. If visualization is not achieved after two and one-half hours, the patient should be returned for a 24-hour film, whenever possible. Occasionally, delayed opacification of the gallbladder will occur in 24 hours. Reference ID: 3788307 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In infants and children, gallbladder visualization may be expected to occur 30 minutes to four hours after administration. Note: In the presence of liver disease (BSP retention greater than 30 to 40 percent), the contrast medium is not excreted efficiently by the liver and visualization is usually not achieved. Visualization is rarely achieved in the presence of a serum bilirubin of 3.0 mg per 100 mL if the elevated bilirubin level is due to mechanical obstruction or hepatocellular damage. In the presence of severe liver damage, the contrast agent is excreted by the kidneys. Interpretation: When intravenous cholecystography and cholangiography are used as an aid in the differential diagnosis of acute abdominal conditions, visualization of the gallbladder is considered strong evidence against a diagnosis of acute cholecystitis, while nonvisualization of the gallbladder two and one-half hours after administration with visualization of the bile ducts is considered strong evidence in favor of a diagnosis of acute cholecystitis (if the bile ducts are only faintly visualized, gallbladder films four hours after administration may occasionally show visualization of the gallbladder). When neither the bile ducts nor the gallbladder is visualized, the study provides no definitive information with regard to determining the presence or absence of acute cholecystitis. HOW SUPPLIED Cholografin Meglumine (lodipamide Meglumine Injection USP 52%) is available in single dose vials of 20 mL (NDC 0270-0265-20). Storage Protect from light; store at 20 -25°C (68-77°F) [See USP]; avoid excessive heat. In the event that crystallization occurs, the solution may be clarified by placing the vial in hot water and shaking gently for several minutes or until the solids redissolve. If cloudiness persists, discard the preparation. Allow the solution to cool to body temperature before administering. Rx only Manufactured for Bracco Diagnostics Inc. Monroe Township, NJ 08831 by Patheon Italia S.p.A. 03013 Ferentino (Italy) Revised June 2015 CL64903 - 000000 Reference ID: 3788307 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:39.526731	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/009321s028lbl.pdf', 'application_number': 9321, 'submission_type': 'SUPPL ', 'submission_number': 28}
10,723	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use COUMADIN safely and effectively. See full prescribing information for COUMADIN. COUMADIN (warfarin sodium) tablets, for oral use COUMADIN (warfarin sodium) for injection, for intravenous use Initial U.S. Approval: 1954 WARNING: BLEEDING RISK See full prescribing information for complete boxed warning. • COUMADIN can cause major or fatal bleeding. (5.1) • Perform regular monitoring of INR in all treated patients. (2.1) • Drugs, dietary changes, and other factors affect INR levels achieved with COUMADIN therapy. (7) • Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding. (17) ---------------------------INDICATIONS AND USAGE--------------------------- COUMADIN is a vitamin K antagonist indicated for: • Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (1) • Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement (1) • Reduction in the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction (1) Limitations of Use COUMADIN has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. (1) ------------------------DOSAGE AND ADMINISTRATION--------------------- • Individualize dosing regimen for each patient, and adjust based on INR response. (2.1, 2.2) • Knowledge of genotype can inform initial dose selection. (2.3) • Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. (2.4) • Review conversion instructions from other anticoagulants. (2.8) ----------------------DOSAGE FORMS AND STRENGTHS-------------------- • Scored tablets: 1, 2, 2-1/2, 3, 4, 5, 6, 7-1/2, or 10 mg (3) • For injection: 5 mg, lyophilized powder in single-use vial for reconstitution (3) ------------------------------CONTRAINDICATIONS------------------------------ • Pregnancy, except in women with mechanical heart valves (4, 5.5, 8.1) • Hemorrhagic tendencies or blood dyscrasias (4) • Recent or contemplated surgery of the central nervous system (CNS) or eye, or traumatic surgery resulting in large open surfaces (4, 5.7) • Bleeding tendencies associated with certain conditions (4) • Threatened abortion, eclampsia, and preeclampsia (4) • Unsupervised patients with potential high levels of non-compliance (4) • Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding (4) • Hypersensitivity to warfarin or any component of the product (4) • Major regional or lumbar block anesthesia (4) • Malignant hypertension (4) ------------------------WARNINGS AND PRECAUTIONS---------------------- • Tissue necrosis: Necrosis or gangrene of skin or other tissues can occur, with severe cases requiring debridement or amputation. Discontinue COUMADIN and consider alternative anticoagulants if necessary. (5.2) • Systemic atheroemboli and cholesterol microemboli: Some cases have progressed to necrosis or death. Discontinue COUMADIN if such emboli occur. (5.3) • Heparin-induced thrombocytopenia (HIT): Initial therapy with COUMADIN in HIT has resulted in cases of amputation and death. COUMADIN may be considered after platelet count has normalized. (5.4) • Pregnant women with mechanical heart valves: COUMADIN may cause fetal harm; however, the benefits may outweigh the risks. (5.5) -------------------------------ADVERSE REACTIONS----------------------------- Most common adverse reactions to COUMADIN are fatal and nonfatal hemorrhage from any tissue or organ. (6) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. --------------------------------DRUG INTERACTIONS---------------------------- • Concomitant use of drugs that increase bleeding risk, antibiotics, antifungals, botanical (herbal) products, and inhibitors and inducers of CYP2C9, 1A2, or 3A4 (7). • Consult labeling of all concurrently used drugs for complete information about interactions with COUMADIN or increased risks for bleeding. (7) ------------------------USE IN SPECIFIC POPULATIONS---------------------- • Pregnant women with mechanical heart valves: COUMADIN may cause fetal harm; however, the benefits may outweigh the risks. (8.1) • Lactation. Monitor breastfeeding infants for bruising or bleeding. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 10/2015 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: BLEEDING RISK 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Individualized Dosing 2.2 Recommended Target INR Ranges and Durations for Individual Indications 2.3 Initial and Maintenance Dosing 2.4 Monitoring to Achieve Optimal Anticoagulation 2.5 Missed Dose 2.6 Intravenous Route of Administration 2.7 Treatment During Dentistry and Surgery 2.8 Conversion From Other Anticoagulants 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hemorrhage 5.2 Tissue Necrosis 5.3 Systemic Atheroemboli and Cholesterol Microemboli 5.4 Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS 5.5 Use in Pregnant Women with Mechanical Heart Valves 5.6 Other Clinical Settings with Increased Risks 5.7 Endogenous Factors Affecting INR 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 7.1 CYP450 Interactions 7.2 Drugs that Increase Bleeding Risk 7.3 Antibiotics and Antifungals 7.4 Botanical (Herbal) Products and Foods 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 10.1 Signs and Symptoms 10.2 Treatment 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacogenomics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Atrial Fibrillation 14.2 Mechanical and Bioprosthetic Heart Valves 14.3 Myocardial Infarction 1 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING * Sections or subsections omitted from the full prescribing information 17 PATIENT COUNSELING INFORMATION are not listed 2 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION WARNING: BLEEDING RISK • COUMADIN can cause major or fatal bleeding [see Warnings and Precautions (5.1)]. • Perform regular monitoring of INR in all treated patients [see Dosage and Administration (2.1)]. • Drugs, dietary changes, and other factors affect INR levels achieved with COUMADIN therapy [see Drug Interactions (7)]. • Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17)]. 1 INDICATIONS AND USAGE COUMADIN is indicated for: • Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE). • Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement. • Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction. Limitations of Use COUMADIN has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. Once a thrombus has occurred, however, the goals of anticoagulant treatment are to prevent further extension of the formed clot and to prevent secondary thromboembolic complications that may result in serious and possibly fatal sequelae. 2 DOSAGE AND ADMINISTRATION 2.1 Individualized Dosing The dosage and administration of COUMADIN must be individualized for each patient according to the patient’s INR response to the drug. Adjust the dose based on the patient’s INR 3 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and the condition being treated. Consult the latest evidence-based clinical practice guidelines regarding the duration and intensity of anticoagulation for the indicated conditions. 2.2 Recommended Target INR Ranges and Durations for Individual Indications An INR of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding. Venous Thromboembolism (including deep venous thrombosis [DVT] and PE) Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows: • For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. • For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient. • For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient. Atrial Fibrillation In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0 3.0). • In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. • In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. • For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended. 4 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors. Mechanical and Bioprosthetic Heart Valves • For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended. • For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. • For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. • For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended. Post-Myocardial Infarction • For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended. Recurrent Systemic Embolism and Other Indications Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients. 2.3 Initial and Maintenance Dosing The appropriate initial dosing of COUMADIN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by: • Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities • Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5)] 5 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation. Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2)]. Dosing Recommendations without Consideration of Genotype If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg once daily. Determine each patient’s dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily. Dosing Recommendations with Consideration of Genotype Table 1 displays three ranges of expected maintenance COUMADIN doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants [see Clinical Pharmacology (12.5)]. If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose. Patients with CYP2C9 1/3, 2/2, 2/3, and 3/3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants. Table 1: Three Ranges of Expected Maintenance COUMADIN Daily Doses Based on CYP2C9 and VKORC1 Genotypes† VKORC1 CYP2C9 1/1 1/2 1/3 2/2 2/3 3/3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg †Ranges are derived from multiple published clinical studies. VKORC1 −1639G>A (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin dose. 6 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2.4 Monitoring to Achieve Optimal Anticoagulation COUMADIN has a narrow therapeutic range (index), and its action may be affected by factors such as other drugs and dietary vitamin K. Therefore, anticoagulation must be carefully monitored during COUMADIN therapy. Determine the INR daily after the administration of the initial dose until INR results stabilize in the therapeutic range. After stabilization, maintain dosing within the therapeutic range by performing periodic INRs. The frequency of performing INR should be based on the clinical situation but generally acceptable intervals for INR determinations are 1 to 4 weeks. Perform additional INR tests when other warfarin products are interchanged with COUMADIN, as well as whenever other medications are initiated, discontinued, or taken irregularly. Heparin, a common concomitant drug, increases the INR [see Dosage and Administration (2.8) and Drug Interactions (7)]. Determinations of whole blood clotting and bleeding times are not effective measures for monitoring of COUMADIN therapy. 2.5 Missed Dose The anticoagulant effect of COUMADIN persists beyond 24 hours. If a patient misses a dose of COUMADIN at the intended time of day, the patient should take the dose as soon as possible on the same day. The patient should not double the dose the next day to make up for a missed dose. 2.6 Intravenous Route of Administration The intravenous dose of COUMADIN is the same as the oral dose. After reconstitution, administer COUMADIN for injection as a slow bolus injection into a peripheral vein over 1 to 2 minutes. COUMADIN for injection is not recommended for intramuscular administration. Reconstitute the vial with 2.7 mL of Sterile Water for Injection. The resulting yield is 2.5 mL of a 2 mg per mL solution (5 mg total). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if particulate matter or discoloration is noted. After reconstitution, COUMADIN for injection is stable for 4 hours at room temperature. It does not contain any antimicrobial preservative and, thus, care must be taken to assure the sterility of the prepared solution. The vial is for single use only, discard any unused solution. 7 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2.7 Treatment During Dentistry and Surgery Some dental or surgical procedures may necessitate the interruption or change in the dose of COUMADIN therapy. Consider the benefits and risks when discontinuing COUMADIN even for a short period of time. Determine the INR immediately prior to any dental or surgical procedure. In patients undergoing minimally invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of COUMADIN to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation. 2.8 Conversion From Other Anticoagulants Heparin Since the full anticoagulant effect of COUMADIN is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with COUMADIN, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to COUMADIN may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure therapeutic anticoagulation, continue full dose heparin therapy and overlap COUMADIN therapy with heparin for 4 to 5 days and until COUMADIN has produced the desired therapeutic response as determined by INR, at which point heparin may be discontinued. As heparin may affect the INR, patients receiving both heparin and COUMADIN should have INR monitoring at least: • 5 hours after the last intravenous bolus dose of heparin, or • 4 hours after cessation of a continuous intravenous infusion of heparin, or • 24 hours after the last subcutaneous heparin injection. COUMADIN may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin. A severe elevation (>50 seconds) in aPTT with an INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage. Other Anticoagulants Consult the labeling of other anticoagulants for instructions on conversion to COUMADIN. 8 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 DOSAGE FORMS AND STRENGTHS Tablets COUMADIN Single-Scored Tablets Strength Color Superimposed Imprint 1 mg Pink 1 2 mg Lavender 2 2.5 mg Green 2-1/2 3 mg Tan 3 4 mg Blue 4 5 mg Peach 5 6 mg Teal 6 7.5 mg Yellow 7-1/2 10 mg White (dye-free) 10 For Injection For injection: 5 mg, lyophilized powder in a single-use vial. 4 CONTRAINDICATIONS COUMADIN is contraindicated in: • Pregnancy COUMADIN is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)]. COUMADIN can cause fetal harm when administered to a pregnant woman. COUMADIN exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If COUMADIN is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. COUMADIN is contraindicated in patients with: 9 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Hemorrhagic tendencies or blood dyscrasias • Recent or contemplated surgery of the central nervous system or eye, or traumatic surgery resulting in large open surfaces [see Warnings and Precautions (5.7)] • Bleeding tendencies associated with: − Active ulceration or overt bleeding of the gastrointestinal, genitourinary, or respiratory tract − Central nervous system hemorrhage − Cerebral aneurysms, dissecting aorta − Pericarditis and pericardial effusions − Bacterial endocarditis • Threatened abortion, eclampsia, and preeclampsia • Unsupervised patients with conditions associated with potential high level of non-compliance • Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding • Hypersensitivity to warfarin or to any other components of this product (e.g., anaphylaxis) [see Adverse Reactions (6)] • Major regional or lumbar block anesthesia • Malignant hypertension 5 WARNINGS AND PRECAUTIONS 5.1 Hemorrhage COUMADIN can cause major or fatal bleeding. Bleeding is more likely to occur within the first month. Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors [see Clinical Pharmacology (12.5)], certain concomitant drugs [see Drug Interactions (7)], and long duration of warfarin therapy. Perform regular monitoring of INR in all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a 10 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda shortest duration of therapy appropriate for the clinical condition. However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding. Drugs, dietary changes, and other factors affect INR levels achieved with COUMADIN therapy. Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs [see Drug Interactions (7)]. Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17)]. 5.2 Tissue Necrosis Necrosis and/or gangrene of skin and other tissues is an uncommon but serious risk (<0.1%). Necrosis may be associated with local thrombosis and usually appears within a few days of the start of COUMADIN therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported. Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. Discontinue COUMADIN therapy if necrosis occurs. Consider alternative drugs if continued anticoagulation therapy is necessary. 5.3 Systemic Atheroemboli and Cholesterol Microemboli Anticoagulation therapy with COUMADIN may enhance the release of atheromatous plaque emboli. Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. A distinct syndrome resulting from microemboli to the feet is known as “purple toes syndrome.” Discontinue COUMADIN therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary. 5.4 Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS Do not use COUMADIN as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when 11 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda heparin treatment was discontinued and warfarin therapy was started or continued. In some patients, sequelae have included amputation of the involved area and/or death. Treatment with COUMADIN may be considered after the platelet count has normalized. 5.5 Use in Pregnant Women with Mechanical Heart Valves COUMADIN can cause fetal harm when administered to a pregnant woman. While COUMADIN is contraindicated during pregnancy, the potential benefits of using COUMADIN may outweigh the risks for pregnant women with mechanical heart valves at high risk of thromboembolism. In those individual situations, the decision to initiate or continue COUMADIN should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient’s medical situation, as well as the most current medical guidelines. COUMADIN exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 5.6 Other Clinical Settings with Increased Risks In the following clinical settings, the risks of COUMADIN therapy may be increased: • Moderate to severe hepatic impairment • Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy) • Use of an indwelling catheter • Severe to moderate hypertension • Deficiency in protein C-mediated anticoagulant response: COUMADIN reduces the synthesis of the naturally occurring anticoagulants, protein C and protein S. Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with COUMADIN may minimize the incidence of tissue necrosis in these patients. • Eye surgery: In cataract surgery, COUMADIN use was associated with a significant increase in minor complications of sharp needle and local anesthesia block but not associated with potentially sight-threatening operative hemorrhagic complications. As COUMADIN cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue COUMADIN before a relatively less invasive and complex eye surgery, such as 12 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda lens surgery, should be based upon the risks of anticoagulant therapy weighed against the benefits. • Polycythemia vera • Vasculitis • Diabetes mellitus 5.7 Endogenous Factors Affecting INR The following factors may be responsible for increased INR response: diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency. The following factors may be responsible for decreased INR response: increased vitamin K intake or hereditary warfarin resistance. 6 ADVERSE REACTIONS The following serious adverse reactions to COUMADIN are discussed in greater detail in other sections of the labeling: • Hemorrhage [see Boxed Warning, Warnings and Precautions (5.1), and Overdosage (10)] • Necrosis of skin and other tissues [see Warnings and Precautions (5.2)] • Systemic atheroemboli and cholesterol microemboli [see Warnings and Precautions (5.3)] Other adverse reactions to COUMADIN include: • Immune system disorders: hypersensitivity/allergic reactions (including urticaria and anaphylactic reactions) • Vascular disorders: vasculitis • Hepatobiliary disorders: hepatitis, elevated liver enzymes. Cholestatic hepatitis has been associated with concomitant administration of COUMADIN and ticlopidine. • Gastrointestinal disorders: nausea, vomiting, diarrhea, taste perversion, abdominal pain, flatulence, bloating • Skin disorders: rash, dermatitis (including bullous eruptions), pruritus, alopecia • Respiratory disorders: tracheal or tracheobronchial calcification • General disorders: chills 13 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 DRUG INTERACTIONS Drugs may interact with COUMADIN through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with COUMADIN are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and alteration of the physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with COUMADIN are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism. More frequent INR monitoring should be performed when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs, including drugs intended for short-term use (e.g., antibiotics, antifungals, corticosteroids) [see Boxed Warning]. Consult the labeling of all concurrently used drugs to obtain further information about interactions with COUMADIN or adverse reactions pertaining to bleeding. 7.1 CYP450 Interactions CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the R-enantiomer is metabolized by CYP1A2 and 3A4. • Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of warfarin by increasing the exposure of warfarin. • Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing the exposure of warfarin. Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in Table 2; however, this list should not be considered all-inclusive. Consult the labeling of all concurrently used drugs to obtain further information about CYP450 interaction potential. The CYP450 inhibition and induction potential should be considered when starting, stopping, or changing dose of concomitant medications. Closely monitor INR if a concomitant drug is a CYP2C9, 1A2, and/or 3A4 inhibitor or inducer. 14 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 2: Examples of CYP450 Interactions with Warfarin Enzyme Inhibitors Inducers CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 7.2 Drugs that Increase Bleeding Risk Examples of drugs known to increase the risk of bleeding are presented in Table 3. Because bleeding risk is increased when these drugs are used concomitantly with warfarin, closely monitor patients receiving any such drug with warfarin. Table 3: Drugs that Can Increase the Risk of Bleeding Drug Class Specific Drugs Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 7.3 Antibiotics and Antifungals There have been reports of changes in INR in patients taking warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of warfarin. 15 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Closely monitor INR when starting or stopping any antibiotic or antifungal in patients taking warfarin. 7.4 Botanical (Herbal) Products and Foods More frequent INR monitoring should be performed when starting or stopping botanicals. Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and COUMADIN exist. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation. Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of COUMADIN. Conversely, some botanicals may decrease the effects of COUMADIN (e.g., co-enzyme Q10, St. John’s wort, ginseng). Some botanicals and foods can interact with COUMADIN through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St. John’s wort). The amount of vitamin K in food may affect therapy with COUMADIN. Advise patients taking COUMADIN to eat a normal, balanced diet maintaining a consistent amount of vitamin K. Patients taking COUMADIN should avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary COUMADIN is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of COUMADIN may outweigh the risks [see Warnings and Precautions (5.5)]. COUMADIN can cause fetal harm. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Because these data were not collected in adequate and well-controlled studies, this incidence of major birth defects are not an 16 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda adequate basis for comparison to the estimated incidences in the control group or the U.S. general population and may not reflect the incidences observed in practice. Consider the benefits and risks of COUMADIN and possible risks to the fetus when prescribing COUMADIN to a pregnant woman. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions In humans, warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal values. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight). Central nervous system and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy. Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following warfarin exposure during the second and third trimesters of pregnancy [see Contraindications (4)]. 8.2 Lactation Risk Summary Warfarin was not present in human milk from mothers treated with warfarin from a limited published study. Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for COUMADIN and any potential adverse effects on the breastfed infant from COUMADIN or from the underlying maternal condition before prescribing COUMADIN to a lactating woman. Clinical Considerations Monitor breastfeeding infants for bruising or bleeding. 17 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Data Human Data Based on published data in 15 nursing mothers, warfarin was not detected in human milk. Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Effects in premature infants have not been evaluated. 8.3 Females and Males of Reproductive Potential Pregnancy Testing COUMADIN can cause fetal harm [see Use in Specific Populations (8.1)]. Verify the pregnancy status of females of reproductive potential prior to initiating COUMADIN therapy. Contraception Females Advise females of reproductive potential to use effective contraception during treatment, and for at least 1 month after the final dose of COUMADIN. 8.4 Pediatric Use Adequate and well-controlled studies with COUMADIN have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown. Pediatric use of COUMADIN is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries. Pediatric patients administered COUMADIN should avoid any activity or sport that may result in traumatic injury. The developing hemostatic system in infants and children results in a changing physiology of thrombosis and response to anticoagulants. Dosing of warfarin in the pediatric population varies by patient age, with infants generally having the highest, and adolescents having the lowest milligram per kilogram dose requirements to maintain target INRs. Because of changing warfarin requirements due to age, concomitant medications, diet, and existing medical condition, 18 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda target INR ranges may be difficult to achieve and maintain in pediatric patients, and more frequent INR determinations are recommended. Bleeding rates varied by patient population and clinical care center in pediatric observational studies and patient registries. Infants and children receiving vitamin K-supplemented nutrition, including infant formulas, may be resistant to warfarin therapy, while human milk-fed infants may be sensitive to warfarin therapy. 8.5 Geriatric Use Of the total number of patients receiving warfarin sodium in controlled clinical trials for which data were available for analysis, 1885 patients (24.4%) were 65 years and older, while 185 patients (2.4%) were 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin [see Clinical Pharmacology (12.3)]. COUMADIN is contraindicated in any unsupervised patient with senility. Observe caution with administration of COUMADIN to elderly patients in any situation or with any physical condition where added risk of hemorrhage is present. Consider lower initiation and maintenance doses of COUMADIN in elderly patients [see Dosage and Administration (2.2, 2.3)]. 8.6 Renal Impairment Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal impairment. 8.7 Hepatic Impairment Hepatic impairment can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin. Use caution when using COUMADIN in these patients. 19 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 OVERDOSAGE 10.1 Signs and Symptoms Bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries, unexplained fall in hemoglobin) is a manifestation of excessive anticoagulation. 10.2 Treatment The treatment of excessive anticoagulation is based on the level of the INR, the presence or absence of bleeding, and clinical circumstances. Reversal of COUMADIN anticoagulation may be obtained by discontinuing COUMADIN therapy and, if necessary, by administration of oral or parenteral vitamin K1. The use of vitamin K1 reduces response to subsequent COUMADIN therapy and patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged INR. Resumption of COUMADIN administration reverses the effect of vitamin K, and a therapeutic INR can again be obtained by careful dosage adjustment. If rapid re-anticoagulation is indicated, heparin may be preferable for initial therapy. Prothrombin complex concentrate (PCC), fresh frozen plasma, or activated Factor VII treatment may be considered if the requirement to reverse the effects of COUMADIN is urgent. A risk of hepatitis and other viral diseases is associated with the use of blood products; PCC and activated Factor VII are also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to COUMADIN overdosage. 11 DESCRIPTION COUMADIN (warfarin sodium) tablets and COUMADIN (warfarin sodium) for Injection contain warfarin sodium, an anticoagulant that acts by inhibiting vitamin K-dependent coagulation factors. The chemical name of warfarin sodium is 3-(α-acetonylbenzyl)-4 hydroxycoumarin sodium salt, which is a racemic mixture of the R- and S-enantiomers. Crystalline warfarin sodium is an isopropanol clathrate. Its empirical formula is C19H15NaO4, and its structural formula is represented by the following: 20 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula Crystalline warfarin sodium occurs as a white, odorless, crystalline powder that is discolored by light. It is very soluble in water, freely soluble in alcohol, and very slightly soluble in chloroform and ether. COUMADIN tablets for oral use also contain: All strengths: Lactose, starch, and magnesium stearate 1 mg: D&C Red No. 6 Barium Lake 2 mg: FD&C Blue No. 2 Aluminum Lake and FD&C Red No. 40 Aluminum Lake 2-1/2 mg: D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake 3 mg: FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, and FD&C Red No. 40 Aluminum Lake 4 mg: FD&C Blue No. 1 Aluminum Lake 5 mg: FD&C Yellow No. 6 Aluminum Lake 6 mg: FD&C Yellow No. 6 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake 7-1/2 mg: D&C Yellow No. 10 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake 10 mg: Dye-free COUMADIN for injection for intravenous use is supplied as a sterile, lyophilized powder, which, after reconstitution with 2.7 mL Sterile Water for Injection, contains: Warfarin sodium 2 mg per mL Sodium phosphate, dibasic, heptahydrate 4.98 mg per mL Sodium phosphate, monobasic, monohydrate 0.194 mg per mL Sodium chloride 0.1 mg per mL Mannitol 38.0 mg per mL Sodium hydroxide, as needed for pH adjustment to 8.1 to 8.3 21 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K-dependent clotting factors. Vitamin K promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins that are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K1 epoxide [see Clinical Pharmacology (12.5)]. 12.2 Pharmacodynamics An anticoagulation effect generally occurs within 24 hours after warfarin administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of COUMADIN may become more pronounced as effects of daily maintenance doses overlap. This is consistent with the half-lives of the affected vitamin K-dependent clotting factors and anticoagulation proteins: Factor II - 60 hours, VII - 4 to 6 hours, IX - 24 hours, X - 48 to 72 hours, and proteins C and S are approximately 8 hours and 30 hours, respectively. 12.3 Pharmacokinetics COUMADIN is a racemic mixture of the R- and S-enantiomers of warfarin. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance. Absorption Warfarin is essentially completely absorbed after oral administration, with peak concentration generally attained within the first 4 hours. Distribution Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 L/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral 22 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda administration of an aqueous solution. Approximately 99% of the drug is bound to plasma proteins. Metabolism The elimination of warfarin is almost entirely by metabolism. Warfarin is stereoselectively metabolized by hepatic cytochrome P-450 (CYP450) microsomal enzymes to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols) with minimal anticoagulant activity. Identified metabolites of warfarin include dehydrowarfarin, two diastereoisomer alcohols, and 4′-, 6-, 7-, 8-, and 10 hydroxywarfarin. The CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. CYP2C9, a polymorphic enzyme, is likely to be the principal form of human liver CYP450 that modulates the in vivo anticoagulant activity of warfarin. Patients with one or more variant CYP2C9 alleles have decreased S-warfarin clearance [see Clinical Pharmacology (12.5)]. Excretion The terminal half-life of warfarin after a single dose is approximately 1 week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites. Geriatric Patients Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin. The cause of the increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown but may be due to a combination of pharmacokinetic and pharmacodynamic factors. Limited information suggests there is no difference in the clearance of S-warfarin; however, there may be a slight decrease in the clearance of R-warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation [see Dosage and Administration (2.3, 2.4)]. 23 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Asian Patients Asian patients may require lower initiation and maintenance doses of warfarin. A non-controlled study of 151 Chinese outpatients stabilized on warfarin for various indications reported a mean daily warfarin requirement of 3.3 ± 1.4 mg to achieve an INR of 2 to 2.5. Patient age was the most important determinant of warfarin requirement in these patients, with a progressively lower warfarin requirement with increasing age. 12.5 Pharmacogenomics CYP2C9 and VKORC1 Polymorphisms The S-enantiomer of warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphic enzyme. The variant alleles, CYP2C92 and CYP2C93, result in decreased in vitro CYP2C9 enzymatic 7-hydroxylation of S-warfarin. The frequencies of these alleles in Caucasians are approximately 11% and 7% for CYP2C92 and CYP2C93, respectively. Other CYP2C9 alleles associated with reduced enzymatic activity occur at lower frequencies, including 5, 6, and 11 alleles in populations of African ancestry and 5, 9, and 11 alleles in Caucasians. Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle through inhibition of VKOR, a multiprotein enzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene (e.g., –1639G>A) have been associated with variable warfarin dose requirements. VKORC1 and CYP2C9 gene variants generally explain the largest proportion of known variability in warfarin dose requirements. CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the initial dose of warfarin [see Dosage and Administration (2.3)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, or fertility studies have not been performed with warfarin. 24 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 CLINICAL STUDIES 14.1 Atrial Fibrillation In five prospective, randomized, controlled clinical trials involving 3711 patients with non- rheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (see Table 4). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%), which was stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6% to 2.7% (see Table 4). Table 4: Clinical Studies of Warfarin in Non-Rheumatic AF Patients* Study N Warfarin- Treated Patients Control Patients PT Ratio INR Thromboembolism % Risk Reduction p-value % Major Bleeding Warfarin- Treated Patients Control Patients AFASAK 335 336 1.5-2.0 2.8-4.2 60 0.027 0.6 0.0 SPAF 210 211 1.3-1.8 2.0-4.5 67 0.01 1.9 1.9 BAATAF 212 208 1.2-1.5 1.5-2.7 86 <0.05 0.9 0.5 CAFA 187 191 1.3-1.6 2.0-3.0 45 0.25 2.7 0.5 SPINAF 260 265 1.2-1.5 1.4-2.8 79 0.001 2.3 1.5 *All study results of warfarin vs. control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhagic stroke and transient ischemic attacks. Trials in patients with both AF and mitral stenosis suggest a benefit from anticoagulation with COUMADIN [see Dosage and Administration (2.2)]. 14.2 Mechanical and Bioprosthetic Heart Valves In a prospective, randomized, open-label, positive-controlled study in 254 patients with mechanical prosthetic heart valves, the thromboembolic-free interval was found to be significantly greater in patients treated with warfarin alone compared with dipyridamole/aspirin treated patients (p<0.005) and pentoxifylline/aspirin-treated patients (p<0.05). The results of this study are presented in Table 5. 25 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 5: Prospective, Randomized, Open-Label, Positive-Controlled Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves Patients Treated With Event Warfarin Dipyridamole/Aspirin Pentoxifylline/Aspirin Thromboembolism 2.2/100 py 8.6/100 py 7.9/100 py Major Bleeding 2.5/100 py 0.0/100 py 0.9/100 py py=patient years In a prospective, open-label, clinical study comparing moderate (INR 2.65) versus high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events per 100 patient years, respectively). Major bleeding was more common in the high intensity group. The results of this study are presented in Table 6. Table 6: Prospective, Open-Label Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves Event Moderate Warfarin Therapy INR 2.65 High Intensity Warfarin Therapy INR 9.0 Thromboembolism 4.0/100 py 3.7/100 py Major Bleeding 0.95/100 py 2.1/100 py py=patient years In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2.0-2.25 vs. INR 2.5-4.0) for a three-month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs. 1.9%, respectively, and minor embolic events 10.8% vs. 10.2%, respectively). Major hemorrhages occurred in 4.6% of patients in the higher intensity INR group compared to zero in the lower intensity INR group. 14.3 Myocardial Infarction WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8. The primary endpoint was a composite of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in Table 7. 26 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 7: WARIS – Endpoint Analysis of Separate Events % Risk Warfarin Placebo Reduction Event (N=607) (N=607) RR (95% CI) (p-value) Total Patient Years of 2018 1944 Follow-up Total Mortality 94 (4.7/100 py) 123 (6.3/100 py) 0.76 (0.60, 0.97) 24 (p=0.030) Vascular Death 82 (4.1/100 py) 105 (5.4/100 py) 0.78 (0.60, 1.02) 22 (p=0.068) Recurrent MI 82 (4.1/100 py) 124 (6.4/100 py) 0.66 (0.51, 0.85) 34 (p=0.001) Cerebrovascular Event 20 (1.0/100 py) 44 (2.3/100 py) 0.46 (0.28, 0.75) 54 (p=0.002) RR=Relative risk; Risk reduction=(1 - RR); CI=Confidence interval; MI=Myocardial infarction; py=patient years WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label, randomized study of 3630 patients hospitalized for acute myocardial infarction treated with warfarin to a target INR 2.8 to 4.2, aspirin 160 mg per day, or warfarin to a target INR 2.0 to 2.5 plus aspirin 75 mg per day prior to hospital discharge. The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke. The mean duration of observation was approximately 4 years. The results for WARIS II are provided in Table 8. Table 8: WARIS II – Distribution of Events According to Treatment Group Event Aspirin (N=1206) Warfarin (N=1216) No. of Events Aspirin plus Warfarin (N=1208) Rate Ratio (95% CI) p-value Major Bleedinga 8 33 28 3.35b (ND) 4.00c (ND) ND ND Minor Bleedingd 39 103 133 3.21b (ND) 2.55c (ND) ND ND Composite Endpointse 241 203 181 0.81 (0.69-0.95)b 0.71 (0.60-0.83)c 0.03 0.001 Reinfarction 117 90 69 0.56 (0.41-0.78)b 0.74 (0.55-0.98)c <0.001 0.03 Thromboembolic Stroke 32 17 17 0.52 (0.28-0.98)b 0.52 (0.28-0.97)c 0.03 0.03 Death 92 96 95 0.82 a Major bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion. b The rate ratio is for aspirin plus warfarin as compared with aspirin. c The rate ratio is for warfarin as compared with aspirin. d Minor bleeding episodes were defined as non-cerebral hemorrhage not necessitating surgical intervention or blood transfusion. 27 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda e Includes death, nonfatal reinfarction, and thromboembolic cerebral stroke. CI=confidence interval ND=not determined There were approximately four times as many major bleeding episodes in the two groups receiving warfarin than in the group receiving aspirin alone. Major bleeding episodes were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group. 15 REFERENCES OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html. 16 HOW SUPPLIED/STORAGE AND HANDLING Tablets COUMADIN tablets are single-scored with one face imprinted numerically with 1, 2, 2-1/2, 3, 4, 5, 6, 7-1/2, or 10 superimposed and inscribed with “COUMADIN” and with the opposite face plain. COUMADIN is available in bottles and hospital unit-dose blister packages with potencies and colors as follows: 28 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hospital Unit-Dose Bottles of 100 Bottles of 1000 Blister Package of 100 1 mg pink NDC 0056-0169-70 NDC 0056-0169-90 NDC 0056-0169-75 2 mg lavender NDC 0056-0170-70 NDC 0056-0170-90 NDC 0056-0170-75 2-1/2 mg green NDC 0056-0176-70 NDC 0056-0176-90 NDC 0056-0176-75 3 mg tan NDC 0056-0188-70 NDC 0056-0188-75 4 mg blue NDC 0056-0168-70 NDC 0056-0168-75 5 mg peach NDC 0056-0172-70 NDC 0056-0172-90 NDC 0056-0172-75 6 mg teal NDC 0056-0189-70 NDC 0056-0189-90 NDC 0056-0189-75 7-1/2 mg yellow NDC 0056-0173-70 NDC 0056-0173-75 10 mg white NDC 0056-0174-70 NDC 0056-0174-75 (dye-free) Protect from light and moisture. Store at controlled room temperature (59°-86°F, 15°-30°C). Dispense in a tight, light-resistant container as defined in the USP. Store the hospital unit-dose blister packages in the carton until contents have been used. Injection COUMADIN for injection vials yield 5 mg of warfarin after reconstitution with 2.7 mL of Sterile Water for Injection (maximum yield is 2.5 mL of a 2 mg/mL solution). Net content of vial is 5.4 mg lyophilized powder. 5-mg vial (box of 6) NDC 0590-0324-35 Protect from light. Keep vial in box until used. Store at controlled room temperature (59°-86°F, 15°-30°C). After reconstitution, store at controlled room temperature (59°-86°F, 15°-30°C) and use within 4 hours. Do not refrigerate. Discard any unused solution. Special Handling Procedures for proper handling and disposal of potentially hazardous drugs should be considered. Guidelines on this subject have been published [see References (15)]. 29 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacy and clinical personnel who are pregnant should avoid exposure to crushed or broken tablets [see Use in Special Populations (8.1)]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Advise patients to: • Tell their physician if they fall often as this may increase their risk for complications. • Strictly adhere to the prescribed dosage schedule. Do not take or discontinue any other drug, including salicylates (e.g., aspirin and topical analgesics), other over-the-counter drugs, and botanical (herbal) products except on advice of your physician. • Notify their physician immediately if any unusual bleeding or symptoms occur. Signs and symptoms of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness. • Contact their doctor − immediately if they think they are pregnant − to discuss pregnancy planning − if they are considering breastfeeding • Avoid any activity or sport that may result in traumatic injury. • Obtain prothrombin time tests and make regular visits to their physician or clinic to monitor therapy. • Carry identification stating that they are taking COUMADIN. • If the prescribed dose of COUMADIN is missed, take the dose as soon as possible on the same day but do not take a double dose of COUMADIN the next day to make up for missed doses. • Eat a normal, balanced diet to maintain a consistent intake of vitamin K. Avoid drastic changes in dietary habits, such as eating large amounts of leafy, green vegetables. • Contact their physician to report any serious illness, such as severe diarrhea, infection, or fever. • Be aware that if therapy with COUMADIN is discontinued, the anticoagulant effects of COUMADIN may persist for about 2 to 5 days. 30 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Distributed by: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA COUMADIN is a trademark of Bristol-Myers Squibb Pharma Company. Copyright  Bristol-Myers Squibb Company 2011 Printed in USA [print code] Rev 10/2015 31 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3839492 32 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE COUMADIN (COU-ma-din) (warfarin sodium) Read this Medication Guide before you start taking COUMADIN (warfarin sodium) and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about COUMADIN when you start taking it and at regular checkups. What is the most important information I should know about COUMADIN? COUMADIN can cause bleeding which can be serious and sometimes lead to death. This is because COUMADIN is a blood thinner medicine that lowers the chance of blood clots forming in your body. • You may have a higher risk of bleeding if you take COUMADIN and: o are 65 years of age or older o have a history of stomach or intestinal bleeding o have high blood pressure (hypertension) o have a history of stroke, or “mini-stroke” (transient ischemic attack or TIA) o have serious heart disease o have a low blood count or cancer o have had trauma, such as an accident or surgery o have kidney problems o take other medicines that increase your risk of bleeding, including: • a medicine that contains heparin • other medicines to prevent or treat blood clots • nonsteroidal anti-inflammatory drugs (NSAIDs) o take warfarin sodium for a long time. Warfarin sodium is the active ingredient in COUMADIN. Tell your healthcare provider if you take any of these medicines. Ask your healthcare provider if you are not sure if your medicine is one listed above. Many other medicines can interact with COUMADIN and affect the dose you need or increase COUMADIN side effects. Do not change or stop any of your medicines or start any new medicines before you talk to your healthcare provider. Do not take other medicines that contain warfarin sodium while taking COUMADIN. • Get your regular blood test to check for your response to COUMADIN. This blood test is called an INR test. The INR test checks to see how fast your blood clots. Your healthcare provider will decide what INR numbers are best for you. Your dose of COUMADIN will be adjusted to keep your INR in a target range for you. • Call your healthcare provider right away if you get any of the following signs or symptoms of bleeding problems: o pain, swelling, or discomfort o headaches, dizziness, or weakness o unusual bruising (bruises that develop without known cause or grow in size) o nosebleeds o bleeding gums o bleeding from cuts takes a long time to stop o menstrual bleeding or vaginal bleeding that is heavier than normal o pink or brown urine o red or black stools o coughing up blood o vomiting blood or material that looks like coffee grounds • Some foods and beverages can interact with COUMADIN and affect your treatment and dose. o Eat a normal, balanced diet. Talk to your healthcare provider before you make any diet changes. Do not eat large amounts of leafy, green vegetables. Leafy, green vegetables contain vitamin K. Certain vegetable oils also contain large amounts of vitamin K. Too much vitamin K can lower the effect of COUMADIN. • Always tell all of your healthcare providers that you take COUMADIN. • Wear or carry information that you take COUMADIN. See “What are the possible side effects of COUMADIN?” for more information about side effects. Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What is COUMADIN? COUMADIN is prescription medicine used to treat blood clots and to lower the chance of blood clots forming in your body. Blood clots can cause a stroke, heart attack, or other serious conditions if they form in the legs or lungs. Who should not take COUMADIN? Do not take COUMADIN if: • your chance of having bleeding problems is higher than the possible benefit of treatment. Your healthcare provider will decide if COUMADIN is right for you. Talk to your healthcare provider about all of your health conditions. • you are pregnant unless you have a mechanical heart valve. COUMADIN may cause birth defects, miscarriage, or death of your unborn baby. • you are allergic to warfarin or any of the other ingredients in COUMADIN. See the end of this leaflet for a complete list of ingredients in COUMADIN. What should I tell my healthcare provider before taking COUMADIN? Before you take COUMADIN, tell your healthcare provider if you: • have bleeding problems • fall often • have liver or kidney problems • have high blood pressure • have a heart problem called congestive heart failure • have diabetes • plan to have any surgery or a dental procedure • have any other medical conditions • are pregnant or plan to become pregnant. See “Who should not take COUMADIN?” Your healthcare provider will do a pregnancy test before you start treatment with COUMADIN. Females who can become pregnant should use effective birth control during treatment, and for at least 1 month after the last dose of COUMADIN. • are breastfeeding. You and your healthcare provider should decide if you will take COUMADIN and breastfeed. Check your baby for bruising or bleeding if you take COUMADIN and breastfeed. Tell all of your healthcare providers and dentists that you are taking COUMADIN. They should talk to the healthcare provider who prescribed COUMADIN for you before you have any surgery or dental procedure. Your COUMADIN may need to be stopped for a short time or you may need your dose adjusted. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some of your other medicines may affect the way COUMADIN works. Certain medicines may increase your risk of bleeding. See “What is the most important information I should know about COUMADIN?” Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take COUMADIN? • Take COUMADIN exactly as prescribed. Your healthcare provider will adjust your dose from time to time depending on your response to COUMADIN. • You must have regular blood tests and visits with your healthcare provider to monitor your condition. • If you miss a dose of COUMADIN, call your healthcare provider. Take the dose as soon as possible on the same day. Do not take a double dose of COUMADIN the next day to make up for a missed dose. • Call your healthcare provider right away if you: o take too much COUMADIN o are sick with diarrhea, an infection, or have a fever o fall or injure yourself, especially if you hit your head. Your healthcare provider may need to check you. What should I avoid while taking COUMADIN? • Do not do any activity or sport that may cause a serious injury. What are the possible side effects of COUMADIN? COUMADIN may cause serious side effects including: • See “What is the most important information I should know about COUMADIN?” • Death of skin tissue (skin necrosis or gangrene). This can happen soon after starting COUMADIN. It happens because blood clots form and block blood flow to an area of your body. Call your healthcare provider right away if you Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda have pain, color, or temperature change to any area of your body. You may need medical care right away to prevent death or loss (amputation) of your affected body part. • “Purple toes syndrome.” Call your healthcare provider right away if you have pain in your toes and they look purple in color or dark in color. Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all of the side effects of COUMADIN. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store COUMADIN? • Store COUMADIN at 59°F to 86°F (15°C to 30°C). • Keep COUMADIN in a tightly closed container, and keep COUMADIN out of the light and moisture. • Follow your healthcare provider or pharmacist instructions about the right way to throw away outdated or unused COUMADIN. • Females who are pregnant should not handle crushed or broken COUMADIN tablets. Keep COUMADIN and all medicines out of the reach of children. General information about COUMADIN. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use COUMADIN for a condition for which it was not prescribed. Do not give COUMADIN to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about COUMADIN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about COUMADIN that is written for health professionals. If you would like more information, go to www.coumadin.com or call 1-800-321-1335. What are the ingredients in COUMADIN? Active ingredient: warfarin sodium Inactive ingredients: COUMADIN tablets also contain lactose, starch, and magnesium stearate, in addition: 1 mg: D&C Red No. 6 Barium Lake 2 mg: FD&C Blue No. 2 Aluminum Lake and FD&C Red No. 40 Aluminum Lake 2.5 mg: D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake 3 mg: FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, and FD&C Red No. 40 Aluminum Lake 4 mg: FD&C Blue No. 1 Aluminum Lake 5 mg: FD&C Yellow No. 6 Aluminum Lake 6 mg: FD&C Yellow No. 6 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake 7.5 mg: D&C Yellow No. 10 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake COUMADIN is distributed by: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA COUMADIN is a registered trademark of Bristol-Myers Squibb Pharma Company. [print code] This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised 10/2015 Reference ID: 3839492 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:39.676782	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/009218s115lbl.pdf', 'application_number': 9218, 'submission_type': 'SUPPL ', 'submission_number': 115}
10,725	1 PRESCRIBING INFORMATION 2 LANOXIN® 3 (digoxin) 4 Injection 5 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25 mg] per mL) 6 DESCRIPTION 7 LANOXIN (digoxin) is one of the cardiac (or digitalis) glycosides, a closely related group of 8 drugs having in common specific effects on the myocardium. These drugs are found in a number 9 of plants. Digoxin is extracted from the leaves of Digitalis lanata. The term “digitalis” is used to 10 designate the whole group of glycosides. The glycosides are composed of 2 portions: a sugar and 11 a cardenolide (hence “glycosides”). 12 Digoxin is described chemically as (3β,5β,12β)-3-[(O-2,6-dideoxy-β-D-ribo-hexopyranosyl 13 (1→4)-O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-2,6-dideoxy-β-D-ribo 14 hexopyranosyl)oxy]-12,14-dihydroxy-card-20(22)-enolide. Its molecular formula is C41H64O14, 15 its molecular weight is 780.95, and its structural formula is: 16 Structural formula 17 18 19 Digoxin exists as odorless white crystals that melt with decomposition above 230°C. The drug 20 is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in 21 chloroform; and freely soluble in pyridine. 22 LANOXIN Injection is a sterile solution of digoxin for intravenous or intramuscular injection. 23 The vehicle contains 40% propylene glycol and 10% alcohol. The injection is buffered to a pH of 24 6.8 to 7.2 with 0.17% dibasic sodium phosphate and 0.08% anhydrous citric acid. Each 2-mL 25 ampul contains 500 mcg (0.5 mg) digoxin (250 mcg [0.25 mg] per mL). Dilution is not required. 1 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 Mechanism of Action: Digoxin inhibits sodium-potassium ATPase, an enzyme that regulates the quantity of sodium and potassium inside cells. Inhibition of the enzyme leads to an increase in the intracellular concentration of sodium and thus (by stimulation of sodium-calcium exchange) an increase in the intracellular concentration of calcium. The beneficial effects of digoxin result from direct actions on cardiac muscle, as well as indirect actions on the cardiovascular system mediated by effects on the autonomic nervous system. The autonomic effects include: (1) a vagomimetic action, which is responsible for the effects of digoxin on the sinoatrial and atrioventricular (AV) nodes; and (2) baroreceptor sensitization, which results in increased afferent inhibitory activity and reduced activity of the sympathetic nervous system and renin-angiotensin system for any given increment in mean arterial pressure. The pharmacologic consequences of these direct and indirect effects are: (1) an increase in the force and velocity of myocardial systolic contraction (positive inotropic action); (2) a decrease in the degree of activation of the sympathetic nervous system and renin-angiotensin system (neurohormonal deactivating effect); and (3) slowing of the heart rate and decreased conduction velocity through the AV node (vagomimetic effect). The effects of digoxin in heart failure are mediated by its positive inotropic and neurohormonal deactivating effects, whereas the effects of the drug in atrial arrhythmias are related to its vagomimetic actions. In high doses, digoxin increases sympathetic outflow from the central nervous system (CNS). This increase in sympathetic activity may be an important factor in digitalis toxicity. Pharmacokinetics: Note: the following data are from studies performed in adults, unless otherwise stated. Absorption: Comparisons of the systemic availability and equivalent doses for preparations of LANOXIN are shown in Table 1. Table 1. Comparisons of the Systemic Availability and Equivalent Doses for Preparations of LANOXIN a For example, 125 mcg LANOXIN Tablets equivalent to 100 mcg LANOXIN Injection/IV. 53 54 55 56 57 58 59 60 61 Distribution: Following drug administration, a 6- to 8-hour tissue distribution phase is observed. This is followed by a much more gradual decline in the serum concentration of the drug, which is dependent on the elimination of digoxin from the body. The peak height and slope of the early portion (absorption/distribution phases) of the serum concentration-time curve are dependent upon the route of administration and the absorption characteristics of the formulation. Clinical evidence indicates that the early high serum concentrations do not reflect the concentration of digoxin at its site of action, but that with chronic use, the steady-state Product Absolute Bioavailability Equivalent Doses (mcg)a Among Dosage Forms LANOXIN Tablets LANOXIN Injection/IV 60 - 80% 100% 62.5 50 125 100 250 200 500 400 2 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 62 post-distribution serum concentrations are in equilibrium with tissue concentrations and correlate 63 with pharmacologic effects. In individual patients, these post-distribution serum concentrations 64 may be useful in evaluating therapeutic and toxic effects (see DOSAGE AND 65 ADMINISTRATION: Serum Digoxin Concentrations). 66 Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution. 67 Digoxin crosses both the blood-brain barrier and the placenta. At delivery, the serum digoxin 68 concentration in the newborn is similar to the serum concentration in the mother. Approximately 69 25% of digoxin in the plasma is bound to protein. Serum digoxin concentrations are not 70 significantly altered by large changes in fat tissue weight, so that its distribution space correlates 71 best with lean (i.e., ideal) body weight, not total body weight. 72 Metabolism: Only a small percentage (16%) of a dose of digoxin is metabolized. The end 73 metabolites, which include 3 β-digoxigenin, 3-keto-digoxigenin, and their glucuronide and 74 sulfate conjugates, are polar in nature and are postulated to be formed via hydrolysis, oxidation, 75 and conjugation. The metabolism of digoxin is not dependent upon the cytochrome P-450 76 system, and digoxin is not known to induce or inhibit the cytochrome P-450 system. 77 Excretion: Elimination of digoxin follows first-order kinetics (that is, the quantity of digoxin 78 eliminated at any time is proportional to the total body content). Following intravenous 79 administration to healthy volunteers, 50% to 70% of a digoxin dose is excreted unchanged in the 80 urine. Renal excretion of digoxin is proportional to glomerular filtration rate and is largely 81 independent of urine flow. In healthy volunteers with normal renal function, digoxin has a 82 half-life of 1.5 to 2.0 days. The half-life in anuric patients is prolonged to 3.5 to 5 days. Digoxin 83 is not effectively removed from the body by dialysis, exchange transfusion, or during 84 cardiopulmonary bypass because most of the drug is bound to tissue and does not circulate in the 85 blood. 86 Special Populations: Race differences in digoxin pharmacokinetics have not been 87 formally studied. Because digoxin is primarily eliminated as unchanged drug via the kidney and 88 because there are no important differences in creatinine clearance among races, pharmacokinetic 89 differences due to race are not expected. 90 The clearance of digoxin can be primarily correlated with renal function as indicated by 91 creatinine clearance. The Cockcroft and Gault formula for estimation of creatinine clearance 92 includes age, body weight, and gender. Table 5 that provides the usual daily maintenance dose 93 requirements of LANOXIN Tablets based on creatinine clearance (per 70 kg) is presented in the 94 DOSAGE AND ADMINISTRATION section. 95 Plasma digoxin concentration profiles in patients with acute hepatitis generally fell within the 96 range of profiles in a group of healthy subjects. 97 Pharmacodynamic and Clinical Effects: The times to onset of pharmacologic effect and to 98 peak effect of preparations of LANOXIN are shown in Table 2. 99 3 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 2. Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of LANOXIN 100 101 a Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes. 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 b Depending upon rate of infusion. Hemodynamic Effects: Digoxin produces hemodynamic improvement in patients with heart failure. Short- and long-term therapy with the drug increases cardiac output and lowers pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic vascular resistance. These hemodynamic effects are accompanied by an increase in the left ventricular ejection fraction and a decrease in end-systolic and end-diastolic dimensions. Chronic Heart Failure: Two 12-week, double-blind, placebo-controlled studies enrolled 178 (RADIANCE trial) and 88 (PROVED trial) patients with NYHA class II or III heart failure previously treated with oral digoxin, a diuretic, and an ACE inhibitor (RADIANCE only) and randomized them to placebo or treatment with LANOXIN Tablets. Both trials demonstrated better preservation of exercise capacity in patients randomized to LANOXIN. Continued treatment with LANOXIN reduced the risk of developing worsening heart failure, as evidenced by heart failure-related hospitalizations and emergency care and the need for concomitant heart failure therapy. The larger study also showed treatment-related benefits in NYHA class and patients’ global assessment. In the smaller trial, these trended in favor of a treatment benefit. The Digitalis Investigation Group (DIG) main trial was a multicenter, randomized, double-blind, placebo-controlled mortality study of 6,801 patients with heart failure and left ventricular ejection fraction ≤0.45. At randomization, 67% were NYHA class I or II, 71% had heart failure of ischemic etiology, 44% had been receiving digoxin, and most were receiving concomitant ACE inhibitor (94%) and diuretic (82%). Patients were randomized to placebo or LANOXIN Tablets, the dose of which was adjusted for the patient’s age, sex, lean body weight, and serum creatinine (see DOSAGE AND ADMINISTRATION), and followed for up to 58 months (median 37 months). The median daily dose prescribed was 0.25 mg. Overall all-cause mortality was 35% with no difference between groups (95% confidence limits for relative risk of 0.91 to 1.07). LANOXIN was associated with a 25% reduction in the number of hospitalizations for heart failure, a 28% reduction in the risk of a patient having at least 1 hospitalization for heart failure, and a 6.5% reduction in total hospitalizations (for any cause). Use of LANOXIN was associated with a trend to increase time to all-cause death or hospitalization. The trend was evident in subgroups of patients with mild heart failure as well as more severe disease, as shown in Table 3. Although the effect on all-cause death or hospitalization was not statistically significant, much of the apparent benefit derived from effects on mortality and hospitalization attributed to heart failure. Product Time to Onset of Effecta Time to Peak Effecta LANOXIN Tablets LANOXIN Injection/IV 0.5 - 2 hours 5 - 30 minutesb 2 - 6 hours 1 - 4 hours 4 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 137 138 Table 3. Subgroup Analyses of Mortality and Hospitalization During the First 2 Years 139 Following Randomization n Risk of All-Cause Mortality or All-Cause Hospitalizationa Risk of HF-Related Mortality or HF-Related Hospitalizationa Placebo LANOXIN Relative riskb Placebo LANOXIN Relative riskb All patients (EF ≤0.45) 6,801 604 593 0.94 (0.88-1.00) 294 217 0.69 (0.63-0.76) NYHA I/II EF 0.25-0.45 CTR ≤0.55 4,571 4,543 4,455 549 568 561 541 571 563 0.96 (0.89-1.04) 0.99 (0.91-1.07) 0.98 (0.91-1.06) 242 244 239 178 190 180 0.70 (0.62-0.80) 0.74 (0.66-0.84) 0.71 (0.63-0.81) NYHA III/IV EF <0.25 CTR >0.55 2,224 2,258 2,346 719 677 687 696 637 650 0.88 (0.80-0.97) 0.84 (0.76-0.93) 0.85 (0.77-0.94) 402 394 398 295 270 287 0.65 (0.57-0.75) 0.61 (0.53-0.71) 0.65 (0.57-0.75) EF >0.45c 987 571 585 1.04 (0.88-1.23) 179 136 0.72 (0.53-0.99) 140 a Number of patients with an event during the first 2 years per 1,000 randomized patients. 141 b Relative risk (95% confidence interval). 142 c DIG Ancillary Study. 143 144 In situations where there is no statistically significant benefit of treatment evident from a 145 trial’s primary endpoint, results pertaining to a secondary endpoint should be interpreted 146 cautiously. 147 Chronic Atrial Fibrillation: In patients with chronic atrial fibrillation, digoxin slows rapid 148 ventricular response rate in a linear dose-response fashion from 0.25 to 0.75 mg/day. Digoxin 149 should not be used for the treatment of multifocal atrial tachycardia. 150 INDICATIONS AND USAGE 151 Heart Failure: LANOXIN is indicated for the treatment of mild to moderate heart failure. 152 LANOXIN increases left ventricular ejection fraction and improves heart failure symptoms as 153 evidenced by exercise capacity and heart failure-related hospitalizations and emergency care, 154 while having no effect on mortality. Where possible, LANOXIN should be used with a diuretic 155 and an angiotensin-converting enzyme inhibitor, but an optimal order for starting these 3 drugs 156 cannot be specified. 5 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 157 Atrial Fibrillation: LANOXIN is indicated for the control of ventricular response rate in 158 patients with chronic atrial fibrillation. 159 CONTRAINDICATIONS 160 Digitalis glycosides are contraindicated in patients with ventricular fibrillation or in patients 161 with a known hypersensitivity to digoxin. A hypersensitivity reaction to other digitalis 162 preparations usually constitutes a contraindication to digoxin. 163 WARNINGS 164 Sinus Node Disease and AV Block: Because digoxin slows sinoatrial and AV conduction, 165 the drug commonly prolongs the PR interval. The drug may cause severe sinus bradycardia or 166 sinoatrial block in patients with pre-existing sinus node disease and may cause advanced or 167 complete heart block in patients with pre-existing incomplete AV block. In such patients 168 consideration should be given to the insertion of a pacemaker before treatment with digoxin. 169 Accessory AV Pathway (Wolff-Parkinson-White Syndrome): After intravenous digoxin 170 therapy, some patients with paroxysmal atrial fibrillation or flutter and a coexisting accessory 171 AV pathway have developed increased antegrade conduction across the accessory pathway 172 bypassing the AV node, leading to a very rapid ventricular response or ventricular fibrillation. 173 Unless conduction down the accessory pathway has been blocked (either pharmacologically or 174 by surgery), digoxin should not be used in such patients. The treatment of paroxysmal 175 supraventricular tachycardia in such patients is usually direct-current cardioversion. 176 Use in Patients With Preserved Left Ventricular Systolic Function: Patients with 177 certain disorders involving heart failure associated with preserved left ventricular ejection 178 fraction may be particularly susceptible to toxicity of the drug. Such disorders include restrictive 179 cardiomyopathy, constrictive pericarditis, amyloid heart disease, and acute cor pulmonale. 180 Patients with idiopathic hypertrophic subaortic stenosis may have worsening of the outflow 181 obstruction due to the inotropic effects of digoxin. Digoxin should generally be avoided in these 182 patients, although it has been used for ventricular rate control in the subgroup of patients with 183 atrial fibrillation. 184 PRECAUTIONS 185 Use in Patients With Impaired Renal Function: Digoxin is primarily excreted by the 186 kidneys; therefore, patients with impaired renal function require smaller than usual maintenance 187 doses of digoxin (see DOSAGE AND ADMINISTRATION). Because of the prolonged 188 elimination half-life, a longer period of time is required to achieve an initial or new steady-state 189 serum concentration in patients with renal impairment than in patients with normal renal 190 function. If appropriate care is not taken to reduce the dose of digoxin, such patients are at high 191 risk for toxicity, and toxic effects will last longer in such patients than in patients with normal 192 renal function. 193 Use in Patients With Electrolyte Disorders: In patients with hypokalemia or 194 hypomagnesemia, toxicity may occur despite serum digoxin concentrations below 2.0 ng/mL, 6 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 195 because potassium or magnesium depletion sensitizes the myocardium to digoxin. Therefore, it is 196 desirable to maintain normal serum potassium and magnesium concentrations in patients being 197 treated with digoxin. Deficiencies of these electrolytes may result from malnutrition, diarrhea, or 198 prolonged vomiting, as well as the use of the following drugs or procedures: diuretics, 199 amphotericin B, corticosteroids, antacids, dialysis, and mechanical suction of gastrointestinal 200 secretions. 201 Hypercalcemia from any cause predisposes the patient to digitalis toxicity. Calcium, 202 particularly when administered rapidly by the intravenous route, may produce serious 203 arrhythmias in digitalized patients. On the other hand, hypocalcemia can nullify the effects of 204 digoxin in humans; thus, digoxin may be ineffective until serum calcium is restored to normal. 205 These interactions are related to the fact that digoxin affects contractility and excitability of the 206 heart in a manner similar to that of calcium. 207 Use in Thyroid Disorders and Hypermetabolic States: Hypothyroidism may reduce the 208 requirements for digoxin. Heart failure and/or atrial arrhythmias resulting from hypermetabolic 209 or hyperdynamic states (e.g., hyperthyroidism, hypoxia, or arteriovenous shunt) are best treated 210 by addressing the underlying condition. Atrial arrhythmias associated with hypermetabolic states 211 are particularly resistant to digoxin treatment. Care must be taken to avoid toxicity if digoxin is 212 used. 213 Use in Patients With Acute Myocardial Infarction: Digoxin should be used with caution 214 in patients with acute myocardial infarction. The use of inotropic drugs in some patients in this 215 setting may result in undesirable increases in myocardial oxygen demand and ischemia. 216 Use During Electrical Cardioversion: It may be desirable to reduce the dose of digoxin for 217 1 to 2 days prior to electrical cardioversion of atrial fibrillation to avoid the induction of 218 ventricular arrhythmias, but physicians must consider the consequences of increasing the 219 ventricular response if digoxin is withdrawn. If digitalis toxicity is suspected, elective 220 cardioversion should be delayed. If it is not prudent to delay cardioversion, the lowest possible 221 energy level should be selected to avoid provoking ventricular arrhythmias. 222 Use in Patients With Myocarditis: Digoxin can rarely precipitate vasoconstriction and 223 therefore should be avoided in patients with myocarditis. 224 Use in Patients With Beri Beri Heart Disease: Patients with beri beri heart disease may 225 fail to respond adequately to digoxin if the underlying thiamine deficiency is not treated 226 concomitantly. 227 Laboratory Test Monitoring: Patients receiving digoxin should have their serum electrolytes 228 and renal function (serum creatinine concentrations) assessed periodically; the frequency of 229 assessments will depend on the clinical setting. For discussion of serum digoxin concentrations, 230 see DOSAGE AND ADMINISTRATION. 231 Drug Interactions: Potassium-depleting diuretics are a major contributing factor to digitalis 232 toxicity. Calcium, particularly if administered rapidly by the intravenous route, may produce 233 serious arrhythmias in digitalized patients. Quinidine, verapamil, amiodarone, propafenone, 234 indomethacin, itraconazole, alprazolam, and spironolactone raise the serum digoxin 7 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 235 concentration due to a reduction in clearance and/or in volume of distribution of the drug, with 236 the implication that digitalis intoxication may result. Erythromycin and clarithromycin (and 237 possibly other macrolide antibiotics) and tetracycline may increase digoxin absorption in 238 patients who inactivate digoxin by bacterial metabolism in the lower intestine, so that digitalis 239 intoxication may result. Propantheline and diphenoxylate, by decreasing gut motility, may 240 increase digoxin absorption. Antacids, kaolin-pectin, sulfasalazine, neomycin, cholestyramine, 241 certain anticancer drugs, and metoclopramide may interfere with intestinal digoxin absorption, 242 resulting in unexpectedly low serum concentrations. Rifampin may decrease serum digoxin 243 concentration, especially in patients with renal dysfunction, by increasing the non-renal 244 clearance of digoxin. There have been inconsistent reports regarding the effects of other drugs 245 (e.g., quinine, penicillamine) on serum digoxin concentration. Thyroid administration to a 246 digitalized, hypothyroid patient may increase the dose requirement of digoxin. Concomitant use 247 of digoxin and sympathomimetics increases the risk of cardiac arrhythmias. Succinylcholine may 248 cause a sudden extrusion of potassium from muscle cells, and may thereby cause arrhythmias in 249 digitalized patients. Although calcium channel blockers and digoxin may be useful in 250 combination to control atrial fibrillation, their additive effects on AV node conduction can result 251 in advanced or complete heart block. Both digitalis glycosides and beta-blockers slow 252 atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of 253 bradycardia. Digoxin concentrations are increased by about 15% when digoxin and carvedilol 254 are administered concomitantly. Therefore, increased monitoring of digoxin is recommended 255 when initiating, adjusting, or discontinuing carvedilol. 256 Due to the considerable variability of these interactions, the dosage of digoxin should be 257 individualized when patients receive these medications concurrently. Furthermore, caution 258 should be exercised when combining digoxin with any drug that may cause a significant 259 deterioration in renal function, since a decline in glomerular filtration or tubular secretion may 260 impair the excretion of digoxin. 261 Drug/Laboratory Test Interactions: The use of therapeutic doses of digoxin may cause 262 prolongation of the PR interval and depression of the ST segment on the electrocardiogram. 263 Digoxin may produce false positive ST-T changes on the electrocardiogram during exercise 264 testing. These electrophysiologic effects reflect an expected effect of the drug and are not 265 indicative of toxicity. 266 Carcinogenesis, Mutagenesis, Impairment of Fertility: Digoxin showed no genotoxic 267 potential in in vitro studies (Ames test and mouse lymphoma). No data are available on the 268 carcinogenic potential of digoxin, nor have studies been conducted to assess its potential to affect 269 fertility. 270 Pregnancy: Teratogenic Effects: Pregnancy Category C. Animal reproduction studies have 271 not been conducted with digoxin. It is also not known whether digoxin can cause fetal harm 272 when administered to a pregnant woman or can affect reproductive capacity. Digoxin should be 273 given to a pregnant woman only if clearly needed. 8 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 274 Nursing Mothers: Studies have shown that digoxin concentrations in the mother’s serum and 275 milk are similar. However, the estimated exposure of a nursing infant to digoxin via 276 breastfeeding will be far below the usual infant maintenance dose. Therefore, this amount should 277 have no pharmacologic effect upon the infant. Nevertheless, caution should be exercised when 278 digoxin is administered to a nursing woman. 279 Pediatric Use: Newborn infants display considerable variability in their tolerance to digoxin. 280 Premature and immature infants are particularly sensitive to the effects of digoxin, and the 281 dosage of the drug must not only be reduced but must be individualized according to their degree 282 of maturity. Digitalis glycosides can cause poisoning in children due to accidental ingestion. 283 Geriatric Use: The majority of clinical experience gained with digoxin has been in the elderly 284 population. This experience has not identified differences in response or adverse effects between 285 the elderly and younger patients. However, this drug is known to be substantially excreted by the 286 kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal 287 function. Because elderly patients are more likely to have decreased renal function, care should 288 be taken in dose selection, which should be based on renal function, and it may be useful to 289 monitor renal function (see DOSAGE AND ADMINISTRATION). 290 ADVERSE REACTIONS 291 In general, the adverse reactions of digoxin are dose-dependent and occur at doses higher than 292 those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when 293 digoxin is used within the recommended dose range or therapeutic serum concentration range 294 and when there is careful attention to concurrent medications and conditions. 295 Because some patients may be particularly susceptible to side effects with digoxin, the dosage 296 of the drug should always be selected carefully and adjusted as the clinical condition of the 297 patient warrants. In the past, when high doses of digoxin were used and little attention was paid 298 to clinical status or concurrent medications, adverse reactions to digoxin were more frequent and 299 severe. Cardiac adverse reactions accounted for about one-half, gastrointestinal disturbances for 300 about one-fourth, and CNS and other toxicity for about one-fourth of these adverse reactions. 301 However, available evidence suggests that the incidence and severity of digoxin toxicity has 302 decreased substantially in recent years. In recent controlled clinical trials, in patients with 303 predominantly mild to moderate heart failure, the incidence of adverse experiences was 304 comparable in patients taking digoxin and in those taking placebo. In a large mortality trial, the 305 incidence of hospitalization for suspected digoxin toxicity was 2% in patients taking LANOXIN 306 Tablets compared to 0.9% in patients taking placebo. In this trial, the most common 307 manifestations of digoxin toxicity included gastrointestinal and cardiac disturbances; CNS 308 manifestations were less common. 309 Adults: Cardiac: Therapeutic doses of digoxin may cause heart block in patients with pre 310 existing sinoatrial or AV conduction disorders; heart block can be avoided by adjusting the dose 311 of digoxin. Prophylactic use of a cardiac pacemaker may be considered if the risk of heart block 312 is considered unacceptable. High doses of digoxin may produce a variety of rhythm disturbances, 9 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 313 such as first-degree, second-degree (Wenckebach), or third-degree heart block (including 314 asystole); atrial tachycardia with block; AV dissociation; accelerated junctional (nodal) rhythm; 315 unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy); 316 ventricular tachycardia; and ventricular fibrillation. Digoxin produces PR prolongation and ST 317 segment depression which should not by themselves be considered digoxin toxicity. Cardiac 318 toxicity can also occur at therapeutic doses in patients who have conditions which may alter their 319 sensitivity to digoxin (see WARNINGS and PRECAUTIONS). 320 Gastrointestinal: Digoxin may cause anorexia, nausea, vomiting, and diarrhea. Rarely, the 321 use of digoxin has been associated with abdominal pain, intestinal ischemia, and hemorrhagic 322 necrosis of the intestines. 323 CNS: Digoxin can produce visual disturbances (blurred or yellow vision), headache, 324 weakness, dizziness, apathy, confusion, and mental disturbances (such as anxiety, depression, 325 delirium, and hallucination). 326 Other: Gynecomastia has been occasionally observed following the prolonged use of 327 digoxin. Thrombocytopenia and maculopapular rash and other skin reactions have been rarely 328 observed. 329 Table 4 summarizes the incidence of those adverse experiences listed above for patients 330 treated with LANOXIN Tablets or placebo from 2 randomized, double-blind, placebo-controlled 331 withdrawal trials. Patients in these trials were also receiving diuretics with or without 332 angiotensin-converting enzyme inhibitors. These patients had been stable on digoxin, and were 333 randomized to digoxin or placebo. The results shown in Table 4 reflect the experience in patients 334 following dosage titration with the use of serum digoxin concentrations and careful follow-up. 335 These adverse experiences are consistent with results from a large, placebo-controlled mortality 336 trial (DIG trial) wherein over half the patients were not receiving digoxin prior to enrollment. 337 338 Table 4. Adverse Experiences In 2 Parallel, Double-Blind, Placebo-Controlled Withdrawal 339 Trials (Number of Patients Reporting) Adverse Experience Digoxin Patients (n = 123) Placebo Patients (n = 125) Cardiac Palpitation Ventricular extrasystole Tachycardia Heart arrest 1 1 2 1 4 1 1 1 Gastrointestinal Anorexia Nausea Vomiting Diarrhea Abdominal pain 1 4 2 4 0 4 2 1 1 6 10 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CNS Headache Dizziness Mental disturbances 4 6 5 4 5 1 Other Rash Death 2 4 1 3 340 341 Infants and Children: The side effects of digoxin in infants and children differ from those 342 seen in adults in several respects. Although digoxin may produce anorexia, nausea, vomiting, 343 diarrhea, and CNS disturbances in young patients, these are rarely the initial symptoms of 344 overdosage. Rather, the earliest and most frequent manifestation of excessive dosing with 345 digoxin in infants and children is the appearance of cardiac arrhythmias, including sinus 346 bradycardia. In children, the use of digoxin may produce any arrhythmia. The most common are 347 conduction disturbances or supraventricular tachyarrhythmias, such as atrial tachycardia (with or 348 without block) and junctional (nodal) tachycardia. Ventricular arrhythmias are less common. 349 Sinus bradycardia may be a sign of impending digoxin intoxication, especially in infants, even in 350 the absence of first-degree heart block. Any arrhythmia or alteration in cardiac conduction that 351 develops in a child taking digoxin should be assumed to be caused by digoxin, until further 352 evaluation proves otherwise. 353 OVERDOSAGE 354 Signs and Symptoms: The signs and symptoms of toxicity are generally similar to those 355 described in the ADVERSE REACTIONS section but may be more frequent and can be more 356 severe. Signs and symptoms of digoxin toxicity become more frequent with levels above 357 2 ng/mL. However, in deciding whether a patient’s symptoms are due to digoxin, the clinical 358 state together with serum electrolyte levels and thyroid function are important factors (see 359 DOSAGE AND ADMINISTRATION). 360 Adults: In adults without heart disease, clinical observation suggests that an overdose of 361 digoxin of 10 to 15 mg was the dose resulting in death of half of the patients. If more than 25 mg 362 of digoxin was ingested by an adult without heart disease, death or progressive toxicity 363 responsive only to digoxin-binding Fab antibody fragments resulted. Cardiac manifestations are 364 the most frequent and serious sign of both acute and chronic toxicity. Peak cardiac effects 365 generally occur 3 to 6 hours following overdosage and may persist for the ensuing 24 hours or 366 longer. Digoxin toxicity may result in almost any type of arrhythmia (see ADVERSE 367 REACTIONS). Multiple rhythm disturbances in the same patient are common. Cardiac arrest 368 from asystole or ventricular fibrillation due to digoxin toxicity is usually fatal. 369 Among the extra-cardiac manifestations, gastrointestinal symptoms (e.g. nausea, vomiting, 370 anorexia) are very common (up to 80% incidence) and precede cardiac manifestations in 371 approximately half of the patients in most literature reports. Neurologic manifestations (e.g. 11 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 372 dizziness, various CNS disturbances), fatigue, and malaise are very common. Visual 373 manifestations may also occur with aberration in color vision (predominance of yellow green) 374 the most frequent. Neurological and visual symptoms may persist after other signs of toxicity 375 have resolved. In chronic toxicity, non-specific extra-cardiac symptoms, such as malaise and 376 weakness, may predominate. 377 Children: In children aged 1 to 3 years without heart disease, clinical observation suggests 378 that an overdose of digoxin of 6 to 10 mg was the dose resulting in death in half of the patients. 379 If more than 10 mg of digoxin was ingested by a child aged 1 to 3 years without heart disease, 380 the outcome was uniformly fatal when Fab fragment treatment was not given. Most 381 manifestations of toxicity in children occur during or shortly after the loading phase with 382 digoxin. The same arrhythmias or combination of arrhythmias that occur in adults can occur in 383 pediatrics. Sinus tachycardia, supraventricular tachycardia, and rapid atrial fibrillation are seen 384 less frequently in the pediatric population. Pediatric patients are more likely to present with an 385 AV conduction disturbance or a sinus bradycardia. Any arrhythmia or alteration in cardiac 386 conduction that develops in a child taking digoxin should be assumed to be caused by digoxin, 387 until further evaluation proves otherwise. 388 The frequent extracardiac manifestations similar to those seen in adults are gastrointestinal, 389 CNS, and visual. However, nausea and vomiting are not frequent in infants and small children. 390 In addition to the undesirable effects seen with recommended doses, weight loss in older age 391 groups and failure to thrive in infants, abdominal pain due to mesenteric artery ischemia, 392 drowsiness, and behavioral disturbances including psychotic manifestations have been reported 393 in overdose. 394 Treatment: In addition to cardiac monitoring, digoxin should be temporarily discontinued until 395 the adverse reaction resolves and may be all that is required to treat the adverse reaction such as 396 in asymptomatic bradycardia or digoxin-related heart block. Every effort should also be made to 397 correct factors that may contribute to the adverse reaction (such as electrolyte disturbances, 398 thyroid function, or concurrent medications) (see WARNINGS and PRECAUTIONS: Drug 399 Interactions). Once the adverse reaction has resolved, therapy with digoxin may be reinstituted, 400 following a careful reassessment of dose. 401 When the primary manifestation of digoxin overdosage is a cardiac arrhythmia, additional 402 therapy may be needed. 403 404 405 If the rhythm disturbance is a symptomatic bradyarrhythmia or heart block, consideration should be given to the reversal of toxicity with Digoxin Immune Fab (Ovine) [DIGIBIND ® or DIGIFAB ®] (see Massive Digitalis Overdosage subsection), the use of atropine, or the insertion 406 of a temporary cardiac pacemaker. Digoxin Immune Fab (Ovine) is a specific antidote for 407 digoxin and may be used to reverse potentially life-threatening ventricular arrhythmias due to 408 digoxin overdosage. 409 If the rhythm disturbance is a ventricular arrhythmia, consideration should be given to the 410 correction of electrolyte disorders, particularly if hypokalemia (see Administration of Potassium 12 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 411 subsection) or hypomagnesemia is present. Ventricular arrhythmias may respond to lidocaine or 412 phenytoin. 413 Administration of Potassium: Before administering potassium in digoxin overdose for 414 hypokalemia, the serum potassium must be known and every effort should be made to maintain 415 the serum potassium concentration between 4 and 5.5 mmol/L. Potassium salts should be 416 avoided as they may be dangerous in patients who manifest bradycardia or heart block due to 417 digoxin (unless primarily related to supraventricular tachycardia) and in the setting of massive 418 digitalis overdosage. Potassium is usually administered orally, but when correction of the 419 arrhythmia is urgent and the serum potassium concentration is low, potassium may be 420 administered cautiously by the intravenous route. The electrocardiogram should be monitored for 421 any evidence of potassium toxicity (e.g., peaking of T waves) and to observe the effect on the 422 arrhythmia. 423 Massive Digitalis Overdosage: Manifestations of life-threatening toxicity include 424 ventricular tachycardia or ventricular fibrillation, or progressive bradyarrhythmias, or heart 425 block. 426 Digoxin Immune Fab (Ovine) should be used to reverse the toxic effects of ingestion of a 427 massive overdose. The decision to administer Digoxin Immune Fab (Ovine) to a patient who has 428 ingested a massive dose of digoxin but who has not yet manifested life-threatening toxicity 429 should depend on the likelihood that life-threatening toxicity will occur (see above). 430 Digoxin is not effectively removed from the body by dialysis due to its large extravascular 431 volume of distribution. Patients with massive digitalis ingestion should receive large doses of 432 activated charcoal to prevent absorption and bind digoxin in the gut during enteroenteric 433 recirculation. Emesis may be indicated especially if ingestion has occurred within 30 minutes of 434 the patient’s presentation at the hospital. Emesis should not be induced in patients who are 435 obtunded. If a patient presents more than 2 hours after ingestion or already has toxic 436 manifestations, it may be unsafe to induce vomiting because such maneuvers may induce an 437 acute vagal episode that can worsen digitalis-related arrhythmias. 438 In cases where a large amount of digoxin has been ingested, hyperkalemia may be present due 439 to release of potassium from skeletal muscle. Hyperkalemia caused by massive digitalis toxicity 440 is best treated with Digoxin Immune Fab (Ovine); initial treatment with glucose and insulin may 441 also be required if hyperkalemia itself is acutely life-threatening. 442 DOSAGE AND ADMINISTRATION 443 General: Recommended dosages of digoxin may require considerable modification because of 444 individual sensitivity of the patient to the drug, the presence of associated conditions, or the use 445 of concurrent medications. 446 Parenteral administration of digoxin should be used only when the need for rapid 447 digitalization is urgent or when the drug cannot be taken orally. Intramuscular injection can lead 448 to severe pain at the injection site, thus intravenous administration is preferred. If the drug must 13 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 449 be administered by the intramuscular route, it should be injected deep into the muscle followed 450 by massage. No more than 500 mcg (2 mL) should be injected into a single site. 451 LANOXIN Injection can be administered undiluted or diluted with a 4-fold or greater volume 452 of Sterile Water for Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection. The 453 use of less than a 4-fold volume of diluent could lead to precipitation of the digoxin. Immediate 454 use of the diluted product is recommended. 455 If tuberculin syringes are used to measure very small doses, one must be aware of the problem 456 of inadvertent overadministration of digoxin. The syringe should not be flushed with the 457 parenteral solution after its contents are expelled into an indwelling vascular catheter. 458 Slow infusion of LANOXIN Injection is preferable to bolus administration. Rapid infusion of 459 digitalis glycosides has been shown to cause systemic and coronary arteriolar constriction, which 460 may be clinically undesirable. Caution is thus advised and LANOXIN Injection should probably 461 be administered over a period of 5 minutes or longer. Mixing of LANOXIN Injection with other 462 drugs in the same container or simultaneous administration in the same intravenous line is not 463 recommended. 464 In selecting a dose of digoxin, the following factors must be considered: 465 1. The body weight of the patient. Doses should be calculated based upon lean (i.e., ideal) body 466 weight. 467 2. The patient’s renal function, preferably evaluated on the basis of estimated creatinine 468 clearance. 469 3. The patient’s age. Infants and children require different doses of digoxin than adults. Also, 470 advanced age may be indicative of diminished renal function even in patients with normal 471 serum creatinine concentration (i.e., below 1.5 mg/dL). 472 4. Concomitant disease states, concurrent medications, or other factors likely to alter the 473 pharmacokinetic or pharmacodynamic profile of digoxin (see PRECAUTIONS). 474 Serum Digoxin Concentrations: In general, the dose of digoxin used should be determined 475 on clinical grounds. However, measurement of serum digoxin concentrations can be helpful to 476 the clinician in determining the adequacy of digoxin therapy and in assigning certain 477 probabilities to the likelihood of digoxin intoxication. About two-thirds of adults considered 478 adequately digitalized (without evidence of toxicity) have serum digoxin concentrations ranging 479 from 0.8 to 2.0 ng/mL (lower serum trough concentrations of 0.5 to 1 ng/mL may be appropriate 480 in some adult patients, see Maintenance Dosing). However, digoxin may produce clinical 481 benefits even at serum concentrations below this range. About two-thirds of adult patients with 482 clinical toxicity have serum digoxin concentrations greater than 2.0 ng/mL. However, since one 483 third of patients with clinical toxicity have concentrations less than 2.0 ng/mL, values below 484 2.0 ng/mL do not rule out the possibility that a certain sign or symptom is related to digoxin 485 therapy. Rarely, there are patients who are unable to tolerate digoxin at serum concentrations 486 below 0.8 ng/mL. Consequently, the serum concentration of digoxin should always be 487 interpreted in the overall clinical context, and an isolated measurement should not be used alone 488 as the basis for increasing or decreasing the dose of the drug. 14 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 489 To allow adequate time for equilibration of digoxin between serum and tissue, sampling of 490 serum concentrations should be done just before the next scheduled dose of the drug. If this is 491 not possible, sampling should be done at least 6 to 8 hours after the last dose, regardless of the 492 route of administration or the formulation used. On a once-daily dosing schedule, the 493 concentration of digoxin will be 10% to 25% lower when sampled at 24 versus 8 hours, 494 depending upon the patient’s renal function. On a twice-daily dosing schedule, there will be only 495 minor differences in serum digoxin concentrations whether sampling is done at 8 or 12 hours 496 after a dose. 497 If a discrepancy exists between the reported serum concentration and the observed clinical 498 response, the clinician should consider the following possibilities: 499 1. Analytical problems in the assay procedure. 500 2. Inappropriate serum sampling time. 501 3. Administration of a digitalis glycoside other than digoxin. 502 4. Conditions (described in WARNINGS and PRECAUTIONS) causing an alteration in the 503 sensitivity of the patient to digoxin. 504 5. Serum digoxin concentration may decrease acutely during periods of exercise without any 505 associated change in clinical efficacy due to increased binding of digoxin to skeletal muscle. 506 Heart Failure: Adults: Digitalization may be accomplished by either of 2 general approaches 507 that vary in dosage and frequency of administration, but reach the same endpoint in terms of total 508 amount of digoxin accumulated in the body. 509 1. If rapid digitalization is considered medically appropriate, it may be achieved by 510 administering a loading dose based upon projected peak digoxin body stores. Maintenance 511 dose can be calculated as a percentage of the loading dose. 512 2. More gradual digitalization may be obtained by beginning an appropriate maintenance dose, 513 thus allowing digoxin body stores to accumulate slowly. Steady-state serum digoxin 514 concentrations will be achieved in approximately 5 half-lives of the drug for the individual 515 patient. Depending upon the patient’s renal function, this will take between 1 and 3 weeks. 516 Rapid Digitalization With a Loading Dose: LANOXIN Injection is frequently used 517 to achieve rapid digitalization, with conversion to LANOXIN Tablets for maintenance therapy. If 518 patients are switched from intravenous to oral digoxin formulations, allowances must be made 519 for differences in bioavailability when calculating maintenance dosages (see Table 1, CLINICAL 520 PHARMACOLOGY: Pharmacokinetics and dosing Table 5). 521 Intramuscular injection of digoxin is extremely painful and offers no advantages unless other 522 routes of administration are contraindicated. 523 Peak digoxin body stores of 8 to 12 mcg/kg should provide therapeutic effect with minimum 524 risk of toxicity in most patients with heart failure and normal sinus rhythm. Because of altered 525 digoxin distribution and elimination, projected peak body stores for patients with renal 526 insufficiency should be conservative (i.e., 6 to 10 mcg/kg) (see PRECAUTIONS). 527 The loading dose should be administered in several portions, with roughly half the total given 528 as the first dose. Additional fractions of this planned total dose may be given at 6- to 8-hour 15 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 529 intervals, with careful assessment of clinical response before each additional dose. If the 530 patient’s clinical response necessitates a change from the calculated loading dose of digoxin, 531 then calculation of the maintenance dose should be based upon the amount actually given. 532 A single initial intravenous dose of 400 to 600 mcg (0.4 to 0.6 mg) of LANOXIN Injection 533 usually produces a detectable effect in 5 to 30 minutes that becomes maximal in 1 to 4 hours. 534 Additional doses of 100 to 300 mcg (0.1 to 0.3 mg) may be given cautiously at 6- to 8-hour 535 intervals until clinical evidence of an adequate effect is noted. The usual amount of LANOXIN 536 Injection that a 70-kg patient requires to achieve 8- to 12-mcg/kg peak body stores is 600 to 537 1,000 mcg (0.6 to 1.0 mg). 538 Maintenance Dosing: The doses of oral digoxin used in controlled trials in patients with 539 heart failure have ranged from 125 to 500 mcg (0.125 to 0.5 mg) once daily. In these studies, the 540 digoxin dose has been generally titrated according to the patient’s age, lean body weight, and 541 renal function. Therapy is generally initiated at a dose of 250 mcg (0.25 mg) once daily in 542 patients under age 70 with good renal function, at a dose of 125 mcg (0.125 mg) once daily in 543 patients over age 70 or with impaired renal function, and at a dose of 62.5 mcg (0.0625 mg) in 544 patients with marked renal impairment. Doses may be increased every 2 weeks according to 545 clinical response. 546 In a subset of approximately 1,800 patients enrolled in the DIG trial (wherein dosing was 547 based on an algorithm similar to that in Table 5) the mean (± SD) serum digoxin concentrations 548 at 1 month and 12 months were 1.01 ± 0.47 ng/mL and 0.97 ± 0.43 ng/mL, respectively. There 549 are no rigid guidelines as to the range of serum concentrations that are most efficacious. Several 550 post hoc analyses of heart failure patients in the DIG trial suggest that the optimal trough digoxin 551 serum level may be 0.5 ng/mL to 1 ng/mL. 552 The maintenance dose should be based upon the percentage of the peak body stores lost each 553 day through elimination. The following formula has had wide clinical use: 554 Maintenance Dose = Peak Body Stores (i.e., Loading Dose) x % Daily Loss/100 555 Where: % Daily Loss = 14 + Ccr/5 556 (Ccr is creatinine clearance, corrected to 70 kg body weight or 1.73 m2 body surface area.) 557 Table 5 provides average daily maintenance dose requirements of LANOXIN Injection for 558 patients with heart failure based upon lean body weight and renal function: 559 560 Table 5. Usual Daily Maintenance Dose Requirements (mcg) of LANOXIN Injection for 561 Estimated Peak Body Stores of 10 mcg/kga Corrected Ccr Lean Body Weight Number of Days (mL/min per 70 kg)b kg 50 60 70 80 90 100 Before Steady lb 110 132 154 176 198 220 State Achievedc 0 75d 75 100 100 125 150 22 10 75 100 100 125 150 150 19 20 100 100 125 150 150 175 16 30 100 125 150 150 175 200 14 16 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 40 100 125 150 175 200 225 13 50 125 150 175 200 225 250 12 60 125 150 175 200 225 250 11 70 150 175 200 225 250 275 10 80 150 175 200 250 275 300 9 90 150 200 225 250 300 325 8 100 175 200 250 275 300 350 7 562 a Daily maintenance doses have been rounded to the nearest 25-mcg increment. 563 b Ccr is creatinine clearance, corrected to 70-kg body weight or 1.73 m2 body surface area. For 564 adults, if only serum creatinine concentrations (Scr) are available, a Ccr (corrected to 70 kg 565 body weight) may be estimated in men as (140 - Age)/Scr. For women, this result should be 566 multiplied by 0.85. Note: This equation cannot be used for estimating creatinine clearance in 567 infants or children. 568 c If no loading dose administered. 569 d 75 mcg = 0.075 mg. 570 571 Example: Based on the above table, a patient in heart failure with an estimated lean body weight 572 of 70 kg and a Ccr of 60 mL/min should be given a dose of 175 mcg (0.175 mg) daily of 573 LANOXIN Injection. If no loading dose is administered, steady-state serum concentrations in 574 this patient should be anticipated at approximately 11 days. 575 Infants and Children: See the full prescribing information for LANOXIN Injection 576 Pediatric for specific recommendations. 577 It cannot be overemphasized that dosage guidelines provided are based upon average 578 patient response and substantial individual variation can be expected. Accordingly, 579 ultimate dosage selection must be based upon clinical assessment of the patient. 580 Atrial Fibrillation: Peak digoxin body stores larger than the 8 to 12 mcg/kg required for most 581 patients with heart failure and normal sinus rhythm have been used for control of ventricular rate 582 in patients with atrial fibrillation. Doses of digoxin used for the treatment of chronic atrial 583 fibrillation should be titrated to the minimum dose that achieves the desired ventricular rate 584 control without causing undesirable side effects. Data are not available to establish the 585 appropriate resting or exercise target rates that should be achieved. 586 Dosage Adjustment When Changing Preparations: The difference in bioavailability 587 between LANOXIN Injection or LANOXIN Tablets must be considered when changing patients 588 from one dosage form to the other. 589 HOW SUPPLIED 590 LANOXIN (digoxin) Injection, 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25 mg] per mL); Boxes 591 of 10 (NDC 0173-0260-10) and 50 ampuls (NDC 0173-0260-35). 592 Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP 593 Controlled Room Temperature] and protect from light. 17 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 594 595 LANOXIN and DIGIBIND are registered trademarks of GlaxoSmithKline 596 DIGIFAB is a registered trademark of Prostherics Inc. 597 GlaxoSmithKline 599 Manufactured by 600 Draxis Pharma Inc. 601 Kirkland, Canada H9H 4J4 for 602 GlaxoSmithKline 603 Research Triangle Park, NC 27709 604 605 ©2011, GlaxoSmithKline. All rights reserved. 606 607 November 2011 608 LNJ:XPI 18 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 2 LANOXIN® 3 (digoxin) 4 Injection Pediatric 5 100 mcg (0.1 mg) in 1 mL 6 DESCRIPTION PRESCRIBING INFORMATION 7 LANOXIN (digoxin) is one of the cardiac (or digitalis) glycosides, a closely related group of 8 drugs having in common specific effects on the myocardium. These drugs are found in a number 9 of plants. Digoxin is extracted from the leaves of Digitalis lanata. The term “digitalis” is used to 10 designate the whole group of glycosides. The glycosides are composed of 2 portions: a sugar and 11 a cardenolide (hence “glycosides”). 12 Digoxin is described chemically as (3β,5β,12β)-3-[(O-2,6-dideoxy-β-D-ribo-hexopyranosyl 13 (1→4)-O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-2,6-dideoxy-β-D-ribo 14 hexopyranosyl)oxy]-12,14-dihydroxy-card-20(22)-enolide. Its molecular formula is C41H64O14, 15 its molecular weight is 780.95, and its structural formula is: 16 Structural formula 17 18 19 Digoxin exists as odorless white crystals that melt with decomposition above 230°C. The drug 20 is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in 21 chloroform; and freely soluble in pyridine. 22 LANOXIN Injection Pediatric is a sterile solution of digoxin for intravenous or intramuscular 23 injection. The vehicle contains 40% propylene glycol and 10% alcohol. The injection is buffered 24 to a pH of 6.8 to 7.2 with 0.17% sodium phosphate and 0.08% anhydrous citric acid. Each 1-mL 25 ampul contains 100 mcg (0.1 mg) digoxin. Dilution is not required. 1 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 Mechanism of Action: Digoxin inhibits sodium-potassium ATPase, an enzyme that regulates the quantity of sodium and potassium inside cells. Inhibition of the enzyme leads to an increase in the intracellular concentration of sodium and thus (by stimulation of sodium-calcium exchange) an increase in the intracellular concentration of calcium. The beneficial effects of digoxin result from direct actions on cardiac muscle, as well as indirect actions on the cardiovascular system mediated by effects on the autonomic nervous system. The autonomic effects include: (1) a vagomimetic action, which is responsible for the effects of digoxin on the sinoatrial and atrioventricular (AV) nodes; and (2) baroreceptor sensitization, which results in increased afferent inhibitory activity and reduced activity of the sympathetic nervous system and renin-angiotensin system for any given increment in mean arterial pressure. The pharmacologic consequences of these direct and indirect effects are: (1) an increase in the force and velocity of myocardial systolic contraction (positive inotropic action); (2) a decrease in the degree of activation of the sympathetic nervous system and renin-angiotensin system (neurohormonal deactivating effect); and (3) slowing of the heart rate and decreased conduction velocity through the AV node (vagomimetic effect). The effects of digoxin in heart failure are mediated by its positive inotropic and neurohormonal deactivating effects, whereas the effects of the drug in atrial arrhythmias are related to its vagomimetic actions. In high doses, digoxin increases sympathetic outflow from the central nervous system (CNS). This increase in sympathetic activity may be an important factor in digitalis toxicity. Pharmacokinetics: Note: The following data are from studies performed in adults, unless otherwise stated. Absorption: Comparisons of the systemic availability and equivalent doses for preparations of digoxin are shown in Table 1. Table 1. Comparisons of the Systemic Availability and Equivalent Doses for Preparations of LANOXIN a For example, 125-mcg LANOXIN Tablets equivalent to 100 mcg LANOXIN Injection/IV. 53 54 55 56 57 58 59 60 61 Distribution: Following drug administration, a 6- to 8-hour tissue distribution phase is observed. This is followed by a much more gradual decline in the serum concentration of the drug, which is dependent on the elimination of digoxin from the body. The peak height and slope of the early portion (absorption/distribution phases) of the serum concentration-time curve are dependent upon the route of administration and the absorption characteristics of the formulation. Clinical evidence indicates that the early high serum concentrations do not reflect the concentration of digoxin at its site of action, but that with chronic use, the steady-state Product Absolute Bioavailability Equivalent Doses (mcg)a Among Dosage Forms LANOXIN Tablets LANOXIN Injection/IV 60 - 80% 100% 62.5 50 125 100 250 200 500 400 2 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 62 post-distribution serum concentrations are in equilibrium with tissue concentrations and correlate 63 with pharmacologic effects. In individual patients, these post-distribution serum concentrations 64 may be useful in evaluating therapeutic and toxic effects (see DOSAGE AND 65 ADMINISTRATION: Serum Digoxin Concentrations). 66 Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution. 67 Digoxin crosses both the blood-brain barrier and the placenta. At delivery, the serum digoxin 68 concentration in the newborn is similar to the serum concentration in the mother. Approximately 69 25% of digoxin in the plasma is bound to protein. Serum digoxin concentrations are not 70 significantly altered by large changes in fat tissue weight, so that its distribution space correlates 71 best with lean (i.e., ideal) body weight, not total body weight. 72 Metabolism: Only a small percentage (16%) of a dose of digoxin is metabolized. The end 73 metabolites, which include 3 β-digoxigenin, 3-keto-digoxigenin, and their glucuronide and 74 sulfate conjugates, are polar in nature and are postulated to be formed via hydrolysis, oxidation, 75 and conjugation. The metabolism of digoxin is not dependent upon the cytochrome P-450 76 system, and digoxin is not known to induce or inhibit the cytochrome P-450 system. 77 Excretion: Elimination of digoxin follows first-order kinetics (that is, the quantity of digoxin 78 eliminated at any time is proportional to the total body content). Following intravenous 79 administration to healthy volunteers, 50% to 70% of a digoxin dose is excreted unchanged in the 80 urine. Renal excretion of digoxin is proportional to glomerular filtration rate and is largely 81 independent of urine flow. In healthy volunteers with normal renal function, digoxin has a half 82 life of 1.5 to 2.0 days. The half-life in anuric patients is prolonged to 3.5 to 5 days. Digoxin is 83 not effectively removed from the body by dialysis, exchange transfusion, or during 84 cardiopulmonary bypass because most of the drug is bound to tissue and does not circulate in the 85 blood. 86 Special Populations: Race differences in digoxin pharmacokinetics have not been 87 formally studied. Because digoxin is primarily eliminated as unchanged drug via the kidney and 88 because there are no important differences in creatinine clearance among races, pharmacokinetic 89 differences due to race are not expected. 90 The clearance of digoxin can be primarily correlated with renal function as indicated by 91 creatinine clearance. In children with renal disease, digoxin must be carefully titrated based upon 92 clinical response. 93 Plasma digoxin concentration profiles in patients with acute hepatitis generally fell within the 94 range of profiles in a group of healthy subjects. 95 Pharmacodynamic and Clinical Effects: The times to onset of pharmacologic effect and to 96 peak effect of preparations of LANOXIN are shown in Table 2. 97 98 Table 2. Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of 99 LANOXIN Product Time to Onset of Effecta Time to Peak Effecta LANOXIN Tablets 0.5 - 2 hours 2 - 6 hours 3 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda LANOXIN Injection/IV 5 - 30 minutesb 1 - 4 hours 100 a Documented for ventricular response rate in atrial fibrillation, inotropic effects and 101 electrocardiographic changes. 102 b Depending upon rate of infusion. 103 104 Hemodynamic Effects: Digoxin produces hemodynamic improvement in patients with 105 heart failure. Short- and long-term therapy with the drug increases cardiac output and lowers 106 pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic vascular 107 resistance. These hemodynamic effects are accompanied by an increase in the left ventricular 108 ejection fraction and a decrease in end-systolic and end-diastolic dimensions. 109 Chronic Heart Failure: Two 12-week, double-blind, placebo-controlled studies enrolled 110 178 (RADIANCE trial) and 88 (PROVED trial) adult patients with NYHA class II or III heart 111 failure previously treated with oral digoxin, a diuretic, and an ACE inhibitor (RADIANCE only) 112 and randomized them to placebo or treatment with LANOXIN Tablets. Both trials demonstrated 113 better preservation of exercise capacity in patients randomized to LANOXIN. Continued 114 treatment with LANOXIN reduced the risk of developing worsening heart failure, as evidenced 115 by heart failure-related hospitalizations and emergency care and the need for concomitant heart 116 failure therapy. The larger study also showed treatment-related benefits in NYHA class and 117 patients’ global assessment. In the smaller trial, these trended in favor of a treatment benefit. 118 The Digitalis Investigation Group (DIG) main trial was a multicenter, randomized, double 119 blind, placebo-controlled mortality study of 6,801 adult patients with heart failure and left 120 ventricular ejection fraction ≤0.45. At randomization, 67% were NYHA class I or II, 71% had 121 heart failure of ischemic etiology, 44% had been receiving digoxin, and most were receiving 122 concomitant ACE inhibitor (94%) and diuretic (82%). Patients were randomized to placebo or 123 LANOXIN Tablets, the dose of which was adjusted for the patient’s age, sex, lean body weight, 124 and serum creatinine (see DOSAGE AND ADMINISTRATION), and followed for up to 125 58 months (median 37 months). The median daily dose prescribed was 0.25 mg. Overall all 126 cause mortality was 35% with no difference between groups (95% confidence limits for relative 127 risk of 0.91 to 1.07). LANOXIN was associated with a 25% reduction in the number of 128 hospitalizations for heart failure, a 28% reduction in the risk of a patient having at least 129 1 hospitalization for heart failure, and a 6.5% reduction in total hospitalizations (for any cause). 130 Use of LANOXIN was associated with a trend to increase time to all-cause death or 131 hospitalization. The trend was evident in subgroups of patients with mild heart failure as well as 132 more severe disease, as shown in Table 3. Although the effect on all-cause death or 133 hospitalization was not statistically significant, much of the apparent benefit derived from effects 134 on mortality and hospitalization attributed to heart failure. 135 4 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 136 Table 3. Subgroup Analyses of Mortality and Hospitalization During the First 2 Years 137 Following Randomization n Risk of All-Cause Mortality or All-Cause Hospitalizationa Risk of HF-Related Mortality or HF-Related Hospitalizationa Placebo LANOXIN Relative riskb Placebo LANOXIN Relative riskb All patients (EF ≤0.45) 6,801 604 593 0.94 (0.88-1.00) 294 217 0.69 (0.63-0.76) NYHA I/II EF 0.25-0.45 CTR ≤0.55 4,571 4,543 4,455 549 568 561 541 571 563 0.96 (0.89-1.04) 0.99 (0.91-1.07) 0.98 (0.91-1.06) 242 244 239 178 190 180 0.70 (0.62-0.80) 0.74 (0.66-0.84) 0.71 (0.63-0.81) NYHA III/IV EF <0.25 CTR >0.55 2,224 2,258 2,346 719 677 687 696 637 650 0.88 (0.80-0.97) 0.84 (0.76-0.93) 0.85 (0.77-0.94) 402 394 398 295 270 287 0.65 (0.57-0.75) 0.61 (0.53-0.71) 0.65 (0.57-0.75) EF >0.45c 987 571 585 1.04 (0.88-1.23) 179 136 0.72 (0.53-0.99) 138 a Number of patients with an event during the first 2 years per 1,000 randomized patients. 139 b Relative risk (95% confidence interval). 140 c DIG Ancillary Study. 141 142 In situations where there is no statistically significant benefit of treatment evident from a 143 trial’s primary endpoint, results pertaining to a secondary endpoint should be interpreted 144 cautiously. 145 Chronic Atrial Fibrillation: In adult patients with chronic atrial fibrillation, digoxin slows 146 rapid ventricular response rate in a linear dose-response fashion from 0.25 to 0.75 mg/day. 147 Digoxin should not be used for the treatment of multifocal atrial tachycardia. 148 INDICATIONS AND USAGE 149 Heart Failure: LANOXIN is indicated for the treatment of mild to moderate heart failure. 150 LANOXIN increases left ventricular ejection fraction and improves heart failure symptoms as 151 evidenced by exercise capacity and heart failure-related hospitalizations and emergency care, 152 while having no effect on mortality. Where possible, LANOXIN should be used with a diuretic 153 and an angiotensin-converting enzyme inhibitor, but an optimal order for starting these 3 drugs 154 cannot be specified. 5 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 155 Atrial Fibrillation: LANOXIN is indicated for the control of ventricular response rate in 156 patients with chronic atrial fibrillation. 157 CONTRAINDICATIONS 158 Digitalis glycosides are contraindicated in patients with ventricular fibrillation or in patients 159 with a known hypersensitivity to digoxin. A hypersensitivity reaction to other digitalis 160 preparations usually constitutes a contraindication to digoxin. 161 WARNINGS 162 Sinus Node Disease and AV Block: Because digoxin slows sinoatrial and AV conduction, 163 the drug commonly prolongs the PR interval. The drug may cause severe sinus bradycardia or 164 sinoatrial block in patients with pre-existing sinus node disease and may cause advanced or 165 complete heart block in patients with pre-existing incomplete AV block. In such patients 166 consideration should be given to the insertion of a pacemaker before treatment with digoxin. 167 Accessory AV Pathway (Wolff-Parkinson-White Syndrome): After intravenous digoxin 168 therapy, some patients with paroxysmal atrial fibrillation or flutter and a coexisting accessory 169 AV pathway have developed increased antegrade conduction across the accessory pathway 170 bypassing the AV node, leading to a very rapid ventricular response or ventricular fibrillation. 171 Unless conduction down the accessory pathway has been blocked (either pharmacologically or 172 by surgery), digoxin should not be used in such patients. The treatment of paroxysmal 173 supraventricular tachycardia in such patients is usually direct-current cardioversion. 174 Use in Patients With Preserved Left Ventricular Systolic Function: Patients with 175 certain disorders involving heart failure associated with preserved left ventricular ejection 176 fraction may be particularly susceptible to toxicity of the drug. Such disorders include restrictive 177 cardiomyopathy, constrictive pericarditis, amyloid heart disease, and acute cor pulmonale. 178 Patients with idiopathic hypertrophic subaortic stenosis may have worsening of the outflow 179 obstruction due to the inotropic effects of digoxin. Digoxin should generally be avoided in these 180 patients, although it has been used for ventricular rate control in the subgroup of patients with 181 atrial fibrillation. 182 PRECAUTIONS 183 Use in Patients With Impaired Renal Function: Digoxin is primarily excreted by the 184 kidneys; therefore, patients with impaired renal function require smaller than usual maintenance 185 doses of digoxin (see DOSAGE AND ADMINISTRATION). Because of the prolonged 186 elimination half-life, a longer period of time is required to achieve an initial or new steady-state 187 serum concentration in patients with renal impairment than in patients with normal renal 188 function. If appropriate care is not taken to reduce the dose of digoxin, such patients are at high 189 risk for toxicity, and toxic effects will last longer in such patients than in patients with normal 190 renal function. 191 Use in Patients With Electrolyte Disorders: In patients with hypokalemia or 192 hypomagnesemia, toxicity may occur despite serum digoxin concentrations below 2.0 ng/mL, 6 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 193 because potassium or magnesium depletion sensitizes the myocardium to digoxin. Therefore, it is 194 desirable to maintain normal serum potassium and magnesium concentrations in patients being 195 treated with digoxin. Deficiencies of these electrolytes may result from malnutrition, diarrhea, or 196 prolonged vomiting, as well as the use of the following drugs or procedures: diuretics, 197 amphotericin B, corticosteroids, antacids, dialysis, and mechanical suction of gastrointestinal 198 secretions. 199 Hypercalcemia from any cause predisposes the patient to digitalis toxicity. Calcium, 200 particularly when administered rapidly by the intravenous route, may produce serious 201 arrhythmias in digitalized patients. On the other hand, hypocalcemia can nullify the effects of 202 digoxin in humans; thus, digoxin may be ineffective until serum calcium is restored to normal. 203 These interactions are related to the fact that digoxin affects contractility and excitability of the 204 heart in a manner similar to that of calcium. 205 Use in Thyroid Disorders and Hypermetabolic States: Hypothyroidism may reduce the 206 requirements for digoxin. Heart failure and/or atrial arrhythmias resulting from hypermetabolic 207 or hyperdynamic states (e.g., hyperthyroidism, hypoxia, or arteriovenous shunt) are best treated 208 by addressing the underlying condition. Atrial arrhythmias associated with hypermetabolic states 209 are particularly resistant to digoxin treatment. Care must be taken to avoid toxicity if digoxin is 210 used. 211 Use in Patients With Acute Myocardial Infarction: Digoxin should be used with caution 212 in patients with acute myocardial infarction. The use of inotropic drugs in some patients in this 213 setting may result in undesirable increases in myocardial oxygen demand and ischemia. 214 Use During Electrical Cardioversion: It may be desirable to reduce the dose of digoxin for 215 1 to 2 days prior to electrical cardioversion of atrial fibrillation to avoid the induction of 216 ventricular arrhythmias, but physicians must consider the consequences of increasing the 217 ventricular response if digoxin is withdrawn. If digitalis toxicity is suspected, elective 218 cardioversion should be delayed. If it is not prudent to delay cardioversion, the lowest possible 219 energy level should be selected to avoid provoking ventricular arrhythmias. 220 Use in Patients With Myocarditis: Digoxin can rarely precipitate vasoconstriction and 221 therefore should be avoided in patients with myocarditis. 222 Use in Patients With Beri Beri Heart Disease: Patients with beri beri heart disease may 223 fail to respond adequately to digoxin if the underlying thiamine deficiency is not treated 224 concomitantly. 225 Laboratory Test Monitoring: Patients receiving digoxin should have their serum electrolytes 226 and renal function (serum creatinine concentrations) assessed periodically; the frequency of 227 assessments will depend on the clinical setting. For discussion of serum digoxin concentrations, 228 see DOSAGE AND ADMINISTRATION. 229 Drug Interactions: Potassium-depleting diuretics are a major contributing factor to digitalis 230 toxicity. Calcium, particularly if administered rapidly by the intravenous route, may produce 231 serious arrhythmias in digitalized patients. Quinidine, verapamil, amiodarone, propafenone, 232 indomethacin, itraconazole, alprazolam, and spironolactone raise the serum digoxin 7 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 233 concentration due to a reduction in clearance and/or volume of distribution of the drug, with the 234 implication that digitalis intoxication may result. Erythromycin and clarithromycin (and possibly 235 other macrolide antibiotics) and tetracycline may increase digoxin absorption in patients who 236 inactivate digoxin by bacterial metabolism in the lower intestine, so that digitalis intoxication 237 may result. Propantheline and diphenoxylate, by decreasing gut motility, may increase digoxin 238 absorption. Antacids, kaolin-pectin, sulfasalazine, neomycin, cholestyramine, certain anticancer 239 drugs, and metoclopramide may interfere with intestinal digoxin absorption, resulting in 240 unexpectedly low serum concentrations. Rifampin may decrease serum digoxin concentration, 241 especially in patients with renal dysfunction, by increasing the non-renal clearance of digoxin. 242 There have been inconsistent reports regarding the effects of other drugs (e.g., quinine, 243 Penicillamine) on serum digoxin concentration. Thyroid administration to a digitalized, 244 hypothyroid patient may increase the dose requirement of digoxin. Concomitant use of digoxin 245 and sympathomimetics increases the risk of cardiac arrhythmias. Succinylcholine may cause a 246 sudden extrusion of potassium from muscle cells, and may thereby cause arrhythmias in 247 digitalized patients. Although calcium channel blockers and digoxin may be useful in 248 combination to control atrial fibrillation, their additive effects on AV node conduction can result 249 in advanced or complete heart block. Both digitalis glycosides and beta-blockers slow 250 atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of 251 bradycardia. Digoxin concentrations are increased by about 15% when digoxin and carvedilol 252 are administered concomitantly. Therefore, increased monitoring of digoxin is recommended 253 when initiating, adjusting, or discontinuing carvedilol. 254 Due to the considerable variability of these interactions, dosage of digoxin should be 255 individualized when patients receive these medications concurrently. Furthermore, caution 256 should be exercised when combining digoxin with any drug that may cause a significant 257 deterioration in renal function, since a decline in glomerular filtration or tubular secretion may 258 impair the excretion of digoxin. 259 Drug/Laboratory Test Interactions: The use of therapeutic doses of digoxin may cause 260 prolongation of the PR interval and depression of the ST segment on the electrocardiogram. 261 Digoxin may produce false positive ST-T changes on the electrocardiogram during exercise 262 testing. These electrophysiologic effects reflect an expected effect of the drug and are not 263 indicative of toxicity. 264 Carcinogenesis, Mutagenesis, Impairment of Fertility: Digoxin showed no genotoxic 265 potential in in vitro studies (Ames test and mouse lymphoma). No data are available on the 266 carcinogenic potential of digoxin, nor have studies been conducted to assess its potential to affect 267 fertility. 268 Pregnancy: Teratogenic Effects: Pregnancy Category C. Animal reproduction studies have 269 not been conducted with digoxin. It is also not known whether digoxin can cause fetal harm 270 when administered to a pregnant woman or can affect reproductive capacity. Digoxin should be 271 given to a pregnant woman only if clearly needed. 8 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 272 Nursing Mothers: Studies have shown that digoxin concentrations in the mother’s serum and 273 milk are similar. However, the estimated exposure of a nursing infant to digoxin via 274 breastfeeding will be far below the usual infant maintenance dose. Therefore, this amount should 275 have no pharmacologic effect upon the infant. Nevertheless, caution should be exercised when 276 digoxin is administered to a nursing woman. 277 Pediatric Use: Newborn infants display considerable variability in their tolerance to digoxin. 278 Premature and immature infants are particularly sensitive to the effects of digoxin, and the 279 dosage of the drug must not only be reduced but must be individualized according to their degree 280 of maturity. Digitalis glycosides can cause poisoning in children due to accidental ingestion. 281 Geriatric Use: The majority of clinical experience gained with digoxin has been in the elderly 282 population. This experience has not identified differences in response or adverse effects between 283 the elderly and younger patients. However, this drug is known to be substantially excreted by the 284 kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal 285 function. Because elderly patients are more likely to have decreased renal function, care should 286 be taken in dose selection, which should be based on renal function, and it may be useful to 287 monitor renal function. 288 ADVERSE REACTIONS 289 In general, the adverse reactions of digoxin are dose-dependent and occur at doses higher than 290 those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when 291 digoxin is used within the recommended dose range or therapeutic serum concentration range 292 and when there is careful attention to concurrent medications and conditions. 293 Because some patients may be particularly susceptible to side effects with digoxin, the dosage 294 of the drug should always be selected carefully and adjusted as the clinical condition of the 295 patient warrants. In the past, when high doses of digoxin were used and little attention was paid 296 to clinical status or concurrent medications, adverse reactions to digoxin were more frequent and 297 severe. Cardiac adverse reactions accounted for about one-half, gastrointestinal disturbances for 298 about one-fourth, and CNS and other toxicity for about one-fourth of these adverse reactions. 299 However, available evidence suggests that the incidence and severity of digoxin toxicity has 300 decreased substantially in recent years. In recent controlled clinical trials, in patients with 301 predominantly mild to moderate heart failure, the incidence of adverse experiences was 302 comparable in patients taking digoxin and in those taking placebo. In a large mortality trial, the 303 incidence of hospitalization for suspected digoxin toxicity was 2% in patients taking LANOXIN 304 Tablets compared to 0.9% in patients taking placebo. In this trial, the most common 305 manifestations of digoxin toxicity included gastrointestinal and cardiac disturbances; CNS 306 manifestations were less common. 307 Adults: Cardiac: Therapeutic doses of digoxin may cause heart block in patients with pre 308 existing sinoatrial or AV conduction disorders; heart block can be avoided by adjusting the dose 309 of digoxin. Prophylactic use of a cardiac pacemaker may be considered if the risk of heart block 310 is considered unacceptable. High doses of digoxin may produce a variety of rhythm disturbances, 9 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 311 such as first-degree, second-degree (Wenckebach), or third-degree heart block (including 312 asystole); atrial tachycardia with block; AV dissociation; accelerated junctional (nodal) rhythm; 313 unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy); 314 ventricular tachycardia; and ventricular fibrillation. Digoxin produces PR prolongation and ST 315 segment depression which should not by themselves be considered digoxin toxicity. Cardiac 316 toxicity can also occur at therapeutic doses in patients who have conditions which may alter their 317 sensitivity to digoxin (see WARNINGS and PRECAUTIONS). 318 Gastrointestinal: Digoxin may cause anorexia, nausea, vomiting, and diarrhea. Rarely, the 319 use of digoxin has been associated with abdominal pain, intestinal ischemia, and hemorrhagic 320 necrosis of the intestines. 321 CNS: Digoxin can produce visual disturbances (blurred or yellow vision), headache, 322 weakness, dizziness, apathy, confusion, and mental disturbances (such as anxiety, depression, 323 delirium, and hallucination). 324 Other: Gynecomastia has been occasionally observed following the prolonged use of 325 digoxin. Thrombocytopenia and maculopapular rash and other skin reactions have been rarely 326 observed. 327 Table 4 summarizes the incidence of those adverse experiences listed above for patients 328 treated with LANOXIN Tablets or placebo from 2 randomized, double-blind, placebo-controlled 329 withdrawal trials. Patients in these trials were also receiving diuretics with or without 330 angiotensin-converting enzyme inhibitors. These patients had been stable on digoxin, and were 331 randomized to digoxin or placebo. The results shown in Table 4 reflect the experience in patients 332 following dosage titration with the use of serum digoxin concentrations and careful follow-up. 333 These adverse experiences are consistent with results from a large, placebo-controlled mortality 334 trial (DIG trial) wherein over half the patients were not receiving digoxin prior to enrollment. 335 336 Table 4. Adverse Experiences In 2 Parallel, Double-Blind, Placebo-Controlled Withdrawal 337 Trials (Number of Patients Reporting) Adverse Experience Digoxin Patients (n = 123) Placebo Patients (n = 125) Cardiac Palpitation Ventricular extrasystole Tachycardia Heart arrest 1 1 2 1 4 1 1 1 Gastrointestinal Anorexia Nausea Vomiting Diarrhea Abdominal pain 1 4 2 4 0 4 2 1 1 6 10 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CNS Headache Dizziness Mental disturbances 4 6 5 4 5 1 Other Rash Death 2 4 1 3 338 339 Infants and Children: The side effects of digoxin in infants and children differ from those 340 seen in adults in several respects. Although digoxin may produce anorexia, nausea, vomiting, 341 diarrhea, and CNS disturbances in young patients, these are rarely the initial symptoms of 342 overdosage. Rather, the earliest and most frequent manifestation of excessive dosing with 343 digoxin in infants and children is the appearance of cardiac arrhythmias, including sinus 344 bradycardia. In children, the use of digoxin may produce any arrhythmia. The most common are 345 conduction disturbances or supraventricular tachyarrhythmias, such as atrial tachycardia (with or 346 without block) and junctional (nodal) tachycardia. Ventricular arrhythmias are less common. 347 Sinus bradycardia may be a sign of impending digoxin intoxication, especially in infants, even in 348 the absence of first-degree heart block. Any arrhythmia or alteration in cardiac conduction that 349 develops in a child taking digoxin should be assumed to be caused by digoxin, until further 350 evaluation proves otherwise. 351 OVERDOSAGE 352 Signs and Symptoms: The signs and symptoms of toxicity are generally similar to those 353 described in the ADVERSE REACTIONS section but may be more frequent and can be more 354 severe. Signs and symptoms of digoxin toxicity become more frequent with levels above 355 2 ng/mL. However, in deciding whether a patient’s symptoms are due to digoxin, the clinical 356 state together with serum electrolyte levels and thyroid function are important factors (see 357 DOSAGE AND ADMINISTRATION). 358 Adults: In adults without heart disease, clinical observation suggests that an overdose of 359 digoxin of 10 to 15 mg was the dose resulting in death of half of the patients. If more than 25 mg 360 of digoxin was ingested by an adult without heart disease, death or progressive toxicity 361 responsive only to digoxin-binding Fab antibody fragments resulted. Cardiac manifestations are 362 the most frequent and serious sign of both acute and chronic toxicity. Peak cardiac effects 363 generally occur 3 to 6 hours following overdosage and may persist for the ensuing 24 hours or 364 longer. Digoxin toxicity may result in almost any type of arrhythmia (see ADVERSE 365 REACTIONS). Multiple rhythm disturbances in the same patient are common. Cardiac arrest 366 from asystole or ventricular fibrillation due to digoxin toxicity is usually fatal. 367 Among the extra-cardiac manifestations, gastrointestinal symptoms (e.g. nausea, vomiting, 368 anorexia) are very common (up to 80% incidence) and precede cardiac manifestations in 369 approximately half of the patients in most literature reports. Neurologic manifestations (e.g. 11 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 370 dizziness, various CNS disturbances), fatigue, and malaise are very common. Visual 371 manifestations may also occur with aberration in color vision (predominance of yellow green) 372 the most frequent. Neurological and visual symptoms may persist after other signs of toxicity 373 have resolved. In chronic toxicity, non-specific extra-cardiac symptoms, such as malaise and 374 weakness, may predominate. 375 Children: In children aged 1 to 3 years without heart disease, clinical observation suggests 376 that an overdose of digoxin of 6 to 10 mg was the dose resulting in death in half of the patients. 377 If more than 10 mg of digoxin was ingested by a child aged 1 to 3 years without heart disease, 378 the outcome was uniformly fatal when Fab fragment treatment was not given. Most 379 manifestations of toxicity in children occur during or shortly after the loading phase with 380 digoxin. The same arrhythmias or combination of arrhythmias that occur in adults can occur in 381 pediatrics. Sinus tachycardia, supraventricular tachycardia, and rapid atrial fibrillation are seen 382 less frequently in the pediatric population. Pediatric patients are more likely to present with an 383 AV conduction disturbance or a sinus bradycardia. Any arrhythmia or alteration in cardiac 384 conduction that develops in a child taking digoxin should be assumed to be caused by digoxin, 385 until further evaluation proves otherwise. 386 The frequent extracardiac manifestations similar to those seen in adults are gastrointestinal, 387 CNS, and visual. However, nausea and vomiting are not frequent in infants and small children. 388 In addition to the undesirable effects seen with recommended doses, weight loss in older age 389 groups and failure to thrive in infants, abdominal pain due to mesenteric artery ischemia, 390 drowsiness, and behavioral disturbances including psychotic manifestations have been reported 391 in overdose. 392 Treatment: In addition to cardiac monitoring, digoxin should be temporarily discontinued until 393 the adverse reaction resolves and may be all that is required to treat the adverse reaction such as 394 in asymptomatic bradycardia or digoxin related heart block. Every effort should also be made to 395 correct factors that may contribute to the adverse reaction (such as electrolyte disturbances, 396 thyroid function, or concurrent medications) (see WARNINGS and PRECAUTIONS: Drug 397 Interactions). Once the adverse reaction has resolved, therapy with digoxin may be reinstituted, 398 following a careful reassessment of dose. 399 When the primary manifestation of digoxin overdosage is a cardiac arrhythmia, additional 400 therapy may be needed. 401 402 403 If the rhythm disturbance is a symptomatic bradyarrhythmia or heart block, consideration should be given to the reversal of toxicity with Digoxin Immune Fab (Ovine) [DIGIBIND ® or DIGIFAB ®] (see Massive Digitalis Overdosage subsection), the use of atropine, or the insertion 404 of a temporary cardiac pacemaker. Digoxin Immune Fab (Ovine) is a specific antidote for 405 digoxin and may be used to reverse potentially life-threatening ventricular arrhythmias due to 406 digoxin overdosage. 407 If the rhythm disturbance is a ventricular arrhythmia, consideration should be given to the 408 correction of electrolyte disorders, particularly if hypokalemia (see Administration of Potassium 12 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 409 subsection) or hypomagnesemia is present. Ventricular arrhythmias may respond to lidocaine or 410 phenytoin. 411 Administration of Potassium: Before administering potassium in digoxin overdose for 412 hypokalemia, the serum potassium must be known and every effort should be made to maintain 413 the serum potassium concentration between 4 and 5.5 mmol/L. Potassium salts should be 414 avoided as they may be dangerous in patients who manifest bradycardia or heart block due to 415 digoxin (unless primarily related to supraventricular tachycardia) and in the setting of massive 416 digitalis overdosage. Potassium is usually administered orally, but when correction of the 417 arrhythmia is urgent and the serum potassium concentration is low, potassium may be 418 administered cautiously by the intravenous route. The electrocardiogram should be monitored for 419 any evidence of potassium toxicity (e.g., peaking of T waves) and to observe the effect on the 420 arrhythmia. 421 Massive Digitalis Overdosage: Manifestations of life-threatening toxicity include 422 ventricular tachycardia or ventricular fibrillation, or progressive bradyarrhythmias, or heart 423 block. 424 Digoxin Immune Fab (Ovine) should be used to reverse the toxic effects of ingestion of a 425 massive overdose. The decision to administer Digoxin Immune Fab (Ovine) to a patient who has 426 ingested a massive dose of digoxin but who has not yet manifested life-threatening toxicity 427 should depend on the likelihood that life-threatening toxicity will occur (see above). 428 Digoxin is not effectively removed from the body by dialysis due to its large extravascular 429 volume of distribution. Patients with massive digitalis ingestion should receive large doses of 430 activated charcoal to prevent absorption and bind digoxin in the gut during enteroenteric 431 recirculation. Emesis may be indicated especially if ingestion has occurred within 30 minutes of 432 the patient’s presentation at the hospital. Emesis should not be induced in patients who are 433 obtunded. If a patient presents more than 2 hours after ingestion or already has toxic 434 manifestations, it may be unsafe to induce vomiting because such maneuvers may induce an 435 acute vagal episode that can worsen digitalis-related arrhythmias. 436 In cases where a large amount of digoxin has been ingested, hyperkalemia may be present due 437 to release of potassium from skeletal muscle. Hyperkalemia caused by massive digitalis toxicity 438 is best treated with Digoxin Immune Fab (Ovine); initial treatment with glucose and insulin may 439 also be required if hyperkalemia itself is acutely life-threatening. 440 DOSAGE AND ADMINISTRATION 441 General: Recommended dosages of digoxin may require considerable modification because of 442 individual sensitivity of the patient to the drug, the presence of associated conditions, or the use 443 of concurrent medications. 444 Parenteral administration of digoxin should be used only when the need for rapid 445 digitalization is urgent or when the drug cannot be taken orally. Intramuscular injection can lead 446 to severe pain at the injection site, thus intravenous administration is preferred. If the drug must 13 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 447 be administered by the intramuscular route, it should be injected deep into the muscle followed 448 by massage. No more than 200 mcg (2 mL) should be injected into a single site. 449 LANOXIN Injection Pediatric can be administered undiluted or diluted with a 4-fold or 450 greater volume of Sterile Water for Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose 451 Injection. The use of less than a 4-fold volume of diluent could lead to precipitation of the 452 digoxin. Immediate use of the diluted product is recommended. 453 If tuberculin syringes are used to measure very small doses, one must be aware of the problem 454 of inadvertent overadministration of digoxin. The syringe should not be flushed with the 455 parenteral solution after its contents are expelled into an indwelling vascular catheter. 456 Slow infusion of LANOXIN Injection Pediatric is preferable to bolus administration. Rapid 457 infusion of digitalis glycosides has been shown to cause systemic and coronary arteriolar 458 constriction, which may be clinically undesirable. Caution is thus advised and LANOXIN 459 Injection Pediatric should probably be administered over a period of 5 minutes or longer. Mixing 460 of LANOXIN Injection Pediatric with other drugs in the same container or simultaneous 461 administration in the same intravenous line is not recommended. 462 In selecting a dose of digoxin, the following factors must be considered: 463 1. The body weight of the patient. Doses should be calculated based upon lean (i.e., ideal) body 464 weight. 465 2. The patient’s renal function, preferably evaluated on the basis of estimated creatinine 466 clearance. 467 3. The patient’s age. Infants and children require different doses of digoxin than adults. Also, 468 advanced age may be indicative of diminished renal function even in patients with normal 469 serum creatinine concentration (i.e., below 1.5 mg/dL). 470 4. Concomitant disease states, concurrent medications, or other factors likely to alter the 471 pharmacokinetic or pharmacodynamic profile of digoxin (see PRECAUTIONS). 472 Serum Digoxin Concentrations: In general, the dose of digoxin used should be determined 473 on clinical grounds. However, measurement of serum digoxin concentrations can be helpful to 474 the clinician in determining the adequacy of digoxin therapy and in assigning certain 475 probabilities to the likelihood of digoxin intoxication. About two-thirds of adults considered 476 adequately digitalized (without evidence of toxicity) have serum digoxin concentrations ranging 477 from 0.8 to 2.0 ng/mL. However, digoxin may produce clinical benefits even at serum 478 concentrations below this range. About two-thirds of adult patients with clinical toxicity have 479 serum digoxin concentrations greater than 2.0 ng/mL. However, since one-third of patients with 480 clinical toxicity have concentrations less than 2.0 ng/mL, values below 2.0 ng/mL do not rule out 481 the possibility that a certain sign or symptom is related to digoxin therapy. Rarely, there are 482 patients who are unable to tolerate digoxin at serum concentrations below 0.8 ng/mL. 483 Consequently, the serum concentration of digoxin should always be interpreted in the overall 484 clinical context, and an isolated measurement should not be used alone as the basis for increasing 485 or decreasing the dose of the drug. 14 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 486 To allow adequate time for equilibration of digoxin between serum and tissue, sampling of 487 serum concentrations should be done just before the next scheduled dose of the drug. If this is 488 not possible, sampling should be done at least 6 to 8 hours after the last dose, regardless of the 489 route of administration or the formulation used. On a once-daily dosing schedule, the 490 concentration of digoxin will be 10% to 25% lower when sampled at 24 versus 8 hours, 491 depending upon the patient’s renal function. On a twice-daily dosing schedule, there will be only 492 minor differences in serum digoxin concentrations whether sampling is done at 8 or 12 hours 493 after a dose. 494 If a discrepancy exists between the reported serum concentration and the observed clinical 495 response, the clinician should consider the following possibilities: 496 1. Analytical problems in the assay procedure. 497 2. Inappropriate serum sampling time. 498 3. Administration of a digitalis glycoside other than digoxin. 499 4. Conditions (described in WARNINGS and PRECAUTIONS) causing an alteration in the 500 sensitivity of the patient to digoxin. 501 5. Serum digoxin concentration may decrease acutely during periods of exercise without any 502 associated change in clinical efficacy due to increased binding of digoxin to skeletal muscle. 503 Heart Failure: Adults: See the full prescribing information for LANOXIN Injection for 504 specific recommendations. 505 Infants and Children: In general, divided daily dosing is recommended for infants and 506 young children (under age 10). In the newborn period, renal clearance of digoxin is diminished 507 and suitable dosage adjustments must be observed. This is especially pronounced in the 508 premature infant. Beyond the immediate newborn period, children generally require 509 proportionally larger doses than adults on the basis of body weight or body surface area. 510 Children over 10 years of age require adult dosages in proportion to their body weight. Some 511 researchers have suggested that infants and young children tolerate slightly higher serum 512 concentrations than do adults. 513 Digitalization may be accomplished by either of two general approaches that vary in dosage 514 and frequency of administration, but reach the same endpoint in terms of total amount of digoxin 515 accumulated in the body. 516 1. If rapid digitalization is considered medically appropriate, it may be achieved by 517 administering a loading dose based upon projected peak digoxin body stores. Maintenance 518 dose can be calculated as a percentage of the loading dose. 519 2. More gradual digitalization may be obtained by beginning an appropriate maintenance dose, 520 thus allowing digoxin body stores to accumulate slowly. Steady-state serum digoxin 521 concentrations will be achieved in approximately five half-lives of the drug for the individual 522 patient. Depending upon the patient’s renal function, this will take between 1 and 3 weeks. 523 Rapid Digitalization With a Loading Dose: LANOXIN Injection Pediatric can be 524 used to achieve rapid digitalization, with conversion to an oral formulation of LANOXIN for 525 maintenance therapy. If patients are switched from intravenous to oral digoxin formulations, 15 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 526 allowances must be made for differences in bioavailability when calculating maintenance 527 dosages (see Table 1 in CLINICAL PHARMACOLOGY: Pharmacokinetics and dosing Table 528 5). 529 Intramuscular injection of digoxin is extremely painful and offers no advantages unless other 530 routes of administration are contraindicated. 531 Peak digoxin body stores of 8 to 12 mcg/kg should provide therapeutic effect with minimum 532 risk of toxicity in most patients with heart failure and normal sinus rhythm. Because of altered 533 digoxin distribution and elimination, projected peak body stores for patients with renal 534 insufficiency should be conservative (i.e., 6 to 10 mcg/kg) (see PRECAUTIONS). 535 Digitalizing and daily maintenance doses for each age group are given in Table 5 and should 536 provide therapeutic effect with minimum risk of toxicity in most patients with heart failure and 537 normal sinus rhythm. These recommendations assume the presence of normal renal function. 538 The loading dose should be administered in several portions, with roughly half the total given 539 as the first dose. Additional fractions of this planned total dose may be given at 4- to 8-hour 540 intervals, with careful assessment of clinical response before each additional dose. If the 541 patient’s clinical response necessitates a change from the calculated loading dose of digoxin, 542 then calculation of the maintenance dose should be based upon the amount actually given. 543 544 Table 5. Usual Digitalizing and Maintenance Dosages for LANOXIN® Injection Pediatric in 545 Children With Normal Renal Function Based on Lean Body Weight Age IV Digitalizinga Dose (mcg/kg) Daily IV Maintenance Doseb (mcg/kg) Premature 15 to 25 20% to 30% of the IV digitalizing dose c Full-Term 1 to 24 Months 2 to 5 Years 5 to 10 Years Over 10 Years 20 to 30 30 to 50 25 to 35 15 to 30 8 to 12 25% to 35% of the IV digitalizing dose c 546 a IV digitalizing doses are 80% of oral digitalizing doses. b 547 Divided daily dosing is recommended for children under 10 years of age. 548 c Projected or actual digitalizing dose providing clinical response. 549 550 In children with renal disease, digoxin dosing must be carefully titrated based on clinical 551 response. 552 Gradual Digitalization With A Maintenance Dose: More gradual digitalization can 553 also be accomplished by beginning an appropriate maintenance dose. The range of percentages 554 provided in Table 5 can be used in calculating this dose for patients with normal renal function. 555 It cannot be overemphasized that these pediatric dosage guidelines are based upon 556 average patient response and substantial individual variation can be expected. 16 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 557 Accordingly, ultimate dosage selection must be based upon clinical assessment of the 558 patient. 559 Atrial Fibrillation: Peak digoxin body stores larger than the 8 to 12 mcg/kg required for most 560 patients with heart failure and normal sinus rhythm have been used for control of ventricular rate 561 in patients with atrial fibrillation. Doses of digoxin used for the treatment of chronic atrial 562 fibrillation should be titrated to the minimum dose that achieves the desired ventricular rate 563 control without causing undesirable side effects. Data are not available to establish the 564 appropriate resting or exercise target rates that should be achieved. 565 Dosage Adjustment When Changing Preparations: The differences in bioavailability 566 between injectable LANOXIN or LANOXIN Tablets must be considered when changing 567 patients from one dosage form to another. 568 HOW SUPPLIED 569 LANOXIN (digoxin) Injection Pediatric, 100 mcg (0.1 mg) in 1 mL; box of 10 ampuls (NDC 570 0173-0262-10). 571 Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP 572 Controlled Room Temperature] and protect from light. 573 574 LANOXIN and DIGIBIND are registered trademarks of GlaxoSmithKline 575 DIGIFAB is a registered trademark of Prostherics Inc. 576 577 578 Manufactured by 579 DSM Pharmaceuticals, Inc. 580 Greenville, NC 27834 for 581 GlaxoSmithKline 582 Research Triangle Park, NC 27709 583 584 ©2011, GlaxoSmithKline. All rights reserved. 585 586 November 2011 587 LNP:XPI 17 Reference ID: 3043945 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:40.025880	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/009330s026lbl.pdf', 'application_number': 9330, 'submission_type': 'SUPPL ', 'submission_number': 26}
10,726	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LANOXIN safely and effectively. See full prescribing information for LANOXIN. LANOXIN (digoxin) injection, for intravenous or intramuscular use Initial U.S. Approval: 1954 --------------------------- INDICATIONS AND USAGE--------------------------- LANOXIN is a cardiac glycoside indicated for: • Treatment of mild to moderate heart failure in adults. (1.1) • Increasing myocardial contractility in pediatric patients with heart failure. (1.2) • Control of resting ventricular rate in adults with chronic atrial fibrillation. (1.3) -----------------------DOSAGE AND ADMINISTRATION ---------------------- LANOXIN dose is based on patient-specific factors (age, lean body weight, renal function, etc.). See full prescribing information. Monitor for toxicity and therapeutic effect. (2) Intravenous administration is preferable to intramuscular. Avoid bolus administration. (2) --------------------- DOSAGE FORMS AND STRENGTHS--------------------- LANOXIN Injection: Ampules containing 500 mcg (0.5 mg) in 2 mL. (3) LANOXIN Injection Pediatric: Ampules of 100 mcg (0.1 mg) in 1 mL. (3) ------------------------------ CONTRAINDICATIONS ----------------------------- • Ventricular fibrillation. (4) • Known hypersensitivity to digoxin or other forms of digitalis. (4) ----------------------- WARNINGS AND PRECAUTIONS----------------------- • Risk of rapid ventricular response leading to ventricular fibrillation in patients with AV accessory pathway. (5.1) • Risk of advanced or complete heart block in patients with sinus node disease and AV block. (5.2) • Digoxin toxicity: Indicated by nausea, vomiting, visual disturbances, and cardiac arrhythmias. Advanced age, low body weight, impaired renal function and electrolyte abnormalities predispose to toxicity. (5.3) • Risk of ventricular arrhythmias during electrical cardioversion. (5.4) • Not recommended in patients with acute myocardial infarction (5.5) • Avoid LANOXIN in patients with myocarditis. (5.6) ------------------------------ ADVERSE REACTIONS ----------------------------- The overall incidence of adverse reactions with digoxin has been reported as 5-20%, with 15-20% of adverse events considered serious. Cardiac toxicity accounts for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse events. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Covis Pharmaceuticals Inc at 1-866-488-4423 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS------------------------------ • PGP Inducers/Inhibitors: Drugs that induce or inhibit PGP have the potential to alter digoxin pharmacokinetics. (7.1) • Many drug interactions. The potential for drug-drug interactions must be considered prior to and during drug therapy. See full prescribing information. (7.3, 12.3) . ---------------------- USE IN SPECIFIC POPULATIONS ---------------------- • Pregnant patients: It is unknown whether use during pregnancy can cause fetal harm. (8.1) • Pediatric patients: Newborn infants display variability in tolerance to LANOXIN. (8.4) • Geriatric patients: Consider renal function in dosage selection, and carefully monitor for side effects. (8.5) • Renal impairment: LANOXIN is excreted by the kidneys. Consider renal function during dosage selection. (8.6) See 17 for PATIENT COUNSELING INFORMATION. Revised 05/2013 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Heart Failure in Adults 1.2 Heart Failure in Pediatric Patients 1.3 Atrial Fibrillation in Adults 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosing and Administration Information 2.2 Loading Dosing Regimen in Adults and Pediatric Patients 2.3 Maintenance Dosing in Adults and Pediatric Patients Over 10 Years Old 2.4 Maintenance Dosing in Pediatric Patients Less Than 10 Years Old 2.5 Monitoring to Assess Safety, Efficacy, and Therapeutic Blood Levels 2.6 Switching from Intravenous Digoxin to Oral Digoxin 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Ventricular Fibrillation in Patients With Accessory AV Pathway (Wolff-Parkinson-White Syndrome) 5.2 Sinus Bradycardia and Sino-atrial Block 5.3 Digoxin Toxicity 5.4 Risk of Ventricular Arrhythmias During Electrical Cardioversion 5.5 Risk of Ischemia in Patients With Acute Myocardial Infarction 5.6 Vasoconstriction In Patients With Myocarditis 5.7 Decreased Cardiac Output in Patients With Preserved Left Ventricular Systolic Function 5.8 Reduced Efficacy In Patients With Hypocalcemia 5.9 Altered Response in Thyroid Disorders and Hypermetabolic States 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 P-Glycoprotein (PGP) Inducers/Inhibitors 7.2 Pharmacokinetic Drug Interactions 7.3 Potentially Significant Pharmacodynamic Drug Interactions 7.4 Drug/Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 8.8 Malabsorption 10 OVERDOSAGE 10.1 Signs and Symptoms in Adults and Children 10.2 Treatment 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Chronic Heart Failure 14.2 Chronic Atrial Fibrillation 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Heart Failure in Adults LANOXIN is indicated for the treatment of mild to moderate heart failure in adults. LANOXIN increases left ventricular ejection fraction and improves heart failure symptoms, as evidenced by improved exercise capacity and decreased heart failure-related hospitalizations and emergency care, while having no effect on mortality. Where possible, LANOXIN should be used in combination with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor. 1.2 Heart Failure in Pediatric Patients LANOXIN increases myocardial contractility in pediatric patients with heart failure. 1.3 Atrial Fibrillation in Adults LANOXIN is indicated for the control of ventricular response rate in adult patients with chronic atrial fibrillation. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosing and Administration Information In selecting a LANOXIN dosing regimen, it is important to consider factors that affect digoxin blood levels (e.g., body weight, age, renal function, concomitant drugs) since toxic levels of digoxin are only slightly higher than therapeutic levels. Dosing can be either initiated with a loading dose followed by maintenance dosing if rapid titration is desired or initiated with maintenance dosing without a loading dose. Parenteral administration of digoxin should be used only when the need for rapid digitalization is urgent or when the drug cannot be taken orally. Intramuscular injection can lead to severe pain at the injection site, thus intravenous administration is preferred. If the drug must be administered by the intramuscular route, it should be injected deep into the muscle followed by massage. For adults, no more than 500 mcg of LANOXIN Injection should be injected into a single site. For pediatric patients, no more than 200 mcg of LANOXIN Injection Pediatric should be injected into a single site. Administer the dose over a period of 5 minutes or longer and avoid bolus administration to prevent systemic and coronary vasoconstriction. Mixing of LANOXIN Injection and Injection Pediatric with other drugs in the same container or simultaneous administration in the same intravenous line is not recommended. 2 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda LANOXIN Injection and Injection Pediatric can be administered undiluted or diluted with a 4-fold or greater volume of Sterile Water for Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection. The use of less than a 4-fold volume of diluent could lead to precipitation of the digoxin. Immediate use of the diluted product is recommended. If tuberculin syringes are used to measure very small doses do not flush with the parenteral solution after its contents are expelled into an indwelling vascular catheter to avoid overadministration of digoxin. Consider interruption or reduction in LANOXIN dose prior to electrical cardioversion [see Warnings and Precautions (5.4)]. 2.2 Loading Dosing Regimen in Adults and Pediatric Patients Table 1. Recommended LANOXIN Injection Loading Dose Age Total IV Loading Dose (mcg/kg) Administer half the total loading dose initially, then ¼ the loading dose every 6-8 hours twice Premature Full-Term 1-24 Months 2-5 Years 5-10 Years Adults and pediatric patients over 10 years 15-25 20-30 30-50 25-35 15-30 8-12 mcg = microgram 2.3 Maintenance Dosing in Adults and Pediatric Patients Over 10 Years Old The maintenance dose is based on lean body weight, renal function, age, and concomitant products [see Clinical Pharmacology (12.3)]. The recommended starting maintenance doses in adults and pediatric patients over 10 years old with normal renal function are given in Table 2. Doses may be increased every 2 weeks according to clinical response, serum drug levels, and toxicity. 3 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 2. Recommended Starting LANOXIN Injection Maintenance Dosage in Adults and Pediatric Patients Over 10 Years Old Age Total Intravenous Maintenance Dose, mcg/kg/day (given once daily) Adults and pediatric patients over 10 years 2.4-3.6 mcg = microgram Table 3 provides the recommended (once daily) maintenance dose for adults and pediatric patients over 10 years old (to be given once daily) according to lean body weight and renal function. The doses are based on studies in adult patients with heart failure. Alternatively, the maintenance dose may be estimated by the following formula (peak body stores lost each day through elimination): Total Maintenance Dose = Loading Dose (i.e., Peak Body Stores) x % Daily Loss/100 (% Daily Loss = 14 + Creatinine clearance/5) Reduce the dose of LANOXIN in patients whose lean weight is an abnormally small fraction of their total body mass because of obesity or edema. 4 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 3. Recommended Maintenance Dose (in micrograms given once daily) of LANOXIN Injection in Pediatric Patients Over 10 Years Old and Adults by Lean Body Weight and by Renal Function Corrected Lean Body Weightc Number of Days Before Steady State Achievedb Creatinine Clearancea kg 40 50 60 70 80 90 100 10 mL/min 64 80 96 112 128 144 160 19 20 mL/min 72 90 108 126 144 162 180 16 30 mL/min 80 100 120 140 160 180 200 14 40 mL/min 88 110 132 154 176 198 220 13 50 mL/min 96 120 144 168 192 216 240 12 60 mL/min 104 130 156 182 208 234 260 11 70 mL/min 112 140 168 196 224 252 280 10 80 mL/min 120 150 180 210 240 270 300 9 90 mL/min 128 160 192 224 256 288 320 8 100 mL/min 136 170 204 238 272 306 340 7 a For adults, creatinine clearance was corrected to 70-kg body weight or 1.73 m2 body surface area. If only serum creatinine concentrations (Scr) are available, a corrected Ccr may be estimated in men as (140 – Age)/Scr. For women, this result should be multiplied by 0.85. For pediatric patients, the modified Schwartz equation may be used. The formula is based on height in cm and Scr in mg/dL where k is a constant. Ccr is corrected to 1.73 m2 body surface area. During the first year of life, the value of k is 0.33 for pre-term babies and 0.45 for term infants. The k is 0.55 for pediatric patients and adolescent girls and 0.7 for adolescent boys. GFR (mL/min/1.73 m2) = (k x Height)/Scr b If no loading dose administered c The doses listed assume average body composition. 2.4 Maintenance Dosing in Pediatric Patients Less Than 10 Years Old The starting maintenance dose for heart failure in pediatric patients less than 10 years old is based on lean body weight, renal function, age, and concomitant products [see Clinical Pharmacology (12.3)]. The recommended starting maintenance doses for pediatric patients are given in Table 4. These recommendations assume the presence of normal renal function. 5 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 4. Recommended Starting LANOXIN Injection Maintenance Dosage in Pediatric Patients Less Than 10 Years Old Age Dose Regimen, mcg/kg/dose (given TWICE daily) Premature Full-Term 1-24 Months 2-5 Years 5-10 Years 1.9-3.1 3.0-4.5 4.5-7.5 3.8-5.3 2.3-4.5 mcg = microgram Table 5 provides average daily maintenance dose requirements for pediatric patients less than 10 years old (to be given twice daily) with heart failure based on age, lean body weight, and renal function. Table 5. Recommended Maintenance Dose (in micrograms given TWICE daily) of LANOXIN Injection in Pediatric Patients Less Than 10 Years of Agea Based upon Lean Body Weight and Renal Functiona Corrected Lean Body Weight Number of Days Before Steady State Achievedc Creatinine Clearanceb kg 5 10 20 30 40 50 60 10 mL/min 8 16 32 48 64 80 96 19 20 mL/min 9 18 36 54 72 90 108 16 30 mL/min 10 20 40 60 80 100 120 14 40 mL/min 11 22 44 66 88 110 132 13 50 mL/min 12 24 48 72 96 120 144 12 60 mL/min 13 26 52 78 104 130 156 11 70 mL/min 14 28 56 84 112 140 168 10 80 mL/min 15 30 60 90 120 150 180 9 90 mL/min 16 32 64 96 128 160 192 8 100 mL/min 17 34 68 102 136 170 204 7 a Recommended are doses to be given twice daily. b The modified Schwartz equation may be used to estimate creatinine clearance. See footnote a under Table 3. c If no loading dose administered. 2.5 Monitoring to Assess Safety, Efficacy, and Therapeutic Blood Levels Monitor for signs and symptoms of digoxin toxicity and clinical response. Adjust dose based on toxicity, efficacy, and blood levels. 6 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Serum digoxin levels less than 0.5 ng/mL have been associated with diminished efficacy, while levels above 2 ng/mL have been associated with increased toxicity without increased benefit. Interpret the serum digoxin concentration in the overall clinical context, and do not use an isolated measurement of serum digoxin concentration as the basis for increasing or decreasing the LANOXIN dose. Serum digoxin concentrations may be falsely elevated by endogenous digoxin-like substances [see Drug Interactions (7.4)]. If the assay is sensitive to these substances, consider obtaining a baseline digoxin level before starting LANOXIN and correct post-treatment values by the reported baseline level. Obtain serum digoxin concentrations just before the next scheduled LANOXIN dose or at least 6 hours after the last dose. The digoxin concentration is likely to be 10-25% lower when sampled right before the next dose (24 hours after dosing) compared to sampling 8 hours after dosing (using once-daily dosing). However, there will be only minor differences in digoxin concentrations using twice daily dosing whether sampling is done at 8 or 12 hours after a dose. 2.6 Switching from Intravenous Digoxin to Oral Digoxin When switching from intravenous to oral digoxin formulations, make allowances for differences in bioavailability when calculating maintenance dosages (see Table 6). Table 6. Comparison of the Systemic Availability and Equivalent Doses of Oral and Intravenous LANOXIN Absolute Bioavailability Equivalent Doses (mcg) LANOXIN Tablets LANOXIN Intravenous Injection 60-80% 100% 62.5 50 125 100 250 200 500 400 3 DOSAGE FORMS AND STRENGTHS LANOXIN Injection: Ampules of 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25 mg] per 1 mL). LANOXIN Injection Pediatric: Ampules of 100 mcg (0.1 mg) in 1 mL. 4 CONTRAINDICATIONS LANOXIN is contraindicated in patients with: • Ventricular fibrillation [see Warnings and Precautions (5.1)] • Known hypersensitivity to digoxin (reactions seen include unexplained rash, swelling of the mouth, lips or throat or a difficulty in breathing). A hypersensitivity reaction to other digitalis preparations usually constitutes a contraindication to digoxin. 7 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 WARNINGS AND PRECAUTIONS 5.1 Ventricular Fibrillation in Patients With Accessory AV Pathway (Wolff-Parkinson- White Syndrome) Patients with Wolff-Parkinson-White syndrome who develop atrial fibrillation are at high risk of ventricular fibrillation. Treatment of these patients with digoxin leads to greater slowing of conduction in the atrioventricular node than in accessory pathways, and the risks of rapid ventricular response leading to ventricular fibrillation are thereby increased. 5.2 Sinus Bradycardia and Sino-atrial Block LANOXIN may cause severe sinus bradycardia or sinoatrial block particularly in patients with pre-existing sinus node disease and may cause advanced or complete heart block in patients with pre-existing incomplete AV block. Consider insertion of a pacemaker before treatment with digoxin. 5.3 Digoxin Toxicity Signs and symptoms of digoxin toxicity include anorexia, nausea, vomiting, visual changes and cardiac arrhythmias [first-degree, second-degree (Wenckebach), or third-degree heart block (including asystole); atrial tachycardia with block; AV dissociation; accelerated junctional (nodal) rhythm; unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy); ventricular tachycardia; and ventricular fibrillation]. Toxicity is usually associated with digoxin levels greater than 2 ng/ml although symptoms may also occur at lower levels. Low body weight, advanced age or impaired renal function, hypokalemia, hypercalcemia, or hypomagnesemia may predispose to digoxin toxicity. Obtain serum digoxin levels in patients with signs or symptoms of digoxin therapy and interrupt or adjust dose if necessary [see Adverse Reactions (6) and Overdosage (10)]. Assess serum electrolytes and renal function periodically. The earliest and most frequent manifestation of digoxin toxicity in infants and children is the appearance of cardiac arrhythmias, including sinus bradycardia. In children, the use of digoxin may produce any arrhythmia. The most common are conduction disturbances or supraventricular tachyarrhythmias, such as atrial tachycardia (with or without block) and junctional (nodal) tachycardia. Ventricular arrhythmias are less common. Sinus bradycardia may be a sign of impending digoxin intoxication, especially in infants, even in the absence of first-degree heart block. Any arrhythmias or alteration in cardiac conduction that develops in a child taking digoxin should initially be assumed to be a consequence of digoxin intoxication. Given that adult patients with heart failure have some symptoms in common with digoxin toxicity, it may be difficult to distinguish digoxin toxicity from heart failure. Misidentification of their etiology might lead the clinician to continue or increase LANOXIN dosing, when dosing 8 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda should actually be suspended. When the etiology of these signs and symptoms is not clear, measure serum digoxin levels. 5.4 Risk of Ventricular Arrhythmias During Electrical Cardioversion It may be desirable to reduce the dose of or discontinue LANOXIN for 1-2 days prior to electrical cardioversion of atrial fibrillation to avoid the induction of ventricular arrhythmias, but physicians must consider the consequences of increasing the ventricular response if digoxin is decreased or withdrawn. If digitalis toxicity is suspected, elective cardioversion should be delayed. If it is not prudent to delay cardioversion, the lowest possible energy level should be selected to avoid provoking ventricular arrhythmias. 5.5 Risk of Ischemia in Patients With Acute Myocardial Infarction LANOXIN is not recommended in patients with acute myocardial infarction because digoxin may increase myocardial oxygen demand and lead to ischemia. 5.6 Vasoconstriction In Patients With Myocarditis LANOXIN can precipitate vasoconstriction and may promote production of pro-inflammatory cytokines; therefore, avoid use in patients with myocarditis. 5.7 Decreased Cardiac Output in Patients With Preserved Left Ventricular Systolic Function Patients with heart failure associated with preserved left ventricular ejection fraction may experience decreased cardiac output with use of LANOXIN. Such disorders include restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, and acute cor pulmonale. Patients with idiopathic hypertrophic subaortic stenosis may have worsening of the outflow obstruction due to the inotropic effects of digoxin. Patients with amyloid heart disease may be more susceptible to digoxin toxicity at therapeutic levels because of an increased binding of digoxin to extracellular amyloid fibrils. LANOXIN should generally be avoided in these patients, although it has been used for ventricular rate control in the subgroup of patients with atrial fibrillation. 5.8 Reduced Efficacy In Patients With Hypocalcemia Hypocalcemia can nullify the effects of digoxin in humans; thus, digoxin may be ineffective until serum calcium is restored to normal. These interactions are related to the fact that digoxin affects contractility and excitability of the heart in a manner similar to that of calcium. 9 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.9 Altered Response in Thyroid Disorders and Hypermetabolic States Hypothyroidism may reduce the requirements for digoxin. Heart failure and/or atrial arrhythmias resulting from hypermetabolic or hyperdynamic states (e.g., hyperthyroidism, hypoxia, or arteriovenous shunt) are best treated by addressing the underlying condition. Atrial arrhythmias associated with hypermetabolic states are particularly resistant to digoxin treatment. Patients with beri beri heart disease may fail to respond adequately to digoxin if the underlying thiamine deficiency is not treated concomitantly. 6 ADVERSE REACTIONS The following adverse reactions are included in more detail in the Warnings and Precautions section of the label: • Cardiac arrhythmias [see Warnings and Precautions (5.1, 5.2)] • Digoxin Toxicity [see Warnings and Precautions (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In general, the adverse reactions of LANOXIN are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when LANOXIN is used within the recommended dose range, is maintained within the therapeutic serum concentration range, and when there is careful attention to concurrent medications and conditions. In the DIG trial (a trial investigating the effect of digoxin on mortality and morbidity in patients with heart failure), the incidence of hospitalization for suspected digoxin toxicity was 2% in patients taking LANOXIN compared to 0.9% in patients taking placebo [see Clinical Studies (14.1)]. The overall incidence of adverse reactions with digoxin has been reported as 5-20%, with 15-20% of adverse events considered serious. Cardiac toxicity accounts for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse events. Gastrointestinal: In addition to nausea and vomiting, the use of digoxin has been associated with abdominal pain, intestinal ischemia, and hemorrhagic necrosis of the intestines. 10 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CNS: Digoxin can cause headache, weakness, dizziness, apathy, confusion, and mental disturbances (such as anxiety, depression, delirium, and hallucination). Other: Gynecomastia has been occasionally observed following the prolonged use of digoxin. Thrombocytopenia and maculopapular rash and other skin reactions have been rarely observed. 7 DRUG INTERACTIONS Digoxin has a narrow therapeutic index, increased monitoring of serum digoxin concentrations and for potential signs and symptoms of clinical toxicity is necessary when initiating, adjusting, or discontinuing drugs that may interact with digoxin. Prescribers should consult the prescribing information of any drug which is co-prescribed with digoxin for potential drug interaction information. 7.1 P-Glycoprotein (PGP) Inducers/Inhibitors Digoxin is a substrate of P-glycoprotein. Drugs that induce or inhibit P-glycoprotein in intestine or kidney have the potential to alter digoxin pharmacokinetics. 7.2 Pharmacokinetic Drug Interactions Pharmacokinetic interactions have been observed and reported primarily when digoxin is co administered by oral route. There are very few studies that have evaluated the drug interaction when digoxin is administered via IV route. The magnitude of digoxin exposure change through IV route is generally lower than that through oral route. Table below provides available interaction data using digoxin IV formulation (NA means not available). 11 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Digoxin concentrations increased greater than 50% Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations Quinidine NA 54-83% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. Ritonavir NA 86% Digoxin concentrations increased less than 50% Amiodarone 17% 40% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Propafenone 28% 29% Quinine NA 34-38% Spironolactone NA 44% Verapamil NA 24% No significant Digoxin exposure changes Please refer to section 12 for a complete list of drugs that were studied but reported no significant changes on digoxin exposure. No additional actions are required. 7.3 Potentially Significant Pharmacodynamic Drug Interactions Because of considerable variability of pharmacodynamic interactions, the dosage of digoxin should be individualized when patients receive these medications concurrently. 12 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors may impair the excretion of digoxin. Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes. Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin. Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin. Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin. Sympathomimetics Epinephrine Norepinephrine Dopamine Can increase the risk of cardiac arrhythmias. Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin. Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block. 7.4 Drug/Laboratory Test Interactions Endogenous substances of unknown composition (digoxin-like immunoreactive substances [DLIS]) can interfere with standard radioimmunoassays for digoxin. The interference most often causes results to be falsely positive or falsely elevated, but sometimes it causes results to be falsely reduced. Some assays are more subject to these failings than others. Several LC/MS/MS methods are available that may provide less susceptibility to DLIS interference. DLIS are present 13 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda in up to half of all neonates and in varying percentages of pregnant women, patients with hypertrophic cardiomyopathy, patients with renal or hepatic dysfunction, and other patients who are volume-expanded for any reason. The measured levels of DLIS (as digoxin equivalents) are usually low (0.2-0.4 ng/mL), but sometimes they reach levels that would be considered therapeutic or even toxic. In some assays, spironolactone, canrenone, and potassium canrenoate may be falsely detected as digoxin, at levels up to 0.5 ng/mL. Some traditional Chinese and Ayurvedic medicine substances like Chan Su, Siberian Ginseng, Asian Ginseng, Ashwagandha, or Dashen can cause similar interference. Spironolactone and DLIS are much more extensively protein-bound than digoxin. As a result, assays of free digoxin levels in protein-free ultrafiltrate (which tend to be about 25% less than total levels, consistent with the usual extent of protein binding) are less affected by spironolactone or DLIS. It should be noted that ultrafiltration does not solve all interference problems with alternative medicines. The use of an LC/MS/MS method may be the better option according to the good results it provides, especially in terms of specificity and limit of quantization. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. LANOXIN should be given to a pregnant woman only if clearly needed. It is also not known whether digoxin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Animal reproduction studies have not been conducted with digoxin. 8.2 Labor and Delivery There are not enough data from clinical trials to determine the safety and efficacy of digoxin during labor and delivery. 8.3 Nursing Mothers Studies have shown that digoxin distributes into breast milk and that the milk-to-serum concentration ratio is approximately 0.6-0.9. However, the estimated exposure of a nursing infant to digoxin via breastfeeding is far below the usual infant maintenance dose. Therefore, this amount should have no pharmacologic effect upon the infant. 14 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8.4 Pediatric Use The safety and effectiveness of LANOXIN in the control of ventricular rate in children with atrial fibrillation have not been established. The safety and effectiveness of LANOXIN in the treatment of heart failure in children have not been established in adequate and well-controlled studies. However, in published literature of children with heart failure of various etiologies (e.g., ventricular septal defects, anthracycline toxicity, patent ductus arteriosus), treatment with digoxin has been associated with improvements in hemodynamic parameters and in clinical signs and symptoms. Newborn infants display considerable variability in their tolerance to digoxin. Premature and immature infants are particularly sensitive to the effects of digoxin, and the dosage of the drug must not only be reduced but must be individualized according to their degree of maturity. 8.5 Geriatric Use The majority of clinical experience gained with digoxin has been in the elderly population. This experience has not identified differences in response or adverse effects between the elderly and younger patients. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, which should be based on renal function, and it may be useful to monitor renal function [see Dosage and Administration (2.1)]. 8.6 Renal Impairment The clearance of digoxin can be primarily correlated with the renal function as indicated by creatinine clearance. Tables 3 and 5 provide the usual daily maintenance dose requirements for digoxin based on creatinine clearance [see Dosage and Administration (2.3)]. Digoxin is primarily excreted by the kidneys; therefore, patients with impaired renal function require smaller than usual maintenance doses of digoxin [see Dosage and Administration (2.3)]. Because of the prolonged elimination half-life, a longer period of time is required to achieve an initial or new steady-state serum concentration in patients with renal impairment than in patients with normal renal function. If appropriate care is not taken to reduce the dose of digoxin, such patients are at high risk for toxicity, and toxic effects will last longer in such patients than in patients with normal renal function. 8.7 Hepatic Impairment Plasma digoxin concentrations in patients with acute hepatitis generally fall within the range of profiles in a group of healthy subjects. 15 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8.8 Malabsorption The absorption of digoxin is reduced in some malabsorption conditions such as chronic diarrhea. 10 OVERDOSAGE 10.1 Signs and Symptoms in Adults and Children The signs and symptoms of toxicity are generally similar to those previously described [see Adverse Reactions (6.1)] but may be more frequent and can be more severe. Signs and symptoms of digoxin toxicity become more frequent with levels above 2 ng/mL. However, in deciding whether a patient’s symptoms are due to digoxin, the clinical state together with serum electrolyte levels and thyroid function are important factors [see Dosage and Administration (2)]. Adults: The most common signs and symptoms of digoxin toxicity are nausea, vomiting, anorexia, and fatigue that occur in 30-70% of patients who are overdosed. Extremely high serum concentrations produce hyperkalemia especially in patients with impaired renal function. Almost every type of cardiac arrhythmia has been associated with digoxin overdose and multiple rhythm disturbances in the same patient are common. Peak cardiac effects occur 3-6 hours following ingestion and may persist for 24 hours or longer. Arrhythmias that are considered more characteristic of digoxin toxicity are new-onset Mobitz type 1 A-V block, accelerated junctional rhythms, non-paroxysmal atrial tachycardia with A-V block, and bi-directional ventricular tachycardia. Cardiac arrest from asystole or ventricular fibrillation is usually fatal. Digoxin toxicity is related to serum concentration. As digoxin serum levels increase above 1.2 ng/mL, there is a potential for increase in adverse reactions. Furthermore, lower potassium levels increases the risk for adverse reactions. In adults with heart disease, clinical observations suggest that an overdose of digoxin of 10-15 mg results in death of half of patients. A dose above 25 mg ingested by an adult without heart disease appeared to be uniformly fatal if no Digoxin Immune Fab (DIGIBIND®, DIGIFAB®) was administered. Among the extra-cardiac manifestations, gastrointestinal symptoms (e.g., nausea, vomiting, anorexia) are very common (up to 80% incidence) and precede cardiac manifestations in approximately half of the patients in most literature reports. Neurologic manifestations (e.g., dizziness, various CNS disturbances), fatigue, and malaise are very common. Visual manifestations may also occur with aberration in color vision (predominance of yellow green) the most frequent. Neurological and visual symptoms may persist after other signs of toxicity have resolved. In chronic toxicity, nonspecific extra-cardiac symptoms, such as malaise and weakness, may predominate. 16 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Children: In pediatric patients, signs and symptoms of toxicity can occur during or shortly after the dose of digoxin. Frequent non-cardiac effects are similar to those observed in adults although nausea and vomiting are not seen frequently in infants and small pediatric patients. Other reported manifestations of overdose are weight loss in older age groups, failure to thrive in infants, abdominal pain caused by mesenteric artery ischemia, drowsiness, and behavioral disturbances including psychotic episodes. Arrhythmias and combinations of arrhythmias that occur in adult patients can also occur in pediatric patients although sinus tachycardia, supraventricular tachycardia, and rapid atrial fibrillation are seen less frequently in pediatric patients. Pediatric patients are more likely to develop A-V conduction disturbances, or sinus bradycardia. Any arrhythmia in a child treated with digoxin should be considered related to digoxin until otherwise ruled out. In pediatric patients aged 1-3 years without heart disease, clinical observations suggest that an overdose of digoxin of 6-10 mg would result in death of half of the patients. In the same population, a dose above 10 mg resulted in death if no Digoxin Immune Fab were administered. 10.2 Treatment Chronic Overdose If there is suspicion of toxicity, discontinue LANOXIN and place the patient on a cardiac monitor. Correct factors such as electrolyte abnormalities, thyroid dysfunction, and concomitant medications [see Dosage and Administration (2.5)]. Correct hypokalemia by administering potassium so that serum potassium is maintained between 4.0 and 5.5 mmol/L. Potassium is usually administered orally, but when correction of the arrhythmia is urgent and serum potassium concentration is low, potassium may be administered by the intravenous route. Monitor electrocardiogram for any evidence of potassium toxicity (e.g., peaking of T waves) and to observe the effect on the arrhythmia. Avoid potassium salts in patients with bradycardia or heart block. Symptomatic arrhythmias may be treated with Digoxin Immune Fab. Acute Overdose Patients who have intentionally or accidently ingested massive doses of digoxin should receive activated charcoal orally or by nasogastric tube regardless of the time since ingestion since digoxin recirculates to the intestine by enterohepatic circulation. In addition to cardiac monitoring, temporarily discontinue LANOXIN until the adverse reaction resolves. Correct factors that may be contributing to the adverse reactions [see Warnings and Precautions (5)]. In particular, correct hypokalemia and hypomagnesemia. Digoxin is not effectively removed from the body by dialysis because of its large extravascular volume of distribution. Life threatening arrhythmias (ventricular tachycardia, ventricular fibrillation, high degree A-V block, bradyarrhythma, sinus arrest) or hyperkalemia requires administration of Digoxin Immune Fab. Digoxin Immune Fab has been shown to be 80-90% effective in reversing signs and symptoms of digoxin toxicity. Bradycardia and heart block caused by digoxin are parasympathetically 17 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda mediated and respond to atropine. A temporary cardiac pacemaker may also be used. Ventricular arrhythmias may respond to lidocaine or phenytoin. When a large amount of digoxin has been ingested, especially in patients with impaired renal function, hyperkalemia may be present due to release of potassium from skeletal muscle. In this case, treatment with Digoxin Immune Fab is indicated; an initial treatment with glucose and insulin may be needed if the hyperkalemia is life- threatening. Once the adverse reaction has resolved, therapy with LANOXIN may be reinstituted following a careful reassessment of dose. 11 DESCRIPTION LANOXIN (digoxin) is one of the cardiac (or digitalis) glycosides, a closely related group of drugs having in common specific effects on the myocardium. These drugs are found in a number of plants. Digoxin is extracted from the leaves of Digitalis lanata. The term “digitalis” is used to designate the whole group of glycosides. The glycosides are composed of 2 portions: a sugar and a cardenolide (hence “glycosides”). Digoxin is described chemically as (3β,5β,12β)-3-[(O-2,6-dideoxy-β-D-ribo-hexopyranosyl (1→4)-O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-2,6-dideoxy-β-D-ribo hexopyranosyl)oxy]-12,14-dihydroxy-card-20(22)-enolide. Its molecular formula is C41H64O14, its molecular weight is 780.95, and its structural formula is: structural formula Digoxin exists as odorless white crystals that melt with decomposition above 230 °C. The drug is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in chloroform; and freely soluble in pyridine. LANOXIN Injection and Injection Pediatric are sterile solutions of digoxin for intravenous or intramuscular injection. The vehicle contains 40% propylene glycol and 10% alcohol. The injection is buffered to a pH of 6.8-7.2 with 0.17% dibasic sodium phosphate and 0.08% 18 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda anhydrous citric acid. Each 2-mL ampule of LANOXIN Injection contains 500 mcg (0.5 mg) digoxin (250 mcg [0.25 mg] per mL). Dilution is not required. Each 1-mL ampule of LANOXIN Injection Pediatric contains 100 mcg (0.1 mg) digoxin. Dilution is not required. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action All of digoxin’s actions are mediated through its effects on Na-K ATPase. This enzyme, the “sodium pump,” is responsible for maintaining the intracellular milieu throughout the body by moving sodium ions out of and potassium ions into cells. By inhibiting Na-K ATPase, digoxin • causes increased availability of intracellular calcium in the myocardium and conduction system, with consequent increased inotropy, increased automaticity, and reduced conduction velocity • indirectly causes parasympathetic stimulation of the autonomic nervous system, with consequent effects on the sino-atrial (SA) and atrioventricular (AV) nodes • reduces catecholamine reuptake at nerve terminals, rendering blood vessels more sensitive to endogenous or exogenous catecholamines • increases baroreceptor sensitization, with consequent increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increment in mean arterial pressure • increases (at higher concentrations) sympathetic outflow from the central nervous system (CNS) to both cardiac and peripheral sympathetic nerves • allows (at higher concentrations) progressive efflux of intracellular potassium, with consequent increase in serum potassium levels. The cardiologic consequences of these direct and indirect effects are an increase in the force and velocity of myocardial systolic contraction (positive inotropic action), a slowing of the heart rate (negative chronotropic effect), decreased conduction velocity through the AV node, and a decrease in the degree of activation of the sympathetic nervous system and renin-angiotensin system (neurohormonal deactivating effect). 12.2 Pharmacodynamics The times to onset of pharmacologic effect and to peak effect of preparations of LANOXIN are shown in Table 7. 19 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 7. Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of LANOXIN Product Time to Onset of Effecta Time to Peak Effecta LANOXIN Tablets LANOXIN Injection/IV 0.5-2 hours 5-30 minutes b 2-6 hours 1-4 hours a Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes. b Depending upon rate of infusion. Hemodynamic Effects: Short- and long-term therapy with the drug increases cardiac output and lowers pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic vascular resistance in patients with heart failure. These hemodynamic effects are accompanied by an increase in the left ventricular ejection fraction and a decrease in end-systolic and end-diastolic dimensions. ECG Changes: The use of therapeutic doses of LANOXIN may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram. LANOXIN may produce false positive ST-T changes on the electrocardiogram during exercise testing. These electrophysiologic effects are not indicative of toxicity. LANOXIN does not significantly reduce heart rate during exercise. 12.3 Pharmacokinetics Note: The following data are from studies performed in adults, unless otherwise stated. Comparisons of the systemic availability and equivalent doses for oral preparations of LANOXIN are shown in Table 6 [see Dosage and Administration (2.6)]. Distribution: Following drug administration, a 6-8 hour tissue distribution phase is observed. This is followed by a much more gradual decline in the serum concentration of the drug, which is dependent on the elimination of digoxin from the body. The peak height and slope of the early portion (absorption/distribution phases) of the serum concentration-time curve are dependent upon the route of administration and the absorption characteristics of the formulation. Clinical evidence indicates that the early high serum concentrations do not reflect the concentration of digoxin at its site of action, but that with chronic use, the steady-state post-distribution serum concentrations are in equilibrium with tissue concentrations and correlate with pharmacologic effects. In individual patients, these post-distribution serum concentrations may be useful in evaluating therapeutic and toxic effects [see Dosage and Administration (2.1)]. Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution (approximately 475-500 L). Digoxin crosses both the blood-brain barrier and the placenta. At delivery, the serum digoxin concentration in the newborn is similar to the serum concentration in 20 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the mother. Approximately 25% of digoxin in the plasma is bound to protein. Serum digoxin concentrations are not significantly altered by large changes in fat tissue weight, so that its distribution space correlates best with lean (i.e., ideal) body weight, not total body weight. Metabolism: Only a small percentage (13%) of a dose of digoxin is metabolized in healthy volunteers. The urinary metabolites, which include dihydrodigoxin, digoxigenin bisdigitoxoside, and their glucuronide and sulfate conjugates are polar in nature and are postulated to be formed via hydrolysis, oxidation, and conjugation. The metabolism of digoxin is not dependent upon the cytochrome P-450 system, and digoxin is not known to induce or inhibit the cytochrome P-450 system. Excretion: Elimination of digoxin follows first-order kinetics (that is, the quantity of digoxin eliminated at any time is proportional to the total body content). Following intravenous administration to healthy volunteers, 50-70% of a digoxin dose is excreted unchanged in the urine. Renal excretion of digoxin is proportional to creatinine clearance and is largely independent of urine flow. In healthy volunteers with normal renal function, digoxin has a half- life of 1.5-2 days. The half-life in anuric patients is prolonged to 3.5-5 days. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to extravascular tissues. Special Populations: Geriatrics: Because of age-related declines in renal function, elderly patients would be expected to eliminate digoxin more slowly than younger subjects. Elderly patients may also exhibit a lower volume of distribution of digoxin due to age-related loss of lean muscle mass. Thus, the dosage of digoxin should be carefully selected and monitored in elderly patients [see Use in Specific Populations (8.5)]. Gender: In a study of 184 patients, the clearance of digoxin was 12% lower in female than in male patients. This difference is not likely to be clinically important. Hepatic Impairment: Because only a small percentage (approximately 13%) of a dose of digoxin undergoes metabolism, hepatic impairment would not be expected to significantly alter the pharmacokinetics of digoxin. In a small study, plasma digoxin concentration profiles in patients with acute hepatitis generally fell within the range of profiles in a group of healthy subjects. No dosage adjustments are recommended for patients with hepatic impairment; however, serum digoxin concentrations should be used, as appropriate, to help guide dosing in these patients. Renal Impairment: Since the clearance of digoxin correlates with creatinine clearance, patients with renal impairment generally demonstrate prolonged digoxin elimination half-lives and greater exposures to digoxin. Therefore, titrate carefully in these patients based on clinical response and based on monitoring of serum digoxin concentrations, as appropriate. 21 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Race: The impact of race differences on digoxin pharmacokinetics has not been formally studied. Because digoxin is primarily eliminated as unchanged drug via the kidney and because there are no important differences in creatinine clearance among races, pharmacokinetic differences due to race are not expected. Drug-drug Interactions Based on literature reports no significant changes in digoxin exposure were reported when IV digoxin was co-administered with the following drugs: clarithromycin, carvedilol, isradipine, losartan and rifampin 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Digoxin showed no genotoxic potential in in vitro studies (Ames test and mouse lymphoma). No data are available on the carcinogenic potential of digoxin, nor have studies been conducted to assess its potential to affect fertility. 14 CLINICAL STUDIES 14.1 Chronic Heart Failure Two 12-week, double-blind, placebo-controlled studies enrolled 178 (RADIANCE trial) and 88 (PROVED trial) adult patients with NYHA Class II or III heart failure previously treated with oral digoxin, a diuretic, and an ACE inhibitor (RADIANCE only) and randomized them to placebo or treatment with LANOXIN Tablets. Both trials demonstrated better preservation of exercise capacity in patients randomized to LANOXIN. Continued treatment with LANOXIN reduced the risk of developing worsening heart failure, as evidenced by heart failure-related hospitalizations and emergency care and the need for concomitant heart failure therapy. DIG Trial of LANOXIN in Patients with Heart Failure The Digitalis Investigation Group (DIG) main trial was a 37-week, multicenter, randomized, double-blind mortality study comparing digoxin to placebo in 6800 adult patients with heart failure and left ventricular ejection fraction less than or equal to 0.45. At randomization, 67% were NYHA class I or II, 71% had heart failure of ischemic etiology, 44% had been receiving digoxin, and most were receiving a concomitant ACE inhibitor (94%) and diuretics (82%). As in the smaller trials described above, patients who had been receiving open-label digoxin were withdrawn from this treatment before randomization. Randomization to digoxin was again associated with a significant reduction in the incidence of hospitalization, whether scored as number of hospitalizations for heart failure (relative risk 75%), risk of having at least one such 22 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hospitalization during the trial (RR 72%), or number of hospitalizations for any cause (RR 94%). On the other hand, randomization to digoxin had no apparent effect on mortality (RR 99%, with confidence limits of 91-107%). 14.2 Chronic Atrial Fibrillation Digoxin has also been studied as a means of controlling the ventricular response to chronic atrial fibrillation in adults. Digoxin reduced the resting heart rate, but not the heart rate during exercise. In 3 different randomized, double-blind trials that included a total of 315 adult patients, digoxin was compared to placebo for the conversion of recent-onset atrial fibrillation to sinus rhythm. Conversion was equally likely, and equally rapid, in the digoxin and placebo groups. In a randomized 120-patient trial comparing digoxin, sotalol, and amiodarone, patients randomized to digoxin had the lowest incidence of conversion to sinus rhythm, and the least satisfactory rate control when conversion did not occur. In at least one study, digoxin was studied as a means of delaying reversion to atrial fibrillation in adult patients with frequent recurrence of this arrhythmia. This was a randomized, double-blind, 43-patient crossover study. Digoxin increased the mean time between symptomatic recurrent episodes by 54%, but had no effect on the frequency of fibrillatory episodes seen during continuous electrocardiographic monitoring. 16 HOW SUPPLIED/STORAGE AND HANDLING LANOXIN (digoxin) Injection, 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25 mg] per mL); box of 10 ampules (NDC 24987 260 10) LANOXIN (digoxin) Injection Pediatric, 100 mcg (0.1 mg) in 1 mL; box of 10 ampules (NDC 24987 262 10) Store at 25 °C (77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature] and protect from light. 17 PATIENT COUNSELING INFORMATION • Advise patients that digoxin is a cardiac glycoside used to treat heart failure and heart arrhythmias. • Instruct patients to take this medication as directed by their physician. • Advise patients that many drugs can interact with LANOXIN. Instruct patients to inform their doctor and pharmacist if they are taking any over the counter medications, including herbal medication, or are started on a new prescription. 23 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Advise patient that blood tests will be necessary to ensure that their LANOXIN dose is appropriate for them. • Advise patients to contact their doctor or a health care professional if they experience nausea, vomiting, persistent diarrhea, confusion, weakness, or visual disturbances (including blurred vision, green-yellow color disturbances, halo effect) as these could be signs that the dose of LANOXIN may be too high. • Advise parents or caregivers that the symptoms of having too high LANOXIN doses may be difficult to recognize in infants and pediatric patients. Symptoms such as weight loss, failure to thrive in infants, abdominal pain, and behavioral disturbances may be indications of digoxin toxicity. • Suggest to the patient to monitor and record their heart rate and blood pressure daily. • Instruct women of childbearing potential who become or are planning to become pregnant to consult a physician prior to initiation or continuing therapy with LANOXIN. LANOXIN is a registered trademark of GlaxoSmithKline. company logo LANOXIN Injection manufactured by Jubilant Hollister. Kirkland, Canada H9H 4J4 LANOXIN Injection Pediatric manufactured by DSM Pharmaceuticals, Inc. Greenville, NC 27834 Distributed by Covis Pharmaceuticals, Inc. Cary, NC 27511 2013, Covis Pharmaceuticals Inc. All rights reserved. 24 Reference ID: 3309965 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:40.057750	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/009330s027lbl.pdf', 'application_number': 9330, 'submission_type': 'SUPPL ', 'submission_number': 27}
10,727	PRESCRIBING INFORMATION 1 MYLERAN® 2 (busulfan) 3 Tablets 4 5 WARNING 6 MYLERAN is a potent drug. It should not be used unless a diagnosis of chronic myelogenous 7 leukemia has been adequately established and the responsible physician is knowledgeable in 8 assessing response to chemotherapy. 9 MYLERAN can induce severe bone marrow hypoplasia. Reduce or discontinue the dosage 10 immediately at the first sign of any unusual depression of bone marrow function as reflected by an 11 abnormal decrease in any of the formed elements of the blood. A bone marrow examination should 12 be performed if the bone marrow status is uncertain. 13 SEE WARNINGS FOR INFORMATION REGARDING BUSULFAN-INDUCED 14 LEUKEMOGENESIS IN HUMANS. 15 16 DESCRIPTION 17 MYLERAN (busulfan) is a bifunctional alkylating agent. Busulfan is known chemically as 1,4- 18 butanediol dimethanesulfonate and has the following structural formula: 19 20 CH3SO2O(CH2)4OSO2CH3 21 22 Busulfan is not a structural analog of the nitrogen mustards. MYLERAN is available in tablet form 23 for oral administration. Each film-coated tablet contains 2 mg busulfan and the inactive ingredients 24 hypromellose, lactose (anhydrous), magnesium stearate, pregelatinized starch, triacetin, and titanium 25 dioxide. 26 The activity of busulfan in chronic myelogenous leukemia was first reported by D.A.G. Galton in 27 1953. 28 29 CLINICAL PHARMACOLOGY 30 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MYLERAN® (busulfan) Tablets 2 Busulfan is a small, highly lipophilic molecule that easily crosses the blood brain barrier. 31 Following absorption, 32% and 47% of busulfan are bound to plasma proteins and red blood cells, 32 respectively. 33 Busulfan absorption from the gastrointestinal tract is essentially complete. This has been 34 demonstrated in radioactive studies after both intravenous and oral administration of 35S-busulfan, 35 14C-busulfan, and 3H-busulfan. Following intravenous administration of a single therapeutic dose of 36 35S-busulfan, there was rapid disappearance of radioactivity from the blood and 90% to 95% of the 37 35S-label disappeared within 3 to 5 minutes after injection. After either oral or intravenous 38 administration of 35S-busulfan, 45% to 60% of the radioactivity was recovered in the urine in the 39 48 hours after administration; the majority of the total urinary excretion occurring in the first 24 hours. 40 Over 95% of the urinary 35S-label occurs as 35S-methanesulfonic acid. Oral and intravenous 41 administration of 1,4-14C-busulfan showed the same rapid initial disappearance of plasma 42 radioactivity as observed following the administration of 35S-labeled drug. Cumulative radioactivity 43 in the urine after 48 hours was 25% to 30% of the administered dose (contrasting with 45% to 60% 44 for 35S-busulfan), and suggests a slower excretion of the alkylating portion of the molecule and its 45 metabolites than for the sulfonoxymethyl moieties. Regardless of the route of administration, 46 1,4-14C-busulfan yielded a complex mixture of at least 12 radiolabeled metabolites in urine; the main 47 metabolite being 3-hydroxytetrahydrothiophene-1,1-dioxide. Pharmacokinetic studies employing 3H- 48 busulfan labeled on the tetramethylene chain confirmed a rapid initial clearance of the radioactivity 49 from plasma, irrespective of whether the drug was given orally or intravenously. 50 A study compared a 2-mg single IV bolus injection to a single oral dose of a 2-mg tablet of 51 nonradioactive busulfan in 8 adult patients 13 to 60 years of age. The study demonstrated that the 52 mean ? SD absolute bioavailability was 80% ? 20% in adults. However, the absolute bioavailability 53 for 8 children 1.5 to 6 years of age was 68% ? 31%. 54 In another study of 2, 4, and 6 mg of busulfan, given as a single oral dose on consecutive days 55 (starting with the lowest dose) in 5 adult patients, the mean dose-normalized (to 2 mg dose) area 56 under the plasma concentration-time curve (AUC) was about 130 ng?hr/mL, while the mean intra- and 57 inter-patient variability was about 16% and 21%, respectively. Busulfan was eliminated with a 58 plasma terminal elimination half-life (t1/2) of about 2.6 hours, and demonstrated linear kinetics within 59 the range of 2 to 6 mg for both the maximum plasma concentration (Cmax) and AUC. The mean Cmax for 60 the 2-, 4-, and 6-mg doses (after dose normalization to 2 mg) was about 30 ng/mL. A recent study of 4 61 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MYLERAN® (busulfan) Tablets 3 to 8 mg as single oral doses in 12 patients showed that the mean ? SD Cmax (after dose normalization 62 to 4 mg) was 68.2 ? 24.4 ng/mL, occurring at about 0.9 hours and the mean ? SD AUC (after dose 63 normalization to 4 mg) was 269 ? 62 ng?hr/mL. These results are consistent with previous results. In 64 addition, the mean ? SD elimination half-life was 2.69 ? 0.49 hours. 65 The elimination of busulfan appears to be independent of renal function. This probably reflects the 66 extensive metabolism of the drug in the liver, since less than 2% of the administered dose is excreted 67 in the urine unchanged within 24 hours. The drug is metabolized by enzymatic activity to at least 68 12 metabolites, among which tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and 69 3-hydroxysulfolane were identified. These metabolites do not have cytotoxic activity. 70 There is no experience with the use of dialysis in an attempt to modify the clinical toxicity of 71 busulfan. One technical difficulty would derive from the extremely poor water solubility of busulfan. 72 Additionally, all studies of the metabolism of busulfan employing radiolabeled materials indicate 73 rapid chemical reactivity of the parent compound with prolonged retention of some of the metabolites 74 (particularly the metabolites arising from the “alkylating” portion of the molecule). The effectiveness 75 of dialysis at removing significant quantities of unreacted drug would be expected to be minimal in 76 such a situation. 77 Currently, there are no available data on the effect of food on busulfan bioavailability. 78 Biochemical Pharmacology: In aqueous media, busulfan undergoes a wide range of nucleophilic 79 substitution reactions. While this chemical reactivity is relatively non-specific, alkylation of the DNA 80 is felt to be an important biological mechanism for its cytotoxic effect. Coliphage T7 exposed to 81 busulfan was found to have the DNA crosslinked by intrastrand crosslinkages, but no interstrand 82 linkages were found. 83 The metabolic fate of busulfan has been studied in rats and humans using 14C- and 35S-labeled 84 materials. In humans, as in the rat, almost all of the radioactivity in 35S-labeled busulfan is excreted in 85 the urine in the form of 35S-methanesulfonic acid. Roberts and Warwick demonstrated that the 86 formation of methanesulfonic acid in vivo in the rat is not due to a simple hydrolysis of busulfan to 87 1,4-butanediol, since only about 4% of 2,3-14C-busulfan was excreted as carbon dioxide, whereas 88 2,3-14C-1,4-butanediol was converted almost exclusively to carbon dioxide. The predominant 89 reaction of busulfan in the rat is the alkylation of sulfhydryl groups (particularly cysteine and 90 cysteine-containing compounds) to produce a cyclic sulfonium compound which is the precursor of 91 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MYLERAN® (busulfan) Tablets 4 the major urinary metabolite of the 4-carbon portion of the molecule, 3-hydroxytetrahydrothiophene- 92 1,1-dioxide. This has been termed a “sulfur-stripping” action of busulfan and it may modify the 93 function of certain sulfur-containing amino acids, polypeptides, and proteins; whether this action 94 makes an important contribution to the cytotoxicity of busulfan is unknown. 95 The biochemical basis for acquired resistance to busulfan is largely a matter of speculation. 96 Although altered transport of busulfan into the cell is one possibility, increased intracellular 97 inactivation of the drug before it reaches the DNA is also possible. Experiments with other alkylating 98 agents have shown that resistance to this class of compounds may reflect an acquired ability of the 99 resistant cell to repair alkylation damage more effectively. 100 Clinical Studies: Although not curative, busulfan reduces the total granulocyte mass, relieves 101 symptoms of the disease, and improves the clinical state of the patient. Approximately 90% of adults 102 with previously untreated chronic myelogenous leukemia will obtain hematologic remission with 103 regression or stabilization of organomegaly following the use of busulfan. It has been shown to be 104 superior to splenic irradiation with respect to survival times and maintenance of hemoglobin levels, 105 and to be equivalent to irradiation at controlling splenomegaly. 106 It is not clear whether busulfan unequivocally prolongs the survival of responding patients beyond 107 the 31 months experienced by an untreated group of historical controls. Median survival figures of 31 108 to 42 months have been reported for several groups of patients treated with busulfan, but concurrent 109 control groups of comparable, untreated patients are not available. The median survival figures 110 reported from different studies will be influenced by the percentage of “poor risk” patients initially 111 entered into the particular study. Patients who are alive 2 years following the diagnosis of chronic 112 myelogenous leukemia, and who have been treated during that period with busulfan, are estimated to 113 have a mean annual mortality rate during the second to fifth year which is approximately two thirds 114 that of patients who received either no treatment, conventional x-ray or 32P-irradiation, or 115 chemotherapy with minimally active drugs. 116 Busulfan is clearly less effective in patients with chronic myelogenous leukemia who lack the 117 Philadelphia (Ph1) chromosome. Also, the so-called “juvenile” type of chronic myelogenous 118 leukemia, typically occurring in young children and associated with the absence of a Philadelphia 119 chromosome, responds poorly to busulfan. The drug is of no benefit in patients whose chronic 120 myelogenous leukemia has entered a “blastic” phase. 121 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MYLERAN® (busulfan) Tablets 5 MYLERAN should not be used in patients whose chronic myelogenous leukemia has demonstrated 122 prior resistance to this drug. 123 MYLERAN is of no value in chronic lymphocytic leukemia, acute leukemia, or in the “blastic 124 crisis” of chronic myelogenous leukemia. 125 126 INDICATIONS AND USAGE 127 MYLERAN (busulfan) is indicated for the palliative treatment of chronic myelogenous (myeloid, 128 myelocytic, granulocytic) leukemia. 129 130 CONTRAINDICATIONS 131 MYLERAN is contraindicated in patients in whom a definitive diagnosis of chronic myelogenous 132 leukemia has not been firmly established. 133 MYLERAN is contraindicated in patients who have previously suffered a hypersensitivity reaction 134 to busulfan or any other component of the preparation. 135 136 WARNINGS 137 The most frequent, serious side effect of treatment with busulfan is the induction of bone marrow 138 failure (which may or may not be anatomically hypoplastic) resulting in severe pancytopenia. The 139 pancytopenia caused by busulfan may be more prolonged than that induced with other alkylating 140 agents. It is generally felt that the usual cause of busulfan-induced pancytopenia is the failure to stop 141 administration of the drug soon enough; individual idiosyncrasy to the drug does not seem to be an 142 important factor. MYLERAN should be used with extreme caution and exceptional vigilance in 143 patients whose bone marrow reserve may have been compromised by prior irradiation or 144 chemotherapy, or whose marrow function is recovering from previous cytotoxic therapy. Although 145 recovery from busulfan-induced pancytopenia may take from 1 month to 2 years, this complication is 146 potentially reversible, and the patient should be vigorously supported through any period of severe 147 pancytopenia. 148 A rare, important complication of busulfan therapy is the development of bronchopulmonary 149 dysplasia with pulmonary fibrosis. Symptoms have been reported to occur within 8 months to 150 10 years after initiation of therapy—the average duration of therapy being 4 years. The histologic 151 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MYLERAN® (busulfan) Tablets 6 findings associated with “busulfan lung” mimic those seen following pulmonary irradiation. 152 Clinically, patients have reported the insidious onset of cough, dyspnea, and low-grade fever. In some 153 cases, however, onset of symptoms may be acute. Pulmonary function studies have revealed 154 diminished diffusion capacity and decreased pulmonary compliance. It is important to exclude more 155 common conditions (such as opportunistic infections or leukemic infiltration of the lungs) with 156 appropriate diagnostic techniques. If measures such as sputum cultures, virologic studies, and 157 exfoliative cytology fail to establish an etiology for the pulmonary infiltrates, lung biopsy may be 158 necessary to establish the diagnosis. Treatment of established busulfan-induced pulmonary fibrosis is 159 unsatisfactory; in most cases the patients have died within 6 months after the diagnosis was 160 established. There is no specific therapy for this complication. MYLERAN should be discontinued if 161 this lung toxicity develops. The administration of corticosteroids has been suggested, but the results 162 have not been impressive or uniformly successful. 163 Busulfan may cause cellular dysplasia in many organs in addition to the lung. Cytologic 164 abnormalities characterized by giant, hyperchromatic nuclei have been reported in lymph nodes, 165 pancreas, thyroid, adrenal glands, liver, and bone marrow. This cytologic dysplasia may be severe 166 enough to cause difficulty in interpretation of exfoliative cytologic examinations from the lung, 167 bladder, breast, and the uterine cervix. 168 In addition to the widespread epithelial dysplasia that has been observed during busulfan therapy, 169 chromosome aberrations have been reported in cells from patients receiving busulfan. 170 Busulfan is mutagenic in mice and, possibly, in humans. 171 Malignant tumors and acute leukemias have been reported in patients who have received busulfan 172 therapy, and this drug may be a human carcinogen. The World Health Organization has concluded that 173 there is a causal relationship between busulfan exposure and the development of secondary 174 malignancies. Four cases of acute leukemia occurred among 243 patients treated with busulfan as 175 adjuvant chemotherapy following surgical resection of bronchogenic carcinoma. All 4 cases were 176 from a subgroup of 19 of these 243 patients who developed pancytopenia while taking busulfan 5 to 8 177 years before leukemia became clinically apparent. These findings suggest that busulfan is 178 leukemogenic, although its mode of action is uncertain. 179 Ovarian suppression and amenorrhea with menopausal symptoms commonly occur during busulfan 180 therapy in premenopausal patients. Busulfan has been associated with ovarian failure including 181 failure to achieve puberty in females. Busulfan interferes with spermatogenesis in experimental 182 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MYLERAN® (busulfan) Tablets 7 animals, and there have been clinical reports of sterility, azoospermia, and testicular atrophy in male 183 patients. 184 Hepatic veno-occlusive disease, which may be life threatening, has been reported in patients 185 receiving busulfan, usually in combination with cyclophosphamide or other chemotherapeutic agents 186 prior to bone marrow transplantation. Possible risk factors for the development of hepatic 187 veno-occlusive disease include: total busulfan dose exceeding 16 mg/kg based on ideal body weight, 188 and concurrent use of multiple alkylating agents (see CLINICAL PHARMACOLOGY and Drug 189 Interactions). 190 A clear cause-and-effect relationship with busulfan has not been demonstrated. Periodic 191 measurement of serum transaminases, alkaline phosphatase, and bilirubin is indicated for early 192 detection of hepatotoxicity. A reduced incidence of hepatic veno-occlusive disease and other 193 regimen-related toxicities have been observed in patients treated with high-dose MYLERAN and 194 cyclophosphamide when the first dose of cyclophosphamide has been delayed for >24 hours after the 195 last dose of busulfan (see CLINICAL PHARMACOLOGY and Drug Interactions). 196 Cardiac tamponade has been reported in a small number of patients with thalassemia (2% in one 197 series) who received busulfan and cyclophosphamide as the preparatory regimen for bone marrow 198 transplantation. In this series, the cardiac tamponade was often fatal. Abdominal pain and vomiting 199 preceded the tamponade in most patients. 200 Pregnancy: Pregnancy Category D. Busulfan may cause fetal harm when administered to a pregnant 201 woman. Although there have been a number of cases reported where apparently normal children have 202 been born after busulfan treatment during pregnancy, one case has been cited where a malformed baby 203 was delivered by a mother treated with busulfan. During the pregnancy that resulted in the malformed 204 infant, the mother received x-ray therapy early in the first trimester, mercaptopurine until the third 205 month, then busulfan until delivery. In pregnant rats, busulfan produces sterility in both male and 206 female offspring due to the absence of germinal cells in testes and ovaries. Germinal cell aplasia or 207 sterility in offspring of mothers receiving busulfan during pregnancy has not been reported in humans. 208 There are no adequate and well-controlled studies in pregnant women. If this drug is used during 209 pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of 210 the potential hazard to the fetus. Women of childbearing potential should be advised to avoid 211 becoming pregnant. 212 213 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MYLERAN® (busulfan) Tablets 8 PRECAUTIONS 214 General: The most consistent, dose-related toxicity is bone marrow suppression. This may be 215 manifest by anemia, leukopenia, thrombocytopenia, or any combination of these. It is imperative that 216 patients be instructed to report promptly the development of fever, sore throat, signs of local 217 infection, bleeding from any site, or symptoms suggestive of anemia. Any one of these findings may 218 indicate busulfan toxicity; however, they may also indicate transformation of the disease to an acute 219 “blastic” form. Since busulfan may have a delayed effect, it is important to withdraw the medication 220 temporarily at the first sign of an abnormally large or exceptionally rapid fall in any of the formed 221 elements of the blood. Patients should never be allowed to take the drug without close medical 222 supervision. 223 Seizures have been reported in patients receiving busulfan. As with any potentially epileptogenic 224 drug, caution should be exercised when administering busulfan to patients with a history of seizure 225 disorder, head trauma, or receiving other potentially epileptogenic drugs. Some investigators have 226 used prophylactic anticonvulsant therapy in this setting. 227 Information for Patients: Patients beginning therapy with busulfan should be informed of the 228 importance of having periodic blood counts and to immediately report any unusual fever or bleeding. 229 Aside from the major toxicity of myelosuppression, patients should be instructed to report any 230 difficulty in breathing, persistent cough, or congestion. They should be told that diffuse pulmonary 231 fibrosis is an infrequent, but serious and potentially life-threatening complication of long-term 232 busulfan therapy. Patients should be alerted to report any signs of abrupt weakness, unusual fatigue, 233 anorexia, weight loss, nausea and vomiting, and melanoderma that could be associated with a 234 syndrome resembling adrenal insufficiency. Patients should never be allowed to take the drug without 235 medical supervision and they should be informed that other encountered toxicities to busulfan include 236 infertility, amenorrhea, skin hyperpigmentation, drug hypersensitivity, dryness of the mucous 237 membranes, and rarely, cataract formation. Women of childbearing potential should be advised to 238 avoid becoming pregnant. The increased risk of a second malignancy should be explained to the 239 patient. 240 Laboratory Tests: It is recommended that evaluation of the hemoglobin or hematocrit, total white 241 blood cell count and differential count, and quantitative platelet count be obtained weekly while the 242 patient is on busulfan therapy. In cases where the cause of fluctuation in the formed elements of the 243 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MYLERAN® (busulfan) Tablets 9 peripheral blood is obscure, bone marrow examination may be useful for evaluation of marrow status. 244 A decision to increase, decrease, continue, or discontinue a given dose of busulfan must be based not 245 only on the absolute hematologic values, but also on the rapidity with which changes are occurring. 246 The dosage of busulfan may need to be reduced if this agent is combined with other drugs whose 247 primary toxicity is myelosuppression. Occasional patients may be unusually sensitive to busulfan 248 administered at standard dosage and suffer neutropenia or thrombocytopenia after a relatively short 249 exposure to the drug. Busulfan should not be used where facilities for complete blood counts, 250 including quantitative platelet counts, are not available at weekly (or more frequent) intervals. 251 Drug Interactions: Busulfan may cause additive myelosuppression when used with other 252 myelosuppressive drugs. 253 In one study, 12 of approximately 330 patients receiving continuous busulfan and thioguanine 254 therapy for treatment of chronic myelogenous leukemia were found to have portal hypertension and 255 esophageal varices associated with abnormal liver function tests. Subsequent liver biopsies were 256 performed in 4 of these patients, all of which showed evidence of nodular regenerative hyperplasia. 257 Duration of combination therapy prior to the appearance of esophageal varices ranged from 6 to 258 45 months. With the present analysis of the data, no cases of hepatotoxicity have appeared in the 259 busulfan-alone arm of the study. Long-term continuous therapy with thioguanine and busulfan should 260 be used with caution. 261 Busulfan-induced pulmonary toxicity may be additive to the effects produced by other cytotoxic 262 agents. 263 The concomitant systemic administration of itraconazole to patients receiving high-dose 264 MYLERAN may result in reduced busulfan clearance (see CLINICAL PHARMACOLOGY). Patients 265 should be monitored for signs of busulfan toxicity when itraconazole is used concomitantly with 266 MYLERAN. 267 Busulfan clearance may be reduced in the presence of cyclophosphamide (see CLINICAL 268 PHARMACOLOGY). 269 Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section. The World 270 Health Organization has concluded that there is a causal relationship between busulfan exposure and 271 the development of secondary malignancies. 272 Pregnancy: Teratogenic Effects: Pregnancy Category D. See WARNINGS section. 273 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MYLERAN® (busulfan) Tablets 10 Nonteratogenic Effects: There have been reports in the literature of small infants being born 274 after the mothers received busulfan during pregnancy, in particular, during the third trimester. One 275 case was reported where an infant had mild anemia and neutropenia at birth after busulfan was 276 administered to the mother from the eighth week of pregnancy to term. 277 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because of the 278 potential for tumorigenicity shown for busulfan in animal and human studies, a decision should be 279 made whether to discontinue nursing or to discontinue the drug, taking into account the importance of 280 the drug to the mother. 281 Pediatric Use: See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION 282 sections. 283 284 ADVERSE REACTIONS 285 Hematological Effects: The most frequent, serious, toxic effect of busulfan is dose-related 286 myelosuppression resulting in leukopenia, thrombocytopenia, and anemia. Myelosuppression is most 287 frequently the result of a failure to discontinue dosage in the face of an undetected decrease in 288 leukocyte or platelet counts. 289 Aplastic anemia (sometimes irreversible) has been reported rarely, often following long-term 290 conventional doses and also high doses of MYLERAN. 291 Pulmonary: Interstitial pulmonary fibrosis has been reported rarely, but it is a clinically significant 292 adverse effect when observed and calls for immediate discontinuation of further administration of the 293 drug. The role of corticosteroids in arresting or reversing the fibrosis has been reported to be 294 beneficial in some cases and without effect in others. 295 Cardiac: Cardiac tamponade has been reported in a small number of patients with thalassemia who 296 received busulfan and cyclophosphamide as the preparatory regimen for bone marrow transplantation 297 (see WARNINGS). 298 One case of endocardial fibrosis has been reported in a 79-year-old woman who received a total 299 dose of 7,200 mg of busulfan over a period of 9 years for the management of chronic myelogenous 300 leukemia. At autopsy, she was found to have endocardial fibrosis of the left ventricle in addition to 301 interstitial pulmonary fibrosis. 302 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MYLERAN® (busulfan) Tablets 11 Ocular: Busulfan is capable of inducing cataracts in rats and there have been several reports 303 indicating that this is a rare complication in humans. 304 Dermatologic: Hyperpigmentation is the most common adverse skin reaction and occurs in 5% to 305 10% of patients, particularly those with a dark complexion. 306 Metabolic: In a few cases, a clinical syndrome closely resembling adrenal insufficiency and 307 characterized by weakness, severe fatigue, anorexia, weight loss, nausea and vomiting, and 308 melanoderma has developed after prolonged busulfan therapy. The symptoms have sometimes been 309 reversible when busulfan was withdrawn. Adrenal responsiveness to exogenously administered 310 ACTH has usually been normal. However, pituitary function testing with metyrapone revealed a 311 blunted urinary 17-hydroxycorticosteroid excretion in 2 patients. Following the discontinuation of 312 busulfan (which was associated with clinical improvement), rechallenge with metyrapone revealed 313 normal pituitary-adrenal function. 314 Hyperuricemia and/or hyperuricosuria are not uncommon in patients with chronic myelogenous 315 leukemia. Additional rapid destruction of granulocytes may accompany the initiation of chemotherapy 316 and increase the urate pool. Adverse effects can be minimized by increased hydration, urine 317 alkalinization, and the prophylactic administration of a xanthine oxidase inhibitor such as allopurinol. 318 Hepatic Effects: Esophageal varices have been reported in patients receiving continuous busulfan 319 and thioguanine therapy for treatment of chronic myelogenous leukemia (see PRECAUTIONS: Drug 320 Interactions). Hepatic veno-occlusive disease has been observed in patients receiving busulfan (see 321 WARNINGS). 322 Miscellaneous: Other reported adverse reactions include: urticaria, erythema multiforme, erythema 323 nodosum, alopecia, porphyria cutanea tarda, excessive dryness and fragility of the skin with 324 anhidrosis, dryness of the oral mucous membranes and cheilosis, gynecomastia, cholestatic jaundice, 325 and myasthenia gravis. Most of these are single case reports, and in many, a clear cause-and-effect 326 relationship with busulfan has not been demonstrated. 327 Seizures (see PRECAUTIONS: General) have been observed in patients receiving higher than 328 recommended doses of busulfan. 329 Observed During Clinical Practice: The following events have been identified during post- 330 approval use of busulfan. Because they are reported voluntarily from a population of unknown size, 331 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MYLERAN® (busulfan) Tablets 12 estimates of frequency cannot be made. These events have been chosen for inclusion due to a 332 combination of their seriousness, frequency of reporting, or potential causal connection to busulfan. 333 Blood and Lymphatic: Aplastic anemia. 334 Eye: Cataracts, corneal thinning, lens changes. 335 Hepatobiliary Tract and Pancreas: Centrilobular sinusoidal fibrosis, hepatic veno-occlusive 336 disease, hepatocellular atrophy, hepatocellular necrosis, hyperbilirubinemia (see WARNINGS). 337 Non-site Specific: Infection, mucositis, sepsis. 338 Respiratory: Pneumonia. 339 Skin: Rash. An increased local cutaneous reaction has been observed in patients receiving 340 radiotherapy soon after busulfan. 341 342 OVERDOSAGE 343 There is no known antidote to busulfan. The principal toxic effects are bone marrow depression 344 and pancytopenia. The hematologic status should be closely monitored and vigorous supportive 345 measures instituted if necessary. Induction of vomiting or gastric lavage followed by administration of 346 charcoal would be indicated if ingestion were recent. Dialysis may be considered in the management 347 of overdose as there is 1 report of successful dialysis of busulfan (see 348 CLINICALPHARMACOLOGY). 349 Gastrointestinal toxicity with mucositis, nausea, vomiting, and diarrhea has been observed when 350 MYLERAN was used in association with bone marrow transplantation. 351 Oral LD50 single doses in mice are 120 mg/kg. Two distinct types of toxic response are seen at 352 median lethal doses given intraperitoneally. Within a matter of hours there are signs of stimulation of 353 the central nervous system with convulsions and death on the first day. Mice are more sensitive to this 354 effect than are rats. With doses at the LD50 there is also delayed death due to damage to the bone 355 marrow. At 3 times the LD50, atrophy of the mucosa of the large intestine is found after a week, 356 whereas that of the small intestine is little affected. After doses in the order of 10 times those used 357 therapeutically were added to the diet of rats, irreversible cataracts were produced after several 358 weeks. Small doses had no such effect. 359 360 DOSAGE AND ADMINISTRATION 361 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MYLERAN® (busulfan) Tablets 13 Busulfan is administered orally. The usual adult dose range for remission induction is 4 to 8 mg, 362 total dose, daily. Dosing on a weight basis is the same for both pediatric patients and adults, 363 approximately 60 mcg/kg of body weight or 1.8 mg/m2 of body surface, daily. Since the rate of fall of 364 the leukocyte count is dose related, daily doses exceeding 4 mg per day should be reserved for 365 patients with the most compelling symptoms; the greater the total daily dose, the greater is the 366 possibility of inducing bone marrow aplasia. 367 A decrease in the leukocyte count is not usually seen during the first 10 to 15 days of treatment; the 368 leukocyte count may actually increase during this period and it should not be interpreted as resistance 369 to the drug, nor should the dose be increased. Since the leukocyte count may continue to fall for more 370 than 1 month after discontinuing the drug, it is important that busulfan be discontinued prior to the 371 total leukocyte count falling into the normal range. When the total leukocyte count has declined to 372 approximately 15,000/mcL, the drug should be withheld. 373 With a constant dose of busulfan, the total leukocyte count declines exponentially; a weekly plot of 374 the leukocyte count on semi-logarithmic graph paper aids in predicting the time when therapy should 375 be discontinued. With the recommended dose of busulfan, a normal leukocyte count is usually 376 achieved in 12 to 20 weeks. 377 During remission, the patient is examined at monthly intervals and treatment resumed with the 378 induction dosage when the total leukocyte count reaches approximately 50,000/mcL. When remission 379 is shorter than 3 months, maintenance therapy of 1 to 3 mg daily may be advisable in order to keep the 380 hematological status under control and prevent rapid relapse. 381 Procedures for proper handling and disposal of anticancer drugs should be considered. Several 382 guidelines on this subject have been published.1-8 383 There is no general agreement that all of the procedures recommended in the guidelines are 384 necessary or appropriate. 385 386 HOW SUPPLIED 387 MYLERAN is supplied as white, film-coated, round, biconvex tablets containing 2 mg busulfan in 388 amber glass bottles with child-resistant closures. One side is imprinted with "GX EF3" and the other 389 side is imprinted with an "M.” 390 Bottle of 25 (NDC 0173-0713 -25) 391 Bottle of 100 (NDC 0173-0713-XX) 392 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MYLERAN® (busulfan) Tablets 14 Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled 393 Room Temperature). 394 395 396 REFERENCES 397 1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for 398 Practice. Pittsburgh, PA. Oncology Nursing Society; 1999:32-41. 399 2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: 400 Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National 401 Institutes of Health; 1992. US Dept of Health and Human Services, Public Health Service 402 publication NIH 92-2621. 403 3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 404 1985;253:1590-1591. 405 4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic 406 agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on 407 Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 408 Longwood Avenue, Boston, MA 02115. 409 5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of 410 antineoplastic agents. Med J Australia. 1983;1:426-428. 411 6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount 412 Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263. 413 7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling 414 cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049. 415 8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) Am 416 J. Health-Syst Pharm. 1996:53:1669-1685. 417 418 419 420 GlaxoSmithKline 421 Research Triangle Park, NC 27709 422 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MYLERAN® (busulfan) Tablets 15 423 ? 2002, GlaxoSmithKline. All rights reserved. 424 425 RL- 426 427 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:40.082656	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/009386s019lbl.pdf', 'application_number': 9386, 'submission_type': 'SUPPL ', 'submission_number': 19}
10,728	NDA 09-402/S-037 and 039 Page 3 DELESTROGEN® (ESTRADIOL VALERATE INJECTION, USP) ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. CARDIOVASCULAR AND OTHER RISKS Estrogens with and without progestins should not be used for the prevention of cardiovascular disease. The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women during 5 years of treatment with conjugated equine estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo (see CLININAL PHARMACOLOGY, Clinical Studies). Other doses of conjugated estrogens with medroxyprogesterone, and other combinations of estrogens and progestins were not studied in the WHI and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. DESCRIPTION DELESTROGEN® (estradiol valerate injection, USP) contains estradiol valerate, a long-acting estrogen in sterile oil solutions for intramuscular use. These solutions are clear, colorless to pale yellow. Formulations (per mL): 10 mg estradiol valerate in a vehicle containing 5 mg chlorobutanol (chloral derivative/preservative) and sesame oil; 20 mg estradiol valerate in a vehicle containing 224 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 4 mg benzyl benzoate, 20 mg benzyl alcohol (preservative), and castor oil; 40 mg estradiol valerate in a vehicle containing 447 mg benzyl benzoate, 20 mg benzyl alcohol, and castor oil. Estradiol valerate is designated chemically as estra-1,3,5(10)-triene-3, 17-diol(17β)-, 17-pentanoate. Graphic formula: C23H32O3 MW 356.50 CLINICAL PHARMACOLOGY Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Absorption Estrogens used in therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. When applied for a local action, absorption is usually sufficient to cause systemic effects. When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 5 preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks. Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. When given orally, naturally-occurring estrogens and their esters are extensively metabolized (first pass effect) and circulate primarily as estrone sulfate, with smaller amounts of other conjugated and unconjugated estrogenic species. This results in limited oral potency. By contrast, synthetic estrogens, such as ethinyl estradiol and the nonsteroidal estrogens, are degraded very slowly in the liver and other tissues, which results in their high intrinsic potency. Estrogen drug products administered by non-oral routes are not subject to first-pass metabolism, but also undergo significant hepatic uptake, metabolism, and enterohepatic recycling. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Drug Interactions In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 6 Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects. Clinical Studies Women’s Health Initiative Studies The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated equine estrogens (CE) per day alone or the use of 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms. The CE-only substudy is continuing and results have not been reported. The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 1 below: Table 1. RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHIa Placebo n = 8102 CE/MPA n = 8506 Eventc Relative Risk CE/MPA vs placebo at 5.2 Years (95% CI) Absolute Risk per 10,000 Person-years CHD events Non-fatal MI CHD death 1.29 (1.02-1.63) 1.32 (1.02-1.72) 1.18 (0.70-1.97) 30 23 6 37 30 7 Invasive breast cancerb 1.26 (1.00-1.59) 30 38 Stroke 1.41 (1.07-1.85) 21 29 Pulmonary embolism 2.13 (1.39-3.25) 8 16 Colorectal cancer 0.63 (0.43-0.92) 16 10 Endometrial cancer 0.83 (0.47-1.47) 6 5 Hip fracture 0.66 (0.45-0.98) 15 10 Death due to causes other than the events above 0.92 (0.74-1.14) 40 37 Global Indexc 1.15 (1.03-1.28) 151 170 Deep vein thrombosisd 2.07 (1.49-2.87) 13 26 Vertebral fracturesd 0.66 (0.44-0.98) 15 9 Other osteoporotic fracturesd 0.77 (0.69-0.86) 170 131 aadapted from JAMA, 2002; 288:321-333 bincludes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer ca subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 7 dnot included in Global Index nominal confidence intervals unadjusted for multiple looks and multiple comparisons For those outcomes included in the “global index,” absolute excess risks per 10,000 person-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index” was 19 per 10,000 person-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNING, WARNINGS, and PRECAUTIONS.) INDICATIONS AND USAGE DELESTROGEN (estradiol valerate injection, USP) is indicated in the: 1. Treatment of moderate to severe vasomotor symptoms associated with the menopause. 2. Treatment of moderate to severe symptoms of vulval and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. 3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure. 4. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only). CONTRAINDICATIONS Estrogens should not be used in individuals with any of the following conditions: 1. Undiagnosed abnormal genital bleeding. 2. Known, suspected, or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease. 3. Known or suspected estrogen-dependent neoplasia. 4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions. 5. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction). 6. DELESTROGEN should not be used in patients with known hypersensitivity to its ingredients. 7. Known or suspected pregnancy. There is no indication for DELESTROGEN in pregnancy. There appears to be little or no increased risk of birth defects in women who have used estrogens This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 8 and progestins from oral contraceptives inadvertently during early pregnancy (see PRECAUTIONS). WARNINGS See BOXED WARNINGS. The use of unopposed estrogens in women who have a uterus is associated with an increased risk of endometrial cancer. 1. Cardiovascular disorders Estrogen and estrogen/progestin therapy have been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately. Risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) should be managed appropriately. a. Coronary heart disease and stroke In the Women’s Health Initiative study (WHI), an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing. (See CLINICAL PHARMACOLOGY, Clinical Studies.) In the CE/MPA substudy of WHI an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 person years). The increase in risk was observed in year one and persisted. In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 person-years). The increase in risk was observed after the first year and persisted. In postmenopausal women with documented heart disease (n=2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA-0.625mg/2.5mg per day demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 9 placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall. Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. b. Venous thromboembolism (VTE) In the Women’s Health Initiative study (WHI), an increase in VTE has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing. (See CLINICAL PHARMACOLOGY, Clinical Studies.) In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 woman-years in the CE/MPA group compared to 16 per 10,000 woman-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2. Malignant neoplasms a. Endometrial cancer The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24- fold for five to ten years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 10 estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. b. Breast cancer Estrogen and estrogen/progestin therapy in postmenopausal women has been associated with an increased risk of breast cancer. In the CE/MPA substudy of the Women’s Health Initiative study (WHI), a 26% increase of invasive breast cancer (38 vs 30 per 10,000 woman-years) after an average of 5.2 years of treatment was observed in women receiving CE/MPA compared to women receiving placebo. The increased risk of breast cancer became apparent after 4 years on CE/MPA. The women reporting prior postmenopausal use of estrogens and/or estrogen with progestin had a higher relative risk for breast cancer associated with CE/MPA than those who had never used these hormones. (See CLINICAL PHARMACOLOGY, Clinical Studies.) In the WHI, no increased risk of breast cancer in CE-treated women compared to placebo was reported after an average of 5.2 years of therapy. These data are preliminary and that substudy of WHI is continuing. Epidemiologic studies have reported an increased risk of breast cancer in association with increasing duration of postmenopausal treatment with estrogens with or without progestin. This association was reanalyzed in original data from 51 studies that involved various doses and types of estrogens, with and without progestins. In the reanalysis, an increased risk of having breast cancer diagnosed became apparent after about 5 years of continued treatment, and subsided after treatment had been discontinued for 5 years or longer. Some later studies have suggested that postmenopausal treatment with estrogens and progestin increase the risk of breast cancer more than treatment with estrogen alone. A postmenopausal woman without a uterus who requires estrogen should receive estrogen-alone therapy, and should not be exposed unnecessarily to progestins. All postmenopausal women should receive yearly breast exams by a health care provider and perform monthly self-examinations. In addition, mammography examinations should be scheduled based on patient age and risk factors. 3. Gallbladder disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. 4. Hypercalcemia This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 11 Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level. 5. Visual abnormalities Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be discontinued. PRECAUTIONS A. General 1. Addition of a progestin when a woman has not had a hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include: a. A possible increased risk of breast cancer b. Adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL) c. Impairment of glucose tolerance 2. Elevated blood pressure In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use. 3. Familial hyperlipoproteinemia In patients with familial defects of lipoprotein metabolism, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. 4. Impaired liver function This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 12 Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. 5. Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. 6. Fluid retention Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. 7. Hypocalcemia Estrogens should be used with caution in individuals with severe hypocalcemia. 8. Ovarian cancer Use of estrogen-only products, in particular for ten or more years, has been associated with an increased risk of ovarian cancer in some epidemiological studies. Other studies did not show a significant association. Data are insufficient to determine whether there is an increased risk with estrogen/progestin combination therapy in postmenopausal women. 9. Exacerbation of endometriosis Endometriosis may be exacerbated with administration of estrogens. 10. Exacerbation of other conditions Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria and should be used with caution in women with these conditions. 11. Hypercoagulability Some studies have shown that women taking estrogen replacement therapy have hypercoagulability, primarily related to decreased antithrombin activity. This effect appears dose- and duration-dependent This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 13 and is less pronounced than that associated with oral contraceptive use. Also, postmenopausal women tend to have increased coagulation parameters at baseline compared to premenopausal women. There is some suggestion that low dose postmenopausal mestranol may increase the risk of thromboembolism, although the majority of studies (of primarily conjugated estrogens users) report no such increase. 12. Uterine bleeding and mastodynia Certain patients may develop undesirable manifestations of estrogenic stimulation, such as abnormal uterine bleeding and mastodynia. B. Patient Information Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe DELESTROGEN. C. Laboratory Tests Estrogen administration should be initiated at the lowest dose for the approved indication and then guided by clinical response, rather than by serum hormone levels (e.g., estradiol, FSH). D. Drug/Laboratory Test Interactions. 1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 2. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG)) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 14 4. Increased plasma HDL and HDL2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels. 5. Impaired glucose tolerance. 6. Reduced response to metyrapone test. E. Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. (See BOXED WARNINGS, CONTRAINDICATIONS, and WARNINGS.) F. Pregnancy Estrogens should not be used during pregnancy. (See CONTRAINDICATIONS.) G. Nursing Mothers Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when DELESTROGEN is administered to a nursing woman. H. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Large and repeated doses of estrogen over an extended period of time may accelerate epiphyseal closure. Therefore, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended in patients in whom bone growth is not complete. I. Geriatric Use Clinical studies of estradiol valerate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. ADVERSE REACTIONS See BOXED WARNINGS, WARNINGS, and PRECAUTIONS. The following additional adverse reactions have been reported with estrogens: 1. Genitourinary system Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 15 change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer. 2. Breasts Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer. 3. Cardiovascular Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure. 4. Gastrointestinal Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis. 5. Skin Chloasma or melasma, which may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash. 6. Eyes Retinal vascular thrombosis; steepening of corneal curvature; intolerance to contact lenses. 7. Central Nervous System Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy. 8. Miscellaneous Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthalgias; leg cramps; changes in libido; anaphylactoid/anaphylactic reactions including urticaria and angioedema; hypocalcemia; exacerbation of asthma; increased triglycerides. OVERDOSAGE Serious ill effects have not been reported following acute ingestion of large doses of estrogen- containing oral contraceptives by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females. DOSAGE AND ADMINISTRATION When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 16 Use of estrogen, alone or in combination with a progestin, should be limited to the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary (See BOXED WARNINGS and WARNINGS). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. Care should be taken to inject deeply into the upper, outer quadrant of the gluteal muscle following the usual precautions for intramuscular administration. By virtue of the low viscosity of the vehicles, the various preparations of DELESTROGEN (estradiol valerate injection, USP) may be administered with a small gauge needle. Since the 40 mg potency provides a high concentration in a small volume, particular care should be observed to administer the full dose. DELESTROGEN should be visually inspected for particulate matter and color prior to administration; the solution is clear, colorless to pale yellow. Storage at low temperatures may result in the separation of some crystalline material which redissolves readily on warming. Note: A dry needle and syringe should be used. Use of a wet needle or syringe may cause the solution to become cloudy; however, this does not affect the potency of the material. Patients should be started at the lowest effective dose for the indication. 1. For treatment of moderate to severe vasomotor symptoms, vulval and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible. Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals. The usual dosage is 10 to 20 mg DELESTROGEN every four weeks. 2. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure. The usual dosage is 10 to 20 mg DELESTROGEN every four weeks. 3. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only. The usual dosage is 30 mg or more administered every one or two weeks. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 17 Treated patients with an intact uterus should be monitored closely for signs of endometrial cancer, and appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding. See PRECAUTIONS A.1 concerning addition of a progestin. HOW SUPPLIED DELESTROGEN® (estradiol valerate injection, USP) Multiple Dose Vials 10 mg/mL (5 mL): NDC 61570-180-01 20 mg/mL (5 mL): NDC 61570-181-01 40 mg/mL (5 mL): NDC 61570-182-01 Storage Store at room temperature. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 18 PATIENT INFORMATION (Updated December 2, 2003) DELESTROGEN® (estradiol valerate injection, USP) Read this PATIENT INFORMATION before you start taking DELESTROGEN and read what you get each time you refill DELESTROGEN. There may be new information. This information does not take the place of talking to your health care provider about your medical condition or your treatment. What is the most important information I should know about DELESTROGEN (an estrogen hormone)? • Estrogens increase the chances of getting cancer of the uterus. Report any unusual vaginal bleeding right away while you are taking estrogens. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your health care provider should check any unusual vaginal bleeding to find out the cause. • Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes. Using estrogens with or without progestins may increase your chances of getting heart attack, strokes, breast cancer, and blood clots. You and your health care provider should talk regularly about whether you still need treatment with DELESTROGEN. What is DELESTROGEN? DELESTROGEN is a medicine that contains estrogen hormones. What is DELESTROGEN used for? DELESTROGEN is used after menopause to: • reduce moderate to severe hot flashes. Estrogens are hormones made by a woman’s ovaries. The ovaries normally stop making estrogens when a woman is between 45 to 55 years old. This drop in body estrogen levels causes the “change in life” or menopause (the end of monthly This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 19 menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause.” When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feeling of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild, and they will not need estrogens. In other women, symptoms can be more severe. You and your health care provider should talk regularly about whether you still need treatment with DELESTROGEN. • treat moderate to severe dryness, itching, and burning in or around the vagina. You and your health care provider should talk regularly about whether you still need treatment with DELESTROGEN to control these problems. • help reduce your chances of getting osteoporosis (thin weak bones). Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use DELESTROGEN only to prevent osteoporosis from menopause, talk with your health care provider about whether a different treatment or medicine without estrogens might be better for you. You and your health care provider should talk regularly about whether you should continue with DELESTROGEN. Weight-bearing exercise, like walking or running, and taking calcium and vitamin D supplements may also lower your chances of getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your health care provider before starting them. Who should not take DELESTROGEN? Do not start taking DELESTROGEN if you: • have unusual vaginal bleeding. • currently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or had cancer, talk with your health care provider about whether you should take DELESTROGEN. • had a stroke or heart attack in the past year. • currently have or have had blood clots. • are allergic to DELESTROGEN or any of its ingredients. See the end of this leaflet for a list of ingredients in DELESTROGEN. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 20 • think you may be pregnant. Tell your health care provider: • if you are breastfeeding. The hormone in DELESTROGEN can pass into your milk. • about all of your medical problems. Your health care provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. • about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how DELESTROGEN works. DELESTROGEN may also affect how your other medicines work. • if you are going to have surgery or will be on bed rest. You may need to stop taking estrogens. How should I take DELESTROGEN? DELESTROGEN should be injected deeply into the upper, outer quadrant of the gluteal muscle following the usual precautions for intramuscular administration. By virtue of the low viscosity of the vehicles, the various preparations of DELESTROGEN (estradiol valerate injection, USP) may be administered with a small gauge needle. Since the 40 mg potency provides a high concentration in a small volume, particular care should be observed to administer the full dose. DELESTROGEN should be visually inspected for particulate matter and color prior to administration; the solution is clear, colorless to pale yellow. Storage at low temperatures may result in the separation of some crystalline material which redissolves readily on warming. Note: A dry needle and syringe should be used. Use of a wet needle or syringe may cause the solution to become cloudy; however, this does not affect the potency of the material. Estrogens should be used only as long as needed. You and your health care provider should talk regularly (for example, every 3 to 6 months) about whether you still need treatment with DELESTROGEN. What are the possible side effects of estrogens? Less common but serious side effects include: • Breast cancer • Cancer of the uterus • Stroke This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 21 • Heart attack • Blood clots • Gallbladder disease • Ovarian cancer These are some of the warning signs of serious side effects: • Breast lumps • Unusual vaginal bleeding • Dizziness and faintness • Changes in speech • Severe headaches • Chest pain • Shortness of breath • Pains in your legs • Changes in vision • Vomiting Call your health care provider right away if you get any of these warning signs, or any other unusual symptom that concerns you. Common side effects include: • Headache • Breast pain • Irregular vaginal bleeding or spotting • Stomach/abdominal cramps, bloating • Nausea and vomiting • Hair loss Other side effects include: • High blood pressure • Liver problems • High blood sugar • Fluid retention • Enlargement of benign tumors of the uterus (“fibroids”) • Vaginal yeast infection These are not all the possible side effects of DELESTROGEN. For more information, ask your health care provider or pharmacist. What can I do to lower my chances of a serious side effect with DELESTROGEN? • Talk with your health care provider regularly about whether you should continue taking DELESTROGEN. • See your health care provider right away if you get vaginal bleeding while taking DELESTROGEN. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 22 • Have a breast exam and mammogram (breast X-ray) every year unless your health care provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. • If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your health care provider for ways to lower your changes for getting heart disease. General information about safe and effective use of DELESTROGEN Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take DELESTROGEN for conditions for which it was not prescribed. Do not give DELESTROGEN to other people, even if they have the same symptoms you have. It may harm them. Keep DELESTROGEN out of the reach of children. This leaflet provides a summary of the most important information about DELESTROGEN. If you would like more information, talk with your health care provider or pharmacist. You can ask for information about DELESTROGEN that is written for health professionals. You can get more information by calling the toll free number 1-800-776-3637, select option 5. What are the ingredients in DELESTROGEN? DELESTROGEN is supplied in three 5 mL multiple dose vials; 10 mg/mL, 20 mg/mL, and 40 mg/mL strengths. The 10 mg/mL strength contains 10 mg estradiol valerate in a solution of chlorobutanol and sesame oil. The 20 mg/mL strength contains 20 mg estradiol valerate in a solution of benzyl benzoate, benzyl alcohol, and castor oil. The 40 mg/mL strength contains 40 mg estradiol valerate in a solution of benzyl benzoate, benzyl alcohol, and castor oil. Distributed by: Monarch Pharmaceuticals, Inc., Bristol, TN 37620 (A wholly owned subsidiary of King Pharmaceuticals, Inc.) Manufactured by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Prescribing Information as of December 2, 2003. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 09-402/S-037 and 039 Page 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:40.159949	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/09402slr037_delestrogen_lbl.pdf', 'application_number': 9402, 'submission_type': 'SUPPL ', 'submission_number': 37}
10,730	KEMADRIN (procyclidine hydrochloride) 5 mg Scored Tablets Description: KEMADRIN (procyclidine hydrochloride) is a synthetic antispasmodic compound of relatively low toxicity. It has been shown to be useful for the symptomatic treatment of parkinsonism (paralysis agitans) and extrapyramidal dysfunction caused by tranquilizer therapy. Procyclidine hydrochloride was developed at The Wellcome Research Laboratories as the most promising of a series of antiparkinsonism compounds produced by chemical modification of antihistamines. Procyclidine hydrochloride is a white crystalline substance which is soluble in water and almost tasteless. It is known chemically asα-cyclohexyl-α-phenyl-1-pyrrolidinepropanol hydrochloride and has the following structural formula: KEMADRIN is available in tablet form for oral administration. Each scored tablet contains5 mg procyclidine hydrochloride and the inactive ingredients corn and potato starch, lactose, and magnesium stearate. Clinical Pharmacology: Pharmacologic tests have shown that procyclidine hydrochloride has an atropine-like action and exerts an antispasmodic effect on smooth muscle. It is a potent mydriatic and inhibits salivation. It has no sympathetic ganglion- blocking activity in doses as high as 4 mg/kg, as measured by the lack of inhibition of the response of the nictitating membrane to preganglionic electrical stimulation. The intravenous LD50 in mice was about 60 mg/kg. Subcutaneously, doses of 300 mg/kg were not toxic. In dogs, the intraperitoneal administration of procyclidine hydrochloride in doses of 5 mg/kg caused maximal dilation of the pupil and inhibition of salivation, but had no toxic action. When the dose was increased to 20 mg/kg, the same symptoms occurred, and in addition there were tremors and ataxia lasting 4 to 5 hours. In one animal, convulsions occurred which were controlled by pentobarbital. In all animals behavior returned to normal within 24 hours. Chronic toxicity tests in rats showed that the compound caused only a very slight retardation in growth, and no change in the erythrocyte count or the histological appearance of the lungs, liver, spleen, and kidney when as much as 10 mg/kg body weight was given subcutaneously daily for 9 weeks. Indications: KEMADRIN (procyclidine hydrochloride) is indicated in the treatment of parkinsonism including the postencephalitic, arteriosclerotic, and idiopathic types. Partial control of the parkinsonism symptoms is the usual therapeutic accomplishment. Procyclidine hydrochloride is usually more efficacious in the relief of rigidity than tremor; but tremor, fatigue, weakness, and sluggishness are frequently beneficially influenced. It can be substituted for all the previous medications in mild and moderate cases. For the control of more severe cases, other drugs may be added to procyclidine therapy as indications warrant. Reference ID: 2968506 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical reports indicate that procyclidine often successfully relieves the symptoms of extrapyramidal dysfunction (dystonia, dyskinesia, akathisia, and parkinsonism) which accompany the therapy of mental disorders with phenothiazine and rauwolfia compounds. In addition to minimizing the symptoms induced by tranquilizing drugs, the drug effectively controls sialorrhea resulting from neuroleptic medication. At the same time, freedom from the side effects induced by tranquilizer drugs, as provided by the administration of procyclidine, permits a more sustained treatment of the patient’s mental disorder. Clinical results in the treatment of parkinsonism indicate that most patients experience subjective improvement characterized by a feeling of well-being and increased alertness, together with diminished salivation and a marked improvement in muscular coordination as demonstrated by objective tests of manual dexterity and by increased ability to carry out ordinary self-care activities. While the drug exerts a mild atropine-like action and therefore causes mydriasis, this may be kept minimal by careful adjustment of the daily dosage. Contraindications: Procyclidine hydrochloride should not be used in angle-closure glaucoma although simple type glaucomas do not appear to be adversely affected. Warnings: Use in Children: Safety and efficacy have not been established in the pediatric age group; therefore, the use of procyclidine hydrochloride in this age group requires that the potential benefits be weighed against the possible hazards to the child. Pregnancy Warning: The safe use of this drug in pregnancy has not been established; therefore, the use of procyclidine hydrochloride in pregnancy, lactation, or in women of childbearing age requires that the potential benefits be weighed against the possible hazards to the mother and child. Precautions: Conditions in which inhibition of the parasympathetic nervous system is undesirable, such as tachycardia and urinary retention (such as may occur with marked prostatic hypertrophy), require special care in the administration of the drug. Hypotensive patients who receive the drug should be observed closely. Occasionally, particularly in older patients, mental confusion and disorientation may occur with the development of agitation, hallucinations, and psychotic-like symptoms. Patients with mental disorders occasionally experience a precipitation of a psychotic episode when the dosage of antiparkinsonism drugs is increased to treat the extrapyramidal side effects of phenothiazine and rauwolfia derivatives. Geriatric Use: Clinical studies of KEMADRIN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should start at the low end of the dosing range(see Dosage and Administration) and the dose should be increased only as needed with monitoring for the emergence of adverse events (see Precautions and Adverse Reactions). Reference ID: 2968506 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Reactions: Anticholinergic effects can be produced by therapeutic doses although these can frequently be minimized or eliminated by careful dosage. They include: dryness of the mouth, mydriasis, blurring of vision, giddiness, lightheadedness, and gastrointestinal disturbances such as nausea, vomiting, epigastric distress, and constipation. Occasionally an allergic reaction such as a skin rash may be encountered. Feelings of muscular weakness may occur. Acute suppurative parotitis as a complication of dry mouth has been reported. Dosage and Administration: For Parkinsonism: The dosage of the drug for the treatment of parkinsonism depends upon the age of the patient, the etiology of the disease, and individual responsiveness. Therefore, the dosage must remain flexible to permit adjustment to the individual tolerance and requirements of each patient. In general, younger and postencephalitic patients require and tolerate a somewhat higher dosage than older patients and those with arteriosclerosis. For Patients Who Have Received No Other Therapy: The usual dose of procyclidine hydrochloride for initial treatment is 2.5 mg administered three times daily after meals. If well tolerated, this dose may be gradually increased to 5 mg three times a day and occasionally 5 mg given before retiring. In some cases smaller doses may be employed with good therapeutic results. Occasionally a patient is encountered who cannot tolerate a bedtime dose of the drug. In such cases it may be desirable to adjust dosage so that the bedtime dose is omitted and the total daily requirement is administered in three equal daytime doses. It is best administered during or after meals to minimize the development of side reactions. To Transfer Patients to KEMADRIN from Other Therapy: Patients who have been receiving other drugs may be transferred to procyclidine hydrochloride. This is accomplished gradually by substituting 2.5 mg three times a day for all or part of the original drug. The dose of procyclidine is then increased as required while that of the other drug is correspondingly omitted or decreased until complete replacement is achieved. The total daily dosage may then be adjusted to the level which produces maximum benefit. For Drug-Induced Extrapyramidal Symptoms: For treatment of symptoms of extrapyramidal dysfunction induced by tranquilizer drugs during the therapy of mental disorders, the dosage of procyclidine hydrochloride will depend on the severity of side effects associated with tranquilizer administration. In general, the larger the dosage of the tranquilizer, the more severe will be the associated symptoms, including rigidity and tremors. Accordingly, the drug dosage should be adjusted to suit the needs of the individual patient and to provide maximum relief of the induced symptoms. A convenient method to establish the daily dosage of procyclidine is to begin with the administration of 2.5 mg three times daily. This may be increased by 2.5 mg daily increments until the patient obtains relief of symptoms. In most cases excellent results will be obtained with 10 to 20 mg daily. Reference ID: 2968506 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda How Supplied: White, scored tablets containing 5 mg procyclidine hydrochloride, imprinted with “KEMADRIN” and “S3A” in bottles of 100 (NDC 61570-059-01). Store at 15° to 25°C (59° to 77°F) in a dry place. Prescribing Information as of August 2003. Distributed by: Monarch Pharmaceuticals, Inc., Bristol, TN 37620 Manufactured by: DSM Pharmaceuticals, Inc., Greenville, NC 27834 Reference ID: 2968506 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:40.302293	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/009818s018lbl.pdf', 'application_number': 9818, 'submission_type': 'SUPPL ', 'submission_number': 18}
10,732	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:40.450359	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/09829s9lbl.pdf', 'application_number': 9830, 'submission_type': 'SUPPL ', 'submission_number': 10}
10,729	1 2 451109C/Revised: February 2010 3 4 Nesacaine® (chloroprocaine HCl Injection, USP) 5 Nesacaine®-MPF (chloroprocaine HCl Injection, USP) 6 For Infiltration and Nerve Block 7 8 DESCRIPTION: 9 Nesacaine and Nesacaine-MPF Injections are sterile non pyrogenic local anesthetics. The 10 active ingredient in Nesacaine and Nesacaine-MPF Injections is chloroprocaine HCl 11 (benzoic acid, 4-amino-2-chloro-2-(diethylamino) ethyl ester, monohydrochloride), 12 which is represented by the following structural formula: 13 14 Table 1: Composition of Available Injections Structural Formula Formula (mg/mL) Product Identification Chloro- procaine HCl Sodium Chloride Disodium EDTA dihydrate Methylparaben Nesacaine 1% Nesacaine 2% Nesacaine-MPF 2% Nesacaine-MPF 3% 10 20 20 30 6.7 4.7 4.7 3.3 0.111 0.111 - - 1 1 - - 15 16 The solutions are adjusted to pH 2.7–4.0 by means of sodium hydroxide and/or 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 hydrochloric acid. Filled under nitrogen. Nesacaine and Nesacaine-MPF Injections 2 should not be resterilized by autoclaving. 3 CLINICAL PHARMACOLOGY: 4 Chloroprocaine, like other local anesthetics, blocks the generation and the conduction of 5 nerve impulses, presumably by increasing the threshold for electrical excitation in the 6 nerve, by slowing the propagation of the nerve impulse and by reducing the rate of rise of 7 the action potential. In general, the progression of anesthesia is related to the diameter, 8 myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss 9 of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, 10 and (5) skeletal muscle tone. 11 Systemic absorption of local anesthetics produces effects on the cardiovascular 12 and central nervous systems. At blood concentrations achieved with normal therapeutic 13 doses, changes in cardiac conduction, excitability, refractoriness, contractility, and 14 peripheral vascular resistance are minimal. However, toxic blood concentrations depress 15 cardiac conduction and excitability, which may lead to atrioventricular block and 16 ultimately to cardiac arrest. In addition, with toxic blood concentrations myocardial 17 contractility may be depressed and peripheral vasodilation may occur, leading to 18 decreased cardiac output and arterial blood pressure. 19 Following systemic absorption, toxic blood concentrations of local anesthetics can 20 produce central nervous system stimulation, depression, or both. Apparent central 21 stimulation may be manifested as restlessness, tremors and shivering, which may 22 progress to convulsions. Depression and coma may occur, possibly progressing 23 ultimately to respiratory arrest. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 However, the local anesthetics have a primary depressant effect on the medulla 2 and on higher centers. The depressed stage may occur without a prior stage of central 3 nervous system stimulation. 4 PHARMACOKINETICS: 5 The rate of systemic absorption of local anesthetic drugs is dependent upon the total dose 6 and concentration of drug administered, the route of administration, the vascularity of the 7 administration site, and the presence or absence of epinephrine in the anesthetic injection. 8 Epinephrine usually reduces the rate of absorption and plasma concentration of local 9 anesthetics and is sometimes added to local anesthetic injections in order to prolong the 10 duration of action. 11 The onset of action with chloroprocaine is rapid (usually within 6 to 12 minutes), 12 and the duration of anesthesia, depending upon the amount used and the route of 13 administration, may be up to 60 minutes. 14 Local anesthetics appear to cross the placenta by passive diffusion. However, the 15 rate and degree of diffusion varies considerably among the different drugs as governed 16 by: (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the 17 degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely 18 related to the degree of plasma protein binding, since only the free, unbound drug is 19 available for placental transfer. Thus, drugs with the highest protein binding capacity 20 may have the lowest fetal/maternal ratios. The extent of placental transfer is also 21 determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, 22 nonionized drugs readily enter the fetal blood from the maternal circulation. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Depending upon the route of administration, local anesthetics are distributed to 2 some extent to all body tissues, with high concentrations found in highly perfused organs 3 such as the liver, lungs, heart, and brain. 4 Various pharmacokinetic parameters of the local anesthetics can be significantly 5 altered by the presence of hepatic or renal disease, addition of epinephrine, factors 6 affecting urinary pH, renal blood flow, the route of administration, and the age of the 7 patient. The in vitro plasma half-life of chloroprocaine in adults is 21 ± 2 seconds for 8 males and 25 ± 1 seconds for females. The in vitro plasma half-life in neonates is 43 ± 2 9 seconds. 10 Chloroprocaine is rapidly metabolized in plasma by hydrolysis of the ester 11 linkage by pseudocholinesterase. The hydrolysis of chloroprocaine results in the 12 production of ß-diethylaminoethanol and 2-chloro-4-aminobenzoic acid, which inhibits 13 the action of the sulfonamides (see PRECAUTIONS). 14 The kidney is the main excretory organ for most local anesthetics and their 15 metabolites. Urinary excretion is affected by urinary perfusion and factors affecting 16 urinary pH. 17 INDICATIONS AND USAGE: 18 Nesacaine 1% and 2% Injections, in multidose vials with methylparaben as preservative, 19 are indicated for the production of local anesthesia by infiltration and peripheral nerve 20 block. They are not to be used for lumbar or caudal epidural anesthesia. 21 Nesacaine-MPF 2% and 3% Injections, in single dose vials without preservative 22 and without EDTA, are indicated for the production of local anesthesia by infiltration, 23 peripheral and central nerve block, including lumbar and caudal epidural blocks. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Nesacaine and Nesacaine-MPF Injections are not to be used for subarachnoid 2 administration. 3 CONTRAINDICATIONS: 4 Nesacaine and Nesacaine-MPF Injections are contraindicated in patients hypersensitive 5 (allergic) to drugs of the PABA ester group. 6 Lumbar and caudal epidural anesthesia should be used with extreme caution in 7 persons with the following conditions: existing neurological disease, spinal deformities, 8 septicemia, and severe hypertension. 9 WARNINGS: 10 LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO 11 ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE RELATED 12 TOXICITY AND OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE FROM 13 THE BLOCK TO BE EMPLOYED, AND THEN ONLY AFTER ENSURING THE 14 IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, 15 CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE PERSONNEL 16 RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS 17 AND RELATED EMERGENCIES (see also ADVERSE REACTIONS and 18 PRECAUTIONS). DELAY IN PROPER MANAGEMENT OF DOSE RELATED 19 TOXICITY, UNDERVENTILATION FROM ANY CAUSE AND/OR ALTERED 20 SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC 21 ARREST AND, POSSIBLY, DEATH. NESACAINE (chloroprocaine HCl Injection, 22 USP) contains methylparaben and should not be used for lumbar or caudal epidural 23 anesthesia because safety of this antimicrobial preservative has not been established with 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 regard to intrathecal injection, either intentional or unintentional. NESACAINE-MPF 2 Injection contains no preservative; discard unused injection remaining in vial after initial 3 use. 4 Intra-articular infusions of local anesthetics following arthroscopic and other 5 surgical procedures is an unapproved use, and there have been post-marketing reports of 6 chondrolysis in patients receiving such infusions. The majority of reported cases of 7 chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have 8 been described in pediatric and adult patients following intra-articular infusions of local 9 anesthetics with and without epinephrine for periods of 48 to 72 hours. There is 10 insufficient information to determine whether shorter infusion periods are not associated 11 with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss 12 of motion can be variable, but may begin as early as the 2nd month after surgery. 13 Currently, there is no effective treatment for chondrolysis; patients who experienced 14 chondrolysis have required additional diagnostic and therapeutic procedures and some 15 required arthroplasty or shoulder replacement. 16 Vasopressors should not be used in the presence of ergot-type oxytocic drugs, 17 since a severe persistent hypertension may occur. 18 To avoid intravascular injection, aspiration should be performed before the 19 anesthetic solution is injected. The needle must be repositioned until no blood return can 20 be elicited. However, the absence of blood in the syringe does not guarantee that 21 intravascular injection has been avoided. 22 Mixtures of local anesthetics are sometimes employed to compensate for the 23 slower onset of one drug and the shorter duration of action of the second drug. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Experiments in primates suggest that toxicity is probably additive when mixtures of local 2 anesthetics are employed, but some experiments in rodents suggest synergism. Caution 3 regarding toxic equivalence should be exercised when mixtures of local anesthetics are 4 employed. 5 PRECAUTIONS: 6 General 7 The safety and effective use of chloroprocaine depend on proper dosage, correct 8 technique, adequate precautions and readiness for emergencies. Resuscitative equipment, 9 oxygen and other resuscitative drugs should be available for immediate use (see 10 WARNINGS and ADVERSE REACTIONS). The lowest dosage that results in 11 effective anesthesia should be used to avoid high plasma levels and serious adverse 12 effects. Injections should be made slowly, with frequent aspirations before and during 13 the injection to avoid intravascular injection. Syringe aspirations should also be 14 performed before and during each supplemental injection in continuous (intermittent) 15 catheter techniques. During the administration of epidural anesthesia, it is recommended 16 that a test dose be administered (3 mL of 3% or 5 mL of 2% Nesacaine-MPF Injection) 17 initially and that the patient be monitored for central nervous system toxicity and 18 cardiovascular toxicity, as well as for signs of unintended intrathecal administration, 19 before proceeding. When clinical conditions permit, consideration should be given to 20 employing a chloroprocaine solution that contains epinephrine for the test dose because 21 circulatory changes characteristic of epinephrine may also serve as a warning sign of 22 unintended intravascular injection. An intravascular injection is still possible even if 23 aspirations for blood are negative. With the use of continuous catheter techniques, it is 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 recommended that a fraction of each supplemental dose be administered as a test dose in 2 order to verify proper location of the catheter. 3 Injection of repeated doses of local anesthetics may cause significant increases in 4 plasma levels with each repeated dose due to slow accumulation of the drug or its 5 metabolites. Tolerance to elevated blood levels varies with the physical condition of the 6 patient. Debilitated, elderly patients, acutely ill patients, and children should be given 7 reduced doses commensurate with their age and physical status. Local anesthetics should 8 also be used with caution in patients with hypotension or heart block. 9 Careful and constant monitoring of cardiovascular and respiratory (adequacy of 10 ventilation) vital signs and the patient’s state of consciousness should be accomplished 11 after each local anesthetic injection. It should be kept in mind at such times that 12 restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression or drowsiness 13 may be early warning signs of central nervous system toxicity. 14 Local anesthetic injections containing a vasoconstrictor should be used cautiously 15 and in carefully circumscribed quantities in areas of the body supplied by end arteries or 16 having otherwise compromised blood supply. Patients with peripheral vascular disease 17 and those with hypertensive vascular disease may exhibit exaggerated vasoconstrictor 18 response. Ischemic injury or necrosis may result. 19 Since ester-type local anesthetics are hydrolyzed by plasma cholinesterase 20 produced by the liver, chloroprocaine should be used cautiously in patients with hepatic 21 disease. Local anesthetics should also be used with caution in patients with impaired 22 cardiovascular function since they may be less able to compensate for functional changes 23 associated with the prolongation of A-V conduction produced by these drugs. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Use in Ophthalmic Surgery: When local anesthetic injections are employed for 2 retrobulbar block, lack of corneal sensation should not be relied upon to determine 3 whether or not the patient is ready for surgery. This is because complete lack of corneal 4 sensation usually precedes clinically acceptable external ocular muscle akinesia. 5 Information for Patients 6 When appropriate, patients should be informed in advance that they may experience 7 temporary loss of sensation and motor activity, usually in the lower half of the body, 8 following proper administration of epidural anesthesia. 9 Clinically Significant Drug Interactions 10 The administration of local anesthetic solutions containing epinephrine or norepinephrine 11 to patients receiving monoamine oxidase inhibitors, tricyclic antidepressants or 12 phenothiazines may produce severe, prolonged hypotension or hypertension. Concurrent 13 use of these agents should generally be avoided. In situations when concurrent therapy is 14 necessary, careful patient monitoring is essential. 15 Concurrent administration of vasopressor drugs (for the treatment of hypotension 16 related to obstetric blocks) and ergot-type oxytocic drugs may cause severe, persistent 17 hypertension or cerebrovascular accidents. 18 The para-aminobenzoic acid metabolite of chloroprocaine inhibits the action of 19 sulfonamides. Therefore, chloroprocaine should not be used in any condition in which a 20 sulfonamide drug is being employed. 21 Carcinogenesis, Mutagenesis, and Impairment of Fertility 22 Long-term studies in animals to evaluate carcinogenic potential and reproduction studies 23 to evaluate mutagenesis or impairment of fertility have not been conducted with 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 chloroprocaine. Pregnancy: Category C Animal reproduction studies have not been conducted with chloroprocaine. It is also not known whether chloroprocaine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Chloroprocaine should be given to a pregnant woman only if clearly needed. This does not preclude the use of chloroprocaine at term for the production of obstetrical anesthesia. Labor and Delivery Local anesthetics rapidly cross the placenta, and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity (see CLINICAL PHARMACOLOGY and PHARMACOKINETICS). The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function. Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Epidural, paracervical, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 paracervical block anesthesia was associated with a decrease in the mean duration of first 2 stage labor and facilitation of cervical dilation. However, epidural anesthesia has also 3 been reported to prolong the second stage of labor by removing the parturient’s reflex 4 urge to bear down or by interfering with motor function. The use of obstetrical 5 anesthesia may increase the need for forceps assistance. 6 The use of some local anesthetic drug products during labor and delivery may be 7 followed by diminished muscle strength and tone for the first day or two of life. The 8 long-term significance of these observations is unknown. 9 Careful adherence to recommended dosage is of the utmost importance in 10 obstetrical paracervical block. Failure to achieve adequate analgesia with recommended 11 doses should arouse suspicion of intravascular or fetal intracranial injection. Cases 12 compatible with unintended fetal intracranial injection of local anesthetic injection have 13 been reported following intended paracervical or pudendal block or both. Babies so 14 affected present with unexplained neonatal depression at birth which correlates with high 15 local anesthetic serum levels and usually manifest seizures within six hours. Prompt use 16 of supportivemeasures combined with forced urinary excretion of the local anesthetic has 17 been used successfully to manage this complication. 18 Case reports of maternal convulsions and cardiovascular collapse following use of 19 some local anesthetics for paracervical block in early pregnancy (as anesthesia for 20 elective abortion) suggest that systemic absorption under these circumstances may be 21 rapid. The recommended maximum dose of each drug should not be exceeded. Injection 22 should be made slowly and with frequent aspiration. Allow a 5-minute interval between 23 sides. 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 There are no data concerning use of chloroprocaine for obstetrical paracervical 2 block when toxemia of pregnancy is present or when fetal distress or prematurity is 3 anticipated in advance of the block; such use is, therefore, not recommended. 4 The following information should be considered by clinicians who select 5 chloroprocaine for obstetrical paracervical block anesthesia: 6 1. Fetal bradycardia (generally a heart rate of less than 120 per minute for more than 2 7 minutes) has been noted by electronic monitoring in about 5 to 10 percent of the cases 8 (various studies) where initial total doses of 120 mg to 400 mg of chloroprocaine were 9 employed. The incidence of bradycardia, within this dose range, might not be dose 10 related. 11 2. Fetal acidosis has not been demonstrated by blood gas monitoring around the time of 12 bradycardia or afterwards. These data are limited and generally restricted to non 13 toxemic cases where fetal distress or prematurity was not anticipated in advance of the 14 block. 15 3. No intact chloroprocaine and only trace quantities of a hydrolysis product, 2-chloro-4 16 aminobenzoic acid, have been demonstrated in umbilical cord arterial or venous 17 plasma following properly administered paracervical block with chloroprocaine. 18 4. The role of drug factors and non-drug factors associated with fetal bradycardia 19 following paracervical block are unexplained at this time. 20 Nursing Mothers 21 It is not known whether this drug is excreted in human milk. Because many drugs are 22 excreted in human milk, caution should be exercised when chloroprocaine is 23 administered to a nursing woman. 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Pediatric Use 2 Guidelines for the administration of Nesacaine and Nesacaine-MPF Injections to children 3 are presented in DOSAGE AND ADMINISTRATION. 4 Geriatric Use 5 Clinical studies of Nesacaine and Nesacaine-MPF did not include sufficient numbers of 6 subjects 65 and over to determine whether they respond differently from younger 7 subjects. Other reported clinical experience has not identified differences in responses 8 between the elderly and younger patients. In general, dose selection for an elderly patient 9 should be cautious usually starting at the low end of the dosing range, reflecting the 10 greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant 11 disease or other drug therapy. 12 This drug and its metabolites are known to be substantially excreted by the 13 kidney, and the risk of toxic reactions to this drug may be greater in patients with 14 impaired renal function. Because elderly patients are more likely to have decreased renal 15 function, care should be taken in dose selection and it may be useful to monitor renal 16 function. 17 ADVERSE REACTIONS: 18 Systemic: The most commonly encountered acute adverse experiences that demand 19 immediate countermeasures are related to the central nervous system and the 20 cardiovascular system. These adverse experiences are generally dose related and may 21 result from rapid absorption from the injection site, diminished tolerance, or from 22 unintentional intravascular injection of the local anesthetic solution. In addition to 23 systemic dose-related toxicity, unintentional subarachnoid injection of drug during the 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 intended performance of caudal or lumbar epidural block or nerve blocks near the 2 vertebral column (especially in the head and neck region) may result in underventilation 3 or apnea (“Total Spinal”). Factors influencing plasma protein binding, such as acidosis, 4 systemic diseases that alter protein production, or competition of other drugs for protein 5 binding sites, may diminish individual tolerance. Plasma cholinesterase deficiency may 6 also account for diminished tolerance to ester-type local anesthetics. 7 Central Nervous System Reactions: These are characterized by excitation and/or 8 depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision or tremors may 9 occur, possibly proceeding to convulsions. However, excitement may be transient or 10 absent, with depression being the first manifestation of an adverse reaction. This may 11 quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. 12 The incidence of convulsions associated with the use of local anesthetics varies 13 with the procedure used and the total dose administered. In a survey of studies of 14 epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 15 0.1 percent of local anesthetic administrations. 16 Cardiovascular System Reactions: High doses, or unintended intravascular injection, 17 may lead to high plasma levels and related depression of the myocardium, hypotension, 18 bradycardia, ventricular arrhythmias, and, possibly, cardiac arrest. 19 Allergic: Allergic type reactions are rare and may occur as a result of sensitivity to the 20 local anesthetic or to other formulation ingredients, such as the antimicrobial preservative 21 methylparaben, contained in multiple dose vials. These reactions are characterized by 22 signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal 23 edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 elevated temperature, and possibly, anaphylactoid type symptomatology (including 2 severe hypotension). Cross sensitivity among members of the ester-type local anesthetic 3 group has been reported. The usefulness of screening for sensitivity has not been 4 definitely established. 5 Neurologic: In the practice of caudal or lumbar epidural block, occasional unintentional 6 penetration of the subarachnoid space by the catheter may occur (see PRECAUTIONS). 7 Subsequent adverse observations may depend partially on the amount of drug 8 administered intrathecally. These observations may include spinal block of varying 9 magnitude (including total spinal block), hypotension secondary to spinal block, loss of 10 bladder and bowel control, and loss of perineal sensation and sexual function. 11 Arachnoiditis, persistent motor, sensory and/or autonomic (sphincter control) deficit of 12 some lower spinal segments with slow recovery (several months) or incomplete recovery 13 have been reported in rare instances (see DOSAGE AND ADMINISTRATION 14 discussion of Caudal and Lumbar Epidural Block). Backache and headache have also 15 been noted following lumbar epidural or caudal block. 16 OVERDOSAGE: 17 Acute emergencies from local anesthetics are generally related to high plasma levels 18 encountered during therapeutic use of local anesthetics or to unintended subarachnoid 19 injection of local anesthetic solution (see ADVERSE REACTIONS, WARNINGS and 20 PRECAUTIONS). 21 In mice, the intravenous LD50 of chloroprocaine HCl is 97 mg/kg and the 22 subcutaneous LD50 of chloroprocaine HCl is 950 mg/kg. 23 Management of Local Anesthetic Emergencies: The first consideration is prevention, 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 best accomplished by careful and constant monitoring of cardiovascular and respiratory 2 vital signs and the patient’s state of consciousness after each local anesthetic injection. 3 At the first sign of change, oxygen should be administered. 4 The first step in the management of convulsions, as well as underventilation or 5 apnea due to unintentional subarachnoid injection of drug solution, consists of immediate 6 attention to the maintenance of a patent airway and assisted or controlled ventilation with 7 oxygen and a delivery system capable of permitting immediate positive airway pressure 8 by mask. Immediately after the institution of these ventilatory measures, the adequacy of 9 the circulation should be evaluated, keeping in mind that drugs used to treat convulsions 10 sometimes depress the circulation when administered intravenously. Should convulsions 11 persist despite adequate respiratory support, and if the status of the circulation permits, 12 small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a 13 benzodiazepine (such as diazepam) may be administered intravenously; the clinician 14 should be familiar, prior to the use of anesthetics, with these anticonvulsant drugs. 15 Supportive treatment of circulatory depression may require administration of intravenous 16 fluids and, when appropriate, a vasopressor dictated by the clinical situation (such as 17 ephedrine to enhance myocardial contractile force). 18 If not treated immediately, both convulsions and cardiovascular depression can 19 result in hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. Underventilation 20 or apnea due to unintentional subarachnoid injection of local anesthetic solution may 21 produce these same signs and also lead to cardiac arrest if ventilatory support is not 22 instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative 23 measures should be instituted. Recovery has been reported after prolonged resuscitative 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 efforts. 2 Endotracheal intubation, employing drugs and techniques familiar to the clinician, 3 may be indicated, after initial administration of oxygen by mask, if difficulty is 4 encountered in the maintenance of a patent airway or if prolonged ventilatory support 5 (assisted or controlled) is indicated. 6 DOSAGE AND ADMINISTRATION: 7 Chloroprocaine may be administered as a single injection or continuously through an 8 indwelling catheter. As with all local anesthetics, the dose administered varies with the 9 anesthetic procedure, the vascularity of the tissues, the depth of anesthesia and degree of 10 muscle relaxation required, the duration of anesthesia desired, and the physical condition 11 of the patient. The smallest dose and concentration required to produce the desired result 12 should be used. Dosage should be reduced for children, elderly and debilitated patients 13 and patients with cardiac and/or liver disease. The maximum single recommended doses 14 of chloroprocaine in adults are: without epinephrine, 11 mg/kg, not to exceed a maximum 15 total dose of 800 mg; with epinephrine (1:200,000), 14 mg/kg, not to exceed a maximum 16 total dose of 1000 mg. For specific techniques and procedures, refer to standard 17 textbooks. 18 There have been adverse event reports of chondrolysis in patients receiving intra 19 articular infusions of local anesthetics following arthroscopic and other surgical 20 procedures. Nesacaine is not approved for this use (see WARNINGS and DOSAGE 21 and ADMINISTRATION). 22 Caudal and Lumbar Epidural Block: In order to guard against adverse experiences 23 sometimes noted following unintended penetration of the subarachnoid space, the 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 following procedure modifications are recommended: 2 1. Use an adequate test dose (3 mL of Nesacaine-MPF 3% Injection or 5 mL of 3 Nesacaine-MPF 2% Injection) prior to induction of complete block. This test dose 4 should be repeated if the patient is moved in such a fashion as to have displaced the 5 epidural catheter. Allow adequate time for onset of anesthesia following 6 administration of each test dose. 7 2. Avoid the rapid injection of a large volume of local anesthetic injection through the 8 catheter. Consider fractional doses, when feasible. 9 3. In the event of the known injection of a large volume of local anesthetic injection into 10 the subarachnoid space, after suitable resuscitation and if the catheter is in place, 11 consider attempting the recovery of drug by draining a moderate amount of 12 cerebrospinal fluid (such as 10 mL ) through the epidural catheter. 13 14 As a guide for some routine procedures, suggested doses are given below: 15 1. Infiltration and Peripheral Nerve Block: NESACAINE or NESACAINE-MPF 16 (chloroprocaine HCl Injection, USP) Anesthetic Procedure Solution Concentration % Volume (mL) Total Dose (mg) Mandibular Infraorbital Brachial plexus Digital (without epinephrine) Pudendal Paracervical (see also PRECAUTIONS) 2 2 2 1 2 1 2 – 3 0.5 – 1 30 – 40 3 – 4 10 on each side 3 per each of 4 sites 40 – 60 10 – 20 600 – 800 30 – 40 400 up to 120 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 2. Caudal and Lumbar Epidural Block: NESACAINE-MPF INJECTION. 2 For caudal anesthesia, the initial dose is 15 to 25 mL of a 2% or 3% solution. 3 Repeated doses may be given at 40 to 60 minute intervals. 4 For lumbar epidural anesthesia, 2 to 2.5 mL per segment of a 2% or 3% solution can 5 be used. The usual total volume of Nesacaine-MPF Injection is from 15 to 25 mL. 6 Repeated doses 2 to 6 mL less than the original dose may be given at 40 to 50 minute 7 intervals. 8 The above dosages are recommended as a guide for use in the average adult. 9 Maximum dosages of all local anesthetics must be individualized after evaluating the size 10 and physical condition of the patient and the rate of systemic absorption from a particular 11 injection site. 12 Pediatric Dosage: It is difficult to recommend a maximum dose of any drug for children, 13 since this varies as a function of age and weight. For children over 3 years of age who 14 have a normal lean body mass and normal body development, the maximum dose is 15 determined by the child’s age and weight and should not exceed 11 mg/kg (5 mg/lb). For 16 example, in a child of 5 years weighing 50 lbs (23 kg), the dose of chloroprocaine HCl 17 without epinephrine would be 250 mg. Concentrations of 0.5–1% are suggested for 18 infiltration and 1–1.5% for nerve block. In order to guard against systemic toxicity, the 19 lowest effective concentration and lowest effective dose should be used at all times. 20 Some of the lower concentrations for use in infants and smaller children are not available 21 in prepackaged containers; it will be necessary to dilute available concentrations with the 22 amount of 0.9% sodium chloride injection necessary to obtain the required final 23 concentration of chloroprocaine injection. 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Preparation of Epinephrine Injections—To prepare a 1:200,000 epinephrine 2 chloroprocaine HCl injection, add 0.1 mL of a 1 to 1000 Epinephrine Injection USP to 20 3 mL of Nesacaine-MPF Injection. 4 Chloroprocaine is incompatible with caustic alkalis and their carbonates, soaps, 5 silver salts, iodine and iodides. 6 Parenteral drug products should be inspected visually for particulate matter and 7 discoloration prior to administration, whenever injection and container permit. As with 8 other anesthetics having a free aromatic amino group, Nesacaine and Nesacaine-MPF 9 Injections are slightly photosensitive and may become discolored after prolonged 10 exposure to light. It is recommended that these vials be stored in the original outer 11 containers, protected from direct sunlight. Discolored injection should not be 12 administered. If exposed to low temperatures, Nesacaine and Nesacaine-MPF Injections 13 may deposit crystals of chloroprocaine HCl which will redissolve with shaking when 14 returned to room temperature. The product should not be used if it contains undissolved 15 (eg, particulate) material. 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 HOW SUPPLIED: 2 NESACAINE (chloroprocaine HCl Injection, USP) with preservatives is supplied as follows: Product No. NDC No. Strength 470530 63323-475-30 1% (10 mg/mL) 470630 63323-476-30 2% (20 mg/mL) 3 4 NESACAINE-MPF (chloroprocaine HCl Injection, USP) without preservatives and without 5 EDTA is supplied as follows: Product No. NDC No. Strength 470720 63323-477-20 2% (20 mg/mL) 470820 63323-478-20 3% (30 mg/mL) 6 7 Vial size 30 mL multiple dose vial packaged individually. 30 mL multiple dose vial packaged individually. Vial size 20 mL single dose vial packaged individually. 20 mL single dose vial packaged individually. Keep from freezing. Protect from light. Store at 20° to 25°C (68° to 77°F) [see USP Controlled 8 Room Temperature]. 9 All trademarks are the property of APP Pharmaceuticals, LLC. 10 Manufactured for: 12 451109C/Revised: February 2010 Company logo 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:40.559646	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/009435s035s036lbl.pdf', 'application_number': 9435, 'submission_type': 'SUPPL ', 'submission_number': 35}
10,731	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:40.565743	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/15193s18lbl.pdf', 'application_number': 9829, 'submission_type': 'SUPPL ', 'submission_number': 9}
10,733	Solu-Cortef® (hydrocortisone sodium succinate for injection, USP) NOT FOR USE IN NEONATES CONTAINS BENZYL ALCOHOL For Intravenous or Intramuscular Administration DESCRIPTION SOLU-CORTEF Sterile Powder is an anti-inflammatory glucocorticoid, which contains hydrocortisone sodium succinate as the active ingredient. SOLU-CORTEF Sterile Powder is available in several packages for intravenous or intramuscular administration. 100 mg Plain-Vials containing hydrocortisone sodium succinate equivalent to 100 mg hydrocortisone, also 0.8 mg monobasic sodium phosphate anhydrous, 8.73 mg dibasic sodium phosphate dried. ACT-O-VIAL & System (Single-Dose Vial) in four strengths: 100 mg 250 mg 500 mg 1000 mg ACT-0-VIAL ACT-0-VIAL ACT-0-VIAL ACT-0-VIAL Each 2 mL Each 2 mL Each 4 mL Each 8 mL contains: contains: contains: contains: (when mixed) (when mixed) (when mixed) (when mixed) Hydrocortisone equiv. to equiv. to equiv. to equiv. to sodium succinate 100 mg 250 mg 500 mg 1000 mg hydrocortisone hydrocortisone hydrocortisone hydrocortisone Monobasic sodium 0.8 mg 2 mg 4 mg 8 mg phosphate anhydrous Dibasic sodium 8.76 mg 21.8 mg 44 mg 87.32 mg phosphate dried Benzyl alcohol 18.1 mg 16.4 mg 33.4 mg 66.9 mg added as preservative When necessary, the pH of each formula was adjusted with sodium hydroxide so that the pH of the reconstituted solution is within the USP specified range of 7 to 8. The chemical name for hydrocortisone sodium succinate is pregn-4-ene-3,20-dione,21-(3carboxy-l oxopropoxy)-11,17-dihydroxy-, monosodium salt, (11β)-, and its molecular weight is 484.51. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 009866/S-077, S-079 Package Insert Page2 The structural formula is represented below: chemical structure Hydrocortisone sodium succinate is a white or nearly white, odorless, hygroscopic amorphous solid. It is very soluble in water and in alcohol, very slightly soluble in acetone and insoluble in chloroform. CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their anti-inflammatory effects in disorders of many organ systems. Hydrocortisone sodium succinate has the same metabolic and anti-inflammatory actions as hydrocortisone. When given parenterally and in equimolar quantities, the two compounds are equivalent in biologic activity. The highly water-soluble sodium succinate ester of hydrocortisone permits the immediate intravenous administration of high doses of hydrocortisone in a small volume of diluent and is particularly useful where high blood levels of hydrocortisone are required rapidly. Following the intravenous injection of hydrocortisone sodium succinate, demonstrable effects are evident within one hour and persist for a variable period. Excretion of the administered dose is nearly complete within 12 hours. Thus, if constantly high blood levels are required, injections should be made every 4 to 6 hours. This preparation is also rapidly absorbed when administered intramuscularly and is excreted in a pattern similar to that observed after intravenous injection. Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body’s immune response to diverse stimuli. INDICATIONS AND USAGE When oral therapy is not feasible, and the strength, dosage form, and route of administration of the drug reasonably lend the preparation to the treatment of the condition, the intravenous or intramuscular use of SOLU-CORTEF Sterile Powder is indicated as follows: Allergic states: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 009866/S-077, S-079 Package Insert Page3 Dermatologic diseases: Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome). Endocrine disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance), congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative thyroiditis. Gastrointestinal diseases: To tide the patient over a critical period of the disease in regional enteritis (systemic therapy) and ulcerative colitis. Hematologic disorders: Acquired (autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia (Diamond-Blackfan anemia), idiopathic thrombocytopenic purpura in adults (intravenous administration only; intramuscular administration is contraindicated), pure red cell aplasia, selected cases of secondary thrombocytopenia. Miscellaneous: Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy. Neoplastic diseases: For the palliative management of leukemias and lymphomas. Nervous System: Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor, or craniotomy. Ophthalmic diseases: Sympathetic ophthalmia, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids. Renal diseases: To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus. Respiratory diseases: Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis. Rheumatic disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, temporal arteritis, polymyositis, and systemic lupus erythematosus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 009866/S-077, S-079 Package Insert Page4 CONTRAINDICATIONS SOLU-CORTEF Sterile Powder is contraindicated in patients with known hypersensitivity to the product and its constituents. Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. SOLU-CORTEF Sterile Powder is contraindicated for use in premature infants because the formulation contains benzyl alcohol. (See WARNINGS and PRECAUTIONS:Pediatric Use) SOLU-CORTEF Sterile Powder is contraindicated for intrathecal administration. Reports of severe medical events have been associated with this route of administration. WARNINGS General: This product contains benzyl alcohol which is potentially toxic when administered locally to neural tissue. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see WARNINGS and PRECAUTIONS: Pediatric Use) Injection of Solu-Cortef may result in dermal and/or subdermal changes forming depressions in the skin at the injection site. In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Injection into the deltoid muscle should be avoided because of a high incidence of subcutaneous atrophy. Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS). Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, and after the stressful situation. Results from one multicenter, randomized, placebo controlled study with methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of systemic corticosteroids, including Solu-Cortef, should not be used for the treatment of traumatic brain injury. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 009866/S-077, S-079 Package Insert Page5 Cardio-renal: Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. Endocrine: Hypothalamic-pituitary adrenal (HPA) axis suppression. Cushing’s syndrome, and hyperglycemia. Monitor patients for these conditions with chronic use. Corticosteroids can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Drug induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Infections General: Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild, but can be severe and at times fatal. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteriods may also mask some signs of current infection. Do not use intra-articularly, intrabursally or for intratendinous administration for local effect in the presence of acute local infection. Fungal infections: Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions, Amphotericin B injection and potassium-depleting agents). Special pathogens: Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococus, Mycobacterium, Nocardia, Pneumocystis, Toxoplasma. It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 009866/S-077, S-079 Package Insert Page6 Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. Corticosteroids should not be used in cerebral malaria. There is currently no evidence of benefit from steroids in this condition. Tuberculosis: The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. Vaccination: Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines can not be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison’s disease. Viral infections: Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents should be considered. Neurologic: Reports of severe medical events have been associated with the intrathecal route of administration (see ADVERSE REACTIONS, Neurologic/Psychiatric). Ophthalmic: Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should be used cautiously in patients with ocular herpes simplex because of corneal perforation. Corticosteroids should not be used in active ocular herpes simplex. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 009866/S-077, S-079 Package Insert Page7 PRECAUTIONS General: This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. The lowest possible dose of corticosteroid should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual. Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement. Cardio-renal: As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency. Endocrine: Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage. Gastrointestinal: Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect due to increased metabolism of corticosteroids in patients with cirrhosis. Musculoskeletal: Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy. Local injection of a steroid into a previously infected site is not usually recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 009866/S-077, S-079 Package Insert Page8 Neurologic-psychiatric: Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. (See DOSAGE AND ADMINISTRATION.) An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Ophthalmic: Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored. Information for Patients: Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay. Drug Interactions: Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered concomitantly with potassium-depleting agents (i.e., amphotericin-B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance. (see DRUG INTERACTIONS, Hepatic Enzyme Inhibitors) Anticholinesterases: Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 009866/S-077, S-079 Package Insert Page9 Anticoagulants, oral: Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Cholestyramine: Cholestyramine may increase the clearance of corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin): Drugs which induce cytochrome P450 3A4 enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Hepatic Enzyme Inhibitors (e.g., ketoconazole, macrolide antibiotics such as erythromycin and troleandomycin): Drugs which inhibit cytochrome P450 3A4 have the potential to result in increased plasma concentrations of corticosteroids. Ketoconazole: Ketoconazole has been reported to significantly decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Nonsteroidal anti-inflammatory agents (NSAIDS): Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. Skin tests: Corticosteroids may suppress reactions to skin tests. Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS, Infections, Vaccination). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 009866/S-077, S-079 Package Insert Page10 Carcinogenesis, Mutagenesis, Impairment of Fertility: No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy: Teratogenic effects: Pregnancy Category C. Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. Nursing Mothers: Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to continue nursing, or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: This product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (>2 years of age), and aggressive lymphomas and leukemias (>1 month of age). Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are based on adequate and well- controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 009866/S-077, S-079 Package Insert Page11 The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use: Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS The following adverse reactions have been reported with Solu-Cortef or other corticosteroids: Allergic reactions: allergic or hypersensitivity reactions, anaphylactoid reaction, anaphylaxis, angioedema. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic: Acne, allergic dermatitis, burning or tingling (especially in the perineal area, after intravenous injection), cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 009866/S-077, S-079 Package Insert Page12 Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic: Negative nitrogen balance due to protein catabolism. Musculoskeletal: Aseptic necrosis of femoral and humeral heads, Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration (see WARNINGS, Neurologic). Ophthalmic: Exophthalmoses, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections. Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, injection site infections following non-sterile administration (see WARNINGS), malaise, moon face, weight gain. OVERDOSAGE Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. DOSAGE AND ADMINISTRATION NOTE: CONTAINS BENZYL ALCOHOL (see WARNINGS and PRECAUTIONS: Pediatric Use) Because of possible physical incompatibilities, Solu-Cortef should not be diluted or mixed with other solutions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. This preparation may be administered by intravenous injection, by intravenous infusion, or by intramuscular injection, the preferred method for initial emergency use being intravenous injection. Following the initial emergency period, consideration should be given to employing a longer acting injectable preparation or an oral preparation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 009866/S-077, S-079 Package Insert Page13 Therapy is initiated by administering SOLU-CORTEF Sterile Powder intravenously over a period of 30 seconds (e.g., 100 mg) to 10 minutes (e.g., 500 mg or more). In general, high dose corticosteroid therapy should be continued only until the patient’s condition has stabilized-usually not beyond 48 to 72 hours. When high dose hydrocortisone therapy must be continued beyond 48-72 hours, hypernatremia may occur. Under such circumstances it may be desirable to replace SOLU-CORTEF with a corticoid such as methylprednisolone sodium succinate which causes little or no sodium retention. The initial dose of SOLU-CORTEF Sterile Powder is 100 mg to 500 mg, depending on the specific disease entity being treated. However, in certain overwhelming, acute, life-threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages. This dose may be repeated at intervals of 2, 4 or 6 hours as indicated by the patient’s response and clinical condition. It Should Be Emphasized that Dosage Requirements are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage that maintains an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient’s condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly. In the treatment of acute exacerbations of multiple sclerosis, daily doses of 800 mg of hydrocortisone for a week followed by 320 mg every other day for one month are recommended (see PRECAUTIONS, Neuro-psychiatric). In pediatric patients, the initial dose of hydrocortisone may vary depending on the specific disease entity being treated. The range of initial doses is 0.56 to 8 mg/kg/day in three or four divided doses (20 to 240 mg/m 2bsa/day). For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids: Cortisone, 25 Triamcinolone, 4 Hydrocortisone, 20 Paramethasone, 2 Prednisolone, 5 Betamethasone, 0.75 Prednisone, 5 Dexamethasone, 0.75 Methylprednisolone, 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 009866/S-077, S-079 Package Insert Page14 These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered. Preparation of Solutions 100 mg Plain-For intravenous or intramuscular injection, prepare solution by aseptically adding not more than 2 mL of Bacteriostatic Water for Injection or Bacteriostatic Sodium Chloride Injection to the contents of one vial. For intravenous infusion, first prepare solution by adding not more than 2 mL of Bacteriostatic Water for Injection to the vial; this solution may then be added to 100 to 1000 mL of the following: 5% dextrose in water (or isotonic saline solution or 5% dextrose in isotonic saline solution if patient is not on sodium restriction). DIRECTIONS FOR USING THE ACT-O-VIAL SYSTEM 1 Press down on plastic activator to force diluent into the lower compartment. 2 Gently agitate to effect solution. 3 Remove plastic tab covering center of stopper. 4 Sterilize top of stopper with a suitable germicide. 5 Insert needle squarely through center of stopper until tip is just visible. Invert vial and withdraw dose. Further dilution is not necessary for intravenous or intramuscular injection. For intravenous infusion, first prepare solution as just described. The 100 mg solution may then be added to 100 to 1000 mL of 5% dextrose in water (or isotonic saline solution or 5% dextrose in isotonic saline solution if patient is not on sodium restriction). The 250 mg solution may be added to 250 to 1000 mL, the 500 mg solution may be added to 500 to 1000 mL and the 1000 mg solution to 1000 mL of the same diluents. In cases where administration of a small volume of fluid is desirable, 100 mg to 3000 mg of SOLU CORTEF may be added to 50 mL of the above diluents. The resulting solutions are stable for at least 4 hours and may be administered either directly or by IV piggyback. When reconstituted as directed, pH’s of the solutions range from 7 to 8 and the tonicities are: 100 mg ACT-0-VIAL, .36 osmolar; 250 mg ACT-O-VIAL, 500 mg ACT-O-VIAL, and the 1000 mg ACT-0 VIAL, .57 osmolar. (Isotonic saline-.28 osmolar.) HOW SUPPLIED SOLU-CORTEF Sterile Powder is available in the following packages: 100 mg Plain-NDC 0009-0825-01 100 mg ACT-0-VIAL (Single-Dose Vial) 2 mL-NDC 0009-0900-13 25 x 2 mL-NDC 0009-0900-20 250 mg ACT-O-VIAL (Single-Dose Vial) 2 mL-NDC 0009-0909-08 25 x 2 mL-NDC 0009-0909-16 500 mg ACT-O-VIAL (Single-Dose Vial)-NDC 0009-0912-05 1000 mg ACT-O-VIAL (Single-Dose Vial)-NDC 0009-0920-03 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 009866/S-077, S-079 Package Insert Page15 STORAGE CONDITIONS Store unreconstituted product at controlled room temperature 20° to 25( C (68° to 77( F). Store solution at controlled room temperature 20° to 25( C (68° to 77( F) and protect from light. Use solution only if it is clear. Unused solution should be discarded after 3 days. Rx only. Pharmacia & Upjohn Kalamazoo, Michigan 49001, USA Revised This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:40.647241	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/009866s77s79lbl.pdf', 'application_number': 9866, 'submission_type': 'SUPPL ', 'submission_number': 79}
10,734	SOLU-CORTEF® (hydrocortisone sodium succinate for injection, USP) For Intravenous or Intramuscular Administration DESCRIPTION SOLU-CORTEF Sterile Powder is an anti-inflammatory glucocorticoid, which contains hydrocortisone sodium succinate as the active ingredient. SOLU-CORTEF Sterile Powder is available in several packages for intravenous or intramuscular administration. 100 mg Plain—Vials containing hydrocortisone sodium succinate equivalent to 100 mg hydrocortisone, also 0.8 mg monobasic sodium phosphate anhydrous, 8.73 mg dibasic sodium phosphate dried. SOLU-CORTEF 100 mg plain does not contain diluent (see DOSAGE AND ADMINISTRATION, Preparation of Solutions). ACT-O-VIAL® System (Single-Dose Vial) in four strengths: 100 mg 250 mg 500 mg 1000 mg ACT-O-VIAL ACT-O-VIAL ACT-O-VIAL ACT-O-VIAL Each 2 mL Each 2 mL Each 4 mL Each 8 mL contains: contains: contains: contains: (when mixed) (when mixed) (when mixed) (when mixed) Hydrocortisone equiv. to equiv. to equiv. to equiv. to sodium succinate 100 mg 250 mg 500 mg 1000 mg Hydrocor- Hydrocor- Hydrocor- Hydrocor- tisone tisone tisone tisone Monobasic sodium phosphate anhydrous 0.8 mg 2 mg 4 mg 8 mg Dibasic sodium phosphate dried 8.73 mg 21.8 mg 44 mg 87.32 mg When necessary, the pH of each formula was adjusted with sodium hydroxide so that the pH of the reconstituted solution is within the USP specified range of 7 to 8. The chemical name for hydrocortisone sodium succinate is pregn-4-ene-3,20-dione,21 (3-carboxy-1-oxopropoxy)-11,17-dihydroxy-, monosodium salt, (11β)- and its molecular weight is 484.52. The structural formula is represented below: 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula Hydrocortisone sodium succinate is a white or nearly white, odorless, hygroscopic amorphous solid. It is very soluble in water and in alcohol, very slightly soluble in acetone and insoluble in chloroform. CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt- retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their anti-inflammatory effects in disorders of many organ systems. Hydrocortisone sodium succinate has the same metabolic and anti-inflammatory actions as hydrocortisone. When given parenterally and in equimolar quantities, the two compounds are equivalent in biologic activity. The highly water-soluble sodium succinate ester of hydrocortisone permits the immediate intravenous administration of high doses of hydrocortisone in a small volume of diluent and is particularly useful where high blood levels of hydrocortisone are required rapidly. Following the intravenous injection of hydrocortisone sodium succinate, demonstrable effects are evident within one hour and persist for a variable period. Excretion of the administered dose is nearly complete within 12 hours. Thus, if constantly high blood levels are required, injections should be made every 4 to 6 hours. This preparation is also rapidly absorbed when administered intramuscularly and is excreted in a pattern similar to that observed after intravenous injection. Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune response to diverse stimuli. INDICATIONS AND USAGE When oral therapy is not feasible, and the strength, dosage form, and route of administration of the drug reasonably lend the preparation to the treatment of the condition, the intravenous or intramuscular use of SOLU-CORTEF Sterile Powder is indicated as follows: 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Allergic states: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions. Dermatologic diseases: Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome). Endocrine disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance), congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative thyroiditis. Gastrointestinal diseases: To tide the patient over a critical period of the disease in regional enteritis (systemic therapy) and ulcerative colitis. Hematologic disorders: Acquired (autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia (Diamond-Blackfan anemia), idiopathic thrombocytopenic purpura in adults (intravenous administration only; intramuscular administration is contraindicated), pure red cell aplasia, selected cases of secondary thrombocytopenia. Miscellaneous: Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy. Neoplastic diseases: For the palliative management of leukemias and lymphomas. Nervous System: Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor, or craniotomy. Ophthalmic diseases: Sympathetic ophthalmia, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids. Renal diseases: To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus. Respiratory diseases: Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis. Rheumatic disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, temporal arteritis, polymyositis, and systemic lupus erythematosus. CONTRAINDICATIONS SOLU-CORTEF Sterile Powder is contraindicated in systemic fungal infections and patients with known hypersensitivity to the product and its constituents. Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. SOLU-CORTEF Sterile Powder is contraindicated for intrathecal administration. Reports of severe medical events have been associated with this route of administration. WARNINGS General: Injection of SOLU-CORTEF may result in dermal and/or subdermal changes forming depressions in the skin at the injection site. In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Injection into the deltoid muscle should be avoided because of a high incidence of subcutaneous atrophy. Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS). Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, and after the stressful situation. Results from one multicenter, randomized, placebo controlled study with methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of systemic corticosteroids, including SOLU-CORTEF, should not be used for the treatment of traumatic brain injury. Cardio-renal: Average and large doses of corticosteriods can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Literature reports suggest an apparent association between use of corticosteriods and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteriods should be used with great caution in these patients. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Endocrine: Hypothalamic-pituitary adrenal (HPA) axis suppression. Cushing’s syndrome, and hyperglycemia. Monitor patients for these conditions with chronic use. Corticosteroids can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Drug induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Infections General: Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild, but can be severe and at times fatal. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteriods may also mask some signs of current infection. Do not use intra articularly, intrabursally or for intratendinous administration for local effect in the presence of acute local infection. Fungal infections: Corticosteriods may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions, Amphotericin B injection and potassium-depleting agents). Special pathogens: Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococus, Mycobacterium, Nocardia, Pneumocystis, Toxoplasma. It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea. Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid- induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Corticosteriods should not be used in cerebral malaria. There is currently no evidence of benefit from steroids in this condition. Tuberculosis: The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. Vaccination: Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteriods as replacement therapy, e.g., for Addison’s disease. Viral infections: Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents should be considered. Neurologic: Reports of severe medical events have been associated with the intrathecal route of administration (see ADVERSE REACTIONS, Neurologic/Psychiatric). Ophthalmic: Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should be used cautiously in patients with ocular herpes simplex because of corneal perforation. Corticosteroids should not be used in active ocular herpes simplex. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General: The lowest possible dose of corticosteroid should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual. Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement. Cardio-renal: As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency. Endocrine: Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage. Gastrointestinal: Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteriods may be minimal or absent. There is an enhanced effect due to increased metabolism of corticosteriods in patients with cirrhosis. Musculoskeletal: Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy. Local injection of a steroid into a previously infected site is not usually recommended. Neurologic-psychiatric: Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. (See DOSAGE AND ADMINISTRATION.) An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Ophthalmic: Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored. Information for Patients: Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay. Drug Interactions: Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered concomitantly with potassium-depleting agents (i.e., amphotericin-B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance (see Drug Interactions, Hepatic Enzyme Inhibitors). Anticholinesterases: Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. Anticoagulants, oral: Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Cholestyramine: Cholestyramine may increase the clearance of corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin): Drugs which induce cytochrome P450 3A4 enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Hepatic Enzyme Inhibitors (e.g., ketoconazole, macrolide antibiotics such as erythromycin and troleandomycin): Drugs which inhibit cytochrome P450 3A4 have the potential to result in increased plasma concentrations of corticosteroids. Ketoconazole: Ketoconazole has been reported to significantly decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Nonsteroidal anti-inflammatory agents (NSAIDS): Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. Skin tests: Corticosteroids may suppress reactions to skin tests. Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS, Infections, Vaccination). Carcinogenesis, Mutagenesis, Impairment of Fertility: No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy: Teratogenic effects: Pregnancy Category C. Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. Nursing Mothers: Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to continue nursing, or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (>2 years of age), and aggressive lymphomas and leukemias (>1 month of age). Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are based on adequate and well- controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use: Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS The following adverse reactions have been reported with SOLU-CORTEF or other corticosteriods: Allergic reactions: Allergic or hypersensitivity reactions, anaphylactoid reaction, anaphylaxis, angioedema. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic: Acne, allergic dermatitis, burning or tingling (especially in the perineal area, after intravenous injection), cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients. Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic: Negative nitrogen balance due to protein catabolism. Musculoskeletal: Aseptic necrosis of femoral and humeral heads, Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration (see WARNINGS, Neurologic). Ophthalmic: Exophthalmoses, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections. Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, injection site infections following non- sterile administration (see WARNINGS), malaise, moon face, weight gain. OVERDOSAGE Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION Because of possible physical incompatibilities, SOLU-CORTEF should not be diluted or mixed with other solutions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. This preparation may be administered by intravenous injection, by intravenous infusion, or by intramuscular injection, the preferred method for initial emergency use being intravenous injection. Following the initial emergency period, consideration should be given to employing a longer acting injectable preparation or an oral preparation. Therapy is initiated by administering SOLU-CORTEF Sterile Powder intravenously over a period of 30 seconds (e.g., 100 mg) to 10 minutes (e.g., 500 mg or more). In general, high dose corticosteroid therapy should be continued only until the patient’s condition has stabilized-usually not beyond 48 to 72 hours. When high dose hydrocortisone therapy must be continued beyond 48–72 hours, hypernatremia may occur. Under such circumstances it may be desirable to replace SOLU-CORTEF with a corticoid such as methylprednisolone sodium succinate which causes little or no sodium retention. The initial dose of SOLU-CORTEF Sterile Powder is 100 mg to 500 mg, depending on the specific disease entity being treated. However, in certain overwhelming, acute, life- threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages. This dose may be repeated at intervals of 2, 4 or 6 hours as indicated by the patient’s response and clinical condition. It Should Be Emphasized that Dosage Requirements are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage that maintains an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient’s condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly. In the treatment of acute exacerbations of multiple sclerosis, daily doses of 800 mg of hydrocortisone for a week followed by 320 mg every other day for one month are recommended (see PRECAUTIONS, Neuro-psychiatric). 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In pediatric patients, the initial dose of hydrocortisone may vary depending on the specific disease entity being treated. The range of initial doses is 0.56 to 8 mg/kg/day in three or four divided doses (20 to 240 mg/m2bsa/day). For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids: Cortisone, 25 Triamcinolone, 4 Hydrocortisone, 20 Paramethasone, 2 Prednisolone, 5 Betamethasone, 0.75 Prednisone, 5 Dexamethasone, 0.75 Methylprednisolone, 4 These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives intramuscularly or into joint spaces, their relative properties may be greatly altered. Preparation of Solutions: 100 mg Plain-For intravenous or intramuscular injection, prepare solution by aseptically adding not more than 2 mL of Bacteriostatic Water for Injection or Bacteriostatic Sodium Chloride Injection to the contents of one vial. For intravenous infusion, first prepare solution by adding not more than 2 mL of Bacteriostatic Water for Injection to the vial; this solution may then be added to 100 to 1000 mL of the following: 5% dextrose in water (or isotonic saline solution or 5% dextrose in isotonic saline solution if patient is not on sodium restriction). This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. DIRECTIONS FOR USING THE ACT-O-VIAL SYSTEM 1. Press down on plastic activator to force diluent into the lower compartment. 2. Gently agitate to effect solution. 3. Remove plastic tab covering center of stopper. 4. Sterilize top of stopper with a suitable germicide. 5. Insert needle squarely through center of stopper until tip is just visible. Invert vial and withdraw dose. usage illustration Further dilution is not necessary for intravenous or intramuscular injection. For intravenous infusion, first prepare solution as just described. The 100 mg solution may then be added to 100 to 1000 mL of 5% dextrose in water (or isotonic saline solution or 5% dextrose in isotonic saline solution if patient is not on sodium restriction). The 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 250 mg solution may be added to 250 to 1000 mL, the 500 mg solution may be added to 500 to 1000 mL and the 1000 mg solution to 1000 mL of the same diluents. In cases where administration of a small volume of fluid is desirable, 100 mg to 3000 mg of SOLU-CORTEF may be added to 50 mL of the above diluents. The resulting solutions are stable for at least 4 hours and may be administered either directly or by IV piggyback. When reconstituted as directed, pH’s of the solutions range from 7 to 8 and the tonicities are: 100 mg ACT-O-VIAL, .36 osmolar; 250 mg ACT-O-VIAL, 500 mg ACT-O-VIAL, and the 1000 mg ACT-O-VIAL, .57 osmolar. (Isotonic saline=.28 osmolar.) HOW SUPPLIED SOLU-CORTEF Sterile Powder is available in the following packages: 100 mg Plain—NDC 0009-0825-01 100 mg ACT-O-VIAL (Single-Dose Vial) 250 mg ACT-O-VIAL (Single-Dose Vial) 2 mL—NDC 0009-0011-03 2 mL—NDC 0009-0013-05 25 x 2 mL—NDC 0009-0011-04 25 x 2 mL—NDC 0009-0013-06 500 mg ACT-O-VIAL (Single-Dose Vial)—NDC 0009-0016-12 1000 mg ACT-O-VIAL (Single-Dose Vial)—NDC 0009-0005-01 STORAGE CONDITIONS Store unreconstituted product at controlled room temperature 20° to 25°C (68° to 77°F). Store solution at controlled room temperature 20° to 25°C (68° to 77°F) and protect from light. Use solution only if it is clear. Unused solution should be discarded after 3 days. Rx only Company logo LAB-0424-1.0 April 2010 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:40.726438	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/009866s080lbl.pdf', 'application_number': 9866, 'submission_type': 'SUPPL ', 'submission_number': 80}
10,735	NDA 10-040; CYSTOGRAFIN ® (Diatrizoate Meglumine Injection USP 30%) CYSTOGRAFIN_PI_(Patheon-CL64A03) CLEAN_Rev June 2015 company logo Bracco Diagnostics CL64A03 - 000000 CYSTOGRAFIN® Diatrizoate Meglumine Injection USP 30% For retrograde cystourethrography Not intended for intravascular injection DESCRIPTION Cystografin is a radiopaque contrast agent supplied as a sterile, clear, colorless to pale yellow, mobile or slightly viscous solution. Each mL provides 300 mg diatrizoate meglumine with 0.4 mg edetate disodium as a sequestering agent. Each mL of solution also contains approximately 141 mg organically bound iodine. At the time of manufacture, the air in the container is replaced by nitrogen. The preparation should be protected from strong light. INDICATION Cystografin is indicated for retrograde cystourethrography. CONTRAINDICATIONS This preparation is contraindicated in patients with a hypersensitivity to salts of diatrizoic acid. WARNINGS Severe sensitivity reactions are more likely to occur in patients with a personal or family history of bronchial asthma, significant allergies, or previous reactions to contrast agents. A history of sensitivity to iodine per se or to other contrast agents is not an absolute contraindication to the use of diatrizoate meglumine, but calls for extreme caution in administration. PRECAUTIONS Safe and effective use of this preparation depends upon proper dosage, correct technique, adequate precautions, and readiness for emergencies. Retrograde cystourethrography should be performed with caution in patients with a known active infectious process of the urinary tract. Sterile technique should be employed in administration. During administration, care should be taken to avoid excessive pressure, rapid or acute distention of the bladder, and trauma. Contrast agents may interfere with some chemical determinations made on urine specimens; therefore, urine should be collected before administration of the contrast medium or two or more days afterwards. Pregnancy—Teratogenic Effects: Pregnancy Category C Animal reproduction studies have not been conducted with diatrizoate meglumine injection. It is also not known whether diatrizoate meglumine injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Cystografin should be administered to a pregnant woman only if clearly needed. Reference ID: 3788310 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS Retrograde genitourinary procedures may cause such complications as hematuria, perforation of the urethra or bladder, introduction of infection into the genitourinary tract, and oliguria or anuria. If intravasation of this drug occurs, the reactions which may be associated with intravenous administration may possibly be encountered. Hypersensitivity or anaphylactoid reactions may occur. Severe reactions may be manifested by edema of the face and glottis, respiratory distress, convulsions or shock; such reactions may prove fatal unless promptly controlled by such emergency measures as maintenance of a clear airway and immediate use of oxygen and resuscitative drugs. Thyroid function tests indicative of hypothyroidism or transient thyroid suppression have been uncommonly reported following iodinated contrast media administration to adult and pediatric patients, including infants. Some patients were treated for hypothyroidism. DOSAGE AND ADMINISTRATION Preparation of the patient: Appropriate preparation is desirable for optimal results. A laxative the night before the examination and a low residue diet the day before the procedure are recommended. Dosage: The dose for retrograde use in cystography and voiding cystourethrography ranges from 25 to 300 mL depending on the age of the patient and the degree of bladder irritability; amounts greater than 300 mL may be used if the bladder capacity allows. Best results are obtained when the bladder is filled with the contrast agent. If desired, the preparation may be diluted with sterile water or sterile saline as indicated in the table below. Administration: After sterile catheterization, the bladder should be filled to capacity with Cystografin using a suitable sterile administration set. Care should be taken to avoid using excessive pressure. The presence of bladder discomfort or reflux and/or spontaneous voiding usually indicates that the bladder is full. Radiography: The commonly employed radiographic techniques should be used. A scout film is recommended before the contrast agent is administered. Dilution Table USE DILUTED SOLUTIONS IMMEDIATELY 100 mL Bottle Sterile Water or Sterile Saline % Diatrizoate Meglumine % Organically Bound Iodine Total Added w/v w/v Volume 0 mL 30.0 14.1 100 mL 25 mL 24.0 11.3 125 mL 50 mL 20.0 9.4 150 mL 67 mL 18.0 8.5 167 mL 300 mL Bottle Sterile Water or Sterile Saline Added 0 mL 30.0 14.1 300 mL 50 mL 25.7 12.1 350 mL Reference ID: 3788310 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED Cystografin (Diatrizoate Meglumine Injection USP 30%) is available in 200 mL and 400 mL bottles containing 100 mL and 300 mL of Cystografin respectively with sufficient capacity for dilution up to 167 mL and 350 mL respectively. Storage Store at 20-25°C (68-77°F) [See USP]. Protect from light. Also Available Cystografin Dilute (Diatrizoate Meglumine Injection USP 18%) is also available, as a 300 mL fill in a 400 mL bottle. Rx only Manufactured for Bracco Diagnostics Inc. Monroe Township, NJ 08831 by Patheon Italia S.p.A. 03013 Ferentino (Italy) Revised June 2015 CL64A03 - 000000 Reference ID: 3788310 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-040; CYSTOGRAFIN ® (Diatrizoate Meglumine Injection USP 30%) CYSTOGRAFIN DILUTE_PI_(Patheon-CL64B03) CLEAN_Rev June 2015 company logo Bracco Diagnostics CL64B03 - 000000 CYSTOGRAFIN® DILUTE Diatrizoate Meglumine Injection USP 18% For retrograde cystourethrography Not intended for intravascular injection DESCRIPTION Cystografin Dilute (Diatrizoate Meglumine Injection USP 18%) is a radiopaque contrast agent supplied as a sterile, aqueous solution. Each mL provides 180 mg diatrizoate meglumine with 0.4 mg edetate disodium as a sequestering agent. Each mL of solution also contains approximately 85 mg organically bound iodine. At the time of manufacture, the air in the container is replaced by nitrogen. INDICATION Cystografin Dilute is indicated for retrograde cystourethrography. CONTRAINDICATIONS This preparation is contraindicated in patients with a hypersensitivity to salts of diatrizoic acid. WARNINGS Severe sensitivity reactions are more likely to occur in patients with a personaI or family history of bronchial asthma, significant allergies, or previous reactions to contrast agents. A history of sensitivity to iodine per se or to other contrast agents is not an absolute contraindication to the use of diatrizoate meglumine, but calls for extreme caution in administration. PRECAUTIONS Safe and effective use of this preparation depends upon proper dosage, correct technique, adequate precautions, and readiness for emergencies. Retrograde cystourethrography should be performed with caution in patients with a known active infectious process of the urinary tract. Sterile technique should be employed in administration. During administration, care should be taken to avoid excessive pressure, rapid or acute distention of the bladder, and trauma. Reference ID: 3788310 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Contrast agents may interfere with some chemical determinations made on urine specimens; therefore, urine should be collected before administration of the contrast medium or two or more days afterwards. Pregnancy–Teratogenic Effects: Pregnancy Category C Animal reproduction studies have not been conducted with diatrizoate meglumine injection. It is also not known whether diatrizoate meglumine injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Cystografin Dilute should be administered to a pregnant woman only if clearly needed. ADVERSE REACTIONS Retrograde genitourinary procedures may cause such complications as hematuria, perforation of the urethra or bladder, introduction of infection into the genitourinary tract, and oliguria or anuria. If intravasation of this drug occurs, the reactions which may be associated with intravenous administration may possibly be encountered. Hypersensitivity or anaphylactoid reactions may occur. Severe reactions may be manifested by edema of the face and glottis, respiratory distress, convulsions or shock; such reactions may prove fatal unless promptly controlled by such emergency measures as maintenance of a clear airway and immediate use of oxygen and resuscitative drugs. Thyroid function tests indicative of hypothyroidism or transient thyroid suppression have been uncommonly reported following iodinated contrast media administration to adult and pediatric patients, including infants. Some patients were treated for hypothyroidism. DOSAGE AND ADMINISTRATION Preparation of the patient: Appropriate preparation is desirable for optimal results. A laxative the night before the examination and a low residue diet the day before the procedure are recommended. Dosage: The dose for retrograde use in cystography and voiding cystourethrography ranges from 25 to 300 mL depending on the age of the patient and the degree of bladder irritability; amounts greater than 300 mL may be used if the bladder capacity allows. Best results are obtained when the bladder is filled with the contrast agent. Administration: After sterile catheterization, the bladder should be filled to capacity with Cystografin Dilute using a suitable sterile administration set. Care should be taken to avoid using excessive pressure. The presence of bladder discomfort or reflux and/or spontaneous voiding usually indicates that the bladder is full. Radiography: The commonly employed radiographic techniques should be used. A scout film is recommended before the contrast agent is administered. HOW SUPPLIED Cystografin Dilute (Diatrizoate Meglumine Injection USP 18%) is available in packages of ten 300 mL bottIes (NDC 0270-1410-30). Reference ID: 3788310 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Storage Store at 20-25°C (68-77°F) [See USP]; protect from light. Rx only Manufactured for Bracco Diagnostics Inc. Monroe Township, NJ 08831 by Patheon Italia S.p.A. 03013 Ferentino (Italy) Revised June 2015 CL64B03 - 000000 Reference ID: 3788310 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:40.852626	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/010040s171lbl.pdf', 'application_number': 10040, 'submission_type': 'SUPPL ', 'submission_number': 171}
10,737	NDA 010151 Dilantin (phenytoin sodium) Injection FDA Approved Labeling Text dated 10/2011 Page 1 of 14 Parenteral Dilantin® (Phenytoin Sodium Injection, USP) WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION The rate of intravenous Dilantin administration should not exceed 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous Dilantin. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed (see WARNINGS and DOSAGE AND ADMINISTRATION). DESCRIPTION Dilantin (phenytoin sodium injection, USP) is a ready-mixed solution of phenytoin sodium in a vehicle containing 40% propylene glycol and 10% alcohol in water for injection, adjusted to pH 12 with sodium hydroxide. Phenytoin sodium is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is sodium 5,5-diphenyl-2, 4- imidazolidinedione represented by the following structural formula: structural formula CLINICAL PHARMACOLOGY Mechanism of Action Phenytoin is an anticonvulsant which may be useful in the treatment of generalized tonic- clonic status epilepticus. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of generalized tonic-clonic seizures. Reference ID: 3038688 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin (phenytoin sodium) Injection FDA Approved Labeling Text dated 10/2011 Page 2 of 14 Pharmacokinetics and Drug Metabolism The plasma half-life in man after intravenous administration ranges from 10 to 15 hours. Optimum control without clinical signs of toxicity occurs most often with serum levels between 10 and 20 mcg/mL. Phenytoin is metabolized by the cytochrome P450 enzymes CYP2C9 and CYP2C19. A fall in plasma levels may occur when patients are changed from oral to intramuscular administration. The drop is caused by slower absorption, as compared to oral administration, due to the poor water solubility of phenytoin. Intravenous administration is the preferred route for producing rapid therapeutic serum levels. When intramuscular administration may be required, a sufficient dose must be administered intramuscularly to maintain the plasma level within the therapeutic range. Where oral dosage is resumed following intramuscular usage, the oral dose should be properly adjusted to compensate for the slow, continuing IM absorption to avoid toxic symptoms. Patients stabilized on a daily oral regimen of Dilantin experience a drop in peak blood levels to 50-60 percent of stable levels if crossed over to an equal dose administered intramuscularly. However, the intramuscular depot of poorly soluble material is eventually absorbed, as determined by urinary excretion of 5-(p-hydroxyphenyl)-5 phenylhydantoin (HPPH), the principal metabolite, as well as the total amount of drug eventually appearing in the blood. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. A short-term (one week) study indicates that patients do not experience the expected drop in blood levels when crossed over to the intramuscular route if the Dilantin IM dose is increased by 50 percent over the previously established oral dose. To avoid drug cumulation due to absorption from the muscle depots, it is recommended that for the first week back on oral Dilantin, the dose be reduced to half of the original oral dose (one third of the IM dose). Experience for periods greater than one week is lacking and blood level monitoring is recommended. Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations. Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION). Reference ID: 3038688 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin (phenytoin sodium) Injection FDA Approved Labeling Text dated 10/2011 Page 3 of 14 Gender and Race: Gender and race have no significant impact on phenytoin pharmacokinetics. Pediatrics: A loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10 20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1 3 mg/kg/min or 50 mg per minute, whichever is slower. INDICATIONS AND USAGE Parenteral Dilantin is indicated for the control of generalized tonic-clonic status epilepticus, and prevention and treatment of seizures occurring during neurosurgery. Parenteral Dilantin should be used only when oral Dilantin administration is not possible. CONTRAINDICATIONS Phenytoin is contraindicated in patients with a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins. Because of its effect on ventricular automaticity, phenytoin is contraindicated in sinus bradycardia, sino-atrial block, second and third degree A-V block, and patients with Adams-Stokes syndrome. Coadministration of Dilantin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non- nucleoside reverse transcriptase inhibitors. WARNINGS Cardiovascular Risk Associated with Rapid Infusion Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, the drug should be administered at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. As non-emergency therapy, Dilantin should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Dilantin. Reduction in rate of administration or discontinuation of dosing may be needed. Reference ID: 3038688 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin (phenytoin sodium) Injection FDA Approved Labeling Text dated 10/2011 Page 4 of 14 Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates. Withdrawal Precipitated Seizure, Status Epilepticus Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class. Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Dilantin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below). Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA B1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B1502. The use of HLA-B1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Dilantin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in Reference ID: 3038688 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin (phenytoin sodium) Injection FDA Approved Labeling Text dated 10/2011 Page 5 of 14 association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Dilantin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Dilantin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to Dilantin. Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, phenytoin should be immediately discontinued and not re-administered. Hematopoietic System Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling DRESS. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs. Local Toxicity (including Purple Glove Syndrome) Soft tissue irritation and inflammation has occurred at the site of injection with and without extravasation of intravenous phenytoin. Reference ID: 3038688 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin (phenytoin sodium) Injection FDA Approved Labeling Text dated 10/2011 Page 6 of 14 Edema, discoloration and pain distal to the site of injection (described as “purple glove syndrome”) have also been reported following peripheral intravenous phenytoin injection. Soft tissue irritation may vary from slight tenderness to extensive necrosis, and sloughing. The syndrome may not develop for several days after injection. Although resolution of symptoms may be spontaneous, skin necrosis and limb ischemia have occurred and required such interventions as fasciotomies, skin grafting, and, in rare cases, amputation. Because of the risk of local toxicity, intravenous Dilantin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the IV catheter should be tested with a flush of sterile saline. Each injection of parenteral Dilantin should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution. Intramuscular Dilantin administration may cause pain, necrosis, and abscess formation at the injection site (see DOSAGE AND ADMINISTRATION). Alcohol Use Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may decrease serum levels. Exacerbation of Porphyria In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease. Usage in Pregnancy Clinical Risks to Mother An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated. Risks to the Fetus If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes. Increased frequencies of major malformations (such as profacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of Reference ID: 3038688 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin (phenytoin sodium) Injection FDA Approved Labeling Text dated 10/2011 Page 7 of 14 malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two to three fold that in the general population. However, the relative contribution of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy. Postpartum Period A potentially life-threatening bleeding disorder related to decreased levels of vitamin K- dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth. Preclinical Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits. PRECAUTIONS General The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early toxicity. A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. Hyperglycemia, resulting from the drug's inhibitory effect on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients. Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin is not effective for absence seizures. If tonic-clonic and absence seizures are present, combined drug therapy is needed. Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as "delirium", "psychosis", or "encephalopathy", or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended. (See Warnings) Laboratory Tests Reference ID: 3038688 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin (phenytoin sodium) Injection FDA Approved Labeling Text dated 10/2011 Page 8 of 14 Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 µg/mL (unbound phenytoin concentrations of 1 to 2 µg/mL). Drug Interactions Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19, and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected. The most commonly occurring drug interactions are listed below: Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. Drugs that affect phenytoin concentrations: • Drugs, which may increase phenytoin serum levels, include: acute alcohol intake, amiodarone, anti-epileptic agents (felbamate, topiramate, oxcarbazepine), azoles (fluconazole, ketoconazole, itraconazole, voriconazole), chloramphenicol, chlordiazepoxide, cimetidine, diazepam, disulfiram, estrogens, ethosuximide, fluorouracil, fluoxetine, fluvoxamine, H2-antagonists, halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides, ticlopidine, tolbutamide, trazodone, and warfarin. • Drugs, which may decrease phenytoin levels, include: carbamazepine, chronic alcohol abuse, nelfinavir, reserpine, ritonavir, and sucralfate. • Drugs, which may either increase or decrease phenytoin serum levels include: phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable. • The addition or withdrawal of the agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome. Drugs affected by phenytoin: • Drugs that should not be coadministered with phenytoin: Delavirdine. • Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contaceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, teniposide, theophylline, Vitamin D, and warfarin. • Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin. • Phenytoin decreases plasma concentrations of certain HIV antivirals (amprenavir, efavirenz, Kaletra (lopinavir/ritonavir), indinavir, nelfinavir, ritonavir, saquinavir), and anti-epileptic agents (felbamate, topiramate, oxcarbazepine, quetiapine). Reference ID: 3038688 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin (phenytoin sodium) Injection FDA Approved Labeling Text dated 10/2011 Page 9 of 14 • The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome. Drug-Enteral Feeding/Nutritional Preparations Interaction Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients. Drug/Laboratory Test Interactions Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may also cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations following fosphenytoin administration. Carcinogenesis See "Warnings" section for information on carcinogenesis. Pregnancy Pregnancy Category D: See WARNINGS. Nursing Mothers Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Pediatric Use See DOSAGE AND ADMINISTRATION Geriatric Use Phenytoin clearance tends to decrease with increasing age (see CLINICAL PHARMACOLOGY: Special Populations). ADVERSE REACTIONS The most notable signs of toxicity associated with the intravenous use of this drug are cardiovascular collapse and/or central nervous system depression. Hypotension does occur when the drug is administered rapidly by the intravenous route. The rate of administration is very important; it should not exceed 50 mg per minute in adults, and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Reference ID: 3038688 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin (phenytoin sodium) Injection FDA Approved Labeling Text dated 10/2011 Page 10 of 14 Body As a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS (see WARNINGS) have been observed. Anaphylaxis has also been reported. There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities. Cardiovascular: Severe cardiovascular events and fatalities have been reported with atrial and ventricular conduction depression and ventricular fibrillation. Severe complications are most commonly encountered in elderly or critically ill patients (see WARNINGS). Nervous System: The most common manifestations encountered with phenytoin therapy are referable to this system and are usually dose-related. These include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, insomnia, transient nervousness, motor twitchings, paresthesia, and headaches have also been observed. There have also been rare reports of phenytoin induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Digestive System: Nausea, vomiting, constipation, enlargement of the lips, gingival hyperplasia, toxic hepatitis and liver damage. Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see WARNINGS section). There have also been reports of hypertrichosis. Local irritation, inflammation, tenderness, necrosis, and sloughing have been reported with or without extravasation of intravenous phenytoin (see WARNINGS). Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy, including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's Disease have been reported (see Warnings). Special Senses: Altered taste sensation including metallic taste. Urogenital: Peyronie’s disease Reference ID: 3038688 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin (phenytoin sodium) Injection FDA Approved Labeling Text dated 10/2011 Page 11 of 14 OVERDOSAGE The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind. DOSAGE AND ADMINISTRATION Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, the drug should be administered at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. As non-emergency therapy, Dilantin should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Dilantin. Reduction in rate of administration or discontinuation of dosing may be needed. Because of the risk of local toxicity, intravenous Dilantin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the IV catheter should be tested with a flush of sterile saline. Each injection of parenteral Dilantin should then be followed Reference ID: 3038688 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin (phenytoin sodium) Injection FDA Approved Labeling Text dated 10/2011 Page 12 of 14 by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution. Dilantin can be given diluted with normal saline. The addition of parenteral Dilantin to dextrose and dextrose-containing solutions should be avoided due to lack of solubility and resultant precipitation. Treatment with Dilantin can be initiated either with a loading dose or an infusion: Loading Dose: A loading dose of parenteral Dilantin should be injected slowly, not exceeding 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Infusion: For infusion administration, parenteral Dilantin should be diluted in normal saline with the final concentration of Dilantin in the solution no less than 5 mg/mL. Administration should commence immediately after the mixture has been prepared and must be completed within 1 to 4 hours (the infusion mixture should not be refrigerated). An in-line filter (0.22-0.55 microns) should be used. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution or container permit. The diluted infusion mixture (Dilantin plus normal saline) should not be refrigerated. If the undiluted parenteral Dilantin is refrigerated or frozen, a precipitate might form: this will dissolve again after the solution is allowed to stand at room temperature. The product is still suitable for use. A faint yellow coloration may develop, however this has no effect on the potency of the solution. Status Epilepticus In adults, a loading dose of 10 to 15 mg/kg should be administered slowly intravenously, at a rate not exceeding 50 mg per minute (this will require approximately 20 minutes in a 70-kg patient). The loading dose should be followed by maintenance doses of 100 mg orally or intravenously every 6-8 hours. In the pediatric population, a loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10-20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. Continuous monitoring of the electrocardiogram and blood pressure is essential. The patient should be observed for signs of respiratory depression. Determination of phenytoin plasma levels is advised when using Dilantin in the management of status epilepticus and in the subsequent establishment of maintenance dosage. Reference ID: 3038688 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin (phenytoin sodium) Injection FDA Approved Labeling Text dated 10/2011 Page 13 of 14 Other measures, including concomitant administration of an intravenous benzodiazepine such as diazepam, or an intravenous short-acting barbiturate, will usually be necessary for rapid control of seizures because of the required slow rate of administration of Dilantin. If administration of Parenteral Dilantin does not terminate seizures, the use of other anticonvulsants, intravenous barbiturates, general anesthesia, and other appropriate measures should be considered. Intramuscular administration should not be used in the treatment of status epilepticus because the attainment of peak plasma levels may require up to 24 hours. Nonemergent Loading and Maintenance Dosing Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. In adults, a loading dose of 10 to 15 mg/kg should be administered slowly. The rate of intravenous administration should not exceed 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Slower administration rates are recommended to minimize the cardiovascular adverse reactions. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential. The loading dose should be followed by maintenance doses of oral or intravenous Dilantin every 6-8 hours. Ordinarily, Dilantin should not be given intramuscularly because of the risk of necrosis, abscess formation, and erratic absorption. If intramuscular administration is required, compensating dosage adjustments are necessary to maintain therapeutic plasma levels. An intramuscular dose 50% greater than the oral dose is necessary to maintain these levels. When returned to oral administration, the dose should be reduced by 50% of the original oral dose for one week to prevent excessive plasma levels due to sustained release from intramuscular tissue sites. Monitoring plasma levels would help prevent a fall into the subtherapeutic range. Serum blood level determinations are especially helpful when possible drug interactions are suspected. IV Substitution For Oral Phenytoin Therapy When treatment with oral phenytoin is not possible, IV Dilantin can be substituted for oral phenytoin at the same total daily dose. Dilantin capsules are approximately 90% bioavailable by the oral route. Phenytoin is 100% bioavailable by the IV route. For this reason, plasma phenytoin concentrations may increase modestly when IV phenytoin is substituted for oral phenytoin sodium therapy. The rate of administration for IV Dilantin should be no greater than 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Dilantin® Kapseals® and Dilantin Parenteral are formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspension and Dilantin Infatabs. Because there is Reference ID: 3038688 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin (phenytoin sodium) Injection FDA Approved Labeling Text dated 10/2011 Page 14 of 14 approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa. Dosing in Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound phenytoin concentrations may be more useful in these patient populations. Elderly Patients: Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required. Pediatric: A loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10 20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1 3 mg/kg/min or 50 mg per minute, whichever is slower. HOW SUPPLIED N 0071-4488--47 (Steri-Dose® 4488) Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in a 2-mL sterile disposable syringe(22 gauge x 1 ¼ inch needle). Packages of ten syringes. N 0071-4488-45 Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in 2-mL Steri-Vials®. Packages of twenty-five. N 0071-4475-45 Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in 5-mL Steri-Vials. Packages of twenty-five. Caution- Federal law prohibits dispensing without prescription. Warning- Manufactured with CFC-12, which harms public health and environment by destroying ozone in the upper atmosphere. Rx only company logo LAB-0383-1.0 October 2011 Reference ID: 3038688 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:40.917096	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/010151s036lbl.pdf', 'application_number': 10151, 'submission_type': 'SUPPL ', 'submission_number': 36}
10,736	Merck logo 7918719 TABLETS MEPHYTON® (PHYTONADIONE) Vitamin K1 DESCRIPTION Phytonadione is a vitamin which is a clear, yellow to amber, viscous, and nearly odorless liquid. It is insoluble in water, soluble in chloroform and slightly soluble in ethanol. It has a molecular weight of 450.70. Phytonadione is 2-methyl-3-phytyl-1, 4-naphthoquinone. Its empirical formula is C31H46O2 and its structural formula is: chemical structure MEPHYTON* (Phytonadione) tablets containing 5 mg of phytonadione are yellow, compressed tablets, scored on one side. Inactive ingredients are acacia, calcium phosphate, colloidal silicon dioxide, lactose, magnesium stearate, starch, and talc. CLINICAL PHARMACOLOGY MEPHYTON tablets possess the same type and degree of activity as does naturally-occurring vitamin K, which is necessary for the production via the liver of active prothrombin (factor II), proconvertin (factor VII), plasma thromboplastin component (factor IX), and Stuart factor (factor X). The prothrombin test is sensitive to the levels of three of these four factors  II, VII, and X. Vitamin K is an essential cofactor for a microsomal enzyme that catalyzes the post-translational carboxylation of multiple, specific, peptide-bound glutamic acid residues in inactive hepatic precursors of factors II, VII, IX, and X. The resulting gamma-carboxyglutamic acid residues convert the precursors into active coagulation factors that are subsequently secreted by liver cells into the blood. Oral phytonadione is adequately absorbed from the gastrointestinal tract only if bile salts are present. After absorption, phytonadione is initially concentrated in the liver, but the concentration declines rapidly. Very little vitamin K accumulates in tissues. Little is known about the metabolic fate of vitamin K. Almost no free unmetabolized vitamin K appears in bile or urine. In normal animals and humans, phytonadione is virtually devoid of pharmacodynamic activity. However, in animals and humans deficient in vitamin K, the pharmacological action of vitamin K is related to its normal physiological function; that is, to promote the hepatic biosynthesis of vitamin K-dependent clotting factors. MEPHYTON tablets generally exert their effect within 6 to 10 hours. INDICATIONS AND USAGE MEPHYTON is indicated in the following coagulation disorders which are due to faulty formation of factors II, VII, IX and X when caused by vitamin K deficiency or interference with vitamin K activity. MEPHYTON tablets are indicated in: — anticoagulant-induced prothrombin deficiency caused by coumarin or indanedione derivatives; — hypoprothrombinemia secondary to antibacterial therapy; — hypoprothrombinemia secondary to administration of salicylates; — hypoprothrombinemia secondary to obstructive jaundice or biliary fistulas but only if bile salts are administered concurrently, since otherwise the oral vitamin K will not be absorbed. * Registered trademark of MERCK & CO., Inc. COPYRIGHT © 1986, 1991, MERCK & CO., Inc. All rights reserved This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEPHYTON® (Phytonadione) 7918719 CONTRAINDICATIONS Hypersensitivity to any component of this medication. WARNINGS An immediate coagulant effect should not be expected after administration of phytonadione. Phytonadione will not counteract the anticoagulant action of heparin. When vitamin K1 is used to correct excessive anticoagulant-induced hypoprothrombinemia, anticoagulant therapy still being indicated, the patient is again faced with the clotting hazards existing prior to starting the anticoagulant therapy. Phytonadione is not a clotting agent, but overzealous therapy with vitamin K1 may restore conditions which originally permitted thromboembolic phenomena. Dosage should be kept as low as possible, and prothrombin time should be checked regularly as clinical conditions indicate. Repeated large doses of vitamin K are not warranted in liver disease if the response to initial use of the vitamin is unsatisfactory. Failure to respond to vitamin K may indicate a congenital coagulation defect or that the condition being treated is unresponsive to vitamin K. PRECAUTIONS General Vitamin K1 is fairly rapidly degraded by light; therefore, always protect MEPHYTON from light. Store MEPHYTON in closed original carton until contents have been used. (See also HOW SUPPLIED, Storage.) Drug Interactions Temporary resistance to prothrombin-depressing anticoagulants may result, especially when larger doses of phytonadione are used. If relatively large doses have been employed, it may be necessary when reinstituting anticoagulant therapy to use somewhat larger doses of the prothrombin-depressing anticoagulant, or to use one which acts on a different principle, such as heparin sodium. Laboratory Tests Prothrombin time should be checked regularly as clinical conditions indicate. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies of carcinogenicity or impairment of fertility have not been performed with MEPHYTON. MEPHYTON at concentrations up to 2000 mcg/plate with or without metabolic activation, was negative in the Ames microbial mutagen test. Pregnancy Pregnancy Category C: Animal reproduction studies have not been conducted with MEPHYTON. It is also not known whether MEPHYTON can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. MEPHYTON should be given to a pregnant woman only if clearly needed. Pediatric Use Safety and effectiveness in pediatric patients have not been established with MEPHYTON. Hemolysis, jaundice, and hyperbilirubinemia in newborns, particularly in premature infants, have been reported with vitamin K. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when MEPHYTON is administered to a nursing woman. Geriatric Use Clinical studies of MEPHYTON did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEPHYTON® (Phytonadione) 7918719 ADVERSE REACTIONS Severe hypersensitivity reactions, including anaphylactoid reactions and deaths have been reported following parenteral administration. The majority of these reported events occurred following intravenous administration. Transient “flushing sensations” and “peculiar” sensations of taste have been observed with parenteral phytonadione, as well as rare instances of dizziness, rapid and weak pulse, profuse sweating, brief hypotension, dyspnea, and cyanosis. Hyperbilirubinemia has been observed in the newborn following administration of parenteral phytonadione. This has occurred rarely and primarily with doses above those recommended. OVERDOSAGE The intravenous and oral LD50s in the mouse are approximately 1.17 g/kg and greater than 24.18 g/kg, respectively. DOSAGE AND ADMINISTRATION MEPHYTON Summary of Dosage Guidelines (See circular text for details) Adults Initial Dosage Anticoagulant-Induced 2.5 mg-10 mg or up to Prothrombin Deficiency 25 mg (rarely 50 mg) (caused by coumarin or indanedione derivatives) Hypoprothrombinemia due 2.5 mg-25 mg or more to other causes (rarely up to 50 mg) (Antibiotics; Salicylates or other drugs; Factors limiting absorption or synthesis) Anticoagulant-Induced Prothrombin Deficiency in Adults To correct excessively prolonged prothrombin times caused by oral anticoagulant therapy  2.5 to 10 mg or up to 25 mg initially is recommended. In rare instances 50 mg may be required. Frequency and amount of subsequent doses should be determined by prothrombin time response or clinical condition. (See WARNINGS.) If, in 12 to 48 hours after oral administration, the prothrombin time has not been shortened satisfactorily, the dose should be repeated. Hypoprothrombinemia Due to Other Causes in Adults If possible, discontinuation or reduction of the dosage of drugs interfering with coagulation mechanisms (such as salicylates, antibiotics) is suggested as an alternative to administering concurrent MEPHYTON. The severity of the coagulation disorder should determine whether the immediate administration of MEPHYTON is required in addition to discontinuation or reduction of interfering drugs. A dosage of 2.5 to 25 mg or more (rarely up to 50 mg) is recommended, the amount and route of administration depending upon the severity of the condition and response obtained. The oral route should be avoided when the clinical disorder would prevent proper absorption. Bile salts must be given with the tablets when the endogenous supply of bile to the gastrointestinal tract is deficient. HOW SUPPLIED No. 7776  Tablets MEPHYTON, 5 mg vitamin K1, are yellow, round, scored, compressed tablets, coded MSD 43 on one side and MEPHYTON on the other. They are supplied as follows: NDC 0006-0043-68 bottles of 100. Storage: Store in tightly closed original container at 25°C (77°F); excursions permitted to 15-30°C (59 86°F) [see USP Controlled Room Temperature]. Always protect MEPHYTON from light. Store in tightly closed original container and carton until contents have been used. (See PRECAUTIONS, General.) Merck logo 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEPHYTON® (Phytonadione) 7918719 Issued April 2004 Printed in USA 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:40.959591	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/010104s023lbl.pdf', 'application_number': 10104, 'submission_type': 'SUPPL ', 'submission_number': 23}
10,738	NDA 10151 Dilantin (Phenytoin Sodium Injection, USP) FDA Approved Labeling Text dated 02/2013 Page 1 of 15 Parenteral Dilantin® (Phenytoin Sodium Injection, USP) WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION The rate of intravenous Dilantin administration should not exceed 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous Dilantin. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed (see WARNINGS and DOSAGE AND ADMINISTRATION). DESCRIPTION Dilantin (phenytoin sodium injection, USP) is a ready-mixed solution of phenytoin sodium in a vehicle containing 40% propylene glycol and 10% alcohol in water for injection, adjusted to pH 12 with sodium hydroxide. Phenytoin sodium is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is sodium 5,5-diphenyl-2, 4- imidazolidinedione represented by the following structural formula: structural formula CLINICAL PHARMACOLOGY Mechanism of Action Phenytoin is an anticonvulsant which may be useful in the treatment of generalized tonic clonic status epilepticus. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of generalized tonic-clonic seizures. Reference ID: 3258649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10151 Dilantin (Phenytoin Sodium Injection, USP) FDA Approved Labeling Text dated 02/2013 Page 2 of 15 Pharmacokinetics and Drug Metabolism The plasma half-life in man after intravenous administration ranges from 10 to 15 hours. Optimum control without clinical signs of toxicity occurs most often with serum levels between 10 and 20 mcg/mL. Phenytoin is metabolized by the cytochrome P450 enzymes CYP2C9 and CYP2C19. A fall in plasma levels may occur when patients are changed from oral to intramuscular administration. The drop is caused by slower absorption, as compared to oral administration, due to the poor water solubility of phenytoin. Intravenous administration is the preferred route for producing rapid therapeutic serum levels. When intramuscular administration may be required, a sufficient dose must be administered intramuscularly to maintain the plasma level within the therapeutic range. Where oral dosage is resumed following intramuscular usage, the oral dose should be properly adjusted to compensate for the slow, continuing IM absorption to avoid toxic symptoms. Patients stabilized on a daily oral regimen of Dilantin experience a drop in peak blood levels to 50-60 percent of stable levels if crossed over to an equal dose administered intramuscularly. However, the intramuscular depot of poorly soluble material is eventually absorbed, as determined by urinary excretion of 5-(p-hydroxyphenyl)-5 phenylhydantoin (HPPH), the principal metabolite, as well as the total amount of drug eventually appearing in the blood. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. A short-term (one week) study indicates that patients do not experience the expected drop in blood levels when crossed over to the intramuscular route if the Dilantin IM dose is increased by 50 percent over the previously established oral dose. To avoid drug cumulation due to absorption from the muscle depots, it is recommended that for the first week back on oral Dilantin, the dose be reduced to half of the original oral dose (one third of the IM dose). Experience for periods greater than one week is lacking and blood level monitoring is recommended. Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations. Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION). Reference ID: 3258649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10151 Dilantin (Phenytoin Sodium Injection, USP) FDA Approved Labeling Text dated 02/2013 Page 3 of 15 Gender and Race: Gender and race have no significant impact on phenytoin pharmacokinetics. Pediatrics: A loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10 20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1 3 mg/kg/min or 50 mg per minute, whichever is slower. INDICATIONS AND USAGE Parenteral Dilantin is indicated for the control of generalized tonic-clonic status epilepticus, and prevention and treatment of seizures occurring during neurosurgery. Parenteral Dilantin should be used only when oral Dilantin administration is not possible. CONTRAINDICATIONS Phenytoin is contraindicated in patients with a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins. Because of its effect on ventricular automaticity, phenytoin is contraindicated in sinus bradycardia, sino-atrial block, second and third degree A-V block, and patients with Adams-Stokes syndrome. Coadministration of Dilantin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non nucleoside reverse transcriptase inhibitors. WARNINGS Cardiovascular Risk Associated with Rapid Infusion Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, the drug should be administered at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. As non-emergency therapy, Dilantin should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Dilantin. Reduction in rate of administration or discontinuation of dosing may be needed. Reference ID: 3258649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10151 Dilantin (Phenytoin Sodium Injection, USP) FDA Approved Labeling Text dated 02/2013 Page 4 of 15 Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates. Withdrawal Precipitated Seizure, Status Epilepticus Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class. Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Dilantin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below). Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA B1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B1502. The use of HLA-B1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Dilantin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in Reference ID: 3258649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10151 Dilantin (Phenytoin Sodium Injection, USP) FDA Approved Labeling Text dated 02/2013 Page 5 of 15 association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Dilantin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Dilantin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to Dilantin. Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, phenytoin should be immediately discontinued and not re-administered. Hematopoietic System Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling DRESS.In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs. Local Toxicity (including Purple Glove Syndrome) Soft tissue irritation and inflammation has occurred at the site of injection with and without extravasation of intravenous phenytoin. Reference ID: 3258649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10151 Dilantin (Phenytoin Sodium Injection, USP) FDA Approved Labeling Text dated 02/2013 Page 6 of 15 Edema, discoloration and pain distal to the site of injection (described as “purple glove syndrome”) have also been reported following peripheral intravenous phenytoin injection. Soft tissue irritation may vary from slight tenderness to extensive necrosis, and sloughing. The syndrome may not develop for several days after injection. Although resolution of symptoms may be spontaneous, skin necrosis and limb ischemia have occurred and required such interventions as fasciotomies, skin grafting, and, in rare cases, amputation. Because of the risk of local toxicity, intravenous Dilantin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the IV catheter should be tested with a flush of sterile saline. Each injection of parenteral Dilantin should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution. Intramuscular Dilantin administration may cause pain, necrosis, and abscess formation at the injection site (see DOSAGE AND ADMINISTRATION). Alcohol Use Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may decrease serum levels. Exacerbation of Porphyria In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease. Usage in Pregnancy Clinical Risks to Mother An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated. Risks to the Fetus If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes. Increased frequencies of major malformations (such as profacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin Reference ID: 3258649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10151 Dilantin (Phenytoin Sodium Injection, USP) FDA Approved Labeling Text dated 02/2013 Page 7 of 15 and/or others) during pregnancy is about 10%, or two to three fold that in the general population. However, the relative contribution of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy. Postpartum Period A potentially life-threatening bleeding disorder related to decreased levels of vitamin K- dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth. Preclinical Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits. PRECAUTIONS General The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early toxicity. A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. Hyperglycemia, resulting from the drug's inhibitory effect on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients. Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin is not effective for absence seizures. If tonic-clonicand absence seizures are present, combined drug therapy is needed. Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as "delirium", "psychosis", or "encephalopathy", or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended. (See Warnings) Laboratory Tests Reference ID: 3258649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10151 Dilantin (Phenytoin Sodium Injection, USP) FDA Approved Labeling Text dated 02/2013 Page 8 of 15 Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 µg/mL (unbound phenytoin concentrations of 1 to 2 µg/mL). Drug Interactions Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected. The most commonly occurring drug interactions are listed below: Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. Drugs that affect phenytoin concentrations: • Drugs that may increase phenytoin serum levels, include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, cimetidine, diazepam, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides(e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin. • Drugs that may decrease phenytoin levels, include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, folic acid, fosamprenavir, nelfinavir, reserpine, ritonavir, St. John’s Wort, and vigabatrin. • Drugs that may either increase or decrease phenytoin serum levels include: phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable. • The addition or withdrawal of the agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome. Drugs affected by phenytoin: • Drugs that should not be coadministered with phenytoin: Delavirdine (see CONTRAINDICATIONS). • Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contaceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, tenisposide, theophylline, and Vitamin D. Reference ID: 3258649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10151 Dilantin (Phenytoin Sodium Injection, USP) FDA Approved Labeling Text dated 02/2013 Page 9 of 15 • Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin. • Phenytoin decreases plasma concentrations of certain HIV antivirals ( efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic agents (felbamate, topiramate, oxcarbazepine, quetiapine), atorvastatin, cyclosporine, digoxin, fluvastatin, folic acid, mexiletine, nisoldipine, praziquantel, and simvastatin. • Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir. • Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher. • The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome. Drug-Enteral Feeding/Nutritional Preparations Interaction Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients. Drug/Laboratory Test Interactions Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may also cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations following fosphenytoin administration. Carcinogenesis See "Warnings" section for information on carcinogenesis. Pregnancy Pregnancy Category D: See WARNINGS. Nursing Mothers Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Pediatric Use See DOSAGE AND ADMINISTRATION Reference ID: 3258649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10151 Dilantin (Phenytoin Sodium Injection, USP) FDA Approved Labeling Text dated 02/2013 Page 10 of 15 Geriatric Use Phenytoin clearance tends to decrease with increasing age (see CLINICAL PHARMACOLOGY: Special Populations). ADVERSE REACTIONS The most notable signs of toxicity associated with the intravenous use of this drug are cardiovascular collapse and/or central nervous system depression. Hypotension does occur when the drug is administered rapidly by the intravenous route. The rate of administration is very important; it should not exceed 50 mg per minute in adults, and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Body As a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS (see WARNINGS) have been observed. Anaphylaxis has also been reported. There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities. Cardiovascular: Severe cardiovascular events and fatalities have been reported with atrial and ventricular conduction depression and ventricular fibrillation. Severe complications are most commonly encountered in elderly or critically ill patients (see WARNINGS). Nervous System: The most common manifestations encountered with phenytoin therapy are referable to this system and are usually dose-related. These include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, insomnia, transient nervousness, motor twitchings, paresthesia, and headaches have also been observed. There have also been rare reports of phenytoin induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Digestive System: Nausea, vomiting, constipation, enlargement of the lips, gingival hyperplasia, toxic hepatitis and liver damage. Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see WARNINGS section). There have also been reports of hypertrichosis. Local irritation, inflammation, tenderness, necrosis, and sloughing have been reported with or without extravasation of intravenous phenytoin (see WARNINGS). Reference ID: 3258649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10151 Dilantin (Phenytoin Sodium Injection, USP) FDA Approved Labeling Text dated 02/2013 Page 11 of 15 Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy, including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's Disease have been reported (see Warnings). Special Senses: Altered taste sensation including metallic taste. Urogenital: Peyronie’s disease OVERDOSAGE The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind. DOSAGE AND ADMINISTRATION Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, the drug should be administered at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. As non-emergency therapy, Dilantin should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local Reference ID: 3258649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10151 Dilantin (Phenytoin Sodium Injection, USP) FDA Approved Labeling Text dated 02/2013 Page 12 of 15 toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Dilantin. Reduction in rate of administration or discontinuation of dosing may be needed. Because of the risk of local toxicity, intravenous Dilantin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the IV catheter should be tested with a flush of sterile saline. Each injection of parenteral Dilantin should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution. Dilantin can be given diluted with normal saline. The addition of parenteral Dilantin to dextrose and dextrose-containing solutions should be avoided due to lack of solubility and resultant precipitation. Treatment with Dilantin can be initiated either with a loading dose or an infusion: Loading Dose: A loading dose of parenteral Dilantin should be injected slowly, not exceeding 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Infusion: For infusion administration, parenteral Dilantin should be diluted in normal saline with the final concentration of Dilantin in the solution no less than 5 mg/mL. Administration should commence immediately after the mixture has been prepared and must be completed within 1 to 4 hours (the infusion mixture should not be refrigerated). An in-line filter (0.22-0.55 microns) should be used. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution or container permit. The diluted infusion mixture (Dilantin plus normal saline) should not be refrigerated. If the undiluted parenteral Dilantin is refrigerated or frozen, a precipitate might form: this will dissolve again after the solution is allowed to stand at room temperature. The product is still suitable for use. A faint yellow coloration may develop, however this has no effect on the potency of the solution. Status Epilepticus In adults, a loading dose of 10 to 15 mg/kg should be administered slowly intravenously, at a rate not exceeding 50 mg per minute (this will require approximately 20 minutes in a 70-kg patient). The loading dose should be followed by maintenance doses of 100 mg orally or intravenously every 6-8 hours. Reference ID: 3258649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10151 Dilantin (Phenytoin Sodium Injection, USP) FDA Approved Labeling Text dated 02/2013 Page 13 of 15 In the pediatric population, a loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10-20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. Continuous monitoring of the electrocardiogram and blood pressure is essential. The patient should be observed for signs of respiratory depression. Determination of phenytoin plasma levels is advised when using Dilantin in the management of status epilepticus and in the subsequent establishment of maintenance dosage. Other measures, including concomitant administration of an intravenous benzodiazepine such as diazepam, or an intravenous short-acting barbiturate, will usually be necessary for rapid control of seizures because of the required slow rate of administration of Dilantin. If administration of Parenteral Dilantin does not terminate seizures, the use of other anticonvulsants, intravenous barbiturates, general anesthesia, and other appropriate measures should be considered. Intramuscular administration should not be used in the treatment of status epilepticus because the attainment of peak plasma levels may require up to 24 hours. Nonemergent Loading and Maintenance Dosing Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. In adults, a loading dose of 10 to 15 mg/kg should be administered slowly. The rate of intravenous administration should not exceed 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Slower administration rates are recommended to minimize the cardiovascular adverse reactions. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential. The loading dose should be followed by maintenance doses of oral or intravenous Dilantin every 6-8 hours. Ordinarily, Dilantin should not be given intramuscularly because of the risk of necrosis, abscess formation, and erratic absorption. If intramuscular administration is required, compensating dosage adjustments are necessary to maintain therapeutic plasma levels. An intramuscular dose 50% greater than the oral dose is necessary to maintain these levels. When returned to oral administration, the dose should be reduced by 50% of the original oral dose for one week to prevent excessive plasma levels due to sustained release from intramuscular tissue sites. Monitoring plasma levels would help prevent a fall into the subtherapeutic range. Serum blood level determinations are especially helpful when possible drug interactions are suspected. IV Substitution For Oral Phenytoin Therapy Reference ID: 3258649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10151 Dilantin (Phenytoin Sodium Injection, USP) FDA Approved Labeling Text dated 02/2013 Page 14 of 15 When treatment with oral phenytoin is not possible, IV Dilantin can be substituted for oral phenytoin at the same total daily dose. Dilantin capsules are approximately 90% bioavailable by the oral route. Phenytoin is 100% bioavailable by the IV route. For this reason, plasma phenytoin concentrations may increase modestly when IV phenytoin is substituted for oral phenytoin sodium therapy. The rate of administration for IV Dilantin should be no greater than 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Dilantin® Kapseals® and Dilantin Parenteral are formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspension and Dilantin Infatabs. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa. Dosing in Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound phenytoin concentrations may be more useful in these patient populations. Elderly Patients: Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required. Pediatric: A loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10 20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1 3 mg/kg/min or 50 mg per minute, whichever is slower. HOW SUPPLIED N 0071-4488--47 (Steri-Dose® 4488) Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in a 2-mL sterile disposable syringe(22 gauge x 1 ¼ inch needle). Packages of ten syringes. N 0071-4488-45 Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in 2-mL Steri-Vials®. Packages of twenty-five. N 0071-4475-45 Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in 5-mL Steri-Vials. Packages of twenty-five. Caution- Federal law prohibits dispensing without prescription. Warning- Manufactured with CFC-12, which harms public health and environment by destroying ozone in the upper atmosphere. Reference ID: 3258649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10151 Dilantin (Phenytoin Sodium Injection, USP) FDA Approved Labeling Text dated 02/2013 Page 15 of 15 Rx only company logo LAB-0383-2.0 February 2013 Reference ID: 3258649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:41.086924	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/010151s037lbl.pdf', 'application_number': 10151, 'submission_type': 'SUPPL ', 'submission_number': 37}
10,739	NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 04/2014 Dilantin-125® (Phenytoin Oral Suspension, USP) (FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE) DESCRIPTION Dilantin (phenytoin) is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-diphenyl-2,4 imidazolidinedione, having the following structural formula: structural formula Each 5 ml of suspension contains 125 mg of phenytoin, USP; alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No. 6. CLINICAL PHARMACOLOGY Mechanism of Action Phenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures. Pharmacokinetics and Drug Metabolism The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5–7 half-lives) after initiation of therapy with recommended doses of 300 mg/day. When serum level determinations are necessary, they should be obtained at least 5–7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient’s next scheduled dose. Peak levels indicate an individual’s threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. For Dilantin-125 Suspension, peak levels occur 1½–3 hours after administration. Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, variant CYP2C9 and CYP2C19 alleles, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin plasma levels, despite standard doses, presents a difficult 1 Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 04/2014 clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high plasma levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more. Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations. Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION). Gender and Race: Gender and race have no significant impact on phenytoin pharmacokinetics. Pediatrics: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day). INDICATIONS AND USAGE Dilantin (phenytoin) is indicated for the control of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures. Phenytoin serum level determinations may be necessary for optimal dosage adjustments (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY sections). CONTRAINDICATIONS Dilantin is contraindicated in those patients with a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins. Coadministration of Dilantin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors. WARNINGS Effects of Abrupt Withdrawal Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When in the judgment of the clinician the need for dosage reduction, discontinuation, or substitution of alternative anticonvulsant medication arises, this should be done gradually. In the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an anticonvulsant not belonging to the hydantoin chemical class. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Dilantin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. 2 Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 04/2014 Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients with Relative Risk: Risk Difference: with Events Per Events Per 1000 Incidence of Events in Additional Drug 1000 Patients Patients Drug Patients with Events Patients/Incidence in Per 1000 Patients Placebo Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Dilantin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is 3 Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 04/2014 usually within 28 days, but can occur later. Dilantin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below). Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B1502. The use of HLA-B1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Dilantin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Dilantin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Dilantin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to Dilantin. Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with Dilantin. These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, Dilantin should be immediately discontinued and not readministered. Hematopoietic System Hematopoietic complications, some fatal, have occasionally been reported in association with administration of Dilantin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of 4 Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 04/2014 lymph node pathology. Lymph node involvement may occur with or without symptoms and signs of DRESS. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs. Effects on Vitamin D and Bone The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures. Phenytoin induces hepatic metabolizing enzymes. This may enhance the metabolism of vitamin D and decrease vitamin D levels, which may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia. Consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines. Effects of Alcohol Use on Phenytoin Serum Levels Acute alcoholic intake may increase phenytoin serum levels, while chronic alcoholic use may decrease serum levels. Exacerbation of Porphyria In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease. Usage in Pregnancy: Clinical: Risks to Mother. An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated. Risks to the Fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy. Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth. Preclinical: Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits. 5 Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 04/2014 PRECAUTIONS General: The liver is the chief site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity. A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. If early signs of dose-related CNS toxicity develop, plasma levels should be checked immediately. Hyperglycemia, resulting from the drug’s inhibitory effects on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients. Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present, combined drug therapy is needed. Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended. (See WARNINGS section.) Information for Patients: Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Dilantin. Instruct patients to take Dilantin only as prescribed. Patients taking phenytoin should be advised of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc. Patients should be instructed to use an accurately calibrated measuring device when using this medication to ensure accurate dosing. Patients should be made aware of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use. Patients should also be cautioned on the use of other drugs or alcoholic beverages without first seeking the physician’s advice. The importance of good dental hygiene should be stressed in order to minimize the development of gingival hyperplasia and its complications. Patients, their caregivers, and families should be counseled that AEDs, including Dilantin, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS: Pregnancy section). 6 Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 04/2014 Laboratory Tests: Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). Drug Interactions: Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19, and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected. The most commonly occurring drug interactions are listed below: Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. Drugs that affect phenytoin concentrations: • Drugs that may increase phenytoin serum levels, include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, miconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, , disulfiram, , estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H 2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, , omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin. • Drugs that may decrease phenytoin levels, include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampin, ritonavir, St. John’s Wort, sucralfate, theophylline, and vigabatrin. • Administration of phenytoin with preparations that increase gastric pH (e.g., supplements or antacids containing calcium carbonate, aluminum hydroxide, and magnesium hydroxide) may affect the absorption of phenytoin. In most cases where interactions were seen, the effect is a decrease in phenytoin levels when the drugs are taken at the same time. When possible, phenytoin and these products should not be taken at the same time of day. • Drugs that may either increase or decrease phenytoin serum levels include: phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid, and sodium valproate serum levels is unpredictable. • The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome. Drugs affected by phenytoin: • Drugs that should not be coadministered with phenytoin: Delavirdine (see CONTRAINDICATIONS) • Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, teniposide, theophylline, and vitamin D. • Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin. • Phenytoin decreases plasma concentrations of active metabolites of albendazole, certain HIV antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic agents (carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, quetiapine), atorvastatin, chlorpropamide, clozapine, cyclosporine, digoxin, fluvastatin, folic acid, methadone, mexiletine, nifedipine, nimodipine, nisoldipine, praziquantel, simvastatin, and verapamil. 7 Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 04/2014 • Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir. • Resistance to the neuromuscular blocking action of the non-depolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher. • The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome. Drug Enteral Feeding/Nutritional Preparations Interaction: Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients. Drug/Laboratory Test Interactions: Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations. Carcinogenesis: See WARNINGS section for information on carcinogenesis. Pregnancy: Pregnancy Category D; See WARNINGS section. To provide information regarding the effects of in utero exposure to Dilantin, physicians are advised to recommend that pregnant patients taking Dilantin enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ . Nursing Mothers: Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Pediatric Use: See DOSAGE AND ADMINISTRATION section. Geriatric Use: Phenytoin clearance tends to decrease with increasing age (see CLINICAL PHARMACOLOGY: Special Populations). ADVERSE REACTIONS Body As a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS (see WARNINGS) have been observed. Anaphylaxis has also been reported. There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities. Nervous System: The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesias, and headaches have also been observed. There have also been rare reports of phenytoin-induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. 8 Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 04/2014 Digestive System: Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia. Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see WARNINGS section). There have also been reports of hypertrichosis. Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease have been reported (see WARNINGS section). Special Senses: Altered taste sensation including metallic taste. Urogenital: Peyronie’s disease OVERDOSAGE The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL; dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind. DOSAGE AND ADMINISTRATION FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Dilantin® Kapseals® is formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspension and Dilantin Infatabs. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa. General: Dosage should be individualized to provide maximum benefit. In some cases serum blood level determinations may be necessary for optimal dosage adjustments—the clinically effective serum level is usually 10–20 mcg/mL. With recommended dosage, a period of seven to ten days may be required to achieve steady-state blood levels with phenytoin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days. Adult Dose: Patients who have received no previous treatment may be started on one teaspoonful (5 mL) of Dilantin-125 Suspension three times daily, and the dose is then adjusted to suit individual requirements. An increase to five teaspoonfuls daily may be made, if necessary. 9 Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 04/2014 Dosing in Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound phenytoin concentrations may be more useful in these patient populations. Elderly Patients: Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required. Pediatric: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day). HOW SUPPLIED NDC 0071-2214-20—Dilantin-125® Suspension (phenytoin oral suspension, USP), 125 mg phenytoin/5 mL with a maximum alcohol content not greater than 0.6 percent, an orange suspension with an orange-vanilla flavor; available in 8-oz bottles. Store at controlled room temperature 20°–25°C (68°–77°F). [See USP.] Protect from freezing and company logo LAB-0203-14.0 Revised March2014 10 Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 04/2014 MEDICATION GUIDE DILANTIN-125® (Dī LAN' tĭn-125) (Phenytoin Oral Suspension, USP) Read this Medication Guide before you start taking DILANTIN and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about DILANTIN, ask your healthcare provider or pharmacist. What is the most important information I should know about DILANTIN? Do not stop taking DILANTIN without first talking to your healthcare provider. Stopping DILANTIN suddenly can cause serious problems. DILANTIN can cause serious side effects including: 1. Like other antiepileptic drugs, DILANTIN may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • acting aggressive, being angry, • attempts to commit suicide or violent • new or worse depression • acting on dangerous impulses • new or worse anxiety • an extreme increase activity • feeling agitated or restless and talking (mania) • panic attacks • other unusual changes in • trouble sleeping (insomnia) behavior or mood • new or worse irritability How can I watch for early symptoms of suicidal thoughts and actions? • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. • Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Do not stop taking DILANTIN without first talking to a healthcare provider. Stopping DILANTIN suddenly can cause serious problems. Stopping a seizure medicine 11 Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 04/2014 suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus). Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. 2. Dilantin may harm your unborn baby. • If you take DILANTIN during pregnancy, your baby is at risk for serious birth defects. • Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors • If you take DILANTIN during pregnancy, your baby is also at risk for bleeding problems right after birth. Your healthcare provider may give you and your baby medicine to prevent this. • All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of DILANTIN. If the decision is made to use DILANTIN, you should use effective birth control (contraception) unless you are planning to become pregnant. • Tell your healthcare provider right away if you become pregnant while taking DILANTIN. You and your healthcare provider should decide if you will take DILANTIN while you are pregnant. • Pregnancy Registry: If you become pregnant while taking DILANTIN, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3. Swollen glands (lymph nodes) 4. Allergic reactions or serious problems which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions. Symptoms can include any of the following: • swelling of your face, eyes, lips, or tongue • trouble swallowing or breathing • a skin rash • hives • fever, swollen glands (lymph nodes), or sore throat that do not go away or come and go • painful sores in the mouth or around your eyes • yellowing of your skin or eyes • bruising or bleeding • severe fatigue or weakness • severe muscle pain • frequent infections or an infection that does not go away • loss of appetite (anorexia) • nausea or vomiting 12 Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 04/2014 Call your healthcare provider right away if you have any of the symptoms listed above. What is DILANTIN? DILANTIN is a prescription medicine used to treat tonic-clonic (grand mal), complex partial (psychomotor or temporal lobe) seizures, and to prevent and treat seizures that happen during or after brain surgery. Who should not take DILANTIN? Do not take DILANTIN if you: • are allergic to phenytoin or any of the ingredients in DILANTIN. See the end of this leaflet for a complete list of ingredients in DILANTIN. • have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin). • take delavirdine What should I tell my healthcare provider before taking DILANTIN? Before you take DILANTIN, tell your healthcare provider if you: • Have or had liver disease • Have or had porphyria • Have or had diabetes • Have or have had depression, mood problems, or suicidal thoughts or behavior • Are pregnant or plan to become pregnant. If you become pregnant while taking DILANTIN, the level of DILANTIN in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of DILANTIN. • Are breast feeding or plan to breastfeed. DILANTIN can pass into breast milk. You and your healthcare provider should decide if you will take DILANTIN or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking DILANTIN with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take DILANTIN? • Take DILANTIN exactly as prescribed. Your healthcare provider will tell you how much DILANTIN to take. 13 Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 08762 Dilantin-125 (Phenytoin Oral Suspension, USP) FDA Approved Labeling Text dated 04/2014 • Your healthcare provider may change your dose. Do not change your dose of DILANTIN without talking to your healthcare provider. • DILANTIN can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking DILANTIN can help prevent this. • If you take too much DILANTIN, call your healthcare provider or local Poison Control Center right away. • Do not stop taking DILANTIN without first talking to your healthcare provider. Stopping DILANTIN suddenly can cause serious problems. What should I avoid while taking DILANTIN? • Do not drink alcohol while you take DILANTIN without first talking to your healthcare provider. Drinking alcohol while taking DILANTIN may change your blood levels of DILANTIN which can cause serious problems. • Do not drive, operate heavy machinery, or do other dangerous activities until you know how DILANTIN affects you. DILANTIN can slow your thinking and motor skills. What are the possible side effects of DILANTIN? See “What is the most important information I should know about DILANTIN?” DILANTIN may cause other serious side effects including: • Softening of your bones (osteopenia, osteoporosis, and osteomalacia). This can cause broken bones. Call your healthcare provider right away, if you have any of the symptoms listed above. The most common side effects of DILANTIN include: • problems with walking and • tremor coordination • headache • slurred speech • nausea • confusion • vomiting • dizziness • constipation • trouble sleeping • rash • nervousness These are not all the possible side effects of DILANTIN. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. 14 Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store DILANTIN? • Store DILANTIN-125 Suspension at room temperature between 68°F to 77°F (20°C to 25°C). Protect from light. Do not freeze. Keep DILANTIN and all medicines out of the reach of children. General information about DILANTIN Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DILANTIN for a condition for which it was not prescribed. Do not give DILANTIN to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about DILANTIN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about DILANTIN that was written for healthcare professionals. For more information about DILANTIN, visit http://www.pfizer.com or call 1-800-438-1985. What are the ingredients in DILANTIN-125? Oral Suspension Active ingredient: phenytoin, USP Inactive ingredients: alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No. 6. This Medication Guide has been approved by the U.S. Food and Drug Administration. company logo LAB-0398-3.0 October 2011 Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin Injection (Phenytoin Injection) 1 FDA Approved Labeling Text dated 04/2014 Parenteral Dilantin (Phenytoin Sodium Injection, USP) WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION The rate of intravenous Dilantin administration should not exceed 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous Dilantin. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed (see WARNINGS and DOSAGE AND ADMINISTRATION). DESCRIPTION Dilantin (phenytoin sodium injection, USP) is a ready-mixed solution of phenytoin sodium in a vehicle containing 40% propylene glycol and 10% alcohol in water for injection, adjusted to pH 12 with sodium hydroxide. Phenytoin sodium is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is sodium 5,5-diphenyl-2, 4- imidazolidinedione represented by the following structural formula: structural formula CLINICAL PHARMACOLOGY Mechanism of Action Phenytoin is an anticonvulsant which may be useful in the treatment of generalized tonic clonic status epilepticus. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of generalized tonic-clonic seizures. Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin Injection (Phenytoin Injection) 2 FDA Approved Labeling Text dated 04/2014 Pharmacokinetics and Drug Metabolism The plasma half-life in man after intravenous administration ranges from 10 to 15 hours. Optimum control without clinical signs of toxicity occurs most often with serum levels between 10 and 20 mcg/mL. Phenytoin is metabolized by the cytochrome P450 enzymes CYP2C9 and CYP2C19. A fall in plasma levels may occur when patients are changed from oral to intramuscular administration. The drop is caused by slower absorption, as compared to oral administration, due to the poor water solubility of phenytoin. Intravenous administration is the preferred route for producing rapid therapeutic serum levels. When intramuscular administration may be required, a sufficient dose must be administered intramuscularly to maintain the plasma level within the therapeutic range. Where oral dosage is resumed following intramuscular usage, the oral dose should be properly adjusted to compensate for the slow, continuing IM absorption to avoid toxic symptoms. Patients stabilized on a daily oral regimen of Dilantin experience a drop in peak blood levels to 50-60 percent of stable levels if crossed over to an equal dose administered intramuscularly. However, the intramuscular depot of poorly soluble material is eventually absorbed, as determined by urinary excretion of 5-(p-hydroxyphenyl)-5 phenylhydantoin (HPPH), the principal metabolite, as well as the total amount of drug eventually appearing in the blood. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. A short-term (one week) study indicates that patients do not experience the expected drop in blood levels when crossed over to the intramuscular route if the Dilantin IM dose is increased by 50 percent over the previously established oral dose. To avoid drug cumulation due to absorption from the muscle depots, it is recommended that for the first week back on oral Dilantin, the dose be reduced to half of the original oral dose (one third of the IM dose). Experience for periods greater than one week is lacking and blood level monitoring is recommended. Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations. Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION). Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin Injection (Phenytoin Injection) 3 FDA Approved Labeling Text dated 04/2014 Gender and Race: Gender and race have no significant impact on phenytoin pharmacokinetics. Pediatrics: A loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10 20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1 3 mg/kg/min or 50 mg per minute, whichever is slower. INDICATIONS AND USAGE Parenteral Dilantin is indicated for the control of generalized tonic-clonic status epilepticus, and prevention and treatment of seizures occurring during neurosurgery. Parenteral Dilantin should be used only when oral Dilantin administration is not possible. CONTRAINDICATIONS Phenytoin is contraindicated in patients with a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins. Because of its effect on ventricular automaticity, phenytoin is contraindicated in sinus bradycardia, sino-atrial block, second and third degree A-V block, and patients with Adams-Stokes syndrome. Coadministration of Dilantin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non nucleoside reverse transcriptase inhibitors. WARNINGS Cardiovascular Risk Associated with Rapid Infusion Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, the drug should be administered at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. As non-emergency therapy, Dilantin should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Dilantin. Reduction in rate of administration or discontinuation of dosing may be needed. Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, ventricular tachycardia, and Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin Injection (Phenytoin Injection) 4 FDA Approved Labeling Text dated 04/2014 ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates. Withdrawal Precipitated Seizure, Status Epilepticus Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class. Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Dilantin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below). Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA B1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B1502. The use of HLA-B1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Dilantin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin Injection (Phenytoin Injection) 5 FDA Approved Labeling Text dated 04/2014 expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Dilantin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Dilantin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to Dilantin. Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, phenytoin should be immediately discontinued and not re-administered. Hematopoietic System Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling DRESS.In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs. Local Toxicity (including Purple Glove Syndrome) Soft tissue irritation and inflammation has occurred at the site of injection with and without extravasation of intravenous phenytoin. Edema, discoloration and pain distal to the site of injection (described as “purple glove syndrome”) have also been reported following peripheral intravenous phenytoin injection. Soft tissue irritation may vary from slight tenderness to extensive necrosis, and sloughing. The syndrome may not develop for several days after injection. Although Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin Injection (Phenytoin Injection) 6 FDA Approved Labeling Text dated 04/2014 resolution of symptoms may be spontaneous, skin necrosis and limb ischemia have occurred and required such interventions as fasciotomies, skin grafting, and, in rare cases, amputation. Because of the risk of local toxicity, intravenous Dilantin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the IV catheter should be tested with a flush of sterile saline. Each injection of parenteral Dilantin should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution. Intramuscular Dilantin administration may cause pain, necrosis, and abscess formation at the injection site (see DOSAGE AND ADMINISTRATION). Alcohol Use Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may decrease serum levels. Exacerbation of Porphyria In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease. Usage in Pregnancy Clinical Risks to Mother An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated. Risks to the Fetus If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two to three fold that in the general population. However, the relative contribution of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin Injection (Phenytoin Injection) 7 FDA Approved Labeling Text dated 04/2014 Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy. Postpartum Period A potentially life-threatening bleeding disorder related to decreased levels of vitamin K- dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth. Preclinical Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits. PRECAUTIONS General The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early toxicity. A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. Hyperglycemia, resulting from the drug's inhibitory effect on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients. Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin is not effective for absence seizures. If tonic-clonicand absence seizures are present, combined drug therapy is needed. Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as "delirium", "psychosis", or "encephalopathy", or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended. (See Warnings) Laboratory Tests Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin Injection (Phenytoin Injection) 8 FDA Approved Labeling Text dated 04/2014 Drug Interactions Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected. The most commonly occurring drug interactions are listed below: Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. Drugs that affect phenytoin concentrations: • Drugs that may increase phenytoin serum levels, include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, miconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, cimetidine, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin. • Drugs that may decrease phenytoin levels, include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampin, ritonavir, St. John’s Wort, theophylline, and vigabatrin. • Drugs that may either increase or decrease phenytoin serum levels include: phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable. • The addition or withdrawal of the agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome. Drugs affected by phenytoin: • Drugs that should not be coadministered with phenytoin: Delavirdine (see CONTRAINDICATIONS). • Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contaceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, tenisposide, theophylline, and Vitamin D. • Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin. • Phenytoin decreases plasma concentrations of active metabolites of albendazole, certain HIV antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic agents (carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, quetiapine), atorvastatin, chlorpropamide, clozapine, cyclosporine, Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010151 Dilantin Injection (Phenytoin Injection) 9 FDA Approved Labeling Text dated 04/2014 digoxin, fluvastatin, folic acid, methadone, mexiletine, nifedipine, nimodipine, nisoldipine, praziquantel, simvastatin, and verapamil. • Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir. • Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher. • The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome. Drug-Enteral Feeding/Nutritional Preparations Interaction Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients. Drug/Laboratory Test Interactions Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may also cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations following fosphenytoin administration. Carcinogenesis See "Warnings" section for information on carcinogenesis. Pregnancy Pregnancy Category D: See WARNINGS. Nursing Mothers Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Pediatric Use See DOSAGE AND ADMINISTRATION Geriatric Use Phenytoin clearance tends to decrease with increasing age (see CLINICAL PHARMACOLOGY: Special Populations). Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 NDA 010151 Dilantin Injection (Phenytoin Injection) FDA Approved Labeling Text dated 04/2014 ADVERSE REACTIONS The most notable signs of toxicity associated with the intravenous use of this drug are cardiovascular collapse and/or central nervous system depression. Hypotension does occur when the drug is administered rapidly by the intravenous route. The rate of administration is very important; it should not exceed 50 mg per minute in adults, and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Body As a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS (see WARNINGS) have been observed. Anaphylaxis has also been reported. There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities. Cardiovascular: Severe cardiovascular events and fatalities have been reported with atrial and ventricular conduction depression and ventricular fibrillation. Severe complications are most commonly encountered in elderly or critically ill patients (see WARNINGS). Nervous System:.The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesia, and headaches have also been observed. There have also been rare reports of phenytoin induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Digestive System: Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia. Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see WARNINGS section). There have also been reports of hypertrichosis. Local irritation, inflammation, tenderness, necrosis, and sloughing have been reported with or without extravasation of intravenous phenytoin (see WARNINGS). Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy, including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's Disease have been reported (see Warnings). Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 NDA 010151 Dilantin Injection (Phenytoin Injection) FDA Approved Labeling Text dated 04/2014 Special Senses: Altered taste sensation including metallic taste. Urogenital: Peyronie’s disease OVERDOSAGE The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind. DOSAGE AND ADMINISTRATION Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, the drug should be administered at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. As non-emergency therapy, Dilantin should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Dilantin. Reduction in rate of administration or discontinuation of dosing may be needed. Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 NDA 010151 Dilantin Injection (Phenytoin Injection) FDA Approved Labeling Text dated 04/2014 Because of the risk of local toxicity, intravenous Dilantin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the IV catheter should be tested with a flush of sterile saline. Each injection of parenteral Dilantin should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution. Dilantin can be given diluted with normal saline. The addition of parenteral Dilantin to dextrose and dextrose-containing solutions should be avoided due to lack of solubility and resultant precipitation. Treatment with Dilantin can be initiated either with a loading dose or an infusion: Loading Dose: A loading dose of parenteral Dilantin should be injected slowly, not exceeding 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Infusion: For infusion administration, parenteral Dilantin should be diluted in normal saline with the final concentration of Dilantin in the solution no less than 5 mg/mL. Administration should commence immediately after the mixture has been prepared and must be completed within 1 to 4 hours (the infusion mixture should not be refrigerated). An in-line filter (0.22-0.55 microns) should be used. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution or container permit. The diluted infusion mixture (Dilantin plus normal saline) should not be refrigerated. If the undiluted parenteral Dilantin is refrigerated or frozen, a precipitate might form: this will dissolve again after the solution is allowed to stand at room temperature. The product is still suitable for use. A faint yellow coloration may develop, however this has no effect on the potency of the solution. Status Epilepticus In adults, a loading dose of 10 to 15 mg/kg should be administered slowly intravenously, at a rate not exceeding 50 mg per minute (this will require approximately 20 minutes in a 70-kg patient). The loading dose should be followed by maintenance doses of 100 mg orally or intravenously every 6-8 hours. In the pediatric population, a loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10-20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. Continuous monitoring of the electrocardiogram and blood pressure is essential. The patient should be observed for signs of respiratory depression. Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 NDA 010151 Dilantin Injection (Phenytoin Injection) FDA Approved Labeling Text dated 04/2014 Determination of phenytoin plasma levels is advised when using Dilantin in the management of status epilepticus and in the subsequent establishment of maintenance dosage. Other measures, including concomitant administration of an intravenous benzodiazepine such as diazepam, or an intravenous short-acting barbiturate, will usually be necessary for rapid control of seizures because of the required slow rate of administration of Dilantin. If administration of Parenteral Dilantin does not terminate seizures, the use of other anticonvulsants, intravenous barbiturates, general anesthesia, and other appropriate measures should be considered. Intramuscular administration should not be used in the treatment of status epilepticus because the attainment of peak plasma levels may require up to 24 hours. Nonemergent Loading and Maintenance Dosing Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. In adults, a loading dose of 10 to 15 mg/kg should be administered slowly. The rate of intravenous administration should not exceed 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Slower administration rates are recommended to minimize the cardiovascular adverse reactions. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential. The loading dose should be followed by maintenance doses of oral or intravenous Dilantin every 6-8 hours. Ordinarily, Dilantin should not be given intramuscularly because of the risk of necrosis, abscess formation, and erratic absorption. If intramuscular administration is required, compensating dosage adjustments are necessary to maintain therapeutic plasma levels. An intramuscular dose 50% greater than the oral dose is necessary to maintain these levels. When returned to oral administration, the dose should be reduced by 50% of the original oral dose for one week to prevent excessive plasma levels due to sustained release from intramuscular tissue sites. Monitoring plasma levels would help prevent a fall into the subtherapeutic range. Serum blood level determinations are especially helpful when possible drug interactions are suspected. IV Substitution For Oral Phenytoin Therapy When treatment with oral phenytoin is not possible, IV Dilantin can be substituted for oral phenytoin at the same total daily dose. Dilantin capsules are approximately 90% bioavailable by the oral route. Phenytoin is 100% bioavailable by the IV route. For this reason, plasma phenytoin concentrations may increase modestly when IV phenytoin is substituted for oral phenytoin sodium therapy. The rate of administration for IV Dilantin should be no greater than 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 NDA 010151 Dilantin Injection (Phenytoin Injection) FDA Approved Labeling Text dated 04/2014 Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Dilantin® Kapseals® and Dilantin Parenteral are formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspension and Dilantin Infatabs. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa. Dosing in Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound phenytoin concentrations may be more useful in these patient populations. Elderly Patients: Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required. Pediatric: A loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10 20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1 3 mg/kg/min or 50 mg per minute, whichever is slower. HOW SUPPLIED NDC 0071-4488--47 (Steri-Dose® 4488) Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in a 2-mL sterile disposable syringe(22 gauge x 1 ¼ inch needle). Packages of ten syringes. NDC 0071-4488-45 Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in 2-mL Steri-Vials®. Packages of twenty-five. NDC 0071-4475-45 Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in 5-mL Steri-Vials. Packages of twenty-five. Caution- Federal law prohibits dispensing without prescription. Warning- Manufactured with CFC-12, which harms public health and environment by destroying ozone in the upper atmosphere. Rx only company logo Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 NDA 010151 Dilantin Injection (Phenytoin Injection) FDA Approved Labeling Text dated 04/2014 LAB-0383-8.0 March2014 Reference ID: 3482047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:41.554012	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/008762s051,010151s039lbl.pdf', 'application_number': 10151, 'submission_type': 'SUPPL ', 'submission_number': 39}
10,742	NDA 010155/S-022 NDA 010155/ S-023 FDA Approved Labeling Text dated 11/10/2011 Page 1 MYTELASE® AMBENONIUM CHLORIDE DESCRIPTION MYTELASE, brand of ambenonium chloride, is [Oxalylbis (iminoethylene)] bis[(o chlorobenzyl) diethylammonium] dichloride, a white crystalline powder, soluble in water to 20 percent (w/v). Inactive Ingredients: Acacia, Dibasic Calcium Phosphate, Gelatin, Lactose, Magnesium Stearate, Starch, Sucrose. CLINICAL PHARMACOLOGY The compound is a cholinesterase inhibitor with all the pharmacologic actions of acetylcholine, both the muscarinic and nicotinic types. Cholinesterase inactivates acetylcholine. Like neostigmine, MYTELASE suppresses cholinesterase but has the advantage of longer duration of action and fewer side effects on the gastrointestinal tract. The longer duration of action also results in more even strength, better endurance, and greater residual effect during the night and on awakening than is produced by shorter-acting anticholinesterase compounds. INDICATION AND USAGE This drug is indicated for the treatment of myasthenia gravis. CONTRAINDICATIONS Routine administration of atropine with MYTELASE is contraindicated since belladonna derivatives may suppress the parasympathomimetic (muscarinic) symptoms of excessive gastrointestinal stimulation, leaving only the more serious symptoms of fasciculation and paralysis of voluntary muscles as signs of overdosage. MYTELASE should not be administered to patients receiving mecamylamine, or any other ganglionic blocking agents. MYTELASE should also not be administered to patients with a known hypersensitivity to ambenonium chloride or any other ingredients of MYTELASE. WARNINGS Because this drug has a more prolonged action than other antimyasthenic drugs, simultaneous administration with other cholinergics is contraindicated except under strict medical supervision. The overlap in duration of action of several drugs complicates dosage schedules. Therefore, when a patient is to be given the drug, the administration of all other cholinergics should be suspended until the patient has been stabilized. In most instances the myasthenic symptoms are effectively controlled by its use alone. Reference ID: 3042808 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010155/S-022 NDA 010155/ S-023 FDA Approved Labeling Text dated 11/10/2011 Page 2 PRECAUTIONS Great care and supervision are required, since the warning of overdosage is minimal and the requirements of patients vary tremendously. It must be borne in mind constantly that a narrow margin exists between the first appearance of side effects and serious toxic effects. Caution in increasing the dosage is essential. The drug should be used with caution in patients with asthma, Parkinson’s Disease or in patients with mechanical intestinal or urinary obstruction. Usage in Pregnancy. Safe use of this drug during pregnancy has not been established. Therefore, before use of MYTELASE in pregnant women or women of childbearing potential, the potential benefits should be weighed against possible risks to mother and fetus. Nursing Mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from MYTELASE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. Safety and effectiveness in pediatric patients have not been established. Geriatric Use. Clinical Studies of MYTELASE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS Adverse effects of anticholinesterase agents such as MYTELASE usually result from overdosage and include muscarinic effects such as excessive salivation, abdominal cramps, diarrhea, miosis, urinary urgency, sweating, nausea, increase in bronchial and lachrymal secretions, and vomiting, and nicotinic effects such as muscle cramps, fasciculation of voluntary muscles, and rarely generalized malaise with anxiety and vertigo. (See OVERDOSAGE.) DOSAGE AND ADMINISTRATION The oral dose must be individualized according to the patient’s response because the disease varies widely in its severity in different patients and because patients vary in their sensitivity to cholinergic drugs. Since the point of maximum therapeutic effectiveness with optimal muscle strength and no gastrointestinal disturbances is a highly critical one, the close supervision of a physician familiar with the disease is necessary. Because its action is longer, administration of MYTELASE is necessary only every three or four hours, depending on the clinical response. Usually medication is not required throughout the night, so that the patient can sleep uninterruptedly. Reference ID: 3042808 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010155/S-022 NDA 010155/ S-023 FDA Approved Labeling Text dated 11/10/2011 Page 3 For the patient with moderately severe myasthenia, from 5 mg to 25 mg of MYTELASE three or four times daily is an effective dose. In some patients a 5 mg dose is effective, whereas other patients require as much as from 50 mg to 75 mg per dose. The physician should start with a 5 mg dose, carefully observing the effect of the drug on the patient. The dosage may then be increased gradually to determine the effective and safe dose. The longer duration of action of MYTELASE makes it desirable to adjust dosage at intervals of one to two days to avoid drug accumulation and overdosage. (See OVERDOSAGE.) In addition to individual variations in dosage requirements, the amount of cholinergic medication necessary to control symptoms may fluctuate in each patient, depending on his activity and the current status of the disease, including spontaneous remission. A few patients have required greater doses for adequate control of myasthenic symptoms, but increasing the dosage above 200 mg daily requires exacting supervision of a physician well aware of the signs and treatment of overdosage with cholinergic medication. Edrophonium (Tensilon®) may be used to evaluate the adequacy of the maintenance dose of anti-cholinesterase medication. Two mg edrophonium are administered intravenously one hour after the last anticholinesterase dose. A transient increase in strength occurring about 30 seconds later and lasting 3 to 5 minutes indicates insufficient maintenance dose. If the dose is adequate or excessive, no change or a transient decrease in strength will occur, sometimes accompanied by muscarinic symptoms. OVERDOSAGE When the drug produces overstimulation, the clinical picture is one of increasing parasympathomimetic action that is more or less characteristic when not masked by the use of atropine. Signs and symptoms of overdosage, including cholinergic crises, vary considerably. They are usually manifested by increasing gastrointestinal stimulation with epigastric distress, abdominal cramps, diarrhea and vomiting, excessive salivation, pallor, pollakiuria, cold sweating, urinary urgency, blurring of vision, and eventually fasciculation and paralysis of voluntary muscles, including those of the tongue (thick tongue and difficulty in swallowing), shoulder, neck, and arms. Rarely, generalized malaise and vertigo may occur. Miosis, increase in blood pressure with or without bradycardia, and finally, subjective sensations of internal trembling, and often severe anxiety and panic may complete the picture. A cholinergic crisis is usually differentiated from the weakness and paralysis of myasthenia gravis insufficiently treated by cholinergic drugs by the fact that myasthenic weakness is not accompanied by any of the above signs and symptoms, except the last two subjective ones (anxiety and panic). Since the warning of overdosage is minimal, the existence of a narrow margin between the first appearance of side effects and serious toxic effects must be borne in mind constantly. If signs of overdosage occur (excessive gastrointestinal stimulation, excessive salivation, miosis, and more serious fasciculations of voluntary muscles) discontinue temporarily all cholinergic medication and administer from 0.5 mg to 1 mg (1/120 to 1/60 grain) of atropine intravenously. It must be noted that atropine reverses effects of excessive acetylcholine due to overdosage at the muscarinic receptors but not the effects at the nicotinic receptors such as fasciculations and paralysis of respiratory muscles. Reference ID: 3042808 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ERT PROOF NDA 010155/S-022 NDA 010155/ S-023 FDA Approved Labeling Text dated 11/10/2011 Page 4 Pralidoxime chloride may be used to alleviate these effects at the nicotinic receptors since pralidoxime has its most critical effect in relieving paralysis of the muscles of respiration. However, because pralidoxime is less effective in relieving depression of the respiratory center, atropine is always required concomitantly to block the effect of accumulated acetylcholine at this site. Give other supportive treatment as indicated (e.g. artificial respiration, tracheotomy, oxygen, and hospitalization). HOW SUPPLIED Scored, white, capsule – shaped tablets (caplets) with a stylized “W” on one side and “M” score “87” on the other side, 10 mg, bottles of 100 (NDC 0024-1287-04) Store at room temperature up to 25° C (77° F). Rx Only Revised August 2011 Manufactured for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 ©2011 sanofi-aventis U.S. LLC Reference ID: 3042808 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:41.554370	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/010155s023lbl.pdf', 'application_number': 10155, 'submission_type': 'SUPPL ', 'submission_number': 23}
10,741	structural formula Dilantin-125® (Phenytoin Oral Suspension, USP) (FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE) DESCRIPTION Dilantin (phenytoin) is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-diphenyl-2,4 imidazolidinedione, having the following structural formula: Each 5 ml of suspension contains 125 mg of phenytoin, USP; alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No. 6. CLINICAL PHARMACOLOGY Mechanism of Action Phenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures. Pharmacokinetics and Drug Metabolism The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5–7 half-lives) after initiation of therapy with recommended doses of 300 mg/day. When serum level determinations are necessary, they should be obtained at least 5–7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient’s next scheduled dose. Peak levels indicate an individual’s threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. For Dilantin-125 Suspension, peak levels occur 1½–3 hours after administration. Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, variant CYP2C9 and CYP2C19 alleles, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin plasma levels, despite standard doses, presents a difficult 1 Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high plasma levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more. Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations. Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION). Gender and Race: Gender and race have no significant impact on phenytoin pharmacokinetics. Pediatrics: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day). INDICATIONS AND USAGE Dilantin (phenytoin) is indicated for the control of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures. Phenytoin serum level determinations may be necessary for optimal dosage adjustments (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY sections). CONTRAINDICATIONS Dilantin is contraindicated in those patients with a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins. Coadministration of Dilantin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors. WARNINGS Effects of Abrupt Withdrawal Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When in the judgment of the clinician the need for dosage reduction, discontinuation, or substitution of alternative anticonvulsant medication arises, this should be done gradually. In the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an anticonvulsant not belonging to the hydantoin chemical class. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Dilantin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. 2 Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients with Relative Risk: Risk Difference: with Events Per Events Per 1000 Incidence of Events in Additional Drug 1000 Patients Patients Drug Patients with Events Patients/Incidence in Per 1000 Patients Placebo Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Dilantin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. 3 Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Dilantin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below). Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B1502. The use of HLA-B1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Dilantin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Dilantin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Dilantin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to Dilantin. Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with Dilantin. These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, Dilantin should be immediately discontinued and not readministered. Hematopoietic System Hematopoietic complications, some fatal, have occasionally been reported in association with administration of Dilantin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, 4 Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda lymphoma, and Hodgkin’s disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs of DRESS. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs. Effects on Vitamin D and Bone The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures. Phenytoin induces hepatic metabolizing enzymes. This may enhance the metabolism of vitamin D and decrease vitamin D levels, which may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia. Consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines. Effects of Alcohol Use on Phenytoin Serum Levels Acute alcoholic intake may increase phenytoin serum levels, while chronic alcoholic use may decrease serum levels. Exacerbation of Porphyria In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease. Usage in Pregnancy Clinical: Risks to Mother. An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated. Risks to the Fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy. Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth. 5 Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nonclinical. Administration of phenytoin to pregnant animals resulted in teratogenicity (increased incidences of fetal malformations) and other developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple animal species at clinically relevant doses. PRECAUTIONS General: The liver is the chief site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity. A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. If early signs of dose-related CNS toxicity develop, plasma levels should be checked immediately. Hyperglycemia, resulting from the drug’s inhibitory effects on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients. Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present, combined drug therapy is needed. Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended. (See WARNINGS section.) Information for Patients: Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Dilantin. Instruct patients to take Dilantin only as prescribed. Patients taking phenytoin should be advised of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc. Patients should be instructed to use an accurately calibrated measuring device when using this medication to ensure accurate dosing. Patients should be made aware of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use. Patients should also be cautioned on the use of other drugs or alcoholic beverages without first seeking the physician’s advice. The importance of good dental hygiene should be stressed in order to minimize the development of gingival hyperplasia and its complications. Patients, their caregivers, and families should be counseled that AEDs, including Dilantin, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic 6 Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS: Pregnancy section). Laboratory Tests: Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). Drug Interactions: Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19, and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected. The most commonly occurring drug interactions are listed below: Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. Drugs that affect phenytoin concentrations:  Drugs that may increase phenytoin serum levels, include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, miconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin.  Drugs that may decrease phenytoin levels, include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampin, ritonavir, St. John’s Wort, sucralfate, theophylline, and vigabatrin.  Administration of phenytoin with preparations that increase gastric pH (e.g., supplements or antacids containing calcium carbonate, aluminum hydroxide, and magnesium hydroxide) may affect the absorption of phenytoin. In most cases where interactions were seen, the effect is a decrease in phenytoin levels when the drugs are taken at the same time. When possible, phenytoin and these products should not be taken at the same time of day.  Drugs that may either increase or decrease phenytoin serum levels include: phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid, and sodium valproate serum levels is unpredictable.  The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome. Drugs affected by phenytoin:  Drugs that should not be coadministered with phenytoin: Delavirdine (see CONTRAINDICATIONS)  Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, teniposide, theophylline, and vitamin D.  Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin.  Phenytoin decreases plasma concentrations of active metabolites of albendazole, certain HIV antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic 7 Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda agents (carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, quetiapine), atorvastatin, chlorpropamide, clozapine, cyclosporine, digoxin, fluvastatin, folic acid, methadone, mexiletine, nifedipine, nimodipine, nisoldipine, praziquantel, simvastatin, and verapamil.  Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir.  Resistance to the neuromuscular blocking action of the non-depolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.  The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome. Drug Enteral Feeding/Nutritional Preparations Interaction: Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients. Drug/Laboratory Test Interactions: Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations. Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: See WARNINGS (Hematopoietic System) section In carcinogenicity studies, phenytoin was administered in the diet to mice (10, 25, or 45 mg/kg/day) and rats (25, 50, or 100 mg/kg/day) for 2 years. The incidences of hepatocellular tumors were increased in male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The highest doses tested in these studies were associated with peak plasma phenytoin levels below human therapeutic concentrations. In carcinogenicity studies reported in the literature, phenytoin was administered in the diet for 2 years at doses up to 600 ppm (approximately 90 mg/kg/day) to mice and up to 2400 ppm (approximately 120 mg/kg/day) to rats. The incidences of hepatocellular tumors were increased in female mice at all but the lowest dose tested. No increases in tumor incidence were observed in rats. Mutagenesis Phenytoin was negative in the Ames test and in the in vitro clastogenicity assay in Chinese hamster ovary (CHO) cells. In studies reported in the literature, phenytoin was negative in the in vitro mouse lymphoma assay and the in vivo micronucleus assay in mouse. Phenytoin was clastogenic in the in vitro sister chromatid exchange assay in CHO cells. Fertility Phenytoin has not been adequately assessed for effects on male or female fertility. Pregnancy Pregnancy Category D; See WARNINGS section. To provide information regarding the effects of in utero exposure to Dilantin, physicians are advised to recommend that pregnant patients taking Dilantin enroll in the NAAED Pregnancy Registry. This can be 8 Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ . Nursing Mothers: Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Pediatric Use: See DOSAGE AND ADMINISTRATION section. Geriatric Use: Phenytoin clearance tends to decrease with increasing age (see CLINICAL PHARMACOLOGY: Special Populations). ADVERSE REACTIONS Body As a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS (see WARNINGS) have been observed. Anaphylaxis has also been reported. There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities. Nervous System: The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesias, and headaches have also been observed. There have also been rare reports of phenytoin-induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Digestive System: Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia. Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see WARNINGS section). There have also been reports of hypertrichosis. Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease have been reported (see WARNINGS section). Special Senses: Altered taste sensation including metallic taste. Urogenital: Peyronie’s disease OVERDOSAGE The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL; dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has 9 Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Irreversible cerebellar dysfunction and atrophy have been reported. Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind. DOSAGE AND ADMINISTRATION FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Dilantin® Kapseals® is formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspension and Dilantin Infatabs. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa. General: Dosage should be individualized to provide maximum benefit. In some cases serum blood level determinations may be necessary for optimal dosage adjustments—the clinically effective serum level is usually 10–20 mcg/mL. With recommended dosage, a period of seven to ten days may be required to achieve steady-state blood levels with phenytoin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days. Adult Dose: Patients who have received no previous treatment may be started on one teaspoonful (5 mL) of Dilantin-125 Suspension three times daily, and the dose is then adjusted to suit individual requirements. An increase to five teaspoonfuls daily may be made, if necessary. Dosing in Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound phenytoin concentrations may be more useful in these patient populations. Elderly Patients: Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required. Pediatric: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day). HOW SUPPLIED NDC 0071-2214-20—Dilantin-125® Suspension (phenytoin oral suspension, USP), 125 mg phenytoin/5 mL with a maximum alcohol content not greater than 0.6 percent, an orange suspension with an orange-vanilla flavor; available in 8-oz bottles. Store at controlled room temperature 20°–25°C (68°–77°F). [See USP.] Protect from freezing and light. 10 Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda company logo LAB-0203-17.0 Revised December 2015 Reference ID: 3946815 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE DILANTIN-125® (Dī LAN' tĭn-125) (Phenytoin Oral Suspension, USP) Read this Medication Guide before you start taking DILANTIN and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about DILANTIN, ask your healthcare provider or pharmacist. What is the most important information I should know about DILANTIN? Do not stop taking DILANTIN without first talking to your healthcare provider. Stopping DILANTIN suddenly can cause serious problems. DILANTIN can cause serious side effects including: 1. Like other antiepileptic drugs, DILANTIN may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:  thoughts about suicide or dying  acting aggressive, being angry,  attempts to commit suicide or violent  new or worse depression  acting on dangerous impulses  new or worse anxiety  an extreme increase activity  feeling agitated or restless and talking (mania)  panic attacks  other unusual changes in  trouble sleeping (insomnia) behavior or mood  new or worse irritability How can I watch for early symptoms of suicidal thoughts and actions?  Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.  Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. 12 Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Do not stop taking DILANTIN without first talking to a healthcare provider. Stopping DILANTIN suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus). Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. 2. Dilantin may harm your unborn baby.  If you take DILANTIN during pregnancy, your baby is at risk for serious birth defects.  Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors  If you take DILANTIN during pregnancy, your baby is also at risk for bleeding problems right after birth. Your healthcare provider may give you and your baby medicine to prevent this.  All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of DILANTIN. If the decision is made to use DILANTIN, you should use effective birth control (contraception) unless you are planning to become pregnant.  Tell your healthcare provider right away if you become pregnant while taking DILANTIN. You and your healthcare provider should decide if you will take DILANTIN while you are pregnant.  Pregnancy Registry: If you become pregnant while taking DILANTIN, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3. Swollen glands (lymph nodes) 4. Allergic reactions or serious problems which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions. Symptoms can include any of the following:  swelling of your face, eyes,  painful sores in the mouth or lips, or tongue around your eyes  trouble swallowing or  yellowing of your skin or eyes breathing  bruising or bleeding  a skin rash  severe fatigue or weakness  hives  severe muscle pain  fever, swollen glands (lymph  frequent infections or an nodes), or sore throat that do infection that does not go away not go away or come and go  loss of appetite (anorexia) 13 Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  nausea or vomiting Call your healthcare provider right away if you have any of the symptoms listed above. What is DILANTIN? DILANTIN is a prescription medicine used to treat tonic-clonic (grand mal), complex partial (psychomotor or temporal lobe) seizures, and to prevent and treat seizures that happen during or after brain surgery. Who should not take DILANTIN? Do not take DILANTIN if you:  are allergic to phenytoin or any of the ingredients in DILANTIN. See the end of this leaflet for a complete list of ingredients in DILANTIN.  have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin).  take delavirdine What should I tell my healthcare provider before taking DILANTIN? Before you take DILANTIN, tell your healthcare provider if you:  Have or had liver disease  Have or had porphyria  Have or had diabetes  Have or have had depression, mood problems, or suicidal thoughts or behavior  Are pregnant or plan to become pregnant. If you become pregnant while taking DILANTIN, the level of DILANTIN in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of DILANTIN.  Are breast feeding or plan to breastfeed. DILANTIN can pass into breast milk. You and your healthcare provider should decide if you will take DILANTIN or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking DILANTIN with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take DILANTIN?  Take DILANTIN exactly as prescribed. Your healthcare provider will tell you how much DILANTIN to take. 14 Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Your healthcare provider may change your dose. Do not change your dose of DILANTIN without talking to your healthcare provider.  DILANTIN can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking DILANTIN can help prevent this.  If you take too much DILANTIN, call your healthcare provider or local Poison Control Center right away.  Do not stop taking DILANTIN without first talking to your healthcare provider. Stopping DILANTIN suddenly can cause serious problems. What should I avoid while taking DILANTIN?  Do not drink alcohol while you take DILANTIN without first talking to your healthcare provider. Drinking alcohol while taking DILANTIN may change your blood levels of DILANTIN which can cause serious problems.  Do not drive, operate heavy machinery, or do other dangerous activities until you know how DILANTIN affects you. DILANTIN can slow your thinking and motor skills. What are the possible side effects of DILANTIN? See “What is the most important information I should know about DILANTIN?” DILANTIN may cause other serious side effects including:  Softening of your bones (osteopenia, osteoporosis, and osteomalacia). This can cause broken bones. Call your healthcare provider right away, if you have any of the symptoms listed above. The most common side effects of DILANTIN include:  problems with walking and  tremor coordination  headache  slurred speech  nausea  confusion  vomiting  dizziness  constipation  trouble sleeping  rash  nervousness These are not all the possible side effects of DILANTIN. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. 15 Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store DILANTIN?  Store DILANTIN-125 Suspension at room temperature between 68°F to 77°F (20°C to 25°C). Protect from light. Do not freeze. Keep DILANTIN and all medicines out of the reach of children. General information about DILANTIN Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DILANTIN for a condition for which it was not prescribed. Do not give DILANTIN to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about DILANTIN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about DILANTIN that was written for healthcare professionals. For more information about DILANTIN, visit http://www.pfizer.com or call 1-800-438-1985. What are the ingredients in DILANTIN-125? Oral Suspension Active ingredient: phenytoin, USP Inactive ingredients: alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No. 6. This Medication Guide has been approved by the U.S. Food and Drug Administration. company logo LAB-0398-3.0 October 2011 Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Parenteral Dilantin (Phenytoin Sodium Injection, USP) WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION The rate of intravenous Dilantin administration should not exceed 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous Dilantin. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed (see WARNINGS and DOSAGE AND ADMINISTRATION). DESCRIPTION Dilantin (phenytoin sodium injection, USP) is a ready-mixed solution of phenytoin sodium in a vehicle containing 40% propylene glycol and 10% alcohol in water for injection, adjusted to pH 12 with sodium hydroxide. Phenytoin sodium is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is sodium 5,5-diphenyl-2, 4- imidazolidinedione represented by the following structural formula: structural formula CLINICAL PHARMACOLOGY Mechanism of Action Phenytoin is an anticonvulsant which may be useful in the treatment of generalized tonic clonic status epilepticus. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of generalized tonic-clonic seizures. Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Pharmacokinetics and Drug Metabolism The plasma half-life in man after intravenous administration ranges from 10 to 15 hours. Optimum control without clinical signs of toxicity occurs most often with serum levels between 10 and 20 mcg/mL. Phenytoin is metabolized by the cytochrome P450 enzymes CYP2C9 and CYP2C19. A fall in plasma levels may occur when patients are changed from oral to intramuscular administration. The drop is caused by slower absorption, as compared to oral administration, due to the poor water solubility of phenytoin. Intravenous administration is the preferred route for producing rapid therapeutic serum levels. When intramuscular administration may be required, a sufficient dose must be administered intramuscularly to maintain the plasma level within the therapeutic range. Where oral dosage is resumed following intramuscular usage, the oral dose should be properly adjusted to compensate for the slow, continuing IM absorption to avoid toxic symptoms. Patients stabilized on a daily oral regimen of Dilantin experience a drop in peak blood levels to 50-60 percent of stable levels if crossed over to an equal dose administered intramuscularly. However, the intramuscular depot of poorly soluble material is eventually absorbed, as determined by urinary excretion of 5-(p-hydroxyphenyl)-5 phenylhydantoin (HPPH), the principal metabolite, as well as the total amount of drug eventually appearing in the blood. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. A short-term (one week) study indicates that patients do not experience the expected drop in blood levels when crossed over to the intramuscular route if the Dilantin IM dose is increased by 50 percent over the previously established oral dose. To avoid drug cumulation due to absorption from the muscle depots, it is recommended that for the first week back on oral Dilantin, the dose be reduced to half of the original oral dose (one third of the IM dose). Experience for periods greater than one week is lacking and blood level monitoring is recommended. Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations. Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION). Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Gender and Race: Gender and race have no significant impact on phenytoin pharmacokinetics. Pediatrics: A loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10 20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1 3 mg/kg/min or 50 mg per minute, whichever is slower. INDICATIONS AND USAGE Parenteral Dilantin is indicated for the control of generalized tonic-clonic status epilepticus, and prevention and treatment of seizures occurring during neurosurgery. Parenteral Dilantin should be used only when oral Dilantin administration is not possible. CONTRAINDICATIONS Phenytoin is contraindicated in patients with a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins. Because of its effect on ventricular automaticity, phenytoin is contraindicated in sinus bradycardia, sino-atrial block, second and third degree A-V block, and patients with Adams-Stokes syndrome. Coadministration of Dilantin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non nucleoside reverse transcriptase inhibitors. WARNINGS Cardiovascular Risk Associated with Rapid Infusion Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, the drug should be administered at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. As non-emergency therapy, Dilantin should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Dilantin. Reduction in rate of administration or discontinuation of dosing may be needed. Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. However, cardiac Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates. Withdrawal Precipitated Seizure, Status Epilepticus Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class. Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Dilantin should be discontinued at the first sign of a rash, unless the rash is clearly not drug- related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below). Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA B1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B1502. The use of HLA-B1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Dilantin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 should be evaluated immediately. Dilantin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Dilantin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to Dilantin. Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, phenytoin should be immediately discontinued and not re-administered. Hematopoietic System Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling DRESS.In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs. Local Toxicity (including Purple Glove Syndrome) Soft tissue irritation and inflammation has occurred at the site of injection with and without extravasation of intravenous phenytoin. Edema, discoloration and pain distal to the site of injection (described as “purple glove syndrome”) have also been reported following peripheral intravenous phenytoin injection. Soft tissue irritation may vary from slight tenderness to extensive necrosis, and sloughing. The syndrome may not develop for several days after injection. Although resolution of symptoms may be spontaneous, skin necrosis and limb ischemia have occurred and required such interventions as fasciotomies, skin grafting, and, in rare cases, amputation. Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Because of the risk of local toxicity, intravenous Dilantin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the IV catheter should be tested with a flush of sterile saline. Each injection of parenteral Dilantin should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution. Intramuscular Dilantin administration may cause pain, necrosis, and abscess formation at the injection site (see DOSAGE AND ADMINISTRATION). Alcohol Use Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may decrease serum levels. Exacerbation of Porphyria In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease. Usage in Pregnancy Clinical Risks to Mother An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated. Risks to the Fetus If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two to three fold that in the general population. However, the relative contribution of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy. Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Postpartum Period A potentially life-threatening bleeding disorder related to decreased levels of vitamin K- dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth. Nonclinical Administration of phenytoin to pregnant animals resulted in teratogenicity (increased incidences of fetal malformations) and other developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple animal species at clinically relevant doses. PRECAUTIONS General The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early toxicity. A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. Hyperglycemia, resulting from the drug's inhibitory effect on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients. Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin is not effective for absence seizures. If tonic-clonicand absence seizures are present, combined drug therapy is needed. Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as "delirium", "psychosis", or "encephalopathy", or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended. (See Warnings) Laboratory Tests Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). Drug Interactions Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected. The most commonly occurring drug interactions are listed below: Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. Drugs that affect phenytoin concentrations:  Drugs that may increase phenytoin serum levels, include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, miconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, cimetidine, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin.  Drugs that may decrease phenytoin levels, include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampin, ritonavir, St. John’s Wort, theophylline, and vigabatrin.  Drugs that may either increase or decrease phenytoin serum levels include: phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable.  The addition or withdrawal of the agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome. Drugs affected by phenytoin:  Drugs that should not be coadministered with phenytoin: Delavirdine (see CONTRAINDICATIONS).  Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contaceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, tenisposide, theophylline, and Vitamin D.  Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin.  Phenytoin decreases plasma concentrations of active metabolites of albendazole, certain HIV antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic agents (carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, quetiapine), atorvastatin, chlorpropamide, clozapine, cyclosporine, digoxin, fluvastatin, folic acid, methadone, mexiletine, nifedipine, nimodipine, nisoldipine, praziquantel, simvastatin, and verapamil. Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9  Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir.  Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.  The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome. Drug-Enteral Feeding/Nutritional Preparations Interaction Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients. Drug/Laboratory Test Interactions Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may also cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations following fosphenytoin administration. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: See WARNINGS (Hematopoietic System) section In carcinogenicity studies, phenytoin was administered in the diet to mice (10, 25, or 45 mg/kg/day) and rats (25, 50, or 100 mg/kg/day) for 2 years. The incidences of hepatocellular tumors were increased in male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The highest doses tested in these studies were associated with peak plasma phenytoin levels below human therapeutic concentrations. In carcinogenicity studies reported in the literature, phenytoin was administered in the diet for 2 years at doses up to 600 ppm (approximately 90 mg/kg/day) to mice and up to 2400 ppm (approximately 120 mg/kg/day) to rats. The incidences of hepatocellular tumors were increased in female mice at all but the lowest dose tested. No increases in tumor incidence were observed in rats. Mutagenesis Phenytoin was negative in the Ames test and in the in vitro clastogenicity assay in Chinese hamster ovary (CHO) cells. Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 In studies reported in the literature, phenytoin was negative in the in vitro mouse lymphoma assay and the in vivo micronucleus assay in mouse. Phenytoin was clastogenic in the in vitro sister chromatid exchange assay in CHO cells. Fertility Phenytoin has not been adequately assessed for effects on male or female fertility. Pregnancy Pregnancy Category D: See WARNINGS. Nursing Mothers Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Pediatric Use See DOSAGE AND ADMINISTRATION Geriatric Use Phenytoin clearance tends to decrease with increasing age (see CLINICAL PHARMACOLOGY: Special Populations). ADVERSE REACTIONS The most notable signs of toxicity associated with the intravenous use of this drug are cardiovascular collapse and/or central nervous system depression. Hypotension does occur when the drug is administered rapidly by the intravenous route. The rate of administration is very important; it should not exceed 50 mg per minute in adults, and 1 3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Body As a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS (see WARNINGS) have been observed. Anaphylaxis has also been reported. There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities. Cardiovascular: Severe cardiovascular events and fatalities have been reported with atrial and ventricular conduction depression and ventricular fibrillation. Severe complications are most commonly encountered in elderly or critically ill patients (see WARNINGS). Nervous System:.The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesia, and headaches have also been observed. There have also been rare reports of phenytoin induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. Cerebellar atrophy has Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Digestive System: Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia. Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see WARNINGS section). There have also been reports of hypertrichosis. Local irritation, inflammation, tenderness, necrosis, and sloughing have been reported with or without extravasation of intravenous phenytoin (see WARNINGS). Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy, including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's Disease have been reported (see Warnings). Special Senses: Altered taste sensation including metallic taste. Urogenital: Peyronie’s disease OVERDOSAGE The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Irreversible cerebellar dysfunction and atrophy have been reported. Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind. DOSAGE AND ADMINISTRATION Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, the drug should be administered at a rate not exceeding 1 3 mg/kg/min or 50 mg per minute, whichever is slower. As non-emergency therapy, Dilantin should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Dilantin. Reduction in rate of administration or discontinuation of dosing may be needed. Because of the risk of local toxicity, intravenous Dilantin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the IV catheter should be tested with a flush of sterile saline. Each injection of parenteral Dilantin should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution. Dilantin can be given diluted with normal saline. The addition of parenteral Dilantin to dextrose and dextrose-containing solutions should be avoided due to lack of solubility and resultant precipitation. Treatment with Dilantin can be initiated either with a loading dose or an infusion: Loading Dose: A loading dose of parenteral Dilantin should be injected slowly, not exceeding 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Infusion: For infusion administration, parenteral Dilantin should be diluted in normal saline with the final concentration of Dilantin in the solution no less than 5 mg/mL. Administration should commence immediately after the mixture has been prepared and must be completed within 1 to 4 hours (the infusion mixture should not be refrigerated). An in-line filter (0.22-0.55 microns) should be used. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution or container permit. Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 The diluted infusion mixture (Dilantin plus normal saline) should not be refrigerated. If the undiluted parenteral Dilantin is refrigerated or frozen, a precipitate might form: this will dissolve again after the solution is allowed to stand at room temperature. The product is still suitable for use. A faint yellow coloration may develop, however this has no effect on the potency of the solution. Status Epilepticus In adults, a loading dose of 10 to 15 mg/kg should be administered slowly intravenously, at a rate not exceeding 50 mg per minute (this will require approximately 20 minutes in a 70-kg patient). The loading dose should be followed by maintenance doses of 100 mg orally or intravenously every 6-8 hours. In the pediatric population, a loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10-20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. Continuous monitoring of the electrocardiogram and blood pressure is essential. The patient should be observed for signs of respiratory depression. Determination of phenytoin plasma levels is advised when using Dilantin in the management of status epilepticus and in the subsequent establishment of maintenance dosage. Other measures, including concomitant administration of an intravenous benzodiazepine such as diazepam, or an intravenous short-acting barbiturate, will usually be necessary for rapid control of seizures because of the required slow rate of administration of Dilantin. If administration of Parenteral Dilantin does not terminate seizures, the use of other anticonvulsants, intravenous barbiturates, general anesthesia, and other appropriate measures should be considered. Intramuscular administration should not be used in the treatment of status epilepticus because the attainment of peak plasma levels may require up to 24 hours. Nonemergent Loading and Maintenance Dosing Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. In adults, a loading dose of 10 to 15 mg/kg should be administered slowly. The rate of intravenous administration should not exceed 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Slower administration rates are recommended to minimize the cardiovascular adverse reactions. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential. The loading dose should be followed by maintenance doses of oral or intravenous Dilantin every 6-8 hours. Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Ordinarily, Dilantin should not be given intramuscularly because of the risk of necrosis, abscess formation, and erratic absorption. If intramuscular administration is required, compensating dosage adjustments are necessary to maintain therapeutic plasma levels. An intramuscular dose 50% greater than the oral dose is necessary to maintain these levels. When returned to oral administration, the dose should be reduced by 50% of the original oral dose for one week to prevent excessive plasma levels due to sustained release from intramuscular tissue sites. Monitoring plasma levels would help prevent a fall into the subtherapeutic range. Serum blood level determinations are especially helpful when possible drug interactions are suspected. IV Substitution For Oral Phenytoin Therapy When treatment with oral phenytoin is not possible, IV Dilantin can be substituted for oral phenytoin at the same total daily dose. Dilantin capsules are approximately 90% bioavailable by the oral route. Phenytoin is 100% bioavailable by the IV route. For this reason, plasma phenytoin concentrations may increase modestly when IV phenytoin is substituted for oral phenytoin sodium therapy. The rate of administration for IV Dilantin should be no greater than 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Dilantin® Kapseals® and Dilantin Parenteral are formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspension and Dilantin Infatabs. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa. Dosing in Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound phenytoin concentrations may be more useful in these patient populations. Elderly Patients: Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required. Pediatric: A loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10 20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1 3 mg/kg/min or 50 mg per minute, whichever is slower. Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 HOW SUPPLIED NDC 0071-4488--47 (Steri-Dose® 4488) Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in a 2-mL sterile disposable syringe(22 gauge x 1 ¼ inch needle). Packages of ten syringes. NDC 0071-4488-45 Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in 2-mL Steri-Vials®. Packages of twenty-five. NDC 0071-4475-45 Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in 5-mL Steri-Vials. Packages of twenty-five. Caution- Federal law prohibits dispensing without prescription. Warning- Manufactured with CFC-12, which harms public health and environment by destroying ozone in the upper atmosphere. Rx only company logo LAB-0383-11.0 Revised December 2015 Reference ID: 3946815 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:41.578490	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/008762s055,010151s042lbl.pdf', 'application_number': 10151, 'submission_type': 'SUPPL ', 'submission_number': 42}
10,740	Dilantin-125® (Phenytoin Oral Suspension, USP) (FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE) DESCRIPTION Dilantin (phenytoin) is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-diphenyl-2,4 imidazolidinedione, having the following structural formula: structural formula Each 5 ml of suspension contains 125 mg of phenytoin, USP; alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No. 6. CLINICAL PHARMACOLOGY Mechanism of Action Phenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures. Pharmacokinetics and Drug Metabolism The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5–7 half-lives) after initiation of therapy with recommended doses of 300 mg/day. When serum level determinations are necessary, they should be obtained at least 5–7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient’s next scheduled dose. Peak levels indicate an individual’s threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. For Dilantin-125 Suspension, peak levels occur 1½–3 hours after administration. Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, variant CYP2C9 and CYP2C19 alleles, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin plasma levels, despite standard doses, presents a difficult 1 Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high plasma levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more. Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations. Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION). Gender and Race: Gender and race have no significant impact on phenytoin pharmacokinetics. Pediatrics: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day). INDICATIONS AND USAGE Dilantin (phenytoin) is indicated for the control of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures. Phenytoin serum level determinations may be necessary for optimal dosage adjustments (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY sections). CONTRAINDICATIONS Dilantin is contraindicated in those patients with a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins. Coadministration of Dilantin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors. WARNINGS Effects of Abrupt Withdrawal Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When in the judgment of the clinician the need for dosage reduction, discontinuation, or substitution of alternative anticonvulsant medication arises, this should be done gradually. In the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an anticonvulsant not belonging to the hydantoin chemical class. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Dilantin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. 2 Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients with Relative Risk: Risk Difference: with Events Per Events Per 1000 Incidence of Events in Additional Drug 1000 Patients Patients Drug Patients with Events Patients/Incidence in Per 1000 Patients Placebo Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Dilantin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. 3 Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Dilantin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below). Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B1502. The use of HLA-B1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Dilantin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Dilantin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Dilantin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to Dilantin. Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with Dilantin. These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, Dilantin should be immediately discontinued and not readministered. Hematopoietic System Hematopoietic complications, some fatal, have occasionally been reported in association with administration of Dilantin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, 4 Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda lymphoma, and Hodgkin’s disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs of DRESS. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs. Effects on Vitamin D and Bone The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures. Phenytoin induces hepatic metabolizing enzymes. This may enhance the metabolism of vitamin D and decrease vitamin D levels, which may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia. Consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines. Effects of Alcohol Use on Phenytoin Serum Levels Acute alcoholic intake may increase phenytoin serum levels, while chronic alcoholic use may decrease serum levels. Exacerbation of Porphyria In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease. Usage in Pregnancy Clinical: Risks to Mother. An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated. Risks to the Fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy. Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth. 5 Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nonclinical. Administration of phenytoin to pregnant animals resulted in teratogenicity (increased incidences of fetal malformations) and other developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple animal species at clinically relevant doses. PRECAUTIONS General: The liver is the chief site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity. A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. If early signs of dose-related CNS toxicity develop, plasma levels should be checked immediately. Hyperglycemia, resulting from the drug’s inhibitory effects on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients. Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present, combined drug therapy is needed. Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended. (See WARNINGS section.) Information for Patients: Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Dilantin. Instruct patients to take Dilantin only as prescribed. Patients taking phenytoin should be advised of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc. Patients should be instructed to use an accurately calibrated measuring device when using this medication to ensure accurate dosing. Patients should be made aware of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use. Patients should also be cautioned on the use of other drugs or alcoholic beverages without first seeking the physician’s advice. The importance of good dental hygiene should be stressed in order to minimize the development of gingival hyperplasia and its complications. Patients, their caregivers, and families should be counseled that AEDs, including Dilantin, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic 6 Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS: Pregnancy section). Laboratory Tests: Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). Drug Interactions: Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19, and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected. The most commonly occurring drug interactions are listed below: Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. Drugs that affect phenytoin concentrations:  Drugs that may increase phenytoin serum levels, include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, miconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin.  Drugs that may decrease phenytoin levels, include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampin, ritonavir, St. John’s Wort, sucralfate, theophylline, and vigabatrin.  Administration of phenytoin with preparations that increase gastric pH (e.g., supplements or antacids containing calcium carbonate, aluminum hydroxide, and magnesium hydroxide) may affect the absorption of phenytoin. In most cases where interactions were seen, the effect is a decrease in phenytoin levels when the drugs are taken at the same time. When possible, phenytoin and these products should not be taken at the same time of day.  Drugs that may either increase or decrease phenytoin serum levels include: phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid, and sodium valproate serum levels is unpredictable.  The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome. Drugs affected by phenytoin:  Drugs that should not be coadministered with phenytoin: Delavirdine (see CONTRAINDICATIONS)  Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, teniposide, theophylline, and vitamin D.  Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin.  Phenytoin decreases plasma concentrations of active metabolites of albendazole, certain HIV antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic 7 Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda agents (carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, quetiapine), atorvastatin, chlorpropamide, clozapine, cyclosporine, digoxin, fluvastatin, folic acid, methadone, mexiletine, nifedipine, nimodipine, nisoldipine, praziquantel, simvastatin, and verapamil.  Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir.  Resistance to the neuromuscular blocking action of the non-depolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.  The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome. Drug Enteral Feeding/Nutritional Preparations Interaction: Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients. Drug/Laboratory Test Interactions: Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations. Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: See WARNINGS (Hematopoietic System) section In carcinogenicity studies, phenytoin was administered in the diet to mice (10, 25, or 45 mg/kg/day) and rats (25, 50, or 100 mg/kg/day) for 2 years. The incidences of hepatocellular tumors were increased in male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The highest doses tested in these studies were associated with peak plasma phenytoin levels below human therapeutic concentrations. In carcinogenicity studies reported in the literature, phenytoin was administered in the diet for 2 years at doses up to 600 ppm (approximately 90 mg/kg/day) to mice and up to 2400 ppm (approximately 120 mg/kg/day) to rats. The incidences of hepatocellular tumors were increased in female mice at all but the lowest dose tested. No increases in tumor incidence were observed in rats. Mutagenesis Phenytoin was negative in the Ames test and in the in vitro clastogenicity assay in Chinese hamster ovary (CHO) cells. In studies reported in the literature, phenytoin was negative in the in vitro mouse lymphoma assay and the in vivo micronucleus assay in mouse. Phenytoin was clastogenic in the in vitro sister chromatid exchange assay in CHO cells. Fertility Phenytoin has not been adequately assessed for effects on male or female fertility. Pregnancy Pregnancy Category D; See WARNINGS section. To provide information regarding the effects of in utero exposure to Dilantin, physicians are advised to recommend that pregnant patients taking Dilantin enroll in the NAAED Pregnancy Registry. This can be 8 Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ . Nursing Mothers: Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Pediatric Use: See DOSAGE AND ADMINISTRATION section. Geriatric Use: Phenytoin clearance tends to decrease with increasing age (see CLINICAL PHARMACOLOGY: Special Populations). ADVERSE REACTIONS Body As a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS (see WARNINGS) have been observed. Anaphylaxis has also been reported. There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities. Nervous System: The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesias, and headaches have also been observed. There have also been rare reports of phenytoin-induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Digestive System: Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia. Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see WARNINGS section). There have also been reports of hypertrichosis. Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease have been reported (see WARNINGS section). Special Senses: Altered taste sensation including metallic taste. Urogenital: Peyronie’s disease OVERDOSAGE The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL; dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. 9 Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind. DOSAGE AND ADMINISTRATION FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Dilantin® Kapseals® is formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspension and Dilantin Infatabs. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa. General: Dosage should be individualized to provide maximum benefit. In some cases serum blood level determinations may be necessary for optimal dosage adjustments—the clinically effective serum level is usually 10–20 mcg/mL. With recommended dosage, a period of seven to ten days may be required to achieve steady-state blood levels with phenytoin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days. Adult Dose: Patients who have received no previous treatment may be started on one teaspoonful (5 mL) of Dilantin-125 Suspension three times daily, and the dose is then adjusted to suit individual requirements. An increase to five teaspoonfuls daily may be made, if necessary. Dosing in Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound phenytoin concentrations may be more useful in these patient populations. Elderly Patients: Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required. Pediatric: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day). HOW SUPPLIED NDC 0071-2214-20—Dilantin-125® Suspension (phenytoin oral suspension, USP), 125 mg phenytoin/5 mL with a maximum alcohol content not greater than 0.6 percent, an orange suspension with an orange-vanilla flavor; available in 8-oz bottles. Store at controlled room temperature 20°–25°C (68°–77°F). [See USP.] Protect from freezing and company logo LAB-0203-16.0 Revised July 2015 10 Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE DILANTIN-125® (Dī LAN' tĭn-125) (Phenytoin Oral Suspension, USP) Read this Medication Guide before you start taking DILANTIN and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about DILANTIN, ask your healthcare provider or pharmacist. What is the most important information I should know about DILANTIN? Do not stop taking DILANTIN without first talking to your healthcare provider. Stopping DILANTIN suddenly can cause serious problems. DILANTIN can cause serious side effects including: 1. Like other antiepileptic drugs, DILANTIN may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:  thoughts about suicide or dying  acting aggressive, being angry,  attempts to commit suicide or violent  new or worse depression  acting on dangerous impulses  new or worse anxiety  an extreme increase activity  feeling agitated or restless and talking (mania)  panic attacks  other unusual changes in  trouble sleeping (insomnia) behavior or mood  new or worse irritability How can I watch for early symptoms of suicidal thoughts and actions?  Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.  Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. 11 Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Do not stop taking DILANTIN without first talking to a healthcare provider. Stopping DILANTIN suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus). Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. 2. Dilantin may harm your unborn baby.  If you take DILANTIN during pregnancy, your baby is at risk for serious birth defects.  Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors  If you take DILANTIN during pregnancy, your baby is also at risk for bleeding problems right after birth. Your healthcare provider may give you and your baby medicine to prevent this.  All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of DILANTIN. If the decision is made to use DILANTIN, you should use effective birth control (contraception) unless you are planning to become pregnant.  Tell your healthcare provider right away if you become pregnant while taking DILANTIN. You and your healthcare provider should decide if you will take DILANTIN while you are pregnant.  Pregnancy Registry: If you become pregnant while taking DILANTIN, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3. Swollen glands (lymph nodes) 4. Allergic reactions or serious problems which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions. Symptoms can include any of the following:  swelling of your face, eyes,  painful sores in the mouth or lips, or tongue around your eyes  trouble swallowing or  yellowing of your skin or eyes breathing  bruising or bleeding  a skin rash  severe fatigue or weakness  hives  severe muscle pain  fever, swollen glands (lymph  frequent infections or an nodes), or sore throat that do infection that does not go away not go away or come and go  loss of appetite (anorexia) 12 Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  nausea or vomiting Call your healthcare provider right away if you have any of the symptoms listed above. What is DILANTIN? DILANTIN is a prescription medicine used to treat tonic-clonic (grand mal), complex partial (psychomotor or temporal lobe) seizures, and to prevent and treat seizures that happen during or after brain surgery. Who should not take DILANTIN? Do not take DILANTIN if you:  are allergic to phenytoin or any of the ingredients in DILANTIN. See the end of this leaflet for a complete list of ingredients in DILANTIN.  have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin).  take delavirdine What should I tell my healthcare provider before taking DILANTIN? Before you take DILANTIN, tell your healthcare provider if you:  Have or had liver disease  Have or had porphyria  Have or had diabetes  Have or have had depression, mood problems, or suicidal thoughts or behavior  Are pregnant or plan to become pregnant. If you become pregnant while taking DILANTIN, the level of DILANTIN in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of DILANTIN.  Are breast feeding or plan to breastfeed. DILANTIN can pass into breast milk. You and your healthcare provider should decide if you will take DILANTIN or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking DILANTIN with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take DILANTIN?  Take DILANTIN exactly as prescribed. Your healthcare provider will tell you how much DILANTIN to take. 13 Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Your healthcare provider may change your dose. Do not change your dose of DILANTIN without talking to your healthcare provider.  DILANTIN can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking DILANTIN can help prevent this.  If you take too much DILANTIN, call your healthcare provider or local Poison Control Center right away.  Do not stop taking DILANTIN without first talking to your healthcare provider. Stopping DILANTIN suddenly can cause serious problems. What should I avoid while taking DILANTIN?  Do not drink alcohol while you take DILANTIN without first talking to your healthcare provider. Drinking alcohol while taking DILANTIN may change your blood levels of DILANTIN which can cause serious problems.  Do not drive, operate heavy machinery, or do other dangerous activities until you know how DILANTIN affects you. DILANTIN can slow your thinking and motor skills. What are the possible side effects of DILANTIN? See “What is the most important information I should know about DILANTIN?” DILANTIN may cause other serious side effects including:  Softening of your bones (osteopenia, osteoporosis, and osteomalacia). This can cause broken bones. Call your healthcare provider right away, if you have any of the symptoms listed above. The most common side effects of DILANTIN include:  problems with walking and  tremor coordination  headache  slurred speech  nausea  confusion  vomiting  dizziness  constipation  trouble sleeping  rash  nervousness These are not all the possible side effects of DILANTIN. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. 14 Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store DILANTIN?  Store DILANTIN-125 Suspension at room temperature between 68°F to 77°F (20°C to 25°C). Protect from light. Do not freeze. Keep DILANTIN and all medicines out of the reach of children. General information about DILANTIN Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DILANTIN for a condition for which it was not prescribed. Do not give DILANTIN to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about DILANTIN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about DILANTIN that was written for healthcare professionals. For more information about DILANTIN, visit http://www.pfizer.com or call 1-800-438-1985. What are the ingredients in DILANTIN-125? Oral Suspension Active ingredient: phenytoin, USP Inactive ingredients: alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No. 6. This Medication Guide has been approved by the U.S. Food and Drug Administration. company logo LAB-0398-3.0 October 2011 Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Parenteral Dilantin (Phenytoin Sodium Injection, USP) WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION The rate of intravenous Dilantin administration should not exceed 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous Dilantin. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed (see WARNINGS and DOSAGE AND ADMINISTRATION). DESCRIPTION Dilantin (phenytoin sodium injection, USP) is a ready-mixed solution of phenytoin sodium in a vehicle containing 40% propylene glycol and 10% alcohol in water for injection, adjusted to pH 12 with sodium hydroxide. Phenytoin sodium is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is sodium 5,5-diphenyl-2, 4- imidazolidinedione represented by the following structural formula: structural formula CLINICAL PHARMACOLOGY Mechanism of Action Phenytoin is an anticonvulsant which may be useful in the treatment of generalized tonic clonic status epilepticus. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of generalized tonic-clonic seizures. Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Pharmacokinetics and Drug Metabolism The plasma half-life in man after intravenous administration ranges from 10 to 15 hours. Optimum control without clinical signs of toxicity occurs most often with serum levels between 10 and 20 mcg/mL. Phenytoin is metabolized by the cytochrome P450 enzymes CYP2C9 and CYP2C19. A fall in plasma levels may occur when patients are changed from oral to intramuscular administration. The drop is caused by slower absorption, as compared to oral administration, due to the poor water solubility of phenytoin. Intravenous administration is the preferred route for producing rapid therapeutic serum levels. When intramuscular administration may be required, a sufficient dose must be administered intramuscularly to maintain the plasma level within the therapeutic range. Where oral dosage is resumed following intramuscular usage, the oral dose should be properly adjusted to compensate for the slow, continuing IM absorption to avoid toxic symptoms. Patients stabilized on a daily oral regimen of Dilantin experience a drop in peak blood levels to 50-60 percent of stable levels if crossed over to an equal dose administered intramuscularly. However, the intramuscular depot of poorly soluble material is eventually absorbed, as determined by urinary excretion of 5-(p-hydroxyphenyl)-5 phenylhydantoin (HPPH), the principal metabolite, as well as the total amount of drug eventually appearing in the blood. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. A short-term (one week) study indicates that patients do not experience the expected drop in blood levels when crossed over to the intramuscular route if the Dilantin IM dose is increased by 50 percent over the previously established oral dose. To avoid drug cumulation due to absorption from the muscle depots, it is recommended that for the first week back on oral Dilantin, the dose be reduced to half of the original oral dose (one third of the IM dose). Experience for periods greater than one week is lacking and blood level monitoring is recommended. Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations. Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION). Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Gender and Race: Gender and race have no significant impact on phenytoin pharmacokinetics. Pediatrics: A loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10 20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1 3 mg/kg/min or 50 mg per minute, whichever is slower. INDICATIONS AND USAGE Parenteral Dilantin is indicated for the control of generalized tonic-clonic status epilepticus, and prevention and treatment of seizures occurring during neurosurgery. Parenteral Dilantin should be used only when oral Dilantin administration is not possible. CONTRAINDICATIONS Phenytoin is contraindicated in patients with a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins. Because of its effect on ventricular automaticity, phenytoin is contraindicated in sinus bradycardia, sino-atrial block, second and third degree A-V block, and patients with Adams-Stokes syndrome. Coadministration of Dilantin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non nucleoside reverse transcriptase inhibitors. WARNINGS Cardiovascular Risk Associated with Rapid Infusion Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, the drug should be administered at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. As non-emergency therapy, Dilantin should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Dilantin. Reduction in rate of administration or discontinuation of dosing may be needed. Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. However, cardiac Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates. Withdrawal Precipitated Seizure, Status Epilepticus Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class. Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Dilantin should be discontinued at the first sign of a rash, unless the rash is clearly not drug- related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below). Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA B1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B1502. The use of HLA-B1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Dilantin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 should be evaluated immediately. Dilantin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Dilantin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to Dilantin. Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, phenytoin should be immediately discontinued and not re-administered. Hematopoietic System Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling DRESS.In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs. Local Toxicity (including Purple Glove Syndrome) Soft tissue irritation and inflammation has occurred at the site of injection with and without extravasation of intravenous phenytoin. Edema, discoloration and pain distal to the site of injection (described as “purple glove syndrome”) have also been reported following peripheral intravenous phenytoin injection. Soft tissue irritation may vary from slight tenderness to extensive necrosis, and sloughing. The syndrome may not develop for several days after injection. Although resolution of symptoms may be spontaneous, skin necrosis and limb ischemia have occurred and required such interventions as fasciotomies, skin grafting, and, in rare cases, amputation. Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Because of the risk of local toxicity, intravenous Dilantin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the IV catheter should be tested with a flush of sterile saline. Each injection of parenteral Dilantin should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution. Intramuscular Dilantin administration may cause pain, necrosis, and abscess formation at the injection site (see DOSAGE AND ADMINISTRATION). Alcohol Use Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may decrease serum levels. Exacerbation of Porphyria In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease. Usage in Pregnancy Clinical Risks to Mother An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated. Risks to the Fetus If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two to three fold that in the general population. However, the relative contribution of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy. Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Postpartum Period A potentially life-threatening bleeding disorder related to decreased levels of vitamin K- dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth. Nonclinical Administration of phenytoin to pregnant animals resulted in teratogenicity (increased incidences of fetal malformations) and other developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple animal species at clinically relevant doses. PRECAUTIONS General The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early toxicity. A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. Hyperglycemia, resulting from the drug's inhibitory effect on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients. Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin is not effective for absence seizures. If tonic-clonicand absence seizures are present, combined drug therapy is needed. Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as "delirium", "psychosis", or "encephalopathy", or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended. (See Warnings) Laboratory Tests Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). Drug Interactions Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected. The most commonly occurring drug interactions are listed below: Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. Drugs that affect phenytoin concentrations:  Drugs that may increase phenytoin serum levels, include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, miconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, cimetidine, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin.  Drugs that may decrease phenytoin levels, include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampin, ritonavir, St. John’s Wort, theophylline, and vigabatrin.  Drugs that may either increase or decrease phenytoin serum levels include: phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable.  The addition or withdrawal of the agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome. Drugs affected by phenytoin:  Drugs that should not be coadministered with phenytoin: Delavirdine (see CONTRAINDICATIONS).  Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contaceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, tenisposide, theophylline, and Vitamin D.  Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin.  Phenytoin decreases plasma concentrations of active metabolites of albendazole, certain HIV antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic agents (carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, quetiapine), atorvastatin, chlorpropamide, clozapine, cyclosporine, digoxin, fluvastatin, folic acid, methadone, mexiletine, nifedipine, nimodipine, nisoldipine, praziquantel, simvastatin, and verapamil.  Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir. Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9  Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.  The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome. Drug-Enteral Feeding/Nutritional Preparations Interaction Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients. Drug/Laboratory Test Interactions Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may also cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations following fosphenytoin administration. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: See WARNINGS (Hematopoietic System) section In carcinogenicity studies, phenytoin was administered in the diet to mice (10, 25, or 45 mg/kg/day) and rats (25, 50, or 100 mg/kg/day) for 2 years. The incidences of hepatocellular tumors were increased in male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The highest doses tested in these studies were associated with peak plasma phenytoin levels below human therapeutic concentrations. In carcinogenicity studies reported in the literature, phenytoin was administered in the diet for 2 years at doses up to 600 ppm (approximately 90 mg/kg/day) to mice and up to 2400 ppm (approximately 120 mg/kg/day) to rats. The incidences of hepatocellular tumors were increased in female mice at all but the lowest dose tested. No increases in tumor incidence were observed in rats. Mutagenesis Phenytoin was negative in the Ames test and in the in vitro clastogenicity assay in Chinese hamster ovary (CHO) cells. Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 In studies reported in the literature, phenytoin was negative in the in vitro mouse lymphoma assay and the in vivo micronucleus assay in mouse. Phenytoin was clastogenic in the in vitro sister chromatid exchange assay in CHO cells. Fertility Phenytoin has not been adequately assessed for effects on male or female fertility. Pregnancy Pregnancy Category D: See WARNINGS. Nursing Mothers Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Pediatric Use See DOSAGE AND ADMINISTRATION Geriatric Use Phenytoin clearance tends to decrease with increasing age (see CLINICAL PHARMACOLOGY: Special Populations). ADVERSE REACTIONS The most notable signs of toxicity associated with the intravenous use of this drug are cardiovascular collapse and/or central nervous system depression. Hypotension does occur when the drug is administered rapidly by the intravenous route. The rate of administration is very important; it should not exceed 50 mg per minute in adults, and 1 3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Body As a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS (see WARNINGS) have been observed. Anaphylaxis has also been reported. There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities. Cardiovascular: Severe cardiovascular events and fatalities have been reported with atrial and ventricular conduction depression and ventricular fibrillation. Severe complications are most commonly encountered in elderly or critically ill patients (see WARNINGS). Nervous System:.The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesia, and headaches have also been observed. There have also been rare reports of phenytoin induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Digestive System: Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia. Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see WARNINGS section). There have also been reports of hypertrichosis. Local irritation, inflammation, tenderness, necrosis, and sloughing have been reported with or without extravasation of intravenous phenytoin (see WARNINGS). Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy, including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's Disease have been reported (see Warnings). Special Senses: Altered taste sensation including metallic taste. Urogenital: Peyronie’s disease OVERDOSAGE The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind. Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 DOSAGE AND ADMINISTRATION Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, the drug should be administered at a rate not exceeding 1 3 mg/kg/min or 50 mg per minute, whichever is slower. As non-emergency therapy, Dilantin should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Dilantin. Reduction in rate of administration or discontinuation of dosing may be needed. Because of the risk of local toxicity, intravenous Dilantin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the IV catheter should be tested with a flush of sterile saline. Each injection of parenteral Dilantin should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution. Dilantin can be given diluted with normal saline. The addition of parenteral Dilantin to dextrose and dextrose-containing solutions should be avoided due to lack of solubility and resultant precipitation. Treatment with Dilantin can be initiated either with a loading dose or an infusion: Loading Dose: A loading dose of parenteral Dilantin should be injected slowly, not exceeding 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Infusion: For infusion administration, parenteral Dilantin should be diluted in normal saline with the final concentration of Dilantin in the solution no less than 5 mg/mL. Administration should commence immediately after the mixture has been prepared and must be completed within 1 to 4 hours (the infusion mixture should not be refrigerated). An in-line filter (0.22-0.55 microns) should be used. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution or container permit. The diluted infusion mixture (Dilantin plus normal saline) should not be refrigerated. If the undiluted parenteral Dilantin is refrigerated or frozen, a precipitate might form: this will dissolve again after the solution is allowed to stand at room temperature. The product is still suitable for use. A faint yellow coloration may develop, however this has no effect on the potency of the solution. Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Status Epilepticus In adults, a loading dose of 10 to 15 mg/kg should be administered slowly intravenously, at a rate not exceeding 50 mg per minute (this will require approximately 20 minutes in a 70-kg patient). The loading dose should be followed by maintenance doses of 100 mg orally or intravenously every 6-8 hours. In the pediatric population, a loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10-20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. Continuous monitoring of the electrocardiogram and blood pressure is essential. The patient should be observed for signs of respiratory depression. Determination of phenytoin plasma levels is advised when using Dilantin in the management of status epilepticus and in the subsequent establishment of maintenance dosage. Other measures, including concomitant administration of an intravenous benzodiazepine such as diazepam, or an intravenous short-acting barbiturate, will usually be necessary for rapid control of seizures because of the required slow rate of administration of Dilantin. If administration of Parenteral Dilantin does not terminate seizures, the use of other anticonvulsants, intravenous barbiturates, general anesthesia, and other appropriate measures should be considered. Intramuscular administration should not be used in the treatment of status epilepticus because the attainment of peak plasma levels may require up to 24 hours. Nonemergent Loading and Maintenance Dosing Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. In adults, a loading dose of 10 to 15 mg/kg should be administered slowly. The rate of intravenous administration should not exceed 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Slower administration rates are recommended to minimize the cardiovascular adverse reactions. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential. The loading dose should be followed by maintenance doses of oral or intravenous Dilantin every 6-8 hours. Ordinarily, Dilantin should not be given intramuscularly because of the risk of necrosis, abscess formation, and erratic absorption. If intramuscular administration is required, compensating dosage adjustments are necessary to maintain therapeutic plasma levels. An intramuscular dose 50% greater than the oral dose is necessary to maintain these levels. When returned to oral administration, the dose should be reduced by 50% of the Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 original oral dose for one week to prevent excessive plasma levels due to sustained release from intramuscular tissue sites. Monitoring plasma levels would help prevent a fall into the subtherapeutic range. Serum blood level determinations are especially helpful when possible drug interactions are suspected. IV Substitution For Oral Phenytoin Therapy When treatment with oral phenytoin is not possible, IV Dilantin can be substituted for oral phenytoin at the same total daily dose. Dilantin capsules are approximately 90% bioavailable by the oral route. Phenytoin is 100% bioavailable by the IV route. For this reason, plasma phenytoin concentrations may increase modestly when IV phenytoin is substituted for oral phenytoin sodium therapy. The rate of administration for IV Dilantin should be no greater than 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Dilantin® Kapseals® and Dilantin Parenteral are formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspension and Dilantin Infatabs. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa. Dosing in Special Populations Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound phenytoin concentrations may be more useful in these patient populations. Elderly Patients: Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required. Pediatric: A loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10 20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1 3 mg/kg/min or 50 mg per minute, whichever is slower. HOW SUPPLIED NDC 0071-4488--47 (Steri-Dose® 4488) Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in a 2-mL sterile disposable syringe(22 gauge x 1 ¼ inch needle). Packages of ten syringes. NDC 0071-4488-45 Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in 2-mL Steri-Vials®. Packages of twenty-five. Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 NDC 0071-4475-45 Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in 5-mL Steri-Vials. Packages of twenty-five. Caution- Federal law prohibits dispensing without prescription. Warning- Manufactured with CFC-12, which harms public health and environment by destroying ozone in the upper atmosphere. Rx only company logo LAB-0383-10.0 Revised July 2015 Reference ID: 3877321 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:41.783598	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/008762s054,010151s041lbl.pdf', 'application_number': 10151, 'submission_type': 'SUPPL ', 'submission_number': 41}
10,744	T2006-56 Ritalin® hydrochloride methylphenidate hydrochloride tablets USP Ritalin-SR® methylphenidate hydrochloride USP sustained-release tablets Rx only Prescribing Information DESCRIPTION Ritalin hydrochloride, methylphenidate hydrochloride USP, is a mild central nervous system (CNS) stimulant, available as tablets of 5, 10, and 20 mg for oral administration; Ritalin-SR is available as sustained-release tablets of 20 mg for oral administration. Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77. Inactive Ingredients. Ritalin tablets: D&C Yellow No. 10 (5-mg and 20-mg tablets), FD&C Green No. 3 (10-mg tablets), lactose, magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg tablets), sucrose, talc, and tragacanth (20-mg tablets). Ritalin-SR tablets: Cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate, mineral oil, povidone, titanium dioxide, and zein. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 2 CLINICAL PHARMACOLOGY Ritalin is a mild central nervous system stimulant. The mode of action in man is not completely understood, but Ritalin presumably activates the brain stem arousal system and cortex to produce its stimulant effect. There is neither specific evidence which clearly establishes the mechanism whereby Ritalin produces its mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system. Ritalin in the SR tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the SR tablet compared to the Ritalin tablet, measured by the urinary excretion of Ritalin major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49%-168%) in children and 101% (85%-152%) in adults. The time to peak rate in children was 4.7 hours (1.3-8.2 hours) for the SR tablets and 1.9 hours (0.3-4.4 hours) for the tablets. An average of 67% of SR tablet dose was excreted in children as compared to 86% in adults. In a clinical study involving adult subjects who received SR tablets, plasma concentrations of Ritalin’s major metabolite appeared to be greater in females than in males. No gender differences were observed for Ritalin plasma concentration in the same subjects. INDICATIONS Attention Deficit Disorders, Narcolepsy Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children). Other terms being used to describe the behavioral syndrome below include: Hyperkinetic Child Syndrome, Minimal Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction. Ritalin is indicated as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 3 Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Characteristics commonly reported include: chronic history of short attention span, distractibility, emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor neurological signs and abnormal EEG. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of one or more of these characteristics. Drug treatment is not indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is generally necessary. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the child’s symptoms. CONTRAINDICATIONS Marked anxiety, tension, and agitation are contraindications to Ritalin, since the drug may aggravate these symptoms. Ritalin is contraindicated also in patients known to be hypersensitive to the drug, in patients with glaucoma, and in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome. Ritalin is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of a monoamine oxidase inhibitor (hypertensive crises may result). WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 4 serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs. Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia. Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Pre-Existing Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Bipolar Illness Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/ manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 5 Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e. g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. Use in Children Under Six Years of Age Ritalin should not be used in children under 6 years, since safety and efficacy in this age group have not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 6 Drug Dependence Ritalin should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. PRECAUTIONS Patients with an element of agitation may react adversely; discontinue therapy if necessary. Periodic CBC, differential, and platelet counts are advised during prolonged therapy. Drug treatment is not indicated in all cases of this behavioral syndrome and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe Ritalin should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with Ritalin is usually not indicated. Drug Interactions Ritalin should not be used in patients being treated (currently or within the proceeding two weeks) with MAO Inhibitors (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors). Because of possible effects on blood pressure, Ritalin should be used cautiously with pressor agents. Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Methylphenidate is metabolized primarily to ritalinic acid by de-esterification and not through oxidative pathways. Human pharmacologic studies have shown that racemic methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine). Downward dose adjustments of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentration (or, in case of coumarin, coagulation times), when initiating or discontinuing methylphenidate. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 7 Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2-agonists has not been systematically evaluated. Carcinogenesis/Mutagenesis/Impairment of Fertility In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and 4 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 5 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60-74 mg/kg/day of methylphenidate. Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Methlyphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 80-fold and 8-fold the highest recommended dose on a mg/kg and mg/m2 basis, respectively. PREGNANCY Pregnancy Category C In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m2 basis. The no effect level for This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 8 embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2 basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (4 times the MRHD on a mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m2 basis). Adequate and well-controlled studies in pregnant women have not been conducted. Ritalin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Ritalin is administered to a nursing woman. Pediatric Use Ritalin should not be used in children under six years of age (see WARNINGS). In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown. ADVERSE REACTIONS Nervousness and insomnia are the most common adverse reactions but are usually controlled by reducing dosage and omitting the drug in the afternoon or evening. Other reactions include hypersensitivity (including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura); anorexia; nausea; dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse changes, both up and down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss during prolonged therapy. There have been rare reports of Tourette’s syndrome. Toxic psychosis has been reported. Although a definite causal relationship has not been established, the following have been reported in patients taking this drug: instances of abnormal liver function, ranging from transaminase elevation to hepatic coma; isolated cases of cerebral arteritis and/or occlusion; leukopenia and/or anemia; transient depressed mood; aggressive behavior; a few instances of scalp This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 9 hair loss. Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed above may also occur. DOSAGE AND ADMINISTRATION Dosage should be individualized according to the needs and responses of the patient. Adults Tablets: Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Average dosage is 20 to 30 mg daily. Some patients may require 40 to 60 mg daily. In others, 10 to 15 mg daily will be adequate. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m. SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or chewed. Children (6 years and over) Ritalin should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is not recommended. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued. Tablets: Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5 to 10 mg weekly. SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or chewed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 10 If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug. Ritalin should be periodically discontinued to assess the child’s condition. Improvement may be sustained when the drug is either temporarily or permanently discontinued. Drug treatment should not and need not be indefinite and usually may be discontinued after puberty. OVERDOSAGE Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice. Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage. In the presence of severe intoxication, use a carefully titrated dosage of a short-acting barbiturate before performing gastric lavage. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia. Efficacy of peritoneal dialysis or extracorporeal hemodialysis for Ritalin overdosage has not been established. HOW SUPPLIED Tablets 5 mg - round, yellow (imprinted CIBA 7) Bottles of 100……………………………………………………………......NDC 0078-0439-05 Tablets 10 mg - round, pale green, scored (imprinted CIBA 3) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 11 Bottles of 100……………………………………………………………......NDC 0078-0440-05 Tablets 20 mg - round, pale yellow, scored (imprinted CIBA 34) Bottles of 100……………………………………………………………......NDC 0078-0441- 05 Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from light. Dispense in tight, light-resistant container (USP). SR Tablets 20 mg - round, white, coated (imprinted CIBA 16) Bottles of 100……………………………………………………………...NDC 0078-0442-05 Note: SR Tablets are color-additive free. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in tight, light-resistant container (USP). T2006-56 REV: JUNE 2006 Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda T2006-62 Ritalin LA® (methylphenidate hydrochloride) extended-release capsules Rx only Prescribing Information DESCRIPTION Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is an extended-release formulation of methylphenidate with a bi-modal release profile. Ritalin LA® uses the proprietary SODAS® (Spheroidal Oral Drug Absorption System) technology. Each bead-filled Ritalin LA capsule contains half the dose as immediate-release beads and half as enteric-coated, delayed-release beads, thus providing an immediate release of methylphenidate and a second delayed release of methylphenidate. Ritalin LA 10, 20, 30, and 40 mg capsules provide in a single dose the same amount of methylphenidate as dosages of 5, 10, 15, or 20 mg of Ritalin® tablets given b.i.d. The active substance in Ritalin LA is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77. Inactive ingredients: ammonio methacrylate copolymer, black iron oxide (10 and 40 mg capsules only), gelatin, methacrylic acid copolymer, polyethylene glycol, red iron oxide (10 and 40 mg capsules only), sugar spheres, talc, titanium dioxide, triethyl citrate, and yellow iron oxide (10, 30, and 40 mg capsules only). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 2 CLINICAL PHARMACOLOGY Pharmacodynamics Methylphenidate hydrochloride, the active ingredient in Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, is a central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Pharmacokinetics Absorption Ritalin LA produces a bi-modal plasma concentration-time profile (i.e., two distinct peaks approximately four hours apart) when orally administered to children diagnosed with ADHD and to healthy adults. The initial rate of absorption for Ritalin LA is similar to that of Ritalin tablets as shown by the similar rate parameters between the two formulations, i.e., initial lag time (Tlag), first peak concentration (Cmax1), and time to the first peak (Tmax1), which is reached in 1-3 hours. The mean time to the interpeak minimum (Tminip), and time to the second peak (Tmax2) are also similar for Ritalin LA given once daily and Ritalin tablets given in two doses 4 hours apart (see Figure 1 and Table 1), although the ranges observed are greater for Ritalin LA. Ritalin LA given once daily exhibits a lower second peak concentration (Cmax2), higher interpeak minimum concentrations (Cminip), and less peak and trough fluctuations than Ritalin tablets given in two doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption from the delayed-release beads (see Figure 1 and Table 1). The relative bioavailability of Ritalin LA given once daily is comparable to the same total dose of Ritalin tablets given in two doses 4 hours apart in both children and in adults. Figure 1. Mean plasma concentration time-profile of methylphenidate after a single dose of Ritalin LA® 40 mg q.d. and Ritalin® 20 mg given in two doses four hours apart This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 3 Table 1. Mean ± SD and range of pharmacokinetic parameters of methylphenidate after a single dose of Ritalin LA® and Ritalin® given in two doses 4 hours apart Population Children Adult Males Formulation Dose Ritalin® 10 mg & 10 mg Ritalin LA® 20 mg Ritalin® 10 mg & 10 mg Ritalin LA® 20 mg N 21 18 9 8 Tlag (h) 0.24 ± 0.44 0.28 ± 0.46 1.0 ± 0.5 0.7 ± 0.2 0 - 1 0 - 1 0.7 - 1.3 0.3 - 1.0 Tmax1 (h) 1.8 ± 0.6 2.0 ± 0.8 1.9 ± 0.4 2.0 ± 0.9 1 - 3 1 - 3 1.3 - 2.7 1.3 - 4.0 Cmax1 (ng/mL) 10.2 ± 4.2 10.3 ± 5.1 4.3 ± 2.3 5.3 ± 0.9 4.2 - 20.2 5.5 - 26.6 1.8 - 7.5 3.8 - 6.9 Tminip (h) 4.0 ± 0.2 4.5 ± 1.2 3.8 ± 0.4 3.6 ± 0.6 4 - 5 2 - 6 3.3 - 4.3 2.7 - 4.3 Cminip (ng/mL) 5.8 ± 2.7 6.1 ± 4.1 1.2 ± 1.4 3.0 ± 0.8 3.1 - 14.4 2.9 - 21.0 0.0 - 3.7 1.7 - 4.0 Tmax2 (h) 5.6 ± 0.7 6.6 ± 1.5 5.9 ± 0.5 5.5 ± 0.8 5 - 8 5 - 11 5.0 - 6.5 4.3 - 6.5 Cmax2 (ng/mL) 15.3 ± 7.0 10.2 ± 5.9 5.3 ± 1.4 6.2 ± 1.6 6.2 - 32.8 4.5 - 31.1 3.6 - 7.2 3.9 - 8.3 AUC(0-∞) 102.4 ± 54.6 86.6 ± 64.0a 37.8 ± 21.9 45.8 ± 10.0 (ng/mL x h-1) 40.5 - 261.6 43.3 - 301.44 14.3 - 85.3 34.0 - 61.6 t1/2 (h) 2.5 ± 0.8 2.4 ± 0.7a 3.5 ± 1.9 3.3 ± 0.4 1.8 - 5.3 1.5 - 4.0 1.3 - 7.7 3.0 - 4.2 a N = 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 4 Dose Proportionality After oral administration of Ritalin LA 20 mg and 40 mg capsules to adults there is a slight upward trend in the methylphenidate area under the curve (AUC) and peak plasma concentrations (Cmax1 and Cmax2). Distribution Binding to plasma proteins is low (10%-33%), and the apparent distribution volume at steady state with intravenous administration has been reported to be approximately 6 L/kg. Metabolism The absolute oral bioavailability of methylphenidate in children has been reported to be about 30% (range 10%-52%), suggesting pronounced presystemic metabolism. Biotransformation of methylphenidate is rapid and extensive leading to the main, de-esterified metabolite α-phenyl- 2-piperidine acetic acid (ritalinic acid). Only small amounts of hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable in plasma. Therapeutic activity is principally due to the parent compound. Elimination In studies with Ritalin LA and Ritalin tablets in adults, methylphenidate from Ritalin tablets is eliminated from plasma with an average half-life of about 3.5 hours, (range 1.3 - 7.7 hours). In children the average half-life is about 2.5 hours, with a range of about 1.5 - 5.0 hours. The rapid half-life in both children and adults may result in unmeasurable concentrations between the morning and mid-day doses with Ritalin tablets. No accumulation of methylphenidate is expected following multiple once a day oral dosing with Ritalin LA. The half-life of ritalinic acid is about 3-4 hours. After oral administration of an immediate release formulation of methylphenidate, 78%-97% of the dose is excreted in the urine and 1%-3% in the feces in the form of metabolites within 48-96 hours. Only small quantities (<1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as ritalinic acid (60%-86%), the remainder being accounted for by minor metabolites. Food Effects Administration times relative to meals and meal composition may need to be individually titrated. When Ritalin LA was administered with a high fat breakfast to adults, Ritalin LA had a longer lag time until absorption began and variable delays in the time until the first peak concentration, the time until the interpeak minimum, and the time until the second peak. The first peak concentration and the extent of absorption were unchanged after food relative to the fasting state, although the second peak was approximately 25% lower. The effect of a high fat lunch was not examined. There were no differences in the pharmacokinetics of Ritalin LA when administered with applesauce, compared to administration in the fasting condition. There is no evidence of dose dumping in the presence or absence of food. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 5 For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered (see DOSAGE AND ADMINISTRATION). Special Populations Age: The pharmacokinetics of Ritalin LA was examined in 18 children with ADHD between 7 and 12 years of age. Fifteen of these children were between 10 and 12 years of age. The time until the between peak minimum, and the time until the second peak were delayed and more variable in children compared to adults. After a 20-mg dose of Ritalin LA, concentrations in children were approximately twice the concentrations observed in 18 to 35 year old adults. This higher exposure is almost completely due to the smaller body size and total volume of distribution in children, as apparent clearance normalized to body weight is independent of age. Gender: There were no apparent gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults when administered Ritalin LA. Renal Insufficiency: Ritalin LA has not been studied in renally-impaired patients. Renal insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. Hepatic Insufficiency: Ritalin LA has not been studied in patients with hepatic insufficiency. Hepatic insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body. CLINICAL STUDIES Ritalin LA® (methylphenidate hydrochloride) extended-release capsules was evaluated in a randomized, double-blind, placebo-controlled, parallel group clinical study in which 134 children, ages 6 to 12, with DSM-IV diagnoses of Attention Deficit Hyperactivity Disorder (ADHD) received a single morning dose of Ritalin LA in the range of 10-40 mg/day, or placebo, for up to 2 weeks. The doses used were the optimal doses established in a previous individual dose titration phase. In that titration phase, 53 of 164 patients (32%) started on a daily dose of 10 mg and 111 of 164 patients (68%) started on a daily dose of 20 mg or higher. The patient’s regular schoolteacher completed the Conners ADHD/DSM-IV Scale for Teachers (CADS-T) at baseline and the end of each week. The CADS-T assesses symptoms of hyperactivity and inattention. The change from baseline of the (CADS-T) scores during the last week of treatment was analyzed as the primary efficacy parameter. Patients treated with Ritalin LA showed a statistically significant improvement in symptom scores from baseline over patients who received placebo. (See Figure 2.) This demonstrates that a single morning dose of Ritalin LA exerts a treatment effect in ADHD. Figure 2. CADS-T total subscale - Mean change from baseline* This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 6 INDICATIONS AND USAGE Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). The efficacy of Ritalin LA in the treatment of ADHD was established in one controlled trial of children aged 6 to 12 who met DSM-IV criteria for ADHD (see CLINICAL PHARMACOLOGY). A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go;” excessive talking; blurting answers; can’t wait turn; intrusive. The Combined Types requires both inattentive and hyperactive-impulsive criteria to be met. Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of the required number of DSM-IV characteristics. Need for Comprehensive Treatment Program Ritalin LA is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 7 placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the child’s symptoms. Long-Term Use The effectiveness of Ritalin LA for long-term use, i.e., for more than 2 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Ritalin LA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS Agitation Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is contraindicated in marked anxiety, tension, and agitation, since the drug may aggravate these symptoms. Hypersensitivity to Methylphenidate Ritalin LA is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product. Glaucoma Ritalin LA is contraindicated in patients with glaucoma. Tics Ritalin LA is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome. (See ADVERSE REACTIONS.) Monoamine Oxidase Inhibitors Ritalin LA is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (hypertensive crises may result). WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 8 serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs. Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia. Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Pre-Existing Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Bipolar Illness Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 9 Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. In the double-blind placebo-controlled study of Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, the mean weight gain was greater for patients receiving placebo (+1.0 kg) than for patients receiving Ritalin LA (+0.1 kg). Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 10 Use in Children Under Six Years of Age Ritalin LA should not be used in children under six years of age, since safety and efficacy in this age group have not been established. Drug Dependence Ritalin LA should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. PRECAUTIONS Hematologic Monitoring Periodic CBC, differential, and platelet counts are advised during prolonged therapy. Information for Patients Patient information is provided at the end of this insert. To assure safe and effective use of Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, the patient information should be discussed with patients. Drug Interactions Methylphenidate is metabolized primarily by de-esterification (nonmicrosomal hydrolytic esterases) to ritalinic acid and not through oxidative pathways. The effects of gastrointestinal pH alterations on the absorption of methylphenidate from Ritalin LA have not been studied. Since the modified release characteristics of Ritalin LA are pH dependent, the coadministration of antacids or acid suppressants could alter the release of methylphenidate. Methylphenidate may decrease the hypotensive effect of guanethidine. Because of possible effects on blood pressure, methylphenidate should be used cautiously with pressor agents. Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine). Downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate. Serious adverse events have been reported in concomitant use of methylphenidate with clonidine, although no causality for the combination has been established. The safety of using This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 11 methylphenidate in combination with clonidine or other centrally acting alpha-2-agonists has not been systematically evaluated. Carcinogenesis/Mutagenesis/Impairment of Fertility In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and 4 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 5 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60-74 mg/kg/day of methylphenidate. Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 80-fold and 8-fold the highest recommended dose on a mg/kg and mg/m2 basis, respectively. Pregnancy Pregnancy Category C In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2 basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 12 decreased at the highest dose (4 times the MRHD on a mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m2 basis). Adequate and well-controlled studies in pregnant women have not been conducted. Ritalin LA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Ritalin LA is administered to a nursing woman. Pediatric Use Long-term effects of methylphenidate in children have not been well established. Ritalin LA should not be used in children under six years of age (see WARNINGS). In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown. ADVERSE REACTIONS The clinical program for Ritalin LA® (methylphenidate hydrochloride) extended-release capsules consisted of six studies: two controlled clinical studies conducted in children with ADHD aged 6-12 years and four clinical pharmacology studies conducted in healthy adult volunteers. These studies included a total of 256 subjects; 195 children with ADHD and 61 healthy adult volunteers. The subjects received Ritalin LA in doses of 10-40 mg per day. Safety of Ritalin LA was assessed by evaluating frequency and nature of adverse events, routine laboratory tests, vital signs, and body weight. Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and listings that follow, MEDRA terminology has been used to classify reported adverse events. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 13 Adverse Events in a Double-Blind, Placebo-Controlled Clinical Trial with Ritalin LA Treatment-Emergent Adverse Events A placebo-controlled, double-blind, parallel-group study was conducted to evaluate the efficacy and safety of Ritalin LA in children with ADHD aged 6-12 years. All subjects received Ritalin LA for up to 4 weeks, and had their dose optimally adjusted, prior to entering the double-blind phase of the trial. In the two-week double-blind treatment phase of this study, patients received either placebo or Ritalin LA at their individually-titrated dose (range 10 mg-40 mg). The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. Adverse events with an incidence >5% during the initial four-week single-blind Ritalin LA titration period of this study were headache, insomnia, upper abdominal pain, appetite decreased, and anorexia. Treatment-emergent adverse events with an incidence >2% among Ritalin LA-treated subjects, during the two-week double-blind phase of the clinical study, were as follows: Preferred term Ritalin LA® N=65 N (%) Placebo N=71 N (%) Anorexia 2 (3.1) 0 (0.0) Insomnia 2 (3.1) 0 (0.0) Adverse Events Associated with Discontinuation of Treatment In the two-week double-blind treatment phase of a placebo-controlled parallel-group study in children with ADHD, only one Ritalin LA-treated subject (1/65, 1.5%) discontinued due to an adverse event (depression). In the single-blind titration period of this study, subjects received Ritalin LA for up to 4 weeks. During this period a total of six subjects (6/161, 3.7%) discontinued due to adverse events. The adverse events leading to discontinuation were anger (in 2 patients), hypomania, anxiety, depressed mood, fatigue, migraine and lethargy. Adverse Events with Other Methylphenidate HCl Dosage Forms Nervousness and insomnia are the most common adverse reactions reported with other methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed below may also occur. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 14 Other reactions include: Cardiac: angina, arrhythmia, palpitations, pulse increased or decreased, tachycardia Gastrointestinal: abdominal pain, nausea Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura. Metabolism/Nutrition: anorexia, weight loss during prolonged therapy Nervous System: dizziness, drowsiness, dyskinesia, headache, rare reports of Tourette’s syndrome, toxic psychosis Vascular: blood pressure increased or decreased, cerebral arteritis and/or occlusion Although a definite causal relationship has not been established, the following have been reported in patients taking methylphenidate: Blood/Lymphatic: leukopenia and/or anemia Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma Psychiatric: transient depressed mood, aggressive behavior Skin/Subcutaneous: scalp hair loss Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause. DRUG ABUSE AND DEPENDENCE Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, like other products containing methylphenidate, is a Schedule II controlled substance. (See WARNINGS for boxed warning containing drug abuse and dependence information.) OVERDOSAGE Signs and Symptoms Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 15 Poison Control Center Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice. Recommended Treatment As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. When treating overdose, practitioners should bear in mind that there is a prolonged release of methylphenidate from Ritalin LA® (methylphenidate hydrochloride) extended- release capsules. Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage as indicated. Before performing gastric lavage, control agitation and seizures if present and protect the airway. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia. Efficacy of peritoneal dialysis or extracorporeal hemodialysis for methylphenidate overdosage has not been established; also, dialysis is considered unlikely to be of benefit due to the large volume of distribution of methylphenidate. DOSAGE AND ADMINISTRATION Administration of Dose Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is for oral administration once daily in the morning. Ritalin LA may be swallowed as whole capsules or alternatively may be administered by sprinkling the capsule contents on a small amount of applesauce (see specific instructions below). Ritalin LA and/or their contents should not be crushed, chewed, or divided. The capsules may be carefully opened and the beads sprinkled over a spoonful of applesauce. The applesauce should not be warm because it could affect the modified release properties of this formulation. The mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use. Dosing Recommendations Dosage should be individualized according to the needs and responses of the patients. Initial Treatment The recommended starting dose of Ritalin LA is 20 mg once daily. Dosage may be adjusted in weekly 10 mg increments to a maximum of 60 mg/day taken once daily in the morning, depending on tolerability and degree of efficacy observed. Daily dosage above 60 mg is not This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 16 recommended. When in the judgement of the clinician a lower initial dose is appropriate, patients may begin treatment with Ritalin LA 10 mg. Patients Currently Receiving Methylphenidate The recommended dose of Ritalin LA for patients currently taking methylphenidate b.i.d. or sustained release (SR) is provided below. Previous Methylphenidate Dose Recommended Ritalin LA® Dose 5 mg methylphenidate-b.i.d. 10 mg q.d. 10 mg methylphenidate b.i.d. or 20 mg methylphenidate-SR 20 mg q.d. 15 mg methylphenidate b.i.d. 30 mg q.d. 20 mg methylphenidate b.i.d. or 40 mg of methylphenidate-SR 40 mg q.d. 30 mg methylphenidate b.i.d. or 60 mg methylphenidate-SR 60 mg q.d. For other methylphenidate regimens, clinical judgment should be used when selecting the starting dose. Ritalin LA dosage may be adjusted at weekly intervals in 10 mg increments. Daily dosage above 60 mg is not recommended. Maintenance/Extended Treatment There is no body of evidence available from controlled trials to indicate how long the patient with ADHD should be treated with Ritalin LA. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. Nevertheless, the physician who elects to use Ritalin LA for extended periods in patients with ADHD should periodically re-evaluate the long-term usefulness of the drug for the individual patient with trials off medication to assess the patient’s functioning without pharmacotherapy. Improvement may be sustained when the drug is either temporarily or permanently discontinued. Dose Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse events occur, the dosage should be reduced, or, if necessary, the drug should be discontinued. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued. HOW SUPPLIED Ritalin LA capsules 10 mg: white/light brown (imprinted NVR R10) Bottles of 100………………………………………………………NDC 0078-0424-05 Ritalin LA capsules 20 mg: white (imprinted NVR R20) Bottles of 100………………………………………………………NDC 0078-0370-05 Ritalin LA capsules 30 mg: yellow (imprinted NVR R30) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 17 Bottles of 100………………………………………………………NDC 0078-0371-05 Ritalin LA capsules 40 mg: light brown (imprinted NVR R40) Bottles of 100………………………………………………………NDC 0078-0372-05 Store at 25°C (77°F), excursions permitted 15°C-30°C (59°F-86°F). [See USP controlled room temperature] Dispense in tight container (USP). Ritalin LA® is a trademark of Novartis AG. SODAS® is a trademark of Elan Corporation, plc. This product is covered by US patents including US 5,837,284 and 6,228,398. REFERENCE American Psychiatric Association. Diagnosis and Statistical Manual of Mental Disorders. 4th edition. Washington DC: American Psychiatric Association 1994. REV: JUNE 2006 T2006-62 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 18 INFORMATION FOR PATIENTS TAKING RITALIN LA®, OR FOR THEIR PARENTS OR CAREGIVERS Once Daily Ritalin LA® (methylphenidate hydrochloride) extended-release capsules This information for patients or their parents or caregivers is about Ritalin LA. Please read this before you start taking Ritalin LA. Also, read the information you get each time you renew your prescription, in case anything has changed. Remember, this information does not take the place of your doctor’s instructions. If you have any questions about this information or about Ritalin LA, talk to your doctor or pharmacist. WHAT IS RITALIN LA? Ritalin LA is a once-a-day treatment for Attention Deficit Hyperactivity Disorder, or ADHD. Ritalin LA contains the drug methylphenidate (Ritalin®), a central nervous system stimulant that has been used to treat ADHD for more than 30 years. Ritalin is available in several forms including Ritalin LA, an extended-release form of methylphenidate hydrochloride available as 10, 20, 30, and 40 mg extended-release capsules. Ritalin LA is taken by mouth, once each day in the morning, before breakfast. WHAT IS ATTENTION DEFICIT HYPERACTIVITY DISORDER? ADHD has three main types of symptoms: inattention, hyperactivity, and impulsiveness. Symptoms of inattention include not paying attention, making careless mistakes, not listening, not finishing tasks, not following directions, and being easily distracted. Symptoms of hyperactivity and impulsiveness include fidgeting, talking excessively, running around at inappropriate times, and interrupting others. Some patients have more symptoms of hyperactivity and impulsiveness while others have more symptoms of inattentiveness. Some patients have all three types of symptoms. Many people have symptoms like these from time to time, but patients with ADHD have these symptoms more than others their age. Symptoms must be present for at least 6 months to be certain of the diagnosis. HOW DOES RITALIN LA WORK? When you take a Ritalin LA capsule, half of the beads provide an immediate dose of methylphenidate and the other half provide a delayed second release of the drug to continue to help lessen the symptoms of ADHD during the day. Methylphenidate, the active ingredient in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 19 Ritalin LA, helps increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. BEFORE RITALIN LA TREATMENT It is very important that ADHD be accurately diagnosed and that the need for medication be carefully assessed. It is important to remember that Ritalin is only part of the overall management of ADHD. Parents, teachers, physicians and other professionals are part of a team that must work together. Before Ritalin treatment, your doctor should be made aware of any current or past physical or mental problems. Tell your doctor if there is a history of drug or alcohol abuse, depression, bipolar disorder, psychosis, epilepsy or seizure disorders, high blood pressure, heart defects, irregular heart rhythms, other heart problems, glaucoma, and facial tics (involuntary movements). Also tell your doctor if there is a family history of sudden death, irregular heart rhythm, suicide, bipolar disorder, depression or Tourette’s syndrome. Both your doctor and your pharmacist should also be informed of all medicines that you are taking, even if these drugs are not taken on a regular basis and are available without prescription. Your doctor will decide whether you can take Ritalin with other medicines. Methylphenidate is known to interact with a number of other drugs. These include medicines to treat depression, such as monoamine oxidase inhibitors; to control seizures; and to thin blood. Sometimes these interactions may require a change in dosage, or occasionally stopping one of the drugs involved. Tell your doctor if you are pregnant or nursing a baby. WHO SHOULD NOT TAKE RITALIN LA ? You should NOT take Ritalin LA if: • You have known serious heart defects, serious heart rhythm irregularities, or other serious heart problems. • You have significant anxiety, tension, or agitation since Ritalin LA may make these conditions worse. • You are allergic to methylphenidate or any of the other ingredients in Ritalin LA. • You have glaucoma, an eye disease. • You have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome. • You are taking a monoamine oxidase inhibitor, a type of drug, or have discontinued a monoamine oxidase inhibitor in the last 14 days. Talk to your doctor if you believe any of these conditions apply to you. HOW SHOULD I TAKE RITALIN LA ? Take Ritalin LA once each day in the morning. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 20 Take the dose prescribed by your doctor. Your doctor may adjust the amount of drug you take until it is right for you. From time to time, your doctor may interrupt your treatment to check your symptoms while you are not taking the drug. Ritalin LA capsules may be taken at the same time as food or without food, although food may delay the absorption of Ritalin LA. The Ritalin LA capsule may be swallowed as whole capsules or the capsule may be opened and sprinkled on a small amount of applesauce. The capsule should not be crushed or chewed or its contents divided. To sprinkle the contents of the capsule, open the capsule carefully and sprinkle the beads over a spoonful of applesauce. The applesauce should not be warm because it could affect the modified release properties of this formulation. The mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use. If you also take antiacids or drugs that suppress stomach acids, you should discuss with your physician or pharmacist how to take these drugs with Ritalin LA. WHAT ARE THE POSSIBLE SIDE EFFECTS OF RITALIN LA? The most common side effects of Ritalin LA are: • Nervousness • Stomach pain • Sleeplessness • Decreased appetite Other side effects seen with methylphenidate, the active ingredient in Ritalin LA, include nausea, vomiting, dizziness, tics, allergic reactions, increased blood pressure and psychosis (abnormal thinking or hallucinations). Dependence Abuse of methylphenidate can lead to dependence. Tell your doctor if you have ever abused or been dependent on alcohol or drugs, or if you are now abusing or dependent on alcohol or drugs. Misuse of stimulants may be associated with sudden death and serious cardiovascular adverse events. Blurred Vision Tell your doctor if you have blurred vision when taking Ritalin LA. This could be a sign of a serious problem. Slower Growth Slower growth (weight gain and/or height) has been reported with long-term use of methylphenidate in children. Your doctor will be carefully watching your height and weight. If you are not growing or gaining weight as your doctor expects, your doctor may stop your Ritalin LA treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 21 This is not a complete list of possible side effects. Ask your doctor about other side effects. If you develop any side effect, talk to your doctor. WHAT MUST I DISCUSS WITH MY DOCTOR BEFORE TAKING RITALIN LA? Talk to your doctor before taking RITALIN LA if you: • Have high blood pressure. • Have an abnormal heart rate or rhythm. • Have had any other current or previous heart problems. • Have a family history of sudden death or heart rhythm problems. • Are being treated for depression or bipolar disorder, or have symptoms of depression such as feelings of sadness, worthlessness, and hopelessness. • Have a family history of suicide, bipolar disorder or depression. • Have motion tics (hard-to-control, repeated twitching of any parts of your body) or verbal tics (hard-to-control repeating of sounds or words). • Have someone in your family with motion tics, verbal tics, or Tourette’s syndrome. • Have abnormal thoughts or visions, hear abnormal sounds, or have been diagnosed with psychosis. • Have had seizures (convulsions, epilepsy) or abnormal EEGs (electroencephalograms). Tell your doctor immediately if you develop any of the above conditions or symptoms while taking Ritalin LA. CAN I TAKE RITALIN LA WITH OTHER MEDICINES? Tell your doctor about all medicines that you are taking or intend to take. Your doctor should decide whether you can take Ritalin LA with other medicines. These include: • Other medicines that a doctor has prescribed. • All medicines that you buy yourself without a prescription. • Any herbal remedies that you may be taking. Monoamine Oxidase (MAO) Inhibitors You should not take Ritalin LA with (MAO) inhibitors or within 14 days of stopping a MAO inhibitor. Starting a New Medicine While on Ritalin LA, do not start taking a new medicine or herbal remedy before checking with your doctor. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 22 Other Medicines You May Be Taking Ritalin LA may change the way your body reacts to certain medicines. These include medicines used to treat depression, prevent seizures, or prevent blood clots (commonly called “blood thinners”). Your doctor may need to change your dose of these medicines if you are taking them with Ritalin LA. Other Important Safety Information Pregnancy and Nursing Before taking Ritalin LA, tell your doctor if you are pregnant or plan on becoming pregnant. If you take methylphenidate, it may be in your breast milk. Tell your doctor if you are nursing a baby. Overdose Call your doctor immediately if you take more than the amount of Ritalin LA prescribed by your doctor. WHAT ELSE SHOULD I KNOW ABOUT RITALIN LA ? Ritalin LA has not been studied in children under 6 years of age. Ritalin LA may be a part of your overall treatment for ADHD. Your doctor may also recommend that you have counseling or other therapy. As with all medicines, never share Ritalin LA with anyone else and take only the number of Ritalin LA capsules prescribed by your doctor. Ritalin LA should be stored in a safe place at room temperature (between 59°F-86°F). Do not store this medicine in hot, damp, or humid places. Keep the container of Ritalin LA in a safe place, away from high-traffic areas where other people could have accidental or unauthorized access to the medication. Keep track of the number of capsules so that you will know if any are missing. Someone who has easy access to Ritalin may be able to give the capsules to others or misuse the medication. Keep out of the reach of children. This leaflet summarizes the most important information about Ritalin LA. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Ritalin LA that is written for health professionals. You can also call 1-888 NOWNOVA (1-888-669-6682). REV: JUNE 2006 T2006-63 REV: JUNE 2006 PRINTED IN U.S.A. T2006-62/ T2006-63 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 23 Manufactured for Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 By ELAN HOLDINGS INC. Pharmaceutical Division Gainesville, GA 30504 ©Novartis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:42.057860	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/010187s66s67,018029s37s38,021284s6s8lbl.pdf', 'application_number': 10187, 'submission_type': 'SUPPL ', 'submission_number': 66}
10,743	NDA 010155/S-024 Mytelase tablet FDA approved labeling text dated Nov 2014 Page 1 MYTELASE® AMBENONIUM CHLORIDE DESCRIPTION MYTELASE, brand of ambenonium chloride, is [Oxalylbis (iminoethylene)] bis[(o chlorobenzyl) diethylammonium] dichloride, a white crystalline powder, soluble in water to 20 percent (w/v). Inactive Ingredients: Acacia, Dibasic Calcium Phosphate, Gelatin, Lactose, Magnesium Stearate, Starch, Sucrose. CLINICAL PHARMACOLOGY The compound is a cholinesterase inhibitor with all the pharmacologic actions of acetylcholine, both the muscarinic and nicotinic types. Cholinesterase inactivates acetylcholine. Like neostigmine, MYTELASE suppresses cholinesterase but has the advantage of longer duration of action and fewer side effects on the gastrointestinal tract. The longer duration of action also results in more even strength, better endurance, and greater residual effect during the night and on awakening than is produced by shorter-acting anticholinesterase compounds. INDICATION AND USAGE This drug is indicated for the treatment of myasthenia gravis. CONTRAINDICATIONS Routine administration of atropine with MYTELASE is contraindicated since belladonna derivatives may suppress the parasympathomimetic (muscarinic) symptoms of excessive gastrointestinal stimulation, leaving only the more serious symptoms of fasciculation and paralysis of voluntary muscles as signs of overdosage. MYTELASE should not be administered to patients receiving mecamylamine, or any other ganglionic blocking agents. MYTELASE should also not be administered to patients with a known hypersensitivity to ambenonium chloride or any other ingredients of MYTELASE. WARNINGS Because this drug has a more prolonged action than other antimyasthenic drugs, simultaneous administration with other cholinergics is contraindicated except under strict medical supervision. The overlap in duration of action of several drugs complicates dosage schedules. Therefore, when a patient is to be given the drug, the administration of all other cholinergics should be suspended until the patient has been stabilized. In most instances the myasthenic symptoms are effectively controlled by its use alone. PRECAUTIONS Great care and supervision are required, since the warning of overdosage is minimal and the requirements of patients vary tremendously. It must be borne in mind constantly that a narrow margin exists between the first appearance of side effects and serious toxic effects. Caution in increasing the dosage is essential. Reference ID: 3664596 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010155/S-024 Mytelase tablet FDA approved labeling text dated Nov 2014 Page 2 The drug should be used with caution in patients with asthma, Parkinson’s Disease or in patients with mechanical intestinal or urinary obstruction. The drug should be used with caution in patients with bradycardia or cardiac conduction disorders. Usage in Pregnancy. Safe use of this drug during pregnancy has not been established. Therefore, before use of MYTELASE in pregnant women or women of childbearing potential, the potential benefits should be weighed against possible risks to mother and fetus. Nursing Mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from MYTELASE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. Safety and effectiveness in pediatric patients have not been established. Geriatric Use. Clinical Studies of MYTELASE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS Adverse effects of anticholinesterase agents such as MYTELASE usually result from overdosage and include muscarinic effects such as excessive salivation, abdominal cramps, diarrhea, miosis, urinary urgency, sweating, nausea, increase in bronchial and lachrymal secretions, and vomiting, nicotinic effects such as muscle cramps, fasciculation of voluntary muscles, and rarely generalized malaise with anxiety and vertigo, and bradycardia and cardiac conduction disorders. (See OVERDOSAGE.) DOSAGE AND ADMINISTRATION The oral dose must be individualized according to the patient’s response because the disease varies widely in its severity in different patients and because patients vary in their sensitivity to cholinergic drugs. Since the point of maximum therapeutic effectiveness with optimal muscle strength and no gastrointestinal disturbances is a highly critical one, the close supervision of a physician familiar with the disease is necessary. Because its action is longer, administration of MYTELASE is necessary only every three or four hours, depending on the clinical response. Usually medication is not required throughout the night, so that the patient can sleep uninterruptedly. For the patient with moderately severe myasthenia, from 5 mg to 25 mg of MYTELASE three or four times daily is an effective dose. In some patients a 5 mg dose is effective, whereas other patients require as much as from 50 mg to 75 mg per dose. The physician should start with a 5 mg dose, carefully observing the effect of the drug on the patient. The dosage may then be increased gradually to determine the effective and safe dose. The longer duration of action of MYTELASE makes it desirable to adjust dosage at intervals of one to two days to avoid drug accumulation and overdosage. (See OVERDOSAGE.) Reference ID: 3664596 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010155/S-024 Mytelase tablet FDA approved labeling text dated Nov 2014 Page 3 In addition to individual variations in dosage requirements, the amount of cholinergic medication necessary to control symptoms may fluctuate in each patient, depending on his activity and the current status of the disease, including spontaneous remission. A few patients have required greater doses for adequate control of myasthenic symptoms, but increasing the dosage above 200 mg daily requires exacting supervision of a physician well aware of the signs and treatment of overdosage with cholinergic medication. Edrophonium (Tensilon®) may be used to evaluate the adequacy of the maintenance dose of anti-cholinesterase medication. Two mg edrophonium are administered intravenously one hour after the last anticholinesterase dose. A transient increase in strength occurring about 30 seconds later and lasting 3 to 5 minutes indicates insufficient maintenance dose. If the dose is adequate or excessive, no change or a transient decrease in strength will occur, sometimes accompanied by muscarinic symptoms. OVERDOSAGE When the drug produces overstimulation, the clinical picture is one of increasing parasympathomimetic action that is more or less characteristic when not masked by the use of atropine. Signs and symptoms of overdosage, including cholinergic crises, vary considerably. They are usually manifested by increasing gastrointestinal stimulation with epigastric distress, abdominal cramps, diarrhea and vomiting, excessive salivation, pallor, pollakiuria, cold sweating, urinary urgency, blurring of vision, and eventually fasciculation and paralysis of voluntary muscles, including those of the tongue (thick tongue and difficulty in swallowing), shoulder, neck, and arms. Rarely, generalized malaise and vertigo may occur. Miosis, increase in blood pressure with or without bradycardia, bradycardia, cardiac conduction disorders, and finally, subjective sensations of internal trembling, and often severe anxiety and panic may complete the picture. A cholinergic crisis is usually differentiated from the weakness and paralysis of myasthenia gravis insufficiently treated by cholinergic drugs by the fact that myasthenic weakness is not accompanied by any of the above signs and symptoms, except the last two subjective ones (anxiety and panic). Since the warning of overdosage is minimal, the existence of a narrow margin between the first appearance of side effects and serious toxic effects must be borne in mind constantly. If signs of overdosage occur (excessive gastrointestinal stimulation, excessive salivation, miosis, and more serious fasciculations of voluntary muscles) discontinue temporarily all cholinergic medication and administer from 0.5 mg to 1 mg (1/120 to 1/60 grain) of atropine intravenously. It must be noted that atropine reverses effects of excessive acetylcholine due to overdosage at the muscarinic receptors but not the effects at the nicotinic receptors such as fasciculations and paralysis of respiratory muscles. Pralidoxime chloride may be used to alleviate these effects at the nicotinic receptors since pralidoxime has its most critical effect in relieving paralysis of the muscles of respiration. However, because pralidoxime is less effective in relieving depression of the respiratory center, atropine is always required concomitantly to block the effect of accumulated acetylcholine at this site. Give other supportive treatment as indicated (e.g. artificial respiration, tracheotomy, oxygen, and hospitalization). Reference ID: 3664596 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 010155/S-024 Mytelase tablet FDA approved labeling text dated Nov 2014 Page 4 HOW SUPPLIED Scored, white, capsule – shaped tablets (caplets) with a stylized “W” on one side and “M” score “87” on the other side, 10 mg, bottles of 100 (NDC 0024-1287-04) Store at room temperature up to 25° C (77° F). Rx Only Revised Nov 2014 Manufactured for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 ©2014 sanofi-aventis U.S. LLC Reference ID: 3664596 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:42.123694	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/010155s024lbl.pdf', 'application_number': 10155, 'submission_type': 'SUPPL ', 'submission_number': 24}
10,745	T2006-56 Ritalin® hydrochloride methylphenidate hydrochloride tablets USP Ritalin-SR® methylphenidate hydrochloride USP sustained-release tablets Rx only Prescribing Information DESCRIPTION Ritalin hydrochloride, methylphenidate hydrochloride USP, is a mild central nervous system (CNS) stimulant, available as tablets of 5, 10, and 20 mg for oral administration; Ritalin-SR is available as sustained-release tablets of 20 mg for oral administration. Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77. Inactive Ingredients. Ritalin tablets: D&C Yellow No. 10 (5-mg and 20-mg tablets), FD&C Green No. 3 (10-mg tablets), lactose, magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg tablets), sucrose, talc, and tragacanth (20-mg tablets). Ritalin-SR tablets: Cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate, mineral oil, povidone, titanium dioxide, and zein. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 2 CLINICAL PHARMACOLOGY Ritalin is a mild central nervous system stimulant. The mode of action in man is not completely understood, but Ritalin presumably activates the brain stem arousal system and cortex to produce its stimulant effect. There is neither specific evidence which clearly establishes the mechanism whereby Ritalin produces its mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system. Ritalin in the SR tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the SR tablet compared to the Ritalin tablet, measured by the urinary excretion of Ritalin major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49%-168%) in children and 101% (85%-152%) in adults. The time to peak rate in children was 4.7 hours (1.3-8.2 hours) for the SR tablets and 1.9 hours (0.3-4.4 hours) for the tablets. An average of 67% of SR tablet dose was excreted in children as compared to 86% in adults. In a clinical study involving adult subjects who received SR tablets, plasma concentrations of Ritalin’s major metabolite appeared to be greater in females than in males. No gender differences were observed for Ritalin plasma concentration in the same subjects. INDICATIONS Attention Deficit Disorders, Narcolepsy Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children). Other terms being used to describe the behavioral syndrome below include: Hyperkinetic Child Syndrome, Minimal Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction. Ritalin is indicated as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 3 Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Characteristics commonly reported include: chronic history of short attention span, distractibility, emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor neurological signs and abnormal EEG. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of one or more of these characteristics. Drug treatment is not indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is generally necessary. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the child’s symptoms. CONTRAINDICATIONS Marked anxiety, tension, and agitation are contraindications to Ritalin, since the drug may aggravate these symptoms. Ritalin is contraindicated also in patients known to be hypersensitive to the drug, in patients with glaucoma, and in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome. Ritalin is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of a monoamine oxidase inhibitor (hypertensive crises may result). WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 4 serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs. Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia. Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Pre-Existing Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Bipolar Illness Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/ manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 5 Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e. g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. Use in Children Under Six Years of Age Ritalin should not be used in children under 6 years, since safety and efficacy in this age group have not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 6 Drug Dependence Ritalin should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. PRECAUTIONS Patients with an element of agitation may react adversely; discontinue therapy if necessary. Periodic CBC, differential, and platelet counts are advised during prolonged therapy. Drug treatment is not indicated in all cases of this behavioral syndrome and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe Ritalin should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with Ritalin is usually not indicated. Drug Interactions Ritalin should not be used in patients being treated (currently or within the proceeding two weeks) with MAO Inhibitors (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors). Because of possible effects on blood pressure, Ritalin should be used cautiously with pressor agents. Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Methylphenidate is metabolized primarily to ritalinic acid by de-esterification and not through oxidative pathways. Human pharmacologic studies have shown that racemic methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine). Downward dose adjustments of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentration (or, in case of coumarin, coagulation times), when initiating or discontinuing methylphenidate. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 7 Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2-agonists has not been systematically evaluated. Carcinogenesis/Mutagenesis/Impairment of Fertility In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and 4 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 5 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60-74 mg/kg/day of methylphenidate. Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Methlyphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 80-fold and 8-fold the highest recommended dose on a mg/kg and mg/m2 basis, respectively. PREGNANCY Pregnancy Category C In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m2 basis. The no effect level for This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 8 embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2 basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (4 times the MRHD on a mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m2 basis). Adequate and well-controlled studies in pregnant women have not been conducted. Ritalin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Ritalin is administered to a nursing woman. Pediatric Use Ritalin should not be used in children under six years of age (see WARNINGS). In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown. ADVERSE REACTIONS Nervousness and insomnia are the most common adverse reactions but are usually controlled by reducing dosage and omitting the drug in the afternoon or evening. Other reactions include hypersensitivity (including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura); anorexia; nausea; dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse changes, both up and down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss during prolonged therapy. There have been rare reports of Tourette’s syndrome. Toxic psychosis has been reported. Although a definite causal relationship has not been established, the following have been reported in patients taking this drug: instances of abnormal liver function, ranging from transaminase elevation to hepatic coma; isolated cases of cerebral arteritis and/or occlusion; leukopenia and/or anemia; transient depressed mood; aggressive behavior; a few instances of scalp This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 9 hair loss. Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed above may also occur. DOSAGE AND ADMINISTRATION Dosage should be individualized according to the needs and responses of the patient. Adults Tablets: Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Average dosage is 20 to 30 mg daily. Some patients may require 40 to 60 mg daily. In others, 10 to 15 mg daily will be adequate. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m. SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or chewed. Children (6 years and over) Ritalin should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is not recommended. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued. Tablets: Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5 to 10 mg weekly. SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or chewed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 10 If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug. Ritalin should be periodically discontinued to assess the child’s condition. Improvement may be sustained when the drug is either temporarily or permanently discontinued. Drug treatment should not and need not be indefinite and usually may be discontinued after puberty. OVERDOSAGE Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice. Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage. In the presence of severe intoxication, use a carefully titrated dosage of a short-acting barbiturate before performing gastric lavage. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia. Efficacy of peritoneal dialysis or extracorporeal hemodialysis for Ritalin overdosage has not been established. HOW SUPPLIED Tablets 5 mg - round, yellow (imprinted CIBA 7) Bottles of 100……………………………………………………………......NDC 0078-0439-05 Tablets 10 mg - round, pale green, scored (imprinted CIBA 3) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 11 Bottles of 100……………………………………………………………......NDC 0078-0440-05 Tablets 20 mg - round, pale yellow, scored (imprinted CIBA 34) Bottles of 100……………………………………………………………......NDC 0078-0441- 05 Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from light. Dispense in tight, light-resistant container (USP). SR Tablets 20 mg - round, white, coated (imprinted CIBA 16) Bottles of 100……………………………………………………………...NDC 0078-0442-05 Note: SR Tablets are color-additive free. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in tight, light-resistant container (USP). T2006-56 REV: JUNE 2006 Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda T2006-62 Ritalin LA® (methylphenidate hydrochloride) extended-release capsules Rx only Prescribing Information DESCRIPTION Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is an extended-release formulation of methylphenidate with a bi-modal release profile. Ritalin LA® uses the proprietary SODAS® (Spheroidal Oral Drug Absorption System) technology. Each bead-filled Ritalin LA capsule contains half the dose as immediate-release beads and half as enteric-coated, delayed-release beads, thus providing an immediate release of methylphenidate and a second delayed release of methylphenidate. Ritalin LA 10, 20, 30, and 40 mg capsules provide in a single dose the same amount of methylphenidate as dosages of 5, 10, 15, or 20 mg of Ritalin® tablets given b.i.d. The active substance in Ritalin LA is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77. Inactive ingredients: ammonio methacrylate copolymer, black iron oxide (10 and 40 mg capsules only), gelatin, methacrylic acid copolymer, polyethylene glycol, red iron oxide (10 and 40 mg capsules only), sugar spheres, talc, titanium dioxide, triethyl citrate, and yellow iron oxide (10, 30, and 40 mg capsules only). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 2 CLINICAL PHARMACOLOGY Pharmacodynamics Methylphenidate hydrochloride, the active ingredient in Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, is a central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Pharmacokinetics Absorption Ritalin LA produces a bi-modal plasma concentration-time profile (i.e., two distinct peaks approximately four hours apart) when orally administered to children diagnosed with ADHD and to healthy adults. The initial rate of absorption for Ritalin LA is similar to that of Ritalin tablets as shown by the similar rate parameters between the two formulations, i.e., initial lag time (Tlag), first peak concentration (Cmax1), and time to the first peak (Tmax1), which is reached in 1-3 hours. The mean time to the interpeak minimum (Tminip), and time to the second peak (Tmax2) are also similar for Ritalin LA given once daily and Ritalin tablets given in two doses 4 hours apart (see Figure 1 and Table 1), although the ranges observed are greater for Ritalin LA. Ritalin LA given once daily exhibits a lower second peak concentration (Cmax2), higher interpeak minimum concentrations (Cminip), and less peak and trough fluctuations than Ritalin tablets given in two doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption from the delayed-release beads (see Figure 1 and Table 1). The relative bioavailability of Ritalin LA given once daily is comparable to the same total dose of Ritalin tablets given in two doses 4 hours apart in both children and in adults. Figure 1. Mean plasma concentration time-profile of methylphenidate after a single dose of Ritalin LA® 40 mg q.d. and Ritalin® 20 mg given in two doses four hours apart This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 3 Table 1. Mean ± SD and range of pharmacokinetic parameters of methylphenidate after a single dose of Ritalin LA® and Ritalin® given in two doses 4 hours apart Population Children Adult Males Formulation Dose Ritalin® 10 mg & 10 mg Ritalin LA® 20 mg Ritalin® 10 mg & 10 mg Ritalin LA® 20 mg N 21 18 9 8 Tlag (h) 0.24 ± 0.44 0.28 ± 0.46 1.0 ± 0.5 0.7 ± 0.2 0 - 1 0 - 1 0.7 - 1.3 0.3 - 1.0 Tmax1 (h) 1.8 ± 0.6 2.0 ± 0.8 1.9 ± 0.4 2.0 ± 0.9 1 - 3 1 - 3 1.3 - 2.7 1.3 - 4.0 Cmax1 (ng/mL) 10.2 ± 4.2 10.3 ± 5.1 4.3 ± 2.3 5.3 ± 0.9 4.2 - 20.2 5.5 - 26.6 1.8 - 7.5 3.8 - 6.9 Tminip (h) 4.0 ± 0.2 4.5 ± 1.2 3.8 ± 0.4 3.6 ± 0.6 4 - 5 2 - 6 3.3 - 4.3 2.7 - 4.3 Cminip (ng/mL) 5.8 ± 2.7 6.1 ± 4.1 1.2 ± 1.4 3.0 ± 0.8 3.1 - 14.4 2.9 - 21.0 0.0 - 3.7 1.7 - 4.0 Tmax2 (h) 5.6 ± 0.7 6.6 ± 1.5 5.9 ± 0.5 5.5 ± 0.8 5 - 8 5 - 11 5.0 - 6.5 4.3 - 6.5 Cmax2 (ng/mL) 15.3 ± 7.0 10.2 ± 5.9 5.3 ± 1.4 6.2 ± 1.6 6.2 - 32.8 4.5 - 31.1 3.6 - 7.2 3.9 - 8.3 AUC(0-∞) 102.4 ± 54.6 86.6 ± 64.0a 37.8 ± 21.9 45.8 ± 10.0 (ng/mL x h-1) 40.5 - 261.6 43.3 - 301.44 14.3 - 85.3 34.0 - 61.6 t1/2 (h) 2.5 ± 0.8 2.4 ± 0.7a 3.5 ± 1.9 3.3 ± 0.4 1.8 - 5.3 1.5 - 4.0 1.3 - 7.7 3.0 - 4.2 a N = 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 4 Dose Proportionality After oral administration of Ritalin LA 20 mg and 40 mg capsules to adults there is a slight upward trend in the methylphenidate area under the curve (AUC) and peak plasma concentrations (Cmax1 and Cmax2). Distribution Binding to plasma proteins is low (10%-33%), and the apparent distribution volume at steady state with intravenous administration has been reported to be approximately 6 L/kg. Metabolism The absolute oral bioavailability of methylphenidate in children has been reported to be about 30% (range 10%-52%), suggesting pronounced presystemic metabolism. Biotransformation of methylphenidate is rapid and extensive leading to the main, de-esterified metabolite α-phenyl- 2-piperidine acetic acid (ritalinic acid). Only small amounts of hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable in plasma. Therapeutic activity is principally due to the parent compound. Elimination In studies with Ritalin LA and Ritalin tablets in adults, methylphenidate from Ritalin tablets is eliminated from plasma with an average half-life of about 3.5 hours, (range 1.3 - 7.7 hours). In children the average half-life is about 2.5 hours, with a range of about 1.5 - 5.0 hours. The rapid half-life in both children and adults may result in unmeasurable concentrations between the morning and mid-day doses with Ritalin tablets. No accumulation of methylphenidate is expected following multiple once a day oral dosing with Ritalin LA. The half-life of ritalinic acid is about 3-4 hours. After oral administration of an immediate release formulation of methylphenidate, 78%-97% of the dose is excreted in the urine and 1%-3% in the feces in the form of metabolites within 48-96 hours. Only small quantities (<1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as ritalinic acid (60%-86%), the remainder being accounted for by minor metabolites. Food Effects Administration times relative to meals and meal composition may need to be individually titrated. When Ritalin LA was administered with a high fat breakfast to adults, Ritalin LA had a longer lag time until absorption began and variable delays in the time until the first peak concentration, the time until the interpeak minimum, and the time until the second peak. The first peak concentration and the extent of absorption were unchanged after food relative to the fasting state, although the second peak was approximately 25% lower. The effect of a high fat lunch was not examined. There were no differences in the pharmacokinetics of Ritalin LA when administered with applesauce, compared to administration in the fasting condition. There is no evidence of dose dumping in the presence or absence of food. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 5 For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered (see DOSAGE AND ADMINISTRATION). Special Populations Age: The pharmacokinetics of Ritalin LA was examined in 18 children with ADHD between 7 and 12 years of age. Fifteen of these children were between 10 and 12 years of age. The time until the between peak minimum, and the time until the second peak were delayed and more variable in children compared to adults. After a 20-mg dose of Ritalin LA, concentrations in children were approximately twice the concentrations observed in 18 to 35 year old adults. This higher exposure is almost completely due to the smaller body size and total volume of distribution in children, as apparent clearance normalized to body weight is independent of age. Gender: There were no apparent gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults when administered Ritalin LA. Renal Insufficiency: Ritalin LA has not been studied in renally-impaired patients. Renal insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. Hepatic Insufficiency: Ritalin LA has not been studied in patients with hepatic insufficiency. Hepatic insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body. CLINICAL STUDIES Ritalin LA® (methylphenidate hydrochloride) extended-release capsules was evaluated in a randomized, double-blind, placebo-controlled, parallel group clinical study in which 134 children, ages 6 to 12, with DSM-IV diagnoses of Attention Deficit Hyperactivity Disorder (ADHD) received a single morning dose of Ritalin LA in the range of 10-40 mg/day, or placebo, for up to 2 weeks. The doses used were the optimal doses established in a previous individual dose titration phase. In that titration phase, 53 of 164 patients (32%) started on a daily dose of 10 mg and 111 of 164 patients (68%) started on a daily dose of 20 mg or higher. The patient’s regular schoolteacher completed the Conners ADHD/DSM-IV Scale for Teachers (CADS-T) at baseline and the end of each week. The CADS-T assesses symptoms of hyperactivity and inattention. The change from baseline of the (CADS-T) scores during the last week of treatment was analyzed as the primary efficacy parameter. Patients treated with Ritalin LA showed a statistically significant improvement in symptom scores from baseline over patients who received placebo. (See Figure 2.) This demonstrates that a single morning dose of Ritalin LA exerts a treatment effect in ADHD. Figure 2. CADS-T total subscale - Mean change from baseline* This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 6 INDICATIONS AND USAGE Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). The efficacy of Ritalin LA in the treatment of ADHD was established in one controlled trial of children aged 6 to 12 who met DSM-IV criteria for ADHD (see CLINICAL PHARMACOLOGY). A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go;” excessive talking; blurting answers; can’t wait turn; intrusive. The Combined Types requires both inattentive and hyperactive-impulsive criteria to be met. Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of the required number of DSM-IV characteristics. Need for Comprehensive Treatment Program Ritalin LA is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 7 placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the child’s symptoms. Long-Term Use The effectiveness of Ritalin LA for long-term use, i.e., for more than 2 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Ritalin LA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS Agitation Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is contraindicated in marked anxiety, tension, and agitation, since the drug may aggravate these symptoms. Hypersensitivity to Methylphenidate Ritalin LA is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product. Glaucoma Ritalin LA is contraindicated in patients with glaucoma. Tics Ritalin LA is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome. (See ADVERSE REACTIONS.) Monoamine Oxidase Inhibitors Ritalin LA is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (hypertensive crises may result). WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 8 serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs. Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia. Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Pre-Existing Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Bipolar Illness Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 9 Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. In the double-blind placebo-controlled study of Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, the mean weight gain was greater for patients receiving placebo (+1.0 kg) than for patients receiving Ritalin LA (+0.1 kg). Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 10 Use in Children Under Six Years of Age Ritalin LA should not be used in children under six years of age, since safety and efficacy in this age group have not been established. Drug Dependence Ritalin LA should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. PRECAUTIONS Hematologic Monitoring Periodic CBC, differential, and platelet counts are advised during prolonged therapy. Information for Patients Patient information is provided at the end of this insert. To assure safe and effective use of Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, the patient information should be discussed with patients. Drug Interactions Methylphenidate is metabolized primarily by de-esterification (nonmicrosomal hydrolytic esterases) to ritalinic acid and not through oxidative pathways. The effects of gastrointestinal pH alterations on the absorption of methylphenidate from Ritalin LA have not been studied. Since the modified release characteristics of Ritalin LA are pH dependent, the coadministration of antacids or acid suppressants could alter the release of methylphenidate. Methylphenidate may decrease the hypotensive effect of guanethidine. Because of possible effects on blood pressure, methylphenidate should be used cautiously with pressor agents. Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine). Downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate. Serious adverse events have been reported in concomitant use of methylphenidate with clonidine, although no causality for the combination has been established. The safety of using This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 11 methylphenidate in combination with clonidine or other centrally acting alpha-2-agonists has not been systematically evaluated. Carcinogenesis/Mutagenesis/Impairment of Fertility In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and 4 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 5 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60-74 mg/kg/day of methylphenidate. Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 80-fold and 8-fold the highest recommended dose on a mg/kg and mg/m2 basis, respectively. Pregnancy Pregnancy Category C In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2 basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 12 decreased at the highest dose (4 times the MRHD on a mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m2 basis). Adequate and well-controlled studies in pregnant women have not been conducted. Ritalin LA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Ritalin LA is administered to a nursing woman. Pediatric Use Long-term effects of methylphenidate in children have not been well established. Ritalin LA should not be used in children under six years of age (see WARNINGS). In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown. ADVERSE REACTIONS The clinical program for Ritalin LA® (methylphenidate hydrochloride) extended-release capsules consisted of six studies: two controlled clinical studies conducted in children with ADHD aged 6-12 years and four clinical pharmacology studies conducted in healthy adult volunteers. These studies included a total of 256 subjects; 195 children with ADHD and 61 healthy adult volunteers. The subjects received Ritalin LA in doses of 10-40 mg per day. Safety of Ritalin LA was assessed by evaluating frequency and nature of adverse events, routine laboratory tests, vital signs, and body weight. Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and listings that follow, MEDRA terminology has been used to classify reported adverse events. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 13 Adverse Events in a Double-Blind, Placebo-Controlled Clinical Trial with Ritalin LA Treatment-Emergent Adverse Events A placebo-controlled, double-blind, parallel-group study was conducted to evaluate the efficacy and safety of Ritalin LA in children with ADHD aged 6-12 years. All subjects received Ritalin LA for up to 4 weeks, and had their dose optimally adjusted, prior to entering the double-blind phase of the trial. In the two-week double-blind treatment phase of this study, patients received either placebo or Ritalin LA at their individually-titrated dose (range 10 mg-40 mg). The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. Adverse events with an incidence >5% during the initial four-week single-blind Ritalin LA titration period of this study were headache, insomnia, upper abdominal pain, appetite decreased, and anorexia. Treatment-emergent adverse events with an incidence >2% among Ritalin LA-treated subjects, during the two-week double-blind phase of the clinical study, were as follows: Preferred term Ritalin LA® N=65 N (%) Placebo N=71 N (%) Anorexia 2 (3.1) 0 (0.0) Insomnia 2 (3.1) 0 (0.0) Adverse Events Associated with Discontinuation of Treatment In the two-week double-blind treatment phase of a placebo-controlled parallel-group study in children with ADHD, only one Ritalin LA-treated subject (1/65, 1.5%) discontinued due to an adverse event (depression). In the single-blind titration period of this study, subjects received Ritalin LA for up to 4 weeks. During this period a total of six subjects (6/161, 3.7%) discontinued due to adverse events. The adverse events leading to discontinuation were anger (in 2 patients), hypomania, anxiety, depressed mood, fatigue, migraine and lethargy. Adverse Events with Other Methylphenidate HCl Dosage Forms Nervousness and insomnia are the most common adverse reactions reported with other methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed below may also occur. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 14 Other reactions include: Cardiac: angina, arrhythmia, palpitations, pulse increased or decreased, tachycardia Gastrointestinal: abdominal pain, nausea Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura. Metabolism/Nutrition: anorexia, weight loss during prolonged therapy Nervous System: dizziness, drowsiness, dyskinesia, headache, rare reports of Tourette’s syndrome, toxic psychosis Vascular: blood pressure increased or decreased, cerebral arteritis and/or occlusion Although a definite causal relationship has not been established, the following have been reported in patients taking methylphenidate: Blood/Lymphatic: leukopenia and/or anemia Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma Psychiatric: transient depressed mood, aggressive behavior Skin/Subcutaneous: scalp hair loss Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause. DRUG ABUSE AND DEPENDENCE Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, like other products containing methylphenidate, is a Schedule II controlled substance. (See WARNINGS for boxed warning containing drug abuse and dependence information.) OVERDOSAGE Signs and Symptoms Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 15 Poison Control Center Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice. Recommended Treatment As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. When treating overdose, practitioners should bear in mind that there is a prolonged release of methylphenidate from Ritalin LA® (methylphenidate hydrochloride) extended- release capsules. Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage as indicated. Before performing gastric lavage, control agitation and seizures if present and protect the airway. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia. Efficacy of peritoneal dialysis or extracorporeal hemodialysis for methylphenidate overdosage has not been established; also, dialysis is considered unlikely to be of benefit due to the large volume of distribution of methylphenidate. DOSAGE AND ADMINISTRATION Administration of Dose Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is for oral administration once daily in the morning. Ritalin LA may be swallowed as whole capsules or alternatively may be administered by sprinkling the capsule contents on a small amount of applesauce (see specific instructions below). Ritalin LA and/or their contents should not be crushed, chewed, or divided. The capsules may be carefully opened and the beads sprinkled over a spoonful of applesauce. The applesauce should not be warm because it could affect the modified release properties of this formulation. The mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use. Dosing Recommendations Dosage should be individualized according to the needs and responses of the patients. Initial Treatment The recommended starting dose of Ritalin LA is 20 mg once daily. Dosage may be adjusted in weekly 10 mg increments to a maximum of 60 mg/day taken once daily in the morning, depending on tolerability and degree of efficacy observed. Daily dosage above 60 mg is not This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 16 recommended. When in the judgement of the clinician a lower initial dose is appropriate, patients may begin treatment with Ritalin LA 10 mg. Patients Currently Receiving Methylphenidate The recommended dose of Ritalin LA for patients currently taking methylphenidate b.i.d. or sustained release (SR) is provided below. Previous Methylphenidate Dose Recommended Ritalin LA® Dose 5 mg methylphenidate-b.i.d. 10 mg q.d. 10 mg methylphenidate b.i.d. or 20 mg methylphenidate-SR 20 mg q.d. 15 mg methylphenidate b.i.d. 30 mg q.d. 20 mg methylphenidate b.i.d. or 40 mg of methylphenidate-SR 40 mg q.d. 30 mg methylphenidate b.i.d. or 60 mg methylphenidate-SR 60 mg q.d. For other methylphenidate regimens, clinical judgment should be used when selecting the starting dose. Ritalin LA dosage may be adjusted at weekly intervals in 10 mg increments. Daily dosage above 60 mg is not recommended. Maintenance/Extended Treatment There is no body of evidence available from controlled trials to indicate how long the patient with ADHD should be treated with Ritalin LA. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. Nevertheless, the physician who elects to use Ritalin LA for extended periods in patients with ADHD should periodically re-evaluate the long-term usefulness of the drug for the individual patient with trials off medication to assess the patient’s functioning without pharmacotherapy. Improvement may be sustained when the drug is either temporarily or permanently discontinued. Dose Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse events occur, the dosage should be reduced, or, if necessary, the drug should be discontinued. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued. HOW SUPPLIED Ritalin LA capsules 10 mg: white/light brown (imprinted NVR R10) Bottles of 100………………………………………………………NDC 0078-0424-05 Ritalin LA capsules 20 mg: white (imprinted NVR R20) Bottles of 100………………………………………………………NDC 0078-0370-05 Ritalin LA capsules 30 mg: yellow (imprinted NVR R30) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 17 Bottles of 100………………………………………………………NDC 0078-0371-05 Ritalin LA capsules 40 mg: light brown (imprinted NVR R40) Bottles of 100………………………………………………………NDC 0078-0372-05 Store at 25°C (77°F), excursions permitted 15°C-30°C (59°F-86°F). [See USP controlled room temperature] Dispense in tight container (USP). Ritalin LA® is a trademark of Novartis AG. SODAS® is a trademark of Elan Corporation, plc. This product is covered by US patents including US 5,837,284 and 6,228,398. REFERENCE American Psychiatric Association. Diagnosis and Statistical Manual of Mental Disorders. 4th edition. Washington DC: American Psychiatric Association 1994. REV: JUNE 2006 T2006-62 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 18 INFORMATION FOR PATIENTS TAKING RITALIN LA®, OR FOR THEIR PARENTS OR CAREGIVERS Once Daily Ritalin LA® (methylphenidate hydrochloride) extended-release capsules This information for patients or their parents or caregivers is about Ritalin LA. Please read this before you start taking Ritalin LA. Also, read the information you get each time you renew your prescription, in case anything has changed. Remember, this information does not take the place of your doctor’s instructions. If you have any questions about this information or about Ritalin LA, talk to your doctor or pharmacist. WHAT IS RITALIN LA? Ritalin LA is a once-a-day treatment for Attention Deficit Hyperactivity Disorder, or ADHD. Ritalin LA contains the drug methylphenidate (Ritalin®), a central nervous system stimulant that has been used to treat ADHD for more than 30 years. Ritalin is available in several forms including Ritalin LA, an extended-release form of methylphenidate hydrochloride available as 10, 20, 30, and 40 mg extended-release capsules. Ritalin LA is taken by mouth, once each day in the morning, before breakfast. WHAT IS ATTENTION DEFICIT HYPERACTIVITY DISORDER? ADHD has three main types of symptoms: inattention, hyperactivity, and impulsiveness. Symptoms of inattention include not paying attention, making careless mistakes, not listening, not finishing tasks, not following directions, and being easily distracted. Symptoms of hyperactivity and impulsiveness include fidgeting, talking excessively, running around at inappropriate times, and interrupting others. Some patients have more symptoms of hyperactivity and impulsiveness while others have more symptoms of inattentiveness. Some patients have all three types of symptoms. Many people have symptoms like these from time to time, but patients with ADHD have these symptoms more than others their age. Symptoms must be present for at least 6 months to be certain of the diagnosis. HOW DOES RITALIN LA WORK? When you take a Ritalin LA capsule, half of the beads provide an immediate dose of methylphenidate and the other half provide a delayed second release of the drug to continue to help lessen the symptoms of ADHD during the day. Methylphenidate, the active ingredient in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 19 Ritalin LA, helps increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. BEFORE RITALIN LA TREATMENT It is very important that ADHD be accurately diagnosed and that the need for medication be carefully assessed. It is important to remember that Ritalin is only part of the overall management of ADHD. Parents, teachers, physicians and other professionals are part of a team that must work together. Before Ritalin treatment, your doctor should be made aware of any current or past physical or mental problems. Tell your doctor if there is a history of drug or alcohol abuse, depression, bipolar disorder, psychosis, epilepsy or seizure disorders, high blood pressure, heart defects, irregular heart rhythms, other heart problems, glaucoma, and facial tics (involuntary movements). Also tell your doctor if there is a family history of sudden death, irregular heart rhythm, suicide, bipolar disorder, depression or Tourette’s syndrome. Both your doctor and your pharmacist should also be informed of all medicines that you are taking, even if these drugs are not taken on a regular basis and are available without prescription. Your doctor will decide whether you can take Ritalin with other medicines. Methylphenidate is known to interact with a number of other drugs. These include medicines to treat depression, such as monoamine oxidase inhibitors; to control seizures; and to thin blood. Sometimes these interactions may require a change in dosage, or occasionally stopping one of the drugs involved. Tell your doctor if you are pregnant or nursing a baby. WHO SHOULD NOT TAKE RITALIN LA ? You should NOT take Ritalin LA if: • You have known serious heart defects, serious heart rhythm irregularities, or other serious heart problems. • You have significant anxiety, tension, or agitation since Ritalin LA may make these conditions worse. • You are allergic to methylphenidate or any of the other ingredients in Ritalin LA. • You have glaucoma, an eye disease. • You have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome. • You are taking a monoamine oxidase inhibitor, a type of drug, or have discontinued a monoamine oxidase inhibitor in the last 14 days. Talk to your doctor if you believe any of these conditions apply to you. HOW SHOULD I TAKE RITALIN LA ? Take Ritalin LA once each day in the morning. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 20 Take the dose prescribed by your doctor. Your doctor may adjust the amount of drug you take until it is right for you. From time to time, your doctor may interrupt your treatment to check your symptoms while you are not taking the drug. Ritalin LA capsules may be taken at the same time as food or without food, although food may delay the absorption of Ritalin LA. The Ritalin LA capsule may be swallowed as whole capsules or the capsule may be opened and sprinkled on a small amount of applesauce. The capsule should not be crushed or chewed or its contents divided. To sprinkle the contents of the capsule, open the capsule carefully and sprinkle the beads over a spoonful of applesauce. The applesauce should not be warm because it could affect the modified release properties of this formulation. The mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use. If you also take antiacids or drugs that suppress stomach acids, you should discuss with your physician or pharmacist how to take these drugs with Ritalin LA. WHAT ARE THE POSSIBLE SIDE EFFECTS OF RITALIN LA? The most common side effects of Ritalin LA are: • Nervousness • Stomach pain • Sleeplessness • Decreased appetite Other side effects seen with methylphenidate, the active ingredient in Ritalin LA, include nausea, vomiting, dizziness, tics, allergic reactions, increased blood pressure and psychosis (abnormal thinking or hallucinations). Dependence Abuse of methylphenidate can lead to dependence. Tell your doctor if you have ever abused or been dependent on alcohol or drugs, or if you are now abusing or dependent on alcohol or drugs. Misuse of stimulants may be associated with sudden death and serious cardiovascular adverse events. Blurred Vision Tell your doctor if you have blurred vision when taking Ritalin LA. This could be a sign of a serious problem. Slower Growth Slower growth (weight gain and/or height) has been reported with long-term use of methylphenidate in children. Your doctor will be carefully watching your height and weight. If you are not growing or gaining weight as your doctor expects, your doctor may stop your Ritalin LA treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 21 This is not a complete list of possible side effects. Ask your doctor about other side effects. If you develop any side effect, talk to your doctor. WHAT MUST I DISCUSS WITH MY DOCTOR BEFORE TAKING RITALIN LA? Talk to your doctor before taking RITALIN LA if you: • Have high blood pressure. • Have an abnormal heart rate or rhythm. • Have had any other current or previous heart problems. • Have a family history of sudden death or heart rhythm problems. • Are being treated for depression or bipolar disorder, or have symptoms of depression such as feelings of sadness, worthlessness, and hopelessness. • Have a family history of suicide, bipolar disorder or depression. • Have motion tics (hard-to-control, repeated twitching of any parts of your body) or verbal tics (hard-to-control repeating of sounds or words). • Have someone in your family with motion tics, verbal tics, or Tourette’s syndrome. • Have abnormal thoughts or visions, hear abnormal sounds, or have been diagnosed with psychosis. • Have had seizures (convulsions, epilepsy) or abnormal EEGs (electroencephalograms). Tell your doctor immediately if you develop any of the above conditions or symptoms while taking Ritalin LA. CAN I TAKE RITALIN LA WITH OTHER MEDICINES? Tell your doctor about all medicines that you are taking or intend to take. Your doctor should decide whether you can take Ritalin LA with other medicines. These include: • Other medicines that a doctor has prescribed. • All medicines that you buy yourself without a prescription. • Any herbal remedies that you may be taking. Monoamine Oxidase (MAO) Inhibitors You should not take Ritalin LA with (MAO) inhibitors or within 14 days of stopping a MAO inhibitor. Starting a New Medicine While on Ritalin LA, do not start taking a new medicine or herbal remedy before checking with your doctor. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 22 Other Medicines You May Be Taking Ritalin LA may change the way your body reacts to certain medicines. These include medicines used to treat depression, prevent seizures, or prevent blood clots (commonly called “blood thinners”). Your doctor may need to change your dose of these medicines if you are taking them with Ritalin LA. Other Important Safety Information Pregnancy and Nursing Before taking Ritalin LA, tell your doctor if you are pregnant or plan on becoming pregnant. If you take methylphenidate, it may be in your breast milk. Tell your doctor if you are nursing a baby. Overdose Call your doctor immediately if you take more than the amount of Ritalin LA prescribed by your doctor. WHAT ELSE SHOULD I KNOW ABOUT RITALIN LA ? Ritalin LA has not been studied in children under 6 years of age. Ritalin LA may be a part of your overall treatment for ADHD. Your doctor may also recommend that you have counseling or other therapy. As with all medicines, never share Ritalin LA with anyone else and take only the number of Ritalin LA capsules prescribed by your doctor. Ritalin LA should be stored in a safe place at room temperature (between 59°F-86°F). Do not store this medicine in hot, damp, or humid places. Keep the container of Ritalin LA in a safe place, away from high-traffic areas where other people could have accidental or unauthorized access to the medication. Keep track of the number of capsules so that you will know if any are missing. Someone who has easy access to Ritalin may be able to give the capsules to others or misuse the medication. Keep out of the reach of children. This leaflet summarizes the most important information about Ritalin LA. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Ritalin LA that is written for health professionals. You can also call 1-888 NOWNOVA (1-888-669-6682). REV: JUNE 2006 T2006-63 REV: JUNE 2006 PRINTED IN U.S.A. T2006-62/ T2006-63 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 23 Manufactured for Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 By ELAN HOLDINGS INC. Pharmaceutical Division Gainesville, GA 30504 ©Novartis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:42.124250	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/010187s66s67,018029s37s38,021284s6s8lbl.pdf', 'application_number': 10187, 'submission_type': 'SUPPL ', 'submission_number': 67}
10,747	company logo Ritalin® hydrochloride methylphenidate hydrochloride tablets USP Ritalin-SR® methylphenidate hydrochloride USP sustained-release tablets Rx only Prescribing Information DESCRIPTION Ritalin hydrochloride, methylphenidate hydrochloride USP, is a mild central nervous system (CNS) stimulant, available as tablets of 5, 10, and 20 mg for oral administration; Ritalin-SR is available as sustained-release tablets of 20 mg for oral administration. Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is structural formula Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77. Inactive Ingredients. Ritalin tablets: D&C Yellow No. 10 (5-mg and 20-mg tablets), FD&C Green No. 3 (10-mg tablets), lactose, magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg tablets), sucrose, talc, and tragacanth (20-mg tablets). Ritalin-SR tablets: Cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate, mineral oil, povidone, titanium dioxide, and zein. CLINICAL PHARMACOLOGY Ritalin is a mild central nervous system stimulant. The mode of action in man is not completely understood, but Ritalin presumably activates the brain stem arousal system and cortex to produce its stimulant effect. There is neither specific evidence which clearly establishes the mechanism whereby Ritalin produces its mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system. Reference ID: 2863882 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ritalin in the SR tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the SR tablet compared to the Ritalin tablet, measured by the urinary excretion of Ritalin major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49%-168%) in children and 101% (85%-152%) in adults. The time to peak rate in children was 4.7 hours (1.3-8.2 hours) for the SR tablets and 1.9 hours (0.3-4.4 hours) for the tablets. An average of 67% of SR tablet dose was excreted in children as compared to 86% in adults. In a clinical study involving adult subjects who received SR tablets, plasma concentrations of Ritalin’s major metabolite appeared to be greater in females than in males. No gender differences were observed for Ritalin plasma concentration in the same subjects. INDICATIONS Attention Deficit Disorders, Narcolepsy Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children). Other terms being used to describe the behavioral syndrome below include: Hyperkinetic Child Syndrome, Minimal Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction. Ritalin is indicated as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted. Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Characteristics commonly reported include: chronic history of short attention span, distractibility, emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor neurological signs and abnormal EEG. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of one or more of these characteristics. Drug treatment is not indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is generally necessary. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the child’s symptoms. CONTRAINDICATIONS Marked anxiety, tension, and agitation are contraindications to Ritalin, since the drug may aggravate these symptoms. Ritalin is contraindicated also in patients known to be hypersensitive to the drug, in patients with glaucoma, and in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome. Reference ID: 2863882 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ritalin is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of a monoamine oxidase inhibitor (hypertensive crises may result). WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs. Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia. Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Pre-Existing Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Reference ID: 2863882 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Bipolar Illness Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/ manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e. g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short- term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. Use in Children Under Six Years of Age Ritalin should not be used in children under 6 years, since safety and efficacy in this age group have not been established. Reference ID: 2863882 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Dependence Ritalin should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. PRECAUTIONS Patients with an element of agitation may react adversely; discontinue therapy if necessary. Periodic CBC, differential, and platelet counts are advised during prolonged therapy. Drug treatment is not indicated in all cases of this behavioral syndrome and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe Ritalin should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with Ritalin is usually not indicated. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with methylphenidate and should counsel them in its appropriate use. A patient Medication Guide is available for Ritalin and Ritalin-SR. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Drug Interactions Ritalin should not be used in patients being treated (currently or within the proceeding two weeks) with MAO Inhibitors (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors). Because of possible effects on blood pressure, Ritalin should be used cautiously with pressor agents. Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Methylphenidate is metabolized primarily to ritalinic acid by de-esterification and not through oxidative pathways. Human pharmacologic studies have shown that racemic methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine). Downward dose adjustments of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentration (or, in case of coumarin, coagulation times), when initiating or discontinuing methylphenidate. Carcinogenesis/Mutagenesis/Impairment of Fertility In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and 4 times the maximum Reference ID: 2863882 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda recommended human dose on a mg/kg and mg/m2 basis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 5 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60-74 mg/kg/day of methylphenidate. Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Methlyphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 80-fold and 8-fold the highest recommended dose on a mg/kg and mg/m2 basis, respectively. PREGNANCY Pregnancy Category C In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2 basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (4 times the MRHD on a mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m2 basis). Adequate and well-controlled studies in pregnant women have not been conducted. Ritalin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Ritalin is administered to a nursing woman. Pediatric Use Ritalin should not be used in children under six years of age (see WARNINGS). Reference ID: 2863882 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown. ADVERSE REACTIONS Nervousness and insomnia are the most common adverse reactions but are usually controlled by reducing dosage and omitting the drug in the afternoon or evening. Other reactions include hypersensitivity (including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura); anorexia; nausea; dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse changes, both up and down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss during prolonged therapy. There have been rare reports of Tourette’s syndrome. Toxic psychosis has been reported. Although a definite causal relationship has not been established, the following have been reported in patients taking this drug: instances of abnormal liver function, ranging from transaminase elevation to hepatic coma; isolated cases of cerebral arteritis and/or occlusion; leukopenia and/or anemia; transient depressed mood; aggressive behavior; a few instances of scalp hair loss. Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed above may also occur. DOSAGE AND ADMINISTRATION Dosage should be individualized according to the needs and responses of the patient. Adults Tablets: Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Average dosage is 20 to 30 mg daily. Some patients may require 40 to 60 mg daily. In others, 10 to 15 mg daily will be adequate. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m. SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or chewed. Reference ID: 2863882 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Children (6 years and over) Ritalin should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is not recommended. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued. Tablets: Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5 to 10 mg weekly. SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or chewed. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug. Ritalin should be periodically discontinued to assess the child’s condition. Improvement may be sustained when the drug is either temporarily or permanently discontinued. Drug treatment should not and need not be indefinite and usually may be discontinued after puberty. OVERDOSAGE Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice. Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage. In the presence of severe intoxication, use a carefully titrated dosage of a short-acting barbiturate before performing gastric lavage. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia. Efficacy of peritoneal dialysis or extracorporeal hemodialysis for Ritalin overdosage has not been established. HOW SUPPLIED Tablets 5 mg - round, yellow (imprinted CIBA 7) Bottles of 100 ...............................................……………………………......NDC 0078-0439-05 Tablets 10 mg - round, pale green, scored (imprinted CIBA 3) Bottles of 100 .................................................................................................NDC 0078-0440-05 Tablets 20 mg - round, pale yellow, scored (imprinted CIBA 34) Bottles of 100 .......………………………………………………………......NDC 0078-0441-05 Reference ID: 2863882 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from light. Dispense in tight, light-resistant container (USP). SR Tablets 20 mg - round, white, coated (imprinted CIBA 16) Bottles of 100……………………………………………………………...NDC 0078-0442-05 Note: SR Tablets are color-additive free. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in tight, light-resistant container (USP). MEDICATION GUIDE RITALIN® (methylphenidate hydrochloride tablets, USP) CII Read the Medication Guide that comes with RITALIN® before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your or your child’s treatment with RITALIN®. What is the most important information I should know about RITALIN®? The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines. 1. Heart-related problems: • sudden death in patients who have heart problems or heart defects • stroke and heart attack in adults • increased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting RITALIN® . Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment with RITALIN® . Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking RITALIN®. 2. Mental (Psychiatric) problems: All Patients • new or worse behavior and thought problems • new or worse bipolar illness • new or worse aggressive behavior or hostility Children and Teenagers • new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking RITALIN®, especially seeing or hearing things that are not real, believing things that are not Reference ID: 2863882 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda real, or are suspicious. What Is RITALIN®? RITALIN® is a central nervous system stimulant prescription medicine. It is used for the treatment of Attention- Deficit Hyperactivity Disorder (ADHD). RITALIN® may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. RITALIN® should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. RITALIN® is also used in the treatment of a sleep disorder called narcolepsy. RITALIN® is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep RITALIN® in a safe place to prevent misuse and abuse. Selling or giving away RITALIN® may harm others, and is against the law. Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs. Who should not take RITALIN®? RITALIN® should not be taken if you or your child: • are very anxious, tense, or agitated • have an eye problem called glaucoma • have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome. Tics are hard to control repeated movements or sounds. • are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI. • are allergic to anything in RITALIN®. See the end of this Medication Guide for a complete list of ingredients. RITALIN® should not be used in children less than 6 years old because it has not been studied in this age group. RITALIN® may not be right for you or your child. Before starting RITALIN® tell your or your child’s doctor about all health conditions (or a family history of) including: • heart problems, heart defects, high blood pressure • mental problems including psychosis, mania, bipolar illness, or depression • tics or Tourette’s syndrome • seizures or have had an abnormal brain wave test (EEG) Tell your doctor if you or your child is pregnant, planning to become pregnant, or breast-feeding. Can RITALIN® be taken with other medicines? Tell your doctor about all of the medicines that you or your child take including prescription and nonprescription medicines, vitamins, and herbal supplements. RITALIN® and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking RITALIN® . Your doctor will decide whether RITALIN® can be taken with other medicines. Especially tell your doctor if you or your child takes: • anti-depression medicines including MAOIs • seizure medicines • blood thinner medicines • blood pressure medicines • cold or allergy medicines that contain decongestants Reference ID: 2863882 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist. Do not start any new medicine while taking RITALIN® without talking to your doctor first. How should RITALIN® be taken? • Take RITALIN® exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child. • Ritalin is usually taken 2 to 3 times a day. • Take RITALIN® 30 to 45 minutes before a meal. • From time to time, your doctor may stop RITALIN® treatment for a while to check ADHD symptoms. • Your doctor may do regular checks of the blood, heart, and blood pressure while taking RITALIN® . Children should have their height and weight checked often while taking RITALIN® . RITALIN® treatment may be stopped if a problem is found during these check-ups. • If you or your child takes too much RITALIN® or overdoses, call your doctor or poison control center right away, or get emergency treatment. What are possible side effects of RITALIN®? See “What is the most important information I should know about RITALIN®?” for information on reported heart and mental problems. Other serious side effects include: • slowing of growth (height and weight) in children • seizures, mainly in patients with a history of seizures • eyesight changes or blurred vision Common side effects include: • headache • decreased appetite • stomach ache • nervousness • trouble sleeping • nausea Talk to your doctor if you or your child has side effects that are bothersome or do not go away. This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information. How should I store RITALIN®? • Store RITALIN in a safe place at room temperature, 59 to 86° F (15 to 30° C). Protect from light. • Keep RITALIN® and all medicines out of the reach of children. General information about RITALIN® Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RITALIN® for a condition for which it was not prescribed. Do not give RITALIN® to other people, even if they have the same condition. It may harm them and it is against the law. This Medication Guide summarizes the most important information about RITALIN®. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about RITALIN® that was written for healthcare professionals. For more information about RITALIN® call 1-888-669-6682. What are the ingredients in RITALIN®? Active Ingredient: methylphenidate HCL Reference ID: 2863882 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Inactive Ingredients: D&C Yellow No.10 (5-mg and 20-mg tablets), FD&C Green No.3 (10-mg tablets), lactose, magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg tablets), sucrose, talc, and tragacanth (20-mg tablets). Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA 1088. This Medication Guide has been approved by the U.S. Food and Drug Administration. MEDICATION GUIDE RITALIN-SR® (methylphenidate hydrochloride, USP) sustained-release tablets CII Read the Medication Guide that comes with RITALIN-SR® before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your or your child’s treatment with RITALIN-SR® . What is the most important information I should know about RITALIN-SR®? The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines. 1. Heart-related problems: • sudden death in patients who have heart problems or heart defects • stroke and heart attack in adults • increased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting RITALIN-SR® . Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment with RITALIN-SR® . Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking RITALIN-SR®. 2. Mental (Psychiatric) problems: All Patients • new or worse behavior and thought problems • new or worse bipolar illness • new or worse aggressive behavior or hostility Children and Teenagers • new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking RITALIN-SR®, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. Reference ID: 2863882 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What Is RITALIN-SR®? RITALIN-SR® is a central nervous system stimulant prescription medicine. It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). RITALIN-SR® may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. RITALIN-SR® should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. RITALIN-SR® is also used in the treatment of a sleep disorder called narcolepsy. RITALIN-SR® is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep RITALIN-SR® in a safe place to prevent misuse and abuse. Selling or giving away RITALIN-SR® may harm others, and is against the law. Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs. Who should not take RITALIN-SR®? RITALIN-SR® should not be taken if you or your child: • are very anxious, tense, or agitated • have an eye problem called glaucoma • have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome. Tics are hard to control repeated movements or sounds. • are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI. • are allergic to anything in RITALIN-SR®. See the end of this Medication Guide for a complete list of ingredients. RITALIN-SR® should not be used in children less than 6 years old because it has not been studied in this age group. RITALIN-SR® may not be right for you or your child. Before starting RITALIN-SR® tell your or your child’s doctor about all health conditions (or a family history of) including: • heart problems, heart defects, high blood pressure • mental problems including psychosis, mania, bipolar illness, or depression • tics or Tourette’s syndrome • seizures or have had an abnormal brain wave test (EEG) Tell your doctor if you or your child is pregnant, planning to become pregnant, or breast-feeding. Can RITALIN-SR® be taken with other medicines? Tell your doctor about all of the medicines that you or your child take including prescription and nonprescription medicines, vitamins, and herbal supplements. RITALIN-SR® and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking RITALIN-SR®. Your doctor will decide whether RITALIN-SR® can be taken with other medicines. Especially tell your doctor if you or your child takes: • anti-depression medicines including MAOIs • seizure medicines • blood thinner medicines • blood pressure medicines • cold or allergy medicines that contain decongestants Reference ID: 2863882 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist. Do not start any new medicine while taking RITALIN-SR® without talking to your doctor first. How should RITALIN-SR® be taken? • Take RITALIN-SR® exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child. • Take RITALIN-SR® 30 to 45 minutes before a meal. The effect of a dose of RITALIN-SR usually lasts about 8 hours. • Do not chew or crush RITALIN-SR® tablets. Swallow RITALIN-SR® tablets whole with water or other liquids. Tell your doctor if you or your child cannot swallow RITALIN-SR® whole. A different medicine may need to be prescribed. • From time to time, your doctor may stop RITALIN-SR® treatment for a while to check ADHD symptoms. • Your doctor may do regular checks of the blood, heart, and blood pressure while taking RITALIN-SR®. Children should have their height and weight checked often while taking RITALIN-SR®. RITALIN-SR® treatment may be stopped if a problem is found during these check-ups. • If you or your child takes too much RITALIN-SR® or overdoses, call your doctor or poison control center right away, or get emergency treatment. What are possible side effects of RITALIN-SR®? See “What is the most important information I should know about RITALIN-SR®?” for information on reported heart and mental problems. Other serious side effects include: • slowing of growth (height and weight) in children • seizures, mainly in patients with a history of seizures • eyesight changes or blurred vision Common side effects include: • headache • decreased appetite • stomach ache • nervousness • trouble sleeping • nausea Talk to your doctor if you or your child has side effects that are bothersome or do not go away. This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information. How should I store RITALIN-SR®? • Store RITALIN-SR® in a safe place at room temperature, 59 to 86° F (15 to 30° C). Protect from moisture. • Keep RITALIN-SR® and all medicines out of the reach of children. General information about RITALIN-SR® Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RITALIN-SR® for a condition for which it was not prescribed. Do not give RITALIN-SR® to other people, even if they have the same condition. It may harm them and it is against the law. This Medication Guide summarizes the most important information about RITALIN-SR®. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about RITALIN-SR® that was written for healthcare professionals. For more information about RITALIN-SR call 1-888-669-6682. What are the ingredients in RITALIN-SR®? Reference ID: 2863882 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Active Ingredient: methylphenidate HCL, USP Inactive Ingredients: cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate, mineral oil, povidone, titanium dioxide, and zein Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA 1088. This Medication Guide has been approved by the U.S. Food and Drug Administration. REV: APRIL 2009Month Year T201X-XX09-56/T2009 57/T2009-58 Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis Reference ID: 2863882 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:42.632623	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/010187s072,018029s042lbl.pdf', 'application_number': 10187, 'submission_type': 'SUPPL ', 'submission_number': 72}
10,748	Ritalin® hydrochloride methylphenidate hydrochloride USP tablets Ritalin-SR® methylphenidate hydrochloride USP sustained-release tablets Rx only Prescribing Information DESCRIPTION Ritalin hydrochloride, methylphenidate hydrochloride USP, is a mild central nervous system (CNS) stimulant, available as tablets of 5, 10, and 20 mg for oral administration; Ritalin-SR is available as sustained-release tablets of 20 mg for oral administration. Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is chemical structure Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77. Inactive Ingredients. Ritalin tablets: D&C Yellow No. 10 (5-mg and 20-mg tablets), FD&C Green No. 3 (10-mg tablets), lactose, magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg tablets), sucrose, talc, and tragacanth (20-mg tablets). Ritalin-SR tablets: Cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate, mineral oil, povidone, titanium dioxide, and zein. CLINICAL PHARMACOLOGY Pharmacodynamics Ritalin is a mild central nervous system stimulant. The mode of action in man is not completely understood, but Ritalin presumably activates the brain stem arousal system and cortex to produce its stimulant effect. There is neither specific evidence which clearly establishes the mechanism whereby Ritalin produces its mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system. Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effects on QT Interval The effect of Focalin® XR (dexmethylphenidate, the pharmacologically active d-enantiomer of Ritalin) on the QT interval was evaluated in a double-blind, placebo- and open label active (moxifloxacin)-controlled study following single doses of Focalin XR 40 mg in 75 healthy volunteers. ECGs were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was <5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident-exposure response relationship. Pharmacokinetics Ritalin in the SR tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the SR tablet compared to the Ritalin tablet, measured by the urinary excretion of Ritalin major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49%-168%) in children and 101% (85%-152%) in adults. The time to peak rate in children was 4.7 hours (1.3-8.2 hours) for the SR tablets and 1.9 hours (0.3-4.4 hours) for the tablets. An average of 67% of SR tablet dose was excreted in children as compared to 86% in adults. In a clinical study involving adult subjects who received SR tablets, plasma concentrations of Ritalin’s major metabolite appeared to be greater in females than in males. No gender differences were observed for Ritalin plasma concentration in the same subjects. INDICATIONS Attention Deficit Disorders, Narcolepsy Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children). Other terms being used to describe the behavioral syndrome below include: Hyperkinetic Child Syndrome, Minimal Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction. Ritalin is indicated as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted. Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Characteristics commonly reported include: chronic history of short attention span, distractibility, emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor neurological signs and abnormal EEG. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of 1 or more of these characteristics. Drug treatment is not indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is generally necessary. When remedial measures alone are insufficient, the decision to Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the child’s symptoms. CONTRAINDICATIONS Marked anxiety, tension, and agitation are contraindications to Ritalin, since the drug may aggravate these symptoms. Ritalin is contraindicated also in patients known to be hypersensitive to the drug, in patients with glaucoma, and in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome. Ritalin is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of a monoamine oxidase inhibitor (hypertensive crises may result). WARNINGS Serious Cardiovascular Events Sudden Death and Preexisting Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs. Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with preexisting hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia. Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Preexisting Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder. Bipolar Illness Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/ manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e. g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short- term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. Peripheral Vasculopathy, Including Raynaud’s Phenomenon Stimulants, including Ritalin and Ritalin-SR, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. Use in Children Under Six Years of Age Ritalin should not be used in children under 6 years, since safety and efficacy in this age group have not been established. Drug Dependence Ritalin should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. PRECAUTIONS Patients with an element of agitation may react adversely; discontinue therapy if necessary. Periodic CBC, differential, and platelet counts are advised during prolonged therapy. Drug treatment is not indicated in all cases of this behavioral syndrome and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe Ritalin should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of 1 or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with Ritalin is usually not indicated. Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with methylphenidate and should counsel them in its appropriate use. A patient Medication Guide is available for Ritalin and Ritalin-SR. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Priapism  Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]  Instruct patients beginning treatment with Ritalin or Ritalin-SR about the risk of peripheral vasculopathy, including Raynaud’s Phenomenon, and in associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red.  Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes.  Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking Ritalin or Ritalin-SR.  Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Drug Interactions Ritalin should not be used in patients being treated (currently or within the proceeding two weeks) with MAO Inhibitors (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors). Because of possible effects on blood pressure, Ritalin should be used cautiously with pressor agents. Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Methylphenidate is metabolized primarily to ritalinic acid by de-esterification and not through oxidative pathways. Human pharmacologic studies have shown that racemic methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine). Downward dose adjustments of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentration (or, in case of coumarin, coagulation times), when initiating or discontinuing methylphenidate. Carcinogenesis/Mutagenesis/Impairment of Fertility In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and 4 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 5 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60-74 mg/kg/day of methylphenidate. Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 80-fold and 8-fold the highest recommended dose on a mg/kg and mg/m2 basis, respectively. PREGNANCY Pregnancy Category C In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m2 basis. The no effect level for embryofetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2 basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m2 basis), which was also maternally toxic. The no effect level for embryofetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (4 times the MRHD on a mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m2 basis). Adequate and well-controlled studies in pregnant women have not been conducted. Ritalin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Ritalin is administered to a nursing woman. Pediatric Use Ritalin should not be used in children under 6 years of age (see WARNINGS). In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown. ADVERSE REACTIONS Nervousness and insomnia are the most common adverse reactions but are usually controlled by reducing dosage and omitting the drug in the afternoon or evening. Other reactions include hypersensitivity (including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura); anorexia; nausea; dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse changes, both up and down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss during prolonged therapy; libido changes. There have been rare reports of Tourette’s syndrome. Toxic psychosis has been reported. Although a definite causal relationship has not been established, the following have been reported in patients taking this drug: instances of abnormal liver function, ranging from transaminase elevation to hepatic coma; isolated cases of cerebral arteritis and/or occlusion; leukopenia and/or anemia; transient depressed mood; aggressive behavior; a few instances of scalp hair loss. Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a 10-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed above may also occur. DOSAGE AND ADMINISTRATION Dosage should be individualized according to the needs and responses of the patient. Adults Tablets: Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Average dosage is 20 to 30 mg daily. Some patients may require 40 to 60 mg daily. In others, 10 to 15 mg daily will be adequate. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m. SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or chewed. Children (6 years and over) Ritalin should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is not recommended. If improvement is not observed after appropriate dosage adjustment over a 1-month period, the drug should be discontinued. Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tablets: Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5 to 10 mg weekly. SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or chewed. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug. Ritalin should be periodically discontinued to assess the child’s condition. Improvement may be sustained when the drug is either temporarily or permanently discontinued. Drug treatment should not and need not be indefinite and usually may be discontinued after puberty. OVERDOSAGE Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice. Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage. In the presence of severe intoxication, use a carefully titrated dosage of a short-acting barbiturate before performing gastric lavage. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia. Efficacy of peritoneal dialysis or extracorporeal hemodialysis for Ritalin overdosage has not been established. HOW SUPPLIED Tablets 5 mg-round, yellow (imprinted CIBA 7) Bottles of 100 ............................................... ……………………………......NDC 0078-0439-05 Tablets 10 mg-round, pale green, scored (imprinted CIBA 3) Bottles of 100 ................................................................................................. NDC 0078-0440-05 Tablets 20 mg-round, pale yellow, scored (imprinted CIBA 34) Bottles of 100 ....... ………………………………………………………......NDC 0078-0441-05 Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Protect from light. Dispense in tight, light-resistant container (USP). SR Tablets 20 mg-round, white, coated (imprinted CIBA 16) Bottles of 100……………………………………………………………...NDC 0078-0442-05 Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Note: SR Tablets are color-additive free. Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in tight, light-resistant container (USP). T201X-XX Month Year Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE RITALIN® (methylphenidate hydrochloride, USP) tablets CII Read the Medication Guide that comes with RITALIN before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your or your child’s treatment with RITALIN. What is the most important information I should know about RITALIN? The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines. 1. Heart-related problems:  sudden death in patients who have heart problems or heart defects  stroke and heart attack in adults  increased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting RITALIN. Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment with RITALIN. Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking RITALIN. 2. Mental (Psychiatric) problems: All Patients  new or worse behavior and thought problems  new or worse bipolar illness  new or worse aggressive behavior or hostility Children and Teenagers  new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking RITALIN, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. 3. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red  Tell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes.  Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking RITALIN. Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What Is RITALIN? RITALIN is a central nervous system stimulant prescription medicine. It is used for the treatment of Attention- Deficit Hyperactivity Disorder (ADHD). RITALIN may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. RITALIN should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. RITALIN is also used in the treatment of a sleep disorder called narcolepsy. RITALIN is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep RITALIN in a safe place to prevent misuse and abuse. Selling or giving away RITALIN may harm others, and is against the law. Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs. Who should not take RITALIN? RITALIN should not be taken if you or your child:  are very anxious, tense, or agitated  have an eye problem called glaucoma  have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome. Tics are hard to control repeated movements or sounds.  are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI.  are allergic to anything in RITALIN. See the end of this Medication Guide for a complete list of ingredients. RITALIN should not be used in children less than 6 years old because it has not been studied in this age group. RITALIN may not be right for you or your child. Before starting RITALIN tell your or your child’s doctor about all health conditions (or a family history of) including:  heart problems, heart defects, high blood pressure  mental problems including psychosis, mania, bipolar illness, or depression  tics or Tourette’s syndrome  seizures or have had an abnormal brain wave test (EEG)  circulation problems in fingers or toes Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding. Can RITALIN be taken with other medicines? Tell your doctor about all of the medicines that you or your child takes including prescription and nonprescription medicines, vitamins, and herbal supplements. RITALIN and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking RITALIN. Your doctor will decide whether RITALIN can be taken with other medicines. Especially tell your doctor if you or your child takes:  anti-depression medicines including MAOIs  seizure medicines  blood thinner medicines  blood pressure medicines  cold or allergy medicines that contain decongestants Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist. Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Do not start any new medicine while taking RITALIN without talking to your doctor first. How should RITALIN be taken?  Take RITALIN exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child.  RITALIN is usually taken 2 to 3 times a day.  Take RITALIN 30 to 45 minutes before a meal.  From time to time, your doctor may stop RITALIN treatment for a while to check ADHD symptoms.  Your doctor may do regular checks of the blood, heart, and blood pressure while taking RITALIN. Children should have their height and weight checked often while taking RITALIN. RITALIN treatment may be stopped if a problem is found during these check-ups.  If you or your child takes too much RITALIN or overdoses, call your doctor or poison control center right away, or get emergency treatment. What are possible side effects of RITALIN? See “What is the most important information I should know about RITALIN?” for information on reported heart and mental problems. Other serious side effects include:  slowing of growth (height and weight) in children  seizures, mainly in patients with a history of seizures  eyesight changes or blurred vision  painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develop priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a doctor immediately. Common side effects include:  headache • decreased appetite  stomach ache • nervousness  trouble sleeping  nausea Talk to your doctor if you or your child has side effects that are bothersome or do not go away. This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information. How should I store RITALIN?  Store RITALIN in a safe place at room temperature, 59°F to 86°F (15°C to 30°C). Protect from light.  Keep RITALIN and all medicines out of the reach of children. General information about RITALIN. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RITALIN for a condition for which it was not prescribed. Do not give RITALIN to other people, even if they have the same condition. It may harm them and it is against the law. This Medication Guide summarizes the most important information about RITALIN. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about RITALIN that was written for healthcare professionals. For more information about RITALIN call 1-888-669-6682. What are the ingredients in RITALIN? Active Ingredient: methylphenidate HCL Inactive Ingredients: D&C Yellow No.10 (5-mg and 20-mg tablets), FD&C Green No.3 (10-mg tablets), lactose, magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg tablets), sucrose, talc, and tragacanth (20-mg tablets). Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA 1088. This Medication Guide has been approved by the U.S. Food and Drug Administration. T201X-XX Month Year Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE RITALIN-SR® (methylphenidate hydrochloride, USP) sustained-release tablets CII Read the Medication Guide that comes with RITALIN-SR before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your or your child’s treatment with RITALIN-SR. What is the most important information I should know about RITALIN-SR? The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines. 1. Heart-related problems:  sudden death in patients who have heart problems or heart defects  stroke and heart attack in adults  increased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting RITALIN-SR. Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment with RITALIN-SR. Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking RITALIN-SR. 2. Mental (Psychiatric) problems: All Patients  new or worse behavior and thought problems  new or worse bipolar illness  new or worse aggressive behavior or hostility Children and Teenagers  new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking RITALIN-SR, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. 3. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red  Tell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes.  Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking RITALIN-SR. Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What Is RITALIN-SR? RITALIN-SR is a central nervous system stimulant prescription medicine. It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). RITALIN-SR may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. RITALIN-SR should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. RITALIN-SR is also used in the treatment of a sleep disorder called narcolepsy. RITALIN-SR is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep RITALIN-SR in a safe place to prevent misuse and abuse. Selling or giving away RITALIN-SR may harm others, and is against the law. Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs. Who should not take RITALIN-SR? RITALIN-SR should not be taken if you or your child:  are very anxious, tense, or agitated  have an eye problem called glaucoma  have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome. Tics are hard to control repeated movements or sounds.  are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI.  are allergic to anything in RITALIN-SR. See the end of this Medication Guide for a complete list of ingredients. RITALIN-SR should not be used in children less than 6 years old because it has not been studied in this age group. RITALIN-SR may not be right for you or your child. Before starting RITALIN-SR tell your or your child’s doctor about all health conditions (or a family history of) including:  heart problems, heart defects, high blood pressure  mental problems including psychosis, mania, bipolar illness, or depression  tics or Tourette’s syndrome  seizures or have had an abnormal brain wave test (EEG)  circulation problems in fingers or toes Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding. Can RITALIN-SR be taken with other medicines? Tell your doctor about all of the medicines that you or your child takes including prescription and nonprescription medicines, vitamins, and herbal supplements. RITALIN-SR and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking RITALIN-SR. Your doctor will decide whether RITALIN-SR can be taken with other medicines. Especially tell your doctor if you or your child takes:  anti-depression medicines including MAOIs  seizure medicines  blood thinner medicines  blood pressure medicines  cold or allergy medicines that contain decongestants Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist. Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Do not start any new medicine while taking RITALIN-SR without talking to your doctor first. How should RITALIN-SR be taken?  Take RITALIN-SR exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child.  Take RITALIN-SR 30 to 45 minutes before a meal. The effect of a dose of RITALIN-SR usually lasts about 8 hours.  Do not chew or crush RITALIN-SR tablets. Swallow RITALIN-SR tablets whole with water or other liquids. Tell your doctor if you or your child cannot swallow RITALIN-SR whole. A different medicine may need to be prescribed.  From time to time, your doctor may stop RITALIN-SR treatment for a while to check ADHD symptoms.  Your doctor may do regular checks of the blood, heart, and blood pressure while taking RITALIN-SR. Children should have their height and weight checked often while taking RITALIN-SR. RITALIN-SR treatment may be stopped if a problem is found during these check-ups.  If you or your child takes too much RITALIN-SR or overdoses, call your doctor or poison control center right away, or get emergency treatment. What are possible side effects of RITALIN-SR? See “What is the most important information I should know about RITALIN-SR?” for information on reported heart and mental problems. Other serious side effects include:  slowing of growth (height and weight) in children  seizures, mainly in patients with a history of seizures  eyesight changes or blurred vision  painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develop priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a doctor immediately. Common side effects include:  headache • decreased appetite  stomach ache • nervousness  trouble sleeping  nausea Talk to your doctor if you or your child has side effects that are bothersome or do not go away. This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information. How should I store RITALIN-SR?  Store RITALIN-SR in a safe place at room temperature, 59°F to 86°F (15°C to 30°C). Protect from moisture.  Keep RITALIN-SR and all medicines out of the reach of children. General information about RITALIN-SR. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RITALIN-SR for a condition for which it was not prescribed. Do not give RITALIN-SR to other people, even if they have the same condition. It may harm them and it is against the law. This Medication Guide summarizes the most important information about RITALIN-SR. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about RITALIN-SR that was written for healthcare professionals. For more information about RITALIN-SR call 1-888-669-6682. What are the ingredients in RITALIN-SR? Active Ingredient: methylphenidate HCL, USP Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Inactive Ingredients: cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate, mineral oil, povidone, titanium dioxide, and zein Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA 1088. This Medication Guide has been approved by the U.S. Food and Drug Administration. Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T201X-XX/T201X-XX/T201X-XX Month Year/Month Year/Month Year Reference ID: 3421576 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:42.675736	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/010187s077lbl.pdf', 'application_number': 10187, 'submission_type': 'SUPPL ', 'submission_number': 77}
10,749	NDA 10-402/S-046 Premarin Intravenous (conjugated estrogens, USP) for injection Specially prepared for Intravenous & Intramuscular use Rx only ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen doses. CARDIOVASCULAR AND OTHER RISKS Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical Studies.) The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy. (See CLINICAL PHARMACOLOGY, Clinical Studies.) Other doses of conjugated estrogens and medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-402/S-046 Page 4 DESCRIPTION Premarin Intravenous (conjugated estrogens, USP) for injection contains a mixture of conjugated estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of materials derived from pregnant mares’ urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as concomitant components, as sodium sulfate conjugates, 17α-dihydroequilin, 17α-estradiol, and 17β-dihydroequilin. Each Secule vial contains 25 mg of conjugated estrogens, USP, in a sterile lyophilized cake which also contains lactose 200 mg, sodium citrate 12.2 mg, and simethicone 0.2 mg. The pH is adjusted with sodium hydroxide or hydrochloric acid. A sterile diluent (5 mL) containing 2% benzyl alcohol in sterile water is provided for reconstitution. The reconstituted solution is suitable for intravenous or intramuscular injection. CLINICAL PHARMACOLOGY Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogen in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women. Pharmacokinetics Absorption Conjugated estrogens are soluble in water and are well absorbed through the skin, mucous membranes, and gastrointestinal tract after release from the drug formulation. Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-402/S-046 Page 5 sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant proportion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Special Populations No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment. Drug Interactions Data from a single-dose drug-drug interaction study involving oral conjugated estrogens and medroxyprogesterone acetate indicate that the pharmacokinetic dispositions of both drugs are not altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been conducted with conjugated estrogens. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects. Clinical Studies Women’s Health Initiative Studies. The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of Premarin tablets (0.625 mg conjugated estrogens per day) alone or the use of PREMPRO tablets (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate per day) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of Premarin tablets or PREMPRO on menopausal symptoms. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-402/S-046 Page 6 The Premarin tablets-only substudy results have not been reported. The estrogen plus progestin substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” Results of the estrogen plus progestin substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years, are presented in Table 1 below: Table 1. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHIa Placebo Prempro n = 8102 n = 8506 Event c Relative Risk Prempro vs Placebo at 5.2 Years (95% CI*) Absolute Risk per 10,000 Women-years CHD events 1.29 (1.02-1.63) 30 37 Non-fatal MI 1.32 (1.02-1.72) 23 30 CHD death 1.18 (0.70-1.97) 6 7 Invasive breast cancer b 1.26 (1.00-1.59) 30 38 Stroke 1.41 (1.07-1.85) 21 29 Pulmonary embolism 2.13 (1.39-3.25) 8 16 Colorectal cancer 0.63 (0.43-0.92) 16 10 Endometrial cancer 0.83 (0.47-1.47) 6 5 Hip fracture 0.66 (0.45-0.98) 15 10 Death due to causes other than the events above 0.92 (0.74-1.14) 40 37 Global Index c 1.15 (1.03-1.28) 151 170 Deep vein thrombosis d 2.07 (1.49-2.87) 13 26 Vertebral fractures d 0.66 (0.44-0.98) 15 9 Other osteoporotic fractures d 0.77 (0.69-0.86) 170 131 a adapted from JAMA, 2002; 288:321-333 b includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer c a subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes d not included in Global Index ∗ nominal confidence intervals unadjusted for multiple looks and multiple comparisons For those outcomes included in the “global index”, the absolute excess risks per 10,000 women-years in the group treated with PREMPRO were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. There was no difference between the groups in terms of all- cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-402/S-046 Page 7 INDICATIONS AND USAGE Premarin Intravenous (conjugated estrogens, USP) for injection is indicated in the treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology. Premarin Intravenous is indicated for short-term use only, to provide a rapid and temporary increase in estrogen levels. CONTRAINDICATIONS Premarin Intravenous should not be used in individuals with any of the following conditions: 1. Undiagnosed abnormal genital bleeding. 2. Known, suspected, or history of cancer of the breast. 3. Known or suspected estrogen-dependent neoplasia. 4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions. 5. Active or recent (e.g., within past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction). 6. Liver dysfunction or disease. 7. Premarin Intravenous for injection should not be used in patients with known hypersensitivity to its ingredients. 8. Known or suspected pregnancy. There is no indication for Premarin Intravenous in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogen and progestins from oral contraceptives inadvertently during pregnancy. (See PRECAUTIONS.) WARNINGS See BOXED WARNINGS. Premarin Intravenous is indicated for short-term use. However, warnings, precautions and adverse reactions associated with Premarin tablets should be taken into account. 1. Cardiovascular disorders. Estrogen and estrogen/progestin therapy have been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately. Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-402/S-046 Page 8 a. Coronary heart disease and stroke. In the Premarin tablets substudy of the Women’s Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed in women receiving Premarin compared to placebo. These observations are preliminary. (See CLINICAL PHARMACOLOGY, Clinical Studies.) In the estrogen plus progestin substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving PREMPRO compared to women receiving placebo (37 vs 30 per 10,000 women-years). The increase in risk was observed in year one and persisted. In the same substudy of WHI, an increased risk of stroke was observed in women receiving PREMPRO compared to women receiving placebo (29 vs 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted. In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/progestin Replacement Study; HERS) treatment with PREMPRO (0.625 mg conjugated estrogen plus 2.5 mg medroxyprogesterone acetate per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with PREMPRO did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the PREMPRO-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the PREMPRO group and the placebo group in HERS, HERS II, and overall. Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. b. Venous thromboembolism (VTE). In the Premarin tablets substudy of the Women’s Health Initiative (WHI), an increase in VTE has been observed in women receiving Premarin compared to placebo. These observations are preliminary. (See CLINICAL PHARMACOLOGY, Clinical Studies.) In the estrogen plus progestin substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving PREMPRO compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the PREMPRO group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-402/S-046 Page 9 2. Malignant neoplasms. a. Endometrial cancer. The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. b. Breast cancer. The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) trial of estrogen plus progestin (see CLINICAL PHARMACOLOGY, Clinical Studies). The results from observational studies are generally consistent with those of the WHI clinical trial. After a mean follow-up of 5.6 years, the WHI trial reported an increased risk of breast cancer in women who took estrogen plus progestin. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. For both findings, the excess risk increased with duration of use, and appeared to return to baseline over about five years after stopping treatment (only the observational studies have substantial data on risk after stopping). In these studies, the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogens or among different estrogen/progestin combinations, doses, or routes of administration. In the WHI trial of estrogen plus progestin, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs. 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years, for estrogen plus progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo. In the WHI trial, invasive breast cancers were larger and diagnosed at a more advanced stage in the estrogen plus progestin group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups. The observational Million Women Study in Europe reported an increased risk of mortality due to breast cancer among current users of estrogens alone or estrogens plus progestins compared to never users, while the estrogen plus progestin sub-study of WHI showed no effect on breast cancer mortality with a mean follow-up of 5.6 years. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-402/S-046 Page 10 The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. 3. Gallbladder disease. A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving postmenopausal estrogens has been reported. 4. Hypercalcemia. Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level. 5. Visual abnormalities. Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be discontinued. PRECAUTIONS A. General Premarin Intravenous is indicated for short-term use. However, warnings, precautions and adverse reactions associated with Premarin tablets should be taken into account. 1. Addition of a progestin when a woman has not had a hysterectomy. Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration or daily with estrogen in a continuous regimen have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks which may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL) and impairment of glucose tolerance. 2. Elevated blood pressure. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use. 3. Hypertriglyceridemia. In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-402/S-046 Page 11 4. Impaired liver function and past history of cholestatic jaundice. Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. 5. Hypothyroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. 6. Fluid retention. Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. 7. Hypocalcemia. Estrogens should be used with caution in individuals with severe hypocalcemia. 8. Ovarian cancer. The estrogen plus progestin substudy of WHI reported that after an average follow-up of 5.6 years, the relative risk of ovarian cancer for estrogen plus progestin versus placebo was 1.58 (95% confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk for estrogen plus progestin versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen-only products, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations. 9. Exacerbation of endometriosis. Endometriosis may be exacerbated with administration of estrogen therapy. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. 10. Exacerbation of other conditions. Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. B. Patient Information Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients who are being treated with Premarin Intravenous. C. Laboratory Tests Estrogen administration should be guided by clinical response at the lowest dose, rather than laboratory monitoring. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-402/S-046 Page 12 D. Drug/Laboratory Test Interactions 1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). 4. Increased plasma HDL and HDL2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglyceride levels. 5. Impaired glucose tolerance. 6. Reduced response to metyrapone test. E. Carcinogenesis, Mutagenesis, and Impairment of Fertility (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.) Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. F. Pregnancy Premarin Intravenous should not be used during pregnancy. (See CONTRAINDICATIONS.) G. Nursing Mothers Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of breast milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving the drug. Caution should be exercised when Premarin Intravenous is administered to a nursing woman. H. Pediatric Use Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established. Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short adult stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-402/S-046 Page 13 Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the normal pubertal process and induce gynecomastia. I. Geriatric Use Of the total number of subjects in the estrogen plus progestin substudy of the Women’s Health Initiative study, 44% (n = 7,320) were 65 years and over, while 6.6% (n = 1,095) were 75 years and over (see CLINICAL PHARMACOLOGY, Clinical Studies). There was a higher incidence of stroke and invasive breast cancer in women 75 and over compared to women less than 75 years of age. There have not been sufficient numbers of geriatric patients involved in studies utilizing Premarin to determine whether those over 65 years of age differ from younger subjects in their response to Premarin. ADVERSE REACTIONS See BOXED WARNINGS, WARNINGS, and PRECAUTIONS. Premarin Intravenous is indicated for short-term use. However, the warnings, precautions and adverse reactions associated with Premarin tablets should be taken into account. 1. Genitourinary system. Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding, spotting. Increase in size of uterine leiomyomata. Vaginal candidiasis. Change in amount of cervical secretion. 2. Breasts. Pain, tenderness, enlargement. 3. Cardiovascular. Venous thrombosis. Pulmonary embolism. Superficial thrombophlebitis. Hypotension. Myocardial infarction. Stroke. 4. Gastrointestinal. Nausea, vomiting. Abdominal cramps, bloating. Cholestatic jaundice. Increased incidence of gallbladder disease. Pancreatitis. Enlargement of hepatic hemangiomas. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-402/S-046 Page 14 5. Skin. Chloasma or melasma that may persist when drug is discontinued. Erythema multiforme. Erythema nodosum. Hemorrhagic eruption. Loss of scalp hair. Hirsutism. Pruritis. Rash. 6. Eyes. Retinal vascular thrombosis. Intolerance to contact lenses. 7. Central Nervous System. Headache. Migraine. Dizziness. Mental depression. Chorea. Nervousness. Exacerbation of epilepsy. Dementia. 8. Miscellaneous. Increase or decrease in weight. Reduced carbohydrate tolerance. Aggravation of porphyria. Edema. Changes in libido. Anaphylactoid/anaphylactic reactions. Urticaria. Angioedema. Injection site pain. Injections site edema. Phlebitis (injection site). Exacerbation of asthma. OVERDOSAGE Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing drug products by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-402/S-046 Page 15 DOSAGE AND ADMINISTRATION For treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology: One 25 mg injection, intravenously or intramuscularly. Intravenous use is preferred since more rapid response can be expected from this mode of administration. Repeat in 6 to 12 hours if necessary. The use of Premarin Intravenous for injection does not preclude the advisability of other appropriate measures. One should adhere to the usual precautionary measures governing intravenous administration. Injection should be made SLOWLY to obviate the occurrence of flushes. Infusion of Premarin Intravenous for injection with other agents is not generally recommended. In emergencies, however, when an infusion has already been started it may be expedient to make the injection into the tubing just distal to the infusion needle. If so used, compatibility of solutions must be considered. COMPATIBILITY OF SOLUTIONS: Premarin Intravenous is compatible with normal saline, dextrose, and invert sugar solutions. It is not compatible with protein hydrolysate, ascorbic acid, or any solution with an acid pH. DIRECTIONS FOR STORAGE AND RECONSTITUTION STORAGE BEFORE RECONSTITUTION: Store package in refrigerator, 2° to 8°C (36° to 46°F). TO RECONSTITUTE: First withdraw air from Secule vial so as to facilitate introduction of sterile diluent. Then, flow the sterile diluent slowly against the side of Secule vial and agitate gently. Do not shake violently. STORAGE AFTER RECONSTITUTION: It is common practice to utilize the reconstituted solution within a few hours. If it is necessary to keep the reconstituted solution for more than a few hours, store the reconstituted solution under refrigeration (2° to 8°C). Under these conditions, the solution is stable for 60 days, and is suitable for use unless darkening or precipitation occurs. HOW SUPPLIED NDC 0046-0749-05−Each package provides: (1) One Secule vial containing 25 mg of conjugated estrogens, USP, for injection (also lactose 200 mg, sodium citrate 12.2 mg, and simethicone 0.2 mg). The pH is adjusted with sodium hydroxide or hydrochloric acid. (2) One 5 mL ampul of sterile diluent with 2% benzyl alcohol in sterile water. Premarin Intravenous (conjugated estrogens, USP) for injection is prepared by cryodesiccation. SECULE-Registered trademark to designate a vial containing an injectable preparation in dry form. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-402/S-046 Page 16 PATIENT INFORMATION Premarin Intravenous (conjugated estrogens, USP) for injection Read this PATIENT INFORMATION which describes the benefit and major risks of your treatment, as well as how and when treatment should be used. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about Premarin Intravenous (an estrogen mixture)? • Estrogens increase the chances of getting cancer of the uterus. Report any unusual vaginal bleeding right away while you are taking Premarin. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. • Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes. Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may increase your risk of dementia, based on a study of women age 65 years or older. You and your healthcare provider should talk regularly about whether you still need treatment with estrogens. What is Premarin Intravenous? Premarin Intravenous is a medicine that contains a mixture of estrogen hormones. Premarin Intravenous is used to: • treat certain types of abnormal uterine bleeding due to hormonal imbalance when your doctor has found no other cause of bleeding. Who should not use Premarin Intravenous? Premarin Intravenous should not be used if you: • have unusual vaginal bleeding that has not been evaluated by your healthcare provider. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-402/S-046 Page 17 • currently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider. • had a stroke or heart attack in the past year. • currently have or have had blood clots. • currently have liver problems. • are allergic to Premarin Intravenous or any of its ingredients. • think you may be pregnant. Tell your healthcare provider: • if you are breast feeding. The hormones in Premarin Intravenous can pass into your milk. • about all of your medical problems. Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. • about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Premarin Intravenous works. What are the possible side effects of Premarin Intravenous? Premarin Intravenous is for short-term use only. However, the risks associated with Premarin tablets should be taken into account. Less common but serious side effects include: • Breast cancer • Cancer of the uterus • Stroke • Heart attack • Blood clots • Dementia • Gallbladder disease • Ovarian cancer These are some of the warning signs of serious side effects: • Breast lumps • Unusual vaginal bleeding • Dizziness and faintness • Changes in speech • Severe headaches • Chest pain This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-402/S-046 Page 18 • Shortness of breath • Pains in your legs • Changes in vision • Vomiting Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you. Common side effects include: • Headache • Breast tenderness • Irregular vaginal bleeding or spotting • Stomach/abdominal cramps, bloating • Nausea and vomiting • Hair loss Other side effects include: • High blood pressure • Liver problems • High blood sugar • Fluid retention • Enlargement of benign tumors of the uterus (“fibroids”) • Vaginal yeast infections These are not all the possible side effects of Premarin. For more information, ask your healthcare provider or pharmacist. What can I do to lower my chances of getting a serious side effect with Premarin Intravenous? • If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease. General information about the safe and effective use of Premarin Intravenous Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Premarin Intravenous for conditions for which it was not prescribed. Do not give Premarin Intravenous to other people, even if they have the same symptoms you have. It may harm them. Keep Premarin Intravenous out of the reach of children. This leaflet provides a summary of the most important information about Premarin Intravenous. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Premarin Intravenous that is written for health professionals. You can get more information by calling the toll free number 1-800-934-5556. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-402/S-046 Page 19 HOW SUPPLIED Each Premarin Intravenous (conjugated estrogens, USP) for injection package provides 25 mg of conjugated estrogens, USP, in dry form and 5 mLs of sterile diluent for intravenous or intramuscular use. This product’s label may have been revised after this insert was used in production. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 Winsert number here ETinsert number here Revised insert full date here This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:42.712227	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/010402S046lbl.pdf', 'application_number': 10402, 'submission_type': 'SUPPL ', 'submission_number': 46}
10,746	T2007-23 Ritalin® hydrochloride methylphenidate hydrochloride tablets USP Ritalin-SR® methylphenidate hydrochloride USP sustained-release tablets Rx only Prescribing Information DESCRIPTION Ritalin hydrochloride, methylphenidate hydrochloride USP, is a mild central nervous system (CNS) stimulant, available as tablets of 5, 10, and 20 mg for oral administration; Ritalin-SR is available as sustained-release tablets of 20 mg for oral administration. Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77. Inactive Ingredients. Ritalin tablets: D&C Yellow No. 10 (5-mg and 20-mg tablets), FD&C Green No. 3 (10-mg tablets), lactose, magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg tablets), sucrose, talc, and tragacanth (20-mg tablets). Ritalin-SR tablets: Cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate, mineral oil, povidone, titanium dioxide, and zein. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 2 CLINICAL PHARMACOLOGY Ritalin is a mild central nervous system stimulant. The mode of action in man is not completely understood, but Ritalin presumably activates the brain stem arousal system and cortex to produce its stimulant effect. There is neither specific evidence which clearly establishes the mechanism whereby Ritalin produces its mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system. Ritalin in the SR tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the SR tablet compared to the Ritalin tablet, measured by the urinary excretion of Ritalin major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49%-168%) in children and 101% (85%-152%) in adults. The time to peak rate in children was 4.7 hours (1.3-8.2 hours) for the SR tablets and 1.9 hours (0.3-4.4 hours) for the tablets. An average of 67% of SR tablet dose was excreted in children as compared to 86% in adults. In a clinical study involving adult subjects who received SR tablets, plasma concentrations of Ritalin’s major metabolite appeared to be greater in females than in males. No gender differences were observed for Ritalin plasma concentration in the same subjects. INDICATIONS Attention Deficit Disorders, Narcolepsy Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children). Other terms being used to describe the behavioral syndrome below include: Hyperkinetic Child Syndrome, Minimal Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction. Ritalin is indicated as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal EEG may or This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 3 may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted. Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Characteristics commonly reported include: chronic history of short attention span, distractibility, emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor neurological signs and abnormal EEG. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of one or more of these characteristics. Drug treatment is not indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is generally necessary. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the child’s symptoms. CONTRAINDICATIONS Marked anxiety, tension, and agitation are contraindications to Ritalin, since the drug may aggravate these symptoms. Ritalin is contraindicated also in patients known to be hypersensitive to the drug, in patients with glaucoma, and in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome. Ritalin is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of a monoamine oxidase inhibitor (hypertensive crises may result). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 4 WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs. Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia. Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 5 Psychiatric Adverse Events Pre-Existing Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Bipolar Illness Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/ manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e. g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 6 Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. Use in Children Under Six Years of Age Ritalin should not be used in children under 6 years, since safety and efficacy in this age group have not been established. Drug Dependence Ritalin should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. PRECAUTIONS Patients with an element of agitation may react adversely; discontinue therapy if necessary. Periodic CBC, differential, and platelet counts are advised during prolonged therapy. Drug treatment is not indicated in all cases of this behavioral syndrome and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe Ritalin should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with Ritalin is usually not indicated. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with methylphenidate and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 7 should counsel them in its appropriate use. A patient Medication Guide is available for Ritalin and Ritalin-SR. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Drug Interactions Ritalin should not be used in patients being treated (currently or within the proceeding two weeks) with MAO Inhibitors (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors). Because of possible effects on blood pressure, Ritalin should be used cautiously with pressor agents. Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Methylphenidate is metabolized primarily to ritalinic acid by de-esterification and not through oxidative pathways. Human pharmacologic studies have shown that racemic methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine). Downward dose adjustments of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentration (or, in case of coumarin, coagulation times), when initiating or discontinuing methylphenidate. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2-agonists has not been systematically evaluated. Carcinogenesis/Mutagenesis/Impairment of Fertility In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and 4 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 5 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 8 In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60-74 mg/kg/day of methylphenidate. Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Methlyphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 80-fold and 8-fold the highest recommended dose on a mg/kg and mg/m2 basis, respectively. PREGNANCY Pregnancy Category C In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2 basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (4 times the MRHD on a mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m2 basis). Adequate and well-controlled studies in pregnant women have not been conducted. Ritalin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 9 Nursing Mothers It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Ritalin is administered to a nursing woman. Pediatric Use Ritalin should not be used in children under six years of age (see WARNINGS). In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown. ADVERSE REACTIONS Nervousness and insomnia are the most common adverse reactions but are usually controlled by reducing dosage and omitting the drug in the afternoon or evening. Other reactions include hypersensitivity (including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura); anorexia; nausea; dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse changes, both up and down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss during prolonged therapy. There have been rare reports of Tourette’s syndrome. Toxic psychosis has been reported. Although a definite causal relationship has not been established, the following have been reported in patients taking this drug: instances of abnormal liver function, ranging from transaminase elevation to hepatic coma; isolated cases of cerebral arteritis and/or occlusion; leukopenia and/or anemia; transient depressed mood; aggressive behavior; a few instances of scalp hair loss. Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 10 In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed above may also occur. DOSAGE AND ADMINISTRATION Dosage should be individualized according to the needs and responses of the patient. Adults Tablets: Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Average dosage is 20 to 30 mg daily. Some patients may require 40 to 60 mg daily. In others, 10 to 15 mg daily will be adequate. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m. SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or chewed. Children (6 years and over) Ritalin should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is not recommended. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued. Tablets: Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5 to 10 mg weekly. SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or chewed. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 11 Ritalin should be periodically discontinued to assess the child’s condition. Improvement may be sustained when the drug is either temporarily or permanently discontinued. Drug treatment should not and need not be indefinite and usually may be discontinued after puberty. OVERDOSAGE Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice. Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage. In the presence of severe intoxication, use a carefully titrated dosage of a short-acting barbiturate before performing gastric lavage. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia. Efficacy of peritoneal dialysis or extracorporeal hemodialysis for Ritalin overdosage has not been established. HOW SUPPLIED Tablets 5 mg - round, yellow (imprinted CIBA 7) Bottles of 100……………………………………………………………......NDC 0078-0439-05 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 12 Tablets 10 mg - round, pale green, scored (imprinted CIBA 3) Bottles of 100……………………………………………………………......NDC 0078-0440-05 Tablets 20 mg - round, pale yellow, scored (imprinted CIBA 34) Bottles of 100……………………………………………………………......NDC 0078- 0441-05 Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from light. Dispense in tight, light-resistant container (USP). SR Tablets 20 mg - round, white, coated (imprinted CIBA 16) Bottles of 100……………………………………………………………...NDC 0078- 0442-05 Note: SR Tablets are color-additive free. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in tight, light-resistant container (USP). REV: APRIL 2007 T2007-23 MEDICATION GUIDE RITALIN® (methylphenidate hydrochloride tablets, USP) CII Read the Medication Guide that comes with RITALIN® before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your or your child’s treatment with RITALIN®. What is the most important information I should know about RITALIN®? This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 13 The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines. 1. Heart-related problems: • sudden death in patients who have heart problems or heart defects • stroke and heart attack in adults • increased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting RITALIN®. Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment with RITALIN®. Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking RITALIN®. 2. Mental (Psychiatric) problems: All Patients • new or worse behavior and thought problems • new or worse bipolar illness • new or worse aggressive behavior or hostility Children and Teenagers • new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking RITALIN®, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. What Is RITALIN®? RITALIN® is a central nervous system stimulant prescription medicine. It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). RITALIN® may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. RITALIN® should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. RITALIN® is also used in the treatment of a sleep disorder called narcolepsy. RITALIN® is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep RITALIN® in a safe place to prevent misuse and abuse. Selling or giving away RITALIN® may harm others, and is against the law. Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription edicines or street drugs. m This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 14 Who should not take RITALIN®? RITALIN® should not be taken if you or your child: • are very anxious, tense, or agitated • have an eye problem called glaucoma • have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome. Tics are hard to control repeated movements or sounds. • are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI. • are allergic to anything in RITALIN®. See the end of this Medication Guide for a complete list of ingredients. RITALIN® should not be used in children less than 6 years old because it has not been studied in this age group. RITALIN® may not be right for you or your child. Before starting RITALIN® tell your or your child’s doctor about all health conditions (or a family history of) including: • heart problems, heart defects, high blood pressure • mental problems including psychosis, mania, bipolar illness, or depression • tics or Tourette’s syndrome • seizures or have had an abnormal brain wave test (EEG) Tell your doctor if you or your child is pregnant, planning to become pregnant, or breast-feeding. Can RITALIN® be taken with other medicines? Tell your doctor about all of the medicines that you or your child take including prescription and nonprescription medicines, vitamins, and herbal supplements. RITALIN® and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking RITALIN®. Y our doctor will decide whether RITALIN® can be taken with other medicines. Especially tell your doctor if you or your child takes: • anti-depression medicines including MAOIs • seizure medicines • blood thinner medicines • blood pressure medicines • cold or allergy medicines that contain decongestants Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist. Do not start any new medicine while taking RITALIN® without talking to your doctor first. How should RITALIN® be taken? • Take RITALIN® exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child. • Ritalin is usually taken 2 to 3 times a day. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 15 • ake RITALIN T ® 30 to 45 minutes before a meal. • rom time to time, your doctor may stop RITALIN F ® treatment for a while to check ADHD symptoms. • Your doctor may do regular checks of the blood, heart, and blood pressure while taking RITALIN®. Children should have their height and weight checked often while taking RITALIN®. RITALIN® treatment may be stopped if a problem is found during hese check-ups. t • If you or your child takes too much RITALIN® or overdoses, call your doctor or poison control center right away, or get emergency treatment. What are possible side effects of RITALIN®? See “What is the most important information I should know about RITALIN®?” for information on reported heart and mental problems. Other serious side effects include: • slowing of growth (height and weight) in children • seizures, mainly in patients with a history of seizures • eyesight changes or blurred vision Common side effects include: • headache • decreased appetite • stomach ache • nervousness • trouble sleeping • nausea Talk to your doctor if you or your child has side effects that are bothersome or do not go away. This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information. How should I store RITALIN®? • Store RITALIN in a safe place at room temperature, 59 to 86° F (15 to 30° C). Protect from light. • Keep RITALIN® and all medicines out of the reach of children. General information about RITALIN® Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RITALIN® for a condition for which it was not prescribed. Do not give RITALIN® to other people, even if they have the same condition. It may harm them and it is against the law. This Medication Guide summarizes the most important information about RITALIN®. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about RITALIN® that was written for healthcare professionals. For more information about RITALIN® call 1-888-669-6682. What are the ingredients in RITALIN®? Active Ingredient: methylphenidate HCL This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 16 Inactive Ingredients: D&C Yellow No.10 (5-mg and 20-mg tablets), FD&C Green No.3 (10-mg tablets), lactose, magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg tablets), sucrose, talc, and tragacanth (20-mg tablets). This Medication Guide has been approved by the U.S. Food and Drug Administration. REV: APRIL 2007 T2007-38 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 17 MEDICATION GUIDE RITALIN-SR® (methylphenidate hydrochloride, USP) sustained-release tablets CII Read the Medication Guide that comes with RITALIN-SR® before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your or your child’s treatment with RITALIN-SR®. What is the most important information I should know about RITALIN-SR®? The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines. 1. Heart-related problems: • sudden death in patients who have heart problems or heart defects • stroke and heart attack in adults • increased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting RITALIN-SR®. Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment with RITALIN-SR®. Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking RITALIN-SR®. 2. Mental (Psychiatric) problems: All Patients • new or worse behavior and thought problems • new or worse bipolar illness • new or worse aggressive behavior or hostility Children and Teenagers • new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking RITALIN-SR®, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. What Is RITALIN-SR®? This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 18 RITALIN-SR® is a central nervous system stimulant prescription medicine. It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). RITALIN-SR® may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. RITALIN-SR® should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. RITALIN-SR® is also used in the treatment of a sleep disorder called narcolepsy. RITALIN-SR® is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep RITALIN-SR® in a safe place to prevent misuse and abuse. Selling or giving away RITALIN-SR® may harm others, and is against the law. Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs. Who should not take RITALIN-SR®? RITALIN-SR® should not be taken if you or your child: • are very anxious, tense, or agitated • have an eye problem called glaucoma • have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome. Tics are hard to control repeated movements or sounds. • are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI. • are allergic to anything in RITALIN-SR®. See the end of this Medication Guide for a complete list of ingredients. RITALIN-SR® should not be used in children less than 6 years old because it has not been studied in this age group. RITALIN-SR® may not be right for you or your child. Before starting RITALIN-SR® tell your or your child’s doctor about all health conditions (or a family history of) including: • heart problems, heart defects, high blood pressure • mental problems including psychosis, mania, bipolar illness, or depression • tics or Tourette’s syndrome • seizures or have had an abnormal brain wave test (EEG) Tell your doctor if you or your child is pregnant, planning to become pregnant, or breast-feeding. Can RITALIN-SR® be taken with other medicines? Tell your doctor about all of the medicines that you or your child take including prescription and nonprescription medicines, vitamins, and herbal supplements. RITALIN-SR® and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking RITALIN-SR®. Y our doctor will decide whether RITALIN-SR® can be taken with other medicines. Especially tell your doctor if you or your child takes: • anti-depression medicines including MAOIs • seizure medicines This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 19 • blood thinner medicines • blood pressure medicines • cold or allergy medicines that contain decongestants Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist. Do not start any new medicine while taking RITALIN-SR® without talking to your doctor first. How should RITALIN-SR® be taken? • Take RITALIN-SR® exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child. • Take RITALIN-SR® 30 to 45 minutes before a meal. The effect of a dose of RITALIN-SR usually lasts about 8 hours. • Do not chew or crush RITALIN-SR® tablets. Swallow RITALIN-SR® tablets whole with water or other liquids. Tell your doctor if you or your child cannot swallow RITALIN-SR® whole. A different medicine may need to be prescribed. • From time to time, your doctor may stop RITALIN-SR® treatment for a while to check ADHD symptoms. • Your doctor may do regular checks of the blood, heart, and blood pressure while taking RITALIN-SR®. Children should have their height and weight checked often while taking RITALIN-SR®. RITALIN-SR® treatment may be stopped if a problem is found during these check-ups. • If you or your child takes too much RITALIN-SR® or overdoses, call your doctor or poison control center right away, or get emergency treatment. What are possible side effects of RITALIN-SR®? See “What is the most important information I should know about RITALIN-SR®?” for information on reported heart and mental problems. Other serious side effects include: • slowing of growth (height and weight) in children • seizures, mainly in patients with a history of seizures • eyesight changes or blurred vision Common side effects include: • headache • decreased appetite • stomach ache • nervousness • trouble sleeping • nausea Talk to your doctor if you or your child has side effects that are bothersome or do not go away. This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information. How should I store RITALIN-SR®? • tore RITALIN-SR S ® in a safe place at room temperature, 59 to 86° F (15 to 30° C). Protect from moisture. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 20 • Keep RITALIN-SR® and all medicines out of the reach of children. General information about RITALIN-SR® Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RITALIN-SR® for a condition for which it was not prescribed. Do not give RITALIN-SR® to other people, even if they have the same condition. It may arm them and it is against the law. h This Medication Guide summarizes the most important information about RITALIN-SR®. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about RITALIN-SR® that was written for healthcare professionals. For more information about RITALIN-SR call 1-888-669-6682. What are the ingredients in RITALIN-SR®? Active Ingredient: methylphenidate HCL, USP Inactive Ingredients: cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate, mineral oil, povidone, titanium dioxide, and zein This Medication Guide has been approved by the U.S. Food and Drug Administration. REV: APRIL 2007 T2007-40 REV: APRIL 2007 Printed in U.S.A. T2007-23/T2007-38/T2007-40 Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda T2007-24 Ritalin LA® (methylphenidate hydrochloride) extended-release capsules Rx only Prescribing Information DESCRIPTION Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is an extended-release formulation of methylphenidate with a bi-modal release profile. Ritalin LA® uses the proprietary SODAS® (Spheroidal Oral Drug Absorption System) technology. Each bead-filled Ritalin LA capsule contains half the dose as immediate-release beads and half as enteric-coated, delayed-release beads, thus providing an immediate release of methylphenidate and a second delayed release of methylphenidate. Ritalin LA 10, 20, 30, and 40 mg capsules provide in a single dose the same amount of methylphenidate as dosages of 5, 10, 15, or 20 mg of Ritalin® tablets given b.i.d. The active substance in Ritalin LA is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77. Inactive ingredients: ammonio methacrylate copolymer, black iron oxide (10 and 40 mg capsules only), gelatin, methacrylic acid copolymer, polyethylene glycol, red iron oxide (10 and 40 mg capsules only), sugar spheres, talc, titanium dioxide, triethyl citrate, and yellow iron oxide (10, 30, and 40 mg capsules only). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 2 CLINICAL PHARMACOLOGY Pharmacodynamics Methylphenidate hydrochloride, the active ingredient in Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, is a central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Pharmacokinetics Absorption Ritalin LA produces a bi-modal plasma concentration-time profile (i.e., two distinct peaks approximately four hours apart) when orally administered to children diagnosed with ADHD and to healthy adults. The initial rate of absorption for Ritalin LA is similar to that of Ritalin tablets as shown by the similar rate parameters between the two formulations, i.e., initial lag time (Tlag), first peak concentration (Cmax1), and time to the first peak (Tmax1), which is reached in 1-3 hours. The mean time to the interpeak minimum (Tminip), and time to the second peak (Tmax2) are also similar for Ritalin LA given once daily and Ritalin tablets given in two doses 4 hours apart (see Figure 1 and Table 1), although the ranges observed are greater for Ritalin LA. Ritalin LA given once daily exhibits a lower second peak concentration (Cmax2), higher interpeak minimum concentrations (Cminip), and less peak and trough fluctuations than Ritalin tablets given in two doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption from the delayed-release beads (see Figure 1 and Table 1). The relative bioavailability of Ritalin LA given once daily is comparable to the same total dose of Ritalin tablets given in two doses 4 hours apart in both children and in adults. Figure 1. Mean plasma concentration time-profile of methylphenidate after a single dose of Ritalin LA® 40 mg q.d. and Ritalin® 20 mg given in two doses four hours apart This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 3 Table 1. Mean ± SD and range of pharmacokinetic parameters of methylphenidate after a single dose of Ritalin LA® and Ritalin® given in two doses 4 hours apart Population Children Adult Males Formulation Dose Ritalin® 10 mg & 10 mg Ritalin LA® 20 mg Ritalin® 10 mg & 10 mg Ritalin LA® 20 mg N 21 18 9 8 Tlag (h) 0.24 ± 0.44 0.28 ± 0.46 1.0 ± 0.5 0.7 ± 0.2 0 - 1 0 - 1 0.7 - 1.3 0.3 - 1.0 Tmax1 (h) 1.8 ± 0.6 2.0 ± 0.8 1.9 ± 0.4 2.0 ± 0.9 1 - 3 1 - 3 1.3 - 2.7 1.3 - 4.0 Cmax1 (ng/mL) 10.2 ± 4.2 10.3 ± 5.1 4.3 ± 2.3 5.3 ± 0.9 4.2 - 20.2 5.5 - 26.6 1.8 - 7.5 3.8 - 6.9 Tminip (h) 4.0 ± 0.2 4.5 ± 1.2 3.8 ± 0.4 3.6 ± 0.6 4 - 5 2 - 6 3.3 - 4.3 2.7 - 4.3 Cminip (ng/mL) 5.8 ± 2.7 6.1 ± 4.1 1.2 ± 1.4 3.0 ± 0.8 3.1 - 14.4 2.9 - 21.0 0.0 - 3.7 1.7 - 4.0 Tmax2 (h) 5.6 ± 0.7 6.6 ± 1.5 5.9 ± 0.5 5.5 ± 0.8 5 - 8 5 - 11 5.0 - 6.5 4.3 - 6.5 Cmax2 (ng/mL) 15.3 ± 7.0 10.2 ± 5.9 5.3 ± 1.4 6.2 ± 1.6 6.2 - 32.8 4.5 - 31.1 3.6 - 7.2 3.9 - 8.3 AUC(0-∞) 102.4 ± 54.6 86.6 ± 64.0a 37.8 ± 21.9 45.8 ± 10.0 (ng/mL x h-1) 40.5 - 261.6 43.3 - 301.44 14.3 - 85.3 34.0 - 61.6 t1/2 (h) 2.5 ± 0.8 2.4 ± 0.7a 3.5 ± 1.9 3.3 ± 0.4 1.8 - 5.3 1.5 - 4.0 1.3 - 7.7 3.0 - 4.2 a N = 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 4 Dose Proportionality After oral administration of Ritalin LA 20 mg and 40 mg capsules to adults there is a slight upward trend in the methylphenidate area under the curve (AUC) and peak plasma concentrations (Cmax1 and Cmax2). Distribution Binding to plasma proteins is low (10%-33%), and the apparent distribution volume at steady state with intravenous administration has been reported to be approximately 6 L/kg. Metabolism The absolute oral bioavailability of methylphenidate in children has been reported to be about 30% (range 10%-52%), suggesting pronounced presystemic metabolism. Biotransformation of methylphenidate is rapid and extensive leading to the main, de-esterified metabolite α-phenyl- 2-piperidine acetic acid (ritalinic acid). Only small amounts of hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable in plasma. Therapeutic activity is principally due to the parent compound. Elimination In studies with Ritalin LA and Ritalin tablets in adults, methylphenidate from Ritalin tablets is eliminated from plasma with an average half-life of about 3.5 hours, (range 1.3 - 7.7 hours). In children the average half-life is about 2.5 hours, with a range of about 1.5 - 5.0 hours. The rapid half-life in both children and adults may result in unmeasurable concentrations between the morning and mid-day doses with Ritalin tablets. No accumulation of methylphenidate is expected following multiple once a day oral dosing with Ritalin LA. The half-life of ritalinic acid is about 3-4 hours. After oral administration of an immediate release formulation of methylphenidate, 78%-97% of the dose is excreted in the urine and 1%-3% in the feces in the form of metabolites within 48-96 hours. Only small quantities (<1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as ritalinic acid (60%-86%), the remainder being accounted for by minor metabolites. Food Effects Administration times relative to meals and meal composition may need to be individually titrated. When Ritalin LA was administered with a high fat breakfast to adults, Ritalin LA had a longer lag time until absorption began and variable delays in the time until the first peak concentration, the time until the interpeak minimum, and the time until the second peak. The first peak concentration and the extent of absorption were unchanged after food relative to the fasting state, although the second peak was approximately 25% lower. The effect of a high fat lunch was not examined. There were no differences in the pharmacokinetics of Ritalin LA when administered with applesauce, compared to administration in the fasting condition. There is no evidence of dose dumping in the presence or absence of food. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 5 For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered (see DOSAGE AND ADMINISTRATION). Special Populations Age: The pharmacokinetics of Ritalin LA was examined in 18 children with ADHD between 7 and 12 years of age. Fifteen of these children were between 10 and 12 years of age. The time until the between peak minimum, and the time until the second peak were delayed and more variable in children compared to adults. After a 20-mg dose of Ritalin LA, concentrations in children were approximately twice the concentrations observed in 18 to 35 year old adults. This higher exposure is almost completely due to the smaller body size and total volume of distribution in children, as apparent clearance normalized to body weight is independent of age. Gender: There were no apparent gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults when administered Ritalin LA. Renal Insufficiency: Ritalin LA has not been studied in renally-impaired patients. Renal insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. Hepatic Insufficiency: Ritalin LA has not been studied in patients with hepatic insufficiency. Hepatic insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body. CLINICAL STUDIES Ritalin LA® (methylphenidate hydrochloride) extended-release capsules was evaluated in a randomized, double-blind, placebo-controlled, parallel group clinical study in which 134 children, ages 6 to 12, with DSM-IV diagnoses of Attention Deficit Hyperactivity Disorder (ADHD) received a single morning dose of Ritalin LA in the range of 10-40 mg/day, or placebo, for up to 2 weeks. The doses used were the optimal doses established in a previous individual dose titration phase. In that titration phase, 53 of 164 patients (32%) started on a daily dose of 10 mg and 111 of 164 patients (68%) started on a daily dose of 20 mg or higher. The patient’s regular schoolteacher completed the Conners ADHD/DSM-IV Scale for Teachers (CADS-T) at baseline and the end of each week. The CADS-T assesses symptoms of hyperactivity and inattention. The change from baseline of the (CADS-T) scores during the last week of treatment was analyzed as the primary efficacy parameter. Patients treated with Ritalin LA showed a statistically significant improvement in symptom scores from baseline over patients who received placebo. (See Figure 2.) This demonstrates that a single morning dose of Ritalin LA exerts a treatment effect in ADHD. Figure 2. CADS-T total subscale - Mean change from baseline* This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 6 INDICATIONS AND USAGE Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). The efficacy of Ritalin LA in the treatment of ADHD was established in one controlled trial of children aged 6 to 12 who met DSM-IV criteria for ADHD (see CLINICAL PHARMACOLOGY). A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go;” excessive talking; blurting answers; can’t wait turn; intrusive. The Combined Types requires both inattentive and hyperactive-impulsive criteria to be met. Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of the required number of DSM-IV characteristics. Need for Comprehensive Treatment Program Ritalin LA is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 7 placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the child’s symptoms. Long-Term Use The effectiveness of Ritalin LA for long-term use, i.e., for more than 2 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Ritalin LA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS Agitation Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is contraindicated in marked anxiety, tension, and agitation, since the drug may aggravate these symptoms. Hypersensitivity to Methylphenidate Ritalin LA is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product. Glaucoma Ritalin LA is contraindicated in patients with glaucoma. Tics Ritalin LA is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome. (See ADVERSE REACTIONS.) Monoamine Oxidase Inhibitors Ritalin LA is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (hypertensive crises may result). WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 8 serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs. Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia. Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Pre-Existing Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Bipolar Illness Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 9 Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. In the double-blind placebo-controlled study of Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, the mean weight gain was greater for patients receiving placebo (+1.0 kg) than for patients receiving Ritalin LA (+0.1 kg). Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 10 Use in Children Under Six Years of Age Ritalin LA should not be used in children under six years of age, since safety and efficacy in this age group have not been established. Drug Dependence Ritalin LA should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. PRECAUTIONS Hematologic Monitoring Periodic CBC, differential, and platelet counts are advised during prolonged therapy. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with methylphenidate and should counsel them in its appropriate use. A patient Medication Guide is available for Ritalin LA. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Drug Interactions Methylphenidate is metabolized primarily by de-esterification (nonmicrosomal hydrolytic esterases) to ritalinic acid and not through oxidative pathways. The effects of gastrointestinal pH alterations on the absorption of methylphenidate from Ritalin LA have not been studied. Since the modified release characteristics of Ritalin LA are pH dependent, the coadministration of antacids or acid suppressants could alter the release of methylphenidate. Methylphenidate may decrease the hypotensive effect of guanethidine. Because of possible effects on blood pressure, methylphenidate should be used cautiously with pressor agents. Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine). Downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 11 concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate. Serious adverse events have been reported in concomitant use of methylphenidate with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2-agonists has not been systematically evaluated. Carcinogenesis/Mutagenesis/Impairment of Fertility In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and 4 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 5 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60-74 mg/kg/day of methylphenidate. Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 80-fold and 8-fold the highest recommended dose on a mg/kg and mg/m2 basis, respectively. Pregnancy Pregnancy Category C In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2 basis). There was no evidence of specific teratogenic This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 12 activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (4 times the MRHD on a mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m2 basis). Adequate and well-controlled studies in pregnant women have not been conducted. Ritalin LA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Ritalin LA is administered to a nursing woman. Pediatric Use Long-term effects of methylphenidate in children have not been well established. Ritalin LA should not be used in children under six years of age (see WARNINGS). In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown. ADVERSE REACTIONS The clinical program for Ritalin LA® (methylphenidate hydrochloride) extended-release capsules consisted of six studies: two controlled clinical studies conducted in children with ADHD aged 6-12 years and four clinical pharmacology studies conducted in healthy adult volunteers. These studies included a total of 256 subjects; 195 children with ADHD and 61 healthy adult volunteers. The subjects received Ritalin LA in doses of 10-40 mg per day. Safety of Ritalin LA was assessed by evaluating frequency and nature of adverse events, routine laboratory tests, vital signs, and body weight. Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 13 standardized event categories. In the tables and listings that follow, MEDRA terminology has been used to classify reported adverse events. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Adverse Events in a Double-Blind, Placebo-Controlled Clinical Trial with Ritalin LA Treatment-Emergent Adverse Events A placebo-controlled, double-blind, parallel-group study was conducted to evaluate the efficacy and safety of Ritalin LA in children with ADHD aged 6-12 years. All subjects received Ritalin LA for up to 4 weeks, and had their dose optimally adjusted, prior to entering the double-blind phase of the trial. In the two-week double-blind treatment phase of this study, patients received either placebo or Ritalin LA at their individually-titrated dose (range 10 mg-40 mg). The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. Adverse events with an incidence >5% during the initial four-week single-blind Ritalin LA titration period of this study were headache, insomnia, upper abdominal pain, appetite decreased, and anorexia. Treatment-emergent adverse events with an incidence >2% among Ritalin LA-treated subjects, during the two-week double-blind phase of the clinical study, were as follows: Preferred term Ritalin LA® N=65 N (%) Placebo N=71 N (%) Anorexia 2 (3.1) 0 (0.0) Insomnia 2 (3.1) 0 (0.0) Adverse Events Associated with Discontinuation of Treatment In the two-week double-blind treatment phase of a placebo-controlled parallel-group study in children with ADHD, only one Ritalin LA-treated subject (1/65, 1.5%) discontinued due to an adverse event (depression). In the single-blind titration period of this study, subjects received Ritalin LA for up to 4 weeks. During this period a total of six subjects (6/161, 3.7%) discontinued due to adverse events. The adverse events leading to discontinuation were anger (in 2 patients), hypomania, anxiety, depressed mood, fatigue, migraine and lethargy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 14 Adverse Events with Other Methylphenidate HCl Dosage Forms Nervousness and insomnia are the most common adverse reactions reported with other methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed below may also occur. Other reactions include: Cardiac: angina, arrhythmia, palpitations, pulse increased or decreased, tachycardia Gastrointestinal: abdominal pain, nausea Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura. Metabolism/Nutrition: anorexia, weight loss during prolonged therapy Nervous System: dizziness, drowsiness, dyskinesia, headache, rare reports of Tourette’s syndrome, toxic psychosis Vascular: blood pressure increased or decreased, cerebral arteritis and/or occlusion Although a definite causal relationship has not been established, the following have been reported in patients taking methylphenidate: Blood/Lymphatic: leukopenia and/or anemia Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma Psychiatric: transient depressed mood, aggressive behavior Skin/Subcutaneous: scalp hair loss Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause. DRUG ABUSE AND DEPENDENCE Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, like other products containing methylphenidate, is a Schedule II controlled substance. (See WARNINGS for boxed warning containing drug abuse and dependence information.) OVERDOSAGE Signs and Symptoms Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 15 following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. Poison Control Center Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice. Recommended Treatment As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. When treating overdose, practitioners should bear in mind that there is a prolonged release of methylphenidate from Ritalin LA® (methylphenidate hydrochloride) extended- release capsules. Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage as indicated. Before performing gastric lavage, control agitation and seizures if present and protect the airway. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia. Efficacy of peritoneal dialysis or extracorporeal hemodialysis for methylphenidate overdosage has not been established; also, dialysis is considered unlikely to be of benefit due to the large volume of distribution of methylphenidate. DOSAGE AND ADMINISTRATION Administration of Dose Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is for oral administration once daily in the morning. Ritalin LA may be swallowed as whole capsules or alternatively may be administered by sprinkling the capsule contents on a small amount of applesauce (see specific instructions below). Ritalin LA and/or their contents should not be crushed, chewed, or divided. The capsules may be carefully opened and the beads sprinkled over a spoonful of applesauce. The applesauce should not be warm because it could affect the modified release properties of this formulation. The mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use. Dosing Recommendations Dosage should be individualized according to the needs and responses of the patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 16 Initial Treatment The recommended starting dose of Ritalin LA is 20 mg once daily. Dosage may be adjusted in weekly 10 mg increments to a maximum of 60 mg/day taken once daily in the morning, depending on tolerability and degree of efficacy observed. Daily dosage above 60 mg is not recommended. When in the judgement of the clinician a lower initial dose is appropriate, patients may begin treatment with Ritalin LA 10 mg. Patients Currently Receiving Methylphenidate The recommended dose of Ritalin LA for patients currently taking methylphenidate b.i.d. or sustained release (SR) is provided below. Previous Methylphenidate Dose Recommended Ritalin LA® Dose 5 mg methylphenidate-b.i.d. 10 mg q.d. 10 mg methylphenidate b.i.d. or 20 mg methylphenidate-SR 20 mg q.d. 15 mg methylphenidate b.i.d. 30 mg q.d. 20 mg methylphenidate b.i.d. or 40 mg of methylphenidate-SR 40 mg q.d. 30 mg methylphenidate b.i.d. or 60 mg methylphenidate-SR 60 mg q.d. For other methylphenidate regimens, clinical judgment should be used when selecting the starting dose. Ritalin LA dosage may be adjusted at weekly intervals in 10 mg increments. Daily dosage above 60 mg is not recommended. Maintenance/Extended Treatment There is no body of evidence available from controlled trials to indicate how long the patient with ADHD should be treated with Ritalin LA. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. Nevertheless, the physician who elects to use Ritalin LA for extended periods in patients with ADHD should periodically re-evaluate the long-term usefulness of the drug for the individual patient with trials off medication to assess the patient’s functioning without pharmacotherapy. Improvement may be sustained when the drug is either temporarily or permanently discontinued. Dose Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse events occur, the dosage should be reduced, or, if necessary, the drug should be discontinued. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued. HOW SUPPLIED Ritalin LA capsules 10 mg: white/light brown (imprinted NVR R10) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 17 Bottles of 100………………………………………………………NDC 0078-0424-05 Ritalin LA capsules 20 mg: white (imprinted NVR R20) Bottles of 100………………………………………………………NDC 0078-0370-05 Ritalin LA capsules 30 mg: yellow (imprinted NVR R30) Bottles of 100………………………………………………………NDC 0078-0371-05 Ritalin LA capsules 40 mg: light brown (imprinted NVR R40) Bottles of 100………………………………………………………NDC 0078-0372-05 Store at 25°C (77°F), excursions permitted 15°C-30°C (59°F-86°F). [See USP controlled room temperature] Dispense in tight container (USP). Ritalin LA® is a trademark of Novartis AG. SODAS® is a trademark of Elan Corporation, plc. This product is covered by US patents including US 5,837,284 and 6,228,398. REFERENCE American Psychiatric Association. Diagnosis and Statistical Manual of Mental Disorders. 4th edition. Washington DC: American Psychiatric Association 1994. REV: APRIL 2007 T2007-24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 18 MEDICATION GUIDE RITALIN LA® (methylphenidate hydrochloride) extended-release capsules CII Read the Medication Guide that comes with RITALIN LA® before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your or your child’s treatment with RITALIN LA®. What is the most important information I should know about RITALIN LA®? The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines. 1. Heart-related problems: • sudden death in patients who have heart problems or heart defects • stroke and heart attack in adults • increased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting RITALIN LA®. Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment with RITALIN LA®. Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking RITALIN LA®. 2. Mental (Psychiatric) problems: All Patients • new or worse behavior and thought problems • new or worse bipolar illness • new or worse aggressive behavior or hostility Children and Teenagers • new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking RITALIN LA®, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. What Is RITALIN LA®? ervous system imulant prescription medicine. It is used for the ity ITALIN LA® should be used as a part of a total ent program for ADHD that may include ontrolled RITALIN LA® is a central n st treatment of Attention-Deficit Hyperactiv Disorder (ADHD). RITALIN LA® may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. R treatm counseling or other therapies. RITALIN LA® is a federally c substance (CII) because it can be abused or lead to dependence. Keep RITALIN LA® in a safe place to prevent misuse and abuse. Selling or giving away RITALIN LA® may harm others, and is against the law. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 19 ell your doctor if you or your child have (or have a T family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs. Who should not take RITALIN LA®? ITALIN LA® should not be taken if you or family • s • ITALIN LA® should not be used in children less ITALIN LA® may not be right for you or your high blood • • ormal brain wave ell your doctor if you or your child is pregnant, an RITALIN LA® be taken with other ell your doctor about all of the medicines that our doctor will decide whether RITALIN LA® can Especially tell your doctor if you or your child i-depression medicines including MAOIs cines that contain Know the medicines that you or your child takes. Do not start any new medicine while taking r How should RITALIN LA® be taken? Take RITALIN LA exactly as prescribed. Take RITALIN LA once a day in the -release Swallow RITALIN LA® capsules whole with ther From time to time, your doctor may stop RITALIN LA® treatment for a while to check ADHD symptoms. R your child: • are very anxious, tense, or agitated • have an eye problem called glaucoma • have tics or Tourette’s syndrome, or a history of Tourette’s syndrome. Tics are hard to control repeated movements or sounds. are taking or have taken within the past 14 day an anti-depression medicine called a monoamine oxidase inhibitor or MAOI. are allergic to anything in RITALIN LA®. See the end of this Medication Guide for a complete list of ingredients. R than 6 years old because it has not been studied in this age group. R child. Before starting RITALIN LA® tell your or your child’s doctor about all health conditions (or a family history of) including: heart problems, heart defects, • pressure mental problems including psychosis, mania, bipolar illness, or depression tics or Tourette’s syndrome • seizures or have had an abn test (EEG) T planning to become pregnant, or breast-feeding. C medicines? T you or your child take including prescription and nonprescription medicines, vitamins, and herbal supplements. RITALIN LA® and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking RITALIN LA®. Y be taken with other medicines. takes: • ant • seizure medicines • blood thinner medi • blood pressure medicines • stomach acid medicines • cold or allergy medicines decongestants Keep a list of your medicines with you to show your doctor and pharmacist. RITALIN LA® without talking to your docto first. ® • Your doctor may adjust the dose until it is right for you or your child. ® • morning. RITALIN LA® is an extended capsule. It releases medicine into your body throughout the day. • water or other liquids. If you cannot swallow the capsule, open it and sprinkle the medicine over a spoonful of applesauce. Swallow the applesauce and medicine mixture without chewing. Follow with a drink of water or o liquid. Never chew or crush the capsule or the medicine inside the capsule. • This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 20 • od pressure while taking RITALIN LA . Children should have their • A or overdoses, call your doctor or poison control center right away, What are possible side effects of RITALIN A®? hat is the most important information I ould know about RITALIN LA®” for formation on reported heart and mental problems. slowing of growth (height and weight) in children a history of headache • decreased appetite e . formation. 2007 T2007-36 EV: APRIL 2007 PRINTED IN U.S.A. T2007-24/ T2007-36 Your doctor may do regular checks of the blood, heart, and blo ® height and weight checked often while taking RITALIN LA®. RITALIN LA® treatment may be stopped if a problem is found during these check-ups. If you or your child takes too much RITALIN L ® or get emergency treatment. L See “W sh in Other serious side effects include: • • seizures, mainly in patients with seizures • eyesight changes or blurred vision Common side effects include: • • stomach ache • trouble sleeping Talk to your doctor if you or your child has side ff cts that are bothersome or do not go away. e This is not a complete list of possible side effects Ask your doctor or pharmacist for more in How should I store RITALIN LA®? • Store RITALIN LA® in a safe place at room temperature, 59 to 86° F (15 to 30° C). • Keep RITALIN LA® and all medicines out of the reach of children. General information about RITALIN LA® Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RITALIN LA® for a condition for which it was not prescribed. Do not give RITALIN LA® to other people, even if they have the same condition. It may harm them and it is against the law. This Medication Guide summarizes the most important information about RITALIN LA®. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about RITALIN LA® that was written for healthcare professionals. For more information about RITALIN LA® call 1-888-669-6682. What are the ingredients in RITALIN LA®? Active Ingredient: methylphenidate HCL Inactive Ingredients: ammonio methacrylate copolymer, black iron oxide (10 and 40 mg capsules only), gelatin, methacrylic acid copolymer, polyethylene glycol, red iron oxide (10 and 40 mg capsules only), sugar spheres, talc, titanium dioxide, triethyl citrate, and yellow iron oxide (10, 30, and 40 mg capsules). This Medication Guide has been approved by the U.S. Food and Drug Administration. REV: APRIL R This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 21 Manufactured for ticals Corporation ©Novartis Novartis Pharmaceu East Hanover, New Jersey 07936 By ELAN HOLDINGS INC. Pharmaceutical Division Gainesville, GA 30504 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:42.945982	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/010187s069,018029s040,021284s011lbl.pdf', 'application_number': 10187, 'submission_type': 'SUPPL ', 'submission_number': 69}
10,751	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:43.140194	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/1999/10515s22lbl.pdf', 'application_number': 10515, 'submission_type': 'SUPPL ', 'submission_number': 22}
10,752	wEN-3173v02 Page 1 of 6 Isuprel™ Rx only Isoproterenol Hydrochloride Injection, USP Sterile Injection DESCRIPTION Isoproterenol hydrochloride is 3,4-Dihydroxy-α-[(isopropylamino)methyl] benzyl alcohol hydrochloride, a synthetic sympathomimetic amine that is structurally related to epinephrine but acts almost exclusively on beta receptors. The molecular formula is C11H17NO3 • HCl. It has a molecular weight of 247.72 and the following structural formula: Isoproterenol hydrochloride is a racemic compound. Each milliliter of the sterile solution contains: Isoproterenol hydrochloride injection, USP 0.2 mg Edetate Disodium (EDTA) 0.2 mg Sodium Chloride 7.0 mg Sodium Citrate, Dihydrate 2.07 mg Citric Acid, Anhydrous 2.5 mg Water for Injection 1.0 mL The pH is adjusted between 2.5 and 4.5 with hydrochloric acid or sodium hydroxide. The sterile solution is nonpyrogenic and can be administered by the intravenous, intramuscular, subcutaneous, or intracardiac routes. CLINICAL PHARMACOLOGY Isoproterenol is a potent nonselective beta-adrenergic agonist with very low affinity for alpha-adrenergic receptors. Intravenous infusion of isoproterenol in man lowers peripheral vascular resistance, primarily in skeletal muscle but also in renal and mesenteric vascular beds. Diastolic pressure falls. Renal blood flow is decreased in normotensive subjects but is increased markedly in shock. Systolic blood pressure may remain unchanged or rise, although mean arterial pressure typically falls. Cardiac output is increased because of the positive inotropic and chronotropic effects of the drug in the face of diminished peripheral vascular resistance. The cardiac effects of isoproterenol may lead to palpitations, sinus tachycardia, and more serious arrhythmias; large doses of isoproterenol may cause myocardial necrosis in animals. Isoproterenol relaxes almost all varieties of smooth muscle when the tone is high, but this action is most pronounced on bronchial and gastrointestinal smooth muscle. It prevents or relieves bronchoconstriction, but tolerance to this effect develops with overuse of the drug. Reference ID: 3280592 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda wEN-3173v02 Page 2 of 6 In man, isoproterenol causes less hyperglycemia than does epinephrine. Isoproterenol and epinephrine are equally effective in stimulating the release of free fatty acids and energy production. Absorption, Fate, and Excretion. Isoproterenol is metabolized primarily in the liver and other tissues by COMT. Isoproterenol is a relatively poor substrate for MAO and is not taken up by sympathetic neurons to the same extent as are epinephrine and norepinephrine. The duration of action of isoproterenol may therefore be longer than that of epinephrine, but is still brief. INDICATIONS AND USAGE Isoproterenol hydrochloride injection is indicated: • For mild or transient episodes of heart block that do not require electric shock or pacemaker therapy. • For serious episodes of heart block and Adams-Stokes attacks (except when caused by ventricular tachycardia or fibrillation). (See CONTRAINDICATIONS.) • For use in cardiac arrest until electric shock or pacemaker therapy, the treatments of choice, is available. (See CONTRAINDICATIONS.) • For bronchospasm occurring during anesthesia. • As an adjunct to fluid and electrolyte replacement therapy and the use of other drugs and procedures in the treatment of hypovolemic and septic shock, low cardiac output (hypoperfusion) states, congestive heart failure, and cardiogenic shock. (See WARNINGS.) CONTRAINDICATIONS Use of isoproterenol hydrochloride injection is contraindicated in patients with tachyarrhythmias; tachycardia or heart block caused by digitalis intoxication; ventricular arrhythmias which require inotropic therapy; and angina pectoris. WARNINGS Isoproterenol hydrochloride injection, by increasing myocardial oxygen requirements while decreasing effective coronary perfusion, may have a deleterious effect on the injured or failing heart. Most experts discourage its use as the initial agent in treating cardiogenic shock following myocardial infarction. However, when a low arterial pressure has been elevated by other means, isoproterenol hydrochloride injection may produce beneficial hemodynamic and metabolic effects. In a few patients, presumably with organic disease of the AV node and its branches, isoproterenol hydrochloride injection has paradoxically been reported to worsen heart block or to precipitate Adams- Stokes attacks during normal sinus rhythm or transient heart block. PRECAUTIONS General Isoproterenol hydrochloride injection should generally be started at the lowest recommended dose. This may be gradually increased if necessary while carefully monitoring the patient. Doses sufficient to increase the heart rate to more than 130 beats per minute may increase the likelihood of inducing ventricular arrhythmias. Such increases in heart rate will also tend to increase cardiac work and oxygen requirements which may adversely affect the failing heart or the heart with a significant degree of arteriosclerosis. Adequate filling of the intravascular compartment by suitable volume expanders is of primary importance in most cases of shock and should precede the administration of vasoactive drugs. In patients with normal cardiac function, determination of central venous pressure is a reliable guide during volume replacement. If evidence of hypoperfusion persists after adequate volume replacement, isoproterenol hydrochloride injection may be given. Reference ID: 3280592 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda wEN-3173v02 Page 3 of 6 In addition to the routine monitoring of systemic blood pressure, heart rate, urine flow, and the electrocardiograph, monitor the response to therapy by frequent determination of the central venous pressure and blood gases. Closely observe patients in shock during isoproterenol hydrochloride injection administration. If the heart rate exceeds 110 beats per minute, it may be advisable to decrease the infusion rate or temporarily discontinue the infusion. Determinations of cardiac output and circulation time may also be helpful. Take appropriate measures to ensure adequate ventilation. Pay attention to acid-base balance and to the correction of electrolyte disturbances. Drug Interactions Isoproterenol hydrochloride injection and epinephrine should not be administered simultaneously because both drugs are direct cardiac stimulants and their combined effects may induce serious arrhythmias. The drugs may, however, be administered alternately provided a proper interval has elapsed between doses. Avoid ISUPREL when potent inhalational anesthetics such as halothane are employed because of potential to sensitize the myocardium to effects of sympathomimetic amines. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate the carcinogenic potential of isoproterenol hydrochloride have not been done. Mutagenic potential and effect on fertility have not been determined. There is no evidence from human experience that isoproterenol hydrochloride injection may be carcinogenic or mutagenic or that it impairs fertility. Pregnancy Category C Animal reproduction studies have not been conducted with isoproterenol hydrochloride. It is also not known whether isoproterenol hydrochloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Isoproterenol hydrochloride should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isoproterenol hydrochloride injection is administered to a nursing woman. Pediatric Use Safety and efficacy of isoproterenol in pediatric patients have not been established. Intravenous infusions of isoproterenol in refractory asthmatic children at rates of 0.05-2.7 mcg/kg/min have caused clinical deterioration, myocardial necrosis, congestive heart failure and death. The risks of cardiac toxicity appear to be increased by some factors [acidosis, hypoxemia, coadministration of corticosteroids, coadministration of methylxanthines (theophylline, theobromine) or aminophylline] that are especially likely to be present in these patients. If I.V. isoproterenol is used in children with refractory asthma, patient monitoring must include continuous assessment of vital signs, frequent electrocardiography, and daily measurements of cardiac enzymes, including CPK-MB. Geriatric Use Clinical studies of Isuprel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects in clinical circumstances. There are, however, some data that suggest that elderly healthy or hypertensive patients are less responsive to beta-adrenergic stimulation than are younger subjects. In general, dose selection for elderly patients should usually start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant diseases or other drug therapy. Reference ID: 3280592 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda wEN-3173v02 Page 4 of 6 ADVERSE REACTIONS The following reactions to isoproterenol hydrochloride injection have been reported: CNS: Nervousness, headache, dizziness, nausea, visual blurring. Cardiovascular: Tachycardia, palpitations, angina, Adams-Stokes attacks, pulmonary edema, hypertension, hypotension, ventricular arrhythmias, tachyarrhythmias. In a few patients, presumably with organic disease of the AV node and its branches, isoproterenol hydrochloride injection has been reported to precipitate Adams-Stokes seizures during normal sinus rhythm or transient heart block. Respiratory: Dyspnea. Other: Flushing of the skin, sweating, mild tremors, weakness, pallor. OVERDOSAGE The acute toxicity of isoproterenol hydrochloride in animals is much less than that of epinephrine. Excessive doses in animals or man can cause a striking drop in blood pressure, and repeated large doses in animals may result in cardiac enlargement and focal myocarditis. In case of accidental overdosage as evidenced mainly by tachycardia or other arrhythmias, palpitations, angina, hypotension, or hypertension, reduce rate of administration or discontinue isoproterenol hydrochloride injection until patient’s condition stabilizes. Blood pressure, pulse, respiration, and ECG should be monitored. It is not known whether isoproterenol hydrochloride is dialyzable. The oral LD50 of isoproterenol hydrochloride in mice is 3,850 mg/kg ± 1,190 mg/kg of pure drug in solution. DOSAGE AND ADMINISTRATION Start ISUPREL injection at the lowest recommended dose and increase the rate of administration gradually if necessary while carefully monitoring the patient. The usual route of administration is by intravenous infusion or bolus intravenous injection. In dire emergencies, the drug may be administered by intracardiac injection. If time is not of the utmost importance, initial therapy by intramuscular or subcutaneous injection is preferred. Reference ID: 3280592 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda wEN-3173v02 Page 5 of 6 Recommended dosage for adults with heart block, Adams-Stokes attacks, and cardiac arrest: Route of Administration Preparation of Dilution Initial Dose Subsequent Dose Range* Bolus intravenous injection Dilute 1 mL (0.2 mg) in 9 mL of Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP 0.02 mg to 0.06 mg (1 mL to 3 mL of diluted solution) 0.01 mg to 0.2 mg (0.5 mL to 10 mL of diluted solution) Intravenous infusion Dilute 10 mL (2 mg) in 500 mL of 5% Dextrose Injection, USP 5 mcg/min. (1.25 mL of diluted solution per minute) Intramuscular Use Solution undiluted 0.2 mg (1 mL) 0.02 mg to 1 mg (0.1 mL to 5 mL) Subcutaneous Use Solution undiluted 0.2 mg (1 mL) 0.15 mg to 0.2 mg (0.75 mL to 1 mL) Intracardiac Use Solution undiluted 0.02 mg (0.1 mL) * Subsequent dosage and method of administration depend on the ventricular rate and the rapidity with which the cardiac pacemaker can take over when the drug is gradually withdrawn. There are no well-controlled studies in children to establish appropriate dosing; however, the American Heart Association recommends an initial infusion rate of 0.1 mcg/kg/min, with the usual range being 0.1 mcg/kg/min to 1 mcg/kg/min. Recommended dosage for adults with shock and hypoperfusion states: Route of Administration Preparation of Dilution† Infusion Rate†† Intravenous infusion Dilute 5 mL (1 mg) in 500 mL of 5% Dextrose Injection, USP 0.5 mcg to 5 mcg per minute (0.25 mL to 2.5 mL of diluted solution) † Concentrations up to 10 times greater have been used when limitation of volume is essential. †† Rates over 30 mcg per minute have been used in advanced stages of shock. The rate of infusion should be adjusted on the basis of heart rate, central venous pressure, systemic blood pressure, and urine flow. If the heart rate exceeds 110 beats per minute, it may be advisable to decrease or temporarily discontinue the infusion. Recommended dosage for adults with bronchospasm occurring during anesthesia: Route of Administration Preparation of Dilution Initial Dose Subsequent Dose Bolus intravenous injection Dilute 1 mL (0.2 mg) in 9 mL of Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP 0.01 mg to 0.02 mg (0.5 mL to 1 mL of diluted solution) The initial dose may be repeated when necessary Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Such solution should not be used. Reference ID: 3280592 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda wEN-3173v02 Page 6 of 6 HOW SUPPLIED NDC Container Concentration Fill Quantity 0409-1442-02 Ampul 0.2 mg/mL 1 mL UNI-AMPTM pak of 25 0409-1442-03 Ampul 1 mg/5 mL (0.2 mg/mL) 5 mL 10 ampuls per carton Protect from light. Keep in opaque container until used. Store at 20º to 25ºC (68º to 77ºF). [See USP Controlled Room Temperature.] Do not use if the injection is pinkish or darker than slightly yellow or contains a precipitate. Revised: 03/2013 EN-3173 Hospira, Inc., Lake Forest, IL 60045 USA Reference ID: 3280592 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:43.268560	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/010515s031lbl.pdf', 'application_number': 10515, 'submission_type': 'SUPPL ', 'submission_number': 31}
10,753	Celontin® (Methsuximide Capsules, USP) DESCRIPTION Celontin (methsuximide) is an anticonvulsant succinimide, chemically designated as N,2-Dimethyl-2 phenylsuccinimide, with the following structural formula: structural formula Each Celontin capsule contains 150 mg or 300 mg methsuximide, USP. Also contains starch, NF. The capsule contains colloidal silicon dioxide, NF; D&C yellow No. 10; FD&C yellow No. 6; gelatin, NF; and sodium lauryl sulfate, NF. CLINICAL PHARMACOLOGY Methsuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli. INDICATIONS AND USAGE Celontin is indicated for the control of absence (petit mal) seizures that are refractory to other drugs. CONTRAINDICATIONS Methsuximide should not be used in patients with a history of hypersensitivity to succinimides. WARNINGS Blood dyscrasias Blood dyscrasias, including some with fatal outcome, have been reported to be associated with the use of succinimides; therefore, periodic blood counts should be performed. Should signs and/or symptoms of infection (eg, sore throat, fever) develop, blood counts should be considered at that point. Effects on Liver It has been reported that succinimides have produced morphological and functional changes in animal liver. For this reason, methsuximide should be administered with extreme caution to patients with known liver or renal disease. Periodic urinalysis and liver function studies are advised for all patients receiving the drug. Systemic Lupus Erythematosus Cases of systemic lupus erythematosus have been reported with the use of succinimides. The physician should be alert to this possibility. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Celontin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients with Relative Risk: Risk Difference: with Events Per Events Per 1000 Incidence of Events in Additional Drug 1000 Patients Patients Drug Patients with Events Patients/Incidence in Per 1000 Patients Placebo Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Celontin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Usage in Pregnancy: Reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to phenytoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs. The reports suggesting an elevated incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors, eg, genetic factors or the epileptic condition itself, may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of childbearing potential. PRECAUTIONS General: It is recommended that the physician withdraw the drug slowly on the appearance of unusual depression, aggressiveness, or other behavioral alterations. As with other anticonvulsants, it is important to proceed slowly when increasing or decreasing dosage, as well as when adding or eliminating other medication. Abrupt withdrawal of anticonvulsant medication may precipitate absence (petit mal) status. Methsuximide, when used alone in mixed types of epilepsy, may increase the frequency of grand mal seizures in some patients. Information for Patients: Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Celontin. Instruct patients to take Celontin only as prescribed. Methsuximide may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a motor vehicle or other such activity requiring alertness; therefore, the patient should be cautioned accordingly. Patients taking methsuximide should be advised of the importance of adhering strictly to the prescribed dosage regimen. Patients should be instructed to promptly contact their physician if they develop signs and/or symptoms suggesting an infection (eg, sore throat, fever). ADVICE TO THE PHARMACIST AND PATIENT: Since methsuximide has a relatively low melting temperature (124° F), storage conditions which may promote high temperatures (closed cars, delivery vans, or storage near steam pipes) should be avoided. Do not dispense or use capsules that are not full or in which contents have melted. Effectiveness may be reduced. Protect from excessive heat (104° F). Patients, their caregivers, and families should be counseled that AEDs, including Celontin, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS: Pregnancy section). Drug Interactions: Since Celontin (methsuximide) may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (eg, methsuximide may increase the plasma concentrations of phenytoin and phenobarbital). Pregnancy: To provide information regarding the effects of in utero exposure to Celontin, physicians are advised to recommend that pregnant patients taking Celontin enroll in the (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website: http://www.aedpregnancyregistry.org/. See WARNINGS. Pediatric Use: See DOSAGE AND ADMINISTRATION. ADVERSE REACTIONS Gastrointestinal System: Gastrointestinal symptoms occur frequently and have included nausea or vomiting, anorexia, diarrhea, weight loss, epigastric and abdominal pain, and constipation. Hemopoietic System: Hemopoietic complications associated with the administration of methsuximide have included eosinophilia, leukopenia, monocytosis, and pancytopenia with or without bone marrow suppression. Nervous System: Neurologic and sensory reactions reported during therapy with methsuximide have included drowsiness, ataxia or dizziness, irritability and nervousness, headache, blurred vision, photophobia, hiccups, and insomnia. Drowsiness, ataxia, and dizziness have been the most frequent side effects noted. Psychologic abnormalities have included confusion, instability, mental slowness, depression, hypochondriacal behavior, and aggressiveness. There have been rare reports of psychosis, suicidal behavior, and auditory hallucinations. Integumentary System: Dermatologic manifestations which have occurred with the administration of methsuximide have included urticaria, Stevens-Johnson syndrome, and pruritic erythematous rashes. Cardiovascular: Hyperemia. Genitourinary System: Proteinuria, microscopic hematuria. Body as a Whole: Periorbital edema. OVERDOSAGE Acute overdoses may produce nausea, vomiting, and CNS depression including coma with respiratory depression. Methsuximide poisoning may follow a biphasic course. Following an initial comatose state, patients have awakened and then relapsed into a coma within 24 hours. It is believed that an active metabolite of methsuximide, N-desmethylmethsuximide, is responsible for this biphasic profile. It is important to follow plasma levels of N-desmethylmethsuximide in methsuximide poisonings. Levels greater than 40 µg/mL have caused toxicity, and coma has been seen at levels of 150 µg/mL. Treatment: Treatment should include emesis (unless the patient is or could rapidly become obtunded, comatose, or convulsing) or gastric lavage, activated charcoal, cathartics, and general supportive measures. Charcoal hemoperfusion may be useful in removing the N-desmethyl metabolite of methsuximide. Forced diuresis and exchange transfusions are ineffective. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION Optimum dosage of Celontin must be determined by trial. A suggested dosage schedule is 300 mg per day for the first week. If required, dosage may be increased thereafter at weekly intervals by 300 mg per day for the three weeks following to a daily dosage of 1.2 g. Because therapeutic effect and tolerance vary among patients, therapy with Celontin must be individualized according to the response of each patient. Optimal dosage is that amount of Celontin which is barely sufficient to control seizures so that side effects may be kept to a minimum. The smaller capsule (150 mg) facilitates administration to small children. Celontin may be administered in combination with other anticonvulsants when other forms of epilepsy coexist with absence (petit mal). HOW SUPPLIED N 0071-0525-24 (P-D 525)–Celontin Capsules, #1 capsule each containing 300 mg methsuximide; bottles of 100. N 0071-0537-24 (P-D 537)–Celontin Capsules, Half-Strength, #3 capsule each containing 150 mg methsuximide; bottles of 100. Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from light and moisture. Protect from excessive heat 40°C (104°F). Pfizer LAB-0156-4.0 Revised July 2010 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------- ---------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. /s/ RUSSELL G KATZ 10/11/2010 Reference ID: 2843346 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:43.272597	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/010596s22lbl.pdf', 'application_number': 10596, 'submission_type': 'SUPPL ', 'submission_number': 22}
10,750	Premarin® Intravenous (conjugated estrogens, USP) for injection Specially prepared for Intravenous & Intramuscular use Rx only WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER and PROBABLE DEMENTIA Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. (See WARNINGS, Malignant Neoplasms, Endometrial cancer.) Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders and Probable Dementia.) The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders.) The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use.) In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens. Estrogens with or without progestins should be prescribed at the lowest effective doses and for 1 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the shortest duration consistent with treatment goals and risks for the individual woman. Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders and Probable Dementia.) The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders.) The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use.) Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer. (See CLINICAL STUDIES and WARNINGS, Malignant Neoplasms, Breast cancer.) In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. DESCRIPTION Premarin Intravenous (conjugated estrogens, USP) for injection contains a mixture of conjugated estrogens obtained exclusively from natural sources, occurring as the sodium salts of water- soluble estrogen sulfates blended to represent the average composition of materials derived from pregnant mares’ urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as concomitant components, as sodium sulfate conjugates, 17α-dihydroequilin, 17α estradiol, and 17β-dihydroequilin. Each Secule vial contains 25 mg of conjugated estrogens, USP, in a sterile lyophilized cake which also contains lactose 200 mg, sodium citrate 12.2 mg, and simethicone 0.2 mg. The pH is adjusted with sodium hydroxide or hydrochloric acid. The reconstituted solution is suitable for intravenous or intramuscular injection. 2 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogen in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women. Pharmacokinetics A. Absorption Conjugated estrogens are water-soluble and are well-absorbed through the skin, mucous membranes, and gastrointestinal tract after release from the drug formulation. B. Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin. C. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. D. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. 3 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda E. Special Populations No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment. F. Drug Interactions Data from a single-dose drug-drug interaction study involving oral CE and MPA indicate that the pharmacokinetic dispositions of both drugs are not altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been conducted with conjugated estrogens. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John’s wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice, may increase plasma concentrations of estrogens and may result in side effects. CLINICAL STUDIES Women’s Health Initiative Studies The Women’s Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease [(CHD) defined as nonfatal MI, silent MI and CHD death], with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These studies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms. WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 7.1 years, are presented in Table 1. 4 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda & TABLE 1. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN-ALONE SUBSTUDY OF WHIa Relative Risk CE Placebo Event CE vs. Placebo (95% nCIb) n = 5,310 n = 5,429 Absolute Risk per 10,000 Women-Years CHD eventsc 0.95 (0.78-1.16) 54 57 Non-fatal MIc 0.91 (0.73-1.14) 40 43 CHD deathc 1.01 (0.71-1.43) 16 16 All Strokesc 1.33 (1.05-1.68) 45 33 Ischemic strokec Deep vein thrombosisc,d 1.55 (1.19-2.01) 1.47 (1.06-2.06) 38 23 25 15 Pulmonary embolismc 1.37 (0.90-2.07) 14 10 Invasive breast cancerc 0.80 (0.62-1.04) 28 34 Colorectal cancere 1.08 (0.75-1.55) 17 16 Hip fracturec Vertebral fracturesc,d Lower arm/wrist fracturesc,d Total fracturesc,d Death due to other causese,f Overall mortalityc,d 0.65 (0.45-0.94) 0.64 (0.44-0.93) 0.58 (0.47-0.72) 0.71 (0.64-0.80) 1.08 (0.88-1.32) 1.04 (0.88-1.22) 12 11 35 144 53 79 19 18 59 197 50 75 Global Indexg 1.02 (0.92-1.13) 206 201 a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. cResults are based on centrally adjudicated data for an average follow-up of 7.1 years. dNot included in Global Index. eResults are based on an average follow-up of 6.8 years. fAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. gA subset of the events was combined in a “global index,” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone were 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. The absolute excess risk of events included in the “global index” was a nonsignificant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was 5 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years. Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen alone increased the risk of ischemic stroke, and this excess was present in all subgroups of women examined. Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)]. WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the estrogen plus progestin substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 2. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. 6 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLE 2. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARSa,b Relative Risk CE/MPA Placebo Event CE/MPA vs. Placebo (95% nCIc) n = 8,506 n = 8,102 Absolute Risk per 10,000 Women-Years CHD events 1.23 (0.99-1.53) 41 34 Non-fatal MI 1.28 (1.00-1.63) 31 25 CHD death 1.10 (0.70-1.75) 8 8 All Strokes 1.31 (1.03-1.68) 33 25 Ischemic Stroke Deep vein thrombosisd 1.44 (1.09-1.90) 1.95 (1.43-2.67) 26 26 18 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive breast cancere 1.24 (1.01-1.54) 41 33 Colorectal cancer Endometrial cancerd Cervical cancerd 0.61 (0.42-0.87) 0.81 (0.48-1.36) 1.44 (0.47-4.42) 10 6 2 16 7 1 Hip fracture Vertebral fracturesd Lower arm/wrist fracturesd Total fracturesd Overall mortalityf 0.67 (0.47-0.96) 0.65 (0.46-0.92) 0.71 (0.59-0.85) 0.76 (0.69-0.83) 1.00 (0.83-1.19) 11 11 44 152 52 16 17 62 199 52 Global Indexg 1.13 (1.02-1.25) 184 165 a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Results are based on centrally adjudicated data. c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. d Not included in “global index”. e Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g A subset of the events was combined in a “global index,” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44-1.07)]. 7 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Women’s Health Initiative Memory Study The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy postmenopausal women 65 to 79 years of age and older (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83–2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use.) The WHIMS estrogen plus progestin ancillary study enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years of age; 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA was 2.05 (95 percent CI, 1.21–3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use.) When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use.) INDICATIONS AND USAGE Premarin Intravenous (conjugated estrogens, USP) for injection is indicated in the treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology. Premarin Intravenous is indicated for short-term use only, to provide a rapid and temporary increase in estrogen levels. 8 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS Premarin Intravenous therapy should not be used in individuals with any of the following conditions: 1. Undiagnosed abnormal genital bleeding. 2. Known, suspected, or history of breast cancer. 3. Known or suspected estrogen-dependent neoplasia. 4. Active DVT, PE or a history of these conditions. 5. Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions. 6. Known anaphylactic reaction and angioedema to Premarin Intravenous therapy. 7. Known liver dysfunction or disease. 8. Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. 9. Known or suspected pregnancy. WARNINGS See BOXED WARNINGS. Premarin Intravenous for injection is indicated for short-term use. However, warnings, precautions and adverse reactions associated with oral Premarin treatment should be taken into account. 1. Cardiovascular Disorders An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke, and MI has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. a. Stroke In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). (See 9 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL STUDIES.) The increase in risk was demonstrated in year 1 and persisted. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years). In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women- years). (See CLINICAL STUDIES.) The increase in risk was demonstrated after the first year and persisted. Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. b. Coronary heart disease In the WHI estrogen-alone substudy, no overall effect on CHD events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo. (See CLINICAL STUDIES.) In the WHI estrogen plus progestin substudy, there was a non-statistically significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE 0.625 mg/MPA 2.5 mg demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE plus MPA- treated group than in the placebo group in year one, but not during the subsequent years. Two thousand three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in the HERS, the HERS II, and overall. c. Venous thromboembolism In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE), was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women- years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years. (See CLINICAL STUDIES.) Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately. 10 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. (See CLINICAL STUDIES.) Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. 2. Malignant Neoplasms a. Endometrial cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. b. Breast cancer The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen- alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80). (See CLINICAL STUDIES.) The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo, respectively. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups. (See CLINICAL STUDIES.) Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen- alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have 11 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. c. Ovarian cancer The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77 – 3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association. 3. Probable Dementia In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.) In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.) When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both substudies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See PRECAUTIONS, Geriatric Use.) 12 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4. Gallbladder Disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving postmenopausal estrogens has been reported. 5. Hypercalcemia Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level. 6. Visual Abnormalities Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued. 7. Anaphylactic Reaction and Angioedema Cases of anaphylaxis, which developed within minutes to hours after using PREMARIN Intravenous and require emergency medical management, have been reported in the postmarketing setting. Skin (hives, pruritis, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) involvement has been noted. Angioedema involving the tongue, larynx, face, hands, and feet requiring medical intervention has occurred postmarketing in patients using PREMARIN Intravenous. If angioedema involves the tongue, glottis, or larynx, airway obstruction may occur. Patients who develop an anaphylactic reaction with or without angioedema after treatment with PREMARIN Intravenous should not receive PREMARIN Intravenous again. 8. Hereditary Angioedema Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema. PRECAUTIONS A. General Premarin Intravenous for injection is indicated for short-term use. However, warnings, precautions and adverse reactions associated with oral Premarin treatment should be taken into account. 1. Addition of a progestin when a woman has not had a hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration or daily with estrogen in a continuous regimen have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks which may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. 13 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2. Elevated blood pressure In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen. 3. Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs. 4. Hepatic impairment and/or past history of cholestatic jaundice Estrogens may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued. 5. Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. 6. Fluid retention Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. 7. Hypocalcemia Estrogen therapy should be used with caution in individuals with hypoparathyroidism as estrogen-induced hypocalcemia may occur. 8. Exacerbation of endometriosis A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. 9. Exacerbation of other conditions Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. B. Patient Information Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients who are being treated with Premarin Intravenous. 14 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda C. Laboratory Tests Estrogen administration should be guided by clinical response at the lowest dose, rather than laboratory monitoring. D. Drug-Laboratory Test Interactions 1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), SHBG, leading to increased total circulating corticosteroids and sex steroids respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). 4. Increased plasma high-density lipoprotein (HDL) and HDL2 subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglyceride levels. 5. Impaired glucose tolerance. E. Carcinogenesis, Mutagenesis, and Impairment of Fertility (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.) Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. F. Pregnancy Premarin Intravenous should not be used during pregnancy. (See CONTRAINDICATIONS.) G. Nursing Mothers Premarin Intravenous should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the breast milk of women receiving estrogens. Caution should be exercised when Premarin Intravenous is administered to a nursing woman. H. Pediatric Use Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established. Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short adult stature if treatment is initiated 15 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration. Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the normal pubertal process and induce gynecomastia. I. Geriatric Use There have not been sufficient numbers of geriatric patients involved in studies utilizing Premarin to determine whether those over 65 years of age differ from younger subjects in their response to Premarin. The Women’s Health Initiative Studies In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age. (See CLINICAL STUDIES.) In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age. (See CLINICAL STUDIES.) The Women’s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo. (See CLINICAL STUDIES and WARNINGS, Probable Dementia.) Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS, Probable Dementia.) ADVERSE REACTIONS See BOXED WARNINGS, WARNINGS, and PRECAUTIONS. Premarin Intravenous for injection is indicated for short-term use. However, the warnings, precautions and adverse reactions associated with oral Premarin treatment should be taken into account. The following adverse reactions have been identified during post-approval use of oral or intravenous Premarin. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Genitourinary system Abnormal uterine bleeding/spotting. 16 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dysmenorrhea or pelvic pain. Increase in size of uterine leiomyomata. Vaginitis, including vaginal candidiasis. Change in amount of cervical secretion. Change in cervical ectropion. Ovarian cancer. Endometrial hyperplasia. Endometrial cancer. Breasts Tenderness, enlargement, pain, discharge, galactorrhea. Fibrocystic breast changes. Breast cancer. Cardiovascular Deep and superficial venous thrombosis. Pulmonary embolism. Thrombophlebitis. Myocardial infarction. Stroke. Increase in blood pressure. Gastrointestinal Nausea, vomiting. Abdominal cramps, bloating. Cholestatic jaundice. Increased incidence of gallbladder disease. Pancreatitis. Enlargement of hepatic hemangiomas. Ischemic colitis. Skin Chloasma or melasma that may persist when drug is discontinued. Erythema multiforme. Erythema nodosum. Hemorrhagic eruption. Loss of scalp hair. Hirsutism. Pruritis. Rash. Eyes Retinal vascular thrombosis. Intolerance to contact lenses. Central Nervous System Headache. 17 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Migraine. Dizziness. Mental depression. Exacerbation of chorea. Nervousness. Exacerbation of epilepsy. Dementia. Possible growth potentiation of benign meningioma. Miscellaneous Increase or decrease in weight. Glucose intolerance. Aggravation of porphyria. Edema. Arthralgia. Leg cramps. Changes in libido. Urticaria. Hypocalcemia (preexisting condition). Injection site pain. Injection site edema. Phlebitis (injection site). Exacerbation of asthma. Increased triglycerides. OVERDOSAGE Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Premarin therapy with institution of appropriate symptomatic care. DOSAGE AND ADMINISTRATION For treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology: One 25 mg injection, intravenously or intramuscularly. Intravenous use is preferred since more rapid response can be expected from this mode of administration. Repeat in 6 to 12 hours if necessary. The use of Premarin Intravenous for injection does not preclude the advisability of other appropriate measures. One should adhere to the usual precautionary measures governing intravenous administration. Injection should be made SLOWLY to obviate the occurrence of flushes. Infusion of Premarin Intravenous for injection with other agents is not generally recommended. In emergencies, however, when an infusion has already been started it may be expedient to make the injection into the tubing just distal to the infusion needle. If so used, compatibility of solutions must be considered. 18 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda COMPATIBILITY OF SOLUTIONS: Premarin Intravenous is compatible with normal saline, dextrose, and invert sugar solutions. It is not compatible with protein hydrolysate, ascorbic acid, or any solution with an acid pH. DIRECTIONS FOR STORAGE AND RECONSTITUTION STORAGE BEFORE RECONSTITUTION: Store package in refrigerator, 2° to 8°C (36° to 46°F). TO RECONSTITUTE: Reconstitute Premarin Intravenous with 5 mL of Sterile Water for Injection, USP. Introduce the sterile diluent slowly against the side of SECULE vial and agitate gently. Do not shake violently. Use immediately after reconstitution. HOW SUPPLIED NDC 0046-0749-05–Each package provides one SECULE vial containing 25 mg of conjugated estrogens, USP, for injection (also lactose 200 mg, sodium citrate 12.2 mg, and simethicone 0.2 mg). The pH is adjusted with sodium hydroxide or hydrochloric acid. Premarin Intravenous (conjugated estrogens, USP) for injection is prepared by cryodesiccation. SECULE-Registered trademark to designate a vial containing an injectable preparation in dry form. 19 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PATIENT INFORMATION Premarin Intravenous (conjugated estrogens, USP) for injection Read this PATIENT INFORMATION which describes the benefit and major risks of your treatment, as well as how and when treatment should be used. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about Premarin Intravenous (an estrogen mixture)?  Using estrogen-alone increases your chance of getting cancer of the uterus (womb) Report any unusual vaginal bleeding right away. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.  Do not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function)  Using estrogen-alone may increase your chances of getting stroke or blood clots  Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age or older  Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or dementia  Using estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots  Using estrogens with progestins may increase your chance of getting dementia, based on a study of women 65 years of age or older  You and your healthcare provider should talk regularly about whether you still need treatment with estrogens What is Premarin Intravenous? Premarin Intravenous is a medicine that contains a mixture of estrogen hormones. Premarin Intravenous is used to:  Treat certain types of abnormal uterine bleeding due to hormonal imbalance when your doctor has found no other cause of bleeding Who should not use Premarin Intravenous? Premarin Intravenous should not be used if you: 20 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Have unusual vaginal bleeding that has not been evaluated by your healthcare provider  Currently have or have had certain cancers Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use Premarin Intravenous.  Had a stroke or heart attack  Currently have or have had blood clots  Currently have or have had liver problems  Have been diagnosed with a bleeding disorder  Are allergic to Premarin Intravenous or any of its ingredients See the list of ingredients in Premarin Intravenous at the end of this leaflet.  Think you may be pregnant Tell your healthcare provider:  If you are breast feeding The hormones in Premarin Intravenous can pass into your breast milk.  About all of your medical problems Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.  About all the medicines you take This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Premarin Intravenous works. What are the possible side effects of Premarin Intravenous? Premarin Intravenous is for short-term use only. However, the risks associated with oral Premarin treatment should be taken into account. Side effects are grouped by how serious they are and how often they happen when you are treated. Serious, but less common side effects include:  Heart attack  Stroke  Blood clots  Dementia  Breast cancer  Cancer of the lining of the uterus (womb)  Cancer of the ovary  High blood pressure 21 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  High blood sugar  Gallbladder disease  Liver problems  Enlargement of benign tumors of the uterus (“fibroids”)  Severe allergic reactions Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:  New breast lumps  Unusual vaginal bleeding  Changes in vision or speech  Sudden new severe headaches  Severe pains in your chest or legs with or without shortness of breath, weakness and fatigue  Swollen lips, tongue and face Less serious, but common side effects include:  Headache  Breast pain  Irregular vaginal bleeding or spotting  Stomach or abdominal cramps, bloating  Nausea and vomiting  Hair loss  Fluid retention  Vaginal yeast infection These are not all the possible side effects of Premarin. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What can I do to lower my chances of getting a serious side effect with Premarin Intravenous?  If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease Ask your healthcare provider for ways to lower your chances for getting heart disease. General information about the safe and effective use of Premarin Intravenous Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Premarin Intravenous for conditions for which it was not prescribed. Do not give Premarin Intravenous to other people, even if they have the same symptoms you have. It may harm them. Keep Premarin Intravenous out of the reach of children. 22 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This leaflet provides a summary of the most important information about Premarin Intravenous. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Premarin Intravenous that is written for health professionals. You can get more information by calling the toll free number 1-800-438-1985. What are the ingredients in Premarin IV? Premarin Intravenous for injection contains a mixture of conjugated estrogens, which are a mixture of sodium estrone sulfate and sodium equilin sulfate and other components including sodium sulfate conjugates: 17α-dihydroequilin, 17α-estradiol, and 17β-dihydroequilin. Premarin Intravenous for injection also contains lactose, sodium citrate, simethicone, and sodium hydroxide or hydrochloric acid in dry form. The reconstituted solution is suitable for intravenous or intramuscular injection. Each Premarin Intravenous (conjugated estrogens, USP) for injection package provides 25 mg of conjugated estrogens, USP, in dry form for intravenous or intramuscular use. This product’s label may have been updated. For current package insert and further product information, please visit www.pfizer.com or call our medical communications department toll-free at 1-800-438-1985. company logo LAB-0505-1.0 Rev 04/2012 23 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PATIENT INFORMATION Premarin Intravenous (conjugated estrogens, USP) for injection Rx only Read this PATIENT INFORMATION which describes the benefit and major risks of your treatment, as well as how and when treatment should be used. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about Premarin Intravenous (an estrogen mixture)?  Using estrogen-alone increases your chance of getting cancer of the uterus (womb) Report any unusual vaginal bleeding right away. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.  Do not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function)  Using estrogen-alone may increase your chances of getting stroke or blood clots  Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age or older  Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or dementia  Using estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots  Using estrogens with progestins may increase your chance of getting dementia, based on a study of women 65 years of age or older  You and your healthcare provider should talk regularly about whether you still need treatment with estrogens What is Premarin Intravenous? Premarin Intravenous is a medicine that contains a mixture of estrogen hormones. Premarin Intravenous is used to: 24 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Treat certain types of abnormal uterine bleeding due to hormonal imbalance when your doctor has found no other cause of bleeding Who should not use Premarin Intravenous? Premarin Intravenous should not be used if you:  Have unusual vaginal bleeding that has not been evaluated by your healthcare provider  Currently have or have had certain cancers Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use Premarin Intravenous.  Had a stroke or heart attack  Currently have or have had blood clots  Currently have or have had liver problems  Have been diagnosed with a bleeding disorder  Are allergic to Premarin Intravenous or any of its ingredients See the list of ingredients in Premarin Intravenous at the end of this leaflet.  Think you may be pregnant Tell your healthcare provider:  If you are breast feeding The hormones in Premarin Intravenous can pass into your breast milk.  About all of your medical problems Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.  About all the medicines you take This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Premarin Intravenous works. What are the possible side effects of Premarin Intravenous? Premarin Intravenous is for short-term use only. However, the risks associated with oral Premarin treatment should be taken into account. Side effects are grouped by how serious they are and how often they happen when you are treated. Serious, but less common side effects include:  Heart attack  Stroke  Blood clots 25 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Dementia  Breast cancer  Cancer of the lining of the uterus (womb)  Cancer of the ovary  High blood pressure  High blood sugar  Gallbladder disease  Liver problems  Enlargement of benign tumors of the uterus (“fibroids”)  Severe allergic reactions Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:  New breast lumps  Unusual vaginal bleeding  Changes in vision or speech  Sudden new severe headaches  Severe pains in your chest or legs with or without shortness of breath, weakness and fatigue  Swollen lips, tongue and face Less serious, but common side effects include:  Headache  Breast pain  Irregular vaginal bleeding or spotting  Stomach or abdominal cramps, bloating  Nausea and vomiting  Hair loss  Fluid retention  Vaginal yeast infection These are not all the possible side effects of Premarin. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report side effects to FDA at 1 800-FDA-1088. What can I do to lower my chances of getting a serious side effect with Premarin Intravenous?  If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease Ask your healthcare provider for ways to lower your chances for getting heart disease. 26 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda General information about the safe and effective use of Premarin Intravenous Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Premarin Intravenous for conditions for which it was not prescribed. Do not give Premarin Intravenous to other people, even if they have the same symptoms you have. It may harm them. Keep Premarin Intravenous out of the reach of children. This leaflet provides a summary of the most important information about Premarin Intravenous. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Premarin Intravenous that is written for health professionals. You can get more information by calling the toll free number 1-800-438-1985. What are the ingredients in Premarin IV? Premarin Intravenous for injection contains a mixture of conjugated estrogens, which are a mixture of sodium estrone sulfate and sodium equilin sulfate and other components including sodium sulfate conjugates: 17α-dihydroequilin, 17α-estradiol, and 17β-dihydroequilin. Premarin Intravenous for injection also contains lactose, sodium citrate, simethicone, and sodium hydroxide or hydrochloric acid in dry form. The reconstituted solution is suitable for intravenous or intramuscular injection. Each Premarin Intravenous (conjugated estrogens, USP) for injection package provides 25 mg of conjugated estrogens, USP, in dry form for intravenous or intramuscular use. This product’s label may have been updated. For current package insert and further product information, please visit www.pfizer.com or call our medical communications department toll-free at 1-800-438-1985. company logo LAB-0518-1.0 Rev 04/2012 27 Reference ID: 3115061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:43.275513	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/010402s063lbl.pdf', 'application_number': 10402, 'submission_type': 'SUPPL ', 'submission_number': 63}
10,757	TESSALON® 100 mg Perles 200 mg Capsules (benzonatate, USP) DESCRIPTION TESSALON, a non-narcotic oral antitussive agent, is 2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-yl p (butylamino) benzoate; with a molecular weight of 603.7. structural formula H3 Each Benzonatate, USP 100 mg Each TESSALON Capsule contains: Benzonatate, USP 200 mg TESSALON Capsules also contain: D&C Yellow 10, gelatin, glycerin, methylparaben and propylparaben. CLINICAL PHARMACOLOGY TESSALON acts peripherally by anesthetizing the stretch receptors located in the respiratory passages, lungs, and pleura by dampening their activity and thereby reducing the cough reflex at its source. It begins to act within 15 to 20 minutes and its effect lasts for 3 to 8 hours. TESSALON has no inhibitory effect on the respiratory center in recommended dosage. INDICATIONS AND USAGE TESSALON is indicated for the symptomatic relief of cough. CONTRAINDICATIONS Hypersensitivity to benzonatate or related compounds. WARNINGS Hypersensitivity Severe hypersensitivity reactions (including bronchospasm, laryngospasm and cardiovascular collapse) have been reported which are possibly related to local anesthesia from sucking or chewing the capsule instead of swallowing it. Severe reactions have required intervention with vasopressor agents and supportive measures. Psychiatric Effects Isolated instances of bizarre behavior, including mental confusion and visual hallucinations, have also been reported in patients taking TESSALON in combination with other prescribed drugs. Accidental Ingestion and Death in Children Keep TESSALON out of reach of children. Accidental ingestion of TESSALON resulting in death has been reported in children below age 10. Signs and symptoms of overdose have been reported within 15-20 minutes and death has been reported within one hour of ingestion. If accidental ingestion occurs, seek medical attention immediately (see OVERDOSAGE). PRECAUTIONS Benzonatate is chemically related to anesthetic agents of the para-amino-benzoic acid class (e.g. procaine; tetracaine) and has been associated with adverse CNS effects possibly related to a prior sensitivity to related agents or interaction with concomitant medication. Information for patients: Swallow TESSALON Capsules and Perles whole. Do not break, chew, dissolve, cut, or crush TESSALON Capsules and Perles. Release of TESSALON from the capsule in the mouth can produce a temporary local anesthesia of the Reference ID: 2893337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda oral mucosa and choking could occur. If numbness or tingling of the tongue, mouth, throat, or face occurs, refrain from oral ingestion of food or liquids until the numbness has resolved. If the symptoms worsen or persist, seek medical attention. Keep TESSALON out of reach of children. Accidental ingestion resulting in death has been reported in children. Signs and symptoms of overdose have been reported within 15-20 minutes and death has been reported within one hour of ingestion. Signs and symptoms may include restlessness, tremors, convulsions, coma and cardiac arrest. If accidental ingestion occurs, seek medical attention immediately. Overdosage resulting in death may occur in adults. Do not exceed a single dose of 200 mg and a total daily dosage of 600 mg. If you miss a dose of TESSALON, skip that dose and take the next dose at the next scheduled time. Do not take 2 doses of TESSALON at one time. Usage in Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted with TESSALON. It is also not known whether TESSALON can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. TESSALON should be given to a pregnant woman only if clearly needed. Nursing mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk caution should be exercised when TESSALON is administered to a nursing woman. Carcinogenesis, mutagenesis, impairment of fertility: Carcinogenicity, mutagenicity, and reproduction studies have not been conducted with TESSALON. Pediatric Use: Safety and effectiveness in children below the age of 10 have not been established. Accidental ingestion resulting in death has been reported in children below age 10. Keep out of reach of children. ADVERSE REACTIONS Potential Adverse Reactions to TESSALON may include: Hypersensitivity reactions including bronchospasm, laryngospasm, cardiovascular collapse possibly related to local anesthesia from chewing or sucking the capsule. CNS: sedation; headache; dizziness; mental confusion; visual hallucinations. GI: constipation; nausea; GI upset. Dermatologic: pruritus; skin eruptions. Other: nasal congestion; sensation of burning in the eyes; vague “chilly” sensation; numbness of the chest; hypersensitivity. Deliberate or accidental overdose has resulted in death, particularly in children. OVERDOSAGE Intentional and unintentional overdose may result in death, particularly in children. The drug is chemically related to tetracaine and other topical anesthetics and shares various aspects of their pharmacology and toxicology. Drugs of this type are generally well absorbed after ingestion. Signs and Symptoms: The signs and symptoms of overdose of benzonatate have been reported within 15-20 minutes. If capsules are chewed or dissolved in the mouth, oropharyngeal anesthesia will develop rapidly, which may cause choking and airway compromise. CNS stimulation may cause restlessness and tremors which may proceed to clonic convulsions followed by profound CNS depression. Convulsions, coma, cerebral edema and cardiac arrest leading to death have been reported within 1 hour of ingestion. Reference ID: 2893337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Treatment: In case of overdose, seek medical attention immediately. Evacuate gastric contents and administer copious amounts of activated charcoal slurry. Even in the conscious patient, cough and gag reflexes may be so depressed as to necessitate special attention to protection against aspiration of gastric contents and orally administered materials. Convulsions should be treated with a short-acting barbiturate given intravenously and carefully titrated for the smallest effective dosage. Intensive support of respiration and cardiovascular-renal function is an essential feature of the treatment of severe intoxication from overdosage. Do not use CNS stimulants. DOSAGE AND ADMINISTRATION Adults and Children over 10 years of age: Usual dose is one 100 mg or 200 mg capsule three times a day as needed for cough. If necessary to control cough, up to 600 mg daily in three divided doses may be given. TESSALON should be swallowed whole. TESSALON Capsules and Perles are not to be broken, chewed, dissolved, cut or crushed. HOW SUPPLIED Perles, 100 mg (yellow); bottles of 100 NDC 0069-0122-01 Imprint: T. Perles, 100 mg (yellow); bottles of 500 NDC 0069-0122-02 Imprint: T Capsules, 200 mg (yellow); bottles of 100 NDC 0069-0124-01 Imprint: 0698. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Rev. 12/15 Mfd by Catalent Pharma Solutions St. Petersburg, Florida 33716 Pfizer Inc. Madison, New Jersey 07940 ©2010 Pfizer Inc. Reference ID: 2893337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:43.545374	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/011210s053lbl.pdf', 'application_number': 11210, 'submission_type': 'SUPPL ', 'submission_number': 53}
10,754	1 PRESCRIBING INFORMATION 1 LEUKERAN® 2 (chlorambucil) 3 Tablets 4 5 WARNING 6 LEUKERAN (chlorambucil) can severely suppress bone marrow function. Chlorambucil is a 7 carcinogen in humans. Chlorambucil is probably mutagenic and teratogenic in humans. 8 Chlorambucil produces human infertility (see WARNINGS and PRECAUTIONS). 9 DESCRIPTION 10 LEUKERAN (chlorambucil) was first synthesized by Everett et al. It is a bifunctional 11 alkylating agent of the nitrogen mustard type that has been found active against selected human 12 neoplastic diseases. Chlorambucil is known chemically as 4-[bis(2- 13 chlorethyl)amino]benzenebutanoic acid and has the following structural formula: 14 15 16 17 Chlorambucil hydrolyzes in water and has a pKa of 5.8. 18 LEUKERAN (chlorambucil) is available in tablet form for oral administration. Each 19 film-coated tablet contains 2 mg chlorambucil and the inactive ingredients colloidal silicon 20 dioxide, hypromellose, lactose (anhydrous), macrogol/PEG 400, microcrystalline cellulose, red 21 iron oxide, stearic acid, titanium dioxide, and yellow iron oxide. 22 CLINICAL PHARMACOLOGY 23 Chlorambucil is rapidly and completely absorbed from the gastrointestinal tract. After single 24 oral doses of 0.6 to 1.2 mg/kg, peak plasma chlorambucil levels (Cmax) are reached within 1 hour 25 and the terminal elimination half-life (t1/2) of the parent drug is estimated at 1.5 hours. 26 Chlorambucil undergoes rapid metabolism to phenylacetic acid mustard, the major metabolite, 27 and the combined chlorambucil and phenylacetic acid mustard urinary excretion is extremely 28 low — less than 1% in 24 hours. In a study of 12 patients given single oral doses of 0.2 mg/kg of 29 LEUKERAN, the mean dose (12 mg) adjusted (± SD) plasma chlorambucil Cmax was 30 492 ± 160 ng/mL, the AUC was 883 ± 329 ng•h/mL, t1/2 was 1.3 ± 0.5 hours, and the tmax was 31 0.83 ± 0.53 hours. For the major metabolite, phenylacetic acid mustard, the mean dose (12 mg) 32 adjusted (± SD) plasma Cmax was 306 ± 73 ng/mL, the AUC was 1204 ± 285 ng•h/mL, the t1/2 33 was 1.8 ± 0.4 hours, and the tmax was 1.9 ± 0.7 hours. 34 Chlorambucil and its metabolites are extensively bound to plasma and tissue proteins. In vitro, 35 chlorambucil is 99% bound to plasma proteins, specifically albumin. Cerebrospinal fluid levels 36 of chlorambucil have not been determined. Evidence of human teratogenicity suggests that the 37 drug crosses the placenta. 38 Chlorambucil is extensively metabolized in the liver primarily to phenylacetic acid mustard, 39 which has antineoplastic activity. Chlorambucil and its major metabolite spontaneously degrade 40 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 in vivo forming monohydroxy and dihydroxy derivatives. After a single dose of radiolabeled 41 chlorambucil (14C), approximately 15% to 60% of the radioactivity appears in the urine after 42 24 hours. Again, less than 1% of the urinary radioactivity is in the form of chlorambucil or 43 phenylacetic acid mustard. In summary, the pharmacokinetic data suggest that oral chlorambucil 44 undergoes rapid gastrointestinal absorption and plasma clearance and that it is almost completely 45 metabolized, having extremely low urinary excretion. 46 INDICATIONS AND USAGE 47 LEUKERAN (chlorambucil) is indicated in the treatment of chronic lymphatic (lymphocytic) 48 leukemia, malignant lymphomas including lymphosarcoma, giant follicular lymphoma, and 49 Hodgkin’s disease. It is not curative in any of these disorders but may produce clinically useful 50 palliation. 51 CONTRAINDICATIONS 52 Chlorambucil should not be used in patients whose disease has demonstrated a prior resistance 53 to the agent. Patients who have demonstrated hypersensitivity to chlorambucil should not be 54 given the drug. There may be cross-hypersensitivity (skin rash) between chlorambucil and other 55 alkylating agents. 56 WARNINGS 57 Because of its carcinogenic properties, chlorambucil should not be given to patients with 58 conditions other than chronic lymphatic leukemia or malignant lymphomas. Convulsions, 59 infertility, leukemia, and secondary malignancies have been observed when chlorambucil was 60 employed in the therapy of malignant and non-malignant diseases. 61 There are many reports of acute leukemia arising in patients with both malignant and 62 non-malignant diseases following chlorambucil treatment. In many instances, these patients also 63 received other chemotherapeutic agents or some form of radiation therapy. The quantitation of 64 the risk of chlorambucil-induction of leukemia or carcinoma in humans is not possible. 65 Evaluation of published reports of leukemia developing in patients who have received 66 chlorambucil (and other alkylating agents) suggests that the risk of leukemogenesis increases 67 with both chronicity of treatment and large cumulative doses. However, it has proved impossible 68 to define a cumulative dose below which there is no risk of the induction of secondary 69 malignancy. The potential benefits from chlorambucil therapy must be weighed on an individual 70 basis against the possible risk of the induction of a secondary malignancy. 71 Chlorambucil has been shown to cause chromatid or chromosome damage in humans. Both 72 reversible and permanent sterility have been observed in both sexes receiving chlorambucil. 73 A high incidence of sterility has been documented when chlorambucil is administered to 74 prepubertal and pubertal males. Prolonged or permanent azoospermia has also been observed in 75 adult males. While most reports of gonadal dysfunction secondary to chlorambucil have related 76 to males, the induction of amenorrhea in females with alkylating agents is well documented and 77 chlorambucil is capable of producing amenorrhea. Autopsy studies of the ovaries from women 78 with malignant lymphoma treated with combination chemotherapy including chlorambucil have 79 shown varying degrees of fibrosis, vasculitis, and depletion of primordial follicles. 80 Rare instances of skin rash progressing to erythema multiforme, toxic epidermal necrolysis, or 81 Stevens-Johnson syndrome have been reported. Chlorambucil should be discontinued promptly 82 in patients who develop skin reactions. 83 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Pregnancy: Pregnancy Category D. Chlorambucil can cause fetal harm when administered to a 84 pregnant woman. Unilateral renal agenesis has been observed in 2 offspring whose mothers 85 received chlorambucil during the first trimester. Urogenital malformations, including absence of 86 a kidney, were found in fetuses of rats given chlorambucil. There are no adequate and 87 well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient 88 becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to 89 the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. 90 PRECAUTIONS 91 General: Many patients develop a slowly progressive lymphopenia during treatment. The 92 lymphocyte count usually rapidly returns to normal levels upon completion of drug therapy. 93 Most patients have some neutropenia after the third week of treatment and this may continue for 94 up to 10 days after the last dose. Subsequently, the neutrophil count usually rapidly returns to 95 normal. Severe neutropenia appears to be related to dosage and usually occurs only in patients 96 who have received a total dosage of 6.5 mg/kg or more in one course of therapy with continuous 97 dosing. About one quarter of all patients receiving the continuous-dose schedule, and one third of 98 those receiving this dosage in 8 weeks or less may be expected to develop severe neutropenia. 99 While it is not necessary to discontinue chlorambucil at the first evidence of a fall in 100 neutrophil count, it must be remembered that the fall may continue for 10 days after the last 101 dose, and that as the total dose approaches 6.5 mg/kg, there is a risk of causing irreversible bone 102 marrow damage. The dose of chlorambucil should be decreased if leukocyte or platelet counts 103 fall below normal values and should be discontinued for more severe depression. 104 Chlorambucil should not be given at full dosages before 4 weeks after a full course of 105 radiation therapy or chemotherapy because of the vulnerability of the bone marrow to damage 106 under these conditions. If the pretherapy leukocyte or platelet counts are depressed from bone 107 marrow disease process prior to institution of therapy, the treatment should be instituted at a 108 reduced dosage. 109 Persistently low neutrophil and platelet counts or peripheral lymphocytosis suggest bone 110 marrow infiltration. If confirmed by bone marrow examination, the daily dosage of chlorambucil 111 should not exceed 0.1 mg/kg. Chlorambucil appears to be relatively free from gastrointestinal 112 side effects or other evidence of toxicity apart from the bone marrow depressant action. In 113 humans, single oral doses of 20 mg or more may produce nausea and vomiting. 114 Children with nephrotic syndrome and patients receiving high pulse doses of chlorambucil 115 may have an increased risk of seizures. As with any potentially epileptogenic drug, caution 116 should be exercised when administering chlorambucil to patients with a history of seizure 117 disorder or head trauma, or who are receiving other potentially epileptogenic drugs. 118 Information for Patients: Patients should be informed that the major toxicities of 119 chlorambucil are related to hypersensitivity, drug fever, myelosuppression, hepatotoxicity, 120 infertility, seizures, gastrointestinal toxicity, and secondary malignancies. Patients should never 121 be allowed to take the drug without medical supervision and should consult their physician if 122 they experience skin rash, bleeding, fever, jaundice, persistent cough, seizures, nausea, vomiting, 123 amenorrhea, or unusual lumps/masses. Women of childbearing potential should be advised to 124 avoid becoming pregnant. 125 Laboratory Tests: Patients must be followed carefully to avoid life-endangering damage to 126 the bone marrow during treatment. Weekly examination of the blood should be made to 127 determine hemoglobin levels, total and differential leukocyte counts, and quantitative platelet 128 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 counts. Also, during the first 3 to 6 weeks of therapy, it is recommended that white blood cell 129 counts be made 3 or 4 days after each of the weekly complete blood counts. Galton et al have 130 suggested that in following patients it is helpful to plot the blood counts on a chart at the same 131 time that body weight, temperature, spleen size, etc., are recorded. It is considered dangerous to 132 allow a patient to go more than 2 weeks without hematological and clinical examination during 133 treatment. 134 Drug Interactions: There are no known drug/drug interactions with chlorambucil. 135 Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section for 136 information on carcinogenesis, mutagenesis, and impairment of fertility. 137 Pregnancy: Teratogenic Effects: Pregnancy Category D: See WARNINGS section. 138 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many 139 drugs are excreted in human milk and because of the potential for serious adverse reactions in 140 nursing infants from chlorambucil, a decision should be made whether to discontinue nursing or 141 to discontinue the drug, taking into account the importance of the drug to the mother. 142 Pediatric Use: The safety and effectiveness in pediatric patients have not been established. 143 Geriatric Use: Clinical studies of chlorambucil did not include sufficient numbers of subjects 144 aged 65 and over to determine whether they respond differently from younger subjects. Other 145 reported clinical experience has not identified differences in responses between the elderly and 146 younger patients. In general, dose selection for an elderly patient should be cautious, usually 147 starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, 148 renal, or cardiac function, and of concomitant disease or other drug therapy. 149 ADVERSE REACTIONS 150 Hematologic: The most common side effect is bone marrow suppression. Although bone 151 marrow suppression frequently occurs, it is usually reversible if the chlorambucil is withdrawn 152 early enough. However, irreversible bone marrow failure has been reported. 153 Gastrointestinal: Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral 154 ulceration occur infrequently. 155 CNS: Tremors, muscular twitching, myoclonia, confusion, agitation, ataxia, flaccid paresis, and 156 hallucinations have been reported as rare adverse experiences to chlorambucil which resolve 157 upon discontinuation of drug. Rare, focal and/or generalized seizures have been reported to occur 158 in both children and adults at both therapeutic daily doses and pulse-dosing regimens, and in 159 acute overdose (see PRECAUTIONS: General). 160 Dermatologic: Allergic reactions such as urticaria and angioneurotic edema have been 161 reported following initial or subsequent dosing. Skin hypersensitivity (including rare reports of 162 skin rash progressing to erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson 163 syndrome) has been reported (see WARNINGS). 164 Miscellaneous: Other reported adverse reactions include: pulmonary fibrosis, hepatotoxicity 165 and jaundice, drug fever, peripheral neuropathy, interstitial pneumonia, sterile cystitis, infertility, 166 leukemia, and secondary malignancies (see WARNINGS). 167 OVERDOSAGE 168 Reversible pancytopenia was the main finding of inadvertent overdoses of chlorambucil. 169 Neurological toxicity ranging from agitated behavior and ataxia to multiple grand mal seizures 170 has also occurred. As there is no known antidote, the blood picture should be closely monitored 171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 and general supportive measures should be instituted, together with appropriate blood 172 transfusions, if necessary. Chlorambucil is not dialyzable. 173 Oral LD50 single doses in mice are 123 mg/kg. In rats, a single intraperitoneal dose of 174 12.5 mg/kg of chlorambucil produces typical nitrogen-mustard effects; these include atrophy of 175 the intestinal mucous membrane and lymphoid tissues, severe lymphopenia becoming maximal 176 in 4 days, anemia, and thrombocytopenia. After this dose, the animals begin to recover within 177 3 days and appear normal in about a week, although the bone marrow may not become 178 completely normal for about 3 weeks. An intraperitoneal dose of 18.5 mg/kg kills about 50% of 179 the rats with development of convulsions. As much as 50 mg/kg has been given orally to rats as a 180 single dose, with recovery. Such a dose causes bradycardia, excessive salivation, hematuria, 181 convulsions, and respiratory dysfunction. 182 DOSAGE AND ADMINISTRATION 183 The usual oral dosage is 0.1 to 0.2 mg/kg body weight daily for 3 to 6 weeks as required. This 184 usually amounts to 4 to 10 mg per day for the average patient. The entire daily dose may be 185 given at one time. These dosages are for initiation of therapy or for short courses of treatment. 186 The dosage must be carefully adjusted according to the response of the patient and must be 187 reduced as soon as there is an abrupt fall in the white blood cell count. Patients with Hodgkin’s 188 disease usually require 0.2 mg/kg daily, whereas patients with other lymphomas or chronic 189 lymphocytic leukemia usually require only 0.1 mg/kg daily. When lymphocytic infiltration of the 190 bone marrow is present, or when the bone marrow is hypoplastic, the daily dose should not 191 exceed 0.1 mg/kg (about 6 mg for the average patient). 192 Alternate schedules for the treatment of chronic lymphocytic leukemia employing 193 intermittent, biweekly, or once-monthly pulse doses of chlorambucil have been reported. 194 Intermittent schedules of chlorambucil begin with an initial single dose of 0.4 mg/kg. Doses are 195 generally increased by 0.1 mg/kg until control of lymphocytosis or toxicity is observed. 196 Subsequent doses are modified to produce mild hematologic toxicity. It is felt that the response 197 rate of chronic lymphocytic leukemia to the biweekly or once-monthly schedule of chlorambucil 198 administration is similar or better to that previously reported with daily administration and that 199 hematologic toxicity was less than or equal to that encountered in studies using daily 200 chlorambucil. 201 Radiation and cytotoxic drugs render the bone marrow more vulnerable to damage, and 202 chlorambucil should be used with particular caution within 4 weeks of a full course of radiation 203 therapy or chemotherapy. However, small doses of palliative radiation over isolated foci remote 204 from the bone marrow will not usually depress the neutrophil and platelet count. In these cases 205 chlorambucil may be given in the customary dosage. 206 It is presently felt that short courses of treatment are safer than continuous maintenance 207 therapy, although both methods have been effective. It must be recognized that continuous 208 therapy may give the appearance of “maintenance” in patients who are actually in remission and 209 have no immediate need for further drug. If maintenance dosage is used, it should not exceed 210 0.1 mg/kg daily and may well be as low as 0.03 mg/kg daily. A typical maintenance dose is 2 mg 211 to 4 mg daily, or less, depending on the status of the blood counts. It may, therefore, be desirable 212 to withdraw the drug after maximal control has been achieved, since intermittent therapy 213 reinstituted at time of relapse may be as effective as continuous treatment. 214 Procedures for proper handling and disposal of anticancer drugs should be considered. Several 215 guidelines on this subject have been published.1-8 216 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 There is no general agreement that all of the procedures recommended in the guidelines are 217 necessary or appropriate. 218 HOW SUPPLIED 219 Leukeran is supplied as brown, film-coated, round, biconvex tablets containing 2 mg 220 chlorambucil in amber glass bottles with child-resistant closures. One side is engraved with “GX 221 EG3” and the other side is engraved with an “L.” 222 Bottle of 50 (NDC 0173-0635-35). 223 Store in a refrigerator, 2°°°° to 8°°°°C (36°°°° to 46°°°°F). 224 REFERENCES 225 1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations 226 for Practice. Pittsburgh, PA: Oncology Nursing Society; 1999:32-41. 227 2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: 228 Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, 229 National Institutes of Health and Human Services, 1992, US Dept of Health and Human 230 Services, Public Health Service publication NIH 92-2621. 231 3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 232 1985;253:1590-1591. 233 4. National Study Commission on Cytotoxic Exposure. Recommendations for handling 234 cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study 235 Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health 236 Sciences, 179 Longwood Avenue, Boston, MA 02115. 237 5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling 238 of antineoplastic agents. Med J Australia. 1983;1:426-428. 239 6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the 240 Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263. 241 7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling 242 cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049. 243 8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) 244 Am J Health-Syst Pharm. 1996;53:1669-1685. 245 246 247 248 GlaxoSmithKline 249 Research Triangle Park, NC 27709 250 251 2003, GlaxoSmithKline 252 All rights reserved. 253 254 Date of Issue RL- 255 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:43.663467	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/10669slr028_leukeran_lbl.pdf', 'application_number': 10669, 'submission_type': 'SUPPL ', 'submission_number': 28}
10,756	NDA 11-011/S-070 NDA 11-011/S-071 Page 3 FDA edits are double underlined. robaxin® (methocarbamol tablets, USP) 500 mg robaxin®-750 (methocarbamol tablets, USP) 750 mg PC4449B Rev. 02/03 Rx Only DESCRIPTION robaxin®/robaxin®-750 (methocarbamol tablets, USP), a carbamate derivative of guaifenesin, is a central nervous system (CNS) depressant with sedative and musculoskeletal relaxant properties. The chemical name of methocarbamol is 3-(2-methoxyphenoxy)-1,2-propanediol 1-carbamate and has the empirical formula C11H15NO5. Its molecular weight is 241.24. The structural formula is shown below. (Structure Inserted Here) Methocarbamol is a white powder, sparingly soluble in water and chloroform, soluble in alcohol (only with heating) and propylene glycol, and insoluble in benzene and n-hexane. robaxin® is available as a light orange, round, film-coated tablet containing 500 mg of methocarbamol, USP for oral administration. The inactive ingredients present are corn starch, FD&C Yellow 6, hydroxypropyl cellulose, hypromellose, magnesium stearate, polysorbate 20, povidone, propylene glycol, saccharin sodium, sodium lauryl sulfate, sodium starch glycolate, stearic acid, titanium dioxide. robaxin®-750 is available as an orange capsule-shaped, film-coated tablet containing 750 mg of methocarbamol, USP for oral administration. In addition to the inactive ingredients present in robaxin®, robaxin®-750 also contains D&C Yellow 10. CLINICAL PHARMACOLOGY The mechanism of action of methocarbamol in humans has not been established, but may be due to general central nervous system (CNS) depression. It has no direct action on the contractile mechanism of striated muscle, the motor end plate or the nerve fiber. Pharmacokinetics In healthy volunteers, the plasma clearance of methocarbamol ranges between 0.20 and 0.80 L/h/kg, the mean plasma elimination half-life ranges between 1 and 2 hours, and the plasma protein binding ranges between 46% and 50%. Methocarbamol is metabolized via dealkylation and hydroxylation. Conjugation of methocarbamol also is likely. Essentially all methocarbamol metabolites are eliminated in the urine. Small amounts of unchanged methocarbamol also are excreted in the urine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-011/S-070 NDA 11-011/S-071 Page 4 Special populations Elderly The mean (± SD) elimination half-life of methocarbamol in elderly healthy volunteers (mean (± SD) age, 69 (± 4) years) was slightly prolonged compared to a younger (mean (± SD) age, 53.3 (± 8.8) years), healthy population (1.5 (± 0.4) hours versus 1.1 (± 0.27) hours, respectively). The fraction of bound methocarbamol was slightly decreased in the elderly versus younger volunteers (41 to 43% versus 46 to 50%, respectively). Renally impaired The clearance of methocarbamol in 8 renally-impaired patients on maintenance hemodialysis was reduced about 40% compared to 17 normal subjects, although the mean (± SD) elimination half-life in these two groups was similar: 1.2 (± 0.6) versus 1.1 (± 0.3) hours, respectively. Hepatically impaired In 8 patients with cirrhosis secondary to alcohol abuse, the mean total clearance of methocarbamol was reduced approximately 70% compared to that obtained in 8 age- and weight-matched normal subjects. The mean (± SD) elimination half-life in the cirrhotic patients and the normal subjects was 3.38 (± 1.62) hours and 1.11 (± 0.27) hours, respectively. The percent of methocarbamol bound to plasma proteins was decreased to approximately 40 to 45% compared to 46 to 50% in the normal subjects. INDICATIONS AND USAGE robaxin® and robaxin®-750 are indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions. The mode of action of methocarbamol has not been clearly identified, but may be related to its sedative properties. Methocarbamol does not directly relax tense skeletal muscles in man. CONTRAINDICATIONS robaxin® and robaxin®-750 are contraindicated in patients hypersensitive to methocarbamol or to any of the tablet components. WARNINGS Since methocarbamol may possess a general CNS depressant effect, patients receiving robaxin® or robaxin®-750 should be cautioned about combined effects with alcohol and other CNS depressants. Safe use of robaxin® and robaxin®-750 has not been established with regard to possible adverse effects upon fetal development. There have been reports of fetal and congenital abnormalities following in utero exposure to methocarbamol. Therefore, robaxin® and robaxin®-750 should not be used in women who are or may become pregnant and particularly during early pregnancy unless in the judgment of the physician the potential benefits outweigh the possible hazards (see PRECAUTIONS, Pregnancy). Use In Activities Requiring Mental Alertness Methocarbamol may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle. Patients should be cautioned about operating machinery, including automobiles, until they are reasonably certain that methocarbamol therapy does not adversely affect their ability to engage in such activities. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-011/S-070 NDA 11-011/S-071 Page 5 PRECAUTIONS Information for Patients Patients should be cautioned that methocarbamol may cause drowsiness or dizziness, which may impair their ability to operate motor vehicles or machinery. Because methocarbamol may possess a general CNS-depressant effect, patients should be cautioned about combined effects with alcohol and other CNS depressants. Drug Interactions See WARNINGS and PRECAUTIONS for interaction with CNS drugs and alcohol. Methocarbamol may inhibit the effect of pyridostigmine bromide. Therefore, methocarbamol should be used with caution in patients with myasthenia gravis receiving anticholinesterase agents. Drug/Laboratory Test Interactions Methocarbamol may cause a color interference in certain screening tests for 5-hydroxyindoleacetic acid (5-HIAA) using nitrosonaphthol reagent and in screening tests for urinary vanillylmandelic acid (VMA) using the Gitlow method. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies to evaluate the carcinogenic potential of methocarbamol have not been performed. No studies have been conducted to assess the effect of methocarbamol on mutagenesis or its potential to impair fertility. Pregnancy Teratogenic Effects – Pregnancy Category C Animal reproduction studies have not been conducted with methocarbamol. It is also not known whether methocarbamol can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. robaxin® and robaxin®-750 should be given to a pregnant woman only if clearly needed. Safe use of robaxin® and robaxin®-750 has not been established with regard to possible adverse effects upon fetal development. There have been reports of fetal and congenital abnormalities following in utero exposure to methocarbamol. Therefore, robaxin® and robaxin®-750 should not be used in women who are or may become pregnant and particularly during early pregnancy unless in the judgment of the physician the potential benefits outweigh the possible hazards (see WARNINGS). Nursing Mothers Methocarbamol and/or its metabolites are excreted in the milk of dogs; however, it is not known whether methocarbamol or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when robaxin® or robaxin®-750 is administered to a nursing woman. Pediatric Use Safety and effectiveness of robaxin® and robaxin®-750 in pediatric patients below the age of 16 have not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-011/S-070 NDA 11-011/S-071 Page 6 ADVERSE REACTIONS Adverse reactions reported coincident with the administration of methocarbamol include: Body as a whole: Anaphylactic reaction, angioneurotic edema, fever, headache Cardiovascular system: Bradycardia, flushing, hypotension, syncope, thrombophlebitis Digestive system: Dyspepsia, jaundice (including cholestatic jaundice), nausea and vomiting Hemic and lymphatic system: Leukopenia Immune system: Hypersensitivity reactions Nervous system: Amnesia, confusion, Diplopia, dizziness or lightheadedness, drowsiness, insomnia, mild muscular incoordination, nystagmus, sedation, seizures (including grand mal), vertigo Skin and special senses: Blurred vision, conjunctivitis, nasal congestion, metallic taste, pruritus, rash, urticaria OVERDOSAGE Limited information is available on the acute toxicity of methocarbamol. Overdose of methocarbamol is frequently in conjunction with alcohol or other CNS depressants and includes the following symptoms: nausea, drowsiness, blurred vision, hypotension, seizures, and coma. In post-marketing experience, deaths have been reported with an overdose of methocarbamol alone or in the presence of other CNS depressants, alcohol or psychotropic drugs. Treatment Management of overdose includes symptomatic and supportive treatment. Supportive measures include maintenance of an adequate airway, monitoring urinary output and vital signs, and administration of intravenous fluids if necessary. The usefulness of hemodialysis in managing overdose is unknown. DOSAGE AND ADMINISTRATION robaxin® (methocarbamol), 500 mg – Adults: Initial dosage: 3 tablets q.i.d. Maintenance dosage: 2 tablets q.i.d. robaxin®-750 (methocarbamol), 750 mg – Adults: Initial dosage: 2 tablets q.i.d. Maintenance dosage: 1 tablet q.4h. or 2 tablets t.i.d. Six grams a day are recommended for the first 48 to 72 hours of treatment. (For severe conditions 8 grams a day may be administered). Thereafter, the dosage can usually be reduced to approximately 4 grams a day. HOW SUPPLIED robaxin® (methocarbamol tablets, USP) 500 mg tablets are light orange, round, film-coated tablets engraved with ROBAXIN 500 on the unscored side and SP above the score on the other side. They are supplied as follows: Bottles of 100 NDC 0091-7429-63 robaxin®-750 (methocarbamol tablets, USP) 750 mg tablets are orange, capsule-shaped, film-coated tablets engraved with ROBAXIN 750 on one side and SP on the other. They are supplied as follows: Bottles of 100 NDC 0091-7449-63 Bottles of 500 NDC 0091-7449-70 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-011/S-070 NDA 11-011/S-071 Page 7 Store at controlled room temperature, between 20°C and 25°C (68°F and 77°F). Dispense in tight container. Manufactured for: Schwarz Pharma, Inc. Milwaukee, WI 53201, USA By: Pharmaceutical Division A.H. Robins Company Richmond, VA 23220, USA Printed in USA PC4449B Rev. 02/03 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------------------- --------------------- ( This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. /s/ Lee Simon 5/1/03 07:16:30 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:43.752368	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/011011Orig1s070s071lbl.pdf', 'application_number': 11011, 'submission_type': 'SUPPL ', 'submission_number': 70}
10,755	NDA 10-926/S-030 Page 3 Phenergan (promethazine HCI) Tablets and Suppositories only DESCRIPTION Each tablet of Phenergan contains 12.5 mg, 25 mg, or 50 mg promethazine HCl. The inactive ingredients present are lactose, magnesium stearate, and methylcellulose. Each dosage strength also contains the following: 12.5 mg−FD&C Yellow 6 and saccharin sodium; 25 mg−saccharin sodium; 50 mg−FD&C Red 40. Each rectal suppository of Phenergan contains 12.5 mg, 25 mg, or 50 mg promethazine HCl with ascorbyl palmitate, silicon dioxide, white wax, and cocoa butter. Phenergan Suppositories are for rectal administration only. Promethazine HCl is a racemic compound; the empirical formula is C17H20N2S•HCl and its molecular weight is 320.88. Promethazine HCl, a phenothiazine derivative, is designated chemically as 10H-Phenothiazine-10-ethanamine, N,N,α-trimethyl-, monohydrochloride, (±)- with the following structural formula: Promethazine HCl occurs as a white to faint yellow, practically odorless, crystalline powder which slowly oxidizes and turns blue on prolonged exposure to air. It is freely soluble in water and soluble in alcohol. CLINICAL PHARMACOLOGY Promethazine is a phenothiazine derivative which differs structurally from the antipsychotic phenothiazines by the presence of a branched side chain and no ring substitution. It is thought that this configuration is responsible for its relative lack (1/10 that of chlorpromazine) of dopamine antagonist properties. Promethazine is an H1 receptor blocking agent. In addition to its antihistaminic action, it provides clinically useful sedative and antiemetic effects. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-926/S-030 Page 4 Promethazine is well absorbed from the gastrointestinal tract. Clinical effects are apparent within 20 minutes after oral administration and generally last four to six hours, although they may persist as long as 12 hours. Promethazine is metabolized by the liver to a variety of compounds; the sulfoxides of promethazine and N-demethylpromethazine are the predominant metabolites appearing in the urine. INDICATIONS AND USAGE Phenergan, either orally or by suppository, is useful for: Perennial and seasonal allergic rhinitis. Vasomotor rhinitis. Allergic conjunctivitis due to inhalant allergens and foods. Mild, uncomplicated allergic skin manifestations of urticaria and angioedema. Amelioration of allergic reactions to blood or plasma. Dermographism. Anaphylactic reactions, as adjunctive therapy to epinephrine and other standard measures, after the acute manifestations have been controlled. Preoperative, postoperative, or obstetric sedation. Prevention and control of nausea and vomiting associated with certain types of anesthesia and surgery. Therapy adjunctive to meperidine or other analgesics for control of post-operative pain. Sedation in both children and adults, as well as relief of apprehension and production of light sleep from which the patient can be easily aroused. Active and prophylactic treatment of motion sickness. Antiemetic therapy in postoperative patients. CONTRAINDICATIONS Phenergan Tablets and Suppositories are contraindicated for use in pediatric patients less than two years of age. Phenergan Tablets and Suppositories are contraindicated in comatose states, and in individuals known to be hypersensitive or to have had an idiosyncratic reaction to promethazine or to other phenothiazines. Antihistamines are contraindicated for use in the treatment of lower respiratory tract symptoms including asthma. WARNINGS PHENERGAN SHOULD NOT BE USED IN PEDIATRIC PATIENTS LESS THAN 2 YEARS OF AGE BECAUSE OF THE POTENTIAL FOR FATAL RESPIRATORY DEPRESSION. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-926/S-030 Page 5 POSTMARKETING CASES OF RESPIRATORY DEPRESSION, INCLUDING FATALITIES, HAVE BEEN REPORTED WITH USE OF PHENERGAN IN PEDIATRIC PATIENTS LESS THAN 2 YEARS OF AGE. A WIDE RANGE OF WEIGHT-BASED DOSES OF PHENERGAN HAVE RESULTED IN RESPIRATORY DEPRESSION IN THESE PATIENTS. CAUTION SHOULD BE EXERCISED WHEN ADMINISTERING PHENERGAN TO PEDIATRIC PATIENTS 2 YEARS OF AGE AND OLDER. IT IS RECOMMENDED THAT THE LOWEST EFFECTIVE DOSE OF PHENERGAN BE USED IN PEDIATRIC PATIENTS 2 YEARS OF AGE AND OLDER AND CONCOMITANT ADMINISTRATION OF OTHER DRUGS WITH RESPIRATORY DEPRESSANT EFFECTS BE AVOIDED. CNS Depression Phenergan Tablets and Suppositories may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The impairment may be amplified by concomitant use of other central-nervous-system depressants such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore such agents should either be eliminated or given in reduced dosage in the presence of promethazine HCl (see PRECAUTIONS−Information for Patients and Drug Interactions). Respiratory Depression Phenergan Tablets and Suppositories may lead to potentially fatal respiratory depression. Use of Phenergan Tablets and Suppositories in patients with compromised respiratory function (e.g., COPD, sleep apnea) should be avoided. Lower Seizure Threshold Phenergan Tablets and Suppositories may lower seizure threshold. It should be used with caution in persons with seizure disorders or in persons who are using concomitant medications, such as narcotics or local anesthetics, which may also affect seizure threshold. Bone-Marrow Depression Phenergan Tablets and Suppositories should be used with caution in patients with bone-marrow depression. Leukopenia and agranulocytosis have been reported, usually when Phenergan (promethazine HCl) has been used in association with other known marrow-toxic agents. Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with promethazine HCl alone or in combination with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias). The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g. pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-926/S-030 Page 6 The management of NMS should include 1) immediate discontinuation of promethazine HCl, antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. Since recurrences of NMS have been reported with phenothiazines, the reintroduction of promethazine HCl should be carefully considered. Use in Pediatric Patients PHENERGAN TABLETS AND SUPPOSITORIES ARE CONTRAINDICATED FOR USE IN PEDIATRIC PATIENTS LESS THAN TWO YEARS OF AGE. CAUTION SHOULD BE EXERCISED WHEN ADMINISTERING PHENERGAN TABLETS AND SUPPOSITORIES TO PEDIATRIC PATIENTS 2 YEARS OF AGE AND OLDER BECAUSE OF THE POTENTIAL FOR FATAL RESPIRATORY DEPRESSION. RESPIRATORY DEPRESSION AND APNEA, SOMETIMES ASSOCIATED WITH DEATH, ARE STRONGLY ASSOCIATED WITH PROMETHAZINE PRODUCTS AND ARE NOT DIRECTLY RELATED TO INDIVIDUALIZED WEIGHT-BASED DOSING, WHICH MIGHT OTHERWISE PERMIT SAFE ADMINISTRATION. CONCOMITANT ADMINISTRATION OF PROMETHAZINE PRODUCTS WITH OTHER RESPIRATORY DEPRESSANTS HAS AN ASSOCIATION WITH RESPIRATORY DEPRESSION, AND SOMETIMES DEATH, IN PEDIATRIC PATIENTS. ANTIEMETICS ARE NOT RECOMMENDED FOR TREATMENT OF UNCOMPLICATED VOMITING IN PEDIATRIC PATIENTS, AND THEIR USE SHOULD BE LIMITED TO PROLONGED VOMITING OF KNOWN ETIOLOGY. THE EXTRAPYRAMIDAL SYMPTOMS WHICH CAN OCCUR SECONDARY TO PHENERGAN TABLETS AND SUPPOSITORIES ADMINISTRATION MAY BE CONFUSED WITH THE CNS SIGNS OF UNDIAGNOSED PRIMARY DISEASE, e.g., ENCEPHALOPATHY OR REYE’S SYNDROME. THE USE OF PHENERGAN TABLETS AND SUPPOSITORIES SHOULD BE AVOIDED IN PEDIATRIC PATIENTS WHOSE SIGNS AND SYMPTOMS MAY SUGGEST REYE’S SYNDROME OR OTHER HEPATIC DISEASES. Excessively large dosages of antihistamines, including Phenergan Tablets and Suppositories, in pediatric patients may cause sudden death (see OVERDOSAGE). Hallucinations and convulsions have occurred with therapeutic doses and overdoses of Phenergan in pediatric patients. In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonias with the use of promethazine HCl. Other Considerations Administration of promethazine HCl has been associated with reported cholestatic jaundice. PRECAUTIONS General Drugs having anticholinergic properties should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, and bladder-neck obstruction. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-926/S-030 Page 7 Phenergan Tablets and Suppositories should be used cautiously in persons with cardiovascular disease or with impairment of liver function. Information for Patients Phenergan Tablets and Suppositories may cause marked drowsiness or impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The use of alcohol or other central-nervous-system depressants such as sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers, may enhance impairment (see WARNINGS−CNS Depression and PRECAUTIONS−Drug Interactions). Pediatric patients should be supervised to avoid potential harm in bike riding or in other hazardous activities. Patients should be advised to report any involuntary muscle movements. Avoid prolonged exposure to the sun. Drug Interactions CNS Depressants - Phenergan Tablets and Suppositories may increase, prolong, or intensify the sedative action of other central-nervous-system depressants, such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore, such agents should be avoided or administered in reduced dosage to patients receiving promethazine HCl. When given concomitantly with Phenergan Tablets and Suppositories, the dose of barbiturates should be reduced by at least one-half, and the dose of narcotics should be reduced by one-quarter to one-half. Dosage must be individualized. Excessive amounts of promethazine HCl relative to a narcotic may lead to restlessness and motor hyperactivity in the patient with pain; these symptoms usually disappear with adequate control of the pain. Epinephrine - Because of the potential for Phenergan to reverse epinephrine’s vasopressor effect, epinephrine should NOT be used to treat hypotension associated with Phenergan Tablets and Suppositories overdose. Anticholinergics - Concomitant use of other agents with anticholinergic properties should be undertaken with caution. Monoamine Oxidase Inhibitors (MAOI) - Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly. This possibility should be considered with Phenergan Tablets and Suppositories. Drug/Laboratory Test Interactions The following laboratory tests may be affected in patients who are receiving therapy with promethazine HCl: Pregnancy Tests Diagnostic pregnancy tests based on immunological reactions between HCG and anti-HCG may result in false-negative or false-positive interpretations. Glucose Tolerance Test An increase in blood glucose has been reported in patients receiving promethazine HCl. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-926/S-030 Page 8 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to assess the carcinogenic potential of promethazine, nor are there other animal or human data concerning carcinogenicity, mutagenicity, or impairment of fertility with this drug. Promethazine was nonmutagenic in the Salmonella test system of Ames. Pregnancy Teratogenic Effects–Pregnancy Category C Teratogenic effects have not been demonstrated in rat-feeding studies at doses of 6.25 and 12.5 mg/kg of promethazine HCl. These doses are from approximately 2.1 to 4.2 times the maximum recommended total daily dose of promethazine for a 50-kg subject, depending upon the indication for which the drug is prescribed. Daily doses of 25 mg/kg intraperitoneally have been found to produce fetal mortality in rats. Specific studies to test the action of the drug on parturition, lactation, and development of the animal neonate were not done, but a general preliminary study in rats indicated no effect on these parameters. Although antihistamines have been found to produce fetal mortality in rodents, the pharmacological effects of histamine in the rodent do not parallel those in man. There are no adequate and well- controlled studies of Phenergan Tablets and Suppositories in pregnant women. Phenergan (promethazine HCl) Tablets and Suppositories should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Phenergan Tablets and Suppositories administered to a pregnant woman within two weeks of delivery may inhibit platelet aggregation in the newborn. Labor and Delivery Promethazine HCl may be used alone or as an adjunct to narcotic analgesics during labor (see DOSAGE AND ADMINISTRATION). Limited data suggest that use of Phenergan during labor and delivery does not have an appreciable effect on the duration of labor or delivery and does not increase the risk of need for intervention in the newborn. The effect on later growth and development of the newborn is unknown. (See also Nonteratogenic Effects.) Nursing Mothers It is not known whether promethazine HCl is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Phenergan Tablets and Suppositories, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use PHENERGAN TABLETS AND SUPPOSITORIES ARE CONTRAINDICATED FOR USE IN PEDIATRIC PATIENTS LESS THAN TWO YEARS OF AGE (see WARNINGS–Black Box Warning and Use in Pediatric Patients). Phenergan Tablets and Suppositories should be used with caution in pediatric patients 2 years of age and older (see WARNINGS−Use in Pediatric Patients). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-926/S-030 Page 9 Geriatric Use Clinical studies of Phenergan formulations did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of Phenergan Tablets and Suppositories and observed closely. ADVERSE REACTIONS Central Nervous System Drowsiness is the most prominent CNS effect of this drug. Sedation, somnolence, blurred vision, dizziness; confusion, disorientation, and extrapyramidal symptoms such as oculogyric crisis, torticollis, and tongue protrusion; lassitude, tinnitus, incoordination, fatigue, euphoria, nervousness, diplopia, insomnia, tremors, convulsive seizures, excitation, catatonic-like states, hysteria. Hallucinations have also been reported. Cardiovascular−Increased or decreased blood pressure, tachycardia, bradycardia, faintness. Dermatologic−Dermatitis, photosensitivity, urticaria. Hematologic−Leukopenia, thrombocytopenia, thrombocytopenic purpura, agranulocytosis. Gastrointestinal−Dry mouth, nausea, vomiting, jaundice. Respiratory−Asthma, nasal stuffiness, respiratory depression (potentially fatal) and apnea (potentially fatal). (See WARNINGS−Respiratory Depression.) Other−Angioneurotic edema. Neuroleptic malignant syndrome (potentially fatal) has also been reported. (See WARNINGS−Neuroleptic Malignant Syndrome.) Paradoxical Reactions Hyperexcitability and abnormal movements have been reported in patients following a single administration of promethazine HCl. Consideration should be given to the discontinuation of promethazine HCl and to the use of other drugs if these reactions occur. Respiratory depression, nightmares, delirium, and agitated behavior have also been reported in some of these patients. OVERDOSAGE Signs and symptoms of overdosage with promethazine HCl range from mild depression of the central nervous system and cardiovascular system to profound hypotension, respiratory depression, unconsciousness, and sudden death. Other reported reactions include hyperreflexia, hypertonia, ataxia, athetosis, and extensor-plantar reflexes (Babinski reflex). Stimulation may be evident, especially in children and geriatric patients. Convulsions may rarely occur. A paradoxical-type reaction has been reported in children receiving single doses of 75 mg to 125 mg orally, characterized by hyperexcitability and nightmares. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-926/S-030 Page 10 Atropine-like signs and symptoms−dry mouth, fixed, dilated pupils, flushing, as well as gastrointestinal symptoms−may occur. Treatment Treatment of overdosage is essentially symptomatic and supportive. Only in cases of extreme overdosage or individual sensitivity do vital signs, including respiration, pulse, blood pressure, temperature, and EKG, need to be monitored. Activated charcoal orally or by lavage may be given, or sodium or magnesium sulfate orally as a cathartic. Attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Diazepam may be used to control convulsions. Acidosis and electrolyte losses should be corrected. Note that any depressant effects of promethazine HCl are not reversed by naloxone. Avoid analeptics which may cause convulsions. The treatment of choice for resulting hypotension is administration of intravenous fluids, accompanied by repositioning if indicated. In the event that vasopressors are considered for the management of severe hypotension which does not respond to intravenous fluids and repositioning, the administration of norepinephrine or phenylephrine should be considered. EPINEPHRINE SHOULD NOT BE USED, since its use in patients with partial adrenergic blockade may further lower the blood pressure. Extrapyramidal reactions may be treated with anticholinergic antiparkinsonian agents, diphenhydramine, or barbiturates. Oxygen may also be administered. Limited experience with dialysis indicates that it is not helpful. DOSAGE AND ADMINISTRATION Phenergan Tablets and Phenergan Rectal Suppositories are contraindicated for children under 2 years of age (see WARNINGS–Black Box Warning and Use in Pediatric Patients). Phenergan Suppositories are for rectal administration only. Allergy The average oral dose is 25 mg taken before retiring; however, 12.5 mg may be taken before meals and on retiring, if necessary. Single 25-mg doses at bedtime or 6.25 to 12.5 mg taken three times daily will usually suffice. After initiation of treatment in children or adults, dosage should be adjusted to the smallest amount adequate to relieve symptoms. The administration of promethazine HCl in 25-mg doses will control minor transfusion reactions of an allergic nature. Motion Sickness The average adult dose is 25 mg taken twice daily. The initial dose should be taken one-half to one hour before anticipated travel and be repeated 8 to 12 hours later, if necessary. On succeeding days of travel, it is recommended that 25 mg be given on arising and again before the evening meal. For children, Phenergan Tablets, Syrup, or Rectal Suppositories, 12.5 to 25 mg, twice daily, may be administered. Nausea and Vomiting Antiemetics should not be used in vomiting of unknown etiology in children and adolescents (see WARNINGS-Use in Pediatric Patients). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-926/S-030 Page 11 The average effective dose of Phenergan for the active therapy of nausea and vomiting in children or adults is 25 mg. When oral medication cannot be tolerated, the dose should be given parenterally (cf. Phenergan Injection) or by rectal suppository. 12.5- to 25-mg doses may be repeated, as necessary, at 4- to 6-hour intervals. For nausea and vomiting in children, the usual dose is 0.5 mg per pound of body weight, and the dose should be adjusted to the age and weight of the patient and the severity of the condition being treated. For prophylaxis of nausea and vomiting, as during surgery and the postoperative period, the average dose is 25 mg repeated at 4- to 6-hour intervals, as necessary. Sedation This product relieves apprehension and induces a quiet sleep from which the patient can be easily aroused. Administration of 12.5 to 25 mg Phenergan by the oral route or by rectal suppository at bedtime will provide sedation in children. Adults usually require 25 to 50 mg for nighttime, presurgical, or obstetrical sedation. Pre- and Postoperative Use Phenergan in 12.5- to 25-mg doses for children and 50-mg doses for adults the night before surgery relieves apprehension and produces a quiet sleep. For preoperative medication, children require doses of 0.5 mg per pound of body weight in combination with an appropriately reduced dose of narcotic or barbiturate and the appropriate dose of an atropine-like drug. Usual adult dosage is 50 mg Phenergan with an appropriately reduced dose of narcotic or barbiturate and the required amount of a belladonna alkaloid. Postoperative sedation and adjunctive use with analgesics may be obtained by the administration of 12.5 to 25 mg in children and 25- to 50-mg doses in adults. Phenergan Tablets and Phenergan Rectal Suppositories are contraindicated for children under 2 years of age. HOW SUPPLIED Phenergan (promethazine HCl) Tablets are available as follows: 12.5 mg, orange tablet with “WYETH” on one side and “19” on the scored reverse side. NDC 0008-0019-01, bottle of 100 tablets. 25 mg, white tablet with “WYETH” and “27” on one side and scored on the reverse side. NDC 0008-0027-02, bottle of 100 tablets. NDC 0008-0027-07, Redipak carton of 100 tablets (10 blister strips of 10). 50 mg, pink tablet with “WYETH” on one side and “227” on the other side. NDC 0008-0227-01, bottle of 100 tablets. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 10-926/S-030 Page 12 Keep tightly closed. Store at controlled room temperature 20º to 25ºC (68º to 77ºF). Protect from light. Dispense in light-resistant, tight container. Use carton to protect contents from light. Phenergan (promethazine HCl) Rectal Suppositories are available in boxes of 12 as follows: 12.5 mg, ivory, torpedo-shaped suppository wrapped in copper-colored foil, NDC 0008-0498-01. 25 mg, ivory, torpedo-shaped suppository wrapped in light-green foil, NDC 0008-0212-01. 50 mg, ivory, torpedo-shaped suppository wrapped in blue foil, NDC 0008-0229-01. Store refrigerated between 2º-8ºC (36º-46ºF). Dispense in well-closed container. Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 --------------- - ------ ------------ (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:43.759942	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/10926s030lbl.pdf', 'application_number': 10926, 'submission_type': 'SUPPL ', 'submission_number': 30}
10,759	Kayexalate® SODIUM POLYSTYRENE SULFONATE, USP Cation-Exchange Resin DESCRIPTION KAYEXALATE, brand of sodium polystyrene sulfonate is a benzene, diethenyl-polymer, with ethenylbenzene, sulfonated, sodium salt and has the following structural formula: Structural Formula The drug is a cream to light brown finely ground, powdered form of sodium polystyrene sulfonate, a cation-exchange resin prepared in the sodium phase with an in vitro exchange capacity of approximately 3.1 mEq (in vivo approximately 1 mEq) of potassium per gram. The sodium content is approximately 100 mg (4.1 mEq) per gram of the drug. It can be administered orally or in an enema. CLINICAL PHARMACOLOGY As the resin passes along the intestine or is retained in the colon after administration by enema, the sodium ions are partially released and are replaced by potassium ions. For the most part, this action occurs in the large intestine, which excretes potassium ions to a greater degree than does the small intestine. The efficiency of this process is limited and unpredictably variable. It commonly approximates the order of 33 percent but the range is so large that definitive indices of electrolyte balance must be clearly monitored. Metabolic data are unavailable. INDICATION AND USAGE KAYEXALATE is indicated for the treatment of hyperkalemia. CONTRAINDICATIONS KAYEXALATE is contraindicated in the following conditions: patients with hypokalemia, patients with a history of hypersensitivity to polystyrene sulfonate resins, obstructive bowel disease, neonates with reduced gut motility (postoperatively or drug induced) and oral administration in neonates (see PRECAUTIONS). WARNINGS Colonic Necrosis: Cases of colonic necrosis and other serious gastrointestinal adverse events (bleeding, ischemic colitis, perforation) have been reported in association with KAYEXALATE use. The majority of these cases reported the concomitant use of sorbitol. Risk factors for 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda gastrointestinal adverse events were present in many of the cases including prematurity, history of intestinal disease or surgery, hypovolemia, and renal insufficiency and failure. Concomitant administration of sorbitol is not recommended (see PRECAUTIONS, Drug Interactions). Alternative Therapy in Severe Hyperkalemia: Since effective lowering of serum potassium with KAYEXALATE may take hours to days, treatment with this drug alone may be insufficient to rapidly correct severe hyperkalemia associated with states of rapid tissue breakdown (e.g., burns and renal failure) or hyperkalemia so marked as to constitute a medical emergency. Therefore, other definitive measures, including dialysis, should always be considered and may be imperative. Hypokalemia: Serious potassium deficiency can occur from therapy with KAYEXALATE. The effect must be carefully controlled by frequent serum potassium determinations within each 24 hour period. Since intracellular potassium deficiency is not always reflected by serum potassium levels, the level at which treatment with KAYEXALATE should be discontinued must be determined individually for each patient. Important aids in making this determination are the patient’s clinical condition and electrocardiogram. Early clinical signs of severe hypokalemia include a pattern of irritable confusion and delayed thought processes. Electrocardiographically, severe hypokalemia is often associated with a lengthened Q-T interval, widening, flattening, or inversion of the T wave, and prominent U waves. Also, cardiac arrhythmias may occur, such as premature atrial, nodal, and ventricular contractions, and supraventricular and ventricular tachycardias. The toxic effects of digitalis are likely to be exaggerated. Marked hypokalemia can also be manifested by severe muscle weakness, at times extending into frank paralysis. Electrolyte Disturbances: Like all cation-exchange resins, KAYEXALATE is not totally selective (for potassium) in its actions, and small amounts of other cations such as magnesium and calcium can also be lost during treatment. Accordingly, patients receiving KAYEXALATE should be monitored for all applicable electrolyte disturbances. Systemic Alkalosis: Systemic alkalosis has been reported after cation-exchange resins were administered orally in combination with nonabsorbable cation-donating antacids and laxatives such as magnesium hydroxide and aluminum carbonate. Magnesium hydroxide should not be administered with KAYEXALATE. One case of grand mal seizure has been reported in a patient with chronic hypocalcemia of renal failure who was given KAYEXALATE with magnesium hydroxide as laxative. (See PRECAUTIONS, Drug Interactions.) PRECAUTIONS Caution is advised when KAYEXALATE is administered to patients who cannot tolerate even a small increase in sodium loads (i.e., severe congestive heart failure, severe hypertension, or marked edema). In such instances compensatory restriction of sodium intake from other sources may be indicated. In the event of clinically significant constipation, treatment with KAYEXALATE should be discontinued until normal bowel motion is resumed. Magnesium-containing laxatives or sorbitol should not be used (see PRECAUTIONS, Drug Interactions). 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Antacids: The simultaneous oral administration of KAYEXALATE with nonabsorbable cation-donating antacids and laxatives may reduce the resin’s potassium exchange capability. Non-absorbable cation-donating antacids and laxatives: Systemic alkalosis has been reported after cation-exchange resins were administered orally in combination with nonabsorbable cation-donating antacids and laxatives such as magnesium hydroxide and aluminum carbonate. Magnesium hydroxide should not be administered with KAYEXALATE. One case of grand mal seizure has been reported in a patient with chronic hypocalcemia of renal failure who was given KAYEXALATE with magnesium hydroxide as a laxative. Intestinal obstruction due to concretions of aluminum hydroxide when used in combination with KAYEXALATE has been reported. Digitalis: The toxic effects of digitalis on the heart, especially various ventricular arrhythmias and A-V nodal dissociation, are likely to be exaggerated by hypokalemia, even in the face of serum digoxin concentrations in the “normal range”. (See WARNINGS.) Sorbitol: Concomitant use of Sorbitol with KAYEXALATE has been implicated in cases of colonic necrosis. Therefore, concomitant administration is not recommended. (See WARNINGS.) Lithium: KAYEXALATE may decrease absorption of lithium. Thyroxine: KAYEXALATE may decrease absorption of thyroxine. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies have not been performed. Pregnancy Category C Animal reproduction studies have not been conducted with KAYEXALATE. It is also not known whether KAYEXALATE can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. KAYEXALATE should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when KAYEXALATE is administered to a nursing woman. Pediatric Use The effectiveness of KAYEXALATE in pediatric patients has not been established. In neonates, KAYEXALATE should not be given by the oral route. In both children and neonates particular care should be observed with rectal administration, as excessive dosage or inadequate dilution could result in impaction of the resin. Due to the risk of digestive hemorrhage or colonic necrosis, particular care should be observed in premature infants or low birth weight infants. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS KAYEXALATE may cause some degree of gastric irritation. Anorexia, nausea, vomiting, and constipation may occur especially if high doses are given. Also, hypokalemia, hypocalcemia, and significant sodium retention, and their related clinical manifestations, may occur (see WARNINGS). Occasionally diarrhea develops. Large doses in elderly individuals may cause fecal impaction (see PRECAUTIONS). Rare instances of colonic necrosis have been reported. Intestinal obstruction due to concretions of aluminum hydroxide, when used in combination with KAYEXALATE, has been reported. The following events have been reported from worldwide post marketing experience: • Fecal impaction following rectal administration, particularly in children; • Gastrointestinal concretions (bezoars) following oral administration; • Gastrointestinal tract ulceration or necrosis which could lead to intestinal perforation; and, • Rare cases of acute bronchitis and/or broncho-pneumonia associated with inhalation of particles of polystyrene sulfonate. OVERDOSAGE Overdosage may result in electrolyte disturbances including hypokalemia, hypocalcemia, and hypomagnesemia. Biochemical disturbances resulting from overdosage may give rise to clinical signs and symptoms of hypokalemia, including: irritability, confusion, delayed thought processes, muscle weakness, hyporeflexia, which may progress to frank paralysis and/or apnea. Tetany may occur. Electrocardiographic changes may be consistent with hypokalemia or hypocalcemia; cardiac arrhythmias may occur. Appropriate measures should be taken to correct serum electrolytes (potassium, calcium, magnesium), and the resin should be removed from the alimentary tract by appropriate use of laxatives or enemas. DOSAGE AND ADMINISTRATION Suspension of this drug should be freshly prepared and not stored beyond 24 hours. The average daily adult dose of the resin is 15 g to 60 g. This is best provided by administering 15 g (approximately 4 level teaspoons) of KAYEXALATE one to four times daily. One gram of KAYEXALATE contains 4.1 mEq of sodium; one level teaspoon contains approximately 3.5 g of KAYEXALATE and 15 mEq of sodium. (A heaping teaspoon may contain as much as 10 g to 12 g of KAYEXALATE.) Since the in vivo efficiency of sodium-potassium exchange resins is approximately 33 percent, about one third of the resin’s actual sodium content is being delivered to the body. In smaller children and infants, lower doses should be employed by using as a guide a rate of 1 mEq of potassium per gram of resin as the basis for calculation. Each dose should be given as a suspension in a small quantity of water or, for greater palatability, in syrup. The amount of fluid usually ranges from 20 mL to 100 mL, depending on the dose, or may be simply determined by allowing 3 mL to 4 mL per gram of resin. Healthcare professionals should follow full aspiration precautions when administering this product, such as placing and maintaining the patient in an upright position while the resin is being administered. The resin may be introduced into the stomach through a plastic tube and, if desired, mixed with a diet appropriate for a patient in renal failure. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The resin may also be given, although with less effective results, in an enema consisting (for adults) of 30 g to 50 g every six hours. Each dose is administered as a warm emulsion (at body temperature) in 100 mL of aqueous vehicle. The emulsion should be agitated gently during administration. The enema should be retained as long as possible and followed by a cleansing enema. After an initial cleansing enema, a soft, large size (French 28) rubber tube is inserted into the rectum for a distance of about 20 cm, with the tip well into the sigmoid colon, and taped in place. The resin is then suspended in the appropriate amount of aqueous vehicle at body temperature and introduced by gravity, while the particles are kept in suspension by stirring. The suspension is flushed with 50 mL or 100 mL of fluid, following which the tube is clamped and left in place. If back leakage occurs, the hips are elevated on pillows or a knee-chest position is taken temporarily. A somewhat thicker suspension may be used, but care should be taken that no paste is formed, because the latter has a greatly reduced exchange surface and will be particularly ineffective if deposited in the rectal ampulla. The suspension is kept in the sigmoid colon for several hours, if possible. Then, the colon is irrigated with nonsodium containing solution at body temperature in order to remove the resin. Two quarts of flushing solution may be necessary. The returns are drained constantly through a Y tube connection. While the use of sorbitol is not recommended, particular attention should be paid to this cleansing enema if sorbitol has been used. The intensity and duration of therapy depend upon the severity and resistance of hyperkalemia. KAYEXALATE should not be heated for to do so may alter the exchange properties of the resin. HOW SUPPLIED KAYEXALATE is available as a cream to light brown, finely ground powder in jars of 1 pound (453.6 g), NDC 0024-1075-01. Store at 25° C (77° F); excursions permitted to 15° - 30° C (59° - 86° F) [see USP Controlled Room Temperature] Rx Only Manufactured for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 Revised XXXXXXX © 2009 sanofi-aventis U.S. LLC 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:43.995483	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/011287s022lbl.pdf', 'application_number': 11287, 'submission_type': 'SUPPL ', 'submission_number': 22}
10,760	NDA 11-340/S-016 Page 3 CERUMENEX® EARDROPS (triethanolamine polypeptide oleate-condensate) This product contains dry natural rubber 064550-OC-001 IT00412 DESCRIPTION CERUMENEX Eardrops contain triethanolamine Polypeptide Oleate-Condensate (10%). Inactive Ingredients: Chlorobutanol 0.5%, Propylene Glycol and Water. Triethanolamine Polypeptide Oleate is a hygroscopic-miscible solution with low surface tension and optimal viscosity of 50-90 cps. It also has a slightly acid pH range (5.0-6.0) to approximate the surface of a normal ear canal. CLINICAL PHARMACOLOGY CERUMENEX Eardrops emulsify and disperse excess or impacted earwax. The triethanolamine polypeptide oleate, a surfactant, in a hygroscopic vehicle lyses cerumen to facilitate removal by subsequent water irrigation. INDICATIONS AND USAGE For removal of impacted cerumen prior to ear examination, otologic therapy and/or audiometry. CONTRAINDICATIONS Perforated tympanic membrane or otitis media is considered a contraindication to the use of this medication in the external ear canal. A history of hypersensitivity to CERUMENEX Eardrops or to any of its components is also a contraindication to the use of this medication. WARNINGS Discontinue promptly if sensitization or irritation occurs. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-340/SLR-016 Page 4 PRECAUTIONS General It is recommended that the following precautions be observed in prescribing and administration of this agent: 1. Extreme caution is indicated in patients with demonstrable dermatologic idiosyncrasies or with history of allergic reactions in general. 2. Exposure of the ear canal to the CERUMENEX Eardrops should be limited to 15-30 minutes. 3. When administering CERUMENEX Eardrops, care must be taken to avoid undue exposure of the skin outside the ear during the instillation and the flushing out of the medication. If the medication comes in contact with the skin, the area should be washed with soap and water. Use of proper technique (see DOSAGE AND ADMINSITRATION) will help avoid such undue exposure. 4. CERUMENEX Eardrops should be used only with caution in external otitis. Information for Patients 1. Patients should be cautioned to avoid placing the applicator tip into the ear canal. 2. Patients should be cautioned to gently flush the ear with lukewarm water. 3. Patients should be warned to use CERUMENEX Eardrops in ears only. Surrounding skin should be promptly rinsed of any excess drops. 4. Patients should be instructed not to leave CERUMENEX Eardrops in the ear for longer than 30 minutes. A second application may be made, if needed, but more frequent use must be indicated by the physician. 5. Patients must be instructed not to exceed the time of exposure, nor to use the medication more frequently than directed by the physician. 6. Patients should be advised to discontinue the use of the medication in case of a possible reaction and to consult their physician promptly. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of CERUMENEX Eardrops. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-340/SLR-016 Page 5 Pregnancy Teratogenic Effects: Pregnancy Category C. Animal reproduction studies have not yet been conducted with CERUMENEX Eardrops. It is also not known whether CERUMENEX Eardrops can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. CERUMENEX Eardrops should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when CERUMENEX Eardrops are administered to a nursing mother. Pediatric Use Safety and effectiveness in children have not been established. Geriatric Use No overall clinical differences in safety or effectiveness have been observed between the elderly and other adult patients. ADVERSE REACTIONS Clinical Reactions of Possible Allergic Origin Localized dermatitis reactions were reported in about 1% of 2,700 patients treated, ranging from a very mild erythema and pruritus of the external canal to a severe eczematoid reaction involving the external ear and periauricular tissue, generally with duration of 2-10 days. Other reactions which have been reported in connection with the use of CERUMENEX Eardrops include allergic contact dermatitis, skin ulcerations, burning and pain at the application site and skin rash. DOSAGE AND ADMINISTRATION 1. Fill ear canal with CERUMENEX Eardrops with the patient’s head tilted at a 45° angle. 2. Insert cotton plug and allow to remain 15-30 minutes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-340/SLR-016 Page 6 3. Then gently flush with lukewarm water, using a soft rubber syringe (avoid excessive pressure). Exposure of skin outside the ear to the drug should be avoided. The procedure may be repeated if the first application fails to clear the impaction. FOR EXTERNAL USE IN THE EAR ONLY HOW SUPPLIED CERUMENEX Eardrops (triethanolamine polypeptide oleate-condensate) are supplied in 6 mL (NDC 0034-5490-06) and 12 mL (NDC 0034-5490-12) bottles with a cellophane wrapped dropper. Store at controlled room temperature 15-30°C (59-86°F). Store in a dry place. The Purdue Frederick Company Stamford, CT 06901-3431 ©1991, 2001 November 13, 2001 064550-0C-001 IT00412 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Wiley Chambers 4/12/02 05:34:47 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:44.075973	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/11340s16lbl.pdf', 'application_number': 11340, 'submission_type': 'SUPPL ', 'submission_number': 16}
10,761	NDA 11-522 Confidential ADDERALL® CII Rx ONLY AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. ADMINISTRATION OF AMPHETAMINES FOR PROLONGED PERIODS OF TIME MAY LEAD TO DRUG DEPENDENCE AND MUST BE AVOIDED. PARTICULAR ATTENTION SHOULD BE PAID TO THE POSSIBILITY OF SUBJECTS OBTAINING AMPHETAMINES FOR NON-THERAPEUTIC USE OR DISTRIBUTION TO OTHERS, AND THE DRUGS SHOULD BE PRESCRIBED OR DISPENSED SPARINGLY. MISUSE OF AMPHETAMINE MAY CAUSE SUDDEN DEATH AND SERIOUS CARDIOVASCULAR ADVERSE EVENTS. DESCRIPTION: A single entity amphetamine product combining the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate and d, l-amphetamine aspartate monohydrate. EACH TABLET CONTAINS: 5 mg 7.5 mg 10 mg 12.5 mg 15 mg 20mg 30 mg Dextroamphetamine Saccharate 1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg 7.5 mg Amphetamine Aspartate Monohydrate1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg 7.5 mg Dextroamphetamine Sulfate USP 1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg 7.5 mg Amphetamine Sulfate USP 1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg 7.5 mg Total amphetamine base equivalence 3.13 mg 4.7 mg 6.3 mg 7.8 mg 9.4 mg 12.6 mg 18.8 mg Inactive Ingredients: lactitol, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate, and other ingredients. Colors: ADDERALL® 5 mg is a white to off-white tablet, which contains no color additives. ADDERALL® 7.5 mg and 10 mg contain FD & C Blue #1. ADDERALL® 12.5 mg, 15 mg, 20 mg and 30 mg contain FD & C Yellow #6 as a color additive. CLINICAL PHARMACOLOGY: Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. Peripheral actions include elevation of systolic and diastolic blood pressures and weak bronchodilator and respiratory stimulant action. There is neither specific evidence which clearly establishes the mechanism whereby amphetamine produces mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system. Pharmacokinetics ADDERALL® tablets contain d-amphetamine and l-amphetamine salts in the ratio of 3:1. Following administration of a single dose 10 or 30 mg of ADDERALL® to healthy volunteers under fasted conditions, peak plasma concentrations occurred approximately 3 hours post-dose for both d- amphetamine and l-amphetamine. The mean elimination half-life (t1/2 ) for d-amphetamine was shorter than the t1/2 of the l-isomer (9.77-11 hours vs. 11.5-13.8 hours). The PK parameters (Cmax, AUC0-inf) of d-and l-amphetamine increased approximately three-fold from 10 mg to 30 mg indicating dose-proportional pharmacokinetics. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-522 Confidential The effect of food on the bioavailability of ADDERALL® has not been studied. INDICATIONS: Attention Deficit Disorder with Hyperactivity: ADDERALL® is indicated as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate to severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted. In Narcolepsy CONTRAINDICATIONS: Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma. Agitated states. Patients with a history of drug abuse. During or within 14 days following the administration of monoamine oxidase inhibitors (hypertensive crises may result). WARNINGS: Psychosis: Clinical experience suggests that in psychotic children, administration of amphetamine may exacerbate symptoms of behavior disturbance and thought disorder. Long-Term Suppression of Growth: Data are inadequate to determine whether chronic administration of amphetamine may be associated with growth inhibition; therefore, growth should be monitored during treatment. Sudden Death and Pre-existing Structural Cardiac Abnormalities: Sudden death has been reported in association with amphetamine treatment at usual doses in children with structural cardiac abnormalities. Adderall generally should not be used in children or adults with structural cardiac abnormalities. Usage in Nursing Mothers: Amphetamines are excreted in human milk. Mothers taking amphetamines should be advised to refrain from nursing. PRECAUTIONS: General: The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage. Hypertension: Caution is to be exercised in prescribing amphetamines for patients with even mild hypertension. Blood pressure and pulse should be monitored at appropriate intervals in patients taking Adderall, especially patients with hypertension. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-522 Confidential Information for Patients: Amphetamines may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or vehicles; the patient should therefore be cautioned accordingly. Drug Interactions: Acidifying agents -Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid HCl, ascorbic acid, fruit juices, etc.) lower absorption of amphetamines. Urinary acidifying agents -(ammonium chloride, sodium acid phosphate, etc.) Increase the concentration of the ionized species of the amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines. Adrenergic blocker -Adrenergic blockers are inhibited by amphetamines. Alkalinizing agents -Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) increase absorption of amphetamines. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase blood levels and therefore potentiate the actions of amphetamines. Antidepressants, tricyclic -Amphetamines may enhance the activity of tricyclic or sympathomimetic agents; d-amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. MAO inhibitors -MAOI antidepressants, as well as a metabolite of furazolidone, slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings; this can cause headaches and other signs of hypertensive crisis. A variety of neurological toxic effects and malignant hyperpyrexia can occur, sometimes with fatal results. Antihistamines -Amphetamines may counteract the sedative effect of antihistamines. Antihypertensives -Amphetamines may antagonize the hypotensive effects of antihypertensives. Chlorpromazine -Chlorpromazine blocks dopamine and norepinephrine receptors, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning. Ethosuximide -Amphetamines may delay intestinal absorption of ethosuximide. Haloperidol -Haloperidol blocks dopamine receptors, thus inhibiting the central stimulant effects of amphetamines. Lithium carbonate -The anorectic and stimulatory effects of amphetamines may be inhibited by lithium carbonate. Meperidine -Amphetamines potentiate the analgesic effect of meperidine. Methenamine therapy -Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy. Norepinephrine -Amphetamines enhance the adrenergic effect of norepinephrine. Phenobarbital -Amphetamines may delay intestinal absorption of phenobarbital; co-administration of phenobarbital may produce a synergistic anticonvulsant action. Phenytoin -Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may produce a synergistic anticonvulsant action. Propoxyphene -In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur. Veratrum alkaloids -Amphetamines inhibit the hypotensive effect of veratrum alkaloids. Drug/Laboratory Test Interactions: • Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. • Amphetamines may interfere with urinary steroid determinations. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-522 Confidential Carcinogenesis/Mutagenesis: Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of amphetamine, have not been performed. Pregnancy - Teratogenic Effects: Pregnancy Category C. Amphetamine has been shown to have embryotoxic and teratogenic effects when administered to A/Jax mice and C57BL mice in doses approximately 41 times the maximum human dose. Embryotoxic effects were not seen in New Zealand white rabbits given the drug in doses 7 times the human dose nor in rats given 12.5 times the maximum human dose. While there are no adequate and well-controlled studies in pregnant women, there has been one report of severe congenital bony deformity, tracheoesophageal fistula, and anal atresia (vater association) in a baby born to a woman who took dextroamphetamine sulfate with lovastatin during the first trimester of pregnancy. Amphetamines should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects: Infants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth weight. Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant lassitude. Pediatric Use: Long-term effects of amphetamines in children have not been well established. Amphetamines are not recommended for use in children under 3 years of age with Attention Deficit Disorder with Hyperactivity described under INDICATIONS AND USAGE. Amphetamines have been reported to exacerbate motor and phonic tics and Tourette’s syndrome. Therefore, clinical evaluation for tics and Tourette’s syndrome in children and their families should precede use of stimulant medications. Drug treatment is not indicated in all cases of Attention Deficit Disorder with Hyperactivity and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe amphetamines should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with amphetamines is usually not indicated. ADVERSE REACTIONS: Cardiovascular: Palpitations, tachycardia, elevation of blood pressure, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use. Central Nervous System: Psychotic episodes at recommended doses (rare), overstimulation, restlessness, dizziness, insomnia, euphoria, dyskinesia, dysphoria, depression, tremor, headache, exacerbation of motor and phonic tics and Tourette’s syndrome, seizures, stroke. Gastrointestinal: Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects when amphetamines are used for other than the anorectic effect. Allergic: Urticaria. Endocrine: Impotence, changes in libido. DRUG ABUSE AND DEPENDENCE: 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-522 Confidential Dextroamphetamine Sulfate, Amphetamine Sulfate, Amphetamine Aspartate Monohydrate, and Dextroamphetamine Saccharate are Schedule II controlled substance. Amphetamines have been extensively abused. Tolerance, extreme psychological dependence, and severe social disability have occurred. There are reports of patients who have increased the dosage to many times than recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with amphetamines include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia. This is rare with oral amphetamines. OVERDOSAGE: Individual patient response to amphetamines varies widely. While toxic symptoms occasionally occur as an idiosyncrasy at doses as low as 2 mg, they are rare with doses of less than 15 mg; 30 mg can produce severe reactions, yet doses of 400 to 500 mg are not necessarily fatal. In rats, the oral LD50 of dextroamphetamine sulfate is 96.8 mg/kg. Symptoms: Manifestations of acute overdosage with amphetamines include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia and rhabdomyolysis. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma. Treatment: Consult with a Certified Poison Control Center for up to date guidance and advice. Management of acute amphetamine intoxication is largely symptomatic and includes gastric lavage, administration of activated charcoal, administration of a cathartic and sedation. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendation in this regard. Acidification of the urine increases amphetamine excretion, but is believed to increase risk of acute renal failure if myoglobinuria is present. If acute, severe hypertension complicates amphetamine overdosage, administration of intravenous phentolamine has been suggested. However, a gradual drop in blood pressure will usually result when sufficient sedation has been achieved. Chlorpromazine antagonizes the central stimulant effects of amphetamines and can be used to treat amphetamine intoxication. DOSAGE AND ADMINISTRATION: Regardless of indication, amphetamines should be administered at the lowest effective dosage and dosage should be individually adjusted. Late evening doses should be avoided because of the resulting insomnia. Attention Deficit Disorder with Hyperactivity: Not recommended for children under 3 years of age. In children from 3 to 5 years of age, start with 2.5 mg daily; daily dosage may be raised in increments of 2.5 mg at weekly intervals until optimal response is obtained. In children 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. Only in rare cases will it 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-522 Confidential be necessary to exceed a total of 40 mg per day. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours. Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy. Narcolepsy: Usual dose 5 mg to 60 mg per day in divided doses, depending on the individual patient response. Narcolepsy seldom occurs in children under 12 years of age; however, when it does, dextroamphetamine sulfate may be used. The suggested initial dose for patients aged 6-12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in increments of 10 mg at weekly intervals until optimal response is obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should be reduced. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours. HOW SUPPLIED: ADDERALL® 5 mg: A round, flat-faced beveled edge, white to off-white tablet, “5” embossed on one side with partial bisect and “AD” embossed on the other side (NDC 54092-371-01) ADDERALL® 7.5 mg: An oval, convex, blue tablet, “7.5” embossed on one side with a partial bisect and “AD” embossed on the other side with a full and partial bisect (NDC 54092-372-01) ADDERALL® 10 mg: A round, convex, blue tablet, “10” embossed on one side with a full and partial bisect and “AD” embossed on the other side (NDC 54092-373-01) ADDERALL® 12.5 mg: A round, flat-faced beveled edge, orange tablet, “12.5” embossed on one side and “AD” embossed on the other side with a full and partial bisect (NDC 54092-374-01) ADDERALL® 15 mg: An oval, convex, orange tablet, “15” embossed on one side with a partial bisect and “AD” embossed on the other side with a full and partial bisect (NDC 54092-375-01) ADDERALL® 20 mg: A round, convex, orange tablet, “20” embossed on one side with a full and partial bisect and “AD” embossed on the other side (NDC 54092-376-01) ADDERALL® 30 mg: A round, flat-faced beveled edge, orange tablet, “30” embossed on one side with a full and partial bisect and “AD” embossed on the other side (NDC 54092-377-01) In bottles of 100 tablets. Dispense in a tight, light-resistant container as defined in the USP. Store at 25°C (77°F), excursions permitted to 15°-30°C (59-86°F) [see USP Controlled Room Temperature] Rx only. MG #XXXXX Revised: 06/05 371 0107 004 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-522 Confidential 7 Manufactured for: Shire US Inc. 725 Chesterbrook Blvd. Wayne, PA 19087 Manufactured by: DSM Pharmaceuticals Inc. 5900 NW Greenville Blvd. Greenville, NC 27834 Made in USA 1-800-828-2088 ©2005 Shire US Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:44.108283	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/011522s032,033lbl.pdf', 'application_number': 11522, 'submission_type': 'SUPPL ', 'submission_number': 32}
10,758	PAGE 1 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 1 TRILAFON   1 brand of perphenazine, USP 2 Tablets, 3 Injection 4 5 DESCRIPTION TRILAFON products contain perphenazine, USP (4-[3-(2- 6 chlorophenothiazin-10-yl)propyl]-1-piper-azineethanol), a piperazinyl phenothiazine 7 having the chemical formula, C21H26CIN3OS. They are available as Tablets, 2, 4, 8 8, and 16 mg; and Injection, perphenazine 5 mg per 1 mL. 9 The inactive ingredients for TRILAFON Tablets, 2, 4, 8, and 16 mg, include: 10 acacia, black iron oxide, butylparaben, calcium phosphate, calcium sulfate, 11 carnauba wax, corn starch, lactose, magnesium stearate, sugar, titanium dioxide, 12 and white wax. The inactive ingredients for TRILAFON Injection include: citric 13 acid, sodium bisulfite, sodium hydroxide, and water. 14 ACTIONS Perphenazine has actions at all levels of the central nervous system, 15 particularly the hypothalamus. However, the site and mechanism of action of 16 therapeutic effect are not known. 17 CLINICAL PHARMACOLOGY Pharmacokinetics: Following oral administration 18 of TRILAFON® Tablets, mean peak plasma perphenazine concentrations were 19 observed between 1 to 3 hours. The plasma elimination half-life of perphenazine 20 was independent of dose and ranged between 9 and 12 hours. In a study in which 21 normal volunteers (n=12) received TRILAFON 4 mg q8h for 5 days, steady-state 22 concentrations of perphenazine were reached within 72 hours. Mean (%CV) Cmax 23 and Cmin values for perphenazine and 7-hydroxyperphenazine at steady-state are 24 listed below: 25 ParameterPerphenazine 7-Hydroxyperphenazine 26 Cmax (pg/mL) 984 (43) 509 (25) 27 Cmin (pg/mL) 442 (76) 350 (56) 28 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 2 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 2 Peak 7-hydroxyperphenazine concentrations were observed between 2 to 4 hours 29 with a terminal phase half-life ranging between 9.9 to 18.8 hours. Perphenazine is 30 extensively metabolized in the liver to a number of metabolites by sulfoxidation, 31 hydroxylation, dealkylation, and glucuronidation. The pharmacokinetics of 32 perphenazine covary with the hydroxylation of debrisoquine which is mediated by 33 cytochrome P450 2D6 (CYP 2D6) and thus is subject to genetic polymorphism— 34 ie, 7%-10% of Caucasians and a low percentage of Asians have little or no activity 35 and are called “poor metabolizers.” Poor metabolizers of CYP 2D6 will metabolize 36 perphenazine more slowly and will experience higher concentrations compared 37 with normal or “extensive” metabolizers. 38 INDICATIONS Perphenazine is indicated for use in the treatment of schizophrenia; 39 and for the control of severe nausea and vomiting in adults. 40 TRILAFON has not been shown effective for the management of behavioral 41 complications in patients with mental retardation. 42 CONTRAINDICATIONS TRILAFON products are contraindicated in comatose or 43 greatly obtunded patients and in patients receiving large doses of central nervous 44 system depressants (barbiturates, alcohol, narcotics, analgesics, or anti- 45 histamines); in the presence of existing blood dyscrasias, bone marrow 46 depression, or liver damage; and in patients who have shown hypersensitivity to 47 TRILAFON products, their components, or related compounds. 48 TRILAFON products are also contraindicated in patients with suspected or 49 established subcortical brain damage, with or without hypothalamic damage, since 50 a hyperthermic reaction with temperatures in excess of 104°F may occur in such 51 patients, sometimes not until 14 to 16 hours after drug administration. Total body 52 ice-packing is recommended for such a reaction; antipyretics may also be useful. 53 WARNINGS Tardive dyskinesia, a syndrome consisting of potentially irreversible, 54 involuntary, dyskinetic movements, may develop in patients treated with 55 antipsychotic drugs. Older patients are at increased risk for development of tardive 56 dyskinesia. Although the prevalence of the syndrome appears to be highest among 57 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 3 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 3 the elderly, especially elderly women, it is impossible to rely upon prevalence 58 estimates to predict, at the inception of antipsychotic treatment, which patients are 59 likely to develop the syndrome. Whether antipsychotic drug products differ in their 60 potential to cause tardive dyskinesia is unknown. 61 Both the risk of developing the syndrome and the likelihood that it will become 62 irreversible are believed to increase as the duration of treatment and the total 63 cumulative dose of antipsychotic drugs administered to the patient increase. 64 However, the syndrome can develop, although much less commonly, after 65 relatively brief treatment periods at low doses. 66 There is no known treatment for established cases of tardive dyskinesia, 67 although the syndrome may remit, partially or completely, if antipsychotic treatment 68 is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially 69 suppress) the signs and symptoms of the syndrome, and thereby may possibly 70 mask the underlying disease process. The effect that symptomatic suppression 71 has upon the long-term course of the syndrome is unknown. 72 Given these considerations, especially in the elderly, antipsychotics should be 73 prescribed in a manner that is most likely to minimize the occurrence of tardive 74 dyskinesia. Chronic antipsychotic treatment should generally be reserved for 75 patients who suffer from a chronic illness that 1) is known to respond to 76 antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially 77 less harmful treatments are not available or appropriate. In patients who do require 78 chronic treatment, the smallest dose and the shortest duration of treatment 79 producing a satisfactory clinical response should be sought. The need for 80 continued treatment should be reassessed periodically. 81 If signs and symptoms of tardive dyskinesia appear in a patient on 82 antipsychotics, drug discontinuation should be considered. However, some 83 patients may require treatment despite the presence of the syndrome. 84 (For further information about the description of tardive dyskinesia and its 85 clinical detection, please refer to Information for Patients and ADVERSE 86 REACTIONS.) 87 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 4 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 4 TRILAFON Injection contains sodium bisulfite, a sulfite that may cause 88 allergic-type reactions including anaphylactic symptoms and life-threatening or less 89 severe asthmatic episodes in certain susceptible people. The overall prevalence of 90 sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. 91 NEUROLEPTIC MALIGNANT SYNDROME (NMS) 92 A potentially fatal symptom complex, sometimes referred to as Neuroleptic 93 Malignant Syndrome (NMS), has been reported in association with antipsychotic 94 drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered 95 mental status and evidence of autonomic instability (irregular pulse or blood 96 pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). 97 The diagnostic evaluation of patients with this syndrome is complicated. In 98 arriving at a diagnosis, it is important to identify cases where the clinical 99 presentation includes both serious medical illness (eg, pneumonia, systemic 100 infection, etc) and untreated or inadequately treated extrapyramidal signs and 101 symptoms (EPS). Other important considerations in the differential diagnosis 102 include central anticholinergic toxicity, heat stroke, drug fever, and primary central 103 nervous system (CNS) pathology. 104 The management of NMS should include 1) immediate discontinuation of 105 antipsychotic drugs and other drugs not essential to concurrent therapy, 2) 106 intensive symptomatic treatment and medical monitoring, and 3) treatment of any 107 concomitant serious medical problems for which specific treatments are available. 108 There is no general agreement about specific pharmacological treatment regimens 109 for uncomplicated NMS. 110 If a patient requires antipsychotic drug treatment after recovery from NMS, the 111 reintroduction of drug therapy should be carefully considered. The patient should 112 be carefully monitored, since recurrences of NMS have been reported. 113 If hypotension develops, epinephrine should not be administered since its 114 action is blocked and partially reversed by perphenazine. If a vasopressor is 115 needed, norepinephrine may be used. Severe, acute hypotension has occurred 116 with the use of phenothiazines and is particularly likely to occur in patients with 117 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 5 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 5 mitral insufficiency or pheochromocytoma. Rebound hypertension may occur in 118 pheochromocytoma patients. 119 TRILAFON products can lower the convulsive threshold in susceptible 120 individuals; they should be used with caution in alcohol withdrawal and in patients 121 with convulsive disorders. If the patient is being treated with an anticonvulsant 122 agent, increased dosage of that agent may be required when TRILAFON products 123 are used concomitantly. 124 TRILAFON products should be used with caution in patients with psychic 125 depression. 126 Perphenazine may impair the mental and/or physical abilities required for the 127 performance of hazardous tasks such as driving a car or operating machinery; 128 therefore, the patient should be warned accordingly. 129 TRILAFON products are not recommended for pediatric patients under 12 130 years of age. 131 Usage in Pregnancy: Safe use of TRILAFON during pregnancy and lactation has 132 not been established; therefore, in administering the drug to pregnant patients, 133 nursing mothers, or women who may become pregnant, the possible benefits must 134 be weighed against the possible hazards to mother and child. 135 PRECAUTIONS The possibility of suicide in depressed patients remains during 136 treatment and until significant remission occurs. This type of patient should not 137 have access to large quantities of this drug. 138 As with all phenothiazine compounds, perphenazine should not be used 139 indiscriminately. Caution should be observed in giving it to patients who have 140 previously exhibited severe adverse reactions to other phenothiazines. Some of 141 the untoward actions of perphenazine tend to appear more frequently when high 142 doses are used. However, as with other phenothiazine compounds, patients 143 receiving TRILAFON products in any dosage should be kept under close 144 supervision. 145 Antipsychotic drugs elevate prolactin levels; the elevation persists during 146 chronic administration. Tissue culture experiments indicate that approximately one- 147 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 6 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 6 third of human breast cancers are prolactin dependent in vitro, a factor of potential 148 importance if the prescription of these drugs is contemplated in a patient with a 149 previously detected breast cancer. Although disturbances such as galactorrhea, 150 amenorrhea, gynecomastia, and impotence have been reported, the clinical 151 significance of elevated serum prolactin levels is unknown for most patients. An 152 increase in mammary neoplasms has been found in rodents after chronic 153 administration of antipsychotic drugs. Neither clinical studies nor epidemiologic 154 studies conducted to date, however, have shown an association between chronic 155 administration of these drugs and mammary tumorigenesis; the available evidence 156 is considered too limited to be conclusive at this time. 157 The antiemetic effect of perphenazine may obscure signs of toxicity due to 158 overdosage of other drugs, or render more difficult the diagnosis of disorders such 159 as brain tumors or intestinal obstruction. 160 A significant, not otherwise explained, rise in body temperature may suggest 161 individual intolerance to perphenazine, in which case it should be discontinued. 162 Patients on large doses of a phenothiazine drug who are undergoing surgery 163 should be watched carefully for possible hypotensive phenomena. Moreover, 164 reduced amounts of anesthetics or central nervous system depressants may be 165 necessary. 166 Since phenothiazines and central nervous system depressants (opiates, 167 analgesics, antihistamines, barbiturates) can potentiate each other, less than the 168 usual dosage of the added drug is recommended and caution is advised when 169 they are administered concomitantly. 170 Use with caution in patients who are receiving atropine or related drugs 171 because of additive anticholinergic effects and also in patients who will be exposed 172 to extreme heat or phosphorus insecticides. 173 The use of alcohol should be avoided, since additive effects and hypotension 174 may occur. Patients should be cautioned that their response to alcohol may be 175 increased while they are being treated with TRILAFON products. The risk of 176 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 7 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 7 suicide and the danger of overdose may be increased in patients who use alcohol 177 excessively due to its potentiation of the drug’s effect. 178 Blood counts and hepatic and renal functions should be checked periodically. 179 The appearance of signs of blood dyscrasias requires the discontinuance of the 180 drug and institution of appropriate therapy. If abnormalities in hepatic tests occur, 181 phenothiazine treatment should be discontinued. Renal function in patients on 182 long-term therapy should be monitored; if blood urea nitrogen (BUN) becomes 183 abnormal, treatment with the drug should be discontinued. 184 The use of phenothiazine derivatives in patients with diminished renal function 185 should be undertaken with caution. 186 Use with caution in patients suffering from respiratory impairment due to acute 187 pulmonary infections, or in chronic respiratory disorders such as severe asthma or 188 emphysema. 189 In general, phenothiazines, including perphenazine, do not produce psychic 190 dependence. Gastritis, nausea and vomiting, dizziness, and tremulousness have 191 been reported following abrupt cessation of high-dose therapy. Reports suggest 192 that these symptoms can be reduced by continuing concomitant antiparkinson 193 agents for several weeks after the phenothiazine is withdrawn. 194 The possibility of liver damage, corneal and lenticular deposits, and irreversible 195 dyskinesias should be kept in mind when patients are on long-term therapy. 196 Because photosensitivity has been reported, undue exposure to the sun should 197 be avoided during phenothiazine treatment. 198 Drug Interactions: Metabolism of a number of medications, including 199 antipsychotics, antidepressants, β- blockers, and antiarrhythmics, occurs through 200 the cytochrome P450 2D6 isoenzyme (debrisoquine hydroxylase). Approximately 201 10% of the Caucasian population has reduced activity of this enzyme, so-called 202 “poor” metabolizers. Among other populations the prevalence is not known. Poor 203 metabolizers demonstrate higher plasma concentrations of antipsychotic drugs at 204 usual doses, which may correlate with emergence of side effects. In one study of 205 45 elderly patients suffering from dementia treated with perphenazine, the 5 206 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 8 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 8 patients who were prospectively identified as poor P450 2D6 metabolizers had 207 reported significantly greater side effects during the first 10 days of treatment than 208 the 40 extensive metabolizers, following which the groups tended to converge. 209 Prospective phenotyping of elderly patients prior to antipsychotic treatment may 210 identify those at risk for adverse events. 211 The concomitant administration of other drugs that inhibit the activity of 212 P450 2D6 may acutely increase plasma concentrations of antipsychotics. Among 213 these are tricyclic antidepressants and selective serotonin reuptake inhibitors, 214 e.g.fluoxetine, sertraline and paroxetine. When prescribing these drugs to patients 215 already receiving antipsychotic therapy, close monitoring is essential and dose 216 reduction may become necessary to avoid toxicity. Lower doses than usually 217 prescribed for either the antipsychotic or the other drug may be required. 218 Information for Patients: This information is intended to aid in the safe and 219 effective use of this medication. It is not a disclosure of all possible adverse or 220 intended effects. 221 Given the likelihood that a substantial proportion of patients exposed 222 chronically to antipsychotics will develop tardive dyskinesia, it is advised that all 223 patients in whom chronic use is contemplated be given, if possible, full information 224 about this risk. The decision to inform patients and/or their guardians must 225 obviously take into account the clinical circumstances and the competency of the 226 patient to understand the information provided. 227 Geriatric Use: Clinical studies of TRILAFON products did not include sufficient 228 numbers of subjects aged 65 and over to determine whether elderly subjects 229 respond differently from younger subjects. Other reported clinical experience has 230 not identified differences in responses between the elderly and younger patients. 231 In general, dose selection for an elderly patient should be cautious, usually starting 232 at the low end of the dosing range, reflecting the greater frequency of decreased 233 hepatic function, concomitant disease or other drug therapy. 234 Geriatric patients are particularly sensitive to the side effects of 235 antipsychotics, including TRILAFON. These side effects include extrapyramidal 236 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 9 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 9 symptoms (tardive dyskinesia, antipsychotic-induced parkinsonism, akathisia), 237 anticholinergic effects, sedation and orthostatic hypotension (See WARNINGS). 238 Elderly patients taking psychotropic drugs may be at increased risk for falling and 239 consequent hip fractures. Elderly patients should be started on lower doses and 240 observed closely. 241 ADVERSE REACTIONS Not all of the following adverse reactions have been 242 reported with this specific drug; however, pharmacological similarities among 243 various phenothiazine derivatives require that each be considered. With the 244 piperazine group (of which perphenazine is an example), the extrapyramidal 245 symptoms are more common, and others (eg, sedative effects, jaundice, and blood 246 dyscrasias) are less frequently seen. 247 CNS Effects: Extrapyramidal reactions: opisthotonus, trismus, torticollis, 248 retrocollis, aching and numbness of the limbs, motor restlessness, oculogyric 249 crisis, hyperreflexia, dystonia, including protrusion, discoloration, aching and 250 rounding of the tongue, tonic spasm of the masticatory muscles, tight feeling in the 251 throat, slurred speech, dysphagia, akathisia, dyskinesia, parkinsonism, and ataxia. 252 Their incidence and severity usually increase with an increase in dosage, but there 253 is considerable individual variation in the tendency to develop such symptoms. 254 Extrapyramidal symptoms can usually be controlled by the concomitant use of 255 effective antiparkinsonian drugs, such as benztropine mesylate, and/or by 256 reduction in dosage. In some instances, however, these extrapyramidal reactions 257 may persist after discontinuation of treatment with perphenazine. 258 Persistent tardive dyskinesia: As with all antipsychotic agents, tardive 259 dyskinesia may appear in some patients on long-term therapy or may appear after 260 drug therapy has been discontinued. Although the risk appears to be greater in 261 elderly patients on high-dose therapy, especially females, it may occur in either 262 sex and in children. The symptoms are persistent and in some patients appear to 263 be irreversible. The syndrome is characterized by rhythmical, involuntary 264 movements of the tongue, face, mouth, or jaw (eg, protrusion of tongue, puffing of 265 cheeks, puckering of mouth, chewing movements). Sometimes these may be 266 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 10 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 10 accompanied by involuntary movements of the extremities. There is no known 267 effective treatment for tardive dyskinesia; antiparkinsonism agents usually do not 268 alleviate the symptoms of this syndrome. It is suggested that all antipsychotic 269 agents be discontinued if these symptoms appear. Should it be necessary to 270 reinstitute treatment, or increase the dosage of the agent, or switch to a different 271 antipsychotic agent, the syndrome may be masked. It has been reported that fine, 272 vermicular movements of the tongue may be an early sign of the syndrome, and if 273 the medication is stopped at that time the syndrome may not develop. 274 Other CNS effects include cerebral edema; abnormality of cerebrospinal fluid 275 proteins; convulsive seizures, particularly in patients with EEG abnormalities or a 276 history of such disorders; and headaches. 277 Neuroleptic malignant syndrome has been reported in patients treated with 278 antipsychotic drugs (see WARNINGS section for further information). 279 Drowsiness may occur, particularly during the first or second week, after which 280 it generally disappears. If troublesome, lower the dosage. Hypnotic effects appear 281 to be minimal, especially in patients who are permitted to remain active. 282 Adverse behavioral effects include paradoxical exacerbation of psychotic 283 symptoms, catatonic-like states, paranoid reactions, lethargy, paradoxical 284 excitement, restlessness, hyperactivity, nocturnal confusion, bizarre dreams, and 285 insomnia. 286 Hyperreflexia has been reported in the newborn when a phenothiazine was 287 used during pregnancy. 288 Autonomic Effects: dry mouth or salivation, nausea, vomiting, diarrhea, 289 anorexia, constipation, obstipation, fecal impaction, urinary retention, frequency or 290 incontinence, bladder paralysis, polyuria, nasal congestion, pallor, myosis, 291 mydriasis, blurred vision, glaucoma, perspiration, hypertension, hypotension, and 292 change in pulse rate occasionally may occur. Significant autonomic effects have 293 been infrequent in patients receiving less than 24 mg perphenazine daily. 294 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 11 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 11 Adynamic ileus occasionally occurs with phenothiazine therapy and if severe 295 can result in complications and death. It is of particular concern in psychiatric 296 patients, who may fail to seek treatment of the condition. 297 Allergic Effects: urticaria, erythema, eczema, exfoliative dermatitis, pruritus, 298 photosensitivity, asthma, fever, anaphylactoid reactions, laryngeal edema, and 299 angioneurotic edema; contact dermatitis in nursing personnel administering the 300 drug; and in extremely rare instances, individual idiosyncrasy or hypersensitivity to 301 phenothiazines has resulted in cerebral edema, circulatory collapse, and death. 302 Endocrine Effects: lactation, galactorrhea, moderate breast enlargement in 303 females and gynecomastia in males on large doses, disturbances in the menstrual 304 cycle, amenorrhea, changes in libido, inhibition of ejaculation, syndrome of 305 inappropriate ADH (antidiuretic hormone) secretion, false positive pregnancy tests, 306 hyperglycemia, hypoglycemia, glycosuria. 307 Cardiovascular Effects: postural hypotension, tachycardia (especially with 308 sudden marked increase in dosage), bradycardia, cardiac arrest, faintness, and 309 dizziness. Occasionally the hypotensive effect may produce a shock-like 310 condition. ECG changes, nonspecific (quinidinelike effect) usually reversible, have 311 been observed in some patients receiving phenothiazine antipsychotics. 312 Sudden death has occasionally been reported in patients who have received 313 phenothiazines. In some cases the death was apparently due to cardiac arrest; in 314 others, the cause appeared to be asphyxia due to failure of the cough reflex. In 315 some patients, the cause could not be determined nor could it be established that 316 the death was due to the phenothiazine. 317 Hematological Effects: agranulocytosis, eosinophilia, leukopenia, hemolytic 318 anemia, thrombocytopenic purpura, and pancytopenia. Most cases of 319 agranulocytosis have occurred between the fourth and tenth weeks of therapy. 320 Patients should be watched closely, especially during that period, for the sudden 321 appearance of sore throat or signs of infection. If white blood cell and differential 322 cell counts show significant cellular depression, discontinue the drug and start 323 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 12 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 12 appropriate therapy. However, a slightly lowered white count is not in itself an 324 indication to discontinue the drug. 325 Other Effects: Special considerations in long-term therapy include 326 pigmentation of the skin, occurring chiefly in the exposed areas; ocular changes 327 consisting of deposition of fine particulate matter in the cornea and lens, 328 progressing in more severe cases to star-shaped lenticular opacities; epithelial 329 keratopathies; and pigmentary retinopathy. Also noted: peripheral edema, 330 reversed epinephrine effect, increase in PBI not attributable to an increase in 331 thyroxine, parotid swelling (rare), hyperpyrexia, systemic lupus erythematosuslike 332 syndrome, increases in appetite and weight, polyphagia, photophobia, and muscle 333 weakness. 334 Liver damage (biliary stasis) may occur. Jaundice may occur, usually between 335 the second and fourth weeks of treatment, and is regarded as a hypersensitivity 336 reaction. Incidence is low. The clinical picture resembles infectious hepatitis but 337 with laboratory features of obstructive jaundice. It is usually reversible; however, 338 chronic jaundice has been reported. 339 Side effects with intramuscular TRILAFON Injection have been infrequent and 340 transient. Dizziness or significant hypotension after treatment with TRILAFON 341 Injection is a rare occurrence. 342 DOSAGE AND ADMINISTRATION Dosage must be individualized and adjusted 343 according to the severity of the condition and the response obtained. As with all 344 potent drugs, the best dose is the lowest dose that will produce the desired clinical 345 effect. Since extrapyramidal symptoms increase in frequency and severity with 346 increased dosage, it is important to employ the lowest effective dose. These 347 symptoms have disappeared upon reduction of dosage, withdrawal of the drug, or 348 administration of an antiparkinsonian agent. 349 Prolonged administration of doses exceeding 24 mg daily should be reserved 350 for hospitalized patients or patients under continued observation for early detection 351 and management of adverse reactions. An antiparkinsonian agent, such as 352 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 13 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 13 trihexyphenidyl hydrochloride or benztropine mesylate, is valuable in controlling 353 drug-induced extrapyramidal symptoms. 354 TRILAFON Tablets 355 Suggested dosages for Tablets for various conditions follow: 356 Moderately disturbed nonhospitalized patients with schizophrenia: Tablets 4 to 357 8 mg tid initially; reduce as soon as possible to minimum effective dosage. 358 Hospitalized patients with schizophrenia: Tablets 8 to 16 mg bid to qid; avoid 359 dosages in excess of 64 mg daily. 360 Severe nausea and vomiting in adults: Tablets 8 to 16 mg daily in divided 361 doses; 24 mg occasionally may be necessary; early dosage reduction is desirable. 362 TRILAFON Injection 363 Intramuscular Administration 364 The injection is used when rapid effect and prompt control of acute or 365 intractable conditions is required or when oral administration is not feasible. 366 TRILAFON Injection, administered by deep intramuscular injection, is well 367 tolerated. The injection should be given with the patient seated or recumbent, and 368 the patient should be observed for a short period after administration. 369 Therapeutic effect is usually evidenced in 10 minutes and is maximal in 1 to 2 370 hours. The average duration of effective action is 6 hours, occasionally 12 to 24 371 hours. 372 Pediatric dosage has not yet been established. Pediatric patients over 12 years 373 may receive the lowest limit of adult dosage. 374 The usual initial dose is 5 mg (1 mL). This may be repeated every 6 hours. 375 Ordinarily, the total daily dosage should not exceed 15 mg in ambulatory patients 376 or 30 mg in hospitalized patients. When required for satisfactory control of 377 symptoms in severe conditions, an initial 10-mg intramuscular dose may be given. 378 Patients should be placed on oral therapy as soon as practicable. Generally, this 379 may be achieved within 24 hours. In some instances, however, patients have been 380 maintained on injectable therapy for several months. It has been established that 381 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 14 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 14 TRILAFON Injection is more potent than TRILAFON Tablets. Therefore, equal or 382 higher dosage should be used when the patient is transferred to oral therapy after 383 receiving the injection. 384 Schizophrenia: While 5 mg of the Injection has a definite tranquilizing effect, it 385 may be necessary to use 10-mg doses to initiate therapy in severely agitated 386 schizophrenic states. Most patients will be controlled and amenable to oral therapy 387 within a maximum of 24 to 48 hours. Acute schizophrenic conditions (hysteria, 388 panic reaction) often respond well to a single dose, whereas in chronic conditions, 389 several injections may be required. When transferring patients to oral therapy, it is 390 suggested that increased dosage be employed to maintain adequate clinical 391 control. This should be followed by gradual reduction to the minimal maintenance 392 dose which is effective. 393 Severe nausea and vomiting in adults: To obtain rapid control of vomiting, 394 administer 5 mg (1 mL); in rare instances it may be necessary to increase the dose 395 to 10 mg; in general, higher doses should be given only to hospitalized patients. 396 Intravenous Administration 397 The intravenous administration of TRILAFON Injection is seldom required. 398 This route of administration should be used with particular caution and care, and 399 only when absolutely necessary to control severe vomiting, intractable hiccoughs, 400 or acute conditions, such as violent retching during surgery. Its use should be 401 limited to recumbent hospitalized adults in doses not exceeding 5 mg. When 402 employed in this manner, intravenous injection ordinarily should be given as a 403 diluted solution by either fractional injection or a slow drip infusion. In the surgical 404 patient, slow infusion of not more than 5 mg is preferred. When administered in 405 divided doses, TRILAFON Injection should be diluted to 0.5 mg/mL (1mL mixed 406 with 9 mL of physiologic saline solution), and not more than 1 mg per injection 407 given at not less than 1- to 2-minute intervals. Intravenous injection should be 408 discontinued as soon as symptoms are controlled and should not exceed 5 mg. 409 The possibility of hypotensive and extrapyramidal side effects should be 410 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 15 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 15 considered and appropriate means for management kept available. Blood pressure 411 and pulse should be monitored continuously during intravenous administration. 412 Pharmacologic and clinical studies indicate that intravenous administration of 413 norepinephrine should be useful in alleviating the hypotensive effect. 414 Elderly patients: With increasing age, plasma concentrations of perphenazine 415 per daily ingested dose increase. Geriatric dosages of perphenazine preparations 416 have not been established, but initiation of lower dosages is recommended. 417 Optimal clinical effect or benefit may require lower doses for a longer duration. 418 Dosing of perphenazine may occur before bedtime, for agitation, if required. 419 OVERDOSAGE In the event of overdosage, emergency treatment should be 420 started immediately. Consultation with a poison center should be considered. All 421 patients suspected of having taken an overdose should be hospitalized as soon as 422 possible. 423 Manifestations The toxic effects of perphenazine are typically mild to 424 moderate with death occurring in cases involving a large overdose. Overdosage of 425 perphenazine primarily involves the extrapyramidal mechanism and produces the 426 same side effects described under ADVERSE REACTIONS, but to a more marked 427 degree. It is usually evidenced by stupor or coma; children may have convulsive 428 seizures. Signs of arousal may not occur for 48 hours. The primary effects of 429 medical concern are cardiac in origin including tachycardia, prolongation of the 430 QRS or QTc intervals, atrioventricular block, torsade de pointes, ventricular 431 dysrhythmia, hypotension or cardiac arrest, which indicate serious poisoning. 432 Deaths by deliberate or accidental overdosage have occurred with this class of 433 drugs. 434 Treatment Treatment is symptomatic and supportive. Induction of emesis is 435 not recommended because of the possibility of a seizure, CNS depression, or 436 dystonic reaction of the head or neck and subsequent aspiration. Gastric lavage 437 (after intubation, if the patient is unconscious) and administration of activated 438 charcoal together with a laxative should be considered. There is no specific 439 antidote. The patient should be induced to vomit even if emesis has occurred 440 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 16 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 16 spontaneously. Pharmacologic vomiting by the administration of ipecac syrup is a 441 preferred method. It should be noted that ipecac has a central mode of action in 442 addition to its local gastric irritant properties, and the central mode of action may 443 be blocked by the antiemetic effect of TRILAFON products. Vomiting should not be 444 induced in patients with impaired consciousness. The action of ipecac is facilitated 445 by physical activity and by the administration of 8 to 12 fluid ounces of water. If 446 emesis does not occur within 15 minutes, the dose of ipecac should be repeated. 447 Precautions against aspiration must be taken, especially in infants and children. 448 Following emesis, any drug remaining in the stomach may be adsorbed by 449 activated charcoal administered as a slurry with water. If vomiting is unsuccessful 450 or contraindicated, gastric lavage should be performed. Isotonic and one-half 451 isotonic saline are the lavage solutions of choice. Saline cathartics, such as milk of 452 magnesia, draw water into the bowel by osmosis and therefore, may be valuable 453 for their action in rapid dilution of bowel content. 454 Standard measures (oxygen, intravenous fluids, corticosteroids) should be 455 used to manage circulatory shock or metabolic acidosis. An open airway and 456 adequate fluid intake should be maintained. Body temperature should be 457 regulated. Hypothermia is expected, but severe hyperthermia may occur and must 458 be treated vigorously. (See CONTRAINDICATIONS.) 459 An electrocardiogram should be taken and close monitoring of cardiac function 460 instituted if there is any sign of abnormality. Cardiac arrhythmias may be treated 461 with neostigmine, pyridostigmine, or propranolol. Digitalis should be considered for 462 cardiac failure. Close monitoring of cardiac function is advisable for not less than 463 five days. Vasopressors such as norepinephrine may be used to treat hypotension, 464 but epinephrine should NOT be used. 465 Anticonvulsants (an inhalation anesthetic, diazepam, or paraldehyde) are 466 recommended for control of convulsions, since perphenazine increases the central 467 nervous system depressant action, but not the anticonvulsant action of 468 barbiturates. 469 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 17 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 17 If acute parkinson like symptoms result from perphenazine intoxication, 470 benztropine mesylate or diphenhydramine may be administered. 471 Central nervous system depression may be treated with nonconvulsant doses 472 of CNS stimulants. Avoid stimulants that may cause convulsions (eg, picrotoxin 473 and pentylenetetrazol). 474 Signs of arousal may not occur for 48 hours. 475 Hemodialysis and peritoneal dialysis is of no value because of low plasma 476 concentrations of the drug. 477 Since overdosage is often deliberate, patients may attempt suicide by other 478 means during the recovery phase. Deaths by deliberate or accidental overdosage 479 have occurred with this class of drugs. 480 HOW SUPPLIED TRILAFON Tablets (2 mg): gray, sugar-coated tablets branded 481 in black with the Schering trademark and the numbers, 1229; bottles of 100 (NDC 482 0085-1229-01). Store between 2° and 25°C (36° and 77°F). 483 TRILAFON Tablets (4 mg): gray, sugar-coated tablets branded in green with the 484 Schering trademark and the numbers, 1232; bottles of 100 (NDC 0085-1232-01). 485 Store between 2° and 25°C (36° and 77°F). 486 TRILAFON Tablets (8 mg): gray, sugar-coated tablets branded in blue with the 487 Schering trademark the numbers, 1251; bottles of 100 (NDC 0085-1251-01). Store 488 between 2° and 25°C (36° and 77°F). 489 TRILAFON Tablets (16 mg): gray, sugar-coated tablets branded in red with the 490 Schering trademark and the numbers, 1237; bottles of 100 (NDC 0085-1237-01). 491 Store between 2° and 25°C (36° and 77°F). 492 TRILAFON Injection, 5 mg per mL, 1-mL ampule for intramuscular or intravenous 493 use, box of 100 (NDC 0085-0012-04). Store between 2° and 30°C (36° and 494 86°F). Keep package closed to protect from light. Exposure may cause 495 discoloration. Slight yellowish discoloration will not alter potency or therapeutic 496 efficacy; if markedly discolored, ampule should be discarded. Protect from light. 497 Store in carton until completely used. 498 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAGE 18 TRILAFON TABLETS & TRILAFON INJECTION FINAL PRINTED LABELING 18 499 TRILAFON ® 500 brand of perphenazine, USP 501 Tablets, 502 Injection 503 Schering Corporation 504 Kenilworth, NJ 07033 USA 505 Rev. 11/00 4/02 506 507 Copyright © 1969, 1991, 1994, 2002 Schering Corporation. 508 All rights reserved. 509 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Russell Katz 5/10/02 08:06:04 AM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:44.127170	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/10775s311213s24lbl.pdf', 'application_number': 11213, 'submission_type': 'SUPPL ', 'submission_number': 24}
10,763	Adderall® CII (Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets) 762 763 764 765 766 767 768 Rx only AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. ADMINISTRATION OF AMPHETAMINES FOR PROLONGED PERIODS OF TIME MAY LEAD TO DRUG DEPENDENCE AND MUST BE AVOIDED. PARTICULAR ATTENTION SHOULD BE PAID TO THE POSSIBILITY OF SUBJECTS OBTAINING AMPHETAMINES FOR NON-THERAPEUTIC USE OR DISTRIBUTION TO OTHERS, AND THE DRUGS SHOULD BE PRESCRIBED OR DISPENSED SPARINGLY. MISUSE OF AMPHETAMINE MAY CAUSE SUDDEN DEATH AND SERIOUS CARDIOVASCULAR ADVERSE EVENTS. DESCRIPTION A single-entity amphetamine product combining the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate and d, l-amphetamine aspartate monohydrate. EACH TABLET CONTAINS 5 mg 7.5 mg 10 mg 12.5 mg 15 mg 20 mg 30 mg Dextroamphetamine Saccharate 1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg 7.5 mg Amphetamine Aspartate 1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg 7.5 mg Monohydrate Dextroamphetamine Sulfate, USP 1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg 7.5 mg Amphetamine Sulfate, USP 1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg 7.5 mg Total Amphetamine Base Equivalence 3.13 mg 4.7 mg 6.3 mg 7.8 mg 9.4 mg 12.6 mg 18.8 mg Inactive Ingredients: lactitol, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, and other ingredients. Colors: Adderall® 5 mg is a white to off-white tablet, which contains no color additives. Adderall ® 7.5 mg and 10 mg contain FD&C Blue #1. Reference ID: 3827706 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adderall ® 12.5 mg, 15 mg, 20 mg and 30 mg contain FD&C Yellow #6 as a color additive. CLINICAL PHARMACOLOGY Pharmacodynamics Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Amphetamines are thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Pharmacokinetics Adderall® tablets contain d-amphetamine and l-amphetamine salts in the ratio of 3:1. Following administration of a single dose 10 or 30 mg of Adderall® to healthy volunteers under fasted conditions, peak plasma concentrations occurred approximately 3 hours post-dose for both d-amphetamine and l-amphetamine. The mean elimination half-life (t1/2) for d-amphetamine was shorter than the t1/2 of the l-isomer (9.77 to 11 hours vs. 11.5 to 13.8 hours). The PK parameters (Cmax, AUC0-inf) of d-and l-amphetamine increased approximately three-fold from 10 mg to 30 mg indicating dose-proportional pharmacokinetics. The effect of food on the bioavailability of Adderall® has not been studied. Metabolism and Excretion Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-hydroxyamphetamine, or on the side chain α or β carbons to form alpha-hydroxy amphetamine or norephedrine, respectively. Norephedrine and 4-hydroxy-amphetamine are both active and each is subsequently oxidized to form 4-hydroxy-norephedrine. Alpha-hydroxy-amphetamine undergoes deamination to form phenylacetone, which ultimately forms benzoic acid and its glucuronide and the glycine conjugate hippuric acid. Although the enzymes involved in amphetamine metabolism have not been clearly defined, CYP2D6 is known to be involved with formation of 4-hydroxy amphetamine. Since CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility. Amphetamine is known to inhibit monoamine oxidase, whereas the ability of amphetamine and its metabolites to inhibit various P450 isozymes and other enzymes has not been adequately elucidated. In vitro experiments with human microsomes indicate minor inhibition of CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and 3A4 by one or more metabolites. However, due to the probability of auto-inhibition and the lack of information on the concentration of these metabolites relative to in vivo concentrations, no predications regarding the potential for amphetamine or its metabolites to inhibit the metabolism of other drugs by CYP isozymes in vivo can be made. With normal urine pHs approximately half of an administered dose of amphetamine is recoverable in urine as derivatives of alpha-hydroxy-amphetamine and approximately another 30% to 40% of the dose is recoverable in urine as amphetamine itself. Since amphetamine has a pKa of 9.9, urinary recovery of amphetamine is highly dependent on pH and urine flow rates. Alkaline urine pHs result in less ionization and reduced renal elimination, and acidic pHs and high flow rates result in increased renal elimination with clearances greater than glomerular filtration rates, indicating the involvement of active secretion. Urinary recovery of amphetamine has been reported to range from 1% to 75%, Reference ID: 3827706 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda depending on urinary pH, with the remaining fraction of the dose hepatically metabolized. Consequently, both hepatic and renal dysfunction have the potential to inhibit the elimination of amphetamine and result in prolonged exposures. In addition, drugs that affect urinary pH are known to alter the elimination of amphetamine, and any decrease in amphetamine’s metabolism that might occur due to drug interactions or genetic polymorphisms is more likely to be clinically significant when renal elimination is decreased (see PRECAUTIONS). INDICATIONS AND USAGE Adderall® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and Narcolepsy. Attention Deficit Hyperactivity Disorder (ADHD) A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV®) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go;” excessive talking; blurting answers; can't wait turn; intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met. Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of the required number of DSM-IV® characteristics. Need for Comprehensive Treatment Program Adderall® is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician's assessment of the chronicity and severity of the child's symptoms. Long-Term Use The effectiveness of Adderall® for long-term use has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Adderall® for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Reference ID: 3827706 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma. Agitated states. Patients with a history of drug abuse. During or within 14 days following the administration of monoamine oxidase inhibitors (hypertensive crises may result). WARNINGS Serious Cardiovascular Events Sudden Death and Preexisting Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some structural heart problems alone may carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug (see CONTRAINDICATIONS). Adults Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs (see CONTRAINDICATIONS). Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2 to 4 mmHg) and average heart rate (about 3 to 6 bpm) [see ADVERSE REACTIONS], and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with preexisting hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia (see CONTRAINDICATIONS). Assessing Cardiovascular Status in Patients Being Treated With Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Reference ID: 3827706 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Psychiatric Adverse Events Preexisting Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting psychotic disorder. Bipolar Illness Particular care should be taken in using stimulants to treat ADHD patients with comorbid bipolar disorder because of concern for possible induction of mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short- term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non- medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they will likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining weight as expected may need to have their treatment interrupted. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizure, in patients with prior EEG abnormalities in absence of seizures, and very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Reference ID: 3827706 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Peripheral Vasculopathy, Including Raynaud’s Phenomenon Stimulants, including Adderall®, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. PRECAUTIONS General The least amount of amphetamine feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage. Adderall® should be used with caution in patients who use other sympathomimetic drugs. Tics Amphetamines have been reported to exacerbate motor and phonic tics and Tourette’s syndrome. Therefore, clinical evaluation for tics and Tourette’s syndrome in children and their families should precede use of stimulant medications. Information for Patients Amphetamines may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or vehicles; the patient should therefore be cautioned accordingly. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with amphetamine or dextroamphetamine and should counsel them in its appropriate use. A patient Medication Guide is available for Adderall® . The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon] • Instruct patients beginning treatment with Adderall® about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. • Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. • Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking Adderall® . Reference ID: 3827706 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Drug Interactions Acidifying Agents Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid HCl, ascorbic acid, fruit juices, etc.) lower absorption of amphetamines. Urinary Acidifying Agents (ammonium chloride, sodium acid phosphate, etc.) increase the concentration of the ionized species of the amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines. Adrenergic Blockers Adrenergic blockers are inhibited by amphetamines. Alkalinizing Agents Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) increase absorption of amphetamines. Coadministration of Adderall® and gastrointestinal alkalizing agents, such as antacids, should be avoided. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase blood levels and therefore potentiate the actions of amphetamines. Antidepressants, Tricyclic Amphetamines may enhance the activity of tricyclic or sympathomimetic agents; d- amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. MAO Inhibitors MAOI antidepressants, as well as a metabolite of furazolidone, slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings; this can cause headaches and other signs of hypertensive crisis. A variety of neurological toxic effects and malignant hyperpyrexia can occur, sometimes with fatal results. Antihistamines Amphetamines may counteract the sedative effect of antihistamines. Antihypertensives Amphetamines may antagonize the hypotensive effects of antihypertensives. Reference ID: 3827706 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Chlorpromazine Chlorpromazine blocks dopamine and norepinephrine receptors, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning. Ethosuximide Amphetamines may delay intestinal absorption of ethosuximide. Haloperidol Haloperidol blocks dopamine receptors, thus inhibiting the central stimulant effects of amphetamines. Lithium Carbonate The anorectic and stimulatory effects of amphetamines may be inhibited by lithium carbonate. Meperidine Amphetamines potentiate the analgesic effect of meperidine. Methenamine Therapy Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy. Norepinephrine Amphetamines enhance the adrenergic effect of norepinephrine. Phenobarbital Amphetamines may delay intestinal absorption of phenobarbital; coadministration of phenobarbital may produce a synergistic anticonvulsant action. Phenytoin Amphetamines may delay intestinal absorption of phenytoin; coadministration of phenytoin may produce a synergistic anticonvulsant action. Propoxyphene In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur. Proton Pump Inhibitors PPIs act on proton pumps by blocking acid production, thereby reducing gastric acidity. When Adderall XR® (20 mg single-dose) was administered concomitantly with the proton pump inhibitor, omeprazole (40 mg once daily for 14 days), the median Tmax of d- amphetamine was decreased by 1.25 hours (from 4 to 2.75 hours), and the median Tmax of l-amphetamine was decreased by 2.5 hours (from 5.5 to 3 hours), compared to Adderall XR® administered alone. The AUC and Cmax of each moiety were unaffected. Therefore, coadministration of Adderall® and proton pump inhibitors should be monitored for changes in clinical effect. Reference ID: 3827706 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Veratrum Alkaloids Amphetamines inhibit the hypotensive effect of veratrum alkaloids. Drug/Laboratory Test Interactions Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations. Carcinogenesis/Mutagenesis and Impairment of Fertility No evidence of carcinogenicity was found in studies in which d,l-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats. These doses are approximately 2.4, 1.5, and 0.8 times, respectively, the maximum recommended human dose of 30 mg/day [child] on a mg/m2 body surface area basis. Amphetamine, in the enantiomer ratio present in Adderall® (immediate-release)(d- to l- ratio of 3:1), was not clastogenic in the mouse bone marrow micronucleus test in vivo and was negative when tested in the E. coli component of the Ames test in vitro. d, l- Amphetamine (1:1 enantiomer ratio) has been reported to produce a positive response in the mouse bone marrow micronucleus test, an equivocal response in the Ames test, and negative responses in the in vitro sister chromatid exchange and chromosomal aberration assays. Amphetamine, in the enantiomer ratio present in Adderall® (immediate-release)(d- to l- ratio of 3:1), did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day (approximately 5 times the maximum recommended human dose of 30 mg/day on a mg/m2 body surface area basis). Pregnancy Teratogenic Effects Pregnancy Category C Amphetamine, in the enantiomer ratio present in Adderall® (d- to l- ratio of 3:1), had no apparent effects on embryofetal morphological development or survival when orally administered to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 6 and 16 mg/kg/day, respectively. These doses are approximately 1.5 and 8 times, respectively, the maximum recommended human dose of 30 mg/day [child] on a mg/m2 body surface area basis. Fetal malformations and death have been reported in mice following parenteral administration of d-amphetamine doses of 50 mg/kg/day (approximately 6 times that of a human dose of 30 mg/day [child] on a mg/m2 basis) or greater to pregnant animals. Administration of these doses was also associated with severe maternal toxicity. A number of studies in rodents indicate that prenatal or early postnatal exposure to amphetamine (d- or d,l-), at doses similar to those used clinically, can result in long-term neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function. There are no adequate and well-controlled studies in pregnant women. There has been one report of severe congenital bony deformity, tracheo-esophageal fistula, and anal atresia (vater association) in a baby born to a woman who took dextroamphetamine Reference ID: 3827706 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda sulfate with lovastatin during the first trimester of pregnancy. Amphetamines should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Infants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth weight. Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant lassitude. Usage in Nursing Mothers Amphetamines are excreted in human milk. Mothers taking amphetamines should be advised to refrain from nursing. Pediatric Use Long-term effects of amphetamines in children have not been well established. Amphetamines are not recommended for use in children under 3 years of age with Attention Deficit Hyperactivity Disorder described under INDICATIONS AND USAGE. Geriatric Use Adderall® has not been studied in the geriatric population. ADVERSE REACTIONS Cardiovascular Palpitations, tachycardia, elevation of blood pressure, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use. Central Nervous System Psychotic episodes at recommended doses, overstimulation, restlessness, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, tics, aggression, anger, logorrhea, dermatillomania. Eye Disorders Vision blurred, mydriasis. Gastrointestinal Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects. Allergic Urticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Endocrine Impotence, changes in libido, frequent or prolonged erections. Skin Alopecia. Musculoskeletal Rhabdomyolysis. DRUG ABUSE AND DEPENDENCE Adderall® (Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets) is a Schedule II controlled substance. Reference ID: 3827706 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Amphetamines have been extensively abused. Tolerance, extreme psychological dependence, and severe social disability have occurred. There are reports of patients who have increased the dosage to levels many times higher than recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with amphetamines include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia. OVERDOSAGE Individual patient response to amphetamines varies widely. Toxic symptoms may occur idiosyncratically at low doses. Symptoms Manifestations of acute overdosage with amphetamines include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia and rhabdomyolysis. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma. Treatment Consult with a Certified Poison Control Center for up to date guidance and advice. Management of acute amphetamine intoxication is largely symptomatic and includes gastric lavage, administration of activated charcoal, administration of a cathartic and sedation. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendation in this regard. Acidification of the urine increases amphetamine excretion, but is believed to increase risk of acute renal failure if myoglobinuria is present. If acute, severe hypertension complicates amphetamine overdosage, administration of intravenous phentolamine has been suggested. However, a gradual drop in blood pressure will usually result when sufficient sedation has been achieved. Chlorpromazine antagonizes the central stimulant effects of amphetamines and can be used to treat amphetamine intoxication. DOSAGE AND ADMINISTRATION Regardless of indication, amphetamines should be administered at the lowest effective dosage, and dosage should be individually adjusted according to the therapeutic needs and response of the patient. Late evening doses should be avoided because of the resulting insomnia. Attention Deficit Hyperactivity Disorder Not recommended for children under 3 years of age. In children from 3 to 5 years of age, start with 2.5 mg daily; daily dosage may be raised in increments of 2.5 mg at weekly intervals until optimal response is obtained. In children 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. Only in rare cases will it be necessary to exceed a total of 40 mg per day. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours. Reference ID: 3827706 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy. Narcolepsy Usual dose 5 mg to 60 mg per day in divided doses, depending on the individual patient response. Narcolepsy seldom occurs in children under 12 years of age; however, when it does, dextroamphetamine sulfate may be used. The suggested initial dose for patients aged 6 to 12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in increments of 10 mg at weekly intervals until optimal response is obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should be reduced. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours. HOW SUPPLIED Adderall® 5 mg: A round, flat-faced beveled edge, white to off-white tablet, “5” embossed on one side with partial bisect and “AD” embossed on the other side, supplied as follows: 100 Tablets Unit-of-use NDC 0555-0762-02 Adderall® 7.5 mg: An oval, convex, blue tablet, “7.5” embossed on one side with a partial bisect and “AD” embossed on the other side with a full and partial bisect, supplied as follows: 100 Tablets Unit-of-use NDC 0555-0763-02 Adderall® 10 mg: A round, convex, blue tablet, “10” embossed on one side with a full and partial bisect and “AD” embossed on the other side, supplied as follows: 100 Tablets Unit-of-use NDC 0555-0764-02 Adderall® 12.5 mg: A round, flat-faced beveled edge, orange tablet, “12.5” embossed on one side and “AD” embossed on the other side with a full and partial bisect, supplied as follows: 100 Tablets Unit-of-use NDC 0555-0765-02 Adderall® 15 mg: An oval, convex, orange tablet, “15” embossed on one side with a partial bisect and “AD” embossed on the other side with a full and partial bisect, supplied as follows: 100 Tablets Unit-of-use NDC 0555-0766-02 Adderall® 20 mg: A round, convex, orange tablet, “20” embossed on one side with a full and partial bisect and “AD” embossed on the other side, supplied as follows: 100 Tablets Unit-of-use NDC 0555-0767-02 Adderall® 30 mg: A round, flat-faced beveled edge, orange tablet, “30” embossed on one side with a full and partial bisect and “AD” embossed on the other side, supplied as follows: Reference ID: 3827706 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 100 Tablets Unit-of-use NDC 0555-0768-02 Dispense in a tight, light-resistant container. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Teva Select Brands, Horsham, PA 19044 Division of Teva Pharmaceuticals USA Revised October 2015 MEDICATION GUIDE Adderall® (ADD-ur-all) CII (Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets) Rx only Read the Medication Guide that comes with Adderall® before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about you or your child’s treatment with Adderall® . What is the most important information I should know about Adderall®? The following have been reported with use of Adderall® and other stimulant medicines. 1. Heart-related problems: • sudden death in patients who have heart problems or heart defects • stroke and heart attack in adults • increased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting Adderall® . Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment with Adderall® . Call your doctor right away if you or your child have any signs of heart problems such as chest pain, shortness of breath, or fainting while taking Adderall® . 2. Mental (Psychiatric) problems: All Patients • new or worse behavior and thought problems • new or worse bipolar illness • new or worse aggressive behavior or hostility Children and Teenagers • new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family Reference ID: 3827706 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking Adderall®, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. 3. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]: • fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red Tell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes. Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking Adderall® . What is Adderall®? Adderall® is a central nervous system stimulant prescription medicine. It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). Adderall® may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. Adderall® should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. Adderall® is also used in the treatment of a sleep disorder called narcolepsy. Adderall® is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep Adderall® in a safe place to prevent misuse and abuse. Selling or giving away Adderall® may harm others, and is against the law. Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs. Who should not take Adderall®? Adderall® should not be taken if you or your child: • have heart disease or hardening of the arteries • have moderate to severe high blood pressure • have hyperthyroidism • have an eye problem called glaucoma • are very anxious, tense, or agitated • have a history of drug abuse • are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI. • are sensitive to, allergic to, or had a reaction to other stimulant medicines Adderall® is not recommended for use in children less than 3 years old. Adderall® may not be right for you or your child. Before starting Adderall® tell your or your child’s doctor about all health conditions (or a family history of) including: • heart problems, heart defects, high blood pressure • mental problems including psychosis, mania, bipolar illness, or depression • tics or Tourette’s syndrome Reference ID: 3827706 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • liver or kidney problems • thyroid problems • seizures or have had an abnormal brain wave test (EEG) • circulation problems in fingers or toes Tell your doctor if you or your child are pregnant, planning to become pregnant, or breastfeeding. Can Adderall® be taken with other medicines? Tell your doctor about all of the medicines that you or your child take including prescription and nonprescription medicines, vitamins, and herbal supplements. Adderall® and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking Adderall® . Your doctor will decide whether Adderall® can be taken with other medicines. Especially tell your doctor if you or your child take: • anti-depression medicines including MAOIs • blood pressure medicines • seizure medicines • blood thinner medicines • cold or allergy medicines that contain decongestants • stomach acid medicines Know the medicines that you or your child take. Keep a list of your medicines with you to show your doctor and pharmacist. Do not start any new medicine while taking Adderall® without talking to your doctor first. How should Adderall® be taken? • Take Adderall® exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child. • Adderall® tablets are usually taken two to three times a day. The first dose is usually taken when you first wake in the morning. One or two more doses may be taken during the day, 4 to 6 hours apart. • Adderall® can be taken with or without food. • From time to time, your doctor may stop Adderall® treatment for a while to check ADHD symptoms. • Your doctor may do regular checks of the blood, heart, and blood pressure while taking Adderall®. Children should have their height and weight checked often while taking Adderall®. Adderall® treatment may be stopped if a problem is found during these check-ups. • If you or your child take too much Adderall® or overdoses, call your doctor or poison control center right away, or get emergency treatment. What are possible side effects of Adderall®? See “What is the most important information I should know about Adderall®?” for information on reported heart and mental problems. Other serious side effects include: • slowing of growth (height and weight) in children Reference ID: 3827706 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • seizures, mainly in patients with a history of seizures • eyesight changes or blurred vision Common side effects include: • stomach ache • decreased appetite • nervousness Adderall® may affect your or your child’s ability to drive or do other dangerous activities. Talk to your doctor if you or your child have side effects that are bothersome or do not go away. This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Adderall®? • Store Adderall® in a safe place at room temperature, 20° to 25°C (68° to 77°F). • Keep Adderall® and all medicines out of the reach of children. General information about Adderall® Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Adderall® for a condition for which it was not prescribed. Do not give Adderall® to other people, even if they have the same condition. It may harm them and it is against the law. This Medication Guide summarizes the most important information about Adderall®. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Adderall® that was written for healthcare professionals. For more information about Adderall® , please contact Teva Pharmaceuticals at 1-888-838-2872. What are the ingredients in Adderall®? Active Ingredient: dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, USP, amphetamine sulfate, USP Inactive Ingredients: lactitol, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, and other ingredients. This Medication Guide has been approved by the U.S. Food and Drug Administration. Teva Select Brands, Horsham, PA 19044 Division of Teva Pharmaceuticals USA Revised October 2015 Reference ID: 3827706 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:44.685316	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/011522s042lbl.pdf', 'application_number': 11522, 'submission_type': 'SUPPL ', 'submission_number': 42}
10,764	_________________________________________________________________________________________ __________________________________________________________________________________________ NDA 11525/S-027 Page 4 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use IC-GREEN® safely and effectively. See full prescribing information for IC-GREEN®. IC-GREEN® ( indoc yanine gre e n for inje c tion, USP) For Intravenous Injection Initial U.S. Approval: 1959 ----------------INIDICATION AND USAGE---------------- IC-GREEN® a tricarbocyanine dye, is indicated: • For determining cardiac output, hepatic function and liver blood flow. (1.1) • For ophthalmic angiography. (1.2) ------------DOSAGE AND ADMINISTRATION---------- Indicator-Dilution Studies. (2.1) Under sterile conditions, the IC-Green® powder should be dissolved with the Sterile Water for Injection, USP provided and the solution used within 6 hours after it is prepared. The usual doses of IC-GREEN® for dilution curves are: Adults – 5.0 mg, Children – 2.5 mg, and Infants – 1.25 mg. Hepatic Function Studies. (2.2) Under sterile conditions, the IC-GREEN® powder should be dissolved with the Sterile Water for Injection, USP provided. The patient should be weighed and the dosage calculated on the basis of 0.5 mg/kg of body weight. Exactly 5 mL of Sterile Water for Injection, USP should be added to the 25 mg vial giving 5 mg of dye per mL of solution. Ophthalmic Angiography Studies. (2.3) Dosages up to 40 mg IC-GREEN® dye in 2 mL of Sterile Water for Injection, USP should be administered. A 5 mL bolus of normal saline should immediately follow the injection of the dye. ----------DOSAGE FORMS AND STRENGTHS--------- • IC-GREEN® is a sterile, lyophilized green powder containing 25 mg of indocyanine green with no more than 5% sodium iodide. (3) -------------------CONTRAINDICATIONS----------------- • IC-GREEN® contains sodium iodide and should be used with caution in patients who have a history of allergy to iodides because of the risk of anaphylaxis. (4) ------------WARNINGS AND PRECAUTIONS----------- • Death due to anaphylaxis have been reported following I C -G R E E N ® adminis tr ation dur ing c ar diac c athe te r ization. (5.1) • IC-GREEN® is unstable in aqueous solution and must be used within 6 hours. (5.2) • Radioac tive iodine uptake s tudie s s hould not be pe r f or me d f or at le as t a we e k f ollowing the us e of IC-GREEN® (5.3) -------------------ADVERSE REACTIONS------------------ Most common adverse reactions are anaphylac tic or ur tic ar ial r e ac tions. These have be e n r e por te d in patie nts wi th and without a his tor y of alle r gy to iodide s . (6) To report SUSPECTED ADVERSE REACTIONS, contact Akorn, Inc. at 1-800-932-5676 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------DRUG INTERACTIONS------------------ Products containing sodium bisulfite reduce the absorption peak of IC-GREEN® in blood. (7) Revised 03/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 For determining cardiac output, hepatic function, and liver blood flow 1.2 For ophthalmic angiography 2 DOSAGE AND ADMINISTRATION 2.1 Indicator-Dilution Studies 2.2 Hepatic Function Studies 2.3 Ophthalmic Angiography Studies 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Anaphylaxis 5.2 Drug Instability 5.3 Drug/Laboratory Te st Inte rac tions 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pre gnanc y 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING Sections or subsections omitted from the full prescribing information are not listed Reference ID: 3829201 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11525/S-027 Page 5 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE IC-GREEN® is indicated: 1.1 For Determining Cardiac Output, Hepatic Function and Liver Blood Flow 1.2 For ophthalmic a ngiography 2 DOSAGE AND ADMINISTRATION 2.1 Indicator-Dilution Studies In the performance of dye dilution curves, a known amount of dye is injected as a single bolus as rapidly as possible via cardiac catheter into selected sites in the vascular system. A recording instrument (oximeter or densitometer) is attached to a needle or catheter for sampling of the dye-blood mixture from a systemic arterial sampling site. Unde r ste rile c onditions, the IC-GREEN® powde r should be dissolve d with the S t e r i l e W a t e r f o r I n j e c t i o n , U S P provide d for this produc t, and the solution use d within 6 hours afte r it is pre pare d. If a pre c ipitate is pre se nt, disc ard the solution. The usual dose s of IC-GREEN® for dilution c urve s are as follows: Adults - 5.0 mg Childre n - 2.5 mg Infants - 1.25 mg The se dose s of the dye are usually inje c te d in 1 mL volume . An ave rage of five dilution c urve s are recommended in the pe rformanc e of a diagnostic c ardiac c athe te rization. The total dose of dye inje c te d should be ke pt be low 2 mg/kg. While sterile water for injection may be used to rinse the syringe, isotonic saline should be used to flush the residual dye from the cardiac catheter into the circulation so as to avoid hemolysis. With the exception of the rinsing of the dye injection syringe, saline should be used in all other parts of the catheterization procedure. Calibrating Dye Curves: To quantitate the dilution c urve s, standard dilutions of IC-GREEN® in whole blood are made as follows. It is strongly re c omme nde d that the same dye that was use d for the inje c tions be use d in the pre paration of the se standard dilutions. The most c onc e ntrate d dye solution is made by ac c urate ly diluting 1 mL of the 5 mg/mL dye with 7 mL of distille d wate r. This c onc e ntration is the n suc c e ssive ly halve d by diluting 4 mL of the pre vious c onc e ntration with 4 mL of distille d wate r. If a 2.5 mg/mL c onc e ntration was use d for the dilution c urve s, 1 mL of the 2.5 mg/mL dye is adde d to 3 mL of distille d wate r to make the most c onc e ntrate d "standard" solution. This c onc e ntration is the n suc c e ssive ly halve d by diluting 2 mL of the pre vious c onc e ntration with 2 mL of distille d wate r. The n 0.2 mL portions (ac c urate ly me asure d from a c alibrate d syringe ) of the se dye solutions are adde d to 5 mL aliquots of the subje c t's blood, giving final c onc e ntrations of the dye in blood be ginning with 24.0 mg/lite r, approximate ly (ac tual c onc e ntration de pe nds on the e xac t volume of dye adde d). This c onc e ntration is, of c ourse , suc c e ssive ly halve d in the suc c e e ding aliquots of the subje c t's blood. The se aliquots of blood c ontaining known amounts of dye , as we ll as a blank sample t o whic h 0.2 mL of saline c ontaining no dye has be e n adde d, are the n passe d through the de te c ting instrume nt and a c alibration c urve is c onstruc te d from the de fle c tions re c orde d. Reference ID: 3829201 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11525/S-027 Page 6 2.2 Hepatic Function Studies Due to its absorption spe c trum, c hanging c onc e ntrations of IC- GREEN® (indoc yanine gre e n for inje c tion) in the blood c an be monitore d by e ar de nsitome try or by obtaining blood spe c ime ns at time d inte rvals. The te c hnique for both me thods is as follows. The patie nt should be studie d in a fasting, basal state . The patie nt should be we ighe d and the dosage c alc ulate d on the basis of 0.5 mg/kg of body we ight. Unde r ste rile c onditions, the IC-GREEN® powde r should be dissolve d with the S t e r i l e W a t e r f o r I n j e c t i o n , U S P provide d. Exac tly 5 mL of Steri le Wa te r for Injection, USP should be adde d to the 25 mg vial giving 5 mg of dye pe r mL of solution. Inje c t the c a l c u l a t e d amount of dye (0.5 mg/kg of body weight) into the lume n of an arm ve in as rapidly as possible , without allowing the dye to e sc ape outside the ve in. (If the photometric method is used, prior to injecting IC-GREEN®, withdraw 6 mL of venous blood from the patients arm for serum blank and standard curve construction, and through the same needle, inject the correct amount of dye.) Ear Densitometry: Ear oxime try has also be e n use d and make s it possible to monitor the appe aranc e and dis appe aranc e of IC-GREEN® without the ne c e ssity of withdrawal and spe c trophotome tric analysis of blood sample s for c alibration. An e ar de nsitome te r whic h has a c ompe nsatory photo- e le c tric c e ll to c orre c t for c hange s in blood volume and he matoc rit, and a de te c tion photo c e ll whic h re giste rs le ve ls should be used. This de vic e pe rmits simultane ous me asure me nt of c ardiac output, blood volume and he patic c le aranc e of IC-GREEN® . This te c hnique has been e mploye d in ne wborn infants, he althy adults and in c hildre n and adults with live r dise ase . The normal subje c t has a re moval rate of 18 to 24% pe r minute . Due to the abs e nc e of e xtra-he patic re moval, IC-GREEN® was found to be suite d for se rial study of se ve re c hronic live r dise ase and to provide a stable me asure me nt of he patic blood flow. In large r dose s, IC-GREEN® can be used in de te c ting drug induc e d alte rations of he patic func tion and in the de te c tion of mild live r injury. Using the e ar de nsitome te r, a dosage of 0.5 mg/kg in normal subje c ts give s the following c le aranc e patte rn. graph Reference ID: 3829201 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11525/S-027 Page 7 graph *Dic hromatic e arpie c e de nsitome te r supplie d by The Wate rs Company, Roc he ste r, Minne sota. Photome tric Me thod Determination Using Percentage Retention of Dye: A typic al c urve obtaine d by plotting dye c onc e ntration ve rsus optic al de nsity is shown. The pe rc e nt re te ntion c an be re ad from this plot. If more ac c urate re sults are de sire d, a c urve using the patie nt's blood and the vial of IC-GREEN® be ing use d in the de te rmination c an be c onstruc te d as follows: 1. Take 6 mL of non-dye -c ontaining ve nous blood from the patie nt's arm. Plac e in a te st tube and allow the blood to c lot. The se rum is se parate d by c e ntrifugation. 2. Pipe tte 1 mL of the se rum into a mic roc uve tte . 3. Add 1 lambda (λ) of the 5 mg/mL aque ous IC-GREEN® (ste rile indoc yanine gre e n) solution to the se rum, giving a dilution of 5 mg/lite r, the standard for 50% re te ntion. (The addition of 2 lambda (λ) of the 5 mg/mL IC-GREEN® solution would give 100% re te ntion; howe ve r, this c onc e ntration c annot be re ad on the spe c trophotome te r.) 4. The optic al de nsity of this solution should be re ad at 805 nm, using normal se rum as the blank. 5. Using graph pape r similar to that use d in the illustration, plot the 50% figure obtaine d in Ste p 4, and draw a line c onne c ting this point with the ze ro c oordinate s. Percentage Retention: A single 20 -minute sample (withdrawn from a ve in in the opposite arm to that inje c te d) should be collected and allowed to clot, centrifuged and its optical density determined at 805 nm using the patient’s normal serum as the blank. The dye concentration can be read from the curve above. A single 20-minute sample of serum in healthy subjects should contain no more than 4% of the initial concentration of the dye. The use of percentage retention is less accurate than percentage disappearance rate. Hemolysis is not expected to interfere with a reading. Determination Using Disappearance Rate of Dye: To c alc ulate the pe rc e ntage disappe aranc e rate , obtain sample s at 5, 10, 15 and 20 minute s afte r inje c ting the dye . Pre pare the sample as in the pre vious se c tion and me asure the optic al de nsitie s at 805 nm, using the patie nt's normal se rum as the Reference ID: 3829201 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11525/S-027 Page 8 blank. The IC-GREEN® c onc e ntration in e ac h time d spe c ime n c an be de te rmine d by using the c onc e ntration c urve illustrate d. Values should be plotted on semilogarithmic paper. Spe c ime ns c ontaining IC-GREEN® should be re ad at the same te mpe rature sinc e its optic al de nsity is influe nc e d by te mpe rature variations. Normal Value s: Pe rc e ntage disappe aranc e rate in he althy subje c ts is 18 to 24 % pe r minute . Normal biologic al half-time is 2.5 to 3.0 minute s. 2.3 Ophthalmic Angiography Studies The e xc itation and e mission spe c tra (Figure 1) and the absorption spe c tra (Figure 2) of IC-GREEN® make it use ful in ophthalmic angiography. graph Dosage s up to 40 mg IC-GREEN® dye in 2 mL of Sterile Water for Inje ct ion, USP should be used de pe nding on the imaging e quipme nt and te c hnique use d. The ante c ubital ve in can be inje c te d with an IC-GREEN® dye bolus should imme diate ly be followe d by a 5 mL bolus of normal saline . 3 DOSAGE FORMS AND STRENGTHS IC-GREEN® is a sterile, lyophilized green powder containing 25 mg of indocyanine green with no more than 5% sodium iodide. 4 CONTRAINDICATIONS IC-GREEN® c ontains sodium iodide and should be use d with c aution in patie nts who have a history of alle rgy to iodide s because of the risk of anaphylaxis. Reference ID: 3829201 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11525/S-027 Page 9 5 WARNINGS AND PRECAUTIONS 5.1 Anaphylaxis Deaths from anaphylaxis have been reported following IC-GREEN® administration during cardiac catheterization. 5.2 Drug Instability IC-GREEN® is unstable in aque ous solution and must be use d within 6 hours. Howe ve r, the dye is stable in plasma and whole blood so that sample s obtaine d in disc ontinuous sampling te c hnique s may be re ad hours late r. Ste rile te c hnique s should be use d in handling the dye solution as we ll as in the pe rformanc e of the dilution c urve s. If a precipitate is present, discard the solution. 5.3 Drug/Laboratory Te st Inte rac tions Radioac tive iodine uptake studie s should not be pe rforme d for at le ast a we e k following the use of IC-GREEN®. 6 ADVERSE REACTIONS Anaphylac tic or urtic arial re ac tions have be e n re porte d in patie nts with or without history of alle rgy to iodide s. If suc h re ac tions oc c ur, treat with the appropriate age nts, e .g., e pine phrine , antihistamine s, and c ortic oste roids. 7 DRUG INTERACTIONS Preparation containing sodium bisulfite, including some heparin products reduce the absorption peak of IC-GREEN® in blood and, therefore, should not be used as an anticoagulant for the collection of samples for analysis. 8 USE IN SPECIFIC POPULATIONS 8.1 Pre gnanc y Animal reproduction studies have not been conducted with IC-GREEN®. It is also not known whether IC-GREEN® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. IC-GREEN® should be given to a pregnant woman only if clearly indicated. 8.3 Nursing Mothe rs It is not known whe the r this drug is e xc re te d in human milk. Be c ause many drugs are e xc re te d in human milk, c aution should be e xe rc ise d whe n IC-GREEN® is administe re d to a nursing woman. 8.4 Pe diatric Use Safe ty and e ffe c tive ne ss in pe diatric patie nts have be e n e stablishe d. See DOSAGE AND ADMINISTRATION (2) for specific dosing information in pediatric patients. 8.5 Ge riatric Use No ove rall diffe re nc e s in safe ty or e ffe c tive ne ss have be e n obse rve d be twe e n e lde rly and younge r patie nts. 10 OVERDOSAGE The re are no data available de sc ribing the signs, symptoms, or laboratory findings ac c ompanying ove rdosage . The LD50 afte r intravenous administration range s be twe e n 60 and 80 mg/kg in mic e , 50 and 70 mg/kg in rats and 50 and 80 mg/kg in rabbits. Based on body surface area, these doses are 2.4 to 13-fold the maximum recommended human (MRHD) dose of 2 mg/kg for indicator-dilution studies, 10 to 52-fold the MRHD of 0.5 mg/kg for hepatic-function studies, and 7 to 39-fold the MRHD of 0.67 mg/kg for ophthalmic angiography studies. Reference ID: 3829201 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11525/S-027 Page 10 11 DESCRIPTION IC-GREEN® is a ste rile , lyophilize d gre e n powde r c ontaining 25 mg of indoc yanine gre e n with no more than 5% sodium iodide . It is pac kage d with Ste rile Wate r for Inje c tion, USP use d to dissolve the indoc yanine gre e n. IC-GREEN® is to be administe re d intrave nously. Indoc yanine gre e n is a wate r soluble , tric arboc yanine dye with a pe ak spe c tral absorption at 800 nm. The c he mic al name for Indoc yanine Gre e n is 1 H-Be nz[e]indolium, 2-[7-[1,3-dihydro-1,1-dime thyl-3 (4-sulfobutyl)-2H-be nz[e]indol-2-ylide ne ]-1,3,5-he ptatrie nyl]-1,1-dime thyl-3-(4-sulfobutyl)-,hydroxide , inne r salt, sodium salt. IC-GREEN® has a pH of approximate ly 6.5 whe n re c onstitute d. Eac h vial of IC GREEN® c ontains 25 mg of indoc yanine gre e n as a ste rile lyophilize d powde r. structural formula 12 CLINICAL PHARMACOLOGY IC-GREEN® permits recording of the indicator-dilution curves for both diagnostic and research purposes independently of fluctuations in oxygen saturation. Following intrave nous inje c tion, IC GREEN® is rapidly bound to plasma prote in, of whic h albumin is the princ iple c arrie r (95%). IC GREEN® unde rgoe s no signific ant e xtrahe patic or e nte rohe patic c irc ulation; simultane ous arte rial and ve nous blood e stimations have shown ne gligible re nal, pe riphe ral, lung or c e re bro-spinal uptake of the dye . IC-GREEN® is take n up from the plasma almost e xc lusive ly by the he patic pare nc hymal c e lls and is se c re te d e ntire ly into the bile . Afte r biliary obstruc tion, the dye appe ars in the he patic lymph, inde pe nde ntly of the bile , sugge sting that the biliary muc osa is suffic ie ntly intac t to pre ve nt diffusion of the dye , though allowing diffusion of bilirubin. The se c harac te ristic s make IC-GREEN® a he lpful inde x of he patic func tion. The peak absorption and emission of IC-GREEN® lie in a region (800 to 850 nm) where transmission of energy by the pigment epithelium is more efficient than in the region of visible light energy. IC-GREEN® also has the property of being nearly 98% bound to blood protein, and therefore, excessive dye extravasation does not take place in the highly fenestrated choroidal vasculature. It is, therefore, useful in both absorption and fluorescence infrared angiography of the choroidal vasculature when using appropriate filters and film in a fundus camera. The plasma frac tional disappe aranc e rate at the re c omme nde d 0.5 mg/kg dose has be e n re porte d to be signific antly gre ate r in wome n than in me n, although the re was no signific ant diffe re nc e in the c alc ulate d value for c le aranc e . 13 NONCLINICAL TOXICOLOGY 13.1 Carc inoge ne sis, Mutage ne sis, Impairme nt of Fe rtility No studie s have be e n pe rforme d to e valuate the c arc inoge nic ity, mutage nic ity, or impairme nt of fe rtility. Reference ID: 3829201 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11525/S-027 Page 11 16 HOW SUPPLIED/STORAGE AND HANDLING IC-GREEN® is supplie d in a kit (NDC 17478-701-02) c ontaining six 25 mg IC-GREEN® vials and six 10 mL Sterile Water for Injection, USP ampule s: NDC 17478-701-25 IC-GREEN® vial. 25 mg fill in 20 mL vial. NDC 17478-701-10 S t e r i l e W a t e r f o r I n j e c t i o n , U S P ampule . 10 mL fill in 10 mL ampule . STORAGE: Store at 20° to 25°C (68° to 77°F). company logo Manufac ture d by: Akorn, Inc . Lake Fore st, IL 60045 IG00N Re v. 03/15 Reference ID: 3829201 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:44.693065	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/011525s027lbl.pdf', 'application_number': 11525, 'submission_type': 'SUPPL ', 'submission_number': 27}
10,762	NDA 11-522/S-034 and S-037 NDA 21-303/S-013 Page 3 ADDERALL® CII Rx ONLY AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. ADMINISTRATION OF AMPHETAMINES FOR PROLONGED PERIODS OF TIME MAY LEAD TO DRUG DEPENDENCE AND MUST BE AVOIDED. PARTICULAR ATTENTION SHOULD BE PAID TO THE POSSIBILITY OF SUBJECTS OBTAINING AMPHETAMINES FOR NON- THERAPEUTIC USE OR DISTRIBUTION TO OTHERS, AND THE DRUGS SHOULD BE PRESCRIBED OR DISPENSED SPARINGLY. MISUSE OF AMPHETAMINE MAY CAUSE SUDDEN DEATH AND SERIOUS CARDIOVASCULAR ADVERSE EVENTS. DESCRIPTION: A single-entity amphetamine product combining the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate and d, l-amphetamine aspartate monohydrate. EACH TABLET CONTAINS: 5 mg 7.5 mg 10 mg 12.5 mg 15 mg 20mg 30 mg Dextroamphetamine Saccharate 1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg 7.5 mg Amphetamine Aspartate Monohydrate 1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg 7.5 mg Dextroamphetamine Sulfate USP 1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg 7.5 mg Amphetamine Sulfate USP 1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg 7.5 mg Total amphetamine base equivalence 3.13 mg 4.7 mg 6.3 mg 7.8 mg 9.4 mg 12.6 mg 18.8 mg Inactive Ingredients: lactitol, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, and other ingredients. Colors: ADDERALL® 5 mg is a white to off-white tablet, which contains no color additives. ADDERALL® 7.5 mg and 10 mg contain FD & C Blue #1. ADDERALL® 12.5 mg, 15 mg, 20 mg and 30 mg contain FD & C Yellow #6 as a color additive. CLINICAL PHARMACOLOGY: Pharmacodynamics Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Amphetamines are thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. PHARMACOKINETICS ADDERALL® tablets contain d-amphetamine and l-amphetamine salts in the ratio of 3:1. Following administration of a single dose 10 or 30 mg of ADDERALL® to healthy volunteers under fasted conditions, peak plasma concentrations occurred approximately 3 hours post-dose for both d-amphetamine and l-amphetamine. The mean elimination half-life (t1/2 ) for d-amphetamine was shorter than the t1/2 of the l-isomer (9.77-11 hours vs. 11.5-13.8 hours). The PK parameters (Cmax, AUC0-inf) of d-and l-amphetamine increased approximately three-fold from 10 mg to 30 mg indicating dose-proportional pharmacokinetics. The effect of food on the bioavailability of ADDERALL® has not been studied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-522/S-034 and S-037 NDA 21-303/S-013 Page 4 Metabolism and Excretion Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-hydroxyamphetamine, or on the side chain α or β carbons to form alpha-hydroxy-amphetamine or norephedrine, respectively. Norephedrine and 4-hydroxy-amphetamine are both active and each is subsequently oxidized to form 4- hydroxy-norephedrine. Alpha-hydroxy-amphetamine undergoes deamination to form phenylacetone, which ultimately forms benzoic acid and its glucuronide and the glycine conjugate hippuric acid. Although the enzymes involved in amphetamine metabolism have not been clearly defined, CYP2D6 is known to be involved with formation of 4-hydroxy-amphetamine. Since CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility. Amphetamine is known to inhibit monoamine oxidase, whereas the ability of amphetamine and its metabolites to inhibit various P450 isozymes and other enzymes has not been adequately elucidated. In vitro experiments with human microsomes indicate minor inhibition of CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and 3A4 by one or more metabolites. However, due to the probability of auto-inhibition and the lack of information on the concentration of these metabolites relative to in vivo concentrations, no predications regarding the potential for amphetamine or its metabolites to inhibit the metabolism of other drugs by CYP isozymes in vivo can be made. With normal urine pHs approximately half of an administered dose of amphetamine is recoverable in urine as derivatives of alpha-hydroxy-amphetamine and approximately another 30%-40% of the dose is recoverable in urine as amphetamine itself. Since amphetamine has a pKa of 9.9, urinary recovery of amphetamine is highly dependent on pH and urine flow rates. Alkaline urine pHs result in less ionization and reduced renal elimination, and acidic pHs and high flow rates result in increased renal elimination with clearances greater than glomerular filtration rates, indicating the involvement of active secretion. Urinary recovery of amphetamine has been reported to range from 1% to 75%, depending on urinary pH, with the remaining fraction of the dose hepatically metabolized. Consequently, both hepatic and renal dysfunction have the potential to inhibit the elimination of amphetamine and result in prolonged exposures. In addition, drugs that effect urinary pH are known to alter the elimination of amphetamine, and any decrease in amphetamine’s metabolism that might occur due to drug interactions or genetic polymorphisms is more likely to be clinically significant when renal elimination is decreased, (See PRECAUTIONS). INDICATIONS: ADDERALL® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and Narcolepsy. Attention Deficit Hyperactivity Disorder (ADHD) A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV®) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; "on the go;" excessive talking; blurting answers; can't wait turn; intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met. Special Diagnostic Considerations: Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-522/S-034 and S-037 NDA 21-303/S-013 Page 5 educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of the required number of DSM-IV® characteristics. Need for Comprehensive Treatment Program: ADDERALL® is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician's assessment of the chronicity and severity of the child's symptoms. Long-Term Use: The effectiveness of ADDERALL® for long-term use has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use ADDERALL® for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. CONTRAINDICATIONS: Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma. Agitated states. Patients with a history of drug abuse. During or within 14 days following the administration of monoamine oxidase inhibitors (hypertensive crises may result). WARNINGS: Serious Cardiovascular Events Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some structural heart problems alone may carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug (see CONTRAINDICATIONS). Adults Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs (see CONTRAINDICATIONS). Hypertension and other Cardiovascular Conditions This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-522/S-034 and S-037 NDA 21-303/S-013 Page 6 Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm) [see ADVERSE REACTIONS], and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre- existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia (see CONTRAINDICATIONS). Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g. electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Pre-Existing Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with pre-existing psychotic disorder. Bipolar Illness Particular care should be taken in using stimulants to treat ADHD patients with comorbid bipolar disorder because of concern for possible induction of mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. Long-Term Suppression of Growth This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-522/S-034 and S-037 NDA 21-303/S-013 Page 7 Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they will likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining weight as expected may need to have their treatment interrupted. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizure, in patients with prior EEG abnormalities in absence of seizures, and very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. PRECAUTIONS: General: The least amount of amphetamine feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage. ADDERALL® should be used with caution in patients who use other sympathomimetic drugs. Tics: Amphetamines have been reported to exacerbate motor and phonic tics and Tourette’s syndrome. Therefore, clinical evaluation for tics and Tourette’s syndrome in children and their families should precede use of stimulant medications. Information for Patients: Amphetamines may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or vehicles; the patient should therefore be cautioned accordingly. Drug Interactions: Acidifying agents -Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid HCl, ascorbic acid, fruit juices, etc.) lower absorption of amphetamines. Urinary acidifying agents -(ammonium chloride, sodium acid phosphate, etc.) Increase the concentration of the ionized species of the amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines. Adrenergic blocker -Adrenergic blockers are inhibited by amphetamines. Alkalinizing agents -Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) increase absorption of amphetamines. Co-administration of ADDERALL® and gastrointestinal alkalizing agents, such as antacids, should be avoided. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase blood levels and therefore potentiate the actions of amphetamines. Antidepressants, tricyclic -Amphetamines may enhance the activity of tricyclic or sympathomimetic agents; d- amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. MAO inhibitors -MAOI antidepressants, as well as a metabolite of furazolidone, slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the release of norepinephrine and other This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-522/S-034 and S-037 NDA 21-303/S-013 Page 8 monoamines from adrenergic nerve endings; this can cause headaches and other signs of hypertensive crisis. A variety of neurological toxic effects and malignant hyperpyrexia can occur, sometimes with fatal results. Antihistamines -Amphetamines may counteract the sedative effect of antihistamines. Antihypertensives -Amphetamines may antagonize the hypotensive effects of antihypertensives. Chlorpromazine -Chlorpromazine blocks dopamine and norepinephrine receptors, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning. Ethosuximide -Amphetamines may delay intestinal absorption of ethosuximide. Haloperidol -Haloperidol blocks dopamine receptors, thus inhibiting the central stimulant effects of amphetamines. Lithium carbonate -The anorectic and stimulatory effects of amphetamines may be inhibited by lithium carbonate. Meperidine -Amphetamines potentiate the analgesic effect of meperidine. Methenamine therapy -Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy. Norepinephrine -Amphetamines enhance the adrenergic effect of norepinephrine. Phenobarbital -Amphetamines may delay intestinal absorption of phenobarbital; co-administration of phenobarbital may produce a synergistic anticonvulsant action. Phenytoin -Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may produce a synergistic anticonvulsant action. Propoxyphene -In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur. Veratrum alkaloids -Amphetamines inhibit the hypotensive effect of veratrum alkaloids. Drug/Laboratory Test Interactions: Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations. Carcinogenesis/Mutagenesis and Impairment of Fertility: No evidence of carcinogenicity was found in studies in which d,l-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats. These doses are approximately 2.4, 1.5, and 0.8 times, respectively, the maximum recommended human dose of 30 mg/day [child] on a mg/m 2 body surface area basis. Amphetamine, in the enantiomer ratio present in ADDERALL® (immediate-release)(d- to l- ratio of 3:1), was not clastogenic in the mouse bone marrow micronucleus test in vivo and was negative when tested in the E. coli component of the Ames test in vitro. d,l-Amphetamine (1:1 enantiomer ratio) has been reported to produce a positive response in the mouse bone marrow micronucleus test, an equivocal response in the Ames test, and negative responses in the in vitro sister chromatid exchange and chromosomal aberration assays. Amphetamine, in the enantiomer ratio present in ADDERALL® (immediate-release)(d- to l- ratio of 3:1), did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day (approximately 5 times the maximum recommended human dose of 30 mg/day on a mg/m2 body surface area basis). Pregnancy - Teratogenic Effects: Pregnancy Category C. Amphetamine, in the enantiomer ratio present in ADDERALL® (d- to l- ratio of 3:1), had no apparent effects on embryofetal morphological development or survival when orally administered to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 6 and 16 mg/kg/day, respectively. These doses are approximately 1.5 and 8 times, respectively, the maximum recommended human dose of 30 mg/day [child] on a mg/m2 body surface area basis. Fetal malformations and death have been reported in mice following parenteral administration of d-amphetamine doses of 50 mg/kg/day (approximately 6 times that of a human dose of 30 mg/day [child] on a mg/m2 basis) or greater to pregnant animals. Administration of these doses was also associated with severe maternal toxicity. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-522/S-034 and S-037 NDA 21-303/S-013 Page 9 A number of studies in rodents indicate that prenatal or early postnatal exposure to amphetamine (d- or d,l-), at doses similar to those used clinically, can result in long-term neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function. There are no adequate and well-controlled studies in pregnant women. There has been one report of severe congenital bony deformity, tracheo-esophageal fistula, and anal atresia (vater association) in a baby born to a woman who took dextroamphetamine sulfate with lovastatin during the first trimester of pregnancy. Amphetamines should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects: Infants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth weight. Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant lassitude. Usage in Nursing Mothers: Amphetamines are excreted in human milk. Mothers taking amphetamines should be advised to refrain from nursing. Pediatric Use: Long-term effects of amphetamines in children have not been well established. Amphetamines are not recommended for use in children under 3 years of age with Attention Deficit Hyperactivity Disorder described under INDICATIONS AND USAGE. Geriatric Use: ADDERALL® has not been studied in the geriatric population. ADVERSE REACTIONS: Cardiovascular: Palpitations, tachycardia, elevation of blood pressure, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use. Central Nervous System: Psychotic episodes at recommended doses, overstimulation, restlessness, dizziness, insomnia, euphoria, dyskinesia, dysphoria, depression, tremor, headache, exacerbation of motor and phonic tics and Tourette’s syndrome, seizures, stroke. Gastrointestinal: Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects. Allergic: Urticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens Johnson Syndrome and toxic epidermal necrolysis have been reported. Endocrine: Impotence, changes in libido. DRUG ABUSE AND DEPENDENCE: ADDERALL® is a Schedule II controlled substance. Amphetamines have been extensively abused. Tolerance, extreme psychological dependence, and severe social disability have occurred. There are reports of patients who have increased the dosage to levels many times higher than recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with amphetamines include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-522/S-034 and S-037 NDA 21-303/S-013 Page 10 OVERDOSAGE: Individual patient response to amphetamines varies widely. Toxic symptoms may occur idiosyncratically at low doses. Symptoms: Manifestations of acute overdosage with amphetamines include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia and rhabdomyolysis. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension and circulatory collapse. GASTROINTESTINAL SYMPTOMS INCLUDE NAUSEA, VOMITING, DIARRHEA, AND ABDOMINAL CRAMPS. FATAL POISONING IS USUALLY PRECEDED BY CONVULSIONS AND COMA. TREATMENT: CONSULT WITH A CERTIFIED POISON CONTROL CENTER FOR UP TO DATE GUIDANCE AND ADVICE. MANAGEMENT OF ACUTE AMPHETAMINE INTOXICATION IS LARGELY SYMPTOMATIC AND INCLUDES GASTRIC LAVAGE, ADMINISTRATION OF ACTIVATED CHARCOAL, ADMINISTRATION OF A CATHARTIC AND SEDATION. EXPERIENCE WITH HEMODIALYSIS OR PERITONEAL DIALYSIS IS INADEQUATE TO PERMIT RECOMMENDATION IN THIS REGARD. ACIDIFICATION OF THE URINE INCREASES AMPHETAMINE EXCRETION, BUT IS BELIEVED TO INCREASE RISK OF ACUTE RENAL FAILURE IF MYOGLOBINURIA IS PRESENT. IF ACUTE, SEVERE HYPERTENSION COMPLICATES AMPHETAMINE OVERDOSAGE, ADMINISTRATION OF INTRAVENOUS PHENTOLAMINE HAS BEEN SUGGESTED. HOWEVER, A GRADUAL DROP IN BLOOD PRESSURE WILL USUALLY RESULT WHEN SUFFICIENT SEDATION HAS BEEN ACHIEVED. CHLORPROMAZINE ANTAGONIZES THE CENTRAL STIMULANT EFFECTS OF AMPHETAMINES AND CAN BE USED TO TREAT AMPHETAMINE INTOXICATION. DOSAGE AND ADMINISTRATION: Regardless of indication, amphetamines should be administered at the lowest effective dosage and dosage should be individually adjusted according to the therapeutic needs and response of the patient. Late evening doses should be avoided because of the resulting insomnia. Attention Deficit Hyperactivity Disorder: Not recommended for children under 3 years of age. In children from 3 to 5 years of age, start with 2.5 mg daily; daily dosage may be raised in increments of 2.5 mg at weekly intervals until optimal response is obtained. In children 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. Only in rare cases will it be necessary to exceed a total of 40 mg per day. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours. Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy. Narcolepsy: Usual dose 5 mg to 60 mg per day in divided doses, depending on the individual patient response. Narcolepsy seldom occurs in children under 12 years of age; however, when it does, dextroamphetamine sulfate may be used. The suggested initial dose for patients aged 6-12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in increments of 10 mg at weekly intervals until optimal response is obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should be reduced. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-522/S-034 and S-037 NDA 21-303/S-013 Page 11 HOW SUPPLIED: ADDERALL® 5 mg: A round, flat-faced beveled edge, white to off-white tablet, “5” embossed on one side with partial bisect and “AD” embossed on the other side (NDC 54092-371-01) ADDERALL® 7.5 mg: An oval, convex, blue tablet, “7.5” embossed on one side with a partial bisect and “AD” embossed on the other side with a full and partial bisect (NDC 54092-372-01) ADDERALL® 10 mg: A round, convex, blue tablet, “10” embossed on one side with a full and partial bisect and “AD” embossed on the other side (NDC 54092-373-01) ADDERALL® 12.5 mg: A round, flat-faced beveled edge, orange tablet, “12.5” embossed on one side and “AD” embossed on the other side with a full and partial bisect (NDC 54092-374-01) ADDERALL® 15 mg: An oval, convex, orange tablet, “15” embossed on one side with a partial bisect and “AD” embossed on the other side with a full and partial bisect (NDC 54092-375-01) ADDERALL® 20 mg: A round, convex, orange tablet, “20” embossed on one side with a full and partial bisect and “AD” embossed on the other side (NDC 54092-376-01) ADDERALL® 30 mg: A round, flat-faced beveled edge, orange tablet, “30” embossed on one side with a full and partial bisect and “AD” embossed on the other side (NDC 54092-377-01) In bottles of 100 tablets. Dispense in a tight, light-resistant container as defined in the USP. Store at 25°C (77°F), excursions permitted to 15°-30°C (59-86°F) [see USP Controlled Room Temperature] Rx only. 003733 Revised: 6/06 371 0107 009 Manufactured for: Shire US Inc. 725 CHESTERBROOK BLVD. Wayne, PA 19087 Manufactured by: DSM Pharmaceuticals Inc. 5900 NW Greenville Blvd. Greenville, NC 27834 Made in USA 1-800-828-2088 ©2006 Shire US Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 ADDERALL XR® CAPSULES CII Rx Only AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. ADMINISTRATION OF AMPHETAMINES FOR PROLONGED PERIODS OF TIME MAY LEAD TO DRUG DEPENDENCE. PARTICULAR ATTENTION SHOULD BE PAID TO THE POSSIBILITY OF SUBJECTS OBTAINING AMPHETAMINES FOR NON-THERAPEUTIC USE OR DISTRIBUTION TO OTHERS AND THE DRUGS SHOULD BE PRESCRIBED OR DISPENSED SPARINGLY. MISUSE OF AMPHETAMINE MAY CAUSE SUDDEN DEATH AND SERIOUS CARDIOVASCULAR ADVERSE EVENTS. DESCRIPTION ADDERALL XR® is a once daily extended-release, single-entity amphetamine product. ADDERALL XR® combines the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate and d,l-amphetamine aspartate monohydrate. The ADDERALL XR® capsule contains two types of drug-containing beads designed to give a double-pulsed delivery of amphetamines, which prolongs the release of amphetamine from ADDERALL XR® compared to the conventional ADDERALL® (immediate- release) tablet formulation. EACH CAPSULE CONTAINS: 5 mg 10 mg 15 mg 20 mg 25 mg 30 mg Dextroamphetamine Saccharate 1.25 mg 2.5 mg 3.75 mg 5.0 mg 6.25 mg 7.5 mg Amphetamine Aspartate Monohydrate 1.25 mg 2.5 mg 3.75 mg 5.0 mg 6.25 mg 7.5 mg Dextroamphetamine Sulfate USP 1.25 mg 2.5 mg 3.75 mg 5.0 mg 6.25 mg 7.5 mg Amphetamine Sulfate USP 1.25 mg 2.5 mg 3.75 mg 5.0 mg 6.25 mg 7.5 mg Total amphetamine base equivalence 3.1 mg 6.3 mg 9.4 mg 12.5 mg 15.6 mg 18.8 mg Inactive Ingredients and Colors: The inactive ingredients in ADDERALL XR® capsules include: gelatin capsules, hydroxypropyl methylcellulose, methacrylic acid copolymer, opadry beige, sugar spheres, talc, and triethyl citrate. Gelatin capsules contain edible inks, kosher gelatin, and titanium dioxide. The 5 mg, 10 mg, and 15 mg capsules also contain FD&C Blue #2. The 20 mg, 25 mg, and 30 mg capsules also contain red iron oxide and yellow iron oxide. CLINICAL PHARMACOLOGY Pharmacodynamics Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Amphetamines are thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Pharmacokinetics Pharmacokinetic studies of ADDERALL XR® have been conducted in healthy adult and pediatric (6-12 yrs) subjects, and adolescent (13-17 yrs) and pediatric patients with ADHD. Both ADDERALL® (immediate- release) tablets and ADDERALL XR® capsules contain d-amphetamine and l-amphetamine salts in the ratio of 3:1. Following administration of ADDERALL® (immediate-release), the peak plasma concentrations occurred in about 3 hours for both d-amphetamine and l-amphetamine. The time to reach maximum plasma concentration (Tmax) for ADDERALL XR® is about 7 hours, which is about 4 hours longer compared to ADDERALL® (immediate-release). This is consistent with the extended-release nature of the product. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Figure 1 Mean d-amphetamine and l-amphetamine plasma concentrations following administration of ADDERALL XR® 20 mg (8am) and ADDERALL® (immediate-release) 10 mg bid (8am and 12 noon) in the fed state. A single dose of ADDERALL XR® 20 mg capsules provided comparable plasma concentration profiles of both d-amphetamine and l-amphetamine to ADDERALL® (immediate-release) 10 mg bid administered 4 hours apart. The mean elimination half-life for d-amphetamine is 10 hours in adults; 11 hours in adolescents aged 13-17 years and weighing less than or equal to 75 kg/165 lbs; and 9 hours in children aged 6 to 12 years. For the l- amphetamine, the mean elimination half-life in adults is 13 hours; 13 to 14 hours in adolescents; and 11 hours in children aged 6 to 12 years. On a mg/kg body weight basis children have a higher clearance than adolescents or adults (See Special Populations). ADDERALL XR® demonstrates linear pharmacokinetics over the dose range of 20 to 60 mg in adults and adolescents weighing greater than 75 kg/165lbs, over the dose range of 10 to 40 mg in adolescents weighing less than or equal to 75 kg/165 lbs, and 5 to 30 mg in children aged 6 to 12 years. There is no unexpected accumulation at steady state in children. Food does not affect the extent of absorption of d-amphetamine and l-amphetamine, but prolongs Tmax by 2.5 hours (from 5.2 hrs at fasted state to 7.7 hrs after a high-fat meal) for d-amphetamine and 2.1 hours (from 5.6 hrs at fasted state to 7.7 hrs after a high fat meal) for l-amphetamine after administration of ADDERALL XR® 30 mg. Opening the capsule and sprinkling the contents on applesauce results in comparable absorption to the intact capsule taken in the fasted state. Equal doses of ADDERALL XR® strengths are bioequivalent. Metabolism and Excretion Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-hydroxyamphetamine, or on the side chain α or β carbons to form alpha-hydroxy-amphetamine or norephedrine, respectively. 0 4 8 12 16 20 24 0 5 10 15 20 25 30 ADDERALL XR® 20 mg qd ADDERALL® 10 mg bid ADDERALL XR® 20 mg qd ADDERALL® 10 mg bid DEXTROAMPHETAMINE LEVOAMPHETAMINE TIME (HOURS) MEAN PLASMA CONCENTRATIONS OF DEXTRO AND LEVOAMPHETAMINE (ng/mL) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Norephedrine and 4-hydroxy-amphetamine are both active and each is subsequently oxidized to form 4-hydroxy- norephedrine. Alpha-hydroxy-amphetamine undergoes deamination to form phenylacetone, which ultimately forms benzoic acid and its glucuronide and the glycine conjugate hippuric acid. Although the enzymes involved in amphetamine metabolism have not been clearly defined, CYP2D6 is known to be involved with formation of 4-hydroxy-amphetamine. Since CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility. Amphetamine is known to inhibit monoamine oxidase, whereas the ability of amphetamine and its metabolites to inhibit various P450 isozymes and other enzymes has not been adequately elucidated. In vitro experiments with human microsomes indicate minor inhibition of CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and 3A4 by one or more metabolites. However, due to the probability of auto-inhibition and the lack of information on the concentration of these metabolites relative to in vivo concentrations, no predications regarding the potential for amphetamine or its metabolites to inhibit the metabolism of other drugs by CYP isozymes in vivo can be made. With normal urine pHs approximately half of an administered dose of amphetamine is recoverable in urine as derivatives of alpha-hydroxy-amphetamine and approximately another 30%-40% of the dose is recoverable in urine as amphetamine itself. Since amphetamine has a pKa of 9.9, urinary recovery of amphetamine is highly dependent on pH and urine flow rates. Alkaline urine pHs result in less ionization and reduced renal elimination, and acidic pHs and high flow rates result in increased renal elimination with clearances greater than glomerular filtration rates, indicating the involvement of active secretion. Urinary recovery of amphetamine has been reported to range from 1% to 75%, depending on urinary pH, with the remaining fraction of the dose hepatically metabolized. Consequently, both hepatic and renal dysfunction have the potential to inhibit the elimination of amphetamine and result in prolonged exposures. In addition, drugs that effect urinary pH are known to alter the elimination of amphetamine, and any decrease in amphetamine’s metabolism that might occur due to drug interactions or genetic polymorphisms is more likely to be clinically significant when renal elimination is decreased, (See PRECAUTIONS). Special Populations Comparison of the pharmacokinetics of d- and l-amphetamine after oral administration of ADDERALL XR® in pediatric (6-12 years) and adolescent (13-17 years) ADHD patients and healthy adult volunteers indicates that body weight is the primary determinant of apparent differences in the pharmacokinetics of d- and l-amphetamine across the age range. Systemic exposure measured by area under the curve to infinity (AUC∞) and maximum plasma concentration (Cmax) decreased with increases in body weight, while oral volume of distribution (Vz/F), oral clearance (CL/F), and elimination half-life (t 1/2) increased with increases in body weight. Pediatric Patients On a mg/kg weight basis, children eliminated amphetamine faster than adults. The elimination half-life (t1/2) is approximately 1 hour shorter for d-amphetamine and 2 hours shorter for l-amphetamine in children than in adults. However, children had higher systemic exposure to amphetamine (Cmax and AUC) than adults for a given dose of ADDERALL XR®, which was attributed to the higher dose administered to children on a mg/kg body weight basis compared to adults. Upon dose normalization on a mg/kg basis, children showed 30% less systemic exposure compared to adults. Gender Systemic exposure to amphetamine was 20-30% higher in women (N=20) than in men (N=20) due to the higher dose administered to women on a mg/kg body weight basis. When the exposure parameters (Cmax and AUC) were normalized by dose (mg/kg), these differences diminished. Age and gender had no direct effect on the pharmacokinetics of d- and l-amphetamine. Race Formal pharmacokinetic studies for race have not been conducted. However, amphetamine pharmacokinetics appeared to be comparable among Caucasians (N=33), Blacks (N=8) and Hispanics (N=10). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Clinical Trials Children A double-blind, randomized, placebo-controlled, parallel-group study was conducted in children aged 6-12 (N=584) who met DSM-IV® criteria for ADHD (either the combined type or the hyperactive-impulsive type). Patients were randomized to fixed dose treatment groups receiving final doses of 10, 20, or 30 mg of ADDERALL XR® or placebo once daily in the morning for three weeks. Significant improvements in patient behavior, based upon teacher ratings of attention and hyperactivity, were observed for all ADDERALL XR® doses compared to patients who received placebo, for all three weeks, including the first week of treatment, when all ADDERALL XR® subjects were receiving a dose of 10 mg/day. Patients who received ADDERALL XR® showed behavioral improvements in both morning and afternoon assessments compared to patients on placebo. In a classroom analogue study, patients (N=51) receiving fixed doses of 10 mg, 20 mg or 30 mg ADDERALL XR® demonstrated statistically significant improvements in teacher-rated behavior and performance measures, compared to patients treated with placebo. Adolescents A double-blind, randomized, multi-center, parallel-group, placebo-controlled study was conducted in adolescents aged 13-17 (N=327) who met DSM-IV® criteria for ADHD. The primary cohort of patients (n=287, weighing ≤ 75kg/165lbs) was randomized to fixed dose treatment groups and received four weeks of treatment. Patients were randomized to receive final doses of 10 mg, 20 mg, 30 mg, and 40 mg ADDERALL XR® or placebo once daily in the morning; patients randomized to doses greater than 10 mg were titrated to their final doses by 10 mg each week. The secondary cohort consisted of 40 subjects weighing >75kg/165lbs who were randomized to fixed dose treatment groups receiving final doses of 50 mg and 60 mg ADDERALL XR® or placebo once daily in the morning for 4 weeks. The primary efficacy variable was the ADHD-RS-IV total scores for the primary cohort. Improvements in the primary cohort were statistically significantly greater in all four primary cohort active treatment groups (ADDERALL XR® 10 mg, 20 mg, 30 mg, and 40 mg) compared with the placebo group. There was not adequate evidence that doses greater than 20 mg/day conferred additional benefit. Adults A double-blind, randomized, placebo-controlled, parallel-group study was conducted in adults (N=255) who met DSM-IV® criteria for ADHD. Patients were randomized to fixed dose treatment groups receiving final doses of 20, 40, or 60 mg of ADDERALL XR® or placebo once daily in the morning for four weeks. Significant improvements, measured with the Attention Deficit Hyperactivity Disorder-Rating Scale (ADHD-RS), an 18- item scale that measures the core symptoms of ADHD, were observed at endpoint for all ADDERALL XR® doses compared to patients who received placebo for all four weeks. There was not adequate evidence that doses greater than 20 mg/day conferred additional benefit. INDICATIONS ADDERALL XR® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). The efficacy of ADDERALL XR® in the treatment of ADHD was established on the basis of two controlled trials in children aged 6 to 12, one controlled trial in adolescents aged 13 to 17, and one controlled trial in adults who met DSM-IV® criteria for ADHD (see CLINICAL PHARMACOLOGY), along with extrapolation from the known efficacy of ADDERALL®, the immediate-release formulation of this substance. A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV®) implies the presence of hyperactive- impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 running/climbing; difficulty with quiet activities; "on the go;" excessive talking; blurting answers; can't wait turn; intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met. Special Diagnostic Considerations: Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of the required number of DSM-IV® characteristics. Need for Comprehensive Treatment Program: ADDERALL XR® is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician's assessment of the chronicity and severity of the child's symptoms. Long-Term Use: The effectiveness of ADDERALL XR® for long-term use, i.e., for more than 3 weeks in children and 4 weeks in adolescents and adults, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use ADDERALL XR® for extended periods should periodically re- evaluate the long-term usefulness of the drug for the individual patient. CONTRAINDICATIONS Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma. Agitated states. Patients with a history of drug abuse. During or within 14 days following the administration of monoamine oxidase inhibitors (hypertensive crises may result). WARNINGS Serious Cardiovascular Events Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug (see CONTRAINDICATIONS). Adults Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs (see CONTRAINDICATIONS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Hypertension and other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm) [see ADVERSE EVENTS], and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre- existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia (see CONTRAINDICATIONS). Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g. electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Pre-Existing Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with pre-existing psychotic disorder. Bipolar Illness Particular care should be taken in using stimulants to treat ADHD patients with comorbid bipolar disorder because of concern for possible induction of mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. In a controlled trial of ADDERALL XR® in adolescents, mean weight change from baseline within the initial 4 weeks of therapy was –1.1 lbs. and –2.8 lbs., respectively, for patients receiving 10 mg and 20 mg ADDERALL XR®. Higher doses were associated with greater weight loss within the initial 4 weeks of treatment. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they will likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining weight as expected may need to have their treatment interrupted. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizure, in patients with prior EEG abnormalities in absence of seizures, and very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. PRECAUTIONS General: The least amount of amphetamine feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage. ADDERALL XR® should be used with caution in patients who use other sympathomimetic drugs. Tics: Amphetamines have been reported to exacerbate motor and phonic tics and Tourette’s syndrome. Therefore, clinical evaluation for tics and Tourette’s Syndrome in children and their families should precede use of stimulant medications. Information for Patients: Amphetamines may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or vehicles; the patient should therefore be cautioned accordingly. Drug Interactions: Acidifying agents -Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid HCl, ascorbic acid, etc.) lower absorption of amphetamines. Urinary acidifying agents -These agents (ammonium chloride, sodium acid phosphate, etc.) increase the concentration of the ionized species of the amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines. Adrenergic blockers -Adrenergic blockers are inhibited by amphetamines. Alkalinizing agents -Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) increase absorption of amphetamines. Co-administration of ADDERALL XR® and gastrointestinal alkalinizing agents, such as antacids, should be avoided. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase blood levels and therefore potentiate the actions of amphetamines. Antidepressants, tricyclic -Amphetamines may enhance the activity of tricyclic antidepressants or sympathomimetic agents; d-amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. MAO inhibitors -MAOI antidepressants, as well as a metabolite of furazolidone, slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the release of norepinephrine and other This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 monoamines from adrenergic nerve endings; this can cause headaches and other signs of hypertensive crisis. A variety of toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal results. Antihistamines -Amphetamines may counteract the sedative effect of antihistamines. Antihypertensives -Amphetamines may antagonize the hypotensive effects of antihypertensives. Chlorpromazine -Chlorpromazine blocks dopamine and norepinephrine receptors, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning. Ethosuximide -Amphetamines may delay intestinal absorption of ethosuximide. Haloperidol -Haloperidol blocks dopamine receptors, thus inhibiting the central stimulant effects of amphetamines. Lithium carbonate -The anorectic and stimulatory effects of amphetamines may be inhibited by lithium carbonate. Meperidine -Amphetamines potentiate the analgesic effect of meperidine. Methenamine therapy -Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy. Norepinephrine -Amphetamines enhance the adrenergic effect of norepinephrine. Phenobarbital -Amphetamines may delay intestinal absorption of phenobarbital; co-administration of phenobarbital may produce a synergistic anticonvulsant action. Phenytoin -Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may produce a synergistic anticonvulsant action. Propoxyphene -In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur. Veratrum alkaloids -Amphetamines inhibit the hypotensive effect of veratrum alkaloids. Drug/Laboratory Test Interactions: Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations. Carcinogenesis/Mutagenesis and Impairment of Fertility: No evidence of carcinogenicity was found in studies in which d,l-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats. These doses are approximately 2.4, 1.5, and 0.8 times, respectively, the maximum recommended human dose of 30 mg/day [child] on a mg/m 2 body surface area basis. Amphetamine, in the enantiomer ratio present in ADDERALL® (immediate-release)(d- to l- ratio of 3:1), was not clastogenic in the mouse bone marrow micronucleus test in vivo and was negative when tested in the E. coli component of the Ames test in vitro. d,l-Amphetamine (1:1 enantiomer ratio) has been reported to produce a positive response in the mouse bone marrow micronucleus test, an equivocal response in the Ames test, and negative responses in the in vitro sister chromatid exchange and chromosomal aberration assays. Amphetamine, in the enantiomer ratio present in ADDERALL® (immediate-release)(d- to l- ratio of 3:1), did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day (approximately 5 times the maximum recommended human dose of 30 mg/day on a mg/m2 body surface area basis). Pregnancy: Pregnancy Category C. Amphetamine, in the enantiomer ratio present in ADDERALL® (d- to l- ratio of 3:1), had no apparent effects on embryofetal morphological development or survival when orally administered to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 6 and 16 mg/kg/day, respectively. These doses are approximately 1.5 and 8 times, respectively, the maximum recommended human dose of 30 mg/day [child] on a mg/m2 body surface area basis. Fetal malformations and death have been reported in mice following parenteral administration of d-amphetamine doses of 50 mg/kg/day (approximately 6 times that of a human dose of 30 mg/day [child] on a mg/m2 basis) or greater to pregnant animals. Administration of these doses was also associated with severe maternal toxicity. A number of studies in rodents indicate that prenatal or early postnatal exposure to amphetamine (d- or d,l-), at doses similar to those used clinically, can result in long-term neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 function. There are no adequate and well-controlled studies in pregnant women. There has been one report of severe congenital bony deformity, tracheo-esophageal fistula, and anal atresia (vater association) in a baby born to a woman who took dextroamphetamine sulfate with lovastatin during the first trimester of pregnancy. Amphetamines should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects: Infants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth weight. Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant lassitude. Usage in Nursing Mothers: Amphetamines are excreted in human milk. Mothers taking amphetamines should be advised to refrain from nursing. Pediatric Use: ADDERALL XR® is indicated for use in children 6 years of age and older. Use in Children Under Six Years of Age: Effects of ADDERALL XR® in 3-5 year olds have not been studied. Long-term effects of amphetamines in children have not been well established. Amphetamines are not recommended for use in children under 3 years of age. Geriatric Use: ADDERALL XR® has not been studied in the geriatric population. ADVERSE EVENTS Hypertension: [See WARNINGS section] In a controlled 4-week outpatient clinical study of adolescents with ADHD, isolated systolic blood pressure elevations ≥15 mmHg were observed in 7/64 (11%) placebo-treated patients and 7/100 (7%) patients receiving ADDERALL XR® 10 or 20 mg. Isolated elevations in diastolic blood pressure ≥ 8 mmHg were observed in 16/64 (25%) placebo-treated patients and 22/100 (22%) ADDERALL XR®-treated patients. Similar results were observed at higher doses. In a single-dose pharmacokinetic study in 23 adolescents, isolated increases in systolic blood pressure (above the upper 95% CI for age, gender and stature) were observed in 2/17 (12%) and 8/23 (35%), subjects administered 10 mg and 20 mg ADDERALL XR®, respectively. Higher single doses were associated with a greater increase in systolic blood pressure. All increases were transient, appeared maximal at 2 to 4 hours post dose and not associated with symptoms. The premarketing development program for ADDERALL XR® included exposures in a total of 1315 participants in clinical trials (635 pediatric patients, 350 adolescent patients, 248 adult patients, and 82 healthy adult subjects). Of these, 635 patients (ages 6 to 12) were evaluated in two controlled clinical studies, one open-label clinical study, and two single-dose clinical pharmacology studies (N= 40). Safety data on all patients are included in the discussion that follows. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs. Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and listings that follow, COSTART terminology has been used to classify reported adverse events. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 Adverse events associated with discontinuation of treatment: In two placebo-controlled studies of up to 5 weeks duration among children with ADHD, 2.4% (10/425) of ADDERALL XR® treated patients discontinued due to adverse events (including 3 patients with loss of appetite, one of whom also reported insomnia) compared to 2.7% (7/259) receiving placebo. The most frequent adverse events associated with discontinuation of ADDERALL XR® in controlled and uncontrolled, multiple-dose clinical trials of pediatric patients (N=595) are presented below. Over half of these patients were exposed to ADDERALL XR® for 12 months or more. Adverse event % of pediatric patients discontinuing (n=595) Anorexia (loss of appetite) 2.9 Insomnia 1.5 Weight loss 1.2 Emotional lability 1.0 Depression 0.7 In a separate placebo-controlled 4-week study in adolescents with ADHD, eight patients (3.4%) discontinued treatment due to adverse events among ADDERALL XR®-treated patients (N=233). Three patients discontinued due to insomnia and one patient each for depression, motor tics, headaches, light-headedness, and anxiety. In one placebo-controlled 4-week study among adults with ADHD, patients who discontinued treatment due to adverse events among ADDERALL XR®-treated patients (N=191) were 3.1% (n=6) for nervousness including anxiety and irritability, 2.6% (n=5) for insomnia, 1% (n=2) each for headache, palpitation, and somnolence; and, 0.5% (n=1) each for ALT increase, agitation, chest pain, cocaine craving, elevated blood pressure, and weight loss. Adverse events occurring in a controlled trial: Adverse events reported in a 3-week clinical trial of pediatric patients and a 4-week clinical trial in adolescents and adults, respectively, treated with ADDERALL XR® or placebo are presented in the tables below. The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. Table 1 Adverse Events Reported by More Than 1% of Pediatric Patients Receiving ADDERALL XR® with Higher Incidence Than on Placebo in a 584 Patient Clinical Study Body System Preferred Term ADDERALL XR® (n=374) Placebo (n=210) General Abdominal Pain (stomachache) Accidental Injury Asthenia (fatigue) Fever Infection Viral Infection 14% 3% 2% 5% 4% 2% 10% 2% 0% 2% 2% 0% Digestive System Loss of Appetite Diarrhea Dyspepsia Nausea Vomiting 22% 2% 2% 5% 7% 2% 1% 1% 3% 4% Nervous System Dizziness Emotional Lability Insomnia Nervousness 2% 9% 17% 6% 0% 2% 2% 2% Metabolic/Nutritional Weight Loss 4% 0% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Table 2 Adverse Events Reported by 5% or more of Adolescents Weighing ≤ 75 kg/165 lbs Receiving ADDERALL XR® with Higher Incidence Than Placebo in a 287 Patient Clinical Forced Weekly-Dose Titration Study* Body System Preferred Term ADDERALL XR® (n=233) Placebo (n=54) General Abdominal Pain (stomachache) 11% 2% Digestive System Loss of Appetite b 36% 2% Nervous System Insomnia b Nervousness 12% 6% 4% 6%a Metabolic/Nutritional Weight Loss b 9% 0% a Appears the same due to rounding b Dose-related adverse events Note: The following events did not meet the criterion for inclusion in Table 2 but were reported by 2% to 4% of adolescent patients receiving ADDERALL XR with a higher incidence than patients receiving placebo in this study: accidental injury, asthenia (fatigue), dry mouth, dyspepsia, emotional lability, nausea, somnolence, and vomiting. Included doses up to 40 mg Table 3 Adverse Events Reported by 5% or More of Adults Receiving ADDERALL XR® with Higher Incidence Than on Placebo in a 255 Patient Clinical Forced Weekly-Dose Titration Study Body System Preferred Term ADDERALL XR® (n=191) Placebo (n=64) General Asthenia Headache 6% 26% 5% 13% Digestive System Loss of Appetite Diarrhea Dry Mouth Nausea 33% 6% 35% 8% 3% 0% 5% 3% Nervous System Agitation Anxiety Dizziness Insomnia 8% 8% 7% 27% 5% 5% 0% 13% Cardiovascular System Tachycardia 6% 3% Metabolic/Nutritional Weight Loss 11% 0% Urogenital System Urinary Tract Infection 5% 0% Note: The following events did not meet the criterion for inclusion in Table 3 but were reported by 2% to 4% of adult patients receiving ADDERALL XR® with a higher incidence than patients receiving placebo in this study: infection, photosensitivity reaction, constipation, tooth disorder, emotional lability, libido decreased, somnolence, speech disorder, palpitation, twitching, dyspnea, sweating, dysmenorrhea, and impotence. *Included doses up to 60 mg. The following adverse reactions have been associated with the use of amphetamine, ADDERALL XR®, or ADDERALL®: Cardiovascular: Palpitations, tachycardia, elevation of blood pressure, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use. Central Nervous System: Psychotic episodes at recommended doses, overstimulation, restlessness, dizziness, insomnia, euphoria, dyskinesia, dysphoria, depression, tremor, headache, exacerbation of motor and phonic tics and Tourette's syndrome, seizures, stroke. Gastrointestinal: Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects. Allergic: Urticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens Johnson Syndrome and toxic epidermal necrolysis have been reported. Endocrine: Impotence, changes in libido. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 DRUG ABUSE AND DEPENDENCE ADDERALL XR® is a Schedule II controlled substance. Amphetamines have been extensively abused. Tolerance, extreme psychological dependence, and severe social disability have occurred. There are reports of patients who have increased the dosage to levels many times higher than recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with amphetamines may include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia. OVERDOSAGE Individual patient response to amphetamines varies widely. Toxic symptoms may occur idiosyncratically at low doses. Symptoms: Manifestations of acute overdosage with amphetamines include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma. Treatment: Consult with a Certified Poison Control Center for up to date guidance and advice. Management of acute amphetamine intoxication is largely symptomatic and includes gastric lavage, administration of activated charcoal, administration of a cathartic and sedation. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendation in this regard. Acidification of the urine increases amphetamine excretion, but is believed to increase risk of acute renal failure if myoglobinuria is present. If acute severe hypertension complicates amphetamine overdosage, administration of intravenous phentolamine has been suggested. However, a gradual drop in blood pressure will usually result when sufficient sedation has been achieved. Chlorpromazine antagonizes the central stimulant effects of amphetamines and can be used to treat amphetamine intoxication. The prolonged release of mixed amphetamine salts from ADDERALL XR® should be considered when treating patients with overdose. DOSAGE AND ADMINISTRATION Dosage should be individualized according to the therapeutic needs and response of the patient. ADDERALL XR® should be administered at the lowest effective dosage. Children In children with ADHD who are 6 years of age and older and are either starting treatment for the first time or switching from another medication, start with 10 mg once daily in the morning; daily dosage may be adjusted in increments of 5 mg or 10 mg at weekly intervals. When in the judgment of the clinician a lower initial dose is appropriate, patients may begin treatment with 5 mg once daily in the morning. The maximum recommended dose for children is 30 mg/day; doses greater than 30 mg/day of ADDERALL XR® have not been studied in children. Amphetamines are not recommended for children under 3 years of age. ADDERALL XR® has not been studied in children under 6 years of age. Adolescents The recommended starting dose for adolescents who are 13-17 years of age with ADHD is 10 mg/day. The dose may be increased to 20 mg/day after one week if ADHD symptoms are not adequately controlled. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Adults In adults with ADHD who are either starting treatment for the first time or switching from another medication, the recommended dose is 20 mg/day. Patients Currently Using ADDERALL®- Based on bioequivalence data, patients taking divided doses of immediate-release ADDERALL®, for example twice a day, may be switched to ADDERALL XR® at the same total daily dose taken once daily. Titrate at weekly intervals to appropriate efficacy and tolerability as indicated. ADDERALL XR® capsules may be taken whole, or the capsule may be opened and the entire contents sprinkled on applesauce. If the patient is using the sprinkle administration method, the sprinkled applesauce should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. The dose of a single capsule should not be divided. The contents of the entire capsule should be taken, and patients should not take anything less than one capsule per day. ADDERALL XR® may be taken with or without food. ADDERALL XR® should be given upon awakening. Afternoon doses should be avoided because of the potential for insomnia. Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy. HOW SUPPLIED: ADDERALL XR® 5 mg Capsules: Clear/blue (imprinted ADDERALL XR 5 mg), bottles of 100, NDC 54092-381-01 ADDERALL XR® 10 mg Capsules: Blue/blue (imprinted ADDERALL XR 10 mg), bottles of 100, NDC 54092-383-01 ADDERALL XR® 15 mg Capsules: Blue/white (imprinted ADDERALL XR 15 mg), bottles of 100, NDC 54092-385-01 ADDERALL XR® 20 mg Capsules: Orange/orange (imprinted ADDERALL XR 20 mg), bottles of 100, NDC 54092-387-01 ADDERALL XR® 25 mg Capsules: Orange/white (imprinted ADDERALL XR 25 mg), bottles of 100, NDC 54092-389-01 ADDERALL XR® 30 mg Capsules: Natural/orange (imprinted ADDERALL XR 30 mg), bottles of 100, NDC 54092-391-01 Dispense in a tight, light-resistant container as defined in the USP. Store at 25º C (77º F). Excursions permitted to 15-30º C (59-86º F) [see USP Controlled Room Temperature] ANIMAL TOXICOLOGY Acute administration of high doses of amphetamine (d- or d,l-) has been shown to produce long-lasting neurotoxic effects, including irreversible nerve fiber damage, in rodents. The significance of these findings to humans is unknown. Manufactured for Shire US Inc., Wayne, PA 19087. Made in USA. For more information call 1-800-828-2088 or visit www.adderallxr.com ADDERALL® and ADDERALL XR® are registered in the US Patent and Trademark Office Copyright ©2006, Shire US Inc. 003734 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 381 0107 0010 Rev. 6/06 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:44.725413	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/011522s034s037,021303s013lbl.pdf', 'application_number': 11522, 'submission_type': 'SUPPL ', 'submission_number': 34}
10,765	N 11-559/S-037 Page 4 4 BREVITAL® SODIUM METHOHEXITAL SODIUM FOR INJECTION, USP For Intravenous Use in Adults For Rectal and Intramuscular Use Only in Pediatric Patients WARNING Brevital should be used only in hospital or ambulatory care settings that provide for continuous monitoring of respiratory (e.g. pulse oximetry) and cardiac function. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation and personnel trained in their use and skilled in airway management should be assured. For deeply sedated patients, a designated individual other than the practitioner performing the procedure should be present to continuously monitor the patient. (See WARNINGS) DESCRIPTION Brevital® Sodium (Methohexital Sodium for Injection, USP) is 2,4,6 (1H, 3H, 5H)- Pyrimidinetrione, 1-methyl-5-(1-methyl-2-pentynyl)-5-(2-propenyl)-, (±)-, monosodium salt and has the empirical formula C14H17N2NaO3. Its molecular weight is 284.29. The structural formula is as follows: ONa N N CH3 O O CH2 CHCH2 CCH C CH2 CH3 CH3 Methohexital sodium is a rapid, ultrashort-acting barbiturate anesthetic. Methohexital sodium for injection is a freeze-dried, sterile, nonpyrogenic mixture of methohexital sodium with 6% anhydrous sodium carbonate added as a buffer. It contains not less than 90% and not more than 110% of the labeled amount of methohexital sodium. It occurs as a white, freeze-dried plug that is freely soluble in water. This product is oxygen sensitive. The pH of the 1% solution is between 10 and 11; the pH of the 0.2% solution in 5% dextrose is between 9.5 and 10.5. Methohexital sodium may be administered by direct intravenous injection or continuous intravenous drip, intramuscular or rectal routes (see PRECAUTIONS—Pediatric Use). Reconstituting instructions vary depending on the route of administration (see DOSAGE AND ADMINISTRATION). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 11-559/S-037 Page 5 5 CLINICAL PHARMACOLOGY Compared with thiamylal and thiopental, methohexital is at least twice as potent on a weight basis, and its duration of action is only about half as long. Although the metabolic fate of methohexital in the body is not clear, the drug does not appear to concentrate in fat depots to the extent that other barbiturate anesthetics do. Thus, cumulative effects are fewer and recovery is more rapid with methohexital than with thiobarbiturates. In experimental animals, the drug cannot be detected in the blood 24 hours after administration. Methohexital differs chemically from the established barbiturate anesthetics in that it contains no sulfur. Little analgesia is conferred by barbiturates; their use in the presence of pain may result in excitation. Intravenous administration of methohexital results in rapid uptake by the brain (within 30 seconds) and rapid induction of sleep. Following intramuscular administration to pediatric patients, the onset of sleep occurs in 2 to 10 minutes. A plasma concentration of 3 µg/mL was achieved in pediatric patients 15 minutes after an intramuscular dose (10 mg/kg) of a 5% solution. Following rectal administration to pediatric patients, the onset of sleep occurs in 5 to 15 minutes. Plasma methohexital concentrations achieved following rectal administration tend to increase both with dose and with the use of more dilute solution concentrations when using the same dose. A 25 mg/kg dose of a 1% methohexital solution yielded plasma concentrations of 6.9 to 7.9 µg/mL 15 minutes after dosing. The absolute bioavailability of rectal methohexital sodium is 17%. With single doses, the rate of redistribution determines duration of pharmacologic effect. Metabolism occurs in the liver through demethylation and oxidation. Side-chain oxidation is the most important biotransformation involved in termination of biologic activity. Excretion occurs via the kidneys through glomerular filtration. INDICATIONS AND USAGE Brevital Sodium can be used in adults as follows: 1. For intravenous induction of anesthesia prior to the use of other general anesthetic agents. 2. For intravenous induction of anesthesia and as an adjunct to subpotent inhalational anesthetic agents (such as nitrous oxide in oxygen) for short surgical procedures; Brevital Sodium may be given by infusion or intermittent injection. 3. For use along with other parenteral agents, usually narcotic analgesics, to supplement subpotent inhalational anesthetic agents (such as nitrous oxide in oxygen) for longer surgical procedures. 4. As intravenous anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli (see WARNINGS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 11-559/S-037 Page 6 6 5. As an agent for inducing a hypnotic state. Brevital Sodium can be used in pediatric patients older than 1 month as follows: 1. For rectal or intramuscular induction of anesthesia prior to the use of other general anesthetic agents. 2. For rectal or intramuscular induction of anesthesia and as an adjunct to subpotent inhalational anesthetic agents for short surgical procedures. 3. As rectal or intramuscular anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli. CONTRAINDICATIONS Brevital Sodium is contraindicated in patients in whom general anesthesia is contraindicated, in those with latent or manifest porphyria, or in patients with a known hypersensitivity to barbiturates. WARNINGS See boxed Warning. As with all potent anesthetic agents and adjuncts, Brevital should be used only in hospital or ambulatory care settings that provide for continuous monitoring of respiratory (e.g. pulse oximetry) and cardiac function. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation and personnel trained in their use and skilled in airway management should be assured. For deeply sedated patients, a designated individual other than the practitioner performing the procedure should be present to continuously monitor the patient. Maintenance of a patent airway and adequacy of ventilation must be ensured during induction and maintenance of anesthesia with methohexital sodium solution. Laryngospasm is common during induction with all barbiturates and may be due to a combination of secretions and accentuated reflexes following induction or may result from painful stimuli during light anesthesia. Apnea/hypoventilation may be noted during induction, which may impair pulmonary ventilation; the duration of apnea may be longer than that produced by other barbiturate anesthetics. Cardiorespiratory arrest may occur. This prescribing information describes intravenous use of methohexital sodium in adults. It also discusses intramuscular and rectal administration in pediatric patients older than one month. Although the published literature discusses intravenous administration in pediatric patients, the safety and effectiveness of intravenous administration of methohexital sodium in pediatric patients have not been established in well-controlled, prospective studies. (See PRECAUTIONS—Pediatric Use) Seizures may be elicited in subjects with a previous history of convulsive activity, especially partial seizure disorders. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 11-559/S-037 Page 7 7 Because the liver is involved in demethylation and oxidation of methohexital and because barbiturates may enhance preexisting circulatory depression, severe hepatic dysfunction, severe cardiovascular instability, or a shock-like condition may be reason for selecting another induction agent. Prolonged administration may result in cumulative effects, including extended somnolence, protracted unconsciousness, and respiratory and cardiovascular depression. Respiratory depression in the presence of an impaired airway may lead to hypoxia, cardiac arrest, and death. The CNS-depressant effect of Brevital Sodium may be additive with that of other CNS depressants, including ethyl alcohol and propylene glycol. DANGER OF INTRA-ARTERIAL INJECTION—Unintended intra-arterial injection of barbiturate solutions may be followed by the production of platelet aggregates and thrombosis, starting in arterioles distal to the site of injection. The resulting necrosis may lead to gangrene, which may require amputation. The first sign in conscious patients may be a complaint of fiery burning that roughly follows the distribution path of the injected artery; if noted, the injection should be stopped immediately and the situation reevaluated. Transient blanching may or may not be noted very early; blotchy cyanosis and dark discoloration may then be the first sign in anesthetized patients. There is no established treatment other than prevention. The following should be considered prior to injection: 1. The extent of injury is related to concentration. Concentrations of 1% methohexital will usually suffice; higher concentrations should ordinarily be avoided. 2. Check the infusion to ensure that the catheter is in the lumen of a vein before injection. Injection through a running intravenous infusion may enhance the possibility of detecting arterial placement; however, it should be remembered that the characteristic bright-red color of arterial blood is often altered by contact with drugs. The possibility of aberrant arteries should always be considered. Postinjury arterial injection of vasodilators and/or arterial infusion of parenteral fluids are generally regarded to be of no value in altering outcome. Animal experiments and published individual case reports concerned with a variety of arteriolar irritants, including barbiturates, suggest that 1 or more of the following may be of benefit in reducing the area of necrosis: 1. Arterial injection of heparin at the site of injury, followed by systemic anticoagulation. 2. Sympathetic blockade (or brachial plexus blockade in the arm). 3. Intra-arterial glucocorticoid injection at the site of injury, followed by systemic steroids. 4. A case report (nonbarbiturate injury) suggests that intra-arterial urokinase may promote fibrinolysis, even if administered late in treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 11-559/S-037 Page 8 8 If extravasation is noted during injection of methohexital, the injection should be discontinued until the situation is remedied. Local irritation may result from extravasation; subcutaneous swelling may also serve as a sign of arterial or periarterial placement of the catheter. PRECAUTIONS General—All routes of administration of Brevital Sodium are often associated with hiccups, coughing, and/or muscle twitching, which may also impair pulmonary ventilation. Following induction, temporary hypotension and tachycardia may occur. Recovery from methohexital anesthesia is rapid and smooth. The incidence of postoperative nausea and vomiting is low if the drug is administered to fasting patients. Postanesthetic shivering has occurred in a few instances. The usual precautions taken with any barbiturate anesthetic should be observed with Brevital Sodium. The drug should be used with caution in patients with asthma, obstructive pulmonary disease, severe hypertension or hypotension, myocardial disease, congestive heart failure, severe anemia, or extreme obesity. Methohexital sodium should be used with extreme caution in patients in status asthmaticus. Caution should be exercised in debilitated patients or in those with impaired function of respiratory, circulatory, renal, hepatic, or endocrine systems. Information for Patients—When appropriate, patients should be instructed as to the hazards of drowsiness that may follow use of Brevital Sodium. Outpatients should be released in the company of another individual, and no skilled activities, such as operating machinery or driving a motor vehicle, should be engaged in for 8 to 12 hours. Laboratory Tests—BSP and liver function studies may be influenced by administration of a single dose of barbiturates. Drug Interactions—Prior chronic administration of barbiturates or phenytoin (e.g. for seizure disorder) appears to reduce the effectiveness of Brevital Sodium. Barbiturates may influence the metabolism of other concomitantly used drugs, such as phentyoin, halothane, anticoagulants, corticosteroids, ethyl alcohol, and propylene glycol-containing solutions. Carcinogenesis, Mutagenesis, Impairment of Fertility—Studies in animals to evaluate the carcinogenic and mutagenic potential of Brevital Sodium have not been conducted. Reproduction studies in animals have revealed no evidence of impaired fertility. Usage in Pregnancy—Pregnancy Category B—Reproduction studies have been performed in rabbits and rats at doses up to 4 and 7 times the human dose respectively and have revealed no evidence of harm to the fetus due to methohexital sodium. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 11-559/S-037 Page 9 9 studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery—Brevital Sodium has been used in cesarean section delivery but, because of its solubility and lack of protein binding, it readily and rapidly traverses the placenta. Nursing Mothers—Caution should be exercised when Brevital Sodium is administered to a nursing woman. Pediatric Use—The safety and effectiveness of methohexital sodium in pediatric patients below the age of 1 month have not been established. Seizures may be elicited in subjects with a previous history of convulsive activity, especially partial seizure disorders. Apnea has been reported following dosing with methohexital regardless of the route of administration used. Studies using methohexital sodium intravenously in pediatric patients have been reported in the published literature. This literature is not adequate to establish the safety and effectiveness of intravenous administration of methohexital sodium in pediatric patients. Due to a variety of limitations such as study design, biopharmaceutic issues, and the wide range of effects observed with similar doses of intravenous methohexital, additional studies of intravenous methohexital in pediatric patients are necessary before this route can be recommended in pediatric patients. (See WARNINGS) Geriatric Use—Clinical studies of Brevital did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Elderly subjects may commonly have conditions in which methohexital should be used cautiously such as obstructive pulmonary disease, severe hypertension or hypotension, preexisting circulatory depression, myocardial disease, congestive heart failure, or severe anemia. Caution should be exercised in debilitated patients or in those with impaired function of respiratory, circulatory, renal, hepatic, or endocrine systems (see WARNINGS, PRECAUTIONS and ADVERSE REACTIONS). Barbiturates may influence the metabolism of other concomitantly used drugs that are commonly taken by the elderly, such as anticoagulants and corticosteroids. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see PRECAUTIONS-Drug Interactions). ADVERSE REACTIONS Side effects associated with Brevital Sodium are extensions of pharmacologic effects and include: Cardiovascular—Circulatory depression, thrombophlebitis, hypotension, tachycardia, peripheral vascular collapse, and convulsions in association with cardiorespiratory arrest Respiratory—Respiratory depression (including apnea), cardiorespiratory arrest, laryngospasm, bronchospasm, hiccups, and dyspnea This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 11-559/S-037 Page 10 10 Neurologic—Skeletal muscle hyperactivity (twitching), injury to nerves adjacent to injection site, and seizures Psychiatric—Emergence delirium, restlessness, and anxiety may occur, especially in the presence of postoperative pain Gastrointestinal—Nausea, emesis, abdominal pain, and liver function tests abnormal Allergic—Erythema, pruritus, urticaria, and cases of anaphylaxis have been reported rarely Other—Other adverse reactions include pain at injection site, salivation, headache, and rhinitis DRUG ABUSE AND DEPENDENCE Controlled Substance—Brevital Sodium is a Schedule IV drug. Brevital Sodium may be habit-forming. OVERDOSAGE Signs and Symptoms—The onset of toxicity following an overdose of intravenously administered methohexital will be within seconds of the infusion. If methohexital is administered rectally or is ingested, the onset of toxicity may be delayed. The manifestations of an ultrashort-acting barbiturate in overdose include central nervous system depression, respiratory depression, hypotension, loss of peripheral vascular resistance, and muscular hyperactivity ranging from twitching to convulsive-like movements. Other findings may include convulsions and allergic reactions. Following massive exposure to any barbiturate, pulmonary edema, circulatory collapse with loss of peripheral vascular tone, and cardiac arrest may occur. Treatment—To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. Establish an airway and ensure oxygenation and ventilation. Resuscitative measures should be initiated promptly. For hypotension, intravenous fluids should be administered and the patient’s legs raised. If desirable increase in blood pressure is not obtained, vasopressor and/or inotropic drugs may be used as dictated by the clinical situation. For convulsions, diazepam intravenously and phenytoin may be required. If the seizures are refractory to diazepam and phenytoin, general anesthesia and paralysis with a neuromuscular blocking agent may be necessary. Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 11-559/S-037 Page 11 11 hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal. DOSAGE AND ADMINISTRATION Facilities for assisting ventilation and administering oxygen are necessary adjuncts for all routes of administration of anesthesia. Since cardiorespiratory arrest may occur, patients should be observed carefully during and after use of Brevital Sodium. Age- and size- appropriate resuscitative equipment (ie, intubation and cardioversion equipment, oxygen, suction, and a secure intravenous line) and personnel qualified in its use must be immediately available. Preanesthetic medication is generally advisable. Brevital Sodium may be used with any of the recognized preanesthetic medications. Preparation of Solution—FOLLOW DILUTING INSTRUCTIONS EXACTLY. Solutions of Brevital Sodium should be freshly prepared and used promptly. Reconstituted solutions of Brevital Sodium are chemically stable at room temperature for 24 hours. Diluents—DO NOT USE DILUENTS CONTAINING BACTERIOSTATS. Preferred diluent: Sterile Water for Injection Acceptable diluents: 5% Dextrose Injection, 0.9% Sodium Chloride Injection Incompatible diluents: Lactated Ringer’s Injection Dilution Instructions—1% solutions (10 mg/mL) should be prepared for intravenous use. Contents of vials should be diluted as follows: Strength Amount of Diluent to Be Added For 1% To the Contents of the Vial solution 500 mg 50 mL no further dilution needed 2.5 g 15 mL add to 235 mL for 250 mL total volume When the first dilution is made with the 2.5 g, the solution in the vial will be yellow. When further diluted to make a 1% solution, it must be clear and colorless or should not be used. For continuous drip anesthesia, prepare a 0.2% solution by adding 500 mg of Brevital Sodium to 250 mL of diluent. For this dilution, either 5% glucose solution or isotonic (0.9%) sodium chloride solution is recommended instead of distilled water in order to avoid extreme hypotonicity. For intramuscular administration, contents of the vials should be diluted as follows: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 11-559/S-037 Page 12 12 FOR INTRAMUSCULAR ADMINISTRATION Strength Amount of Diluent to Be Added Concentration To the Contents of the Vial after Duration 500 mg vial 10 mL 5% Solution (50 mg/mL) 2.5 g vial 50 mL 5% Solution (50 mg/mL) For rectal administration, contents of the vials should be diluted as follows: FOR RECTAL ADMINISTRATION Strength Amount of Diluent to Be Added Concentration To the Contents of the Vial after Duration 500 mg vial 50 mL 1% Solution (10 mg/mL) 2.5 g vial 250 mL 1% Solution (larger vial needed) (10 mg/mL) Administration—Dosage is highly individualized; the drug should be administered only by those completely familiar with its quantitative differences from other barbiturate anesthetics. Adults—Brevital Sodium is administered intravenously in a concentration of no higher than 1%. Higher concentrations markedly increase the incidence of muscular movements and irregularities in respiration and blood pressure. Induction of anesthesia—For induction of anesthesia, a 1% solution is administered at a rate of about 1 mL/5 seconds. Gaseous anesthetics and/or skeletal muscle relaxants may be administered concomitantly. The dose required for induction may range from 50 to 120 mg or more but averages about 70 mg. The usual dosage in adults ranges from 1 to 1.5 mg/kg. The induction dose usually provides anesthesia for 5 to 7 minutes. Maintenance of anesthesia—Maintenance of anesthesia may be accomplished by intermittent injections of the 1% solution or, more easily, by continuous intravenous drip of a 0.2% solution. Intermittent injections of about 20 to 40 mg (2 to 4 mL of a 1% solution) may be given as required, usually every 4 to 7 minutes. For continuous drip, the average rate of administration is about 3 mL of a 0.2% solution/minute (1 drop/second). The rate of flow must be individualized for each patient. For longer surgical procedures, gradual reduction in the rate of administration is recommended (see discussion of prolonged administration in WARNINGS). Other parenteral agents, usually narcotic analgesics, are ordinarily employed along with Brevital Sodium during longer procedures. Pediatric Patients—Brevital Sodium is administered intramuscularly in a 5% concentration and administered rectally as a 1% solution. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 11-559/S-037 Page 13 13 Induction of anesthesia—For the induction of anesthesia by the intramuscular route of administration, the usual dose ranges from 6.6 to 10 mg/kg of the 5% concentration. For rectal administration, the usual dose for induction is 25 mg/kg using the 1% solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. COMPATIBILITY INFORMATION Solutions of Brevital Sodium should not be mixed in the same syringe or administered simultaneously during intravenous infusion through the same needle with acid solutions, such as atropine sulfate, metocurine iodide, and succinylcholine chloride. Alteration of pH may cause free barbituric acid to be precipitated. Solubility of the soluble sodium salts of barbiturates, including Brevital Sodium, is maintained only at a relatively high (basic) pH. Because of numerous requests from anesthesiologists for information regarding the chemical compatibility of these mixtures, the following chart contains information obtained from compatibility studies in which a 1% solution of Brevital Sodium was mixed with therapeutic amounts of agents whose solutions have a low (acid) pH. Active Potency Volume Physical Change Ingredient per mL Used Immediate 15 min 30 min 1 h Brevital Sodium 10 mg 10 mL CONTROL Atropine Sulfate 1/150 gr 1 mL None Haze Atropine Sulfate 1/100 gr 1 mL None Ppt Ppt Succinylcholine chloride 0.5 mg 4 mL None None Haze Succinylcholine chloride 1 mg 4 mL None None Haze Metocurine Iodide 0.5 mg 4 mL None None Ppt Metocurine Iodide 1 mg 4 mL None None Ppt Scopolamine hydrobromide1/120 gr 1 mL None None None Haze Tubocurarine chloride 3 mg 4 mL None Haze HOW SUPPLIED Store at controlled room temperature (20° to 25°C) (68° to 77°F) [see USP]. The expiration period for the vials is 2 years. Brevital® Sodium Vials: 500 mg (with 30 mg anhydrous sodium carbonate) are available as follows: 50-mL size, multiple dose—1’s (NDC 61570-095-01) 50-mL size, multiple dose—25’s (NDC 61570-095-25) The 2.5 g vials (with 150 mg anhydrous sodium carbonate) are available as follows: 50-mL size, multiple dose—25’s (NDC 61570-096-25) In crystalline form. Prescribing Information as of April 2004. Update Rev Date This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 11-559/S-037 Page 14 14 Distributed for: Monarch Pharmaceuticals, Inc., Bristol, TN 37620 (A wholly owned subsidiary of King Pharmaceuticals, Inc.) Distributed by: King Pharmaceuticals, Inc., Bristol, TN 37620 Manufactured by: Cardinal Health, Albuquerque, NM 87109 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:44.735805	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/11559slr037_brevital_lbl.pdf', 'application_number': 11559, 'submission_type': 'SUPPL ', 'submission_number': 37}
10,769	DIABINESE® (chlorpropamide) TABLETS, USP For Oral Use DESCRIPTION DIABINESE® (chlorpropamide), is an oral blood-glucose-lowering drug of the sulfonylurea class. Chlorpropamide is 1-[(p-Chlorophenyl)sulfonyl]-3-propylurea, C10H13ClN2O3S, and has the structural formula: str uctu ral f orm ula Chlorpropamide is a white crystalline powder, that has a slight odor. It is practically insoluble in water at pH 7.3 (solubility at pH 6 is 2.2 mg/mL). It is soluble in alcohol and moderately soluble in chloroform. The molecular weight of chlorpropamide is 276.74. DIABINESE is available as 100 mg and 250 mg tablets. Inert ingredients are: alginic acid; Blue 1 Lake; hydroxypropyl cellulose; magnesium stearate; precipitated calcium carbonate; sodium lauryl sulfate; starch. CLINICAL PHARMACOLOGY DIABINESE appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which DIABINESE lowers blood glucose during long-term administration has not been clearly established. Extra-pancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. While chlorpropamide is a sulfonamide derivative, it is devoid of antibacterial activity. DIABINESE may also prove effective in controlling certain patients who have experienced primary or secondary failure to other sulfonylurea agents. - 1 Reference ID: 2898856 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda A method developed which permits easy measurement of the drug in blood is available on request. Chlorpropamide does not interfere with the usual tests to detect albumin in the urine. DIABINESE is absorbed rapidly from the gastrointestinal tract. Within one hour after a single oral dose, it is readily detectable in the blood, and the level reaches a maximum within two to four hours. It undergoes metabolism in humans and it is excreted in the urine as unchanged drug and as hydroxylated or hydrolyzed metabolites. The biological half-life of chlorpropamide averages about 36 hours. Within 96 hours, 80-90% of a single oral dose is excreted in the urine. However, long-term administration of therapeutic doses does not result in undue accumulation in the blood, since absorption and excretion rates become stabilized in about 5 to 7 days after the initiation of therapy. DIABINESE exerts a hypoglycemic effect in healthy subjects within one hour, becoming maximal at 3 to 6 hours and persisting for at least 24 hours. The potency of chlorpropamide is approximately six times that of tolbutamide. Some experimental results suggest that its increased duration of action may be the result of slower excretion and absence of significant deactivation. INDICATIONS AND USAGE DIABINESE is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. CONTRAINDICATIONS DIABINESE is contraindicated in patients with: 1. Known hypersensitivity to any component of this medicine. 2. Type 1 diabetes mellitus, diabetic ketoacidosis, with or without coma. This condition should be treated with insulin. WARNINGS SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes, 19 [supp. 2]:747-830, 1970). - 2 Reference ID: 2898856 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in over-all mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of DIABINESE and of alternative modes of therapy. Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure. PRECAUTIONS General Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with DIABINESE or any other anti-diabetic drug. Hypoglycemia: All sulfonylurea drugs including chlorpropamide are capable of producing severe hypoglycemia, which may result in coma, and may require hospitalization. Patients experiencing hypoglycemia should be managed with appropriate glucose therapy and be monitored for a minimum of 24 to 48 hours (see Overdosage section). Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Regular, timely carbohydrate intake is important to avoid hypoglycemic events occurring when a meal is delayed or insufficient food is eaten or carbohydrate intake is unbalanced. Renal or hepatic insufficiency may affect the disposition of DIABINESE and may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. - 3 Reference ID: 2898856 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Because of the long half-life of chlorpropamide, patients who become hypoglycemic during therapy require careful supervision of the dose and frequent feedings for at least 3 to 5 days. Hospitalization and intravenous glucose may be necessary. Loss of control of blood glucose: When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it may be necessary to discontinue DIABINESE and administer insulin. The effectiveness of any oral hypoglycemic drug, including DIABINESE, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure. Hemolytic Anemia: Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because DIABINESE belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In post marketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency. Geriatric Use The safety and effectiveness of DIABINESE in patients aged 65 and over has not been properly evaluated in clinical studies. Adverse event reporting suggests that elderly patients may be more prone to developing hypoglycemia and/or hyponatremia when using DIABINESE. Although the underlying mechanisms are unknown, abnormal renal function, drug interaction and poor nutrition appear to contribute to these events. INFORMATION FOR PATIENTS Patients should be informed of the potential risks and advantages of DIABINESE and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose. The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure should also be explained. Patients should be instructed to contact their physician promptly if they experience symptoms of hypoglycemia or other adverse reactions. Physician Counseling Information for Patients: In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and - 4 Reference ID: 2898856 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda cardiovascular risk factors should be identified and corrective measures taken where possible. Use of DIABINESE or other antidiabetic medications must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitution or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of DIABINESE or other antidiabetic medications. Maintenance or discontinuation of DIABINESE or other antidiabetic medications should be based on clinical judgment using regular clinical and laboratory evaluations. LABORATORY TESTS Blood glucose should be monitored periodically. Measurement of glycosylated hemoglobin should be performed and goals assessed by the current standard of care. DRUG INTERACTIONS The following products can lead to hypoglycemia: The hypoglycemic action of sulfonylurea may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving DIABINESE, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving DIABINESE, the patient should be observed closely for loss of control. Miconazole: A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with intravenous, topical, or vaginal preparations of miconazole is not known. Alcohol: In some patients, a disulfiram-like reaction may be produced by the ingestion of alcohol. Moderate to large amounts of alcohol may increase the risk of hypoglycemia (ref.1), (ref. 2). The following products can lead to hyperglycemia: Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. - 5 Reference ID: 2898856 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda When such drugs are administered to a patient receiving DIABINESE, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving DIABINESE, the patient should be observed closely for hypoglycemia. Since animal studies suggest that the action of barbiturates may be prolonged by therapy with chlorpropamide, barbiturates should be employed with caution. Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with DIABINESE have not been conducted to evaluate carcinogenic or mutagenic potential. Rats treated with continuous DIABINESE therapy for 6 to 12 months showed varying degrees of suppression of spermatogenesis at a dose level of 250 mg/kg (five times the human dose based on body surface area). The extent of suppression seemed to follow that of growth retardation associated with chronic administration of high-dose DIABINESE in rats. The human dose of chlorpropamide is 500 mg/day (300 mg/M2). Six- and 12-month toxicity work in the dog and rat, respectively, indicates the 150 mg/kg is well tolerated. Therefore, the safety margins based upon body-surface-area comparisons are three times human exposure in the rat and 10 times human exposure in the dog. Pregnancy Teratogenic Effects: Pregnancy Category C. Animal reproductive studies have not been conducted with DIABINESE. It is also not known whether DIABINESE can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. DIABINESE should be given to a pregnant woman only if the potential benefits justify the potential risk to the patient and fetus. Because data suggest that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If DIABINESE is used during pregnancy, it should be discontinued at least one month before the expected delivery date and other therapies instituted to maintain blood glucose levels as close to normal as possible. Nursing Mothers: An analysis of a composite of two samples of human breast milk, each taken five hours after ingestion of 500 mg of chlorpropamide by a patient, revealed a concentration of 5 mcg/mL. For reference, the normal peak blood level of chlorpropamide after a single 250 mg dose is 30 mcg/mL. Therefore, it is not recommended that a woman breast feed while taking this medication. Use in Children: Safety and effectiveness in children have not been established. - 6 Reference ID: 2898856 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ability to Drive and Use Machines: The effect of DIABINESE on the ability to drive or operate machinery has not been studied. However, there is no evidence to suggest that DIABINESE may affect these abilities. Patients should be aware of the symptoms of hypoglycemia and take caution while driving and operating machinery. ADVERSE REACTIONS Body as a Whole: Disulfiram-like reactions have rarely been reported with DIABINESE (see DRUG INTERACTIONS). Central and Peripheral Nervous System: Dizziness and headache. . Hypoglycemia: See PRECAUTIONS and OVERDOSAGE sections. Gastrointestinal: Gastrointestinal disturbances are the most common reactions; nausea has been reported in less than 5% of patients, and diarrhea, vomiting, anorexia, and hunger in less than 2%. Other gastrointestinal disturbances have occurred in less than 1% of patients including proctocolitis. They tend to be dose-related and may disappear when dosage is reduced. Liver/Biliary: Cholestatic jaundice and hepatitis may occur rarely, which may progress to liver failure; DIABINESE should be discontinued if this occurs. Hepatic porphyria and disulfiram-like reactions have been reported with DIABINESE. Skin/Appendages: Pruritus has been reported in less than 3% of patients. Other allergic skin reactions, e.g., urticaria and maculopapular eruptions have been reported in approximately 1% or less of patients. These may be transient and may disappear despite continued use of DIABINESE; if skin reactions persist the drug should be discontinued. As with other sulfonylureas, porphyria cutanea tarda and photosensitivity reactions have been reported. Skin eruptions rarely progressing to erythema multiforme and exfoliative dermatitis have also been reported. Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia (see PRECAUTIONS), aplastic anemia, pancytopenia, and eosinophilia have been reported with sulfonylureas. Metabolic/Nutritional Reactions: Hypoglycemia (see PRECAUTIONS and OVERDOSAGE sections). Hepatic porphyria and disulfiram-like reactions have been reported with DIABINESE. See DRUG INTERACTIONS section. Endocrine Reactions: On rare occasions, chlorpropamide has caused a reaction identical to the syndrome of inappropriate antidiuretic hormone (ADH) secretion. The features of this syndrome - 7 Reference ID: 2898856 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda result from excessive water retention and include hyponatremia, low serum osmolality, and high urine osmolality. This reaction has also been reported for other sulfonylureas. OVERDOSAGE Overdosage of sulfonylureas including DIABINESE can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. DOSAGE AND ADMINISTRATION There is no fixed dosage regimen for the management of type 2 diabetes with DIABINESE or any other hypoglycemic agent. The patient's blood glucose must be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient's response to therapy. Short-term administration of DIABINESE may be sufficient during periods of transient loss of control in patients usually controlled well on diet. The total daily dosage is generally taken at a single time each morning with breakfast. Occasionally cases of gastrointestinal intolerance may be relieved by dividing the daily dosage. A LOADING OR PRIMING DOSE IS NOT NECESSARY AND SHOULD NOT BE USED. Initial Therapy: 1. The mild to moderately severe, middle-aged, stable type 2 diabetes patient should be started on 250 mg daily. In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS section). Older patients should be started on smaller amounts of DIABINESE, in the range of 100 to 125 mg daily. 2. No transition period is necessary when transferring patients from other oral hypoglycemic agents to DIABINESE. The other agent may be discontinued abruptly and chlorpropamide started at once. In prescribing chlorpropamide, due consideration must be given to its greater potency. - 8 Reference ID: 2898856 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Many mild to moderately severe, middle-aged, stable type 2 diabetes patients receiving insulin can be placed directly on the oral drug and their insulin abruptly discontinued. For patients requiring more than 40 units of insulin daily, therapy with DIABINESE may be initiated with a 50 per cent reduction in insulin for the first few days, with subsequent further reductions dependent upon the response. During the initial period of therapy with chlorpropamide, hypoglycemic reactions may occasionally occur, particularly during the transition from insulin to the oral drug. Hypoglycemia within 24 hours after withdrawal of the intermediate or long-acting types of insulin will usually prove to be the result of insulin carry-over and not primarily due to the effect of chlorpropamide. During the insulin withdrawal period, the patient should self-monitor glucose levels at least three times daily. If they are abnormal, the physician should be notified immediately. In some cases, it may be advisable to consider hospitalization during the transition period. Five to seven days after the initial therapy, the blood level of chlorpropamide reaches a plateau. Dosage may subsequently be adjusted upward or downward by increments of not more than 50 to l25 mg at intervals of three to five days to obtain optimal control. More frequent adjustments are usually undesirable. Maintenance Therapy: Most moderately severe, middle-aged, stable type 2 diabetes patients are controlled by approximately 250 mg daily. Many investigators have found that some milder diabetics do well on daily doses of 100 mg or less. Many of the more severe diabetics may require 500 mg daily for adequate control. PATIENTS WHO DO NOT RESPOND COMPLETELY TO 500 MG DAILY WILL USUALLY NOT RESPOND TO HIGHER DOSES. MAINTENANCE DOSES ABOVE 750 mg DAILY SHOULD BE AVOIDED. HOW SUPPLIED Strength Tablet Description Tablet Code NDC Package Size DIABINESE (chlorpro- pamide) 100 mg Blue, D-shaped, scored 393 0069-3930-66 100's DIABINESE (chlorpro- pamide) 250 mg Blue, D-shaped, scored 394 0069-3940-66 0069-3940-82 100's 1000's RECOMMENDED STORAGE: Store below 86°F (30°C). - 9 Reference ID: 2898856 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rx only company logo LAB-0039-6.0 Revised July 2010 - 10 Reference ID: 2898856 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:44.975974	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/011641s066lbl.pdf', 'application_number': 11641, 'submission_type': 'SUPPL ', 'submission_number': 66}
10,766	BREVITAL® SODIUM METHOHEXITAL SODIUM FOR INJECTION, USP Logo For Intravenous Use in Adults For Rectal and Intramuscular Use Only in Pediatric Patients WARNING Brevital should be used only in hospital or ambulatory care settings that provide for continuous monitoring of respiratory (e.g. pulse oximetry) and cardiac function. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation and personnel trained in their use and skilled in airway management should be assured. For deeply sedated patients, a designated individual other than the practitioner performing the procedure should be present to continuously monitor the patient. (See WARNINGS) DESCRIPTION Brevital® Sodium (Methohexital Sodium for Injection, USP) is 2,4,6 (1H, 3H, 5H)- Pyrimidinetrione, 1-methyl-5-(1-methyl-2-pentynyl)-5-(2-propenyl)-, (±)-, monosodium salt and has the empirical formula C14H17N2NaO3. Its molecular weight is 284.29. The structural formula is as follows: Chemical Structure Methohexital sodium is a rapid, ultrashort-acting barbiturate anesthetic. Methohexital sodium for injection is a freeze-dried, sterile, nonpyrogenic mixture of methohexital sodium with 6% anhydrous sodium carbonate added as a buffer. It contains not less than 90% and not more than 110% of the labeled amount of methohexital sodium. It occurs as a white, freeze-dried plug that is freely soluble in water. This product is oxygen sensitive. The pH of the 1% solution is between 10 and 11; the pH of the 0.2% solution in 5% dextrose is between 9.5 and 10.5. Methohexital sodium may be administered by direct intravenous injection or continuous intravenous drip, intramuscular or rectal routes (see PRECAUTIONS—Pediatric Use). Reconstituting instructions vary depending on the route of administration (see DOSAGE AND ADMINISTRATION). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Compared with thiamylal and thiopental, methohexital is at least twice as potent on a weight basis, and its duration of action is only about half as long. Although the metabolic fate of methohexital in the body is not clear, the drug does not appear to concentrate in fat depots to the extent that other barbiturate anesthetics do. Thus, cumulative effects are fewer and recovery is more rapid with methohexital than with thiobarbiturates. In experimental animals, the drug cannot be detected in the blood 24 hours after administration. Methohexital differs chemically from the established barbiturate anesthetics in that it contains no sulfur. Little analgesia is conferred by barbiturates; their use in the presence of pain may result in excitation. Intravenous administration of methohexital results in rapid uptake by the brain (within 30 seconds) and rapid induction of sleep. Following intramuscular administration to pediatric patients, the onset of sleep occurs in 2 to 10 minutes. A plasma concentration of 3 µg/mL was achieved in pediatric patients 15 minutes after an intramuscular dose (10 mg/kg) of a 5% solution. Following rectal administration to pediatric patients, the onset of sleep occurs in 5 to 15 minutes. Plasma methohexital concentrations achieved following rectal administration tend to increase both with dose and with the use of more dilute solution concentrations when using the same dose. A 25 mg/kg dose of a 1% methohexital solution yielded plasma concentrations of 6.9 to 7.9 µg/mL 15 minutes after dosing. The absolute bioavailability of rectal methohexital sodium is 17%. With single doses, the rate of redistribution determines duration of pharmacologic effect. Metabolism occurs in the liver through demethylation and oxidation. Side-chain oxidation is the most important biotransformation involved in termination of biologic activity. Excretion occurs via the kidneys through glomerular filtration. INDICATIONS AND USAGE Brevital Sodium can be used in adults as follows: 1. For intravenous induction of anesthesia prior to the use of other general anesthetic agents. 2. For intravenous induction of anesthesia and as an adjunct to subpotent inhalational anesthetic agents (such as nitrous oxide in oxygen) for short surgical procedures; Brevital Sodium may be given by infusion or intermittent injection. 3. For use along with other parenteral agents, usually narcotic analgesics, to supplement subpotent inhalational anesthetic agents (such as nitrous oxide in oxygen) for longer surgical procedures. 4. As intravenous anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli (see WARNINGS). 5. As an agent for inducing a hypnotic state. Brevital Sodium can be used in pediatric patients older than 1 month as follows: 1. For rectal or intramuscular induction of anesthesia prior to the use of other general anesthetic agents. 2. For rectal or intramuscular induction of anesthesia and as an adjunct to subpotent inhalational anesthetic agents for short surgical procedures. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3. As rectal or intramuscular anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli. CONTRAINDICATIONS Brevital Sodium is contraindicated in patients in whom general anesthesia is contraindicated, in those with latent or manifest porphyria, or in patients with a known hypersensitivity to barbiturates. WARNINGS See boxed Warning. As with all potent anesthetic agents and adjuncts, Brevital should be used only in hospital or ambulatory care settings that provide for continuous monitoring of respiratory (e.g. pulse oximetry) and cardiac function. Immediate availability of resuscitative drugs and age- and size- appropriate equipment for bag/valve/mask ventilation and intubation and personnel trained in their use and skilled in airway management should be assured. For deeply sedated patients, a designated individual other than the practitioner performing the procedure should be present to continuously monitor the patient. Maintenance of a patent airway and adequacy of ventilation must be ensured during induction and maintenance of anesthesia with methohexital sodium solution. Laryngospasm is common during induction with all barbiturates and may be due to a combination of secretions and accentuated reflexes following induction or may result from painful stimuli during light anesthesia. Apnea/hypoventilation may be noted during induction, which may impair pulmonary ventilation; the duration of apnea may be longer than that produced by other barbiturate anesthetics. Cardiorespiratory arrest may occur. This prescribing information describes intravenous use of methohexital sodium in adults. It also discusses intramuscular and rectal administration in pediatric patients older than one month. Although the published literature discusses intravenous administration in pediatric patients, the safety and effectiveness of intravenous administration of methohexital sodium in pediatric patients have not been established in well-controlled, prospective studies. (See PRECAUTIONS— Pediatric Use) Seizures may be elicited in subjects with a previous history of convulsive activity, especially partial seizure disorders. Because the liver is involved in demethylation and oxidation of methohexital and because barbiturates may enhance preexisting circulatory depression, severe hepatic dysfunction, severe cardiovascular instability, or a shock-like condition may be reason for selecting another induction agent. Prolonged administration may result in cumulative effects, including extended somnolence, protracted unconsciousness, and respiratory and cardiovascular depression. Respiratory depression in the presence of an impaired airway may lead to hypoxia, cardiac arrest, and death. The CNS-depressant effect of Brevital Sodium may be additive with that of other CNS depressants, including ethyl alcohol and propylene glycol. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DANGER OF INTRA-ARTERIAL INJECTION—Unintended intra-arterial injection of barbiturate solutions may be followed by the production of platelet aggregates and thrombosis, starting in arterioles distal to the site of injection. The resulting necrosis may lead to gangrene, which may require amputation. The first sign in conscious patients may be a complaint of fiery burning that roughly follows the distribution path of the injected artery; if noted, the injection should be stopped immediately and the situation reevaluated. Transient blanching may or may not be noted very early; blotchy cyanosis and dark discoloration may then be the first sign in anesthetized patients. There is no established treatment other than prevention. The following should be considered prior to injection: 1. The extent of injury is related to concentration. Concentrations of 1% methohexital will usually suffice; higher concentrations should ordinarily be avoided. 2. Check the infusion to ensure that the catheter is in the lumen of a vein before injection. Injection through a running intravenous infusion may enhance the possibility of detecting arterial placement; however, it should be remembered that the characteristic bright-red color of arterial blood is often altered by contact with drugs. The possibility of aberrant arteries should always be considered. Postinjury arterial injection of vasodilators and/or arterial infusion of parenteral fluids are generally regarded to be of no value in altering outcome. Animal experiments and published individual case reports concerned with a variety of arteriolar irritants, including barbiturates, suggest that 1 or more of the following may be of benefit in reducing the area of necrosis: 1. Arterial injection of heparin at the site of injury, followed by systemic anticoagulation. 2. Sympathetic blockade (or brachial plexus blockade in the arm). 3. Intra-arterial glucocorticoid injection at the site of injury, followed by systemic steroids. 4. A case report (nonbarbiturate injury) suggests that intra-arterial urokinase may promote fibrinolysis, even if administered late in treatment. If extravasation is noted during injection of methohexital, the injection should be discontinued until the situation is remedied. Local irritation may result from extravasation; subcutaneous swelling may also serve as a sign of arterial or periarterial placement of the catheter. PRECAUTIONS General—All routes of administration of Brevital Sodium are often associated with hiccups, coughing, and/or muscle twitching, which may also impair pulmonary ventilation. Following induction, temporary hypotension and tachycardia may occur. Recovery from methohexital anesthesia is rapid and smooth. The incidence of postoperative nausea and vomiting is low if the drug is administered to fasting patients. Postanesthetic shivering has occurred in a few instances. The usual precautions taken with any barbiturate anesthetic should be observed with Brevital Sodium. The drug should be used with caution in patients with asthma, obstructive pulmonary disease, severe hypertension or hypotension, myocardial disease, congestive heart failure, severe anemia, or extreme obesity. Methohexital sodium should be used with extreme caution in patients in status asthmaticus. Caution should be exercised in debilitated patients or in those with impaired function of respiratory, circulatory, renal, hepatic, or endocrine systems. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Information for Patients—-When appropriate, patients should be instructed as to the hazards of drowsiness that may follow use of Brevital Sodium. Outpatients should be released in the company of another individual, and no skilled activities, such as operating machinery or driving a motor vehicle, should be engaged in for 8 to 12 hours. Laboratory Tests—BSP and liver function studies may be influenced by administration of a single dose of barbiturates. Drug Interactions—Prior chronic administration of barbiturates or phenytoin (e.g. for seizure disorder) appears to reduce the effectiveness of Brevital Sodium. Barbiturates may influence the metabolism of other concomitantly used drugs, such as phenytoin, halothane, anticoagulants, corticosteroids, ethyl alcohol, and propylene glycol-containing solutions. Carcinogenesis, Mutagenesis, Impairment of Fertility—Studies in animals to evaluate the carcinogenic and mutagenic potential of Brevital Sodium have not been conducted. Reproduction studies in animals have revealed no evidence of impaired fertility. Usage in Pregnancy—Pregnancy Category B—Reproduction studies have been performed in rabbits and rats at doses up to 4 and 7 times the human dose respectively and have revealed no evidence of harm to the fetus due to methohexital sodium. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery—Brevital Sodium has been used in cesarean section delivery but, because of its solubility and lack of protein binding, it readily and rapidly traverses the placenta. Nursing Mothers—Caution should be exercised when Brevital Sodium is administered to a nursing woman. Pediatric Use—The safety and effectiveness of methohexital sodium in pediatric patients below the age of 1 month have not been established. Seizures may be elicited in subjects with a previous history of convulsive activity, especially partial seizure disorders. Apnea has been reported following dosing with methohexital regardless of the route of administration used. Studies using methohexital sodium intravenously in pediatric patients have been reported in the published literature. This literature is not adequate to establish the safety and effectiveness of intravenous administration of methohexital sodium in pediatric patients. Due to a variety of limitations such as study design, biopharmaceutic issues, and the wide range of effects observed with similar doses of intravenous methohexital, additional studies of intravenous methohexital in pediatric patients are necessary before this route can be recommended in pediatric patients. (See WARNINGS) Geriatric Use—Clinical studies of Brevital did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Elderly subjects may commonly have conditions in which methohexital should be used cautiously such as obstructive pulmonary disease, severe hypertension or hypotension, preexisting circulatory depression, myocardial disease, congestive heart failure, or severe anemia. Caution should be exercised in debilitated patients or in those with impaired function of respiratory, circulatory, renal, hepatic, or endocrine systems (see WARNINGS, PRECAUTIONS and ADVERSE REACTIONS). Barbiturates may influence the metabolism of other concomitantly used drugs that are commonly taken by the elderly, such as anticoagulants and corticosteroids. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see PRECAUTIONS-Drug Interactions). ADVERSE REACTIONS Side effects associated with Brevital Sodium are extensions of pharmacologic effects and include: Cardiovascular—Circulatory depression, thrombophlebitis, hypotension, tachycardia, peripheral vascular collapse, and convulsions in association with cardiorespiratory arrest Respiratory—Respiratory depression (including apnea), cardiorespiratory arrest, laryngospasm, bronchospasm, hiccups, and dyspnea Neurologic—Skeletal muscle hyperactivity (twitching), injury to nerves adjacent to injection site, and seizures Psychiatric—Emergence delirium, restlessness, and anxiety may occur, especially in the presence of postoperative pain Gastrointestinal—Nausea, emesis, abdominal pain, and liver function tests abnormal Allergic—Erythema, pruritus, urticaria, and cases of anaphylaxis have been reported rarely Other—Other adverse reactions include pain at injection site, salivation, headache, and rhinitis DRUG ABUSE AND DEPENDENCE Controlled Substance—Brevital Sodium is a Schedule IV drug. Brevital Sodium may be habit-forming. OVERDOSAGE Signs and Symptoms—The onset of toxicity following an overdose of intravenously administered methohexital will be within seconds of the infusion. If methohexital is administered rectally or is ingested, the onset of toxicity may be delayed. The manifestations of an ultrashort-acting barbiturate in overdose include central nervous system depression, respiratory depression, hypotension, loss of peripheral vascular resistance, and muscular hyperactivity ranging from twitching to convulsive-like movements. Other findings may include convulsions and allergic reactions. Following massive exposure to any barbiturate, pulmonary edema, circulatory collapse with loss of peripheral vascular tone, and cardiac arrest may occur. Treatment—To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. Establish an airway and ensure oxygenation and ventilation. Resuscitative measures should be initiated promptly. For hypotension, intravenous fluids should be administered and the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda patient’s legs raised. If desirable increase in blood pressure is not obtained, vasopressor and/or inotropic drugs may be used as dictated by the clinical situation. For convulsions, diazepam intravenously and phenytoin may be required. If the seizures are refractory to diazepam and phenytoin, general anesthesia and paralysis with a neuromuscular blocking agent may be necessary. Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal. DOSAGE AND ADMINISTRATION Facilities for assisting ventilation and administering oxygen are necessary adjuncts for all routes of administration of anesthesia. Since cardiorespiratory arrest may occur, patients should be observed carefully during and after use of Brevital Sodium. Age- and size- appropriate resuscitative equipment (ie, intubation and cardioversion equipment, oxygen, suction, and a secure intravenous line) and personnel qualified in its use must be immediately available. Preanesthetic medication is generally advisable. Brevital Sodium may be used with any of the recognized preanesthetic medications. Preparation of Solution—FOLLOW DILUTING INSTRUCTIONS EXACTLY. Solutions of Brevital Sodium should be freshly prepared and used promptly. Reconstituted solutions of Brevital Sodium are chemically stable at room temperature for 24 hours. Diluents—DO NOT USE DILUENTS CONTAINING BACTERIOSTATS. Preferred diluent: Sterile Water for Injection Acceptable diluents: 5% Dextrose Injection (for IV or rectal administration only), 0.9% Sodium Chloride Injection Incompatible diluents: Lactated Ringer’s Injection Dilution Instructions—1% solutions (10 mg/mL) should be prepared for intravenous use. Contents of vials should be diluted as follows: FOR INTRAVENOUS ADMINISTRATION Amount of Diluent to Be Strength Added to the Contents of the For 1% methohexital solution Vial 500 mg 50 mL no further dilution needed 2.5 g 15 mL add to 235 mL for 250 mL total volume This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda When the first dilution is made with the 2.5 g, the solution in the vial will be yellow. When further diluted to make a 1% solution, it must be clear and colorless or should not be used. For continuous drip anesthesia, prepare a 0.2% solution by adding 500 mg of Brevital Sodium to 250 mL of diluent. For this dilution, either 5% glucose solution or isotonic (0.9%) sodium chloride solution is recommended instead of distilled water in order to avoid extreme hypotonicity. For intramuscular administration, contents of the vials should be diluted as follows: FOR INTRAMUSCULAR ADMINISTRATION Strength Amount of Diluent* to Be Added to the Contents of the Vial Methohexital Concentration after Dilution 500 mg vial 10 mL 5% Solution (50 mg/mL) 2.5 g vial 50 mL 5% Solution (50 mg/mL) Sterile water for injection or 0.9% sodium chloride injection only. For rectal administration, contents of the vials should be diluted as follows: FOR RECTAL ADMINISTRATION Strength Amount of Diluent to Be Added to the Contents of the Vial Methohexital Concentration after Dilution 500 mg vial 50 mL 1% Solution (10 mg/mL) 2.5 g vial (larger vial needed) 250 mL 1% Solution (10 mg/mL) Administration—Dosage is highly individualized; the drug should be administered only by those completely familiar with its quantitative differences from other barbiturate anesthetics. Adults—Brevital Sodium is administered intravenously in a concentration of no higher than 1%. Higher concentrations markedly increase the incidence of muscular movements and irregularities in respiration and blood pressure. Induction of anesthesia—For induction of anesthesia, a 1% solution is administered at a rate of about 1 mL/5 seconds. Gaseous anesthetics and/or skeletal muscle relaxants may be administered concomitantly. The dose required for induction may range from 50 to 120 mg or more but averages about 70 mg. The usual dosage in adults ranges from 1 to 1.5 mg/kg. The induction dose usually provides anesthesia for 5 to 7 minutes. Maintenance of anesthesia—Maintenance of anesthesia may be accomplished by intermittent injections of the 1% solution or, more easily, by continuous intravenous drip of a 0.2% solution. Intermittent injections of about 20 to 40 mg (2 to 4 mL of a 1% solution) may be given as required, usually every 4 to 7 minutes. For continuous drip, the average rate of administration is about 3 mL of a 0.2% solution/minute (1 drop/second). The rate of flow must be individualized for each patient. For longer surgical procedures, gradual reduction in the rate of administration is recommended (see discussion of prolonged administration in WARNINGS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Other parenteral agents, usually narcotic analgesics, are ordinarily employed along with Brevital Sodium during longer procedures. Pediatric Patients—Brevital Sodium is administered intramuscularly in a 5% concentration and administered rectally as a 1% solution. Induction of anesthesia—For the induction of anesthesia by the intramuscular route of administration, the usual dose ranges from 6.6 to 10 mg/kg of the 5% concentration. For rectal administration, the usual dose for induction is 25 mg/kg using the 1% solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. COMPATIBILITY INFORMATION Solutions of Brevital Sodium should not be mixed in the same syringe or administered simultaneously during intravenous infusion through the same needle with acid solutions, such as atropine sulfate, metocurine iodide, and succinylcholine chloride. Alteration of pH may cause free barbituric acid to be precipitated. Solubility of the soluble sodium salts of barbiturates, including Brevital Sodium, is maintained only at a relatively high (basic) pH. Because of numerous requests from anesthesiologists for information regarding the chemical compatibility of these mixtures, the following chart contains information obtained from compatibility studies in which a 1% solution of Brevital Sodium was mixed with therapeutic amounts of agents whose solutions have a low (acid) pH. Active Potency Volume 15 Physical Change Ingredient per mL Used Immediate min 30 min 1 h Brevital Sodium 10 mg 10 mL CONTROL Atropine Sulfate 1/150 gr 1 mL None Haze Atropine Sulfate 1/100 gr 1 mL None Ppt Ppt Succinylcholine chloride 0.5 mg 4 mL None None Haze Succinylcholine chloride 1 mg 4 mL None None Haze Metocurine Iodide 0.5 mg 4 mL None None Ppt Metocurine Iodide 1 mg 4 mL None None Ppt Scopolamine hydrobromide 1/120 gr 1 mL None None None Haze Tubocurarine chloride 3 mg 4 mL None Haze HOW SUPPLIED Store at controlled room temperature (20° to 25°C) (68° to 77°F) [see USP]. Brevital® Sodium Vials: 500 mg (with 30 mg anhydrous sodium carbonate) are available as follows: -50-mL size, multiple dose—1’s (NDC 61570-095-01) -50-mL size, multiple dose—25’s (NDC 61570-095-25) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The 2.5 g vials (with 150 mg anhydrous sodium carbonate) are available as follows: -50-mL size, multiple dose—25’s (NDC 61570-096-25) *In crystalline form. Rx Only. Prescribing Information as of July 2007. Monarch Pharmaceuticals Logo Distributed for: Monarch Pharmaceuticals, Inc., Bristol, TN 37620 (A wholly owned subsidiary of King Pharmaceuticals, Inc.) Manufactured by: King Pharmaceuticals, Inc., Bristol, TN 37620 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:45.065914	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/011559s041lbl.pdf', 'application_number': 11559, 'submission_type': 'SUPPL ', 'submission_number': 41}
10,768	DIABINESE® (chlorpropamide) TABLETS, USP For Oral Use DESCRIPTION DIABINESE® (chlorpropamide), is an oral blood-glucose-lowering drug of the sulfonylurea class. Chlorpropamide is 1-[(p-Chlorophenyl)sulfonyl]-3-propylurea, C10H13ClN2O3S, and has the structural formula: Structural Formula of Diabinese (Chlorpropamide) O SO2 NH C NH CH2CH2CH3 Chlorpropamide is a white crystalline powder, that has a slight odor. It is practically insoluble in water at pH 7.3 (solubility at pH 6 is 2.2 mg/mL). It is soluble in alcohol and moderately soluble in chloroform. The molecular weight of chlorpropamide is 276.74. DIABINESE is available as 100 mg and 250 mg tablets. Inert ingredients are: alginic acid; Blue 1 Lake; hydroxypropyl cellulose; magnesium stearate; precipitated calcium carbonate; sodium lauryl sulfate; starch. CLINICAL PHARMACOLOGY DIABINESE appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which DIABINESE lowers blood glucose during long-term administration has not been clearly established. Extra-pancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. While chlorpropamide is a sulfonamide derivative, it is devoid of antibacterial activity. DIABINESE may also prove effective in controlling certain patients who have experienced primary or secondary failure to other sulfonylurea agents. - 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda A method developed which permits easy measurement of the drug in blood is available on request. Chlorpropamide does not interfere with the usual tests to detect albumin in the urine. DIABINESE is absorbed rapidly from the gastrointestinal tract. Within one hour after a single oral dose, it is readily detectable in the blood, and the level reaches a maximum within two to four hours. It undergoes metabolism in humans and it is excreted in the urine as unchanged drug and as hydroxylated or hydrolyzed metabolites. The biological half-life of chlorpropamide averages about 36 hours. Within 96 hours, 80-90% of a single oral dose is excreted in the urine. However, long-term administration of therapeutic doses does not result in undue accumulation in the blood, since absorption and excretion rates become stabilized in about 5 to 7 days after the initiation of therapy. DIABINESE exerts a hypoglycemic effect in healthy subjects within one hour, becoming maximal at 3 to 6 hours and persisting for at least 24 hours. The potency of chlorpropamide is approximately six times that of tolbutamide. Some experimental results suggest that its increased duration of action may be the result of slower excretion and absence of significant deactivation. INDICATIONS AND USAGE DIABINESE is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. CONTRAINDICATIONS DIABINESE is contraindicated in patients with: 1. Known hypersensitivity to any component of this medicine. 2. Type 1 diabetes mellitus, diabetic ketoacidosis, with or without coma. This condition should be treated with insulin. WARNINGS SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes, 19 [supp. 2]:747-830, 1970). - 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in over-all mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of DIABINESE and of alternative modes of therapy. Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure. PRECAUTIONS General Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with DIABINESE or any other anti-diabetic drug. Hypoglycemia: All sulfonylurea drugs including chlorpropamide are capable of producing severe hypoglycemia, which may result in coma, and may require hospitalization. Patients experiencing hypoglycemia should be managed with appropriate glucose therapy and be monitored for a minimum of 24 to 48 hours (see Overdosage section). Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Regular, timely carbohydrate intake is important to avoid hypoglycemic events occurring when a meal is delayed or insufficient food is eaten or carbohydrate intake is unbalanced. Renal or hepatic insufficiency may affect the disposition of DIABINESE and may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. - 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Because of the long half-life of chlorpropamide, patients who become hypoglycemic during therapy require careful supervision of the dose and frequent feedings for at least 3 to 5 days. Hospitalization and intravenous glucose may be necessary. Loss of control of blood glucose: When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it may be necessary to discontinue DIABINESE and administer insulin. The effectiveness of any oral hypoglycemic drug, including DIABINESE, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure. Hemolytic Anemia: Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because DIABINESE belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In post marketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency. Geriatric Use The safety and effectiveness of DIABINESE in patients aged 65 and over has not been properly evaluated in clinical studies. Adverse event reporting suggests that elderly patients may be more prone to developing hypoglycemia and/or hyponatremia when using DIABINESE. Although the underlying mechanisms are unknown, abnormal renal function, drug interaction and poor nutrition appear to contribute to these events. INFORMATION FOR PATIENTS Patients should be informed of the potential risks and advantages of DIABINESE and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose. The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure should also be explained. Patients should be instructed to contact their physician promptly if they experience symptoms of hypoglycemia or other adverse reactions. Physician Counseling Information for Patients: In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and - 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda cardiovascular risk factors should be identified and corrective measures taken where possible. Use of DIABINESE or other antidiabetic medications must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitution or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of DIABINESE or other antidiabetic medications. Maintenance or discontinuation of DIABINESE or other antidiabetic medications should be based on clinical judgment using regular clinical and laboratory evaluations. LABORATORY TESTS Blood glucose should be monitored periodically. Measurement of glycosylated hemoglobin should be performed and goals assessed by the current standard of care. DRUG INTERACTIONS The following products can lead to hypoglycemia: The hypoglycemic action of sulfonylurea may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving DIABINESE, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving DIABINESE, the patient should be observed closely for loss of control. Miconazole: A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with intravenous, topical, or vaginal preparations of miconazole is not known. Alcohol: In some patients, a disulfiram-like reaction may be produced by the ingestion of alcohol. Moderate to large amounts of alcohol may increase the risk of hypoglycemia (ref.1), (ref. 2). The following products can lead to hyperglycemia: Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. - 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda When such drugs are administered to a patient receiving DIABINESE, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving DIABINESE, the patient should be observed closely for hypoglycemia. Since animal studies suggest that the action of barbiturates may be prolonged by therapy with chlorpropamide, barbiturates should be employed with caution. Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with DIABINESE have not been conducted to evaluate carcinogenic or mutagenic potential. Rats treated with continuous DIABINESE therapy for 6 to 12 months showed varying degrees of suppression of spermatogenesis at a dose level of 250 mg/kg (five times the human dose based on body surface area). The extent of suppression seemed to follow that of growth retardation associated with chronic administration of high-dose DIABINESE in rats. The human dose of chlorpropamide is 500 mg/day (300 mg/M2). Six- and 12-month toxicity work in the dog and rat, respectively, indicates the 150 mg/kg is well tolerated. Therefore, the safety margins based upon body-surface-area comparisons are three times human exposure in the rat and 10 times human exposure in the dog. Pregnancy Teratogenic Effects: Pregnancy Category C. Animal reproductive studies have not been conducted with DIABINESE. It is also not known whether DIABINESE can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. DIABINESE should be given to a pregnant woman only if the potential benefits justify the potential risk to the patient and fetus. Because data suggest that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If DIABINESE is used during pregnancy, it should be discontinued at least one month before the expected delivery date and other therapies instituted to maintain blood glucose levels as close to normal as possible. Nursing Mothers: An analysis of a composite of two samples of human breast milk, each taken five hours after ingestion of 500 mg of chlorpropamide by a patient, revealed a concentration of 5 mcg/mL. For reference, the normal peak blood level of chlorpropamide after a single 250 mg dose is 30 mcg/mL. Therefore, it is not recommended that a woman breast feed while taking this medication. Use in Children: Safety and effectiveness in children have not been established. - 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ability to Drive and Use Machines: The effect of DIABINESE on the ability to drive or operate machinery has not been studied. However, there is no evidence to suggest that DIABINESE may affect these abilities. Patients should be aware of the symptoms of hypoglycemia and take caution while driving and operating machinery. ADVERSE REACTIONS Body as a Whole: Disulfiram-like reactions have rarely been reported with DIABINESE (see DRUG INTERACTIONS). Central and Peripheral Nervous System: Dizziness and headache. . Hypoglycemia: See PRECAUTIONS and OVERDOSAGE sections. Gastrointestinal: Gastrointestinal disturbances are the most common reactions; nausea has been reported in less than 5% of patients, and diarrhea, vomiting, anorexia, and hunger in less than 2%. Other gastrointestinal disturbances have occurred in less than 1% of patients including proctocolitis. They tend to be dose-related and may disappear when dosage is reduced. Liver/Biliary: Cholestatic jaundice may occur rarely; DIABINESE should be discontinued if this occurs. Hepatic porphyria and disulfiram-like reactions have been reported with DIABINESE. Skin/Appendages: Pruritus has been reported in less than 3% of patients. Other allergic skin reactions, e.g., urticaria and maculopapular eruptions have been reported in approximately 1% or less of patients. These may be transient and may disappear despite continued use of DIABINESE; if skin reactions persist the drug should be discontinued. As with other sulfonylureas, porphyria cutanea tarda and photosensitivity reactions have been reported. Skin eruptions rarely progressing to erythema multiforme and exfoliative dermatitis have also been reported. Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia (see PRECAUTIONS), aplastic anemia, pancytopenia, and eosinophilia have been reported with sulfonylureas. Metabolic/Nutritional Reactions: Hypoglycemia (see PRECAUTIONS and OVERDOSAGE sections). Hepatic porphyria and disulfiram-like reactions have been reported with DIABINESE. See DRUG INTERACTIONS section. Endocrine Reactions: On rare occasions, chlorpropamide has caused a reaction identical to the syndrome of inappropriate antidiuretic hormone (ADH) secretion. The features of this syndrome - 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda result from excessive water retention and include hyponatremia, low serum osmolality, and high urine osmolality. This reaction has also been reported for other sulfonylureas. OVERDOSAGE Overdosage of sulfonylureas including DIABINESE can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. DOSAGE AND ADMINISTRATION There is no fixed dosage regimen for the management of type 2 diabetes with DIABINESE or any other hypoglycemic agent. The patient's blood glucose must be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient's response to therapy. Short-term administration of DIABINESE may be sufficient during periods of transient loss of control in patients usually controlled well on diet. The total daily dosage is generally taken at a single time each morning with breakfast. Occasionally cases of gastrointestinal intolerance may be relieved by dividing the daily dosage. A LOADING OR PRIMING DOSE IS NOT NECESSARY AND SHOULD NOT BE USED. Initial Therapy: 1. The mild to moderately severe, middle-aged, stable type 2 diabetes patient should be started on 250 mg daily. In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS section). Older patients should be started on smaller amounts of DIABINESE, in the range of 100 to 125 mg daily. 2. No transition period is necessary when transferring patients from other oral hypoglycemic agents to DIABINESE. The other agent may be discontinued abruptly and chlorpropamide started at once. In prescribing chlorpropamide, due consideration must be given to its greater potency. - 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Many mild to moderately severe, middle-aged, stable type 2 diabetes patients receiving insulin can be placed directly on the oral drug and their insulin abruptly discontinued. For patients requiring more than 40 units of insulin daily, therapy with DIABINESE may be initiated with a 50 per cent reduction in insulin for the first few days, with subsequent further reductions dependent upon the response. During the initial period of therapy with chlorpropamide, hypoglycemic reactions may occasionally occur, particularly during the transition from insulin to the oral drug. Hypoglycemia within 24 hours after withdrawal of the intermediate or long-acting types of insulin will usually prove to be the result of insulin carry-over and not primarily due to the effect of chlorpropamide. During the insulin withdrawal period, the patient should self-monitor glucose levels at least three times daily. If they are abnormal, the physician should be notified immediately. In some cases, it may be advisable to consider hospitalization during the transition period. Five to seven days after the initial therapy, the blood level of chlorpropamide reaches a plateau. Dosage may subsequently be adjusted upward or downward by increments of not more than 50 to l25 mg at intervals of three to five days to obtain optimal control. More frequent adjustments are usually undesirable. Maintenance Therapy: Most moderately severe, middle-aged, stable type 2 diabetes patients are controlled by approximately 250 mg daily. Many investigators have found that some milder diabetics do well on daily doses of 100 mg or less. Many of the more severe diabetics may require 500 mg daily for adequate control. PATIENTS WHO DO NOT RESPOND COMPLETELY TO 500 MG DAILY WILL USUALLY NOT RESPOND TO HIGHER DOSES. MAINTENANCE DOSES ABOVE 750 mg DAILY SHOULD BE AVOIDED. HOW SUPPLIED Strength Tablet Description Tablet Code NDC Package Size DIABINESE (chlorpro- pamide) 100 mg Blue, D-shaped, scored 393 0069-3930-66 100's DIABINESE (chlorpro- pamide) 250 mg Blue, D-shaped, scored 394 0069-3940-66 0069-3940-82 100's 1000's RECOMMENDED STORAGE: Store below 86°F (30°C). - 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rx only Pfizer Logo LAB-0039-5.03.3 Revised FebruarySeptember 20098 - 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:45.146337	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/011641s065lbl.pdf', 'application_number': 11641, 'submission_type': 'SUPPL ', 'submission_number': 65}
10,771	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:45.238888	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/15193s18lbl.pdf', 'application_number': 11665, 'submission_type': 'SUPPL ', 'submission_number': 15}
10,770	TABLETS DECADRON® (DEXAMETHASONE TABLETS, USP) DESCRIPTION DECADRON* (dexamethasone tablets, USP) tablets, for oral administration, are supplied in two potencies, 0.5 mg and 0.75 mg. Inactive ingredients are calcium phosphate, lactose, magnesium stearate, and starch. Tablets DECADRON 0.5 mg also contain D&C Yellow 10 and FD&C Yellow 6. Tablets DECADRON 0.75 mg also contain FD&C Blue 1. The molecular weight for dexamethasone is 392.47. It is designated chemically as 9-fluoro-11β,17,21 trihydroxy-16α-methylpregna-1,4-diene-3,20-dione. The empirical formula is C22H29FO5 and the structural formula is: structural formula Dexamethasone, a synthetic adrenocortical steroid, is a white to practically white, odorless, crystalline powder. It is stable in air. It is practically insoluble in water. CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Glucocorticoids cause varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have sodium-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs including dexamethasone are primarily used for their anti-inflammatory effects in disorders of many organ systems. At equipotent anti-inflammatory doses, dexamethasone almost completely lacks the sodium-retaining property of hydrocortisone and closely related derivatives of hydrocortisone. INDICATIONS AND USAGE Allergic states: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, and serum sickness. Dermatologic diseases: Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, and severe erythema multiforme (Stevens-Johnson syndrome). Endocrine disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; may be used in conjunction with synthetic mineralocorticoid analogs where applicable; in infancy mineralocorticoid supplementation is of particular importance), congenital adrenal hyperplasia, hypercalcemia associated with cancer, and nonsuppurative thyroiditis. Gastrointestinal diseases: To tide the patient over a critical period of the disease in regional enteritis and ulcerative colitis. Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Reference ID: 3965705 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hematologic disorders: Acquired (autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia (Diamond-Blackfan anemia), idiopathic thrombocytopenic purpura in adults, pure red cell aplasia, and selected cases of secondary thrombocytopenia. Miscellaneous: Diagnostic testing of adrenocortical hyperfunction, trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used with appropriate antituberculous chemotherapy. Neoplastic diseases: For the palliative management of leukemias and lymphomas. Nervous system: Acute exacerbations of multiple sclerosis, cerebral edema associated with primary or metastatic brain tumor, craniotomy, or head injury. Ophthalmic diseases: Sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammatory conditions unresponsive to topical corticosteroids. Renal diseases: To induce a diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus. Respiratory diseases: Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis. Rheumatic disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus. CONTRAINDICATIONS Systemic fungal infections (see W ARNINGS, Fungal infections). DECADRON tablets are contraindicated in patients who are hypersensitive to any components of this product. WARNINGS General Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS). Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, and after the stressful situation. Cardio-renal Average and large doses of corticosteroids can cause elevation of blood pressure, sodium and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. Endocrine Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Adrenocortical insufficiency may result from too rapid withdrawal of corticosteroids and may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. If the patient is receiving steroids already, dosage may have to be increased. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage. Infections General Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. W ith increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection. 2 Reference ID: 3965705 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Fungal Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control life-threatening drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS, Drug Interactions, Amphotericin B injection and potassium-depleting agents). Special Pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, Toxoplasma. It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or any patient with unexplained diarrhea. Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. Corticosteroids should not be used in cerebral malaria. Tuberculosis The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. Vaccination Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison’s disease. Viral Infections Chickenpox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immune globulin (IG) may be indicated. (See the respective package inserts for VZIG and IG for complete prescribing information.) If chickenpox develops, treatment with antiviral agents should be considered. Ophthalmic Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should not be used in active ocular herpes simplex. PRECAUTIONS General The lowest possible dose of corticosteroids should be used to control the condition under treatment. W hen reduction in dosage is possible, the reduction should be gradual. Since complications of treatment with corticosteroids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement. Cardio-renal As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency. 3 Reference ID: 3965705 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Endocrine Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. Gastrointestinal Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect due to decreased metabolism of corticosteroids in patients with cirrhosis. Musculoskeletal Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (e.g., postmenopausal women) before initiating corticosteroid therapy. Neuro-psychiatric Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. (See DOSAGE AND ADMINISTRATION.) An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Ophthalmic Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored. Information for Patients Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision. As prolonged use may cause adrenal insufficiency and make patients dependent on corticosteroids, they should advise any medical attendants that they are taking corticosteroids and they should seek medical advice at once should they develop an acute illness including fever or other signs of infection. Following prolonged therapy, withdrawal of corticosteroids may result in symptoms of the corticosteroid withdrawal syndrome including myalgia, arthralgia, and malaise. Persons who are on corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay. Drug Interactions Aminoglutethimide: Aminoglutethimide may diminish adrenal suppression by corticosteroids. Amphotericin B injection and potassium-depleting agents: W hen corticosteroids are administered concomitantly with potassium-depleting agents (e.g., amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. In addition, there have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance (see Drug Interactions, Hepatic Enzyme Inducers, Inhibitors and Substrates). Anticholinesterases: Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. Anticoagulants, oral: Co-administration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. 4 Reference ID: 3965705 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Cholestyramine: Cholestyramine may increase the clearance of corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Dexamethasone suppression test (DST): False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients. Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Ephedrine: Ephedrine may enhance the metabolic clearance of corticosteroids, resulting in decreased blood levels and lessened physiologic activity, thus requiring an increase in corticosteroid dosage. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic Enzyme Inducers, Inhibitors and Substrates: Drugs which induce cytochrome P450 3A4 (CYP 3A4) enzyme activity (e.g., barbiturates, phenytoin, carbamazepine, rifampin) may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Drugs which inhibit CYP 3A4 (e.g., ketoconazole, macrolide antibiotics such as erythromycin) have the potential to result in increased plasma concentrations of corticosteroids. Dexamethasone is a moderate inducer of CYP 3A4. Co-administration with other drugs that are metabolized by CYP 3A4 (e.g., indinavir, erythromycin) may increase their clearance, resulting in decreased plasma concentration. Ketoconazole: Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects. In addition, ketoconazole alone can inhibit adrenal corticosteroid synthesis and may cause adrenal insufficiency during corticosteroid withdrawal. Nonsteroidal anti-inflammatory agents (NSAIDS): Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. Phenytoin: In post-marketing experience, there have been reports of both increases and decreases in phenytoin levels with dexamethasone co-administration, leading to alterations in seizure control. Skin tests: Corticosteroids may suppress reactions to skin tests. Thalidomide: Co-administration with thalidomide should be employed cautiously, as toxic epidermal necrolysis has been reported with concomitant use. Vaccines: Patients on corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see W ARNINGS, Infections, Vaccination). Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy Teratogenic Effects: Pregnancy Category C. Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. Nursing Mothers Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 5 Reference ID: 3965705 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Use The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids, which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (patients >2 years of age), and aggressive lymphomas and leukemias (patients >1 month of age). Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In particular, the increased risk of diabetes mellitus, fluid retention and hypertension in elderly patients treated with corticosteroids should be considered. ADVERSE REACTIONS (listed alphabetically, under each subsection) The following adverse reactions have been reported with DECADRON or other corticosteroids: Allergic reactions: Anaphylactoid reaction, anaphylaxis, angioedema. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see W ARNINGS, Cardio-renal), edema, pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic: Acne, allergic dermatitis, dry scaly skin, ecchymoses and petechiae, erythema, impaired wound healing, increased sweating, rash, striae, suppression of reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, hyperglycemia, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients. Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention, tumor lysis syndrome. Gastrointestinal: Abdominal distention, elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic: Negative nitrogen balance due to protein catabolism. Musculoskeletal: Aseptic necrosis of femoral and humeral heads, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, steroid myopathy, tendon rupture, vertebral compression fractures. Neurological/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. 6 Reference ID: 3965705 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts. Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain. OVERDOSAGE Treatment of overdosage is by supportive and symptomatic therapy. In the case of acute overdosage, according to the patient’s condition, supportive therapy may include gastric lavage or emesis. DOSAGE AND ADMINISTRATION For oral administration The initial dosage varies from 0.75 to 9 mg a day depending on the disease being treated. It Should Be Emphasized That Dosage Requirements Are Variable And Must Be Individualized On The Basis Of The Disease Under Treatment And The Response Of The Patient. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage that maintains an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient’s condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly. In the treatment of acute exacerbations of multiple sclerosis, daily doses of 30 mg of dexamethasone for a week followed by 4 to 12 mg every other day for one month have been shown to be effective (see PRECAUTIONS, Neuro-psychiatric). In pediatric patients, the initial dose of dexamethasone may vary depending on the specific disease entity being treated. The range of initial doses is 0.02 to 0.3 mg/kg/day in three or four divided doses (0.6 to 9 mg/m2bsa/day). For the purpose of comparison, the following is the equivalent milligram dosage of the various corticosteroids: Cortisone, 25 Triamcinolone, 4 Hydrocortisone, 20 Paramethasone, 2 Prednisolone, 5 Betamethasone, 0.75 Prednisone, 5 Dexamethasone, 0.75 Methylprednisolone, 4 These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered. In acute, self-limited allergic disorders or acute exacerbations of chronic allergic disorders, the following dosage schedule combining parenteral and oral therapy is suggested: Dexamethasone Sodium Phosphate injection, USP 4 mg per mL: First Day 1 or 2 mL, intramuscularly DECADRON tablets, 0.75 mg: Second Day 4 tablets in two divided doses Third Day 4 tablets in two divided doses Fourth Day 2 tablets in two divided doses Fifth Day 1 tablet Sixth Day 1 tablet Seventh Day No treatment 7 Reference ID: 3965705 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Eighth Day Follow-up visit This schedule is designed to ensure adequate therapy during acute episodes, while minimizing the risk of overdosage in chronic cases. In cerebral edema, Dexamethasone Sodium Phosphate injection, USP is generally administered initially in a dosage of 10 mg intravenously followed by 4 mg every six hours intramuscularly until the symptoms of cerebral edema subside. Response is usually noted within 12 to 24 hours and dosage may be reduced after two to four days and gradually discontinued over a period of five to seven days. For palliative management of patients with recurrent or inoperable brain tumors, maintenance therapy with either Dexamethasone Sodium Phosphate injection, USP or DECADRON tablets in a dosage of 2 mg two or three times daily may be effective. Dexamethasone suppression tests 1. Tests for Cushing's syndrome Give 1.0 mg of DECADRON orally at 11:00 p.m. Blood is drawn for plasma cortisol determination at 8:00 a.m. the following morning. For greater accuracy, give 0.5 mg of DECADRON orally every 6 hours for 48 hours. Twenty-four hour urine collections are made for determination of 17-hydroxycorticosteroid excretion. 2. Test to distinguish Cushing's syndrome due to pituitary ACTH excess from Cushing's syndrome due to other causes. Give 2.0 mg of DECADRON orally every 6 hours for 48 hours. Twenty-four hour urine collections are made for determination of 17-hydroxycorticosteroid excretion. HOW SUPPLIED Tablets DECADRON are compressed, pentagonal-shaped tablets, colored to distinguish potency. They are scored and coded on one side and embossed with DECADRON on the other. They are available as follows: No. 7601  0.75 mg, bluish-green in color and coded MSD 63. NDC 0006-0063-12 5-12 PAK (package of 12) NDC 0006-0063-68 bottles of 100. No. 7598  0.5 mg, yellow in color and coded MSD 41. NDC 0006-0041-68 bottles of 100. Storage Store at controlled room temperature 20 to 25°C (68 to 77°F). Rx only company logo For patent information: www.merck.com/product/patent/home.html Copyright © 2004-2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. Revised: 07/2016 uspi-mk0125-t-xxxxrxxx 8 Reference ID: 3965705 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:45.328693	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/011664s063lbl.pdf', 'application_number': 11664, 'submission_type': 'SUPPL ', 'submission_number': 63}
10,767	1 KENALOG OINTMENTS Rx only Triamcinolone Acetonide Ointment USP 0.025%, 0.1%, 0.5% DESCRIPTION The topical corticosteroids constitute a class of primarily synthetic steroids used as anti- inflammatory and antipruritic agents. The steroids in this class include triamcinolone acetonide. Triamcinolone acetonide is designated chemically as 9-Fluoro-11β, 16α, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone. Graphic Formula: C24H31FO6, MW 434.50 Each gram of 0.025%, 0.1%, and 0.5% Kenalog Ointment (Triamcinolone Acetonide Ointment) provides 0.25 mg, 1 mg, or 5 mg triamcinolone acetonide, respectively, in Plastibase(Plasticized Hydrocarbon Gel), a polyethylene and mineral oil gel base. 2 CLINICAL PHARMACOLOGY Topical corticosteroids share anti-inflammatory, antipruritic and vasoconstrictive actions. The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man. Pharmacokinetics The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses (see DOSAGE AND ADMINISTRATION). Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. INDICATIONS AND USAGE Kenalog Ointment (Triamcinolone Acetonide Ointment) 0.025%, 0.1%, and 0.5% are indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid- responsive dermatoses. CONTRAINDICATIONS Topical corticosteroids are contraindicated in those patients with a history of hypersensitivity to any of the components of the preparations. 3 PRECAUTIONS General Systemic absorption of topical corticosteroids has produced reversible hypothalamic- pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Therefore, patients receiving a large dose of any potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests, and for impairment of thermal homeostasis. If HPA axis suppression or elevation of the body temperature occurs, an attempt should be made to withdraw the drug, to reduce the frequency of application, substitute a less potent steroid, or use a sequential approach when utilizing the occlusive technique. Recovery of HPA axis function and thermal homeostasis are generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Occasionally, a patient may develop a sensitivity reaction to a particular occlusive dressing material or adhesive and a substitute material may be necessary. Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity (see PRECAUTIONS, Pediatric Use). If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled. These preparations are not for ophthalmic use. 4 Information for the Patient Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. 2. Patients should be advised not to use this medication for any disorder other than for which it was prescribed. 3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician. 4. Patients should report any signs of local adverse reactions especially under occlusive dressing. 5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings. Laboratory Tests A urinary free cortisol test and ACTH stimulation test may be helpful in evaluating HPA axis suppression. Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids. Studies to determine mutagenicity with prednisolone and hydrocortisone showed negative results. 5 Pregnancy: Teratogenic Effects Category C. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time. Nursing Mothers It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman. Pediatric Use Pediatric patients may demonstrate greater susceptibility to topical corticosteroid- induced HPA axis suppression and Cushing’s syndrome than mature patients because of a larger skin surface area to body weight ratio. HPA axis suppression, Cushing’s syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children. 6 ADVERSE REACTIONS The following local adverse reactions are reported infrequently with topical corticosteroids, but may occur more frequently with the use of occlusive dressings (reactions are listed in an approximate decreasing order of occurrence): burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae, and miliaria. OVERDOSAGE Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects (see PRECAUTIONS, General). DOSAGE AND ADMINISTRATION Apply a thin film of Kenalog Ointment (Triamcinolone Acetonide Ointment) 0.025% to the affected area two to four times daily. Apply a thin film of the 0.1% or the 0.5% Kenalog Ointment (Triamcinolone Acetonide Ointment), as appropriate, to the affected area two to three times daily. Occlusive Dressing Technique Occlusive dressings may be used for the management of psoriasis or other recalcitrant conditions. Apply a thin film of ointment to the lesion, cover with a pliable nonporous film, and seal the edges. If needed, additional moisture may be provided by covering the lesion with a dampened clean cotton cloth before the nonporous film is applied or by briefly wetting the affected area with water immediately prior to applying the medication. The frequency of changing dressings is best determined on an individual basis. It may be convenient to apply Kenalog ointment under an occlusive dressing in the evening and to remove the dressing in the morning (i.e., 12-hour occlusion). When utilizing the 12-hour occlusion regimen, additional ointment should be applied, without occlusion, during the day. Reapplication is essential at each dressing change. If an infection develops, the use of occlusive dressings should be discontinued and appropriate antimicrobial therapy instituted. 7 HOW SUPPLIED Kenalog Ointment (Triamcinolone Acetonide Ointment USP) 0.025%: tubes containing 15 g (NDC 0003-0495-22) and 80 g (NDC 0003-0495-60); and jars containing 240 g (NDC 0003-0495-70) of ointment. 0.1%: tubes containing 15 g (NDC 0003-0508-20), 60 g (NDC 0003-0508-56), and 80 g (NDC 0003-0508-58); and jars containing 240 g (NDC 0003- 0508-60) of ointment. 0.5%: tubes containing 20 g (NDC 0003-1484-20) of ointment. Storage Store at room temperature. APOTHECON A Bristol-Myers Squibb Company Princeton, NJ 08540 USA J3-557E+ May 1994+ J3-557E+	custom-source	2025-02-12T13:43:45.439630	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/pre96/011600s026lbl.pdf', 'application_number': 11600, 'submission_type': 'SUPPL ', 'submission_number': 26}
10,772	NDA 11-689/S-024 Page 3 Phenergan® (promethazine HCI) Tablets and Suppositories only DESCRIPTION Each tablet of Phenergan contains 12.5 mg, 25 mg, or 50 mg promethazine HCl. The inactive ingredients present are lactose, magnesium stearate, and methylcellulose. Each dosage strength also contains the following: 12.5 mg−FD&C Yellow 6 and saccharin sodium; 25 mg−saccharin sodium; 50 mg−FD&C Red 40. Each rectal suppository of Phenergan contains 12.5 mg, 25 mg, or 50 mg promethazine HCl with ascorbyl palmitate, silicon dioxide, white wax, and cocoa butter. Phenergan Suppositories are for rectal administration only. Promethazine HCl is a racemic compound; the empirical formula is C17H20N2S•HCl and its molecular weight is 320.88. Promethazine HCl, a phenothiazine derivative, is designated chemically as 10H-Phenothiazine-10-ethanamine, N,N,α-trimethyl-, monohydrochloride, (±)- with the following structural formula: Promethazine HCl occurs as a white to faint yellow, practically odorless, crystalline powder which slowly oxidizes and turns blue on prolonged exposure to air. It is freely soluble in water and soluble in alcohol. CLINICAL PHARMACOLOGY Promethazine is a phenothiazine derivative which differs structurally from the antipsychotic phenothiazines by the presence of a branched side chain and no ring substitution. It is thought that this configuration is responsible for its relative lack (1/10 that of chlorpromazine) of dopamine antagonist properties. Promethazine is an H1 receptor blocking agent. In addition to its antihistaminic action, it provides clinically useful sedative and antiemetic effects. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-689/S-024 Page 4 Promethazine is well absorbed from the gastrointestinal tract. Clinical effects are apparent within 20 minutes after oral administration and generally last four to six hours, although they may persist as long as 12 hours. Promethazine is metabolized by the liver to a variety of compounds; the sulfoxides of promethazine and N-demethylpromethazine are the predominant metabolites appearing in the urine. INDICATIONS AND USAGE Phenergan, either orally or by suppository, is useful for: Perennial and seasonal allergic rhinitis. Vasomotor rhinitis. Allergic conjunctivitis due to inhalant allergens and foods. Mild, uncomplicated allergic skin manifestations of urticaria and angioedema. Amelioration of allergic reactions to blood or plasma. Dermographism. Anaphylactic reactions, as adjunctive therapy to epinephrine and other standard measures, after the acute manifestations have been controlled. Preoperative, postoperative, or obstetric sedation. Prevention and control of nausea and vomiting associated with certain types of anesthesia and surgery. Therapy adjunctive to meperidine or other analgesics for control of post-operative pain. Sedation in both children and adults, as well as relief of apprehension and production of light sleep from which the patient can be easily aroused. Active and prophylactic treatment of motion sickness. Antiemetic therapy in postoperative patients. CONTRAINDICATIONS Phenergan Tablets and Suppositories are contraindicated for use in pediatric patients less than two years of age. Phenergan Tablets and Suppositories are contraindicated in comatose states, and in individuals known to be hypersensitive or to have had an idiosyncratic reaction to promethazine or to other phenothiazines. Antihistamines are contraindicated for use in the treatment of lower respiratory tract symptoms including asthma. WARNINGS PHENERGAN SHOULD NOT BE USED IN PEDIATRIC PATIENTS LESS THAN 2 YEARS OF AGE BECAUSE OF THE POTENTIAL FOR FATAL RESPIRATORY DEPRESSION. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-689/S-024 Page 5 POSTMARKETING CASES OF RESPIRATORY DEPRESSION, INCLUDING FATALITIES, HAVE BEEN REPORTED WITH USE OF PHENERGAN IN PEDIATRIC PATIENTS LESS THAN 2 YEARS OF AGE. A WIDE RANGE OF WEIGHT-BASED DOSES OF PHENERGAN HAVE RESULTED IN RESPIRATORY DEPRESSION IN THESE PATIENTS. CAUTION SHOULD BE EXERCISED WHEN ADMINISTERING PHENERGAN TO PEDIATRIC PATIENTS 2 YEARS OF AGE AND OLDER. IT IS RECOMMENDED THAT THE LOWEST EFFECTIVE DOSE OF PHENERGAN BE USED IN PEDIATRIC PATIENTS 2 YEARS OF AGE AND OLDER AND CONCOMITANT ADMINISTRATION OF OTHER DRUGS WITH RESPIRATORY DEPRESSANT EFFECTS BE AVOIDED. CNS Depression Phenergan Tablets and Suppositories may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The impairment may be amplified by concomitant use of other central-nervous-system depressants such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore such agents should either be eliminated or given in reduced dosage in the presence of promethazine HCl (see PRECAUTIONS−Information for Patients and Drug Interactions). Respiratory Depression Phenergan Tablets and Suppositories may lead to potentially fatal respiratory depression. Use of Phenergan Tablets and Suppositories in patients with compromised respiratory function (e.g., COPD, sleep apnea) should be avoided. Lower Seizure Threshold Phenergan Tablets and Suppositories may lower seizure threshold. It should be used with caution in persons with seizure disorders or in persons who are using concomitant medications, such as narcotics or local anesthetics, which may also affect seizure threshold. Bone-Marrow Depression Phenergan Tablets and Suppositories should be used with caution in patients with bone-marrow depression. Leukopenia and agranulocytosis have been reported, usually when Phenergan (promethazine HCl) has been used in association with other known marrow-toxic agents. Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with promethazine HCl alone or in combination with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias). The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g. pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-689/S-024 Page 6 The management of NMS should include 1) immediate discontinuation of promethazine HCl, antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. Since recurrences of NMS have been reported with phenothiazines, the reintroduction of promethazine HCl should be carefully considered. Use in Pediatric Patients PHENERGAN TABLETS AND SUPPOSITORIES ARE CONTRAINDICATED FOR USE IN PEDIATRIC PATIENTS LESS THAN TWO YEARS OF AGE. CAUTION SHOULD BE EXERCISED WHEN ADMINISTERING PHENERGAN TABLETS AND SUPPOSITORIES TO PEDIATRIC PATIENTS 2 YEARS OF AGE AND OLDER BECAUSE OF THE POTENTIAL FOR FATAL RESPIRATORY DEPRESSION. RESPIRATORY DEPRESSION AND APNEA, SOMETIMES ASSOCIATED WITH DEATH, ARE STRONGLY ASSOCIATED WITH PROMETHAZINE PRODUCTS AND ARE NOT DIRECTLY RELATED TO INDIVIDUALIZED WEIGHT-BASED DOSING, WHICH MIGHT OTHERWISE PERMIT SAFE ADMINISTRATION. CONCOMITANT ADMINISTRATION OF PROMETHAZINE PRODUCTS WITH OTHER RESPIRATORY DEPRESSANTS HAS AN ASSOCIATION WITH RESPIRATORY DEPRESSION, AND SOMETIMES DEATH, IN PEDIATRIC PATIENTS. ANTIEMETICS ARE NOT RECOMMENDED FOR TREATMENT OF UNCOMPLICATED VOMITING IN PEDIATRIC PATIENTS, AND THEIR USE SHOULD BE LIMITED TO PROLONGED VOMITING OF KNOWN ETIOLOGY. THE EXTRAPYRAMIDAL SYMPTOMS WHICH CAN OCCUR SECONDARY TO PHENERGAN TABLETS AND SUPPOSITORIES ADMINISTRATION MAY BE CONFUSED WITH THE CNS SIGNS OF UNDIAGNOSED PRIMARY DISEASE, e.g., ENCEPHALOPATHY OR REYE’S SYNDROME. THE USE OF PHENERGAN TABLETS AND SUPPOSITORIES SHOULD BE AVOIDED IN PEDIATRIC PATIENTS WHOSE SIGNS AND SYMPTOMS MAY SUGGEST REYE’S SYNDROME OR OTHER HEPATIC DISEASES. Excessively large dosages of antihistamines, including Phenergan Tablets and Suppositories, in pediatric patients may cause sudden death (see OVERDOSAGE). Hallucinations and convulsions have occurred with therapeutic doses and overdoses of Phenergan in pediatric patients. In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonias with the use of promethazine HCl. Other Considerations Administration of promethazine HCl has been associated with reported cholestatic jaundice. PRECAUTIONS General Drugs having anticholinergic properties should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, and bladder-neck obstruction. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-689/S-024 Page 7 Phenergan Tablets and Suppositories should be used cautiously in persons with cardiovascular disease or with impairment of liver function. Information for Patients Phenergan Tablets and Suppositories may cause marked drowsiness or impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The use of alcohol or other central-nervous-system depressants such as sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers, may enhance impairment (see WARNINGS−CNS Depression and PRECAUTIONS−Drug Interactions). Pediatric patients should be supervised to avoid potential harm in bike riding or in other hazardous activities. Patients should be advised to report any involuntary muscle movements. Avoid prolonged exposure to the sun. Drug Interactions CNS Depressants - Phenergan Tablets and Suppositories may increase, prolong, or intensify the sedative action of other central-nervous-system depressants, such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore, such agents should be avoided or administered in reduced dosage to patients receiving promethazine HCl. When given concomitantly with Phenergan Tablets and Suppositories, the dose of barbiturates should be reduced by at least one-half, and the dose of narcotics should be reduced by one-quarter to one-half. Dosage must be individualized. Excessive amounts of promethazine HCl relative to a narcotic may lead to restlessness and motor hyperactivity in the patient with pain; these symptoms usually disappear with adequate control of the pain. Epinephrine - Because of the potential for Phenergan to reverse epinephrine’s vasopressor effect, epinephrine should NOT be used to treat hypotension associated with Phenergan Tablets and Suppositories overdose. Anticholinergics - Concomitant use of other agents with anticholinergic properties should be undertaken with caution. Monoamine Oxidase Inhibitors (MAOI) - Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly. This possibility should be considered with Phenergan Tablets and Suppositories. Drug/Laboratory Test Interactions The following laboratory tests may be affected in patients who are receiving therapy with promethazine HCl: Pregnancy Tests Diagnostic pregnancy tests based on immunological reactions between HCG and anti-HCG may result in false-negative or false-positive interpretations. Glucose Tolerance Test An increase in blood glucose has been reported in patients receiving promethazine HCl. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-689/S-024 Page 8 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to assess the carcinogenic potential of promethazine, nor are there other animal or human data concerning carcinogenicity, mutagenicity, or impairment of fertility with this drug. Promethazine was nonmutagenic in the Salmonella test system of Ames. Pregnancy Teratogenic Effects–Pregnancy Category C Teratogenic effects have not been demonstrated in rat-feeding studies at doses of 6.25 and 12.5 mg/kg of promethazine HCl. These doses are from approximately 2.1 to 4.2 times the maximum recommended total daily dose of promethazine for a 50-kg subject, depending upon the indication for which the drug is prescribed. Daily doses of 25 mg/kg intraperitoneally have been found to produce fetal mortality in rats. Specific studies to test the action of the drug on parturition, lactation, and development of the animal neonate were not done, but a general preliminary study in rats indicated no effect on these parameters. Although antihistamines have been found to produce fetal mortality in rodents, the pharmacological effects of histamine in the rodent do not parallel those in man. There are no adequate and well- controlled studies of Phenergan® Tablets and Suppositories in pregnant women. Phenergan (promethazine HCl) Tablets and Suppositories should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Phenergan Tablets and Suppositories administered to a pregnant woman within two weeks of delivery may inhibit platelet aggregation in the newborn. Labor and Delivery Promethazine HCl may be used alone or as an adjunct to narcotic analgesics during labor (see DOSAGE AND ADMINISTRATION). Limited data suggest that use of Phenergan during labor and delivery does not have an appreciable effect on the duration of labor or delivery and does not increase the risk of need for intervention in the newborn. The effect on later growth and development of the newborn is unknown. (See also Nonteratogenic Effects.) Nursing Mothers It is not known whether promethazine HCl is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Phenergan Tablets and Suppositories, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use PHENERGAN TABLETS AND SUPPOSITORIES ARE CONTRAINDICATED FOR USE IN PEDIATRIC PATIENTS LESS THAN TWO YEARS OF AGE (see WARNINGS–Black Box Warning and Use in Pediatric Patients). Phenergan Tablets and Suppositories should be used with caution in pediatric patients 2 years of age and older (see WARNINGS−Use in Pediatric Patients). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-689/S-024 Page 9 Geriatric Use Clinical studies of Phenergan formulations did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of Phenergan Tablets and Suppositories and observed closely. ADVERSE REACTIONS Central Nervous System Drowsiness is the most prominent CNS effect of this drug. Sedation, somnolence, blurred vision, dizziness; confusion, disorientation, and extrapyramidal symptoms such as oculogyric crisis, torticollis, and tongue protrusion; lassitude, tinnitus, incoordination, fatigue, euphoria, nervousness, diplopia, insomnia, tremors, convulsive seizures, excitation, catatonic-like states, hysteria. Hallucinations have also been reported. Cardiovascular−Increased or decreased blood pressure, tachycardia, bradycardia, faintness. Dermatologic−Dermatitis, photosensitivity, urticaria. Hematologic−Leukopenia, thrombocytopenia, thrombocytopenic purpura, agranulocytosis. Gastrointestinal−Dry mouth, nausea, vomiting, jaundice. Respiratory−Asthma, nasal stuffiness, respiratory depression (potentially fatal) and apnea (potentially fatal). (See WARNINGS−Respiratory Depression.) Other−Angioneurotic edema. Neuroleptic malignant syndrome (potentially fatal) has also been reported. (See WARNINGS−Neuroleptic Malignant Syndrome.) Paradoxical Reactions Hyperexcitability and abnormal movements have been reported in patients following a single administration of promethazine HCl. Consideration should be given to the discontinuation of promethazine HCl and to the use of other drugs if these reactions occur. Respiratory depression, nightmares, delirium, and agitated behavior have also been reported in some of these patients. OVERDOSAGE Signs and symptoms of overdosage with promethazine HCl range from mild depression of the central nervous system and cardiovascular system to profound hypotension, respiratory depression, unconsciousness, and sudden death. Other reported reactions include hyperreflexia, hypertonia, ataxia, athetosis, and extensor-plantar reflexes (Babinski reflex). Stimulation may be evident, especially in children and geriatric patients. Convulsions may rarely occur. A paradoxical-type reaction has been reported in children receiving single doses of 75 mg to 125 mg orally, characterized by hyperexcitability and nightmares. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-689/S-024 Page 10 Atropine-like signs and symptoms−dry mouth, fixed, dilated pupils, flushing, as well as gastrointestinal symptoms−may occur. Treatment Treatment of overdosage is essentially symptomatic and supportive. Only in cases of extreme overdosage or individual sensitivity do vital signs, including respiration, pulse, blood pressure, temperature, and EKG, need to be monitored. Activated charcoal orally or by lavage may be given, or sodium or magnesium sulfate orally as a cathartic. Attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Diazepam may be used to control convulsions. Acidosis and electrolyte losses should be corrected. Note that any depressant effects of promethazine HCl are not reversed by naloxone. Avoid analeptics which may cause convulsions. The treatment of choice for resulting hypotension is administration of intravenous fluids, accompanied by repositioning if indicated. In the event that vasopressors are considered for the management of severe hypotension which does not respond to intravenous fluids and repositioning, the administration of norepinephrine or phenylephrine should be considered. EPINEPHRINE SHOULD NOT BE USED, since its use in patients with partial adrenergic blockade may further lower the blood pressure. Extrapyramidal reactions may be treated with anticholinergic antiparkinsonian agents, diphenhydramine, or barbiturates. Oxygen may also be administered. Limited experience with dialysis indicates that it is not helpful. DOSAGE AND ADMINISTRATION Phenergan Tablets and Phenergan Rectal Suppositories are contraindicated for children under 2 years of age (see WARNINGS–Black Box Warning and Use in Pediatric Patients). Phenergan Suppositories are for rectal administration only. Allergy The average oral dose is 25 mg taken before retiring; however, 12.5 mg may be taken before meals and on retiring, if necessary. Single 25-mg doses at bedtime or 6.25 to 12.5 mg taken three times daily will usually suffice. After initiation of treatment in children or adults, dosage should be adjusted to the smallest amount adequate to relieve symptoms. The administration of promethazine HCl in 25-mg doses will control minor transfusion reactions of an allergic nature. Motion Sickness The average adult dose is 25 mg taken twice daily. The initial dose should be taken one-half to one hour before anticipated travel and be repeated 8 to 12 hours later, if necessary. On succeeding days of travel, it is recommended that 25 mg be given on arising and again before the evening meal. For children, Phenergan Tablets, Syrup, or Rectal Suppositories, 12.5 to 25 mg, twice daily, may be administered. Nausea and Vomiting Antiemetics should not be used in vomiting of unknown etiology in children and adolescents (see WARNINGS-Use in Pediatric Patients). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-689/S-024 Page 11 The average effective dose of Phenergan for the active therapy of nausea and vomiting in children or adults is 25 mg. When oral medication cannot be tolerated, the dose should be given parenterally (cf. Phenergan Injection) or by rectal suppository. 12.5- to 25-mg doses may be repeated, as necessary, at 4- to 6-hour intervals. For nausea and vomiting in children, the usual dose is 0.5 mg per pound of body weight, and the dose should be adjusted to the age and weight of the patient and the severity of the condition being treated. For prophylaxis of nausea and vomiting, as during surgery and the postoperative period, the average dose is 25 mg repeated at 4- to 6-hour intervals, as necessary. Sedation This product relieves apprehension and induces a quiet sleep from which the patient can be easily aroused. Administration of 12.5 to 25 mg Phenergan by the oral route or by rectal suppository at bedtime will provide sedation in children. Adults usually require 25 to 50 mg for nighttime, presurgical, or obstetrical sedation. Pre- and Postoperative Use Phenergan in 12.5- to 25-mg doses for children and 50-mg doses for adults the night before surgery relieves apprehension and produces a quiet sleep. For preoperative medication, children require doses of 0.5 mg per pound of body weight in combination with an appropriately reduced dose of narcotic or barbiturate and the appropriate dose of an atropine-like drug. Usual adult dosage is 50 mg Phenergan with an appropriately reduced dose of narcotic or barbiturate and the required amount of a belladonna alkaloid. Postoperative sedation and adjunctive use with analgesics may be obtained by the administration of 12.5 to 25 mg in children and 25- to 50-mg doses in adults. Phenergan Tablets and Phenergan Rectal Suppositories are contraindicated for children under 2 years of age. HOW SUPPLIED Phenergan® (promethazine HCl) Tablets are available as follows: 12.5 mg, orange tablet with “WYETH” on one side and “19” on the scored reverse side. NDC 0008-0019-01, bottle of 100 tablets. 25 mg, white tablet with “WYETH” and “27” on one side and scored on the reverse side. NDC 0008-0027-02, bottle of 100 tablets. NDC 0008-0027-07, Redipak® carton of 100 tablets (10 blister strips of 10). 50 mg, pink tablet with “WYETH” on one side and “227” on the other side. NDC 0008-0227-01, bottle of 100 tablets. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-689/S-024 Page 12 Keep tightly closed. Store at controlled room temperature 20º to 25ºC (68º to 77ºF). Protect from light. Dispense in light-resistant, tight container. Use carton to protect contents from light. Phenergan® (promethazine HCl) Rectal Suppositories are available in boxes of 12 as follows: 12.5 mg, ivory, torpedo-shaped suppository wrapped in copper-colored foil, NDC 0008-0498-01. 25 mg, ivory, torpedo-shaped suppository wrapped in light-green foil, NDC 0008-0212-01. 50 mg, ivory, torpedo-shaped suppository wrapped in blue foil, NDC 0008-0229-01. Store refrigerated between 2º-8ºC (36º-46ºF). Dispense in well-closed container. Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 -- ------- -- ---- ----- - -- - - ------- (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:45.564765	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/11689s024lbl.pdf', 'application_number': 11689, 'submission_type': 'SUPPL ', 'submission_number': 24}
10,773	1 003466/September 2006 OPANA® (Oxymorphone Hydrochloride) INJECTION 1mg/mL CII Opioid Analgesic Rx only DESCRIPTION OPANA (oxymorphone hydrochloride) Injection, is a semi-synthetic opioid analgesic. OPANA Injection is available in 1 mg/mL, 1 mL ampules of oxymorphone hydrochloride. In addition, each 1 mg/mL ampule contains 8.0 mg/mL sodium chloride. pH is adjusted with hydrochloric acid. Chemically, oxymorphone hydrochloride is 4, 5a-epoxy-3, 14-dihydroxy-17- methylmorphinan-6-one hydrochloride, a white or slightly off-white, odorless powder, which is sparingly soluble in alcohol and ether, but freely soluble in water. The molecular weight of oxymorphone hydrochloride is 337.80. The pKa1 and pKa2 of oxymorphone at 37°C are 8.17 and 9.54, respectively. The octanol/aqueous partition coefficient at 37°C and pH 7.4 is 0.98. The structural formula for oxymorphone hydrochloride is as follows: CLINICAL PHARMACOLOGY Oxymorphone is an opioid agonist whose principal therapeutic action is analgesia. Administered parenterally, 1 mg of OPANA Injection is approximately equivalent in analgesic activity to 10 mg of morphine sulfate. Other members of the class known as opioid agonists include substances such as morphine, oxycodone, hydromorphone, fentanyl, codeine, hydrocodone and tramadol. In addition to analgesia, other pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 relaxation, respiratory depression, constipation, miosis, and cough suppression. Like all pure opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed agonist/antagonists or non-opioid analgesics, where there is a limit to the analgesic effect with increasing doses. With pure opioid agonist analgesics, there is no defined maximum dose; the ceiling to analgesic effectiveness is imposed only by side effects, the more serious of which may include somnolence and respiratory depression. Central Nervous System The precise mechanism of the analgesic action is unknown. However, specific CNS (central nervous system) opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug. In addition, opioid receptors have been identified within the PNS (peripheral nervous system). The role that these receptors play in these drugs’ analgesic effects is unknown. Opioids produce respiratory depression, likely by a direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Opioids depress the cough reflex by direct effect on the cough center in the medulla oblongata. Antitussive effects may occur with doses lower than those usually required for analgesia. Opioids cause miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations (see OVERDOSAGE: Signs and Symptoms). Gastrointestinal Tract and Other Smooth Muscle Opioids cause a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasms of sphincter of Oddi, and transient elevations in serum amylase. Cardiovascular System Opioids produce peripheral vasodilation which may result in orthostatic hypotension. Release of histamine can occur and may contribute to opioid-induced hypotension. Manifestations of histamine release may include orthostatic hypotension, pruritus, flushing, red eyes, and sweating. Animal studies have shown that oxymorphone has a lower propensity to cause histamine release than other opioids. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Endocrine System Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon in humans and other species, rats and dogs. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids. Immune System Opioids have been shown to have a variety of effects on components of the immune system in in-vitro and animal models. The clinical significance of these findings is unknown. Pharmacodynamics Concentration-Efficacy Relationships The minimum effective plasma concentration of oxymorphone for analgesia varies widely among patients, especially among patients who have been previously treated with potent agonist opioids. As a result, patients need to be individually titrated to achieve a balance between therapeutic and adverse effects. The minimum effective analgesic concentration of oxymorphone for any individual patient may increase over time due to an increase in pain, progression of disease, development of a new pain syndrome and/or development of analgesic tolerance. Concentration-Adverse Experience Relationships OPANA Injection is associated with typical opioid-related adverse experiences. There is a general relationship between increasing opioid plasma concentration and increasing frequency of adverse experiences such as nausea, vomiting, CNS effects, and respiratory depression. As with all opioids, the dose must be individualized (see DOSAGE AND ADMINISTRATION ). The effective analgesic dose for some patients will be too high to be tolerated by other patients. Pharmacokinetics The onset of action of parenterally administered OPANA Injection is rapid; initial effects are usually perceived within 5 to 10 minutes. Its duration of action is approximately 3 to 6 hours. Distribution After an IV dose, the steady state volume of distribution was 3.08 ± 1.14 L/kg in healthy male and female subjects. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Metabolism Oxymorphone is highly metabolized, principally in the liver, and undergoes reduction or conjugation with glucuronic acid to form both active and inactive products. The two major metabolites of oxymorphone are oxymorphone-3-glucuronide and 6-OH-oxymorphone. The mean plasma AUC for oxymorphone-3-glucuronide is approximately 90-fold higher than the parent compound. The pharmacologic activity of the glucuronide metabolite has not been evaluated. 6-OH-oxymorphone has been shown in animal studies to have analgesic bioactivity. The mean plasma 6-OH-oxymorphone AUC is approximately 70% of the oxymorphone AUC following single oral doses but is essentially equivalent to the parent compound at steady-state. Excretion Because oxymorphone is extensively metabolized, <1% of the administered dose is excreted unchanged in the urine. On average, 33% to 38% of the administered dose is excreted in the urine as oxymorphone-3-glucuronide and 0.25% to 0.62% is excreted as 6- OH-oxymorphone in subjects with normal hepatic and renal function. In animals given radiolabeled oxymorphone, approximately 90% of the administered radioactivity was recovered within 5 days of dosing. The majority of oxymorphone-derived radioactivity was found in the urine and feces. Special Populations Elderly The effects of OPANA Injection on the elderly have not been studied. However, the plasma levels of oral oxymorphone administered as an extended-release tablet were about 40% higher in elderly than in younger subjects. Gender The effects of OPANA Injection on gender have not been studied. However, in a study with an extended-release formulation of oral oxymorphone, there was a consistent tendency for female subjects to have slightly higher AUCss and Cmax values than male subjects. However, gender differences were not observed when AUCss and Cmax were adjusted by body weight. Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of OPANA Injection have not been studied. The liver plays an important role in the pre-systemic clearance of orally administered oxymorphone. Accordingly the bioavailability of orally administered oxymorphone may be markedly increased in patients with moderate-severe liver disease. In a study with an extended-release formulation of oral oxymorphone (OPANA ER), the disposition of oxymorphone was compared in 6 patients with mild, 5 patients with moderate, and one patient with severe hepatic impairment, and 12 subjects with normal hepatic function. The bioavailability of oral oxymorphone was increased by 1.6-fold in patients with mild hepatic impairment and by 3.7-fold in patients with moderate hepatic impairment. In one patient with severe hepatic impairment, the bioavailability was This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 increased by 12.2-fold. The half-life of oral oxymorphone was not significantly affected by hepatic impairment. Pre-systemic clearance of OPANA Injection is not expected, however, oxymorphone is extensively metabolized by the liver. Renal Impairment The effects of renal impairment on the pharmacokinetics of OPANA Injection have not been studied. However, in a study with an extended-release formulation of oral oxymorphone, an increase of 26%, 57%, and 65% in oxymorphone bioavailability was observed in mild (creatinine clearance 51-80 mL/min; n=8), moderate (creatinine clearance 30-50 mL/min; n=8), and severe (creatinine clearance <30 mL/min; n=8) patients, respectively, compared to healthy controls. Drug-Drug Interactions In vitro studies revealed little to no biotransformation of oxymorphone to 6-OH- oxymorphone by any of the major cytochrome P450 (CYP P450) isoforms at therapeutically relevant oxymorphone plasma concentrations. No inhibition of any of the major CYP P450 isoforms was observed when oxymorphone was incubated with human liver microsomes at concentrations of =50 µM. An inhibition of CYP 3A4 activity occurred at oxymorphone concentrations =150 µM. Therefore, it is not expected that oxymorphone, or its metabolites will act as inhibitors of any of the major CYP P450 enzymes in vivo. Increases in the activity of the CYP 2C9 and CYP 3A4 isoforms occurred when oxymorphone was incubated with human hepatocytes. However, clinical drug interaction studies with OPANA ER showed no induction of CYP450 3A4 or 2C9 enzyme activity, indicating that no dose adjustment for CYP 3A4- or 2C9-mediated drug-drug interactions is required. Studies with OPANA Injection have not been conducted. INDICATIONS AND USAGE OPANA Injection is indicated for the relief of moderate to severe pain. It is also indicated for preoperative medication, for support of anesthesia, for obstetrical analgesia, and for relief of anxiety in patients with dyspnea associated with pulmonary edema secondary to acute left ventricular dysfunction. CONTRAINDICATIONS OPANA Injection should not be administered to patients with a known hypersensitivity to oxymorphone hydrochloride or to any of the other ingredients in OPANA Injection, or with known hypersensitivity to morphine analogs such as codeine. OPANA Injection is contraindicated in patients with respiratory depression except in monitored settings and in the presence of resuscitative equipment and in patients with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 acute or severe bronchial asthma, upper airway obstruction, or hypercarbia. OPANA Injection is contraindicated in any patient who has or is suspected of having paralytic ileus. OPANA Injection should not be used in the treatment of pulmonary edema secondary to a chemical respiratory irritant. Opioid analgesics cause pooling of blood in the extremities by decreasing peripheral vascular resistance. This effect results in decreases in venous return, cardiac work, and pulmonary venous pressure, and blood is shifted from the central to peripheral circulation which would not be beneficial in the treatment of pulmonary edema secondary to a chemical respiratory irritant. OPANA Injection is contraindicated in patients with moderate and severe hepatic impairment (see CLINICAL PHARMACOLOGY, PRECAUTIONS and DOSAGE AND ADMINISTRATION ). WARNINGS OPANA Injection is an opioid agonist and a Schedule II controlled substance with an abuse liability similar to morphine. Respiratory Depression Respiratory depression is the chief hazard of OPANA Injection. Respiratory depression is a particular potential problem in elderly or debilitated patients as well as in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation. OPANA Injection should be administered with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, CNS depression or coma. In these patients, even usual therapeutic doses of oxymorphone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Alternative non-opioid analgesics should be considered, and oxymorphone should be employed only under careful medical supervision at the lowest effective dose in such patients. Misuse, Abuse and Diversion of Opioids OPANA Injection contains oxymorphone, an opioid agonist with an abuse liability similar to morphine and a Schedule II controlled substance. Opioid agonists have the potential for being abused and are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Oxymorphone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing oxymorphone in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Interactions with Alcohol and Drugs of Abuse Oxymorphone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression because respiratory depression, hypotension, and profound sedation or coma may result. Drug Abuse and Addiction Controlled Substance OPANA Injection contains oxymorphone, an opioid with an abuse liability similar to morphine and other opioids and is a Schedule II controlled substance. Oxymorphone, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion (see WARNINGS : Misuse, Abuse and Diversion of Opioids ). Drug addiction is characterized by a preoccupation with the procurement, hoarding, and abuse of drugs for non-medicinal purposes. Drug addiction is treatable, utilizing a multi- disciplinary approach, but relapse is common. “Drug seeking” behavior is very common to addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non- medical purposes, often in combination with other psychoactive substances. OPANA Injection, like other opioids, may be diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Abuse of OPANA Injection poses a risk of overdose and death. This risk is increased with concurrent abuse of OPANA Injection with alcohol and other substances. In addition, parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms (see PRECAUTIONS: Pregnancy and PRECAUTIONS: Labor and Delivery ). Interactions with Other Central Nervous System Depressants Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with oxymorphone may exhibit an additive CNS depression (see PRECAUTIONS: Drug -Drug Interactions ). Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual dose of OPANA Injection. Head Injury and Increased Intracranial Pressure In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the possible respiratory depressant effects of opioid analgesics and their potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated. Furthermore, opioid analgesics can produce effects on pupillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries. Hypotensive Effect OPANA Injection, like all opioid analgesics, may cause severe hypotension in an individual whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. OPANA Injection, like all opioid analgesics, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. Hepatic Impairment The effects of OPANA Injection on hepatic impairment have not been studied. However, a study of OPANA ER in patients with hepatic disease indicated greater plasma concentrations than those with normal hepatic function (see CLINICAL PHARMACOLOGY). OPANA Injection should be used with caution in patients with mild impairment. These patients should be started with the lowest dose and titrated slowly while carefully monitoring for side effects. OPANA Injection is contraindicated for patients with moderate and severe hepatic impairment (see CONTRAINDICATIONS, WARNINGS , and DOSAGE AND ADMINISTRATION ). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 PRECAUTIONS General Opioid analgesics should be used with caution, especially when combined with other drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known potential risks of respiratory depression, altered mental state and postural hypotension. OPANA Injection should be used with caution in elderly and debilitated patients and in patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease. OPANA Injection should be used with caution in the following conditions: acute alcoholism; adrenocortical insufficiency (e.g., Addison’s disease); CNS depression or coma; delirium tremens; kyphoscoliosis associated with respiratory depression; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; severe impairment of pulmonary or renal function; moderate impairment of hepatic function; and toxic psychosis. The administration of all opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions. All opioids may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings. Interactions with Mixed Agonist/Antagonist Opioid Analgesics Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as oxymorphone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxymorphone and/or may precipitate withdrawal symptoms in these patients. Ambulatory Surgery and Post-Operative Use OPANA Injection, like other opioids, decreases bowel motility. Ileus is a common post- operative complication, especially after intra-abdominal surgery with opioid analgesia. Caution should be taken to monitor for decreased bowel motility in post-operative patients receiving opioids. Standard supportive therapy should be implemented. Use in Pancreatic/Biliary Tract Disease OPANA Injection, like other opioids, may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Physical Dependence and Tolerance Physical dependence is the occurrence of withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an opioid antagonist or mixed opioid agonist/antagonist agent. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 factors). The development of physical dependence and/or tolerance is not unusual during chronic opioid therapy. If OPANA Injection is abruptly discontinued in a physically-dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, OPANA Injection should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION : Cessation of Therapy ). Use in Drug and Alcohol Addiction OPANA Injection is not approved for use in detoxification or maintenance treatment of opioid addiction. However, the history of an addictive disorder does not necessarily preclude the use of this medication for the treatment of chronic pain. These patients will require intensive monitoring for signs of misuse, abuse, or addiction. Drug-Drug Interactions Oxymorphone is highly metabolized principally in the liver and undergoes reduction or conjugation with glucuronic acid to form both active and inactive products (see CLINICAL PHARMACOLOGY and PHARMACOKINETICS : Metabolism). Use with CNS Depressants The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol may produce additive CNS depressant effects. OPANA Injection, like all opioid analgesics, should be started at 1/3 to 1/2 of the usual dose in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol because respiratory depression, hypotension, and profound sedation or coma may result, and titrated slowly as necessary for adequate pain relief. Additive effects resulting in respiratory depression, hypotension, profound sedation or coma may result if these drugs are taken in combination with the usual doses of OPANA Injection. No specific interaction between oxymorphone and monoamine oxidase inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate. When combined therapy with any of the above medications is contemplated, the dose of one or both agents should be reduced (see WARNINGS and DOSAGE AND ADMINISTRATION ). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Use with Mixed Agonist/Antagonist Opioid Analgesics Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should not be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic, such as OPANA Injection. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of OPANA Injection and/or may precipitate withdrawal symptoms. Other Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS side effects have been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; a causal relationship has not been established. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Long-term studies have been completed to evaluate the carcinogenic potential of oxymorphone in both Sprague-Dawley rats and CD-1 mice. Oxymorphone HCl was administered to Sprague-Dawley rats (2.5, 5, and 10 mg/kg/day in males and 5, 10, and 25 mg/kg/day in females) for 2 years by oral gavage. The systemic drug exposure (AUC ng•h/mL) at the 10 mg/kg/day dose in male rats was 0.34-fold and at the 25 mg/kg/day dose in female rats was 1.5-fold the human exposure at a dose of 260 mg/day. No evidence of carcinogenic potential was observed in rats. Oxymorphone HCl was administered to CD-1 mice (10, 25, 75 and 150 mg/kg/day) for 2 years by oral gavage. The systemic drug exposure (AUC ng•h/mL) at the 150 mg/kg/day dose in mice was 14.5- fold (in males) and 17.3-fold (in females) times the human exposure at a dose of 260 mg/day. No evidence of carcinogenic potential was observed in mice. Mutagenesis: Oxymorphone hydrochloride was not mutagenic when tested in the in vitro bacterial reverse mutation assay (Ames test) at concentrations of =5270 µg/plate, or in an in vitro mammalian cell chromosome aberration assay performed with human peripheral blood lymphocytes at concentrations =5000 µg/ml with or without metabolic activation. Oxymorphone hydrochloride tested positive in both the rat and mouse in vivo micronucleus assays. An increase in micronucleated polychromatic erythrocytes occurred in mice given doses of =250 mg/kg and in rats given doses of 20 and 40 mg/kg. A subsequent study demonstrated that oxymorphone hydrochloride was not aneugenic in mice following administration of up to 500 mg/kg. Additional studies indicate that the increased incidence of micronucleated polychromatic erythrocytes in rats may be secondary to increased body temperature following oxymorphone administration. Doses associated with increased micronucleated polychromatic erythrocytes also produce a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 marked, rapid increase in body temperature. Pretreatment of animals with sodium salicylate minimized the increase in body temperature and prevented the increase in micronucleated polychromatic erythrocytes after administration of 40 mg/kg oxymorphone. Impairment of fertility: Oxymorphone hydrochloride did not affect reproductive function or sperm parameters in male rats at any dose tested (=50 mg/kg/day via oral gavage). In female rats, an increase in the length of the estrus cycle and decrease in the mean number of viable embryos, implantation sites and corpora lutea were observed at doses of oxymorphone =10 mg/kg/day via oral gavage. The dose of oxymorphone associated with reproductive findings in female rats is 0.8 times a total human daily dose of 120 mg OPANA based on a body surface area. The dose of oxymorphone that produced no adverse effects on reproductive findings in female rats (i.e., NOAEL) is 0.4-times a total human daily dose of 120 mg OPANA based on body surface area. Pregnancy The safety of using oxymorphone in pregnancy has not been established with regard to possible adverse effects on fetal development. The use of OPANA Injection in pregnancy, in nursing mothers, or in women of child-bearing potential requires that the possible benefits of the drug be weighted against the possible hazards to the mother and the child (see PRECAUTIONS). Teratogenic Effects Pregnancy Category C Oxymorphone hydrochloride administration did not cause malformations at any doses evaluated during developmental toxicity studies in rats (=25 mg/kg/day via oral gavage) or rabbits (=50 mg/kg/day via oral gavage). These doses are ~2 times and 8 times a total human daily dose of 120 mg of OPANA (an immediate-release oral tablet formulation), based on body surface area. There were no developmental effects in rats treated with 5 mg/kg/day or rabbits treated with 25 mg/kg/day. Fetal weights were reduced in rats and rabbits given doses of =10 mg/kg/day and 50 mg/kg/day, respectively. These doses are ~0.8 and 4 times respectively a total human daily dose of 120 mg of OPANA, based on body surface area. There were no effects of oxymorphone hydrochloride on intrauterine survival at doses =25 mg/kg/day in rats, or =50 mg/kg/day in rabbits (see Non-teratogenic Effects, below). In a study that was conducted prior to the establishment of Good Laboratory Practices (GLP) and not according to current recommended methodology, a single subcutaneous injection of oxymorphone hydrochloride on gestation day 8 was reported to produce malformations in offspring of hamsters that received 10 times a total human daily dose of 120 mg of OPANA, based on body surface area. This dose also produced 83% maternal lethality. There are no adequate and well-controlled studies in pregnant women. OPANA Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Non-teratogenic Effects This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Oxymorphone hydrochloride administration to female rats during gestation in a pre- and postnatal developmental toxicity study reduced mean litter size (18%) at a dose of 25 mg/kg/day via oral gavage, attributed to an increase in the incidence of stillborn pups. An increase in neonatal death occurred at doses =5 mg/kg/day. Post-natal survival of the pups was reduced throughout weaning following treatment of the dams with 25 mg/kg/day. Low pup birth weight and decreased postnatal weight gain occurred in pups born to oxymorphone-treated female rats given a dose of 25 mg/kg/day. This dose is ~2 times a total human daily dose of 120 mg of OPANA, based on body surface area. Prolonged use of opioid analgesics during pregnancy may cause fetal-neonatal physical dependence. Neonatal withdrawal may occur. Symptoms usually appear during the first days of life and may include convulsions, irritability, excessive crying, tremors, hyperactive reflexes, fever, vomiting, diarrhea, sneezing, yawning, and increased respiratory rate. Labor and Delivery OPANA Injection should be used with caution during labor. Sinusoidal fetal heart rate patterns may occur with the use of opioid analgesics. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. Occasionally, opioid analgesics may prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression. A specific opioid antagonist, such as naloxone or nalmefene, should be available for reversal of opioid-induced respiratory depression in the neonate. Opioid analgesics, including OPANA Injection, may cause respiratory depression in the newborn. The effect of OPANA Injection, if any, on the later growth, development, and functional maturation of the child is unknown. Nursing Mothers It is not known whether oxymorphone is excreted in human milk. Because many drugs, including some opioids, are excreted in human milk, caution should be exercised when OPANA Injection is administered to a nursing woman. Ordinarily, nursing should not be undertaken while a patient is receiving oxymorphone because of the possibility of sedation and/or respiratory depression in the infant. Pediatric Use Safety and effectiveness of OPANA Injection in pediatric patients below the age of 18 years have not been established. Geriatric Use OPANA Injection should be used with caution in elderly patients. Though not studied with the injection formulation, the plasma levels of OPANA ER tablets are about 40% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 higher in elderly (=65 years of age) than in younger subjects (see CLINICAL PHARMACOLOGY). However, of the total number of subjects in clinical studies of OPANA (immediate release formulation) tablet, 31 percent were 65 and over, while 7 percent were 75 and over. No overall differences in effectiveness were observed between these subjects and younger subjects. There were several adverse events that were more frequently observed in subjects 65 and over compared to younger subjects. These adverse events included dizziness, somnolence, confusion, and nausea. In general, dose selection for elderly patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Hepatic Impairment The effects of OPANA Injection on hepatic impairment have not been studied. However, a study of OPANA ER in patients with hepatic disease indicated greater plasma concentrations than those with normal hepatic function (see CLINICAL PHARMACOLOGY). OPANA Injection should be used with caution in patients with mild impairment. These patients should be started with the lowest dose and titrated slowly while carefully monitoring for side effects. OPANA Injection is contraindicated for patients with moderate and severe hepatic impairment (see CONTRAINDICATIONS, WARNINGS , and DOSAGE AND ADMINISTRATION ). Renal Impairment The effects of OPANA Injection on renal impairment have not been studied. However, in a study of OPANA ER, patients with moderate to severe renal impairment were shown to have an increase in bioavailability ranging from 57- 65% (see CLINICAL PHARMACOLOGY). These patients should be started cautiously with lower doses of OPANA Injection and titrated slowly while carefully monitored for side effects (see DOSAGE AND ADMINISTRATION ). Gender Differences The effects of OPANA Injection on gender have not been studied. However, in clinical trials with OPANA, the overall incidence rates for one or more adverse events were similar among females and male subjects receiving OPANA and placebo. ADVERSE REACTIONS Cardiac disorders: tachycardia, bradycardia, palpitations Eye disorders: miosis, diplopia, vision blurred Gastrointestinal disorders: nausea, vomiting, dry mouth, constipation, abdominal pain, ileus paralytic General disorders and administration site conditions: fatigue, asthenia, injection site reaction Hepatobilliary disorders: biliary colic This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 Immune system disorders: hypersensitivity (dermatitis allergic, urticaria NOS, pruritus, swelling face) Metabolism and nutrition disorders: anorexia, Nervous system disorders: somnolence, sedation, dizziness, headache, mental impairment NOS, central nervous system depression NOS Psychiatric disorders: dysphoria, euphoric mood, nervousness, restlessness, confusional state, insomnia, agitation, hallucination, depression, drug dependence Renal and urinary disorders: ureteral spasm, urinary hesitation, urinary retention, oliguria Respiratory, thoracic, and mediastinal disorders: respiratory depression, atelectasis, bronchospasm, laryngospasm, laryngeal oedema, apnoea Skin and subcutaneous tissue disorders: pruritus, sweating increased Social circumstances: drug abuser Vascular disorders: hypotension, orthostatic hypotension, flushing OVERDOSAGE Signs and Symptoms Acute overdosage with OPANA Injection is characterized by respiratory depression, (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. OPANA Injection may cause miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations (see CLINICAL PHARMACOLOGY: Central Nervous System). Treatment In the treatment of OPANA Injection overdosage, primary attention should be given to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. The opioid antagonist naloxone hydrochloride is a specific antidote against respiratory depression, which may result from overdosage or unusual sensitivity to opioids including OPANA Injection. Therefore, an appropriate dose of naloxone hydrochloride should be administered (usual initial adult dose 0.4 mg-2 mg) preferably by the intravenous route and simultaneously with efforts at respiratory resuscitation. Nalmefene is an alternative pure opioid antagonist, which may be administered as a specific antidote to respiratory depression resulting from opioid overdose. Since the duration of action of OPANA Injection may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered according to the antagonist labeling as needed to maintain adequate respiration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 In patients receiving OPANA Injection, opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression. They should be administered cautiously to persons who are known, or suspected to be, physically dependent on any opioid agonist including OPANA Injection. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. In an individual physically dependent on opioids, administration of the usual dose of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. If respiratory depression is associated with muscular rigidity, administration of a neuromuscular blocking agent may be necessary to facilitate assisted or controlled ventilation. Muscular rigidity may also respond to opioid antagonist therapy. DOSAGE AND ADMINISTRATION OPANA Injection is an opioid agonist and a Schedule II controlled substance with an abuse liability similar to morphine and other opioids. OPANA Injection, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion. Selection of patients for treatment with OPANA Injection should be governed by the same principles that apply to the use of similar opioid analgesics (see INDICATIONS AND USAGE). Physicians sho uld individualize treatment in every case (see DOSAGE AND ADMINISTRATION ), using non- opioid analgesics, prn opioids and/or combination products, and chronic opioid therapy in a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Healthcare Research and Quality, and the American Pain Society. As with any opioid drug product, it is necessary to adjust the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience. In the selection of the initial dose of OPANA Injection, attention should be given to the following: 1. The total daily dose, potency and specific characteristics of the opioid the patient has been taking previously; 2. The relative potency estimate used to calculate the equivalent oxymorphone dose needed; 3. The patient’s degree of opioid tolerance; 4. The age, general condition, and medical status of the patient; 5. Concurrent non-opioid analgesic and other medications; 6. The type and severity of the patient's pain; 7. The balance between pain control and adverse experiences. 8. Risk factors for abuse, addiction or diversion, including a prior history of abuse, addiction or diversion. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 The following dosing recommendations, therefore, can only be considered as suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient. Initiation of Therapy Subcutaneous or intramuscular administration: initially 1 mg to 1.5 mg, repeated every 4 to 6 hours as needed. Intravenous: 0.5 mg initially. In non debilitated patients the dose can be cautiously increased until satisfactory pain relief is obtained. For analgesia during labor 0.5 mg to 1 mg intramuscularly is recommended. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Conversion from Oral OPANA to OPANA Injection Given the absolute oral bioavailability of approximately 10%, patients receiving oral OPANA may be converted to OPANA Injection by administering one-tenth the patient’s total daily oral oxymorphone dose as OPANA Injectable in four or six equally divided doses (e.g., total daily Oral dose/ [10 x 4]). For example, approximately 1 mg of OPANA Injectable IM every 6 hours (4 mg total IM dose) may be required to provide pain relief equivalent to a total daily dose of 40 mg oral OPANA. The dose can be titrated to optimal pain relief or combined with acetaminophen/NSAIDs for optimal pain relief. Due to patient variability with regard to opioid analgesic response, upon conversion patients should be closely monitored to ensure adequate analgesia and to minimize side effects. Individualization of Dose Once therapy is initiated, pain relief and other opioid effects should be frequently assessed. Patients should be titrated to adequate pain relief (generally mild or no pain). Patients who experience breakthrough pain may require dosage adjustment or non-opioid therapy such as acetaminophen or NSAIDs. If signs of excessive opioid-related adverse experiences are observed, the next dose may be reduced. Dose adjustments should be made to obtain an appropriate balance between pain relief and opioid-related adverse experiences. If significant adverse events occur before the therapeutic goal of mild or no pain is achieved, the events should be treated aggressively. Once adverse events are under control, upward titration should continue to an acceptable level of pain control. During periods of changing analgesic requirements, including initial titration, frequent contact is recommended between physician, other members of the health-care team, the patient and the caregiver/family. Patients and family members should be advised of the potential common side effects to decrease fear of the use of opioids and promote their optimal use. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 Patients with Hepatic Impairment The effects of OPANA Injection on hepatic impairment have not been studied. However, OPANA Injection is contraindicated in patients with moderate and severe hepatic dysfunction. OPANA Injection should be used with caution in patients with mild hepatic impairment. These patients with mild hepatic impairment should be started with the lowest dose and titrated slowly while carefully monitoring side effects (see CLINICAL PHARMACOLOGY, CONTRAINDICATIONS, and PRECAUTIONS). Patients with Renal Impairment The effects of OPANA Injection on renal impairment have not been studied. However, there are 57% and 65% increases in oxymorphone bioavailability in patients with moderate to severe renal impairment, respectively, treated with OPANA ER ( see CLINICAL PHARMACOLOGY and PRECAUTIONS). Accordingly, OPANA Injection should be administered cautiously and in reduced dosages to patients with creatinine clearance rate less than 50 mL/min. Use with CNS depressants OPANA Injection, like all opioid analgesics, should be started at 1/3 to 1/2 of the usual dose in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol because respiratory depression, hypotension and profound sedation or coma may result. No specific interaction between oxymorphone and monoamine oxidase inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate (see PRECAUTIONS : General and PRECAUTIONS: Drug -Drug Interactions ) Geriatrics Caution should be exercised in the selection of the starting dose of OPANA Injection for an elderly patient starting at the low end of the dosing range. Maintenance of Therapy OPANA Injection is intended as an opioid analgesic for the management of moderate to severe pain where the use of an opioid analgesic is appropriate. During therapy, continual re-evaluation of the patient receiving OPANA Injection is important, with special attention to the maintenance of pain control and the relative incidence of side effects associated with therapy. If the level of pain increases, effort should be made to identify the source of increased pain, while adjusting the dose and/or using adjuvant analgesics such as acetaminophen or NSAIDs. Cessation of Therapy When the patient no longer requires therapy with OPANA Injection, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 SAFETY AND HANDLING OPANA Injection contains oxymorphone, which is a controlled substance. Oxymorphone is controlled under Schedule II of the Controlled Substances Act. Oxymorphone, like all opioids, is liable to diversion and misuse and should be handled accordingly. OPANA Injection may be targeted for theft and diversion. Healthcare professionals should contact their State Medical Board, State Board of Pharmacy or State Control Board for information on how to detect or prevent diversion of this product. HOW SUPPLIED OPANA (oxymorphone hydrochloride) Injection is supplied as follows: 1 mg/mL 1 mL ampules (paraben/sodium dithionite-free) (box of 10) NDC 63481-624-10 Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.] DEA Order Form Required Protect from light. Manufactured for: Endo Pharmaceuticals Inc. Chadds Ford, Pennsylvania 19317 OPANA ® is a Registered Trademark of Endo Pharmaceuticals Inc. Copyright © Endo Pharmaceuticals Inc. 2006 Printed in U.S.A. 003466 /September 2006 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Each 1 mL contains: Oxymorphone Hydrochloride, USP . . . 1 mg Sodium chloride 8 mg/mL. pH is adjusted with hydrochloric acid. Usual Dosage: See package insert for complete prescribing information. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). PROTECT FROM LIGHT. NDC 63481-624-10 1 mL X 10 ampules OPANA ® (oxymorphone hydrochloride) Injection ® Rx only Manufactured for: Endo Pharmaceuticals Inc. Chadds Ford, Pennsylvania 19317 Manufactured by: DSM Pharmaceuticals, Inc. Greenville, North Carolina 27834 1 mg per mL 1 mg per mL 1 mg per mL OPANA ® (oxymorphone hydrochloride) Injection OPANA ® (oxymorphone hydrochloride) Injection OPANA ® (oxymorphone hydrochloride) Injection 1 mL X 10 ampules 1 mg per mL 003455 FOR INTRAMUSCULAR, SUBCUTANEOUS OR INTRAVENOUS USE Each 1 mL contains: Oxymorphone Hydrochloride, USP . . . 1 mg Sodium chloride 8 mg/mL. pH is adjusted with hydrochloric acid. Usual Dosage: See package insert for complete prescribing information. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). PROTECT FROM LIGHT. NDC 63481-624-10 1 mL X 10 ampules OPANA ® (oxymorphone hydrochloride) Injection ® Rx only 1 mg per mL FOR INTRAMUSCULAR, SUBCUTANEOUS OR INTRAVENOUS USE FPO - Code 128 542787 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OPANA®(oxymorphone hydrochloride) Injection 1mg/mL 1mL ampule NDC 63481-624-01 For Intramuscular, Subcutaneous, or Intravenous Use Only Manufactured for Endo Pharmaceuticals Inc. Chadds Ford, PA 19317 00363481624014 003465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:45.756703	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/011707s031lbl.pdf', 'application_number': 11707, 'submission_type': 'SUPPL ', 'submission_number': 31}
10,776	Page 1 Rev. November 2003 TENUATE® IV (diethylpropion hydrochloride USP) immediate-release 25 mg tablets TENUATE® DOSPAN® IV (diethylpropion hydrochloride USP) controlled-release 75 mg tablets DESCRIPTION TENUATE® is available for oral administration in immediate-release tablets containing 25 mg diethylpropion hydrochloride and in controlled-release tablets containing 75 mg diethylpropion hydrochloride. The inactive ingredients in each immediate-release tablet are: corn starch, lactose, magnesium stearate, pregelatinized corn starch, talc, and tartaric acid. The inactive ingredients in each controlled-release tablet are: carbomer 934P, mannitol, povidone, tartaric acid, zinc stearate. Diethylpropion hydrochloride is a sympathomimetic agent. The chemical name for diethylpropion hydrochloride is 1-phenyl-2-diethyl-amino-1-propanone hydrochloride. Its chemical structure is: In TENUATE DOSPAN tablets, diethylpropion hydrochloride is dispersed in a hydrophilic matrix. On exposure to water, the diethylpropion hydrochloride is released at a relatively uniform rate as a result of slow hydration of the matrix. The result is controlled release of the anorectic agent. CLINICAL PHARMACOLOGY Diethylpropion hydrochloride is a sympathomimetic amine with some pharmacologic activity similar to that of the prototype drugs of this class used in obesity, the amphetamines. Actions include some central nervous system stimulation and elevation of blood pressure. Tolerance has been demonstrated with all drugs of this class in which these phenomena have been looked for. Drugs of this class used in obesity are commonly known as "anorectics" or "anorexigenics." It has not been established, however, that the action of such drugs in treating obesity is primarily one of appetite suppression. For example, other central nervous system actions or metabolic effects may be involved. Adult obese subjects instructed in dietary management and treated with "anorectic" drugs lose more weight on the average than those treated with placebo and diet, as determined in relatively short-term clinical trials. The magnitude of increased weight loss of drug-treated patients over placebo-treated patients averages some fraction of a pound a week. However, individual weight loss may vary substantially from patient to patient. The rate of weight loss is greatest in the first weeks of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 2 therapy for both drug and placebo subjects and tends to decrease in succeeding weeks. The possible origins of the increased weight loss due to the various drug effects are not established. The amount of weight loss associated with the use of an "anorectic" drug varies from trial to trial, and the increased weight loss appears to be related in part to variables other than the drug prescribed, such as the physician/investigator relationship, the population treated, and the diet prescribed. Studies do not permit conclusions as to the relative importance of the drug and non- drug factors on weight loss. The natural history of obesity is measured in years, whereas most studies cited are restricted to a few weeks duration; thus, the total impact of drug-induced weight loss over that of diet alone is unknown. Diethylpropion is rapidly absorbed from the GI tract after oral administration and is extensively metabolized through a complex pathway of biotransformation involving N-dealkylation and reduction. Many of these metabolites are biologically active and may participate in the therapeutic action of TENUATE or TENUATE DOSPAN. Due to the varying lipid solubilities of these metabolites, their circulating levels are affected by urinary pH. Diethylpropion and/or its active metabolites are believed to cross the blood-brain barrier and the placenta. Diethylpropion and its metabolites are excreted mainly by the kidney. It has been reported that between 75-106% of the dose is recovered in the urine within 48 hours after dosing. Using a phosphorescence assay that is specific for basic compounds containing benzoyl group, the plasma half-life of the aminoketone metabolites is estimated to be between 4 to 6 hours. The controlled-release characteristics of TENUATE DOSPAN have been demonstrated by studies in humans in which plasma levels of diethylpropion-related materials were measured by phosphorescence analysis. Plasma levels obtained with the 75 mg TENUATE DOSPAN formulation administered once daily indicated a more gradual release than the immediate-release formulation (three 25 mg tablets given in a single dose). TENUATE DOSPAN has not been shown superior in effectiveness to the same dosage of the immediate-release formulation (one 25 mg tablet three times daily). After administration of a single dose of TENUATE DOSPAN (one 75 mg controlled-release tablet) or diethylpropion hydrochloride solution (75 mg dose) in a cross-over study using normal human subjects, the amount of parent compound and its active metabolites recovered in the urine within 48 hours for the two dosage forms were not statistically different. INDICATIONS AND USAGE TENUATE and TENUATE DOSPAN are indicated in the management of exogenous obesity as a short-term adjunct (a few weeks) in a regimen of weight reduction based on caloric restriction in patients with an initial body mass index (BMI) of 30 kg/m2 or higher and who have not responded to appropriate weight reducing regimen (diet and/or exercise) alone. Below is a chart of BMI based on various heights and weights. BMI is calculated by taking the patients weight, in kilograms (kg), divided by the patient’s height, in meters (m), squared. Metric conversions are as follows: pounds divided by 2.2 = kg; inches x 0.0254 = meters. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 3 Body Mass Index (BMI), kg/m2 Weight (pounds) Height (feet, inches) 5’0” 5’3” 5’6” 5’9” 6’0” 6’3” 140 27 25 23 21 19 18 150 29 27 24 22 20 19 160 31 28 26 24 22 20 170 33 30 28 25 23 21 180 35 32 29 27 25 23 190 37 34 31 28 26 24 200 39 36 32 30 27 25 210 41 37 34 31 29 26 220 43 39 36 33 30 28 230 45 41 37 34 31 29 240 47 43 39 36 33 30 250 49 44 40 37 34 31 The usefulness of agents of this class (see CLINICAL PHARMACOLOGY) should be measured against possible risk factors inherent in their use such as those described below. TENUATE and TENUATE DOSPAN are indicated for use as monotherapy only. CONTRAINDICATIONS Pulmonary hypertension, advanced arteriosclerosis, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma, severe hypertension. (See PRECAUTIONS.) Agitated states. Patients with a history of drug abuse. Use in combination with other anorectic agents is contraindicated. During or within 14 days following the administration of monoamine oxidase inhibitors, hypertensive crises may result. WARNINGS TENUATE and TENUATE DOSPAN should not be used in combination with other anorectic agents, including prescribed drugs, over-the-counter preparations, and herbal products. In a case-control epidemiological study, the use of anorectic agents, including diethylpropion, was associated with an increased risk of developing pulmonary hypertension, a rare, but often fatal disorder. The use of anorectic agents for longer than 3 months was associated with a 23-fold increase in the risk of developing pulmonary hypertension. Increased risk of pulmonary hypertension with repeated courses of therapy cannot be excluded. The onset or aggravation of exertional dyspnea, or unexplained symptoms of angina pectoris, syncope, or lower extremity edema suggest the possibility of occurrence of pulmonary hypertension. Under these circumstances, TENUATE or TENUATE DOSPAN should be immediately discontinued, and the patient should be evaluated for the possible presence of pulmonary hypertension. Valvular heart disease associated with the use of some anorectic agents such as fenfluramine and dexfenfluramine has been reported. Possible contributing factors include use for extended periods of time, higher than recommended dose, and/or use in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 4 combination with other anorectic drugs. Valvulopathy has been very rarely reported with TENUATE and TENUATE DOSPAN monotherapy, but the causal relationship remains uncertain. The potential risk of possible serious adverse effects such as valvular heart disease and pulmonary hypertension should be assessed carefully against the potential benefit of weight loss. Baseline cardiac evaluation should be considered to detect preexisting valvular heart diseases or pulmonary hypertension prior to initiation of TENUATE or TENUATE DOSPAN treatment. TENUATE and TENUATE DOSPAN are not recommended in patients with known heart murmur or valvular heart disease. Echocardiogram during and after treatment could be useful for detecting any valvular disorders which may occur. To limit unwarranted exposure and risks, treatment with TENUATE or TENUATE DOSPAN should be continued only if the patient has satisfactory weight loss within the first 4 weeks of treatment (e.g., weight loss of at least 4 pounds, or as determined by the physician and patient). TENUATE and TENUATE DOSPAN are not recommended for patients who used any anorectic agents within the prior year. If tolerance develops, the recommended dose should not be exceeded in an attempt to increase the effect; rather, the drug should be discontinued. TENUATE or TENUATE DOSPAN may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or driving a motor vehicle; the patient should therefore be cautioned accordingly. Prolonged use of diethylpropion hydrochloride may induce dependence with withdrawal syndrome on cessation of therapy. Hallucinations have occurred rarely following high doses of the drug. Several cases of toxic psychosis have been reported following the excessive use of the drug and some have been reported in which the recommended dose appears not to have been exceeded. Psychosis abated after the drug was discontinued. When central nervous system active agents are used, consideration must always be given to the possibility of adverse interactions with alcohol. PRECAUTIONS General Caution is to be exercised in prescribing TENUATE or TENUATE DOSPAN for patients with hypertension or with symptomatic cardiovascular disease, including arrhythmias. TENUATE or TENUATE DOSPAN should not be administered to patients with severe hypertension. Reports suggest that diethylpropion hydrochloride may increase convulsions in some epileptics. Therefore, epileptics receiving TENUATE or TENUATE DOSPAN should be carefully monitored. Titration of dose or discontinuance of TENUATE or TENUATE DOSPAN may be necessary. The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage. Information for Patient The patient should be cautioned about concomitant use of alcohol or other CNS-active drugs and TENUATE or TENUATE DOSPAN. (See WARNINGS.) The patient should be advised to observe caution when driving or engaging in any potentially hazardous activity. Laboratory Tests None This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 5 Drug Interactions Because TENUATE and TENUATE DOSPAN are monoamines, hypertension may result when either agent is used with monoamine oxidase (MAO) inhibitors (See CONTRAINDICATIONS). Efficacy of diethylpropion with other anorectic agents has not been studied and the combined use may have the potential for serious cardiac problems; therefore, the concomitant use with other anorectic agents is contraindicated. Antidiabetic drug requirements (i.e., insulin) may be altered. Concurrent use with general anesthetics may result in arrhythmias. The pressor effects of diethylpropion and those of other drugs may be additive when the drugs are used concomitantly; conversely, diethylpropion may interfere with antihypertensive drugs (i.e., guanethidine, a-methyldopa). Concurrent use of phenothiazines may antagonize the anorectic effect of diethylpropion. Carcinogenesis, Mutagenesis, and Impairment of Fertility No long-term animal studies have been done to evaluate diethylpropion hydrochloride for carcinogenicity. Mutagenicity studies have not been conducted. Animal reproduction studies have revealed no evidence of impairment of fertility (see Pregnancy). Pregnancy Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in rats at doses up to 1.6 times the human dose (based on mg/m2) and have revealed no evidence of impaired fertility or harm to the fetus due to diethylpropion hydrochloride. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Spontaneous reports of congenital malformations have been recorded in humans, but no causal relationship to diethylpropion has been established. Non-Teratogenic Effects. Abuse with diethylpropion hydrochloride during pregnancy may result in withdrawal symptoms in the human neonate. Nursing Mothers Since diethylpropion hydrochloride and/or its metabolites have been shown to be excreted in human milk, caution should be exercised when TENUATE or TENUATE DOSPAN is administered to a nursing woman. Geriatric Use Clinical studies of TENUATE or TENUATE DOSPAN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug in known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 6 Pediatric Use Since safety and effectiveness in pediatric patients below the age of 16 have not been established, TENUATE or TENUATE DOSPAN is not recommended for use in pediatric patients 16 years of age and under. ADVERSE REACTIONS Cardiovascular: Precordial pain, arrhythmia (including ventricular), ECG changes, tachycardia, elevation of blood pressure, palpitation and rare reports of pulmonary hypertension. Valvular heart disease associated with the use of some anorectic agents such as fenfluramine and dexfenfluramine, both independently and especially when used in combination, have been reported. Valvulopathy has been very rarely reported with TENUATE or TENUATE DOSPAN monotherapy, but the causal relationship remains uncertain. Central Nervous System: In a few epileptics an increase in convulsive episodes has been reported; rarely psychotic episodes at recommended doses; dyskinesia, blurred vision, overstimulation, nervousness, restlessness, dizziness, jitteriness, insomnia, anxiety, euphoria, depression, dysphoria, tremor, mydriasis, drowsiness, malaise, headache, and cerebrovascular accident Gastrointestinal: Vomiting, diarrhea, abdominal discomfort, dryness of the mouth, unpleasant taste, nausea, constipation, other gastrointestinal disturbances Allergic: Urticaria, rash, ecchymosis, erythema Endocrine: Impotence, changes in libido, gynecomastia, menstrual upset Hematopoietic System: Bone marrow depression, agranulocytosis, leukopenia Miscellaneous: A variety of miscellaneous adverse reactions has been reported by physicians. These include complaints such as dysuria, dyspnea, hair loss, muscle pain, increased sweating, and polyuria. DRUG ABUSE AND DEPENDENCE TENUATE and TENUATE DOSPAN are schedule IV controlled substances. Diethylpropion hydrochloride has some chemical and pharmacologic similarities to the amphetamines and other related stimulant drugs that have been extensively abused. There have been reports of subjects becoming psychologically dependent on diethylpropion. The possibility of abuse should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. Abuse of amphetamines and related drugs may be associated with varying degrees of psychologic dependence and social dysfunction which, in the case of certain drugs, may be severe. There are reports of patients who have increased the dosage to many times that recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with anorectic drugs include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia. OVERDOSAGE Manifestations of acute overdosage include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, and mydriasis. Fatigue and depression usually follow the central stimulation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 7 Cardiovascular effects include tachycardia, arrhythmias, hypertension or hypotension and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Overdose of pharmacologically similar compounds has resulted in convulsions, coma and death. The reported oral LD50 for mice is 600 mg/kg, for rats is 250 mg/kg and for dogs is 225 mg/kg. Management of acute diethylpropion hydrochloride intoxication is largely symptomatic and includes lavage and sedation with a barbiturate. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendation in this regard. Intravenous phentolamine (Regitine®) has been suggested on pharmacologic grounds for possible acute, severe hypertension, if this complicates TENUATE or TENUATE DOSPAN overdosage. DOSAGE AND ADMINISTRATION TENUATE (diethylpropion hydrochloride) immediate-release: One immediate-release 25 mg tablet three times daily, one hour before meals, and in midevening if desired to overcome night hunger. TENUATE DOSPAN (diethylpropion hydrochloride) controlled-release: One controlled-release 75 mg tablet daily, swallowed whole, in midmorning. Geriatric use: This drug in known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See PRECAUTIONS, Geriatric Use.) HOW SUPPLIED NDC 0068-0697-61 25 mg immediate-release tablets in bottles of 100 Each white, round tablet is debossed TENUATE 25 or MERRELL 697 Keep tightly closed, store at room temperature, preferably below 86°F. Protect from excessive heat. NDC 0068-0698-61 75 mg controlled-release tablets in bottles of 100 NDC 0068-0698-62 75 mg controlled-release tablets in bottles of 250 Each white, capsule-shaped tablet is debossed TENUATE 75 or MERRELL 698 Keep tightly closed. Store at room temperature, below 86°F. Rx only Rev. November 2003 Manufactured by: Patheon Pharmaceuticals Inc. Cincinnati, OH 45215 USA Manufactured for: Merrell Pharmaceuticals Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 8 An Aventis Pharmaceuticals Company Bridgewater, NJ 08807 USA www.aventis-us.com ©2003 Aventis Pharmaceuticals Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:45.791883	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/11722s029,12546s032lbl.pdf', 'application_number': 11722, 'submission_type': 'SUPPL ', 'submission_number': 29}
10,774	1 METHOTREXATE SODIUM FOR INJECTION Rx only WARNINGS METHOTREXATE SHOULD BE USED ONLY BY PHYSICIANS WHOSE KNOWLEDGE AND EXPERIENCE INCLUDE THE USE OF ANTIMETABOLITE THERAPY. BECAUSE OF THE POSSIBILITY OF SERIOUS TOXIC REACTIONS (WHICH CAN BE FATAL): METHOTREXATE SHOULD BE USED ONLY IN LIFE THREATENING NEOPLASTIC DISEASES, OR IN PATIENTS WITH PSORIASIS OR RHEUMATOID ARTHRITIS WITH SEVERE, RECALCITRANT, DISABLING DISEASE WHICH IS NOT ADEQUATELY RESPONSIVE TO OTHER FORMS OF THERAPY. DEATHS HAVE BEEN REPORTED WITH THE USE OF METHOTREXATE IN THE TREATMENT OF MALIGNANCY, PSORIASIS, AND RHEUMATOID ARTHRITIS. PATIENTS SHOULD BE CLOSELY MONITORED FOR BONE MARROW, LIVER, LUNG AND KIDNEY TOXICITIES. (See PRECAUTIONS.) PATIENTS SHOULD BE INFORMED BY THEIR PHYSICIAN OF THE RISKS INVOLVED AND BE UNDER A PHYSICIAN’S CARE THROUGHOUT THERAPY. THE USE OF METHOTREXATE HIGH DOSE REGIMENS RECOMMENDED FOR OSTEOSARCOMA REQUIRES METICULOUS CARE. (See DOSAGE AND ADMINISTRATION.) HIGH DOSE REGIMENS FOR OTHER NEOPLASTIC DISEASES ARE INVESTIGATIONAL AND A THERAPEUTIC ADVANTAGE HAS NOT BEEN ESTABLISHED. METHOTREXATE FORMULATIONS AND DILUENTS CONTAINING PRESERVATIVES MUST NOT BE USED FOR INTRATHECAL OR HIGH DOSE METHOTREXATE THERAPY. 1. Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore, it is not recommended for women of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant women with psoriasis or rheumatoid arthritis should not receive methotrexate. (See CONTRAINDICATIONS.) 2. Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 3. Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs). (See PRECAUTIONS, Drug Interactions.) 4. Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population. (See PRECAUTIONS, Organ System Toxicity, Hepatic.) 5. Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation. 6. Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur. 7. Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted. 8. Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication. 9. Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy. (See PRECAUTIONS, Organ System Toxicity, Skin.) 10. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. 11. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis. DESCRIPTION Methotrexate (formerly Amethopterin) is an antimetabolite used in the treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Chemically methotrexate is N-[4-[[(2,4-diamino-6-pteridinyl)methyl]-methylamino]benzoyl]-L- glutamic acid. The structural formula is: Molecular weight: 454.45 C20H22N8O5 Methotrexate Sodium for Injection products are sterile and non-pyrogenic and may be given by the intramuscular, intravenous, intra-arterial or intrathecal route. (See DOSAGE AND ADMINISTRATION.) Methotrexate Sodium for Injection, Lyophilized, Preservative Free, for single use only, is available in 20 mg and 1 gram vials. Each 20 mg and 1 g vial of lyophilized powder contains methotrexate sodium equivalent to 20 mg and 1 g methotrexate respectively. Contains no preservative. Sodium Hydroxide and, if necessary, Hydrochloric Acid are added during manufacture to adjust the pH. The 20 mg vial contains approximately 0.14 mEq of Sodium and the 1 g vial contains approximately 7 mEq Sodium. CLINICAL PHARMACOLOGY Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. When cellular proliferation in malignant tissues is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues. The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function. Two reports describe in vitro methotrexate inhibition of DNA precursor uptake by stimulated mononuclear cells, and another describes in animal polyarthritis partial correction by methotrexate of spleen cell hyporesponsiveness and suppressed IL 2 production. Other laboratories, however, have been unable to demonstrate similar effects. Clarification of methotrexate’s effect on immune activity and its relation to rheumatoid immunopathogenesis await further studies. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 In patients with rheumatoid arthritis, effects of methotrexate on articular swelling and tenderness can be seen as early as 3 to 6 weeks. Although methotrexate clearly ameliorates symptoms of inflammation (pain, swelling, stiffness), there is no evidence that it induces remission of rheumatoid arthritis nor has a beneficial effect been demonstrated on bone erosions and other radiologic changes which result in impaired joint use, functional disability, and deformity. Most studies of methotrexate in patients with rheumatoid arthritis are relatively short term (3 to 6 months). Limited data from long-term studies indicate that an initial clinical improvement is maintained for at least two years with continued therapy. In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process. Methotrexate in high doses, followed by leucovorin rescue, is used as a part of the treatment of patients with non-metastatic osteosarcoma. The original rationale for high dose methotrexate therapy was based on the concept of selective rescue of normal tissues by leucovorin. More recent evidence suggests that high dose methotrexate may also overcome methotrexate resistance caused by impaired active transport, decreased affinity of dihydrofolic acid reductase for methotrexate, increased levels of dihydrofolic acid reductase resulting from gene amplification, or decreased polyglutamation of methotrexate. The actual mechanism of action is unknown. In a 6-month double-blind, placebo-controlled trial of 127 pediatric patients with juvenile rheumatoid arthritis (JRA) (mean age, 10.1 years; age range, 2.5 to 18 years; mean duration of disease, 5.1 years) on background nonsteroidal anti-inflammatory drugs (NSAIDs) and/or prednisone, methotrexate given weekly at an oral dose of 10 mg/m2 provided significant clinical improvement compared to placebo as measured by either the physician’s global assessment, or by a patient composite (25% reduction in the articular-severity score plus improvement in parent and physician global assessments of disease activity). Over two-thirds of the patients in this trial had polyarticular-course JRA, and the numerically greatest response was seen in this subgroup treated with 10 mg/m2/wk methotrexate. The overwhelming majority of the remaining patients had systemic-course JRA. All patients were unresponsive to NSAIDs; approximately one-third were using low dose corticosteroids. Weekly methotrexate at a dose of 5 mg/m2 was not significantly more effective than placebo in this trial. Two Pediatric Oncology Group studies (one randomized and one non-randomized) demonstrated a significant improvement in relapse-free survival in patients with non-metastatic osteosarcoma, when high dose methotrexate with leucovorin rescue was used in combination with other chemotherapeutic agents following surgical resection of the primary tumor. These studies were not designed to demonstrate the specific contribution of high dose methotrexate/leucovorin rescue therapy to the efficacy of the combination. However, a contribution can be inferred from the reports of objective responses to this therapy in patients with metastatic osteosarcoma, and from reports of extensive tumor necrosis following preoperative administration of this therapy to patients with non-metastatic osteosarcoma. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Pharmacokinetics Absorption – In adults, oral absorption appears to be dose dependent. Peak serum levels are reached within one to two hours. At doses of 30 mg/m2 or less, methotrexate is generally well absorbed with a mean bioavailability of about 60%. The absorption of doses greater than 80 mg/m2 is significantly less, possibly due to a saturation effect. In leukemic pediatric patients, oral absorption of methotrexate also appears to be dose dependent and has been reported to vary widely (23% to 95%). A twenty fold difference between highest and lowest peak levels (Cmax: 0.11 to 2.3 micromolar after a 20 mg/m2 dose) has been reported. Significant interindividual variability has also been noted in time to peak concentration (Tmax: 0.67 to 4 hrs after a 15 mg/m2 dose) and fraction of dose absorbed. The absorption of doses greater than 40 mg/m2 has been reported to be significantly less than that of lower doses. Food has been shown to delay absorption and reduce peak concentration. Methotrexate is generally completely absorbed from parenteral routes of injection. After intramuscular injection, peak serum concentrations occur in 30 to 60 minutes. As in leukemic pediatric patients, a wide interindividual variability in the plasma concentrations of methotrexate has been reported in pediatric patients with JRA. Following oral administration of methotrexate in doses of 6.4 to 11.2 mg/m2/week in pediatric patients with JRA, mean serum concentrations were 0.59 micromolar (range, 0.03 to 1.40) at 1 hour, 0.44 micromolar (range, 0.01 to 1.00) at 2 hours, and 0.29 micromolar (range, 0.06 to 0.58) at 3 hours. In pediatric patients receiving methotrexate for acute lymphocytic leukemia (6.3 to 30 mg/m2), or for JRA (3.75 to 26.2 mg/m2), the terminal half-life has been reported to range from 0.7 to 5.8 hours or 0.9 to 2.3 hours, respectively. Distribution – After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40% to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound. Laboratory studies demonstrate that it may be displaced from plasma albumin by various compounds including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally. High CSF concentrations of the drug may be attained by intrathecal administration. In dogs, synovial fluid concentrations after oral dosing were higher in inflamed than uninflamed joints. Although salicylates did not interfere with this penetration, prior prednisone treatment reduced penetration into inflamed joints to the level of normal joints. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Metabolism – After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues and tumors. A small amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed. Accumulation of this metabolite may become significant at the high doses used in osteogenic sarcoma. The aqueous solubility of 7-hydroxymethotrexate is 3 to 5 fold lower than the parent compound. Methotrexate is partially metabolized by intestinal flora after oral administration. Half-Life – The terminal half-life reported for methotrexate is approximately three to ten hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low dose antineoplastic therapy (less than 30 mg/m2). For patients receiving high doses of methotrexate, the terminal half-life is eight to 15 hours. Excretion – Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 and 30 mg. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. Excellent correlation has been reported between methotrexate clearance and endogenous creatinine clearance. Methotrexate clearance rates vary widely and are generally decreased at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. It has been postulated that the toxicity of methotrexate for normal tissues is more dependent upon the duration of exposure to the drug rather than the peak level achieved. When a patient has delayed drug elimination due to compromised renal function, a third space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods. The potential for toxicity from high dose regimens or delayed excretion is reduced by the administration of leucovorin calcium during the final phase of methotrexate plasma elimination. Pharmacokinetic monitoring of methotrexate serum concentrations may help identify those patients at high risk for methotrexate toxicity and aid in proper adjustment of leucovorin dosing. Guidelines for monitoring serum methotrexate levels, and for adjustment of leucovorin dosing to reduce the risk of methotrexate toxicity, are provided below in DOSAGE AND ADMINISTRATION. Methotrexate has been detected in human breast milk. The highest breast milk to plasma concentration ratio reached was 0.08:1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 INDICATIONS AND USAGE Neoplastic Diseases Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. In acute lymphocytic leukemia, methotrexate is indicated in the prophylaxis of meningeal leukemia and is used in maintenance therapy in combination with other chemotherapeutic agents. Methotrexate is also indicated in the treatment of meningeal leukemia. Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell and small cell types. Methotrexate is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin’s lymphomas. Methotrexate in high doses followed by leucovorin rescue in combination with other chemotherapeutic agents is effective in prolonging relapse-free survival in patients with non-metastatic osteosarcoma who have undergone surgical resection or amputation for the primary tumor. Psoriasis Methotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due to an undiagnosed concomitant disease affecting immune responses. Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid Arthritis Methotrexate is indicated in the management of selected adults with severe, active rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis, who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs). Aspirin, (NSAIDs), and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. (See PRECAUTIONS, Drug Interactions.) Steroids may be reduced gradually in patients who respond to methotrexate. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects. Rest and physiotherapy as indicated should be continued. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 CONTRAINDICATIONS Methotrexate can cause fetal death or teratogenic effects when administered to a pregnant woman. Methotrexate is contraindicated in pregnant women with psoriasis or rheumatoid arthritis and should be used in the treatment of neoplastic diseases only when the potential benefit outweighs the risk to the fetus. Women of childbearing potential should not be started on methotrexate until pregnancy is excluded and should be fully counseled on the serious risk to the fetus (See PRECAUTIONS) should they become pregnant while undergoing treatment. Pregnancy should be avoided if either partner is receiving methotrexate; during and for a minimum of three months after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients. (See Boxed WARNINGS.) Because of the potential for serious adverse reactions from methotrexate in breast fed infants, it is contraindicated in nursing mothers. Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease should not receive methotrexate. Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes should not receive methotrexate. Patients with psoriasis or rheumatoid arthritis who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anemia, should not receive methotrexate. Patients with a known hypersensitivity to methotrexate should not receive the drug. WARNINGS – SEE BOXED WARNINGS. Methotrexate formulations and diluents containing preservatives must not be used for intrathecal or high dose methotrexate therapy. PRECAUTIONS General Methotrexate has the potential for serious toxicity. (See Boxed WARNINGS.) Toxic effects may be related in frequency and severity to dose or frequency of administration but have been seen at all doses. Because they can occur at any time during therapy, it is necessary to follow patients on methotrexate closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer. (See OVERDOSAGE.) If methotrexate therapy is reinstituted, it should be carried out with caution, with adequate consideration of further need for the drug and with increased alertness as to possible recurrence of toxicity. The clinical pharmacology of methotrexate has not been well studied in older individuals. Due to diminished hepatic and renal function as well as decreased folate stores in this population, relatively low doses should be considered, and these patients should be closely monitored for early signs of toxicity. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Some of the effects mentioned under ADVERSE REACTIONS, such as dizziness and fatigue, may affect the ability to drive or operate machinery. Information for Patients Patients should be informed of the early signs and symptoms of toxicity, of the need to see their physician promptly if they occur, and the need for close follow-up, including periodic laboratory tests to monitor toxicity. Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken weekly in rheumatoid arthritis and psoriasis, and that mistaken daily use of the recommended dose has led to fatal toxicity. Prescriptions should not be written or refilled on a PRN basis. Patients should be informed of the potential benefit and risk in the use of methotrexate. The risk of effects on reproduction should be discussed with both male and female patients taking methotrexate. Laboratory Tests Patients undergoing methotrexate therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests, and a chest X-ray. During therapy of rheumatoid arthritis and psoriasis, monitoring of these parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months. More frequent monitoring is usually indicated during antineoplastic therapy. During initial or changing doses, or during periods of increased risk of elevated methotrexate blood levels (eg, dehydration), more frequent monitoring may also be indicated. Transient liver function test abnormalities are observed frequently after methotrexate administration and are usually not cause for modification of methotrexate therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation. (See PRECAUTIONS, Organ System Toxicity, Hepatic.) A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established for patients with psoriasis. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population. Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available. Drug Interactions Nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with the high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use of methotrexate with this drug should be carefully monitored. In the treatment of patients with osteosarcoma, caution must be exercised if high-dose methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (eg, cisplatin). Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and mercaptopurine may therefore require dose adjustment. Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose methotrexate. Use of methotrexate with penicillins should be carefully monitored. The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (eg, azathioprine, retinoids, sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity. Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate. Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 - 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Folate deficiency states may increase methotrexate toxicity. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or additive antifolate effect. Carcinogenesis, Mutagenesis, and Impairment of Fertility No controlled human data exist regarding the risk of neoplasia with methotrexate. Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. Although there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells, the clinical significance remains uncertain. Non-Hodgkin’s lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate. However, there have been instances of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed completely following withdrawal of methotrexate, without requiring active anti-lymphoma treatment. Benefits should be weighed against the potential risks before using methotrexate alone or in combination with other drugs, especially in pediatric patients or young adults. Methotrexate causes embryotoxicity, abortion, and fetal defects in humans. It has also been reported to cause impairment of fertility, oligospermia and menstrual dysfunction in humans, during and for a short period after cessation of therapy. Pregnancy Psoriasis and rheumatoid arthritis: Methotrexate is in Pregnancy Category X. See CONTRAINDICATIONS. Nursing Mothers See CONTRAINDICATIONS. Pediatric Use Safety and effectiveness in pediatric patients have been established only in cancer chemotherapy and in polyarticular-course juvenile rheumatoid arthritis. Published clinical studies evaluating the use of methotrexate in children and adolescents (i.e., patients 2 to 16 years of age) with JRA demonstrated safety comparable to that observed in adults with rheumatoid arthritis. (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION.) Methotrexate injectable formulations containing the preservative benzyl alcohol are not recommended for use in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administrations of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m2). (See PRECAUTIONS, Organ System Toxicity, Neurologic.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease or other drug therapy (ie, that interfere with renal function, methotrexate or folate metabolism) in this population (See PRECAUTIONS, Drug Interactions). Since decline in renal function may be associated with increases in adverse events and serum creatinine measurements may over estimate renal function in the elderly, more accurate methods (ie, creatinine clearance) should be considered. Serum methotrexate levels may also be helpful. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity. In chronic use situations, certain toxicities may be reduced by folate supplementation. Post-marketing experience suggests that the occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age. See Boxed WARNINGS and ADVERSE REACTIONS. Organ System Toxicity Gastrointestinal: If vomiting, diarrhea, or stomatitis occur, which may result in dehydration, methotrexate should be discontinued until recovery occurs. Methotrexate should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis. Hematologic: Methotrexate can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with malignancy and preexisting hematopoietic impairment, the drug should be used with caution, if at all. In controlled clinical trials in rheumatoid arthritis (n=128), leukopenia (WBC <3000/mm3) was seen in 2 patients, thrombocytopenia (platelets <100,000/mm3) in 6 patients, and pancytopenia in 2 patients. In psoriasis and rheumatoid arthritis, methotrexate should be stopped immediately if there is a significant drop in blood counts. In the treatment of neoplastic diseases, methotrexate should be continued only if the potential benefit warrants the risk of severe myelosuppression. Patients with profound granulocytopenia and fever should be evaluated immediately and usually require parenteral broad-spectrum antibiotic therapy. Hepatic: Methotrexate has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally two years or more) and after a total dose of at least 1.5 grams. In studies in psoriatic patients, hepatotoxicity appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes and advanced age. An accurate incidence rate has not been determined; the rate of progression and reversibility of lesions is not known. Special caution is indicated in the presence of preexisting liver damage or impaired hepatic function. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 In psoriasis, liver function tests, including serum albumin, should be performed periodically prior to dosing but are often normal in the face of developing fibrosis or cirrhosis. These lesions may be detectable only by biopsy. The usual recommendation is to obtain a liver biopsy at 1) pretherapy or shortly after initiation of therapy (2 - 4 months), 2) a total cumulative dose of 1.5 grams, and 3) after each additional 1.0 to 1.5 grams. Moderate fibrosis or any cirrhosis normally leads to discontinuation of the drug; mild fibrosis normally suggests a repeat biopsy in 6 months. Milder histologic findings such as fatty change and low grade portal inflammation are relatively common pretherapy. Although these mild changes are usually not a reason to avoid or discontinue methotrexate therapy, the drug should be used with caution. In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks. Liver function tests should be performed at baseline and at 4-8 week intervals in patients receiving methotrexate for rheumatoid arthritis. Pretreatment liver biopsy should be performed for patients with a history of excessive alcohol consumption, persistently abnormal baseline liver function test values or chronic hepatitis B or C infection. During therapy, liver biopsy should be performed if there are persistent liver function test abnormalities or there is a decrease in serum albumin below the normal range (in the setting of well controlled rheumatoid arthritis). If the results of a liver biopsy show mild changes (Roenigk grades I, II, IIIa), methotrexate may be continued and the patient monitored as per recommendations listed above. Methotrexate should be discontinued in any patient who displays persistently abnormal liver function tests and refuses liver biopsy or in any patient whose liver biopsy shows moderate to severe changes (Roenigk grade IIIb or IV). Infection or Immunologic States: Methotrexate should be used with extreme caution in the presence of active infection, and is usually contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes. Immunization may be ineffective when given during methotrexate therapy. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated vaccinia infections after smallpox immunization in patients receiving methotrexate therapy. Hypogammaglobulinemia has been reported rarely. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Neurologic: There have been reports of leukoencephalopathy following intravenous administration of methotrexate to patients who have had craniospinal irradiation. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m2). Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies. Chronic leukoencephalopathy has also been reported in patients who received repeated doses of high-dose methotrexate with leucovorin rescue even without cranial irradiation. Discontinuation of methotrexate does not always result in complete recovery. A transient acute neurologic syndrome has been observed in patients treated with high dosage regimens. Manifestations of this stroke-like encephalopathy may include confusion, hemiparesis, transient blindness, seizures and coma. The exact cause is unknown. After the intrathecal use of methotrexate, the central nervous system toxicity which may occur can be classified as follows: acute chemical arachnoiditis manifested by such symptoms as headache, back pain, nuchal rigidity, and fever; sub-acute myelopathy characterized by paraparesis/paraplegia associated with involvement with one or more spinal nerve roots; chronic leukoencephalopathy manifested by confusion, irritability, somnolence, ataxia, dementia, seizures and coma. This condition can be progressive and even fatal. Pulmonary: Pulmonary symptoms (especially a dry nonproductive cough) or a nonspecific pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages. Renal: Methotrexate may cause renal damage that may lead to acute renal failure. High doses of methotrexate used in the treatment of osteosarcoma may cause renal damage leading to acute renal failure. Nephrotoxicity is due primarily to the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. Close attention to renal function including adequate hydration, urine alkalinization and measurement of serum methotrexate and creatinine levels are essential for safe administration. Skin: Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple, low, intermediate or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases. Other Precautions: Methotrexate should be used with extreme caution in the presence of debility. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 Methotrexate exits slowly from third space compartments (eg, pleural effusions or ascites). This results in a prolonged terminal plasma half-life and unexpected toxicity. In patients with significant third space accumulations, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be “recalled” by the use of methotrexate. ADVERSE REACTIONS IN GENERAL, THE INCIDENCE AND SEVERITY OF ACUTE SIDE EFFECTS ARE RELATED TO DOSE AND FREQUENCY OF ADMINISTRATION. THE MOST SERIOUS REACTIONS ARE DISCUSSED ABOVE UNDER ORGAN SYSTEM TOXICITY IN THE PRECAUTION SECTION. THAT SECTION SHOULD ALSO BE CONSULTED WHEN LOOKING FOR INFORMATION ABOUT ADVERSE REACTIONS WITH METHOTREXATE. The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. Other adverse reactions that have been reported with methotrexate are listed below by organ system. In the oncology setting, concomitant treatment and the underlying disease make specific attribution of a reaction to methotrexate difficult. Alimentary System: gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis. Blood and Lymphatic System Disorders: suppressed hematopoiesis, anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, agranulocytosis, eosinophilia, lymphadenopathy and lymphoproliferative disorders (including reversible). Hypogammaglobulinemia has been reported rarely. Cardiovascular: pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus). Central Nervous System: headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions have also occurred following administration of methotrexate. Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy. Hepatobiliary Disorders: hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, hepatic failure, decrease in serum albumin, liver enzyme elevations. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 Infection: There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis carinii pneumonia was the most common opportunistic infection. There have also been reports of infections, pneumonia, Cytomegalovirus infection, including cytomegaloviral pneumonia, sepsis, fatal sepsis, nocardiosis; histoplasmosis, cryptococcosis, Herpes zoster, H. simplex hepatitis, and disseminated H. simplex. Musculoskeletal System: stress fracture. Ophthalmic: conjunctivitis, serious visual changes of unknown etiology. Pulmonary System: respiratory fibrosis, respiratory failure, alveolitis, interstitial pneumonitis deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred. Skin: erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration, and exfoliative dermatitis. Urogenital System: severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal death, fetal defects. Other rarer reactions related to or attributed to the use of methotrexate such as nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, lymphoma, including reversible lymphomas, tumor lysis syndrome, soft tissue necrosis and osteonecrosis. Anaphylactoid reactions have been reported. Adverse Reactions in Double-Blind Rheumatoid Arthritis Studies The approximate incidences of methotrexate-attributed (ie, placebo rate subtracted) adverse reactions in 12 to 18 week double-blind studies of patients (n=128) with rheumatoid arthritis treated with low-dose oral (7.5 to 15 mg/week) pulse methotrexate, are listed below. Virtually all of these patients were on concomitant nonsteroidal anti-inflammatory drugs and some were also taking low dosages of corticosteroids. Hepatic histology was not examined in these short-term studies. (See PRECAUTIONS.) Incidence greater than 10%: Elevated liver function tests 15%, nausea/vomiting 10%. Incidence 3% to 10%: Stomatitis, thrombocytopenia (platelet count less than 100,000/mm3). Incidence 1% to 3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (WBC less than 3000/mm3), pancytopenia, dizziness. Two other controlled trials of patients (n=680) with Rheumatoid Arthritis on 7.5 mg – 15 mg/wk oral doses showed an incidence of interstitial pneumonitis of 1%. (See PRECAUTIONS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 Other less common reactions included decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, and vaginal discharge. Adverse Reactions in Psoriasis There are no recent placebo-controlled trials in patients with psoriasis. There are two literature reports (Roenigk, 1969 and Nyfors, 1978) describing large series (n=204, 248) of psoriasis patients treated with methotrexate. Dosages ranged up to 25 mg per week and treatment was administered for up to four years. With the exception of alopecia, photosensitivity, and “burning of skin lesions” (each 3% to 10%), the adverse reaction rates in these reports were very similar to those in the rheumatoid arthritis studies. Rarely, painful plaque erosions may appear (Pearce, HP and Wilson, BB: Am Acad Dermatol 35: 835-838, 1996). Adverse Reactions in JRA Studies The approximate incidences of adverse reactions reported in pediatric patients with JRA treated with oral, weekly doses of methotrexate (5 to 20 mg/m2/wk or 0.1 to 0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (eg, nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m2/wk in JRA, the published data for doses above 20 mg/m2/wk are too limited to provide reliable estimates of adverse reaction rates. OVERDOSAGE Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Leucovorin administration should begin as promptly as possible. As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin. In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Generally speaking, neither hemodialysis nor peritoneal dialysis have been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer (Wall, SM et al: Am J Kidney Dis 28(6):846-854, 1996). Accidental intrathecal overdosage may require intensive systemic support, high-dose systemic leucovorin, alkaline diuresis and rapid CSF drainage and ventriculolumbar perfusion. In postmarketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose have also been reported. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 Reports of oral overdose often indicate accidental daily administration instead of weekly (single or divided doses). Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and gastrointestinal reaction. For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anemia were also reported. Symptoms of intrathecal overdose are generally central nervous system (CNS) symptoms, including headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy. In some cases, no symptoms were reported. There have been reports of death following intrathecal overdose. In these cases, cerebellar herniation associated with increased intracranial pressure, and acute toxic encephalopathy have also been reported. There are published case reports of intravenous and intrathecal carboxypeptidase G2 treatment to hasten clearance of methotrexate in cases of overdose. DOSAGE AND ADMINISTRATION Neoplastic Diseases Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained. Methotrexate sodium for injection may be given by the intramuscular, intravenous, intra-arterial or intrathecal route. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Choriocarcinoma and similar trophoblastic diseases: Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course. Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalization of hCG is usually recommended. Before each course of the drug careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful. Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended. Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole. Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma. Leukemia: Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions. When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen. A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in antileukemic therapy. Meningeal Leukemia: In the treatment or prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally. Preservative free methotrexate is diluted to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP. The cerebrospinal fluid volume is dependent on age and not on body surface area. The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years. Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults. The following dosage regimen is based on age instead of body surface area: Age (years) Dose (mg) < 1 6 1 8 2 10 3 or older 12 In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age. Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 For the treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days. However, administration at intervals of less than 1 week may result in increased subacute toxicity. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal. At this point one additional dose is advisable. For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration. On this subject, it is advisable for the physician to consult the medical literature. Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character. Large doses may cause convulsions. Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity. Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced, or discontinued. Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy. Lymphomas: In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases. Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days. In Stage III, methotrexate is commonly given concomitantly with other antitumor agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods. Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily. Mycosis Fungoides (cutaneous T cell lymphoma): Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated. Dosage in early stages is usually 5 to 50 mg once weekly. Dose reduction or cessation is guided by patient response and hematologic monitoring. Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy. Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in advanced stages of the disease. Osteosarcoma: An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents. In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below. The starting dose for high dose methotrexate treatment is 12 grams/m2. If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments. If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 Drug* Dose* Treatment Week After Surgery Methotrexate 12 g/m2 IV as 4 hour infusion (starting dose) 4,5,6,7,11,12,15, 16,29,30,44,45 Leucovorin 15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion. Doxorubicin† as a single drug 30 mg/m2/day IV x 3 days 8,17 Doxorubicin† 50 mg/m2 IV 20,23,33,36 Cisplatin† 100 mg/m2 IV 20,23,33,36 Bleomycin† 15 units/m2 IV x 2 days 2,13,26,39,42 Cyclophosphamide† 600 mg/m2 IV x 2 days 2,13,26,39,42 Dactinomycin† 0.6 mg/m2 IV x 2 days 2,13,26,39,42 *Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314(No.25):1600-1606. †See each respective package insert for full prescribing information. Dosage modifications may be necessary because of drug-induced toxicity. When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed. GUIDELINES FOR METHOTREXATE THERAPY WITH LEUCOVORIN RESCUE 1. Administration of methotrexate should be delayed until recovery if: • the WBC count is less than 1500/microliter • the neutrophil count is less than 200/microliter • the platelet count is less than 75,000/microliter • the serum bilirubin level is greater than 1.2 mg/dL This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 • the SGPT level is greater than 450 U • mucositis is present, until there is evidence of healing • persistent pleural effusion is present; this should be drained dry prior to infusion. 2. Adequate renal function must be documented. a. Serum creatinine must be normal, and creatinine clearance must be greater than 60 mL/min, before initiation of therapy. b. Serum creatinine must be measured prior to each subsequent course of therapy. If serum creatinine has increased by 50% or more compared to a prior value, the creatinine clearance must be measured and documented to be greater than 60 mL/min (even if the serum creatinine is still within the normal range). 3. Patients must be well hydrated, and must be treated with sodium bicarbonate for urinary alkalinization. a. Administer 1,000 mL/m2 of intravenous fluid over 6 hours prior to initiation of the methotrexate infusion. Continue hydration at 125 mL/m2/hr (3 liters/m2/day) during the methotrexate infusion, and for 2 days after the infusion has been completed. b. Alkalinize urine to maintain pH above 7.0 during methotrexate infusion and leucovorin calcium therapy. This can be accomplished by the administration of sodium bicarbonate orally or by incorporation into a separate intravenous solution. 4. Repeat serum creatinine and serum methotrexate 24 hours after starting methotrexate and at least once daily until the methotrexate level is below 5x10-8 mol/L (0.05 micromolar). 5. The table below provides guidelines for leucovorin calcium dosage based upon serum methotrexate levels. (See table below. ‡) Patients who experience delayed early methotrexate elimination are likely to develop nonreversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent hemodialysis with a high-flux dialyzer may also be beneficial in these patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 6. Some patients will have abnormalities in methotrexate elimination, or abnormalities in renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table below. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (eg, medications which may interfere with methotrexate binding to serum albumin, or elimination) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed. CAUTION: DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY. Psoriasis, Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis Adult Rheumatoid Arthritis: Recommended Starting Dosage Schedules 1. Single oral doses of 7.5 mg once weekly. † 2. Divided oral dosages of 2.5 mg at 12 hour intervals for 3 doses given as a course once weekly. † †Methotrexate Sodium Tablets for oral administration are available. Polyarticular-Course Juvenile Rheumatoid Arthritis: The recommended starting dose is 10 mg/m2 given once weekly. For either adult RA or polyarticular-course JRA dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m2/wk in children, there are too few published data to assess how doses over 20 mg/m2/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk (0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously. Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more. The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 The patient should be fully informed of the risks involved and should be under constant supervision of the physician. (See Information for Patients under PRECAUTIONS.) Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy. (See PRECAUTIONS.) Appropriate steps should be taken to avoid conception during methotrexate therapy. (See PRECAUTIONS and CONTRAINDICATIONS.) All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects. (See ADVERSE REACTIONS.) Maximal myelosuppression usually occurs in seven to ten days. Psoriasis: Recommended Starting Dose Schedules 1. Weekly single oral, IM or IV dose schedule: 10 to 25 mg per week until adequate response is achieved. † 2. Divided oral dose schedule: 2.5 mg at 12-hour intervals for three doses. † †Methotrexate Sodium Tablets for oral administration are available. Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded. Once optimal clinical response has been achieved, each dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged. HANDLING AND DISPOSAL Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. RECONSTITUTION OF LYOPHILIZED POWDERS Reconstitute immediately prior to use. Methotrexate Sodium for Injection should be reconstituted with an appropriate sterile, preservative free medium such as 5% Dextrose Solution, USP, or Sodium Chloride Injection, USP. Reconstitute the 20 mg vial to a concentration no greater than 25 mg/mL. The 1 gram vial should be reconstituted with 19.4 mL to a concentration of 50 mg/mL. When high doses of methotrexate are administered by IV infusion, the total dose is diluted in 5% Dextrose Solution. For intrathecal injection, reconstitute to a concentration of 1 mg/mL with an appropriate sterile, preservative free medium such as Sodium Chloride Injection, USP. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 HOW SUPPLIED Parenteral: Methotrexate Sodium for Injection, Lyophilized, Preservative Free, for Single Use Only. Each 20 mg and 1 g vial of lyophilized powder contains methotrexate sodium equivalent to 20 mg and 1 g methotrexate respectively. 20 mg Vial – NDC 66479-137-21 1 g Vial – NDC 66479-139-29 Store at controlled room temperature, 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F). PROTECT FROM LIGHT. Manufactured for Xanodyne Pharmacal, Inc. Florence, KY 41042 by LEDERLE PARENTERALS, INC. Carolina, Puerto Rico 00987 W10456C002 ET02 Rev 10/03 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 REFERENCES 1. Controlling Occupational Exposure to Hazardous Drugs (OSHA Work-Practice Guidelines). Am J Health Syst Pharm 1996: 53:1669-1685. 2. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC 20402. 3. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA, March 15, 1985. 4. National Study Commission on Cytotoxic Exposure – Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115. 5. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1:426-428. 6. Jones RB, et al. Safe Handling of Chemotherapeutic Agents: A Report From the Mount Sinai Medical Center. Ca – A Cancer Journal for Clinicians Sept/Oct 1983; 258-263. 7. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033-1049. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 ‡LEUCOVORIN RESCUE SCHEDULES FOLLOWING TREATMENT WITH HIGHER DOSES OF METHOTREXATE Clinical Situation Laboratory Findings Leucovorin Dosage and Duration Normal Methotrexate Elimination Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours. 15 mg PO, IM or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). Delayed Late Methotrexate Elimination Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration. Continue 15 mg PO, IM or IV q six hours, until methotrexate level is less than 0.05 micromolar. Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (eg, an increase from 0.5 mg/dL to a level of 1 mg/dL or more). 150 mg IV q three hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q three hours, until methotrexate level is less than 0.05 micromolar. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:46.074456	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/11719slr106_methotrexate_lbl.pdf', 'application_number': 11719, 'submission_type': 'SUPPL ', 'submission_number': 106}
10,775	c o mpany logo Methotrexate Injection, USP (Contains Preservative) WARNINGS • FOR INTRATHECAL AND HIGH-DOSE THERAPY, USE THE PRESERVATIVE-FREE FORMULATION OF METHOTREXATE. DO NOT USE THE PRESERVED FORMULATION FOR INTRATHECAL OR HIGH-DOSE THERAPY BECAUSE IT CONTAINS BENZYL ALCOHOL. • METHOTREXATE SHOULD BE USED ONLY IN LIFE THREATENING NEOPLASTIC DISEASES, OR IN PATIENTS WITH PSORIASIS OR RHEUMATOID ARTHRITIS WITH SEVERE, RECALCITRANT, DISABLING DISEASE WHICH IS NOT ADEQUATELY RESPONSIVE TO OTHER FORMS OF THERAPY. • DEATHS HAVE BEEN REPORTED WITH THE USE OF METHOTREXATE IN THE TREATMENT OF MALIGNANCY, PSORIASIS, AND RHEUMATOID ARTHRITIS. • PATIENTS SHOULD BE CLOSELY MONITORED FOR BONE MARROW, LIVER, LUNG AND KIDNEY TOXICITIES. (See PRECAUTIONS.) • PATIENTS SHOULD BE INFORMED BY THEIR PHYSICIAN OF THE RISKS INVOLVED AND BE UNDER A PHYSICIAN’S CARE THROUGHOUT THERAPY. • THE USE OF METHOTREXATE HIGH-DOSE REGIMENS RECOMMENDED FOR OSTEOSARCOMA REQUIRES METICULOUS CARE. (See DOSAGE AND ADMINISTRATION.) HIGH-DOSE REGIMENS FOR OTHER NEOPLASTIC DISEASES ARE INVESTIGATIONAL AND A THERAPEUTIC ADVANTAGE HAS NOT BEEN ESTABLISHED. • Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore, it is not recommended for women of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant women with psoriasis or rheumatoid arthritis should not receive methotrexate. (See CONTRAINDICATIONS.) • Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration. • Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs). (See PRECAUTIONS, Drug Interactions.) • Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population. (See PRECAUTIONS, Organ System Toxicity, Hepatic.) w434139v04 Page 1 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation. • Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur. • Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted. • Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication. • Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy. (See PRECAUTIONS, Organ System Toxicity, Skin.) • Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. • Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis. DESCRIPTION Methotrexate (formerly Amethopterin) is an antimetabolite used in the treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. Chemically methotrexate is N-[4-[[(2,4-diamino-6-pteridinyl) methyl]methylamino]benzoyl]-L-glutamic acid. The structural formula is: structural formula Methotrexate Injection, USP is sterile and non-pyrogenic and may be given by the intramuscular, intravenous or intra-arterial route. (See DOSAGE AND ADMINISTRATION.) The preserved formulation contains benzyl alcohol; do not use for intrathecal or high-dose therapy. Methotrexate Injection, USP, Isotonic Liquid, Contains Preservative is available in 25 mg/mL, 2 mL (50 mg) vials. Each 25 mg/mL, 2 mL vial contains methotrexate sodium equivalent to 50 mg methotrexate, 0.9% w/v of Benzyl Alcohol as a preservative, and the following inactive ingredients: Sodium Chloride 0.260% w/v w434139v04 Page 2 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and Water for Injection qs ad 100% v. Sodium Hydroxide and, if necessary, Hydrochloric Acid are added to adjust the pH to approximately 8.5. CLINICAL PHARMACOLOGY Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. When cellular proliferation in malignant tissues is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues. The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function. Two reports describe in vitro methotrexate inhibition of DNA precursor uptake by stimulated mononuclear cells, and another describes in animal polyarthritis partial correction by methotrexate of spleen cell hyporesponsiveness and suppressed IL 2 production. Other laboratories, however, have been unable to demonstrate similar effects. Clarification of methotrexate’s effect on immune activity and its relation to rheumatoid immunopathogenesis await further studies. In patients with rheumatoid arthritis, effects of methotrexate on articular swelling and tenderness can be seen as early as 3 to 6 weeks. Although methotrexate clearly ameliorates symptoms of inflammation (pain, swelling, stiffness), there is no evidence that it induces remission of rheumatoid arthritis nor has a beneficial effect been demonstrated on bone erosions and other radiologic changes which result in impaired joint use, functional disability, and deformity. Most studies of methotrexate in patients with rheumatoid arthritis are relatively short term (3 to 6 months). Limited data from long-term studies indicate that an initial clinical improvement is maintained for at least two years with continued therapy. In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process. Methotrexate in high doses, followed by leucovorin rescue, is used as a part of the treatment of patients with non-metastatic osteosarcoma. The original rationale for high-dose methotrexate therapy was based on the concept of selective rescue of normal tissues by leucovorin. More recent evidence suggests that high-dose methotrexate may also overcome methotrexate resistance caused by impaired active transport, decreased affinity of dihydrofolic acid reductase for methotrexate, increased levels of dihydrofolic acid reductase resulting from gene amplification, or decreased polyglutamation of methotrexate. The actual mechanism of action is unknown. In a 6-month double-blind, placebo-controlled trial of 127 pediatric patients with juvenile rheumatoid arthritis (JRA) (mean age, 10.1 years; age range, 2.5 to 18 years; mean duration of disease, 5.1 years) on background nonsteroidal anti-inflammatory drugs (NSAIDs) and/or prednisone, methotrexate given weekly at an oral dose of 10 mg/m2 provided significant clinical improvement compared to placebo as measured by either the physician’s global assessment, or by a patient composite (25% reduction in the articular-severity score plus improvement in parent and physician global assessments of disease activity). Over two-thirds of the patients in this trial had polyarticular-course JRA, and the numerically greatest response was seen in this subgroup treated with 10 mg/m2/wk methotrexate. The overwhelming majority of the remaining patients had systemic-course JRA. All patients were unresponsive to NSAIDs; approximately one-third were using low dose corticosteroids. Weekly methotrexate at a dose of 5 mg/m2 was not significantly more effective than placebo in this trial. w434139v04 Page 3 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Two Pediatric Oncology Group studies (one randomized and one non-randomized) demonstrated a significant improvement in relapse-free survival in patients with nonmetastatic osteosarcoma, when high- dose methotrexate with leucovorin rescue was used in combination with other chemotherapeutic agents following surgical resection of the primary tumor. These studies were not designed to demonstrate the specific contribution of high-dose methotrexate/leucovorin rescue therapy to the efficacy of the combination. However, a contribution can be inferred from the reports of objective responses to this therapy in patients with metastatic osteosarcoma, and from reports of extensive tumor necrosis following preoperative administration of this therapy to patients with non-metastatic osteosarcoma. Pharmacokinetics Absorption - In adults, oral absorption appears to be dose dependent. Peak serum levels are reached within one to two hours. At doses of 30 mg/m2 or less, methotrexate is generally well absorbed with a mean bioavailability of about 60%. The absorption of doses greater than 80 mg/m2 is significantly less, possibly due to a saturation effect. In leukemic pediatric patients, oral absorption of methotrexate also appears to be dose dependent and has been reported to vary widely (23% to 95%). A twenty fold difference between highest and lowest peak levels (C max : 0.11 to 2.3 micromolar after a 20 mg/m2 dose) has been reported. Significant interindividual variability has also been noted in time to peak concentration (Tmax : 0.67 to 4 hrs after a 15 mg/m2 dose) and fraction of dose absorbed. The absorption of doses greater than 40 mg/m2 has been reported to be significantly less than that of lower doses. Food has been shown to delay absorption and reduce peak concentration. Methotrexate is generally completely absorbed from parenteral routes of injection. After intramuscular injection, peak serum concentrations occur in 30 to 60 minutes. As in leukemic pediatric patients, a wide interindividual variability in the plasma concentrations of methotrexate has been reported in pediatric patients with JRA. Following oral administration of methotrexate in doses of 6.4 to 11.2 mg/m2/week in pediatric patients with JRA, mean serum concentrations were 0.59 micromolar (range, 0.03 to 1.40) at 1 hour, 0.44 micromolar (range, 0.01 to 1.00) at 2 hours, and 0.29 micromolar (range, 0.06 to 0.58) at 3 hours. In pediatric patients receiving methotrexate for acute lymphocytic leukemia (6.3 to 30 mg/m2), or for JRA (3.75 to 26.2 mg/m2), the terminal half-life has been reported to range from 0.7 to 5.8 hours or 0.9 to 2.3 hours, respectively. Distribution - After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40 to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound. Laboratory studies demonstrate that it may be displaced from plasma albumin by various compounds including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally. High CSF concentrations of the drug may be attained by intrathecal administration. In dogs, synovial fluid concentrations after oral dosing were higher in inflamed than uninflamed joints. Although salicylates did not interfere with this penetration, prior prednisone treatment reduced penetration into inflamed joints to the level of normal joints. Metabolism - After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged w434139v04 Page 4 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda drug action of these active metabolites vary among different cells, tissues and tumors. A small amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed. Accumulation of this metabolite may become significant at the high doses used in osteogenic sarcoma. The aqueous solubility of 7-hydroxymethotrexate is 3 to 5 fold lower than the parent compound. Methotrexate is partially metabolized by intestinal flora after oral administration. Half-Life - The terminal half-life reported for methotrexate is approximately three to ten hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low dose antineoplastic therapy (less than 30 mg/m2). For patients receiving high doses of methotrexate, the terminal half-life is eight to 15 hours. Excretion - Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 and 30 mg. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. Excellent correlation has been reported between methotrexate clearance and endogenous creatinine clearance. Methotrexate clearance rates vary widely and are generally decreased at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. It has been postulated that the toxicity of methotrexate for normal tissues is more dependent upon the duration of exposure to the drug rather than the peak level achieved. When a patient has delayed drug elimination due to compromised renal function, a third space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods. The potential for toxicity from high-dose regimens or delayed excretion is reduced by the administration of leucovorin calcium during the final phase of methotrexate plasma elimination. Pharmacokinetic monitoring of methotrexate serum concentrations may help identify those patients at high risk for methotrexate toxicity and aid in proper adjustments of leucovorin dosing. Guidelines for monitoring serum methotrexate levels, and for adjustment of leucovorin dosing to reduce the risk of methotrexate toxicity, are provided below in DOSAGE AND ADMINISTRATION. Methotrexate has been detected in human breast milk. The highest breast milk to plasma concentration ratio reached was 0.08:1. INDICATIONS AND USAGE Neoplastic Diseases Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. In acute lymphocytic leukemia, methotrexate is indicated for use in maintenance therapy in combination with other chemotherapeutic agents. Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell and small cell types. Methotrexate is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin’s lymphomas. w434139v04 Page 5 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Methotrexate in high doses followed by leucovorin rescue in combination with other chemotherapeutic agents is effective in prolonging relapse-free survival in patients with non-metastatic osteosarcoma who have undergone surgical resection or amputation for the primary tumor. Psoriasis Methotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due to an undiagnosed concomitant disease affecting immune responses. Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid Arthritis Methotrexate is indicated in the management of selected adults with severe, active rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis, who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs). Aspirin, (NSAIDs), and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. (See PRECAUTIONS, Drug Interactions.) Steroids may be reduced gradually in patients who respond to methotrexate. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects. Rest and physiotherapy as indicated should be continued. CONTRAINDICATIONS Methotrexate can cause fetal death or teratogenic effects when administered to a pregnant woman. Methotrexate is contraindicated in pregnant women with psoriasis or rheumatoid arthritis and should be used in the treatment of neoplastic diseases only when the potential benefit outweighs the risk to the fetus. Women of childbearing potential should not be started on methotrexate until pregnancy is excluded and should be fully counseled on the serious risk to the fetus (see PRECAUTIONS) should they become pregnant while undergoing treatment. Pregnancy should be avoided if either partner is receiving methotrexate; during and for a minimum of three months after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients. (See Boxed WARNINGS.) Because of the potential for serious adverse reactions from methotrexate in breast fed infants, it is contraindicated in nursing mothers. Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease should not receive methotrexate. Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes should not receive methotrexate. Patients with psoriasis or rheumatoid arthritis who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia, should not receive methotrexate. Patients with a known hypersensitivity to methotrexate should not receive the drug. WARNINGS - SEE BOXED WARNINGS. For intrathecal and high-dose methotrexate therapy, use the preservative-free formulation of methotrexate. Do not use the preserved formulation of methotrexate for intrathecal or high dose therapy because it contains benzyl alcohol. w434139v04 Page 6 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor (PPI) therapy. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high doses), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. PRECAUTIONS General Methotrexate has the potential for serious toxicity. (See Boxed WARNINGS.) Toxic effects may be related in frequency and severity to dose or frequency of administration but have been seen at all doses. Because they can occur at any time during therapy, it is necessary to follow patients on methotrexate closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer. (See OVERDOSAGE.) If methotrexate therapy is reinstituted, it should be carried out with caution, with adequate consideration of further need for the drug and increased alertness as to possible recurrence of toxicity. The clinical pharmacology of methotrexate has not been well studied in older individuals. Due to diminished hepatic and renal function as well as decreased folate stores in this population, relatively low doses should be considered, and these patients should be closely monitored for early signs of toxicity. Some of the effects mentioned under ADVERSE REACTIONS, such as dizziness and fatigue, may affect the ability to drive or operate machinery. Information for Patients Patients should be informed of the early signs and symptoms of toxicity, of the need to see their physician promptly if they occur, and the need for close follow-up, including periodic laboratory tests to monitor toxicity. Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken weekly in rheumatoid arthritis and psoriasis, and that mistaken daily use of the recommended dose has led to fatal toxicity. Prescriptions should not be written or refilled on a PRN basis. Patients should be informed of the potential benefit and risk in the use of methotrexate. The risk of effects on reproduction should be discussed with both male and female patients taking methotrexate. Laboratory Tests Patients undergoing methotrexate therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests and a chest X-ray. During therapy of rheumatoid arthritis and psoriasis, monitoring of these parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months. More frequent monitoring is usually indicated during antineoplastic therapy. During initial or changing doses, or during periods of increased risk of elevated methotrexate blood levels (e.g., dehydration), more frequent monitoring may also be indicated. Transient liver function test abnormalities are observed frequently after methotrexate administration and are usually not cause for modification of methotrexate therapy. Persistent liver function test abnormalities, w434139v04 Page 7 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation. (See PRECAUTIONS, Organ System Toxicity, Hepatic.) A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established for patients with psoriasis. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population. Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available. Drug Interactions Nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use of methotrexate with this drug should be carefully monitored. In the treatment of patients with osteosarcoma, caution must be exercised if high-dose methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (e.g., cisplatin). Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and mercaptopurine may therefore require dose adjustment. Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose methotrexate. Use of methotrexate with penicillins should be carefully monitored. The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (e.g., azathioprine, retinoids, sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity. Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate. Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Preliminary animal and human studies have shown that small quantities of w434139v04 Page 8 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda intravenously administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate. Folate deficiency states may increase methotrexate toxicity. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect. Carcinogenesis, Mutagenesis, Impairment of Fertility No controlled human data exist regarding the risk of neoplasia with methotrexate. Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. Although there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells, the clinical significance remains uncertain. Non-Hodgkin’s lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate. However, there have been instances of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed completely following withdrawal of methotrexate, without requiring active anti-lymphoma treatment. Benefits should be weighed against the potential risk before using methotrexate alone or in combination with other drugs, especially in pediatric patients or young adults. Methotrexate causes embryotoxicity, abortion, and fetal defects in humans. It has also been reported to cause impairment of fertility, oligospermia and menstrual dysfunction in humans, during and for a short period after cessation of therapy. Pregnancy Psoriasis and rheumatoid arthritis: Methotrexate is in Pregnancy Category X. See CONTRAINDICATIONS. Nursing Mothers See CONTRAINDICATIONS. Pediatric Use Safety and effectiveness in pediatric patients have been established only in cancer chemotherapy and in polyarticular-course juvenile rheumatoid arthritis. Published clinical studies evaluating the use of methotrexate in children and adolescents (i.e., patients 2 to 16 years of age) with JRA demonstrated safety comparable to that observed in adults with rheumatoid arthritis. (See CLINICAL PHARMACOLOGY, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION.) For intrathecal and high-dose methotrexate therapy, use the preservative-free formulation of methotrexate. Do not use the preserved formulation of Methotrexate for intrathecal or high-dose therapy because it contains benzyl alcohol. Use the preservative-free formulation of methotrexate in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m2). (See PRECAUTIONS, Organ System Toxicity, Neurologic.) w434139v04 Page 9 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease or other drug therapy (i.e., that interfere with renal function, methotrexate or folate metabolism) in this population. (See PRECAUTIONS, Drug Interactions.) Since decline in renal function may be associated with increases in adverse events and serum creatinine measurements may over estimate renal function in the elderly, more accurate methods (i.e., creatinine clearance) should be considered. Serum methotrexate levels may also be helpful. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity. In chronic use situations, certain toxicities may be reduced by folate supplementation. Post-marketing experience suggests that the occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age. See Boxed WARNINGS and ADVERSE REACTIONS. Organ System Toxicity Gastrointestinal: If vomiting, diarrhea, or stomatitis occur, which may result in dehydration, methotrexate should be discontinued until recovery occurs. Methotrexate should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis. Hematologic: Methotrexate can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with malignancy and preexisting hematopoietic impairment, the drug should be used with caution, if at all. In controlled clinical trials in rheumatoid arthritis (n=128), leukopenia (WBC <3000/mm3) was seen in 2 patients, thrombocytopenia (platelets <100,000/mm3) in 6 patients, and pancytopenia in 2 patients. In psoriasis and rheumatoid arthritis, methotrexate should be stopped immediately if there is a significant drop in blood counts. In the treatment of neoplastic diseases, methotrexate should be continued only if the potential benefit warrants the risk of severe myelosuppression. Patients with profound granulocytopenia and fever should be evaluated immediately and usually require parenteral broad-spectrum antibiotic therapy. Hepatic: Methotrexate has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally two years or more) and after a total dose of at least 1.5 grams. In studies in psoriatic patients, hepatotoxicity appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes and advanced age. An accurate incidence rate has not been determined; the rate of progression and reversibility of lesions is not known. Special caution is indicated in the presence of preexisting liver damage or impaired hepatic function. In psoriasis, liver function tests, including serum albumin, should be performed periodically prior to dosing but are often normal in the face of developing fibrosis or cirrhosis. These lesions may be detectable only by biopsy. The usual recommendation is to obtain a liver biopsy at 1) pretherapy or shortly after initiation of therapy (2 to 4 months), 2) a total cumulative dose of 1.5 grams, and 3) after each additional 1.0 to 1.5 grams. Moderate fibrosis or any cirrhosis normally leads to discontinuation of the drug; mild fibrosis normally suggests a repeat biopsy in 6 months. Milder histologic findings such as fatty change and low grade portal inflammation, are relatively common pretherapy. Although these mild changes are usually not a reason to avoid or discontinue methotrexate therapy, the drug should be used with caution. In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in w434139v04 Page 10 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks. Liver function tests should be performed at baseline at 4 to 8 week intervals in patients receiving methotrexate for rheumatoid arthritis. Pretreatment liver biopsy should be performed for patients with a history of excessive alcohol consumption, persistently abnormal baseline liver function test values or chronic hepatitis B or C infection. During therapy, liver biopsy should be performed if there are persistent liver function test abnormalities or there is a decrease in serum albumin below the normal range (in the setting of well controlled rheumatoid arthritis). If the results of a liver biopsy show mild changes (Roenigk, grades I, II, IIIa), methotrexate may be continued and the patient monitored as per recommendations listed above. Methotrexate should be discontinued in any patient who displays persistently abnormal liver function tests and refuses liver biopsy or in any patient whose liver biopsy shows moderate to severe changes (Roenigk grade IIIb or IV). Infection or Immunologic States: Methotrexate should be used with extreme caution in the presence of active infection, and is usually contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes. Immunization may be ineffective when given during methotrexate therapy. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated vaccinia infections after smallpox immunizations in patients receiving methotrexate therapy. Hypogammaglobulinemia has been reported rarely. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered. Neurologic: There have been reports of leukoencephalopathy following intravenous administration of methotrexate to patients who have had craniospinal irradiation. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m2). Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies. Chronic leukoencephalopathy has also been reported in patients who received repeated doses of high-dose methotrexate with leucovorin rescue even without cranial irradiation. Discontinuation of methotrexate does not always result in complete recovery. A transient acute neurologic syndrome has been observed in patients treated with high-dose regimens. Manifestations of this stroke-like encephalopathy may include confusion, hemiparesis, transient blindness, seizures and coma. The exact cause is unknown. After the intrathecal use of methotrexate, the central nervous system toxicity which may occur can be classified as follows: acute chemical arachnoiditis manifested by such symptoms as headache, back pain, nuchal rigidity, and fever; sub-acute myelopathy characterized by paraparesis/paraplegia associated with involvement with one or more spinal nerve roots; chronic leukoencephalopathy manifested by confusion, irritability, somnolence, ataxia, dementia, seizures and coma. This condition can be progressive and even fatal. w434139v04 Page 11 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pulmonary: Pulmonary symptoms (especially a dry nonproductive cough) or a non-specific pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages. Renal: Methotrexate may cause renal damage that may lead to acute renal failure. High doses of methotrexate used in the treatment of osteosarcoma may cause renal damage leading to acute renal failure. Nephrotoxicity is due primarily to the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. Close attention to renal function including adequate hydration, urine alkalinization and measurement of serum methotrexate and creatinine levels are essential for safe administration. Skin: Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens- Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases. Other precautions: Methotrexate should be used with extreme caution in the presence of debility. Methotrexate exits slowly from third space compartments (e.g., pleural effusions or ascites). This results in a prolonged terminal plasma half-life and unexpected toxicity. In patients with significant third space accumulations, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be “recalled” by the use of methotrexate. ADVERSE REACTIONS IN GENERAL, THE INCIDENCE AND SEVERITY OF ACUTE SIDE EFFECTS ARE RELATED TO DOSE AND FREQUENCY OF ADMINISTRATION. THE MOST SERIOUS REACTIONS ARE DISCUSSED ABOVE UNDER ORGAN SYSTEM TOXICITY IN THE PRECAUTION SECTION. THAT SECTION SHOULD ALSO BE CONSULTED WHEN LOOKING FOR INFORMATION ABOUT ADVERSE REACTIONS WITH METHOTREXATE. The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. Other adverse reactions that have been reported with methotrexate are listed below by organ system. In the oncology setting, concomitant treatment and the underlying disease make specific attribution of a reaction to methotrexate difficult. Alimentary System: gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis. Blood and Lymphatic System Disorders: suppressed hematopoiesis, anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, agranulocytosis, eosinophilia, lymphadenopathy and lymphoproliferative disorders (including reversible). Hypogammaglobulinemia has been reported rarely. Cardiovascular: pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus). w434139v04 Page 12 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Central Nervous System: headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions have also occurred following administration of methotrexate. Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration or unusual cranial sensations, leukoencephalopathy, or encephalopathy. Hepatobiliary Disorders: hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, hepatic failure, decrease in serum albumin, liver enzyme elevations. Infection: There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis carinii pneumonia was the most common opportunistic infection. There have also been reports of infections, pneumonia, Cytomegalovirus infection, including cytomegaloviral pneumonia, sepsis, fatal sepsis, nocardiosis; histoplasmosis, cryptococcosis, Herpes zoster, H. simplex hepatitis, and disseminated H. simplex. Musculoskeletal System: stress fracture. Ophthalmic: conjunctivitis, serious visual changes of unknown etiology. Pulmonary System: respiratory fibrosis, respiratory failure, alveolitis, interstitial pneumonitis deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred. Skin: erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration and exfoliative dermatitis. Urogenital System: severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal death, fetal defects. Other rarer reactions related to or attributed to the use of methotrexate such as nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, lymphoma, including reversible lymphomas, tumor lysis syndrome, soft tissue necrosis and osteonecrosis. Anaphylactoid reactions have been reported. Adverse Reactions in Double-Blind Rheumatoid Arthritis Studies The approximate incidences of methotrexate-attributed (i.e. placebo rate subtracted) adverse reactions in 12 to 18 week double-blind studies of patients (n=128) with rheumatoid arthritis treated with low-dose oral (7.5 to 15 mg/week) pulse methotrexate, are listed below. Virtually all of these patients were on concomitant nonsteroidal anti-inflammatory drugs and some were also taking low dosages of corticosteroids. Hepatic histology was not examined in these short-term studies. (See PRECAUTIONS.) Incidence greater than 10%: Elevated liver function tests 15%, nausea/vomiting 10%. Incidence 3% to 10%: Stomatitis, thrombocytopenia (platelet count less than 100,000/mm3). Incidence 1% to 3%: Rash/pruritis/dermatitis, diarrhea, alopecia, leukopenia (WBC less than 3000/mm3), pancytopenia, dizziness. Two other controlled trials of patients (n=680) with Rheumatoid Arthritis on 7.5 mg to 15 mg/wk oral doses showed an incidence of interstitial pneumonitis of 1%. (See PRECAUTIONS.) Other less common reactions included decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistatix, fever, infection, sweating, tinnitus, and vaginal discharge. w434139v04 Page 13 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Reactions in Psoriasis There are no recent placebo-controlled trials in patients with psoriasis. There are two literature reports (Roenigk, 1969, and Nyfors, 1978) describing large series (n=204, 248) of psoriasis patients treated with methotrexate. Dosages ranged up to 25 mg per week and treatment was administered for up to four years. With the exception of alopecia, photosensitivity, and “burning of skin lesions” (each 3% to 10%), the adverse reaction rates in these reports were very similar to those in the rheumatoid arthritis studies. Rarely, painful plaque erosions may appear (Pearce, HP and Wilson, BB: Am Acad Dermatol 35: 835-838, 1996). Adverse Reactions in JRA Studies The approximate incidences of adverse reactions reported in pediatric patients with JRA treated with oral, weekly doses of methotrexate (5 to 20 mg/m2/wk or 0.1 to 0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m2/wk in JRA, the published data for doses above 20 mg/m2/wk are too limited to provide reliable estimates of adverse reaction rates. OVERDOSAGE Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Leucovorin administration should begin as promptly as possible. As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin. In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Generally speaking, neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high- flux dialyzer (Wall, SM et al: Am J Kidney Dis 28 (6): 846-854, 1996). Accidental intrathecal overdosage may require intensive systemic support, high-dose systemic leucovorin, alkaline diuresis and rapid CSF drainage and ventriculolumbar perfusion. In postmarketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose have also been reported. Reports of oral overdose often indicate accidental daily administration instead of weekly (single or divided doses). Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and gastrointestinal reaction. For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anemia were also reported. Symptoms of intrathecal overdose are generally central nervous system (CNS) symptoms, including headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy. In some cases, no symptoms were reported. There have been reports of death following intrathecal overdose. In these cases, cerebellar herniation associated with increased intracranial pressure, and acute toxic encephalopathy have also been reported. w434139v04 Page 14 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Glucarpidase is indicated for the treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information). If glucarpidase is used, do not administer leucovorin within two hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase. There are published case reports of intravenous and intrathecal glucarpidase treatment to hasten clearance of methotrexate in cases of overdose. DOSAGE AND ADMINISTRATION Neoplastic Diseases For intrathecal and high-dose methotrexate therapy, use the preservative-free formulation of methotrexate. Do not use the preserved formulation of methotrexate for intrathecal or high-dose therapy because it contains benzyl alcohol. Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained. Methotrexate injection may be given by the intramuscular, intravenous or intra-arterial route. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Choriocarcinoma and similar trophoblastic diseases: Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course. Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalization of hCG is usually recommended. Before each course of the drug careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful. Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended. Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole. Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma. Leukemia: Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common. Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions. When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen. w434139v04 Page 15 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in antileukemic therapy. Lymphomas: In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases. Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days. In Stage III, methotrexate is commonly given concomitantly with other antitumor agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods. Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily. Mycosis fungoides (cutaneous T cell lymphoma): Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated. Dosage in early stages is usually 5 to 50 mg once weekly. Dose reduction or cessation is guided by patient response and hematologic monitoring. Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy. Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in advanced stages of the disease. Osteosarcoma: An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents. In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below. The starting dose for high-dose methotrexate treatment is 12 grams/m2. If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments. If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule. Drug* Dose* Treatment Week After Surgery Methotrexate Leucovorin 12 g/m2 IV as 4 hour infusion (starting dose) 15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion 4,5,6,7,11,12,15,16,29,30,44,45 - - - Doxorubicin† as a single drug 30 mg/m2 day IV x 3 days 8,17 Doxorubicin† Cisplatin† 50 mg/m2 IV 100 mg/m2 IV 20,23,33,36 20,23,33,36 Bleomycin† Cyclophosphamide† Dactinomycin† 15 units/m2 IV x 2 days 600 mg/m2 IV x 2 days 0.6 mg/m2 IV x 2 days 2,13,26,39,42 2,13,26,39,42 2,13,26,39,42 * Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314 (No.25): 1600-1606. † See each respective package insert for full prescribing information. Dosage modifications may be necessary because of drug-induced toxicity. When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed. GUIDELINES FOR METHOTREXATE THERAPY WITH LEUCOVORIN RESCUE 1. Administration of methotrexate should be delayed until recovery if: • the WBC count is less than 1500/microliter w434139v04 Page 16 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • the neutrophil count is less than 200/microliter • the platelet count is less than 75,000/microliter • the serum bilirubin level is greater than 1.2 mg/dL • the SGPT level is greater than 450 U • mucositis is present, until there is evidence of healing • persistent pleural effusion is present; this should be drained dry prior to infusion. 2. Adequate renal function must be documented. a. Serum creatinine must be normal, and creatinine clearance must be greater than 60 mL/min, before initiation of therapy. b. Serum creatinine must be measured prior to each subsequent course of therapy. If serum creatinine has increased by 50% or more compared to a prior value, the creatinine clearance must be measured and documented to be greater than 60 mL/min (even if the serum creatinine is still within the normal range). 3. Patients must be well hydrated, and must be treated with sodium bicarbonate for urinary alkalinization. a. Administer 1,000 mL/m2 of intravenous fluid over 6 hours prior to initiation of the methotrexate infusion. Continue hydration at 125 mL/m2/hr (3 liters/m2/day) during the methotrexate infusion, and for 2 days after the infusion has been completed. b. Alkalinize urine to maintain pH above 7.0 during methotrexate infusion and leucovorin calcium therapy. This can be accomplished by the administration of sodium bicarbonate orally or by incorporation into a separate intravenous solution. 4. Repeat serum creatinine and serum methotrexate 24 hours after starting methotrexate and at least once daily until the methotrexate level is below 5 x 10-8 mol/L (0.05 micromolar). 5. The table below provides guidelines for leucovorin calcium dosage based upon serum methotrexate levels. (See table below.‡) Patients who experience delayed early methotrexate elimination are likely to develop nonreversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent hemodialysis with a high-flux dialyzer may also be beneficial in these patients. 6. Some patients will have abnormalities in methotrexate elimination, or abnormalities in renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table below. These abnormalities may or may not be associated with significant clinical toxicity. If significant toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate binding to serum albumin, or elimination) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed. CAUTION: DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY. Psoriasis, Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis Adult Rheumatoid Arthritis: Recommended Starting Dosage Schedules 1. Single oral doses of 7.5 mg once weekly.† 2. Divided oral dosages of 2.5 mg at 12 hour intervals for 3 doses given as a course once weekly.† † Methotrexate Sodium Tablets for oral administration are available. Polyarticular-Course Juvenile Rheumatoid Arthritis: The recommended starting dose is 10 mg/m2 given once weekly. w434139v04 Page 17 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For either adult RA or polyarticular-course JRA, dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m2/wk in children, there are too few published data to assess how doses over 20 mg/m2/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk (0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously. Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more. The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks. The patient should be fully informed of the risks involved and should be under constant supervision of the physician. (See Information for Patients under PRECAUTIONS.) Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy. (See PRECAUTIONS.) Appropriate steps should be taken to avoid conception during methotrexate therapy. (See PRECAUTIONS and CONTRAINDICATIONS.) All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects (See ADVERSE REACTIONS.) Maximal myelosuppression usually occurs in seven to ten days. Psoriasis: Recommended Starting Dose Schedule: 1. Weekly single oral, IM or IV dosage schedule: 10 to 25 mg per week until adequate response is achieved.† 2. Divided oral dose schedule 2.5 mg at 12 hour intervals for three doses.† † Methotrexate Sodium Tablets for oral administration are available. Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded. Once optimal clinical response has been achieved, each dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged. HANDLING AND DISPOSAL Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. DILUTION INSTRUCTIONS FOR LIQUID METHOTREXATE INJECTION PRODUCT Methotrexate Injection USP, Isotonic Liquid, Contains Preservative If desired, the solution may be further diluted with a compatible medium such as Sodium Chloride Injection, USP. Storage for 24 hours at a temperature of 21° to 25°C results in a product which is within 90% of label potency. w434139v04 Page 18 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED Parenteral: Methotrexate Injection, USP, Isotonic Liquid, Contains Preservative. Each 25 mg/mL, 2 mL vial contains methotrexate sodium equivalent to 50 mg methotrexate. Unit of Sale Concentration Each NDC 61703-350-38 50 mg/2 mL NDC 61703-350-37 Carton containing (25 mg/mL) 2 mL Vial 5 Vials Store at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]; excursions permitted to 15° to 30°C (59° to 86°F). PROTECT FROM LIGHT. ‡LEUCOVORIN RESCUE SCHEDULES FOLLOWING TREATMENT WITH HIGHER DOSES OF METHOTREXATE Clinical Situation Normal Methotrexate Elimination Delayed Late Methotrexate Elimination Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury Laboratory Findings Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours. Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration. Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration, (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more). Leucovorin Dosage and Duration 15 mg PO, IM, or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). Continue 15 mg PO, IM, or IV q six hours, until methotrexate level is less than 0.05 micromolar. 150 mg IV q three hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q three hours until methotrexate level is less than 0.05 micromolar. REFERENCES 1. Controlling Occupation Exposure to Hazardous Drugs (OSHA Work-Practice Guidelines). Am J Health Syst Pharma 1996: 53:1669-1685. 2. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83 2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402. 3. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA, 1985; 253(11):1590-1592. 4. National Study Commission on Cytotoxic Exposure - Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115. 5. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1:426-428. 6. Jones RB, et al. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. Ca- A Cancer Journal for Clinicians Sept/Oct 1983; 258-263. w434139v04 Page 19 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033-1049. 434139 Hospira, Inc. company logo Lake Forest, IL 60045 USA Product of Australia Revised: 11/2014 w434139v04 Page 20 of 20 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Methotrexate Injection, USP Rx only company logo WARNINGS • FOR INTRATHECAL AND HIGH-DOSE THERAPY, USE THE PRESERVATIVE-FREE FORMULTION OF METHOTREXATE. DO NOT USE THE PRESERVED FORMULATION FOR INTRATHECAL OR HIGH-DOSE THERAPY BECAUSE IT CONTAINS BENZYL ALCOHOL. • METHOTREXATE SHOULD BE USED ONLY IN LIFE THREATENING NEOPLASTIC DISEASES, OR IN PATIENTS WITH PSORIASIS OR RHEUMATOID ARTHRITIS WITH SEVERE, RECALCITRANT, DISABLING DISEASE WHICH IS NOT ADEQUATELY RESPONSIVE TO OTHER FORMS OF THERAPY. • DEATHS HAVE BEEN REPORTED WITH THE USE OF METHOTREXATE IN THE TREATMENT OF MALIGNANCY, PSORIASIS, AND RHEUMATOID ARTHRITIS. • PATIENTS SHOULD BE CLOSELY MONITORED FOR BONE MARROW, LIVER, LUNG AND KIDNEY TOXICITIES. (See PRECAUTIONS). • PATIENTS SHOULD BE INFORMED BY THEIR PHYSICIAN OF THE RISKS INVOLVED AND BE UNDER A PHYSICIAN’S CARE THROUGHOUT THERAPY. • THE USE OF METHOTREXATE HIGH-DOSE REGIMENS RECOMMENDED FOR OSTEOSARCOMA REQUIRES METICULOUS CARE. (See DOSAGE AND ADMINISTRATION.) HIGH-DOSE REGIMENS FOR OTHER NEOPLASTIC DISEASES ARE INVESTIGATIONAL AND A THERAPEUTIC ADVANTAGE HAS NOT BEEN ESTABLISHED. • Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore, it is not recommended for women of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant women with psoriasis or rheumatoid arthritis should not receive methotrexate. (See CONTRAINDICATIONS). • Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration. • Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs). (See PRECAUTIONS, Drug Interactions). • Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population. (See PRECAUTIONS, Organ System Toxicity, Hepatic). w434140v03 Page 1 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation. • Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur. • Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted. • Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication. • Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy. (See PRECAUTIONS, Organ System Toxicity, Skin.) • Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. • Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis. DESCRIPTION Methotrexate (formerly Amethopterin) is an antimetabolite used in the treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. Chemically methotrexate is N-[4-[[(2,4-diamino-6-pteridinyl) methyl]methylamino]benzoyl]-L-glutamic acid. The structural formula is: structural formula Molecular weight: 454.45 C20 H22 N8O5 Methotrexate Injection, USP is sterile and non-pyrogenic and may be given by the intramuscular, intravenous or intra-arterial route. (See DOSAGE AND ADMINISTRATION.) The preserved formulation contains benzyl alcohol; do not use for intrathecal or high-dose therapy. Methotrexate Injection, USP, Isotonic Liquid, Preservative Free, for single use only, is available in 25 mg/mL, 40 mL (1 g) vials. w434140v03 Page 2 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Each 25 mg/mL, 40 mL vial contains methotrexate sodium equivalent to 1 g methotrexate and the following inactive ingredients: Sodium Chloride 0.490% w/v. Sodium Hydroxide and, if necessary, Hydrochloric Acid are added to adjust the pH to approximately 8.5. CLINICAL PHARMACOLOGY Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. When cellular proliferation in malignant tissues is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues. The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function. Two reports describe in vitro methotrexate inhibition of DNA precursor uptake by stimulated mononuclear cells, and another describes in animal polyarthritis partial correction by methotrexate of spleen cell hyporesponsiveness and suppressed IL 2 production. Other laboratories, however, have been unable to demonstrate similar effects. Clarification of methotrexate’s effect on immune activity and its relation to rheumatoid immunopathogenesis await further studies. In patients with rheumatoid arthritis, effects of methotrexate on articular swelling and tenderness can be seen as early as 3 to 6 weeks. Although methotrexate clearly ameliorates symptoms of inflammation (pain, swelling, stiffness), there is no evidence that it induces remission of rheumatoid arthritis nor has a beneficial effect been demonstrated on bone erosions and other radiologic changes which result in impaired joint use, functional disability, and deformity. Most studies of methotrexate in patients with rheumatoid arthritis are relatively short term (3 to 6 months). Limited data from long-term studies indicate that an initial clinical improvement is maintained for at least two years with continued therapy. In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process. Methotrexate in high doses, followed by leucovorin rescue, is used as a part of the treatment of patients with non-metastatic osteosarcoma. The original rationale for high-dose methotrexate therapy was based on the concept of selective rescue of normal tissues by leucovorin. More recent evidence suggests that high-dose methotrexate may also overcome methotrexate resistance caused by impaired active transport, decreased affinity of dihydrofolic acid reductase for methotrexate, increased levels of dihydrofolic acid reductase resulting from gene amplification, or decreased polyglutamation of methotrexate. The actual mechanism of action is unknown. In a 6-month double-blind, placebo-controlled trial of 127 pediatric patients with juvenile rheumatoid arthritis (JRA) (mean age, 10.1 years; age range, 2.5 to 18 years; mean duration of disease, 5.1 years) on background nonsteroidal anti-inflammatory drugs (NSAIDs) and/or prednisone, methotrexate given weekly at an oral dose of 10 mg/m2 provided significant clinical improvement compared to placebo as measured by either the physician’s global assessment, or by a patient composite (25% reduction in the articular-severity score plus improvement in parent and physician global assessments of disease activity). Over two-thirds of the patients in this trial had polyarticular-course JRA, and the numerically greatest response was seen in this subgroup treated with 10 mg/m2/wk methotrexate. The overwhelming majority of the remaining patients had systemic-course JRA. All patients were unresponsive to NSAIDs; approximately one-third were using low dose corticosteroids. Weekly methotrexate at a dose of 5 mg/m2 was not significantly more effective than placebo in this trial. w434140v03 Page 3 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Two Pediatric Oncology Group studies (one randomized and one non-randomized) demonstrated a significant improvement in relapse-free survival in patients with nonmetastatic osteosarcoma, when high- dose methotrexate with leucovorin rescue was used in combination with other chemotherapeutic agents following surgical resection of the primary tumor. These studies were not designed to demonstrate the specific contribution of high-dose methotrexate/leucovorin rescue therapy to the efficacy of the combination. However, a contribution can be inferred from the reports of objective responses to this therapy in patients with metastatic osteosarcoma, and from reports of extensive tumor necrosis following preoperative administration of this therapy to patients with non-metastatic osteosarcoma. Pharmacokinetics Absorption- In adults, oral absorption appears to be dose dependent. Peak serum levels are reached within one to two hours. At doses of 30 mg/m2 or less, methotrexate is generally well absorbed with a mean bioavailability of about 60%. The absorption of doses greater than 80 mg/m2 is significantly less, possibly due to a saturation effect. In leukemic pediatric patients, oral absorption of methotrexate also appears to be dose dependent and has been reported to vary widely (23% to 95%). A twenty fold difference between highest and lowest peak levels (C max : 0.11 to 2.3 micromolar after a 20 mg/m2 dose) has been reported. Significant interindividual variability has also been noted in time to peak concentration (Tmax : 0.67 to 4 hrs after a 15 mg/m2 dose) and fraction of dose absorbed. The absorption of doses greater than 40 mg/m2 has been reported to be significantly less than that of lower doses. Food has been shown to delay absorption and reduce peak concentration. Methotrexate is generally completely absorbed from parenteral routes of injection. After intramuscular injection, peak serum concentrations occur in 30 to 60 minutes. As in leukemic pediatric patients, a wide interindividual variability in the plasma concentrations of methotrexate has been reported in pediatric patients with JRA. Following oral administration of methotrexate in doses of 6.4 to 11.2 mg/m2/week in pediatric patients with JRA, mean serum concentrations were 0.59 micromolar (range, 0.03 to 1.40) at 1 hour, 0.44 micromolar (range, 0.01 to 1.00) at 2 hours, and 0.29 micromolar (range, 0.06 to 0.58) at 3 hours. In pediatric patients receiving methotrexate for acute lymphocytic leukemia (6.3 to 30 mg/m2), or for JRA (3.75 to 26.2 mg/m2), the terminal half-life has been reported to range from 0.7 to 5.8 hours or 0.9 to 2.3 hours, respectively. Distribution- After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40 to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound. Laboratory studies demonstrate that it may be displaced from plasma albumin by various compounds including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally. High CSF concentrations of the drug may be attained by intrathecal administration. In dogs, synovial fluid concentrations after oral dosing were higher in inflamed than uninflamed joints. Although salicylates did not interfere with this penetration, prior prednisone treatment reduced penetration into inflamed joints to the level of normal joints. Metabolism- After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged w434140v03 Page 4 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda drug action of these active metabolites vary among different cells, tissues and tumors. A small amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed. Accumulation of this metabolite may become significant at the high doses used in osteogenic sarcoma. The aqueous solubility of 7-hydroxymethotrexate is 3 to 5 fold lower than the parent compound. Methotrexate is partially metabolized by intestinal flora after oral administration. Half-Life - The terminal half-life reported for methotrexate is approximately three to ten hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low dose antineoplastic therapy (less than 30 mg/m2). For patients receiving high doses of methotrexate, the terminal half-life is eight to 15 hours. Excretion - Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 and 30 mg. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. Excellent correlation has been reported between methotrexate clearance and endogenous creatinine clearance. Methotrexate clearance rates vary widely and are generally decreased at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. It has been postulated that the toxicity of methotrexate for normal tissues is more dependent upon the duration of exposure to the drug rather than the peak level achieved. When a patient has delayed drug elimination due to compromised renal function, a third space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods. The potential for toxicity from high-dose regimens or delayed excretion is reduced by the administration of leucovorin calcium during the final phase of methotrexate plasma elimination. Pharmacokinetic monitoring of methotrexate serum concentrations may help identify those patients at high risk for methotrexate toxicity and aid in proper adjustments of leucovorin dosing. Guidelines for monitoring serum methotrexate levels, and for adjustment of leucovorin dosing to reduce the risk of methotrexate toxicity, are provided below in DOSAGE AND ADMINISTRATION. Methotrexate has been detected in human breast milk. The highest breast milk to plasma concentration ratio reached was 0.08:1. INDICATIONS AND USAGE Neoplastic Diseases Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. In acute lymphocytic leukemia, methotrexate is indicated in the prophylaxis of meningeal leukemia and is used in maintenance therapy in combination with other chemotherapeutic agents. Methotrexate is also indicated in the treatment of meningeal leukemia. Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell and small cell types. Methotrexate is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin’s lymphomas. w434140v03 Page 5 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Methotrexate in high doses followed by leucovorin rescue in combination with other chemotherapeutic agents is effective in prolonging relapse-free survival in patients with non-metastatic osteosarcoma who have undergone surgical resection or amputation for the primary tumor. Psoriasis Methotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due to an undiagnosed concomitant disease affecting immune responses. Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid Arthritis Methotrexate is indicated in the management of selected adults with severe, active rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis, who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs). Aspirin, (NSAIDs), and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. (See PRECAUTIONS, Drug Interactions.) Steroids may be reduced gradually in patients who respond to methotrexate. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects. Rest and physiotherapy as indicated should be continued. CONTRAINDICATIONS Methotrexate can cause fetal death or teratogenic effects when administered to a pregnant woman. Methotrexate is contraindicated in pregnant women with psoriasis or rheumatoid arthritis and should be used in the treatment of neoplastic diseases only when the potential benefit outweighs the risk to the fetus. Women of childbearing potential should not be started on methotrexate until pregnancy is excluded and should be fully counseled on the serious risk to the fetus (see PRECAUTIONS) should they become pregnant while undergoing treatment. Pregnancy should be avoided if either partner is receiving methotrexate; during and for a minimum of three months after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients. (See Boxed WARNINGS). Because of the potential for serious adverse reactions from methotrexate in breast fed infants, it is contraindicated in nursing mothers. Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease should not receive methotrexate. Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes should not receive methotrexate. Patients with psoriasis or rheumatoid arthritis who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia, should not receive methotrexate. Patients with a known hypersensitivity to methotrexate should not receive the drug. WARNINGS - SEE BOXED WARNINGS. For intrathecal and high-dose methotrexate therapy, use the preservative-free formulation of methotrexate. Do not use the preserved formulation of methotrexate for intrathecal or high dose therapy because it contains benzyl alcohol. w434140v03 Page 6 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor (PPI) therapy. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high doses), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. PRECAUTIONS General Methotrexate has the potential for serious toxicity (See Boxed WARNINGS). Toxic effects may be related in frequency and severity to dose or frequency of administration but have been seen at all doses. Because they can occur at any time during therapy, it is necessary to follow patients on methotrexate closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer. (See OVERDOSAGE). If methotrexate therapy is reinstituted, it should be carried out with caution, with adequate consideration of further need for the drug and increased alertness as to possible recurrence of toxicity. The clinical pharmacology of methotrexate has not been well studied in older individuals. Due to diminished hepatic and renal function as well as decreased folate stores in this population, relatively low doses should be considered, and these patients should be closely monitored for early signs of toxicity. Some of the effects mentioned under ADVERSE REACTIONS, such as dizziness and fatigue, may affect the ability to drive or operate machinery. Information for Patients Patients should be informed of the early signs and symptoms of toxicity, of the need to see their physician promptly if they occur, and the need for close follow-up, including periodic laboratory tests to monitor toxicity. Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken weekly in rheumatoid arthritis and psoriasis, and that mistaken daily use of the recommended dose has led to fatal toxicity. Prescriptions should not be written or refilled on a PRN basis. Patients should be informed of the potential benefit and risk in the use of methotrexate. The risk of effects on reproduction should be discussed with both male and female patients taking methotrexate. Laboratory Tests Patients undergoing methotrexate therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests and a chest X-ray. During therapy of rheumatoid arthritis and psoriasis, monitoring of these parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months. More frequent monitoring is usually indicated during antineoplastic therapy. During initial or changing doses, or during periods of increased risk of elevated methotrexate blood levels (e.g., dehydration), more frequent monitoring may also be indicated. Transient liver function test abnormalities are observed frequently after methotrexate administration and are usually not cause for modification of methotrexate therapy. Persistent liver function test abnormalities, w434140v03 Page 7 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation. (See PRECAUTIONS, Organ System Toxicity, Hepatic). A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established for patients with psoriasis. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population. Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available. Drug Interactions Nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use of methotrexate with this drug should be carefully monitored. In the treatment of patients with osteosarcoma, caution must be exercised if high-dose methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (e.g., cisplatin). Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and mercaptopurine may therefore require dose adjustment. Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose methotrexate. Use of methotrexate with penicillins should be carefully monitored. The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (e.g., azathioprine, retinoids, sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity. Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate. Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Preliminary animal and human studies have shown that small quantities of w434140v03 Page 8 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda intravenously administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate. Folate deficiency states may increase methotrexate toxicity. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect. Carcinogenesis, Mutagenesis, Impairment of Fertility No controlled human data exist regarding the risk of neoplasia with methotrexate. Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. Although there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells, the clinical significance remains uncertain. Non-Hodgkin’s lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate. However, there have been instances of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed completely following withdrawal of methotrexate, without requiring active anti-lymphoma treatment. Benefits should be weighed against the potential risk before using methotrexate alone or in combination with other drugs, especially in pediatric patients or young adults. Methotrexate causes embryotoxicity, abortion, and fetal defects in humans. It has also been reported to cause impairment of fertility, oligospermia and menstrual dysfunction in humans, during and for a short period after cessation of therapy. Pregnancy Psoriasis and rheumatoid arthritis: Methotrexate is in Pregnancy Category X. See CONTRAINDICATIONS. Nursing Mothers See CONTRAINDICATIONS. Pediatric Use Safety and effectiveness in pediatric patients have been established only in cancer chemotherapy and in polyarticular-course juvenile rheumatoid arthritis. Published clinical studies evaluating the use of methotrexate in children and adolescents (i.e., patients 2 to 16 years of age) with JRA demonstrated safety comparable to that observed in adults with rheumatoid arthritis (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION.) For intrathecal and high-dose methotrexate therapy, use the preservative-free formulation of methotrexate. Do not use the preserved formulation of methotrexate for intrathecal or high-dose therapy because it contains benzyl alcohol. Use the preservative-free formulation of methotrexate in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m2). (See PRECAUTIONS, Organ System Toxicity, Neurologic). w434140v03 Page 9 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease or other drug therapy (i.e., that interfere with renal function, methotrexate or folate metabolism) in this population (See PRECAUTIONS, Drug Interactions). Since decline in renal function may be associated with increases in adverse events and serum creatinine measurements may over estimate renal function in the elderly, more accurate methods (i.e., creatinine clearance) should be considered. Serum methotrexate levels may also be helpful. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity. In chronic use situations, certain toxicities may be reduced by folate supplementation. Post-marketing experience suggests that the occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age. See Boxed WARNINGS and ADVERSE REACTIONS. Organ System Toxicity Gastrointestinal: If vomiting, diarrhea, or stomatitis occur, which may result in dehydration, methotrexate should be discontinued until recovery occurs. Methotrexate should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis. Hematologic: Methotrexate can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with malignancy and preexisting hematopoietic impairment, the drug should be used with caution, if at all. In controlled clinical trials in rheumatoid arthritis (n=128), leukopenia (WBC <3000/mm3) was seen in 2 patients, thrombocytopenia (platelets <100,000/mm3) in 6 patients, and pancytopenia in 2 patients. In psoriasis and rheumatoid arthritis, methotrexate should be stopped immediately if there is a significant drop in blood counts. In the treatment of neoplastic diseases, methotrexate should be continued only if the potential benefit warrants the risk of severe myelosuppression. Patients with profound granulocytopenia and fever should be evaluated immediately and usually require parenteral broad-spectrum antibiotic therapy. Hepatic: Methotrexate has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally two years or more) and after a total dose of at least 1.5 grams. In studies in psoriatic patients, hepatotoxicity appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes and advanced age. An accurate incidence rate has not been determined; the rate of progression and reversibility of lesions is not known. Special caution is indicated in the presence of preexisting liver damage or impaired hepatic function. In psoriasis, liver function tests, including serum albumin, should be performed periodically prior to dosing but are often normal in the face of developing fibrosis or cirrhosis. These lesions may be detectable only by biopsy. The usual recommendation is to obtain a liver biopsy at 1) pretherapy or shortly after initiation of therapy (2 to 4 months), 2) a total cumulative dose of 1.5 grams, and 3) after each additional 1.0 to 1.5 grams. Moderate fibrosis or any cirrhosis normally leads to discontinuation of the drug; mild fibrosis normally suggests a repeat biopsy in 6 months. Milder histologic findings such as fatty change and low grade portal inflammation, are relatively common pretherapy. Although these mild changes are usually not a reason to avoid or discontinue methotrexate therapy, the drug should be used with caution. In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in w434140v03 Page 10 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks. Liver function tests should be performed at baseline at 4 to 8 week intervals in patients receiving methotrexate for rheumatoid arthritis. Pretreatment liver biopsy should be performed for patients with a history of excessive alcohol consumption, persistently abnormal baseline liver function test values or chronic hepatitis B or C infection. During therapy, liver biopsy should be performed if there are persistent liver function test abnormalities or there is a decrease in serum albumin below the normal range (in the setting of well controlled rheumatoid arthritis). If the results of a liver biopsy show mild changes (Roenigk, grades I, II, IIIa), methotrexate may be continued and the patient monitored as per recommendations listed above. Methotrexate should be discontinued in any patient who displays persistently abnormal liver function tests and refuses liver biopsy or in any patient whose liver biopsy shows moderate to severe changes (Roenigk grade IIIb or IV). Infection or Immunologic States: Methotrexate should be used with extreme caution in the presence of active infection, and is usually contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes. Immunization may be ineffective when given during methotrexate therapy. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated vaccinia infections after smallpox immunizations in patients receiving methotrexate therapy. Hypogammaglobulinemia has been reported rarely. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered. Neurologic: There have been reports of leukoencephalopathy following intravenous administration of methotrexate to patients who have had craniospinal irradiation. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m2). Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies. Chronic leukoencephalopathy has also been reported in patients who received repeated doses of high-dose methotrexate with leucovorin rescue even without cranial irradiation. Discontinuation of methotrexate does not always result in complete recovery. A transient acute neurologic syndrome has been observed in patients treated with high-dose regimens. Manifestations of this stroke-like encephalopathy may include confusion, hemiparesis, transient blindness, seizures and coma. The exact cause is unknown. After the intrathecal use of methotrexate, the central nervous system toxicity which may occur can be classified as follows: acute chemical arachnoiditis manifested by such symptoms as headache, back pain, nuchal rigidity, and fever; sub-acute myelopathy characterized by paraparesis/paraplegia associated with involvement with one or more spinal nerve roots; chronic leukoencephalopathy manifested by confusion, irritability, somnolence, ataxia, dementia, seizures and coma. This condition can be progressive and even fatal. w434140v03 Page 11 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pulmonary: Pulmonary symptoms (especially a dry nonproductive cough) or a non-specific pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages. Renal: Methotrexate may cause renal damage that may lead to acute renal failure. High doses of methotrexate used in the treatment of osteosarcoma may cause renal damage leading to acute renal failure. Nephrotoxicity is due primarily to the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. Close attention to renal function including adequate hydration, urine alkalinization and measurement of serum methotrexate and creatinine levels are essential for safe administration. Skin: Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens- Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases. Other precautions: Methotrexate should be used with extreme caution in the presence of debility. Methotrexate exits slowly from third space compartments (e.g., pleural effusions or ascites). This results in a prolonged terminal plasma half-life and unexpected toxicity. In patients with significant third space accumulations, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be “recalled” by the use of methotrexate. ADVERSE REACTIONS IN GENERAL, THE INCIDENCE AND SEVERITY OF ACUTE SIDE EFFECTS ARE RELATED TO DOSE AND FREQUENCY OF ADMINISTRATION. THE MOST SERIOUS REACTIONS ARE DISCUSSED ABOVE UNDER ORGAN SYSTEM TOXICITY IN THE PRECAUTION SECTION. THAT SECTION SHOULD ALSO BE CONSULTED WHEN LOOKING FOR INFORMATION ABOUT ADVERSE REACTIONS WITH METHOTREXATE. The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. Other adverse reactions that have been reported with methotrexate are listed below by organ system. In the oncology setting, concomitant treatment and the underlying disease make specific attribution of a reaction to methotrexate difficult. Alimentary System: gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis. Blood and Lymphatic System Disorders: suppressed hematopoiesis, anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, agranulocytosis, eosinophilia, lymphadenopathy and lymphoproliferative disorders (including reversible). Hypogammaglobulinemia has been reported rarely. Cardiovascular: pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus). w434140v03 Page 12 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Central Nervous System: headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions have also occurred following administration of methotrexate. Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration or unusual cranial sensations, leukoencephalopathy, or encephalopathy. Hepatobiliary Disorders: hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, hepatic failure, decrease in serum albumin, liver enzyme elevations. Infection: There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis carinii pneumonia was the most common opportunistic infection. There have also been reports of infections, pneumonia, Cytomegalovirus infection, including cytomegaloviral pneumonia, sepsis, fatal sepsis, nocardiosis; histoplasmosis, cryptococcosis, Herpes zoster, H. simplex hepatitis, and disseminated H. simplex. Musculoskeletal System: stress fracture. Ophthalmic: conjunctivitis, serious visual changes of unknown etiology. Pulmonary System: respiratory fibrosis, respiratory failure, alveolitis, interstitial pneumonitis deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred. Skin: erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration and exfoliative dermatitis. Urogenital System: severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal death, fetal defects. Other rarer reactions related to or attributed to the use of methotrexate such as nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, lymphoma, including reversible lymphomas, tumor lysis syndrome, soft tissue necrosis and osteonecrosis. Anaphylactoid reactions have been reported. Adverse Reactions in Double-Blind Rheumatoid Arthritis Studies The approximate incidences of methotrexate-attributed (i.e. placebo rate subtracted) adverse reactions in 12 to 18 week double-blind studies of patients (n=128) with rheumatoid arthritis treated with low-dose oral (7.5 to 15 mg/week) pulse methotrexate, are listed below. Virtually all of these patients were on concomitant nonsteroidal anti-inflammatory drugs and some were also taking low dosages of corticosteroids. Hepatic histology was not examined in these short-term studies. (See PRECAUTIONS). Incidence greater than 10%: Elevated liver function tests 15%, nausea/vomiting 10%. Incidence 3% to 10%: Stomatitis, thrombocytopenia (platelet count less than 100,000/mm3). Incidence 1% to 3%: Rash/pruritis/dermatitis, diarrhea, alopecia, leukopenia (WBC less than 3000/mm3), pancytopenia, dizziness. Two other controlled trials of patients (n=680) with Rheumatoid Arthritis on 7.5 mg to 15 mg/wk oral doses showed an incidence of interstitial pneumonitis of 1%. (See PRECAUTIONS.) Other less common reactions included decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistatix, fever, infection, sweating, tinnitus, and vaginal discharge. w434140v03 Page 13 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Reactions in Psoriasis: There are no recent placebo-controlled trials in patients with psoriasis. There are two literature reports (Roenigk, 1969, and Nyfors, 1978) describing large series (n=204, 248) of psoriasis patients treated with methotrexate. Dosages ranged up to 25 mg per week and treatment was administered for up to four years. With the exception of alopecia, photosensitivity, and “burning of skin lesions” (each 3% to 10%), the adverse reaction rates in these reports were very similar to those in the rheumatoid arthritis studies. Rarely, painful plaque erosions may appear (Pearce, HP and Wilson, BB: Am Acad Dermatol 35: 835-838, 1996). Adverse Reactions in JRA Studies The approximate incidences of adverse reactions reported in pediatric patients with JRA treated with oral, weekly doses of methotrexate (5 to 20 mg/m2/wk or 0.1 to 0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m2/wk in JRA, the published data for doses above 20 mg/m2/wk are too limited to provide reliable estimates of adverse reaction rates. OVERDOSAGE Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Leucovorin administration should begin as promptly as possible. As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin. In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Generally speaking, neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high- flux dialyzer (Wall, SM et al: Am J Kidney Dis 28 (6): 846-854, 1996). Accidental intrathecal overdosage may require intensive systemic support, high-dose systemic leucovorin, alkaline diuresis and rapid CSF drainage and ventriculolumbar perfusion. In postmarketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose have also been reported. Reports of oral overdose often indicate accidental daily administration instead of weekly (single or divided doses). Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and gastrointestinal reaction. For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anemia were also reported. Symptoms of intrathecal overdose are generally central nervous system (CNS) symptoms, including headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy. In some cases, no symptoms were reported. There have been reports of death following intrathecal overdose. In these cases, cerebellar herniation associated with increased intracranial pressure, and acute toxic encephalopathy have also been reported. Glucarpidase is indicated for the treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information). w434140v03 Page 14 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If glucarpidase is used, do not administer leucovorin within two hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase. There are published case reports of intravenous and intrathecal glucarpidase treatment to hasten clearance of methotrexate in cases of overdose. DOSAGE AND ADMINISTRATION Neoplastic Diseases For intrathecal and high-dose methotrexate therapy, use the preservative-free formulation of methotrexate. Do not use the preserved formulation of methotrexate for intrathecal or high-dose therapy because it contains benzyl alcohol. Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained. Methotrexate injection may be given by the intramuscular, intravenous or intra-arterial route. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Choriocarcinoma and similar trophoblastic diseases: Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course. Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalization of hCG is usually recommended. Before each course of the drug careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful. Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended. Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole. Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma. Leukemia: Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common. Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions. When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen. w434140v03 Page 15 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in antileukemic therapy. Meningeal Leukemia: In the treatment of prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally. Dilute preservative free methotrexate to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP. The cerebrospinal fluid volume is dependent on age and not on body surface area. The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years. Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults. The following dosage regimen is based on age instead of body surface area: AGE (years) DOSE (mg) <1 6 1 8 2 10 3 or older 12 In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age. Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients. For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days. However, administration at intervals of less than 1 week may result in increased subacute toxicity. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal. At this point one additional dose is advisable. For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration. On this subject, it is advisable for the physician to consult the medical literature. Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character. Large doses may cause convulsions. Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity. Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced or discontinued. Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy. Lymphomas: In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases. Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days. In Stage III, methotrexate is commonly given concomitantly with other antitumor agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods. Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily. w434140v03 Page 16 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Mycosis fungoides (cutaneous T cell lymphoma): Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated. Dosage in early stages is usually 5 to 50 mg once weekly. Dose reduction or cessation is guided by patient response and hematologic monitoring. Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy. Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in advanced stages of the disease. Osteosarcoma: An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents. In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below. The starting dose for high-dose methotrexate treatment is 12 grams/m2. If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments. If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule. Drug* Dose* Treatment Week After Surgery Methotrexate Leucovorin 12 g/m2 IV as 4 hour infusion (starting dose) 15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion 4,5,6,7,11,12,15,16,29,30,44,45 - - - Doxorubicin† as a single drug 30 mg/m2 day IV x 3 days 8,17 Doxorubicin† Cisplatin† 50 mg/m2 IV 100 mg/m2 IV 20,23,33,36 20,23,33,36 Bleomycin† Cyclophosphamide† Dactinomycin† 15 units/m2 IV x 2 days 600 mg/m2 IV x 2 days 0.6 mg/m2 IV x 2 days 2,13,26,39,42 2,13,26,39,42 2,13,26,39,42 * Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314 (No.25): 1600-1606. † See each respective package insert for full prescribing information. Dosage modifications may be necessary because of drug-induced toxicity. When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed. GUIDELINES FOR METHOTREXATE THERAPY WITH LEUCOVORIN RESCUE 1. Administration of methotrexate should be delayed until recovery if: • the WBC count is less than 1500/microliter • the neutrophil count is less than 200/microliter • the platelet count is less than 75,000/microliter • the serum bilirubin level is greater than 1.2 mg/dL • the SGPT level is greater than 450 U • mucositis is present, until there is evidence of healing • persistent pleural effusion is present; this should be drained dry prior to infusion. 2. Adequate renal function must be documented. w434140v03 Page 17 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda a. Serum creatinine must be normal, and creatinine clearance must be greater than 60 mL/min, before initiation of therapy. b. Serum creatinine must be measured prior to each subsequent course of therapy. If serum creatinine has increased by 50% or more compared to a prior value, the creatinine clearance must be measured and documented to be greater than 60 mL/min (even if the serum creatinine is still within the normal range). 3. Patients must be well hydrated, and must be treated with sodium bicarbonate for urinary alkalinization. a. Administer 1,000 mL/m2 of intravenous fluid over 6 hours prior to initiation of the methotrexate infusion. Continue hydration at 125 mL/m2/hr (3 liters/m2/day) during the methotrexate infusion, and for 2 days after the infusion has been completed. b. Alkalinize urine to maintain pH above 7.0 during methotrexate infusion and leucovorin calcium therapy. This can be accomplished by the administration of sodium bicarbonate orally or by incorporation into a separate intravenous solution. 4. Repeat serum creatinine and serum methotrexate 24 hours after starting methotrexate and at least once daily until the methotrexate level is below 5 x 10-8 mol/L (0.05 micromolar). 5. The table below provides guidelines for leucovorin calcium dosage based upon serum methotrexate levels. (See table below.‡) Patients who experience delayed early methotrexate elimination are likely to develop nonreversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent hemodialysis with a high-flux dialyzer may also be beneficial in these patients. 6. Some patients will have abnormalities in methotrexate elimination, or abnormalities in renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table below. These abnormalities may or may not be associated with significant clinical toxicity. If significant toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate binding to serum albumin, or elimination) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed. CAUTION: DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY. Psoriasis, Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis Adult Rheumatoid Arthritis: Recommended Starting Dosage Schedules 1. Single oral doses of 7.5 mg once weekly.† 2. Divided oral dosages of 2.5 mg at 12 hour intervals for 3 doses given as a course once weekly.† † Methotrexate Sodium Tablets for oral administration are available. Polyarticular-Course Juvenile Rheumatoid Arthritis: The recommended starting dose is 10 mg/m2 given once weekly. For either adult RA or polyarticular-course JRA, dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m2/wk in children, there are too few published data to assess how doses over 20 mg/m2/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk (0.65 to 1.0 mg/kg/wk) may have better absorption w434140v03 Page 18 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously. Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more. The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks. The patient should be fully informed of the risks involved and should be under constant supervision of the physician. (See Information for Patients under PRECAUTIONS). Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy. (See PRECAUTIONS). Appropriate steps should be taken to avoid conception during methotrexate therapy. (See PRECAUTIONS and CONTRAINDICATIONS). All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects (See ADVERSE REACTIONS). Maximal myelosuppression usually occurs in seven to ten days. Psoriasis: Recommended Starting Dose Schedule: 1. Weekly single oral, IM or IV dosage schedule: 10 to 25 mg per week until adequate response is achieved.† 2. Divided oral dose schedule 2.5 mg at 12 hour intervals for three doses.† †Methotrexate Sodium Tablets for oral administration are available. Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded. Once optimal clinical response has been achieved, each dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged. HANDLING AND DISPOSAL Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. DILUTION INSTRUCTIONS FOR LIQUID METHOTREXATE INJECTION PRODUCT Methotrexate Injection, USP, Isotonic Liquid, Preservative Free, for Single Use Only If desired, the solution may be further diluted immediately prior to use with an appropriate sterile, preservative free medium such as 5% Dextrose Solution, USP or Sodium Chloride Injection, USP. HOW SUPPLIED Parenteral: Methotrexate Injection, USP, Isotonic Liquid, Preservative Free, for Single Use Only. Each 25 mg/mL, 40 mL vial contains methotrexate sodium equivalent to 1 g methotrexate. 1 g, 40 mL Vial NDC 61703-408-41 Store at controlled room temperature, 20 to 25°C (68 to 77°F) [see USP Controlled Room Temperature]; excursions permitted to 15° to 30°C (59° to 86°F). PROTECT FROM LIGHT. w434140v03 Page 19 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 434140 Hospira, Inc. Lake Forest, IL 60045 USA Product of Australia Revised: 11/2014 company logo w434140v03 Page 20 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ‡LEUCOVORIN RESCUE SCHEDULES FOLLOWING TREATMENT WITH HIGHER DOSES OF METHOTREXATE Clinical Situation Normal Methotrexate Elimination Delayed Late Methotrexate Elimination Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury Laboratory Findings Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours. Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration. Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration, (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more). Leucovorin Dosage and Duration 15 mg PO, IM, or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). Continue 15 mg PO, IM, or IV q six hours, until methotrexate level is less than 0.05 micromolar. 150 mg IV q three hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q three hours until methotrexate level is less than 0.05 micromolar. REFERENCES 1. Controlling Occupation Exposure to Hazardous Drugs (OSHA Work-Practice Guidelines). Am J Health Syst Pharma 1996: 53:1669-1685. 2. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83 2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402. 3. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA,1985; 253(11):1590-1592. 4. National Study Commission on Cytotoxic Exposure-Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115. 5. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1:426-428. 6. Jones RB, et al. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. Ca- A Cancer Journal for Clinicians Sept/Oct 1983; 258-263. 7. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033-1049. w434140v03 Page 21 of 21 Reference ID: 3850228 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:46.074858	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/011719s122lbl.pdf', 'application_number': 11719, 'submission_type': 'SUPPL ', 'submission_number': 122}
10,777	Depo-Medrol® methylprednisolone acetate injectable suspension, USP NOT FOR USE IN NEONATES CONTAINS BENZYL ALCOHOL Not For Intravenous Use DESCRIPTION DEPO-MEDROL is an anti-inflammatory glucocorticoid for intramuscular, intra-articular, soft tissue or intralesional injection. It is available in three strengths: 20 mg/mL; 40 mg/mL; 80 mg/mL. Each mL of these preparations contains: Methylprednisolone acetate..................................20 mg Polyethylene glycol 3350.....................................29.5 mg Polysorbate 80 .....................................................1.97 mg Monobasic sodium phosphate ...............................6.9 mg Dibasic sodium phosphate USP...........................1.44 mg Benzyl alcohol added as a preservative...................9.3 mg 40 mg 29.1 mg 1.94 mg 6.8 mg 1.42 mg 9.16 mg 80 mg 28.2 mg 1.88 mg 6.59 mg 1.37 mg 8.88 mg Sodium Chloride was added to adjust tonicity. When necessary, pH was adjusted with sodium hydroxide and/or hydrochloric acid. The pH of the finished product remains within the USP specified range; e.g., 3.5 to 7.0. The chemical name for methylprednisolone acetate is pregna-1,4-diene-3,20-dione, 21 (acetyloxy)-11,17-dihydroxy-6-methyl-,(6α,11ß)-and the molecular weight is 416.51. The Structural Formula DEPO-MEDROL Sterile Aqueous Suspension contains methylprednisolone acetate which is the 6-methyl derivative of prednisolone. Methylprednisolone acetate is a white or practically white, odorless, crystalline powder which melts at about 215° with some decomposition. It is soluble in dioxane, sparingly soluble in acetone, in alcohol, in chloroform, and in methanol, and slightly soluble in ether. It is practically insoluble in water. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol/S-085 Label Page 2 CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic are adrenocortical steroids. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt retaining properties, are used in replacement therapy in adrenocortical deficiency states. Their synthetic analogs are used primarily for their anti-inflammatory effects in disorders of many organ systems. Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body’s immune response to diverse stimuli. INDICATIONS AND USAGE A. For Intramuscular Administration When oral therapy is not feasible and the strength, dosage form, and route of administration of the drug reasonably lend the preparation to the treatment of the condition, the intramuscular use of DEPO-MEDROL Sterile Aqueous Suspension is indicated as follows: Allergic States: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, seasonal or perennial allergic rhinitis, serum sickness, transfusion reactions. Dermatologic Diseases: Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome). Endocrine Disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance) congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative thyroiditis. Gastrointestinal Diseases: To tide the patient over a critical period of the disease in regional enteritis (systemic therapy), ulcerative colitis. Hematologic Disorders: Acquired (autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia ( Diamond blackfan anemia), pure red cell aplasia, select cases of secondary thrombocytopenia. Miscellaneous: Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy. Neoplastic Diseases: For palliative management of leukemias and lymphomas. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol/S-085 Label Page 3 Nervous System: Acute exacerbations of multiple sclerosis. Cerebral edema associated with primary or metastatic brain tumor or craniotomy. Ophthalmic Diseases: Sympathetic ophthalmia, temporal arteritis, Uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids. Renal Diseases: To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome, or that due to lupus erythematosus. Respiratory Diseases: Berylliosis, symptomatic sarcoidosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis. Rheumatic Disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus. B. FOR INTRA-ARTICULAR OR SOFT TISSUE ADMINISTRATION (See WARNINGS) DEPO-MEDROL is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis. C. FOR INTRALESIONAL ADMINISTRATION DEPO-MEDROL is indicated for intralesional use in alopecia areata, discoid lupus erythematosus, keloids, localized hypertrophic, infiltrated, inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), and psoriatic plaques, necrobiosis lipoidica diabeticorum. DEPO-MEDROL also may be useful in cystic tumors of an aponeurosis or tendon (ganglia). CONTRAINDICATIONS DEPO-MEDROL is contraindicated in patients with known hypersensitivity to the product and its constituents. Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. DEPO-MEDROL Sterile Aqueous Suspension is contraindicated for intrathecal administration. Reports of severe medical events have been associated with this route of administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol/S-085 Label Page 4 DEPO-MEDROL is contraindicated for use in premature infants because the formulation contains benzyl alcohol. (See WARNINGS and PRECAUTIONS:Pediatric Use) DEPO-MEDROL is contraindicated in systemic fungal infections, except when administered as an intra-articular injection for localized joint conditions (see WARNINGS, Infections, Fungal Infections) WARNINGS General This product contains benzyl alcohol which is potentially toxic when administered locally to neural tissue. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see PRECAUTIONS: Pediatric Use) Multidose use of DEPO-MEDROL Sterile Aqueous Suspension from a single vial requires special care to avoid contamination. Although initially sterile, any multidose use of vials may lead to contamination unless strict aseptic technique is observed. Particular care, such as use of disposable sterile syringes and needles is necessary. Injection of Depo-Medrol may result in dermal and/or subdermal changes forming depressions in the skin at the injection site. In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Multiple small injections into the area of the lesion should be made whenever possible. The technique of intra-articular and intramuscular injection should include precautions against injection or leakage into the dermis. Injection into the deltoid muscle should be avoided because of a high incidence of subcutaneous atrophy. It is critical that, during administration of DEPO-MEDROL, appropriate technique be used and care taken to assure proper placement of drug. Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy. (see ADVERSE REACTIONS) Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, or after the stressful situation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol/S-085 Label Page 5 Results from one multicenter, randomized, placebo controlled study with methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of systemic corticosteroids, including DEPO MEDROL, should not be used for the treatment of traumatic brain injury. Cardio-renal Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Literature reports suggest an apparent association between the use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. Endocrine Hypothalamic-pituitary adrenal (HPA) axis suppression. Cushing’s syndrome, and hyperglycemia. Monitor patients for these conditions with chronic use. Corticosteroids can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Drug induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Infections General Persons who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infections with any pathogen (viral, fungal, protozoan, or helminthic), in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild, but can be severe and at times fatal. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may mask some signs of current infection. Do not use intra-articularly, intrabursally or for intratendinous administration for local effect in the presence of acute local infection. Fungal Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions, Amphotericin B injections and potassium depleting agents) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol/S-085 Label Page 6 Special pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, Taxoplasma. It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea. Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Stronglyoides hyperinfection and dissemination with wide spread larval migration, often accompanied by severe entercolitis and potentially fatal gram- negative septicemia. Corticosteroids should not be used in cerebral malaria. There is currently no evidence of benefit from steroids in this condition. Tuberculosis The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. Vaccinations Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines can not be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids, as replacement therapy, e.g. for Addison’s disease. Viral Infections Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents should be considered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol/S-085 Label Page 7 Ophthalmic Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi or viruses. The use of systemic corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should be used cautiously in patients with active ocular herpes simplex because of corneal perforation. Corticosteroids should not be used in active ocular herpes simplex. PRECAUTIONS General When multidose vials are used, special care to prevent contamination of the contents is essential. A povidone-iodine solution or similar product is recommended to cleanse the vial top prior to aspiration of contents. (See WARNINGS) This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the outside of the vial. The lowest possible dose of corticosteroid should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual. Since complications of treatment with glucocorticosteroids are dependent on the size of the dose and duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement. Cardio-renal As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency. Endocrine Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineral corticosteroid secretion may be impaired, salt and/or a mineral corticosteroid should be administered concurrently. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol/S-085 Label Page 8 Gastrointestinal Steroids should be used in caution in active or latent peptic ulcer, diverticulitis, fresh intestinal anastomoses, and non-specific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect due to increased metabolism of corticosteroids in patients with cirrhosis. Parenteral Administration Intra-articular injected corticosteroids may be systemically absorbed. Appropriate examination of any joint fluid is necessary to exclude a septic process. A marked increase in pain associated by local swelling, further restriction of joint motion, fever, malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted. Injection of a steroid into an infected site is to be avoided. Local injection of a steroid into a previously infected joint is not usually recommended. Musculoskeletal Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (e.g., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age (e.g., postmenopausal women) before initiating corticosteroid therapy. Neuro-psychiatric Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that corticosteroids affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. (See DOSAGE AND ADMINISTRATION) An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may results in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol/S-085 Label Page 9 Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Ophthalmic Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored. Corticosteroids should be used cautiously in patients with ocular herpes simplex for fear of corneal perforation. Information for the Patient Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay. DRUG INTERACTIONS: Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B injection and potassium- depleting agents: When corticosteroids are administered concomitantly with potassium-depleting agents (e.g., amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause significant decrease in corticosteroid clearance (see DRUG INTERACTIONS, Hepatic Enzyme Inhibitors) Anticholinesterases: Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. Anticoagulants, oral: Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol/S-085 Label Page 10 Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Cholestyramine: Cholestyramine may increase the clearance of oral corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with concurrent use. Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin): Drugs which induce cytochrome P450 3A4 enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of corticosteroid be increased. Hepatic Enzyme Inhibitors (e.g., ketoconazole, macrolide antibiotics such as erythromycin and troleandomycin): Drugs which inhibit cytochrome P450 3A4 have the potential to result in increased plasma concentrations of corticosteroids. Ketoconazole: Ketoconazole has been reported to significantly decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Non-steroidal anti-inflammatory agents (NSAIDs): Concomitant use of aspirin (or other non steroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side- effects. Aspirin should be used cautiously in conjunction with concurrent use of corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. Skin Tests: Corticosteroids may suppress reactions to skin tests. Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or attenuated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS, Infections, Vaccinations) Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol/S-085 Label Page 11 Pregnancy: Teratogenic effects: Pregnancy Category C Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits, have yielded an increase incidence of cleft palate in the off-spring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. Nursing Mothers Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to continue nursing, or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use This product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. The efficacy and safety of corticosteroids in the pediatric population are based on the well- established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephritic syndrome (patients >2 years of age), and aggressive lymphomas and leukemias (patients >1 month of age). Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are based on adequate and well-controlled clinical trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol/S-085 Label Page 12 ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression (e.g., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the ability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS The following adverse reactions have been reported with Depo-Medrol or other corticosteroids: Allergic reactions: Allergic or hypersensitivity reactions, anaphylactoid reaction, anaphylaxis, angioedema. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopthy in premature infants, myocardial rupture following recent mycocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increase sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients. Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, Fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol/S-085 Label Page 13 Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzymes levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible subsequent perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic: Negative nitrogen balance due to protein catabolism. Musculoskeletal: Aseptic necrosis of femoral and humeral heads, calcinosis (following intra- articular or intra-lesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Ophthalmic: Exophthalmoses, glaucoma, increased intraocular pressure, posterior subcapsular cataracts. Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, injection site infections following non-sterile administration (see WARNINGS), malaise, moon face, weight gain. The following adverse reactions have been reported with the following routes of administration: Intrathecal/Epidural: Arachnoiditis, bowel/bladder dysfunction, headache, meningitis, parapareisis/paraplegia, seizures, sensory disturbances. Intranasal: Allergic reactions, rhinitis, temporary/permanent visual impairment including blindness. Ophthalmic: Increased intraocular pressure, infection, ocular and periocular inflammation including allergic reactions, residue or slough at injection site, temporary/permanent visual impairment including blindness. Miscellaneous injection sites: (scalp, tonsillar fauces, sphenopalatine ganglion): Blindness. OVERDOSAGE Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol/S-085 Label Page 14 DOSAGE AND ADMINISTRATION NOTE: CONTAINS BENZYL ALCOHOL (see WARNINGS and PRECAUTIONS: Pediatric Use) Because of possible physical incompatibilities, DEPO-MEDROL Sterile Aqueous Suspension should not be diluted or mixed with other solutions. The initial dosage of parenterally administered DEPO-MEDROL will vary from 4 to 120 mg depending on the specific disease entity being treated. However, in certain overwhelming, acute, life-threatening situations, administrations in dosages exceeding the usual dosages may be justified and may be in multiples of the oral doses. It Should Be Emphasized that Dosage Requirements are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient. After a favorable response is noted, the proper maintenance dose should be determined by decreasing the initial drug dosage in small increments at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient’s condition. If after long term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly. A. Administration for Local Effect Therapy with DEPO-MEDROL does not obviate the need for the conventional measures usually employed. Although this method of treatment will ameliorate symptoms, it is in no sense a cure and the hormone has no effect on the cause of the inflammation. 1. Rheumatoid and Osteoarthritis. The dose for intra-articular administration depends upon the size of the joint and varies with the severity of the condition in the individual patient. In chronic cases, injections may be repeated at intervals ranging from one to five or more weeks depending upon the degree of relief obtained from the initial injection. The doses in the following table are given as a general guide: Size of Joint Examples Range of Dosage Knees Large Ankles 20 to 80 mg Shoulders Medium Elbows Wrists 10 to 40 mg Small Metacarpophalangeal Interphalangeal Sternoclavicular Acromioclavicular 4 to 10 mg This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol/S-085 Label Page 15 Procedure: It is recommended that the anatomy of the joint involved be reviewed before attempting intra-articular injection. In order to obtain the full anti-inflammatory effect it is important that the injection be made into the synovial space. Employing the same sterile technique as for a lumbar puncture, a sterile 20 to 24 gauge needle (on a dry syringe) is quickly inserted into the synovial cavity. Procaine infiltration is elective. The aspiration of only a few drops of joint fluid proves the joint space has been entered by the needle. The injection site for each joint is determined by that location where the synovial cavity is most superficial and most free of large vessels and nerves. With the needle in place, the aspirating syringe is removed and replaced by a second syringe containing the desired amount of DEPO-MEDROL. The plunger is then pulled outward slightly to aspirate synovial fluid and to make sure the needle is still in the synovial space. After injection, the joint is moved gently a few times to aid mixing of the synovial fluid and the suspension. The site is covered with a small sterile dressing. Suitable sites for intra-articular injection are the knee, ankle, wrist, elbow, shoulder, phalangeal, and hip joints. Since difficulty is not infrequently encountered in entering the hip joint, precautions should be taken to avoid any large blood vessels in the area. Joints not suitable for injection are those that are anatomically inaccessible such as the spinal joints and those like the sacroiliac joints that are devoid of synovial space. Treatment failures are most frequently the result of failure to enter the joint space. Little or no benefit follows injection into surrounding tissue. If failures occur when injections into the synovial spaces are certain, as determined by aspiration of fluid, repeated injections are usually futile. If a local anesthetic is used prior to injection of DEPO-MEDROL, the anesthetic package insert should be read carefully and all the precautions observed. 2. Bursitis. The area around the injection site is prepared in a sterile way and a wheal at the site made with 1 percent procaine hydrochloride solution. A 20 to 24 gauge needle attached to a dry syringe is inserted into the bursa and the fluid aspirated. The needle is left in place and the aspirating syringe changed for a small syringe containing the desired dose. After injection, the needle is withdrawn and a small dressing applied. 3. Miscellaneous: Ganglion, Tendinitis, Epicondylitis. In the treatment of conditions such as tendinitis or tenosynovitis, care should be taken, following application of a suitable antiseptic to the overlying skin, to inject the suspension into the tendon sheath rather than into the substance of the tendon. The tendon may be readily palpated when placed on a stretch. When treating conditions such as epicondylitis, the area of greatest tenderness should be outlined carefully and the suspension infiltrated into the area. For ganglia of the tendon sheaths, the suspension is injected directly into the cyst. In many cases, a single injection causes a marked decrease in the size of the cystic tumor and may effect disappearance. The usual sterile precautions should be observed, of course, with each injection. The dose in the treatment of the various conditions of the tendinous or bursal structures listed above varies with the condition being treated and ranges from 4 to 30 mg. In recurrent or chronic conditions, repeated injections may be necessary. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol/S-085 Label Page 16 4. Injections for Local Effect in Dermatologic Conditions. Following cleansing with an appropriate antiseptic such as 70% alcohol, 20 to 60 mg of the suspension is injected into the lesion. It may be necessary to distribute doses ranging from 20 to 40 mg by repeated local injections in the case of large lesions. Care should be taken to avoid injection of sufficient material to cause blanching since this may be followed by a small slough. One to four injections are usually employed, the intervals between injections varying with the type of lesion being treated and the duration of improvement produced by the initial injection. When multidose vials are used, special care to prevent contamination of the contents is essential. (See WARNINGS) B. Administration for Systemic Effect. The intramuscular dosage will vary with the condition being treated. When employed as a temporary substitute for oral therapy, a single injection during each 24-hour period of a dose of the suspension equal to the total daily oral dose of MEDROL® Tablets (methylprednisolone tablets, USP) is usually sufficient. When a prolonged effect is desired, the weekly dose may be calculated by multiplying the daily oral dose by 7 and given as a single intramuscular injection. In pediatric patients, the initial dose of methylprednisolone may vary depending upon the specific disease entity being treated. The range of initial doses is 0.11 to 1.6 mg/kg/day. Dosage must be individualized according to the severity of the disease and response of the patient. In patients with the adrenogenital syndrome, a single intramuscular injection of 40 mg every two weeks may be adequate. For maintenance of patients with rheumatoid arthritis, the weekly intramuscular dose will vary from 40 to 120 mg. The usual dosage for patients with dermatologic lesions benefited by systemic corticoid therapy is 40 to 120 mg of methylprednisolone acetate administered intramuscularly at weekly intervals for one to four weeks. In acute severe dermatitis due to poison ivy, relief may result within 8 to 12 hours following intramuscular administration of a single dose of 80 to 120 mg. In chronic contact dermatitis repeated injections at 5 to 10 day intervals may be necessary. In seborrheic dermatitis, a weekly dose of 80 mg may be adequate to control the condition. Following intramuscular administration of 80 to 120 mg to asthmatic patients, relief may result within 6 to 48 hours and persist for several days to two weeks. Similarly in patients with allergic rhinitis (hay fever) an intramuscular dose of 80 to 120 mg may be followed by relief of coryzal symptoms within six hours persisting for several days to three weeks. If signs of stress are associated with the condition being treated, the dosage of the suspension should be increased. If a rapid hormonal effect of maximum intensity is required, the intravenous administration of highly soluble methylprednisolone sodium succinate is indicated. In treatment of acute exacerbations of multiple sclerosis daily doses of 160 mg of methylprednisolone for a week followed by 64 mg every other day for 1 month have been shown to be effective. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol/S-085 Label Page 17 For the purpose of comparison, the following is the equivalent milligram dose of the various glucocorticoids: Cortisone, 25 Triamcinolone, 4 Hydrocortisone, 20 Paramethasone, 2 Prednisolone, 5 Netamethasone, 0.75 Prednisone, 5 Dexamethasone, 0.75 Methylprednisolone, 4 Those dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered. HOW SUPPLIED DEPO-MEDROL Sterile Aqueous Suspension is available in the following strengths and package sizes: 20 mg per mL 5 mL multidose vials NDC 0009-0274-01 40 mg per mL 5 mL multidose vials NDC 0009-0280-02 25 x 5 mL multidose vials NDC 0009-0280-51 10 mL multidose vials NDC 0009-0280-03 25 x 10 mL multidose vials NDC 0009-0280-52 80 mg per mL 5 mL multidose vials NDC 0009-0306-02 25 x 5 mL multidose vials NDC 0009-0306-12 Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Rx only LAB-0159-2.2 Revised May 2008 Pfizer logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol S-086 Label Page 1 Depo-Medrol® methylprednisolone acetate injectable suspension, USP Single-Dose Vial Not For Intravenous Use DESCRIPTION DEPO-MEDROL is an anti-inflammatory glucocorticoid for intramuscular, intra-articular, soft tissue or intralesional injection. It is available as single-dose vials in two strengths: 40 mg/mL; 80 mg/mL. Each mL of these preparations contains: Methylprednisolone acetate ...........................................40 mg ............80 mg Polyethylene glycol 3350 ..............................................29 mg ............28 mg Myristyl-gamma-picolinium chloride............................0.195 mg .......0.189 mg Sodium Chloride was added to adjust tonicity. When necessary, pH was adjusted with sodium hydroxide and/or hydrochloric acid. The pH of the finished product remains within the USP specified range; e.g., 3.5 to 7.0. The chemical name for methylprednisolone acetate is pregna-1,4-diene-3,20-dione, 21 (acetyloxy)-11,17-dihydroxy-6-methyl-,(6α,11β)-and the molecular weight is 416.51. The structural formula is represented below: Chemical Structure DEPO-MEDROL Sterile Aqueous Suspension contains methylprednisolone acetate which is the 6 methyl derivative of prednisolone. Methylprednisolone acetate is a white or practically white, odorless, crystalline powder which melts at about 215° with some decomposition. It is soluble in dioxane, sparingly soluble in acetone, in alcohol, in chloroform, and in methanol, and slightly soluble in ether. It is practically insoluble in water. CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol S-086 Label Page 2 Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt retaining properties, are used in replacement therapy in adrenocortical deficiency states. Their synthetic analogs are used primarily for their anti-inflammatory effects in disorders of many organ systems. INDICATIONS AND USAGE A. For Intramuscular Administration When oral therapy is not feasible and the strength, dosage form, and route of administration of the drug reasonably lend the preparation to the treatment of the condition, the intramuscular use of DEPO-MEDROL Sterile Aqueous Suspension is indicated as follows: Allergic States: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, seasonal or perennial allergic rhinitis, serum sickness, transfusion reactions. Dermatologic Diseases: Bullous dermatitis herpetiformis, exfoliative dermatitis mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome). Endocrine Disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance), congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsupportive thyroiditis. Gastrointestinal Diseases: To tide the patient over a critical period of the disease in regional enteritis (systemic therapy), ulcerative colitis. Hematologic Disorders: Acquired (autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia ( Diamond blackfan anemia), pure red cell aplasia, select cases of secondary thrombocytopenia. Miscellaneous: Trichinosis with neurologic or myocardial involvement tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy. Neoplastic Diseases: For palliative management of: leukemias and lymphomas. Nervous System: Acute exacerbations of multiple sclerosis. Cerebral edema associated with primary or metastatic brain tumor or craniotomy. Ophthalmic Diseases: Sympathetic opthalmia, temporal arteritis, uveitis, and ocular inflammatory conditions unresponsive to topical corticosteroids. Renal Diseases: To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome, or that due to lupus erythematosus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol S-086 Label Page 3 Respiratory Diseases: Berylliosis, symptomatic sarcoidosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis. Rheumatic Disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus. B. For Intra-articular Or Soft Tissue Administration (See WARNINGS) DEPO-MEDROL is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis. C. For Intralesional Administration DEPO-MEDROL is indicated for intralesional use in alopecia areata, discoid lupus erythematosus; keloids, localized hypertrophic, infiltrated inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis) and psoriatic plaques; necrobiosis lipoidica diabeticorum. DEPO-MEDROL also may be useful in cystic tumors of an aponeurosis or tendon (ganglia). CONTRAINDICATIONS DEPO-MEDROL is contraindicated in patients with known hypersensitivity to the product and its constituents. Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. DEPO-MEDROL is contraindicated for intrathecal administration. This formulation of methylprednisolone acetate has been associated with reports of severe medical events when administered by this route. DEPO-MEDROL is contraindicated in systemic fungal infections, except when administered as an intra-articular injection for localized joint conditions (see WARNINGS, Infections, Fungal Infections) WARNINGS General This product is not suitable for multi-dose use. Following administration of the desired dose, any remaining suspension should be discarded. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol S-086 Label Page 4 Injection of Depo-Medrol may result in dermal and/or subdermal changes forming depressions in the skin at the injection site. In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Multiple small injections into the area of the lesion should be made whenever possible. The technique of intra-articular and intramuscular injection should include precautions against injection or leakage into the dermis. Injection into the deltoid muscle should be avoided because of a high incidence of subcutaneous atrophy. It is critical that, during administration of DEPO-MEDROL, appropriate technique be used and care taken to assure proper placement of drug. Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS) Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, and after the stressful situation. Results from one multicenter, randomized, placebo controlled study with methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of systemic corticosteroids, including DEPO MEDROL, should not be used for the treatment of traumatic brain injury. Cardio-renal Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with synthetic derivatives when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. Endocrine Hypothalamic-pituitary adrenal (HPA) axis suppression. Cushing’s syndrome, and hyperglycemia. Monitor patients for these conditions with chronic use. Corticosteroids can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Drug induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol S-086 Label Page 5 Infections General Persons who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infections with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body, may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild, but can be severe and at times fatal. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Do not use intra articularly, intrabursally or for intratendinous administration for local affect in the presence of an acute infection. Corticosteroids may mask some signs of infection and new infections may appear during their use. Fungal Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug interactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions, Amphotericin B injections and potassium-depleting agents) Special Pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, and Toxoplasma. It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea. Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. Corticosteroids should not be used in cerebral malaria. There is currently no evidence of benefit from steroids in this condition. Tuberculosis The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol S-086 Label Page 6 If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary, as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. Vaccinations Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive does of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines ca not be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g. for Addison’s disease. Viral Infections Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated (See the respective package inserts for complete VZIG and IG prescribing information). If chicken pox develops, treatment with antiviral agents should be considered. Ophthalmic Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi or viruses. The use of systemic corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should be used cautiously in patients with active ocular herpes simplex because of corneal perforation. Corticosteroids should not be used in active ocular herpes simplex. PRECAUTIONS General This product, like many other corticosteroids, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. The lowest possible dose of corticosteroid should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual. Since complications of treatment with glucocorticosteroids are dependant on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment as to whether daily or intermittent therapy should be used. Karposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol S-086 Label Page 7 Cardio-renal As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, or renal insufficiency. Endocrine Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage. Gastrointestinal Steroids should be used with caution in active or latent peptic ulcer, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect due to decreased metabolism of corticosteroids in patients with cirrhosis. Parenteral Administration Intra-articularly injected corticosteroids may be systemically absorbed. Appropriate examination of any joint fluid present is necessary to exclude a septic process. A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted. Injection of a steroid into an infected site is to be avoided. Local injection of a steroid into a previously infected joint is not usually recommended. Musculoskeletal Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (e.g. decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to an inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol S-086 Label Page 8 consideration should be given to increased risk of osteoporosis (e.g. postmenopausal women) before initiating corticosteroid therapy. Neuro-psychiatric Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that corticosteroids affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect (see DOSAGE AND ADMINISTRATION) An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Ophthalmic Intraocular pressure may become elevated in some individuals. If steroid therapy is continued long-term, intraocular pressure should be monitored. Corticosteroids should be used cautiously in patients with ocular herpes simplex for fear of corneal perforation. Information for the Patient Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that are taking corticosteroids to seek medical advice at once should they develop a fever or other signs of infection. Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay. DRUG INTERACTIONS Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered concomitantly with potassium depleting agents (e.g., amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol S-086 Label Page 9 concomitant use of Amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance (see DRUG INTERACTIONS, Hepatic Enzyme Inhibitors) Anticholinesterases: Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. Anticoagulants, oral: Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. Antidiabetics: Because corticosteroids may increase blood glucose concentration, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Cholestyramine: Cholestyramine may increase the clearance of oral corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Digitalis glycosides: Patients on digitalis glycosides may be at risk of arrhythmias due to hypokalemia. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic Enzyme Inducers (e.g. barbiturates, phenytoin, carbamazepine, rifampin): Drugs which induce cytochrome P450 3A4 enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Hepatic Enzyme Inhibitors (e.g., ketoconazole, macrolide antibiotics such as erythromycin and troleandomycin): Drugs which inhibit cytochrome P450 3A4 have the potential to result in increased plasma concentrations of corticosteroids. Ketoconazole: Ketoconazole has been reported to significantly decrease the metabolism of certain corticosteroids by up to 60%,, leading to an increased risk of corticosteroid side effects. Non-steroidal anti-inflammatory agents (NSAIDs): Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol S-086 Label Page 10 Skin tests: Corticosteroids may suppress reactions to skin tests. Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS, Infections, Vaccination) Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy: Teratogenic effects: Pregnancy Category C Corticosteroids have been shown to be Teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increase incidence of cleft palate in the off-spring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadernalism. Nursing Mothers Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The efficacy and safety of corticosteroids in the pediatric population are based on the well- established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephritic syndrome (patients >2 years of age), and aggressive lymphomas and leukemias (patients >1 month of age). Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are based on adequate and well-controlled clinical trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol S-086 Label Page 11 route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression (e.g., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the ability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS The following adverse reactions have been reported with Depo-Medrol or other corticosteroids: Allergic reactions: Allergic or hypersensitivity reactions, anaphylactoid reaction, anaphylaxis, angioedema. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopthy in premature infants, myocardial rupture following recent mycocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increase sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients. Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, Fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol S-086 Label Page 12 Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzymes levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible subsequent perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic: Negative nitrogen balance due to protein catabolism. Musculoskeletal: Aseptic necrosis of femoral and humeral heads, calcinosis (following intra- articular or intra-lesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Ophthalmic: Exophthalmoses, glaucoma, increased intraocular pressure, posterior subcapsular cataracts. Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, injection site infections following non-sterile administration (see WARNINGS), malaise, moon face, weight gain. The following adverse reactions have been reported with the following routes of administration: Intrathecal/Epidural: Arachnoiditis, bowel/bladder dysfunction, headache, meningitis, parapareisis/paraplegia, seizures, sensory disturbances. Intranasal: Allergic reactions, rhinitis, temporary/permanent visual impairment including blindness. Ophthalmic: Increased intraocular pressure, infection, ocular and periocular inflammation including allergic reactions, residue or slough at injection site, temporary/permanent visual impairment including blindness. Miscellaneous injection sites: (scalp, tonsillar fauces, sphenopalatine ganglion): blindness OVERDOSAGE Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol S-086 Label Page 13 DOSAGE AND ADMINISTRATION Because of possible physical incompatibilities, DEPO-MEDROL Sterile Aqueous Suspension should not be diluted or mixed with other solutions. The initial dosage of parenterally administered DEPO-MEDROL will vary from 4 to 120 mg depending on the specific disease entity being treated. However, in certain overwhelming, acute, life-threatening situations, administrations in dosages exceeding the usual dosages may be justified and may be in multiples of the oral doses. It Should Be Emphasized that Dosage Requirements are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient. After a favorable response is noted, the proper maintenance dose should be determined by decreasing the initial drug dosage in small increments at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient’s condition. If after long term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly. A. Administration for Local Effect Therapy with DEPO-MEDROL does not obviate the need for the conventional measures usually employed. Although this method of treatment will ameliorate symptoms, it is in no sense a cure and the hormone has no effect on the cause of the inflammation. 1. Rheumatoid and Osteoarthritis. The dose for intra-articular administration depends upon the size of the joint and varies with the severity of the condition in the individual patient. In chronic cases, injections may be repeated at intervals ranging from one to five or more weeks depending upon the degree of relief obtained from the initial injection. The doses in the following table are given as a general guide: Size Examples Range of Joint of Dosage Knees Large Ankles 20 to 80 mg Shoulders Medium Elbows Wrists 10 to 40 mg Metacarpophalangeal Small Interphalangeal Sternoclavicular 4 to 10 mg Acromioclavicular This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol S-086 Label Page 14 Procedure: It is recommended that the anatomy of the joint involved be reviewed before attempting intra-articular injection. In order to obtain the full anti-inflammatory effect it is important that the injection be made into the synovial space. Employing the same sterile technique as for a lumbar puncture, a sterile 20 to 24 gauge needle (on a dry syringe) is quickly inserted into the synovial cavity. Procaine infiltration is elective. The aspiration of only a few drops of joint fluid proves the joint space has been entered by the needle. The injection site for each joint is determined by that location where the synovial cavity is most superficial and most free of large vessels and nerves. With the needle in place, the aspirating syringe is removed and replaced by a second syringe containing the desired amount of DEPO-MEDROL. The plunger is then pulled outward slightly to aspirate synovial fluid and to make sure the needle is still in the synovial space. After injection, the joint is moved gently a few times to aid mixing of the synovial fluid and the suspension. The site is covered with a small sterile dressing. Suitable sites for intra-articular injection are the knee, ankle, wrist, elbow, shoulder, phalangeal, and hip joints. Since difficulty is not infrequently encountered in entering the hip joint, precautions should be taken to avoid any large blood vessels in the area. Joints not suitable for injection are those that are anatomically inaccessible such as the spinal joints and those like the sacroiliac joints that are devoid of synovial space. Treatment failures are most frequently the result of failure to enter the joint space. Little or no benefit follows injection into surrounding tissue. If failures occur when injections into the synovial spaces are certain, as determined by aspiration of fluid, repeated injections are usually futile. If a local anesthetic is used prior to injection of DEPO-MEDROL, the anesthetic package insert should be read carefully and all the precautions observed. 2. Bursitis. The area around the injection site is prepared in a sterile way and a wheal at the site made with 1 percent procaine hydrochloride solution. A 20 to 24 gauge needle attached to a dry syringe is inserted into the bursa and the fluid aspirated. The needle is left in place and the aspirating syringe changed for a small syringe containing the desired dose. After injection, the needle is withdrawn and a small dressing applied. 3. Miscellaneous: Ganglion, Tendinitis, Epicondylitis. In the treatment of conditions such as tendinitis or tenosynovitis, care should be taken, following application of a suitable antiseptic to the overlying skin, to inject the suspension into the tendon sheath rather than into the substance of the tendon. The tendon may be readily palpated when placed on a stretch. When treating conditions such as epicondylitis, the area of greatest tenderness should be outlined carefully and the suspension infiltrated into the area. For ganglia of the tendon sheaths, the suspension is injected directly into the cyst. In many cases, a single injection causes a marked decrease in the size of the cystic tumor and may effect disappearance. The usual sterile precautions should be observed, of course, with each injection. The dose in the treatment of the various conditions of the tendinous or bursal structures listed above varies with the condition being treated and ranges from 4 to 30 mg. In recurrent or chronic conditions, repeated injections may be necessary. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol S-086 Label Page 15 4. Injections for Local Effect in Dermatologic Conditions. Following cleansing with an appropriate antiseptic such as 70% alcohol, 20 to 60 mg of the suspension is injected into the lesion. It may be necessary to distribute doses ranging from 20 to 40 mg by repeated local injections in the case of large lesions. Care should be taken to avoid injection of sufficient material to cause blanching since this may be followed by a small slough. One to four injections are usually employed, the intervals between injections varying with the type of lesion being treated and the duration of improvement produced by the initial injection. B. Administration for Systemic Effect The intramuscular dosage will vary with the condition being treated. When employed as a temporary substitute for oral therapy, a single injection during each 24-hour period of a dose of the suspension equal to the total daily oral dose of MEDROL® Tablets (methylprednisolone tablets, USP) is usually sufficient. When a prolonged effect is desired, the weekly dose may be calculated by multiplying the daily oral dose by 7 and given as a single intramuscular injection. In pediatric patients, the initial dose of methylprednisolone may vary depending on the specific disease entity being treated. Dosage must be individualized according to the severity of the disease and response of the patient. The recommended dosage may be reduced for pediatric patients, but dosage should be governed by the severity of the condition rather than by strict adherence to the ratio indicated by age or body weight. In patients with the adrenogenital syndrome, a single intramuscular injection of 40 mg every two weeks may be adequate. For maintenance of patients with rheumatoid arthritis, the weekly intramuscular dose will vary from 40 to 120 mg. The usual dosage for patients with dermatologic lesions benefited by systemic corticoid therapy is 40 to 120 mg of methylprednisolone acetate administered intramuscularly at weekly intervals for one to four weeks. In acute severe dermatitis due to poison ivy, relief may result within 8 to 12 hours following intramuscular administration of a single dose of 80 to 120 mg. In chronic contact dermatitis repeated injections at 5 to 10 day intervals may be necessary. In seborrheic dermatitis, a weekly dose of 80 mg may be adequate to control the condition. Following intramuscular administration of 80 to 120 mg to asthmatic patients, relief may result within 6 to 48 hours and persist for several days to two weeks. Similarly in patients with allergic rhinitis (hay fever) an intramuscular dose of 80 to 120 mg may be followed by relief of coryzal symptoms within six hours persisting for several days to three weeks. If signs of stress are associated with the condition being treated, the dosage of the suspension should be increased. If a rapid hormonal effect of maximum intensity is required, the intravenous administration of highly soluble methylprednisolone sodium succinate is indicated. In treatment of acute exacerbations of multiple sclerosis daily doses of 160 mg of methylprednisolone for a week followed by 64 mg every other day for 1 month have been shown to be effective. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depo-Medrol S-086 Label Page 16 For the purpose of comparison, the following is the equivalent milligram dose of the various glucocorticoids: Cortisone, 25 Triamcinolone, 4 Hydrocortisone, 20 Paramethasone, 2 Prednisolone, 5 Netamethasone, 0.75 Prednisone, 5 Dexamethasone, 0.75 Methylprednisolone, 4 Those dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered. HOW SUPPLIED DEPO-MEDROL Sterile Aqueous Suspension is available as single-dose vials in the following strengths and package sizes: 40 mg per mL 80 mg per mL 1 mL vials NDC 0009-3073-01 1 mL vials NDC 0009-3475-01 25 x 1 mL vials NDC 0009-3073-03 25 x 1 mL vials NDC 0009-3475-03 Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Rx only Pfizer logo LAB-0160-3.0 Revised August 2008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:46.209022	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/011757s085s086lbl.pdf', 'application_number': 11757, 'submission_type': 'SUPPL ', 'submission_number': 85}
10,778	DEPO-MEDROL® (methylprednisolone acetate injectable suspension, USP) NOT FOR USE IN NEONATES CONTAINS BENZYL ALCOHOL Not For Intravenous Use DESCRIPTION DEPO-MEDROL is an anti-inflammatory glucocorticoid for intramuscular, intra articular, soft tissue, or intralesional injection. It is available in three strengths: 20 mg/mL, 40 m g/mL, 80 mg/mL. Each mL of these preparations contains: Methylprednisolone acetate.............................. 20 mg 40 mg 80 mg Polyethylene glycol 3350....................................29.5 mg 29.1 mg 28.2 mg Polysorbate 80 ....................................................1.97 mg 1.94 mg 1.88 mg Monobasic sodium phosphate ..............................6.9 mg 6.8 mg 6.59 mg Dibasic sodium phosphate USP..........................1.44 mg 1.42 mg 1.37 mg Benzyl alcohol added as a preservative................9.3 mg 9.16 mg 8.88 mg Sodium Chloride was added to adjust tonicity. When necessary, pH was adjusted with sodium hydroxide and/or hydrochloric acid. The pH of the finished product remains within the USP specified range (e.g., 3.5 to 7.0). The chemical name for methylprednisolone acetate is pregna-1,4-diene-3,20 dione, 21-(acetyloxy)-11,17-dihydroxy-6-methyl-,(6α,11ß)- and the molecular weight is 416.51. The structural formula is represented below: structural formula DEPO-MEDROL Sterile Aqueous Suspension contains methylprednisolone acetate which is the 6-methyl derivative of prednisolone. Methylprednisolone acetate is a white or practically white, odorless, crystalline powder which melts at Reference ID: 3537246 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda about 215° with some decomposition. It is soluble in dioxane, sparingly soluble in acetone, alcohol, chloroform, and methanol, and slightly soluble in ether. It is practically insoluble in water. CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt retaining properties, are used in replacement therapy in adrenocortical deficiency states. Their synthetic analogs are used primarily for their anti- inflammatory effects in disorders of many organ systems. Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body’s immune response to diverse stimuli. INDICATIONS AND USAGE A. FOR INTRAMUSCULAR ADMINISTRATION When oral therapy is not feasible and the strength, dosage form, and route of administration of the drug reasonably lend the preparation to the treatment of the condition, the intramuscular use of DEPO-MEDROL Sterile Aqueous Suspension is indicated as follows: Allergic States: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, seasonal or perennial allergic rhinitis, serum sickness, transfusion reactions. Dermatologic Diseases: Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome). Endocrine Disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance), congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative thyroiditis. Gastrointestinal Diseases: To tide the patient over a critical period of the disease in regional enteritis (systemic therapy) and ulcerative colitis. Hematologic Disorders: Acquired (autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia (Diamond Blackfan anemia), pure red cell aplasia, select cases of secondary thrombocytopenia. Reference ID: 3537246 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Miscellaneous: Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy. Neoplastic Diseases: For palliative management of leukemias and lymphomas. Nervous System: Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor or craniotomy. Ophthalmic Diseases: Sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids. Renal Diseases: To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome, or that due to lupus erythematosus. Respiratory Diseases: Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis. Rheumatic Disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus. B. FOR INTRA-ARTICULAR OR SOFT TISSUE ADMINISTRATION (See WARNINGS) DEPO-MEDROL is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis. C. FOR INTRALESIONAL ADMINISTRATION DEPO-MEDROL is indicated for intralesional use in alopecia areata, discoid lupus erythematosus, keloids, localized hypertrophic, infiltrated, inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), and psoriatic plaques, necrobiosis lipoidica diabeticorum. DEPO-MEDROL also may be useful in cystic tumors of an aponeurosis or tendon (ganglia). CONTRAINDICATIONS DEPO-MEDROL is contraindicated in patients with known hypersensitivity to the product and its constituents. Reference ID: 3537246 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. DEPO-MEDROL Sterile Aqueous Suspension is contraindicated for intrathecal administration. Reports of severe medical events have been associated with this route of administration. DEPO-MEDROL is contraindicated for use in premature infants because the formulation contains benzyl alcohol. (See WARNINGS and PRECAUTIONS: Pediatric Use.) DEPO-MEDROL is contraindicated in systemic fungal infections, except when administered as an intra-articular injection for localized joint conditions (see WARNINGS: Infections, Fungal Infections). WARNINGS Serious Neurologic Adverse Reactions with Epidural Administration Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic events have been reported with and without use of fluoroscopy. The safety and effectiveness of epidural administration of corticosteroids have not been established, and corticosteroids are not approved for this use. General This product contains benzyl alcohol, which is potentially toxic when administered locally to neural tissue. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol in medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see PRECAUTIONS: Pediatric Use). Multidose use of DEPO-MEDROL Sterile Aqueous Suspension from a single vial requires special care to avoid contamination. Although initially sterile, any multidose use of vials may lead to contamination unless strict aseptic technique is observed. Particular care, such as use of disposable sterile syringes and needles, is necessary. Reference ID: 3537246 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Injection of DEPO-MEDROL may result in dermal and/or subdermal changes, forming depressions in the skin at the injection site. In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Multiple small injections into the area of the lesion should be made whenever possible. The technique of intra-articular and intramuscular injection should include precautions against injection or leakage into the dermis. Injection into the deltoid muscle should be avoided because of a high incidence of subcutaneous atrophy. It is critical that, during administration of DEPO-MEDROL, appropriate technique be used and care taken to ensure proper placement of drug. Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy. Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, or after the stressful situation (see ADVERSE REACTIONS). Results from one multicenter, randomized, placebo-controlled study with methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of systemic corticosteroids, including DEPO-MEDROL, should not be used for the treatment of traumatic brain injury. Cardio-renal Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Literature reports suggest an apparent association between the use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. Endocrine Hypothalamic-pituitary adrenal (HPA) axis suppression, Cushing’s syndrome, and hyperglycemia: Monitor patients for these conditions with chronic use. Corticosteroids can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Drug induced Reference ID: 3537246 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Infections General Persons who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infections with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild, but can be severe and at times fatal. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may mask some signs of current infection. Do not use intra-articularly, intrabursally, or for intratendinous administration for local effect in the presence of acute local infection. Fungal Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions, Amphotericin B injection and potassium-depleting agents). Special Pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, and Toxoplasma. It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea. Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. Corticosteroids should not be used in cerebral malaria. There is currently no evidence of benefit from steroids in this condition. Reference ID: 3537246 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tuberculosis The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary, as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. Vaccinations Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy (e.g., for Addison’s disease). Viral Infections Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents should be considered. Ophthalmic Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. The use of systemic corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should be used cautiously in patients with ocular herpes simplex because of corneal perforation. Corticosteroids should not be used in active ocular herpes simplex. PRECAUTIONS General When multidose vials are used, special care to prevent contamination of the contents is essential. A povidone-iodine solution or similar product is recommended to cleanse the vial top prior to aspiration of contents. (See WARNINGS.) Reference ID: 3537246 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the outside of the vial. The lowest possible dose of corticosteroid should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual. Since complications of treatment with glucocorticoids are dependent on the size of the dose and duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement. Cardio-renal As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency. Endocrine Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage. Gastrointestinal Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and non-specific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect due to decreased metabolism of corticosteroids in patients with cirrhosis. Parenteral Administration Intra-articular injected corticosteroids may be systemically absorbed. Reference ID: 3537246 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Appropriate examination of any joint fluid is necessary to exclude a septic process. A marked increase in pain associated by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted. Injection of a steroid into an infected site is to be avoided. Local injection of a steroid into a previously infected joint is not usually recommended. Musculoskeletal Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (e.g., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy. Neuro-psychiatric Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that corticosteroids affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. (See DOSAGE AND ADMINISTRATION.) An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Ophthalmic Reference ID: 3537246 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored. Corticosteroids should be used cautiously in patients with ocular herpes simplex for fear of corneal perforation. Information for the Patient Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids, and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay. Drug Interactions Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid induced adrenal suppression. Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered concomitantly with potassium-depleting agents (e.g., amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance (see PRECAUTIONS: Drug Interactions, Hepatic Enzyme Inhibitors). Anticholinesterases: Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. Anticoagulants, oral: Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Reference ID: 3537246 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cholestyramine: Cholestyramine may increase the clearance of oral corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with concurrent use. Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin): Drugs which induce cytochrome P450 3A4 enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Hepatic Enzyme Inhibitors (e.g., ketoconazole, macrolide antibiotics such as erythromycin and troleandomycin): Drugs which inhibit cytochrome P450 3A4 have the potential to result in increased plasma concentrations of corticosteroids. Ketoconazole: Ketoconazole has been reported to significantly decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs): Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with concurrent use of corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. Skin Tests: Corticosteroids may suppress reactions to skin tests. Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or attenuated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS: Infections, Vaccinations). Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Reference ID: 3537246 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy: Teratogenic Effects: Pregnancy Category C Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. This product contains benzyl alcohol as a preservative. Benzyl alcohol can cross the placenta. See PRECAUTIONS: Pediatric use. Nursing Mothers Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to continue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use This product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product ordinarily delivers amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on the quantity administered and the hepatic capacity to detoxify the chemical. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids, which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephritic syndrome (patients >2 years of age) and aggressive lymphomas and leukemias (patients >1 month of age). Other Reference ID: 3537246 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda indications for pediatric use of corticosteroids (e.g., severe asthma and wheezing) are based on adequate and well-controlled clinical trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS The following adverse reactions have been reported with DEPO-MEDROL or other corticosteroids: Allergic reactions: Allergic or hypersensitivity reactions, anaphylactoid reaction, anaphylaxis, angioedema. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Reference ID: 3537246 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients. Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible subsequent perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic: Negative nitrogen balance due to protein catabolism. Musculoskeletal: Aseptic necrosis of femoral and humeral heads, calcinosis (following intra-articular or intralesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Ophthalmic: Exophthalmoses, glaucoma, increased intraocular pressure, posterior subcapsular cataracts. Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, injection site infections following non-sterile administration (see WARNINGS), malaise, moon face, weight gain. The following adverse reactions have been reported with the following routes of administration: Reference ID: 3537246 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Intrathecal/Epidural: Arachnoiditis, bowel/bladder dysfunction, headache, meningitis, parapareisis/paraplegia, seizures, sensory disturbances. Intranasal: Allergic reactions, rhinitis, temporary/permanent visual impairment including blindness. Ophthalmic: Increased intraocular pressure, infection, ocular and periocular inflammation including allergic reactions, residue or slough at injection site, temporary/permanent visual impairment including blindness. Miscellaneous injection sites (scalp, tonsillar fauces, sphenopalatine ganglion): Blindness. OVERDOSAGE Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. DOSAGE AND ADMINISTRATION NOTE: CONTAINS BENZYL ALCOHOL (see WARNINGS and PRECAUTIONS: Pediatric Use) Because of possible physical incompatibilities, DEPO-MEDROL Sterile Aqueous Suspension should not be diluted or mixed with other solutions. The initial dosage of parenterally administered DEPO-MEDROL will vary from 4 to 120 mg, depending on the specific disease entity being treated. However, in certain overwhelming, acute, life-threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages. It Should Be Emphasized that Dosage Requirements Are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation, it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient’s condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly. Reference ID: 3537246 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda A. Administration for Local Effect Therapy with DEPO-MEDROL does not obviate the need for the conventional measures usually employed. Although this method of treatment will ameliorate symptoms, it is in no sense a cure and the hormone has no effect on the cause of the inflammation. 1. Rheumatoid Arthritis and Osteoarthritis. The dose for intra-articular administration depends upon the size of the joint and varies with the severity of the condition in the individual patient. In chronic cases, injections may be repeated at intervals ranging from one to five or more weeks, depending upon the degree of relief obtained from the initial injection. The doses in the following table are given as a general guide: Size of Joint Examples Range of Dosage Knees Large Ankles Shoulders 20 to 80 mg Medium Elbows Wrists 10 to 40 mg Small Metacarpophalangeal Interphalangeal Sternoclavicular Acromioclavicular 4 to 10 mg Procedure: It is recommended that the anatomy of the joint involved be reviewed before attempting intra-articular injection. In order to obtain the full anti- inflammatory effect, it is important that the injection be made into the synovial space. Employing the same sterile technique as for a lumbar puncture, a sterile 20 to 24 gauge needle (on a dry syringe) is quickly inserted into the synovial cavity. Procaine infiltration is elective. The aspiration of only a few drops of joint fluid proves the joint space has been entered by the needle. The injection site for each joint is determined by that location where the synovial cavity is most superficial and most free of large vessels and nerves. With the needle in place, the aspirating syringe is removed and replaced by a second syringe containing the desired amount of DEPO-MEDROL. The plunger is then pulled outward slightly to aspirate synovial fluid and to make sure the needle is still in the synovial space. After injection, the joint is moved gently a few times to aid mixing of the synovial fluid and the suspension. The site is covered with a small sterile dressing. Suitable sites for intra-articular injection are the knee, ankle, wrist, elbow, shoulder, phalangeal, and hip joints. Since difficulty is not infrequently encountered in entering the hip joint, precautions should be taken to avoid any large blood vessels in the area. Joints not suitable for injection are those that are anatomically inaccessible such as the spinal joints and those like the sacroiliac joints that are devoid of synovial space. Treatment failures are most frequently the Reference ID: 3537246 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda result of failure to enter the joint space. Little or no benefit follows injection into surrounding tissue. If failures occur when injections into the synovial spaces are certain, as determined by aspiration of fluid, repeated injections are usually futile. If a local anesthetic is used prior to injection of DEPO-MEDROL, the anesthetic package insert should be read carefully and all the precautions observed. 2. Bursitis. The area around the injection site is prepared in a sterile way and a wheal at the site made with 1 percent procaine hydrochloride solution. A 20 to 24 gauge needle attached to a dry syringe is inserted into the bursa and the fluid aspirated. The needle is left in place and the aspirating syringe changed for a small syringe containing the desired dose. After injection, the needle is withdrawn and a small dressing applied. 3. Miscellaneous: Ganglion, Tendinitis, Epicondylitis. In the treatment of conditions such as tendinitis or tenosynovitis, care should be taken following application of a suitable antiseptic to the overlying skin to inject the suspension into the tendon sheath rather than into the substance of the tendon. The tendon may be readily palpated when placed on a stretch. When treating conditions such as epicondylitis, the area of greatest tenderness should be outlined carefully and the suspension infiltrated into the area. For ganglia of the tendon sheaths, the suspension is injected directly into the cyst. In many cases, a single injection causes a marked decrease in the size of the cystic tumor and may effect disappearance. The usual sterile precautions should be observed, of course, with each injection. The dose in the treatment of the various conditions of the tendinous or bursal structures listed above varies with the condition being treated and ranges from 4 to 30 mg. In recurrent or chronic conditions, repeated injections may be necessary. 4. Injections for Local Effect in Dermatologic Conditions. Following cleansing with an appropriate antiseptic such as 70% alcohol, 20 to 60 mg of the suspension is injected into the lesion. It may be necessary to distribute doses ranging from 20 to 40 mg by repeated local injections in the case of large lesions. Care should be taken to avoid injection of sufficient material to cause blanching since this may be followed by a small slough. One to four injections are usually employed, the intervals between injections varying with the type of lesion being treated and the duration of improvement produced by the initial injection. When multidose vials are used, special care to prevent contamination of the contents is essential. (See WARNINGS.) B. Administration for Systemic Effect The intramuscular dosage will vary with the condition being treated. When employed as a temporary substitute for oral therapy, a single injection during each Reference ID: 3537246 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24-hour period of a dose of the suspension equal to the total daily oral dose of MEDROL® Tablets (methylprednisolone tablets, USP) is usually sufficient. When a prolonged effect is desired, the weekly dose may be calculated by multiplying the daily oral dose by 7 and given as a single intramuscular injection. In pediatric patients, the initial dose of methylprednisolone may vary depending upon the specific disease entity being treated. The range of initial doses is 0.11 to 1.6 mg/kg/day. Dosage must be individualized according to the severity of the disease and response of the patient. In patients with the adrenogenital syndrome, a single intramuscular injection of 40 mg every two weeks may be adequate. For maintenance of patients with rheumatoid arthritis, the weekly intramuscular dose will vary from 40 to 120 mg. The usual dosage for patients with dermatologic lesions benefited by systemic corticoid therapy is 40 to 120 mg of methylprednisolone acetate administered intramuscularly at weekly intervals for one to four weeks. In acute severe dermatitis due to poison ivy, relief may result within 8 to 12 hours following intramuscular administration of a single dose of 80 to 120 mg. In chronic contact dermatitis, repeated injections at 5 to 10 day intervals may be necessary. In seborrheic dermatitis, a weekly dose of 80 mg may be adequate to control the condition. Following intramuscular administration of 80 to 120 mg to asthmatic patients, relief may result within 6 to 48 hours and persist for several days to two weeks. Similarly, in patients with allergic rhinitis (hay fever), an intramuscular dose of 80 to 120 mg may be followed by relief of coryzal symptoms within six hours persisting for several days to three weeks. If signs of stress are associated with the condition being treated, the dosage of the suspension should be increased. If a rapid hormonal effect of maximum intensity is required, the intravenous administration of highly soluble methylprednisolone sodium succinate is indicated. In treatment of acute exacerbations of multiple sclerosis, daily doses of 160 mg of methylprednisolone for a week followed by 64 mg every other day for 1 month have been shown to be effective. For the purpose of comparison, the following is the equivalent milligram dose of the various glucocorticoids: Cortisone, 25 Triamcinolone, 4 Hydrocortisone, 20 Paramethasone, 2 Prednisolone, 5 Betamethasone, 0.75 Prednisone, 5 Dexamethasone, 0.75 Methylprednisolone, 4 Reference ID: 3537246 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered. HOW SUPPLIED DEPO-MEDROL Sterile Aqueous Suspension is available in the following strengths and package sizes: 20 mg per mL 5 mL multidose vials NDC 0009-0274-01 40 mg per mL 5 mL multidose vials NDC 0009-0280-02 25 x 5 mL multidose vials NDC 0009-0280-51 10 mL multidose vials NDC 0009-0280-03 25 x 10 mL multidose vials NDC 0009-0280-52 80 mg per mL 5 mL multidose vials NDC 0009-0306-02 25 x 5 mL multidose vials NDC 0009-0306-12 Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. company logo LAB-0159-8.4 Revised July 2014 Reference ID: 3537246 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DEPO-MEDROL® (methylprednisolone acetate injectable suspension, USP) Single-Dose Vial Not For Intravenous Use DESCRIPTION DEPO-MEDROL is an anti-inflammatory glucocorticoid for intramuscular, intra articular, soft tissue or intralesional injection. It is available as single-dose vials in two strengths: 40 mg/mL, 80 mg/mL. Each mL of these preparations contains: Methylprednisolone acetate ...........................................40 mg ............80 mg Polyethylene glycol 3350 ..............................................29 mg ............28 mg Myristyl-gamma-picolinium chloride.......................0.195 mg .......0.189 mg Sodium Chloride was added to adjust tonicity. When necessary, pH was adjusted with sodium hydroxide and/or hydrochloric acid. The pH of the finished product remains within the USP specified range (e.g., 3.0 to 7.0.) The chemical name for methylprednisolone acetate is pregna-1,4-diene-3,20-dione, 21-(acetyloxy)-11,17-dihydroxy-6-methyl-,(6α,11β)- and the molecular weight is 416.51. The structural formula is represented below: structural formula DEPO-MEDROL Sterile Aqueous Suspension contains methylprednisolone acetate which is the 6-methyl derivative of prednisolone. Methylprednisolone acetate is a white or practically white, odorless, crystalline powder which melts at about 215° with some decomposition. It is soluble in dioxane, sparingly soluble in acetone, alcohol, chloroform, and methanol, and slightly soluble in ether. It is practically insoluble in water. Reference ID: 3537246 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt retaining properties, are used in replacement therapy in adrenocortical deficiency states. Their synthetic analogs are used primarily for their anti- inflammatory effects in disorders of many organ systems. INDICATIONS AND USAGE A. For Intramuscular Administration When oral therapy is not feasible and the strength, dosage form, and route of administration of the drug reasonably lend the preparation to the treatment of the condition, the intramuscular use of DEPO-MEDROL Sterile Aqueous Suspension is indicated as follows: Allergic States: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, seasonal or perennial allergic rhinitis, serum sickness, transfusion reactions. Dermatologic Diseases: Bullous dermatitis herpetiformis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome). Endocrine Disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance), congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsupportive thyroiditis. Gastrointestinal Diseases: To tide the patient over a critical period of the disease in regional enteritis (systemic therapy) and ulcerative colitis. Hematologic Disorders: Acquired (autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia (Diamond Blackfan anemia), pure red cell aplasia, select cases of secondary thrombocytopenia. Miscellaneous: Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy. Neoplastic Diseases: For palliative management of: leukemias and lymphomas. Nervous System: Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor or craniotomy. Reference ID: 3537246 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ophthalmic Diseases: Sympathetic opthalmia, temporal arteritis, uveitis, ocular inflammatory conditions unresponsive to topical corticosteroids. Renal Diseases: To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome, or that due to lupus erythematosus. Respiratory Diseases: Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis. Rheumatic Disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus. B. For Intra-articular Or Soft Tissue Administration (See WARNINGS) DEPO-MEDROL is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis. C. For Intralesional Administration DEPO-MEDROL is indicated for intralesional use in alopecia areata, discoid lupus erythematosus; keloids, localized hypertrophic, infiltrated inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis) and psoriatic plaques; necrobiosis lipoidica diabeticorum. DEPO-MEDROL also may be useful in cystic tumors of an aponeurosis or tendon (ganglia). CONTRAINDICATIONS DEPO-MEDROL is contraindicated in patients with known hypersensitivity to the product and its constituents. Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. DEPO-MEDROL is contraindicated for intrathecal administration. This formulation of methylprednisolone acetate has been associated with reports of severe medical events when administered by this route. Reference ID: 3537246 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DEPO-MEDROL is contraindicated in systemic fungal infections, except when administered as an intra-articular injection for localized joint conditions (see WARNINGS: Infections, Fungal Infections). WARNINGS Serious Neurologic Adverse Reactions with Epidural Administration Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic events have been reported with and without use of fluoroscopy. The safety and effectiveness of epidural administration of corticosteroids have not been established, and corticosteroids are not approved for this use. General This product is not suitable for multi-dose use. Following administration of the desired dose, any remaining suspension should be discarded. Injection of DEPO-MEDROL may result in dermal and/or subdermal changes forming depressions in the skin at the injection site. In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Multiple small injections into the area of the lesion should be made whenever possible. The technique of intra-articular and intramuscular injection should include precautions against injection or leakage into the dermis. Injection into the deltoid muscle should be avoided because of a high incidence of subcutaneous atrophy. It is critical that, during administration of DEPO-MEDROL, appropriate technique be used and care taken to ensure proper placement of drug. Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS). Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, and after the stressful situation. Results from one multicenter, randomized, placebo-controlled study with methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of systemic corticosteroids, including DEPO-MEDROL, should not be used for the treatment of traumatic brain injury. Reference ID: 3537246 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cardio-renal Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with synthetic derivatives when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. Endocrine Hypothalamic-pituitary adrenal (HPA) axis suppression. Cushing’s syndrome, and Hyperglycemia: Monitor patients for these conditions with chronic use. Corticosteroids can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Drug induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Infections General Persons who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infections with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body, may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild, but can be severe and at times fatal. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Do not use intra-articularly, intrabursally, or for intratendinous administration for local effect in the presence of an acute infection. Corticosteroids may mask some signs of infection and new infections may appear during their use. Fungal Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug interactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions, Amphotericin B injection and potassium-depleting agents). Special Pathogens Reference ID: 3537246 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, and Toxoplasma. It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea. Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. Corticosteroids should not be used in cerebral malaria. There is currently no evidence of benefit from steroids in this condition. Tuberculosis The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary, as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. Vaccinations Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy (e.g., for Addison’s disease). Viral Infections Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated (see the respective package inserts for Reference ID: 3537246 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda complete VZIG and IG prescribing information). If chicken pox develops, treatment with antiviral agents should be considered. Ophthalmic Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. The use of systemic corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should be used cautiously in patients with ocular herpes simplex because of corneal perforation. Corticosteroids should not be used in active ocular herpes simplex. PRECAUTIONS General This product, like many other corticosteroids, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. The lowest possible dose of corticosteroid should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual. Since complications of treatment with glucocorticosteroids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. Karposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement. Cardio-renal As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure or renal insufficiency. Endocrine Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage. Reference ID: 3537246 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Gastrointestinal Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect due to decreased metabolism of corticosteroids in patients with cirrhosis. Parenteral Administration Intra-articularly injected corticosteroids may be systemically absorbed. Appropriate examination of any joint fluid present is necessary to exclude a septic process. A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted. Injection of a steroid into an infected site is to be avoided. Local injection of a steroid into a previously infected joint is not usually recommended. Musculoskeletal Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (e.g., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to an inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy. Neuro-psychiatric Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that corticosteroids affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect (see DOSAGE AND ADMINISTRATION). An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., Reference ID: 3537246 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Ophthalmic Intraocular pressure may become elevated in some individuals. If steroid therapy is continued long-term, intraocular pressure should be monitored. Corticosteroids should be used cautiously in patients with ocular herpes simplex for fear of corneal perforation. Information for the Patient Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop a fever or other signs of infection. Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay. Drug Interactions Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered concomitantly with potassium depleting agents (e.g., amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance (see PRECAUTIONS: Drug Interactions, Hepatic Enzyme Inhibitors). Anticholinesterases: Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. Reference ID: 3537246 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Anticoagulants, oral: Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. Antidiabetics: Because corticosteroids may increase blood glucose concentration, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Cholestyramine: Cholestyramine may increase the clearance of oral corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Digitalis glycosides: Patients on digitalis glycosides may be at risk of arrhythmias due to hypokalemia. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin): Drugs which induce cytochrome P450 3A4 enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Hepatic Enzyme Inhibitors (e.g., ketoconazole, macrolide antibiotics such as erythromycin and troleandomycin): Drugs which inhibit cytochrome P450 3A4 have the potential to result in increased plasma concentrations of corticosteroids. Ketoconazole: Ketoconazole has been reported to significantly decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs): Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. Skin tests: Corticosteroids may suppress reactions to skin tests. Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody Reference ID: 3537246 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS: Infections, Vaccinations). Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy: Teratogenic Effects: Pregnancy Category C Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. Nursing Mothers Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephritic syndrome (patients >2 years of age) and aggressive lymphomas and leukemias (patients >1 month of age). Other indications for pediatric use of corticosteroids (e.g., severe asthma and wheezing) are based on adequate and well-controlled clinical trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and Reference ID: 3537246 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS The following adverse reactions have been reported with DEPO-MEDROL or other corticosteroids: Allergic reactions: Allergic or hypersensitivity reactions, anaphylactoid reaction, anaphylaxis, angioedema. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary Reference ID: 3537246 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients. Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible subsequent perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic: Negative nitrogen balance due to protein catabolism. Musculoskeletal: Aseptic necrosis of femoral and humeral heads, calcinosis (following intra-articular or intra-lesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Ophthalmic: Exophthalmoses, glaucoma, increased intraocular pressure, posterior subcapsular cataracts. Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, injection site infections following non-sterile administration (see WARNINGS), malaise, moon face, weight gain. The following adverse reactions have been reported with the following routes of administration: Intrathecal/Epidural: Arachnoiditis, bowel/bladder dysfunction, headache, meningitis, parapareisis/paraplegia, seizures, sensory disturbances. Intranasal: Allergic reactions, rhinitis, temporary/permanent visual impairment including blindness. Ophthalmic: Increased intraocular pressure, infection, ocular and periocular inflammation including allergic reactions, residue or slough at injection site, temporary/permanent visual impairment including blindness. Reference ID: 3537246 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Miscellaneous injection sites (scalp, tonsillar fauces, sphenopalatine ganglion): blindness. OVERDOSAGE Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. DOSAGE AND ADMINISTRATION Because of possible physical incompatibilities, DEPO-MEDROL Sterile Aqueous Suspension should not be diluted or mixed with other solutions. The initial dosage of parenterally administered DEPO-MEDROL will vary from 4 to 120 mg, depending on the specific disease entity being treated. However, in certain overwhelming, acute, life-threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages. It Should Be Emphasized that Dosage Requirements Are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation, it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient’s condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly. A. Administration for Local Effect Therapy with DEPO-MEDROL does not obviate the need for the conventional measures usually employed. Although this method of treatment will ameliorate symptoms, it is in no sense a cure and the hormone has no effect on the cause of the inflammation. 1. Rheumatoid Arthritis and Osteoarthritis. The dose for intra-articular administration depends upon the size of the joint and varies with the severity of the condition in the individual patient. In chronic cases, injections may be repeated at intervals ranging from one to five or more weeks, depending upon the degree of relief obtained from the initial injection. The doses in the following table are given as a general guide: Reference ID: 3537246 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Size Examples Range of Joint of Dosage Knees Large Ankles 20 to 80 mg Shoulders Medium Elbows Wrists 10 to 40 mg Metacarpophalangeal Small Interphalangeal Sternoclavicular 4 to 10 mg Acromioclavicular Procedure: It is recommended that the anatomy of the joint involved be reviewed before attempting intra-articular injection. In order to obtain the full anti- inflammatory effect, it is important that the injection be made into the synovial space. Employing the same sterile technique as for a lumbar puncture, a sterile 20 to 24 gauge needle (on a dry syringe) is quickly inserted into the synovial cavity. Procaine infiltration is elective. The aspiration of only a few drops of joint fluid proves the joint space has been entered by the needle. The injection site for each joint is determined by that location where the synovial cavity is most superficial and most free of large vessels and nerves. With the needle in place, the aspirating syringe is removed and replaced by a second syringe containing the desired amount of DEPO-MEDROL. The plunger is then pulled outward slightly to aspirate synovial fluid and to make sure the needle is still in the synovial space. After injection, the joint is moved gently a few times to aid mixing of the synovial fluid and the suspension. The site is covered with a small sterile dressing. Suitable sites for intra-articular injection are the knee, ankle, wrist, elbow, shoulder, phalangeal, and hip joints. Since difficulty is not infrequently encountered in entering the hip joint, precautions should be taken to avoid any large blood vessels in the area. Joints not suitable for injection are those that are anatomically inaccessible such as the spinal joints and those like the sacroiliac joints that are devoid of synovial space. Treatment failures are most frequently the result of failure to enter the joint space. Little or no benefit follows injection into surrounding tissue. If failures occur when injections into the synovial spaces are certain, as determined by aspiration of fluid, repeated injections are usually futile. If a local anesthetic is used prior to injection of DEPO-MEDROL, the anesthetic package insert should be read carefully and all the precautions observed. 2. Bursitis. The area around the injection site is prepared in a sterile way and a wheal at the site made with 1 percent procaine hydrochloride solution. A 20 to 24 gauge needle attached to a dry syringe is inserted into the bursa and the fluid aspirated. The needle is left in place and the aspirating syringe changed for a Reference ID: 3537246 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda small syringe containing the desired dose. After injection, the needle is withdrawn and a small dressing applied. 3. Miscellaneous: Ganglion, Tendinitis, Epicondylitis. In the treatment of conditions such as tendinitis or tenosynovitis, care should be taken following application of a suitable antiseptic to the overlying skin to inject the suspension into the tendon sheath rather than into the substance of the tendon. The tendon may be readily palpated when placed on a stretch. When treating conditions such as epicondylitis, the area of greatest tenderness should be outlined carefully and the suspension infiltrated into the area. For ganglia of the tendon sheaths, the suspension is injected directly into the cyst. In many cases, a single injection causes a marked decrease in the size of the cystic tumor and may effect disappearance. The usual sterile precautions should be observed, of course, with each injection. The dose in the treatment of the various conditions of the tendinous or bursal structures listed above varies with the condition being treated and ranges from 4 to 30 mg. In recurrent or chronic conditions, repeated injections may be necessary. 4. Injections for Local Effect in Dermatologic Conditions. Following cleansing with an appropriate antiseptic such as 70% alcohol, 20 to 60 mg of the suspension is injected into the lesion. It may be necessary to distribute doses ranging from 20 to 40 mg by repeated local injections in the case of large lesions. Care should be taken to avoid injection of sufficient material to cause blanching since this may be followed by a small slough. One to four injections are usually employed, the intervals between injections varying with the type of lesion being treated and the duration of improvement produced by the initial injection. B. Administration for Systemic Effect. The intramuscular dosage will vary with the condition being treated. When employed as a temporary substitute for oral therapy, a single injection during each 24-hour period of a dose of the suspension equal to the total daily oral dose of MEDROL® Tablets (methylprednisolone tablets, USP) is usually sufficient. When a prolonged effect is desired, the weekly dose may be calculated by multiplying the daily oral dose by 7 and given as a single intramuscular injection. In pediatric patients, the initial dose of methylprednisolone may vary depending on the specific disease entity being treated. Dosage must be individualized according to the severity of the disease and response of the patient. The recommended dosage may be reduced for pediatric patients, but dosage should be governed by the severity of the condition rather than by strict adherence to the ratio indicated by age or body weight. In patients with the adrenogenital syndrome, a single intramuscular injection of 40 mg every two weeks may be adequate. For maintenance of patients with Reference ID: 3537246 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda rheumatoid arthritis, the weekly intramuscular dose will vary from 40 to 120 mg. The usual dosage for patients with dermatologic lesions benefited by systemic corticoid therapy is 40 to 120 mg of methylprednisolone acetate administered intramuscularly at weekly intervals for one to four weeks. In acute severe dermatitis due to poison ivy, relief may result within 8 to 12 hours following intramuscular administration of a single dose of 80 to 120 mg. In chronic contact dermatitis, repeated injections at 5 to 10 day intervals may be necessary. In seborrheic dermatitis, a weekly dose of 80 mg may be adequate to control the condition. Following intramuscular administration of 80 to 120 mg to asthmatic patients, relief may result within 6 to 48 hours and persist for several days to two weeks. Similarly, in patients with allergic rhinitis (hay fever), an intramuscular dose of 80 to 120 mg may be followed by relief of coryzal symptoms within six hours persisting for several days to three weeks. If signs of stress are associated with the condition being treated, the dosage of the suspension should be increased. If a rapid hormonal effect of maximum intensity is required, the intravenous administration of highly soluble methylprednisolone sodium succinate is indicated. In treatment of acute exacerbations of multiple sclerosis, daily doses of 160 mg of methylprednisolone for a week followed by 64 mg every other day for 1 month have been shown to be effective. For the purpose of comparison, the following is the equivalent milligram dose of the various glucocorticoids: Cortisone, 25 Triamcinolone, 4 Hydrocortisone, 20 Paramethasone, 2 Prednisolone, 5 Betamethasone, 0.75 Prednisone, 5 Dexamethasone, 0.75 Methylprednisolone, 4 These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered. HOW SUPPLIED DEPO-MEDROL Sterile Aqueous Suspension is available as single-dose vials in the following strengths and package sizes: 40 mg per mL 80 mg per mL 1 mL vials NDC 0009-3073-01 1 mL vials NDC 0009-3475-01 25 x 1 mL vials NDC 0009-3073-03 25 x 1 mL vials NDC 0009-3475-03 Reference ID: 3537246 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:46.368327	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/011757s103lbl.pdf', 'application_number': 11757, 'submission_type': 'SUPPL ', 'submission_number': 103}
10,779	NDA 11-790/S-046 Page 3 Additions are underlined and deletions are strikethrough ROBAXIN Injectable (methocarbamol injection, USP) Rx Only DESCRIPTION ROBAXIN (methocarbamol injection, USP) Injectable, a carbamate derivative of guaifenesin, is a central nervous system (CNS) depressant with sedative and musculoskeletal relaxant properties. It is a sterile, pyrogen-free solution intended for intramuscular or intravenous administration. Each mL contains: methocarbamol, USP 100 mg, polyethylene glycol 300, NF 0.5 mL, Water for Injection, USP q. s. The pH is adjusted, when necessary, with hydrochloric acid and/or sodium hydroxide. The chemical name of methocarbamol is 3-(2-methoxyphenoxy)-1,2-propanediol 1-carbamate and has the empirical formula of C11H15NO5. Its molecular weight is 241.24. The structural formula is shown below: [insert structural formula] Methocarbamol is a white powder, sparingly soluble in water and chloroform, soluble in alcohol (only with heating) and propylene glycol, and insoluble in benzene and n-hexane. ROBAXIN Injectable has a pH between 3.5 and 6.0. AFTER MIXING WITH I.V. INFUSION FLUIDS, DO NOT REFRIGERATE. CLINICAL PHARMACOLOGY The mechanism of action of methocarbamol in humans has not been established, but may be due to general CNS depression. It has no direct action on the contractile mechanism of striated muscle, the motor end plate or the nerve fiber. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-790/S-046 Page 4 Pharmacokinetics In healthy volunteers, the plasma clearance of methocarbamol ranges between 0.20 and 0.80 L/h/kg, the mean plasma elimination half-life ranges between 1 and 2 hours, and the plasma protein binding ranges between 46% and 50%. Methocarbamol is metabolized via dealkylation and hydroxylation. Conjugation of methocarbamol also is likely. Essentially all methocarbamol metabolites are eliminated in the urine. Small amounts of unchanged methocarbamol also are excreted in the urine. Special populations Elderly The mean (" SD) elimination half-life of methocarbamol in elderly healthy volunteers (mean (" SD) age, 69 (" 4) years was slightly prolonged compared to a younger (mean (" SD) age, 53.3 (" 8.8) years), healthy population (1.5 (" 0.4) hours versus 1.1 (" 0.27) hour, respectively). The fraction of bound methocarbamol was slightly decreased in the elderly versus younger volunteers (41 to 43% versus 46 to 50%, respectively). Renally impaired The clearance of methocarbamol in 8 renally-impaired patients on maintenance hemodialysis was reduced about 40% compared to 17 normal subjects, although the mean (" SD) elimination half-life in these two groups was similar: 1.2 ("0.6) versus 1.1 (" 0.3) hours, respectively. Hepatically impaired In 8 patients with cirrhosis secondary to alcohol abuse, the mean total clearance of methocarbamol was reduced approximately 70% compared to that obtained in 8 age- and weight-matched normal subjects. The mean (" SD) elimination half-life in the cirrhotic patients and the normal subjects was 3.38 (" 1.62) hours and 1.11 (" 0.27) hours respectively. The percent of methocarbamol bound to plasma proteins was decreased to approximately 40 to 45% compared to 46 to 50% in the normal subjects. INDICATIONS AND USAGE The injectable form of methocarbamol is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions. The mode of action of this drug has not been clearly identified, but may be related to its sedative properties. Methocarbamol does not directly relax tense skeletal muscles in man. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-790/S-046 Page 5 CONTRAINDICATIONS ROBAXIN Injectable should not be administered to patients with known or suspected renal pathology. This caution is necessary because of the presence of polyethylene glycol 300 in the vehicle. A much larger amount of polyethylene glycol 300 than is present in recommended doses of ROBAXIN Injectable is known to have increased pre-existing acidosis and urea retention in patients with renal impairment. Although the amount present in this preparation is well within the limits of safety, caution dictates this contraindication. ROBAXIN Injectable is contraindicated in patients hypersensitive to methocarbamol or to any of the injection components. WARNINGS Since methocarbamol may posses a general CNS depressant effect, patients receiving ROBAXIN Injectable should be cautioned about combined effects with alcohol and other CNS depressants. Safe use of ROBAXIN Injectable has not been established with regard to possible adverse effects upon fetal development. There have been very rare reports of fetal and congenital abnormalities following in utero exposure to methocarbamol. Therefore, ROBAXIN Injectable should not be used in women who are or may become pregnant and particularly during early pregnancy unless in the judgment of the physician the potential benefits outweigh the possible hazards (see PRECAUTIONS, Pregnancy). Use in Activities Requiring Mental Alertness Methocarbamol may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle. Patients should be cautioned about operating machinery, including automobiles, until they are reasonably certain that methocarbamol therapy does not adversely affect their ability to engage in such activities. Use in Patients with Hypersensitivity to Latex The vial stopper contains dry natural rubber that may cause hypersensitivity reactions when handled by or when the product is injected in persons with known or possible latex sensitivity. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-790/S-046 Page 6 PRECAUTIONS General As with other agents administered either intravenously or intramuscularly, careful supervision of dose and rate of injection should be observed. Rate of injection should not exceed 3 mL per minute-i.e., one 10 mL vial in approximately three minutes. Since ROBAXIN Injectable is hypertonic, vascular extravasation must be avoided. A recumbent position will reduce the likelihood of side reactions. Blood aspirated into the syringe does not mix with the hypertonic solution. This phenomenon occurs with many other intravenous preparations. The blood may be injected with the methocarbamol, or the injection may be stopped when the plunger reaches the blood, whichever the physician prefers. The total dosage should not exceed 30 mL (three vials) a day for more than three consecutive days except in the treatment of tetanus. Caution should be observed in using the injectable form in patients with suspected or known seizure disorders. Information for Patients Patients should be cautioned that methocarbamol may cause drowsiness or dizziness, which may impair their ability to operate motor vehicles or machinery. Because methocarbamol may possess a general CNS-depressant effect, patients should be cautioned about combined effects with alcohol and other CNS depressants. Drug Interactions See WARNINGS and PRECAUTIONS for interaction with CNS drugs and alcohol. Methocarbamol may inhibit the effect of pyridostigmine bromide. Therefore, methocarbamol should be used with caution in patients with myasthenia gravis receiving anticholinesterase agents. Drug/Laboratory Test Interactions Methocarbamol may cause a color interference in certain screening tests for 5-hydroxy-indoleacetic acid (5-HIAA) using nitrosonaphthol reagent and in screening tests for urinary vanillylmandelic acid (VMA) using the Gitlow method. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-790/S-046 Page 7 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies to evaluate the carcinogenic potential of methocarbamol have not been performed. No studies have been conducted to assess the effect of methocarbamol on mutagenesis or its potential to impair fertility. Pregnancy Teratogenic Effects-Pregnancy Category C Animal reproduction studies have not been conducted with methocarbamol. It is also not known whether methocarbamol can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ROBAXIN Injectable should be given to a pregnant woman only if clearly needed. Safe use of ROBAXIN Injectable has not been established with regard to possible adverse effects upon fetal development. There have been reports of fetal and congenital abnormalities following in utero exposure to methocarbamol. Therefore, ROBAXIN Injectable should not be used in women who are or may become pregnant and particularly during early pregnancy unless in the judgment of the physician the potential benefits outweigh the possible hazards (see WARNINGS). Nursing Mothers Methocarbamol and/or its metabolites are excreted in the milk of dogs; however, it is not known whether methocarbamol or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ROBAXIN Injectable is administered to a nursing woman. Pediatric Use Safety and effectiveness of ROBAXIN Injectable in pediatric patients have not been established except in tetanus. See Dosage and Administration, Special Directions for Use in Tetanus, For pediatric patients. ADVERSE REACTIONS The following adverse reactions have been reported coincident with the administration of methocarbamol. Some events may have been due to an overly rapid rate of intravenous injection. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-790/S-046 Page 8 Body as a whole: Anaphylactic reaction, angioneurotic edema, fever, headache Cardiovascular system: Bradycardia, flushing, hypotension, syncope, thrombophlebitis In most cases of syncope there was spontaneous recovery. In others, epinephrine, injectable steroids, and/or injectable antihistamines were employed to hasten recovery. Digestive system, Dyspepsia, jaundice (including cholestatic jaundice), nausea and vomiting Hemic and lymphatic system: Leukopenia Immune system: Hypersensitivity reactions Nervous system: Amnesia, confusion, diplopia, dizziness or light-headedness, drowsiness, insomnia, mild muscular incoordination, nystagmus, sedation, seizures (including grand mal), vertigo The onset of convulsive seizures during intravenous administration of methocarbamol has been reported in patients with seizure disorders. The psychic trauma of the procedure may have been a contributing factor. Although several observers have reported success in terminating epileptiform seizures with ROBAXIN Injectable, its administration to patients with epilepsy is not recommended (see PRECAUTIONS, General). Skin and special senses: Blurred vision, conjunctivitis, nasal congestion, metallic taste, pruritus, rash, urticaria Other: Pain and sloughing at the site of injection OVERDOSAGE Limited information is available on the acute toxicity of methocarbamol. Overdose of methocarbamol is frequently in conjunction with alcohol or other CNS depressants and includes the following symptoms: nausea, drowsiness, blurred vision, hypotension, seizures, and coma. In post-marketing experience deaths have been reported with an overdose of methocarbamol alone or in the presence of other CNS depressants, alcohol or psychotropic drugs. Treatment Management of overdose includes symptomatic and supportive treatment. Supportive measures include maintenance of an adequate airway, monitoring urinary output and vital signs, and administration of intravenous fluids if necessary. The usefulness of hemodialysis in managing overdose is unknown. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-790/S-046 Page 9 DOSAGE AND ADMINISTRATION For Intravenous and Intramuscular Use Only. Total adult dosage should not exceed 30 mL (3 vials) a day for more than 3 consecutive days except in the treatment of tetanus. A like course may be repeated after a lapse of 48 hours if the condition persists. If the condition persists, a like course may be repeated after a drug-free interval of 48 hours. Dosage and frequency of injection should be based on the severity of the condition being treated and therapeutic response noted. For the relief of symptoms of moderate degree, one dose of 1 gram 10 mL (one 10 mL vial) may be adequate. Ordinarily this injection need not be repeated, as the administration of the oral form will usually sustain the relief initiated by the injection. For the severest cases or in postoperative conditions in which oral administration is not feasible, additional doses of 1 gram may be repeated every 8 hours up to a maximum of 3 g/day for no more than 3 consecutive days. 20 to 30 mL (two to three vials) may be required. Directions for Intravenous Use ROBAXIN Injectable may be administered undiluted directly into the vein at a maximum rate of three mL per minute. It may also be added to an intravenous drip of Sodium Chloride Injection (Sterile Isotonic Sodium Chloride Solution for Parenteral Use) or five percent Dextrose Injection (Sterile 5 percent Dextrose Solution); one vial given as a single dose should not be diluted to more than 250 mL for I.V. infusion. AFTER MIXING WITH I.V. INFUSION FLUIDS, DO NOT REFRIGERATE. Care should be exercised to avoid vascular extravasation of this hypertonic solution, which may result in thrombophlebitis. It is preferable that the patient be in a recumbent position during and for at least 10 to 15 minutes following the injection. Directions for Intramuscular Use When the intramuscular route is indicated, not more than five mL (one-half vial) should be injected into each gluteal region. The injections may be repeated at eight hour intervals, if necessary. When satisfactory relief of symptoms is achieved, it can usually be maintained with tablets. Not Recommended for Subcutaneous Administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-790/S-046 Page 10 Special Directions for Use in Tetanus There is clinical evidence which suggests that methocarbamol may have a beneficial effect in the control of the neuromuscular manifestations of tetanus. It does not, however, replace the usual procedure of debridement, tetanus antitoxin, penicillin, tracheotomy, attention to fluid balance, and supportive care. ROBAXIN Injectable should be added to the regimen as soon as possible. For adults: Inject one or two vials directly into the tubing of the previously inserted indwelling needle. An additional 10 mL or 20 mL may be added to the infusion bottle so that a total of up to 30 mL (three vials) is given as the initial dose (see PRECAUTIONS). This procedure should be repeated every six hours until conditions allow for the insertion of a nasogastric tube. Crushed ROBAXIN (methocarbamol) methocarbamol tablets suspended in water or saline may then be given through this tube. Total daily oral doses up to 24 grams may be required as judged by patient response. For pediatric patients: A minimum initial dose of 15 mg/kg or 500 mg/m 2 is recommended. This dosage may be repeated every six hours as indicated if required. The total dose should not exceed 1.8 g/m 2 for 3 consecutive days. The maintenance dosage may be given by injection into tubing or by I.V. infusion with an appropriate quantity of fluid. See directions for I.V. use. HOW SUPPLIED ROBAXIN Injectable (100 mg/mL) supplied in 10 mL single dose vials in packages of 5 (NDC 0031- 7409-87) and 25 (NDC 60977-150-01). 0031-7409-94). Store at controlled room temperature, between 20°C and - 25°C (68°F - 77°F), excursions permitted to 15° - 30°C (59°F - 86°F). [insert necessary information here to reflect the change in NDA ownership from Wyeth-Ayerst to Baxter Healthcare Corporation] Revised November 2003 Printed in U.S This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:46.428912	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/11790slr046_robaxin_lbl.pdf', 'application_number': 11790, 'submission_type': 'SUPPL ', 'submission_number': 46}
10,780	IN-090H2-14 Rev. 5/05 SOMA® (carisoprodol) Tablets, USP DESCRIPTION `SOMA' (carisoprodol) Tablets, USP is available as 350 mg round, white tablets. Chemically, carisoprodol is N-isopropyl-2-methyl-2-propyl-1,3-propanediol dicarbamate. Carisoprodol is a white, crystalline powder, having a mild, characteristic odor and a bitter taste. It is very slightly soluble in water; freely soluble in alcohol, in chloroform, and in acetone; its solubility is practically independent of pH. Carisoprodol is present as a racemic mixture. The molecular formula is C 12 H 24 N 2 O 4 , with a molecular weight of 260.33. The structural formula is: Other ingredients: alginic acid, magnesium stearate, potassium sorbate, starch, tribasic calcium phosphate. CLINICAL PHARMACOLOGY Carisoprodol is a centrally acting skeletal muscle relaxant that does not directly relax tense skeletal muscles in man. The mode of action of carisoprodol in relieving acute muscle spasm of local origin has not been clearly identified, but may be related to its sedative properties. In animals, carisoprodol has been shown to produce muscle relaxation by blocking interneuronal activity and depressing transmission of polysynaptic neurons in the spinal cord and in the descending reticular formation of the brain. The onset of action is rapid and lasts four to six hours. Carisoprodol is metabolized in the liver and is excreted by the kidneys. One of the products of metabolism, meprobamate, is active as an anxiolytic. The degree to which it contributes to the efficacy of carisoprodol is unknown. Carisoprodol is dialyzable by peritoneal and hemodialysis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Absorption, Distribution, Metabolism, Excretion Following a single oral dose of carisoprodol, the time to maximum concentration (Tmax) was 1.98 ± 1.16 hours and the terminal elimination half-life was 2.44 ± 0.93 hours. By normalizing to a single 350 mg carisoprodol tablet, the mean peak plasma concentration (Cmax) was 2.29 ±- 0.68 ug/mL, the area under the plasma level time curve (AUC 0-∞ ) was 10.33 ± 3.87 ug/mL* hour, and the oral clearance (Cl/F) was 39.52 ± 16.83 L/hour. The mean Cmax of metabolite, meprobamate, was 2.08 ± 0.48 ug/mL, a subtherapeutic concentration when compared to a plasma concentration of a single oral meprobamate 400 mg tablet which would yield a meprobamate concentration of approximately 8.0 ug/mL. Pharmacokinetics Absorption The pharmacokinetics of carisoprodol was determined in a small in vivo biostudy of 5 men and 5 women. When the dose was normalized to 350 mg, the mean peak plasma concentration (Cmax) achieved was 2.29 ± 0.68 ug/mL. Women tended to reach peak plasma concentrations earlier than men (1.45 vs. 2.5 hours) and had a faster apparent oral clearance (0.772 vs. 0.38 L/hour/kg). The clinical significance of these findings is unknown and they may in part be due to the small number of subjects present in the trial. Metabolism Carisoprodol is metabolized in the liver via cytochrome P450 enzyme, CYP2C19. This enzyme exhibits genetic polymorphism. For example, 15-20% of Asian populations may be expected to be poor metabolizers. For Caucasians and Blacks, the prevalence of poor metabolizers is 3-5%. Following a single 350 mg dose of carisoprodol, the corresponding normalized peak concentration of meprobamate, which is a metabolite of carisoprodol, was 2.08 ± 0.48 ug/mL. These levels are approximately ¼ of those seen following a single 400 mg dose of meprobamate. Elimination Carisoprodol is eliminated by both renal and non-renal routes with a terminal elimination half-life of 2.44 ± 0.93 hours. It is dialyzable by peritoneal and hemodialysis. Special Populations The pharmacokinetic profile of carisoprodol in patients with renal impairment or hepatic impairment has not been evaluated. Because carisoprodol is metabolized by the liver and excreted by the kidneys, possible increased exposure of carisoprodol is expected if hepatic and/or renal function is impaired. The drug should be used with caution in patients with impaired hepatic or renal function. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The pharmacokinetic profile of carisoprodol in elderly patients has not been evaluated. INDICATIONS Carisoprodol is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions. CONTRAINDICATIONS Soma is contraindicated in patients with acute intermittent porphyria, and in patients who are allergic to or who have had idiosyncratic reactions to carisoprodol or meprobamate related compounds. WARNINGS Potentially Hazardous Tasks -- Patients should be warned that carisoprodol may have sedative properties and may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a motor vehicle or operating machinery. Drug Dependence, Withdrawal and Abuse - In postmarketing experience, cases of drug abuse, dependence and withdrawal have been reported. Carisoprodol should be used with caution in addiction-prone individuals. (See DRUG ABUSE AND DEPENDENCE). Additive Effects --Since the effects of carisoprodol and alcohol or carisoprodol and other CNS depressants or psychotropic drugs may be additive, appropriate caution should be exercised with patients who take more than one of these agents simultaneously. Concomitant use of carisoprodol and meprobamate is not recommended. Idiosyncratic Reactions --On very rare occasions, the first dose of carisoprodol has been followed by idiosyncratic symptoms appearing within minutes or hours. Symptoms reported include: extreme weakness, transient quadriplegia, dizziness, ataxia, temporary loss of vision, diplopia, mydriasis, dysarthria, agitation, euphoria, confusion, and disorientation. Symptoms usually subside over the course of the next several hours. Supportive and symptomatic therapy, including hospitalization, may be necessary. Allergic Reactions -- Occasionally, within the period of the first to fourth dose of carisoprodol allergic reactions have occurred in patients who have had no previous contact with the drug. Skin rash, erythema multiforme, pruritus, eosinophilia, and fixed drug eruption have been reported with carisoprodol with cross reaction to meprobamate. Severe reactions have been manifested by asthmatic episodes, fever, weakness, dizziness, angioneurotic edema, smarting eyes, hypotension, and anaphylactoid shock. (See also Idiosyncratic Reactions under "Warnings." ) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In case of allergic or idiosyncratic reactions to carisoprodol, discontinue the drug and initiate appropriate symptomatic therapy, which may include epinephrine, antihistamines, and in severe cases corticosteroids. Usage in Pregnancy and Lactation –The safety of this drug in pregnancy or lactation has not been established. Therefore, use of this drug in pregnancy, in nursing mothers, or in women of childbearing potential requires that the potential benefits of the drug be weighed against the potential hazards to mother and child. Carisoprodol is present in breast milk of lactating mothers at concentrations two to four times that of maternal plasma. This factor should be taken into account when use of the drug is contemplated in breast-feeding patients. Usage in Children --The efficacy and safety of carisoprodol in patients under 12 years of age has not been determined. PRECAUTIONS Seizure Disorders: There have been rare reports of seizures in postmarketing surveillance in temporal association with carisoprodol. These events have involved patients with and without previous medical histories of seizures and have occurred during therapeutic use, with overdose and during withdrawal from prolonged use. The role of carisoprodol in the causality of these seizures has not been established. Carisoprodol is metabolized in the liver and excreted by the kidney; to avoid its excess accumulation, caution should be exercised in administration to patients with compromised liver or kidney function. ADVERSE REACTIONS Cardiovascular --Tachycardia, postural hypotension, and facial flushing. Central Nervous System --Drowsiness and other CNS effects may require dosage reduction. Also observed: dizziness, vertigo, ataxia, tremor, agitation, irritability, headache, depressive reactions, syncope, seizures, and insomnia. (See also Idiosyncratic Reactions under "Warnings." ) Gastrointestinal --Nausea, vomiting, hiccup, and epigastric distress. Hematologic --Leukopenia, in which other drugs or viral infection may have been responsible, and pancytopenia, attributed to phenylbutazone, have been reported. No serious blood dyscrasias have been attributed to carisoprodol. DRUG ABUSE AND DEPENDENCE In post-marketing experience, drug abuse and dependence have been reported. The majority of cases of drug abuse, dependence and withdrawal have been reported with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda prolonged use of carisoprodol (beyond several months of treatment) or in combination with other CNS depressant or psychotropic drugs. However, there have been cases reported with carisoprodol alone. Withdrawal symptoms including abdominal cramps, insomnia, headache, nausea, and seizure, have been reported following abrupt cessation after prolonged use. One of the metabolites of carisoprodol, meprobamate, may be habit forming. (See Pharmacokinetics). Carisoprodol should be used with caution in addiction-prone individuals, and its use should generally be limited to the acute treatment setting and not for more than 2 – 3 weeks. OVERDOSAGE Overdosage of carisoprodol produces CNS depression, and in severe cases coma. Shock, respiratory depression, seizures and death have also been reported rarely. The following signs and symptoms may be associated with carisoprodol overdosage: horizontal and vertical nystagmus, blurred vision, mydriasis, mild tachycardia and hypotension, respiratory depression, euphoria, CNS stimulation, muscular incoordination, and/or rigidity, confusion, headache, hallucinations, and dystonic reactions. The effects of an overdosage of carisoprodol and alcohol or other CNS depressants or psychotropic agents can be additive even when one of the drugs has been taken in the usual recommended dosage. Fatal accidental and non-accidental overdoses have been reported alone or in combination with alcohol or psychotropic drugs. Treatment of Overdosage: Basic life support measures should be instituted as dictated by the clinical presentation. Induced emesis is not recommended due to the risk of CNS and respiratory depression. Gastric lavage should be considered soon after ingestion (usually within 1 hour.) In cases of severe CNS depression, airway protective reflexes may be compromised. In such cases, tracheal intubation should be considered for airway protection and respiratory support. Circulatory support should be administered with volume infusion and pressor agents as indicated. Seizures should be treated with a benzodiazepine IV and may be followed with phenobarbital if seizures recur. Carisoprodol is metabolized in the liver and excreted by the kidney. The following types of treatment have been used successfully with the related drug meprobamate: activated charcoal (oral or via nasogastric tube), forced diuresis, peritoneal dialysis, and hemodialysis (carisoprodol is dialyzable). Careful monitoring of urinary output is necessary and caution should be taken to avoid overhydration. Observe for possible relapse due to incomplete gastric emptying and delayed absorption. Carisoprodol can be measured in biological fluids by gas chromatography (Douglas, J. F. et al.: J Pharm Sci 58: 145, 1969). For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION The usual adult dosage of `SOMA' (carisoprodol) Tablets, USP is one 350 mg tablet, three times daily and at bedtime. Usage in patients under age 12 is not recommended. HOW SUPPLIED `SOMA' (carisoprodol) Tablets, USP 350 mg: Round, convex, white tablets, inscribed with SOMA 350, are available in bottles of 100 (NDC 0037-2001-01). Storage: Store at controlled room temperature 20 to 25° C (68 to 77° F). Dispense in a tight container. MedPointe Pharmaceuticals MedPointe Healthcare Inc. Somerset, NJ 08873 IN-090H2-14 Rev. 5/05 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:46.493504	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/011792s035lbl.pdf', 'application_number': 11792, 'submission_type': 'SUPPL ', 'submission_number': 35}
10,781	PROVERA® (medroxyprogesterone acetate tablets, USP) WARNINGS CARDIOVASCULAR AND OTHER RISKS Estrogens with progestins should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Dementia.) The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Malignant neoplasms, Breast cancer.) The Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI study, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE 0.625 mg combined with MPA 2.5 mg, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.) In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. DESCRIPTION PROVERA® tablets contain medroxyprogesterone acetate, which is a derivative of progesterone. It is a white to off-white, odorless crystalline powder, stable in air, melting between 200 and 210°C. It is freely soluble in chloroform, soluble in acetone and in dioxane, sparingly soluble in alcohol and in methanol, slightly soluble in ether, and insoluble in water. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The chemical name for medroxyprogesterone acetate is pregn-4-ene-3, 20-dione, 17-(acetyloxy)-6-methyl-, (6α)-. The structural formula is: Each PROVERA tablet for oral administration contains 2.5 mg, 5 mg or 10 mg of medroxyprogesterone acetate and the following inactive ingredients: calcium stearate, corn starch, lactose, mineral oil, sorbic acid, sucrose, and talc. The 2.5 mg tablet contains FD&C Yellow No. 6. CLINICAL PHARMACOLOGY Medroxyprogesterone acetate (MPA) administered orally or parenterally in the recommended doses to women with adequate endogenous estrogen, transforms proliferative into secretory endometrium. Androgenic and anabolic effects have been noted, but the drug is apparently devoid of significant estrogenic activity. While parenterally administered MPA inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation, available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses. Pharmacokinetics The pharmacokinetics of MPA were determined in 20 postmenopausal women following a single-dose administration of eight PROVERA 2.5 mg tablets or a single administration of two PROVERA 10 mg tablets under fasting conditions. In another study, the steady- state pharmacokinetics of MPA were determined under fasting conditions in 30 postmenopausal women following daily administration of one PROVERA 10 mg tablet for 7 days. In both studies, MPA was quantified in serum using a validated gas chromatography-mass spectrometry (GC-MS) method. Estimates of the pharmacokinetic parameters of MPA after single and multiple doses of PROVERA tablets were highly variable and are summarized in Table 1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1. Mean (SD) Pharmacokinetic Parameters for Medroxyprogesterone Acetate (MPA) Tablet Strength C max (ng/mL) T max (h) Auc 0-(∞) (ng·h/mL) t 1/2 (h) Vd/f (L) CL/f (mL/min) Single Dose 2 × 10 mg 1.01 (0.599) 2.65 (1.41) 6.95 (3.39) 12.1 (3.49) 78024 (47220) 64110 (42662) 8 × 2.5 mg 0.805 (0.413) 2.22 (1.39) 5.62 (2.79) 11.6 (2.81) 62748 (40146) 74123 (35126) Multiple Dose 10 mg * 0.71 (0.35) 2.83 (1.83) 6.01 (3.16) 16.6 (15.0) 40564 (38256) 41963 (38402) Following Day 7 dose A. Absorption: No specific investigation on the absolute bioavailability of MPA in humans has been conducted. MPA is rapidly absorbed from the gastrointestinal tract, and maximum MPA concentrations are obtained between 2 to 4 hours after oral administration. Administration of PROVERA with food increases the bioavailability of MPA. A 10 mg dose of PROVERA, taken immediately before or after a meal, increased MPA Cmax (50 to 70%) and AUC (18 to 33%). The half-life of MPA was not changed with food. B. Distribution: MPA is approximately 90% protein bound, primarily to albumin; no MPA binding occurs with sex hormone binding globulin. C. Metabolism: Following oral dosing, MPA is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine. D. Excretion: Most MPA metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates. E. Special Populations Renal Insufficiency The pharmacokinetics of MPA in patients with varying degrees of renal insufficiency have not been investigated. Hepatic Insufficiency MPA is almost exclusively eliminated via hepatic metabolism. In 14 patients with advanced liver disease, MPA disposition was significantly altered (reduced elimination). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In patients with fatty liver, the mean percent dose excreted in the 24-hour urine as intact MPA after a 10 mg or 100 mg dose was 7.3% and 6.4%, respectively. F. Drug Interactions No formal pharmacokinetic drug interaction studies have been conducted with PROVERA CLINICAL STUDIES Effects on the Endometrium In a 3-year, double-blind, placebo-controlled study of 356 nonhysterectomized, postmenopausal women between 45 and 64 years of age randomized to receive placebo (n=119), 0.625 mg conjugated estrogen only (n=119), or 0.625 mg conjugated estrogen plus cyclic PROVERA (n=118), results showed a reduced risk of endometrial hyperplasia in the treatment group receiving 10 mg PROVERA plus 0.625 mg conjugated estrogens compared to the group receiving 0.625 mg conjugated estrogens only. See Table 2. Table 2. Number (%) of Endometrial Biopsy Changes Since Baseline After 3 Years of Treatment Histological Results Placebo (n=119) CEE † (n=119) PROVERA ‡ + CEE (n=118) Normal/No hyperplasia (%) 116 (97) 45 (38) 112 (95) Simple (cystic) hyperplasia (%) 1 (1) 33 (28) 4 (3) Complex (adenomatous) hyperplasia (%) 1 (1) 27 (22) 2 (2) Atypia (%) 0 14 (12) 0 Adenocarcinoma (%) 1 (1) 0 0 Includes most extreme abnormal result † CEE = conjugated equine estrogens 0.625 mg/day ‡ PROVERA = medroxyprogesterone acetate tablets 10 mg/day for 12 days In a second 1-year study, 832 postmenopausal women between 45 and 65 years of age were treated with daily 0.625 mg conjugated estrogen (days 1-28), plus either 5 mg cyclic PROVERA or 10 mg cyclic PROVERA (days 15-28), or daily 0.625 mg conjugated estrogen only. The treatment groups receiving 5 or 10 mg cyclic PROVERA (days 15- 28) plus daily conjugated estrogens showed a significantly lower rate of hyperplasia as compared to the conjugated estrogens only group. See Table 3. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 3. Number (%) of Women with Endometrial Hyperplasia at 1 Year CEE MPA † + CEE * (n=283) MPA 5 mg (n=277) MPA 10 mg (n=272) Cystic hyperplasia (%) 55 (19) 3 (1) 0 Adenomatous hyperplasia without atypia 2 (1) 0 0 * CEE = conjugated equine estrogen 0.625 mg every day of a 28-day cycle. † Cyclic medroxyprogesterone acetate on days 15 to 28 Women’s Health Initiative Studies The Women’s Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of either the use of daily oral conjugated estrogens (CE 0.625 mg) alone or in combination with medroxyprogesterone acetate (MPA 2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction (MI), silent MI and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in the CE/MPA substudy), colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms. The estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.2 years of treatment, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years (relative risk [RR] 1.15, 95 percent, nominal confidence interval [nCI], 1.03-1.28). For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women- years in the group treated with CE/MPA were 6 more CHD events, 7 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reduction per 10,000 women-years were 7 fewer colorectal cancers and 5 fewer hip fractures. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS.) Results of the CE/MPA substudy which included 16,608 women (average age of 63 years, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 4. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 4 : RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARS a Placebo n = 8102 CE/MPA n = 8506 Event c Relative Risk CE/MPA vs placebo (95%nCI b) Absolute Risk per 10,000 Women-Years CHD events Non-fatal MI CHD death 1.24 (1.00-1.54) 1.28 (1.00-1.63) 1.10 (0.70-1.75) 33 25 8 39 31 8 All strokes 1.31 (1.02-1.68) 24 31 Ischemic stroke 1.44 (1.09-1.90) 18 26 Deep vein thrombosis 1.95 (1.43-2.67) 13 26 Pulmonary embolism 2.13 (1.45-3.11) 8 18 Invasive breast cancerc 1.24 (1.01-1.54) 33 41 Invasive colorectal cancer 0.56 (0.38-0.81) 16 9 Endometrial cancer 0.81 (0.48-1.36) 7 6 Cervical Cancer 1.44 (0.47-4.42) 1 2 Hip fracture 0.67 (0.47–0.96) 16 11 Vertebral fractures 0.65 (0.46-0.92) 17 11 Lower arm/wrist fractures 0.71 (0.59-0.85) 62 44 Total fractures 0.76 (0.69-0.83) 199 152 a Results are based on centrally adjudicated data. Mortality data was not part of the adjudicated data; however, data at 5.2 years of follow-up showed no difference between the groups in terms of all-cause mortality (RR 0.98, 95 percent nCI, 0.82-1.18). b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons c Includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer Women's Health Initiative Memory Study The estrogen plus progestin Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were aged 65 to 69 years, 35 percent were 70 to 74 years, and 18 percent were 75 years of age and older) to evaluate the effects of daily conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) on the incidence of probable dementia (primary outcome) compared with placebo. After an average follow-up of 4 years, 40 women in the estrogen plus progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95 percent CI, 1.21-3.48) compared to placebo. INDICATIONS AND USAGE PROVERA tablets (medroxyprogesterone acetate tablet) is a progestin indicated for the treatment of secondary amenorrhea and abnormal uterine bleeding due to hormonal This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda imbalance in the absence of organic pathology, such as fibroids or uterine cancer. PROVERA is also indicated to reduce the incidence of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving daily oral conjugated estrogens 0.625 mg tablets. CONTRAINDICATIONS PROVERA should not be used in women with any of the following conditions: 1. Undiagnosed abnormal genital bleeding 2. Known, suspected, or history of cancer of the breast 3. Known or suspected estrogen- or progesterone-dependent neoplasia 4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions 5. Active or recent (within the past year) arterial thromboembolic disease (for example, stroke and myocardial infarction) 6. Known liver dysfunction or disease 7. Missed abortion 8. As a diagnostic test for pregnancy 9. Known hypersensitivity to the ingredients in PROVERA tablets 10. Known or suspected pregnancy. WARNINGS See BOXED WARNINGS. 1. Cardiovascular disorders. An increased risk of stroke, deep vein thrombosis (DVT), pulmonary embolism, and myocardial infarction has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (for example, personal history or family history of venous thromboembolism [VTE]), obesity, and systemic lupus erythematosus should be managed appropriately. a. Stroke In the estrogen plus progestin substudy of the Women’s Health Initiative (WHI) a statistically significant increased risk of stroke was reported in women receiving daily conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5mg) compared to women receiving placebo (31 versus 24 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. (See CLINICAL STUDIES.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda b. Coronary heart disease In the estrogen plus progestin substudy of WHI, no statistically significant increase of CHD events (defined as non-fatal myocardial infarction [MI], silent MI or CHD death was reported in women receiving CE/MPA compared to women receiving placebo (39 versus 33 per 10,000 women-years). An increase in relative risk was demonstrated in year one, and a trend toward decreasing relative risk was reported in years 2 through 5. (See CLINICAL STUDIES.) In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE 0.625 mg/ MPA 2.5mg per day demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall. c. Venous thromboembolism (VTE) In the estrogen plus progestin substudy of WHI, a statistically significant two-fold greater rate of VTE, (DVT and pulmonary embolism [PE]), was reported in women receiving daily CE/MPA compared to women receiving placebo (35 versus 17 per 10,000 women- years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was observed during the first year and persisted. (See CLINICAL STUDIES.) 2. Malignant neoplasms a. Breast cancer The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer in some studies. Observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. The risk increased with duration of use and appeared to return to baseline in about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogens or among different estrogen plus progestin combinations, doses, or routes of administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) substudy of daily conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) (See CLINICAL STUDIES.) In the estrogen plus progestin substudy of WHI, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer in women who took daily CE/MPA. In this substudy, prior use of estrogen alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24 (95 percent nominal confidence interval [nCI], 1.01-1.54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo, respectively. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years, for estrogen plus progestin compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade, and hormone receptor status did not differ between the groups. The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a health care provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. b. Endometrial cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12 times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women using estrogen plus progestin therapy is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c. Ovarian cancer The estrogen plus progestin substudy of WHI reported that daily CE/MPA increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95 percent nCI, 0.77-3.24) but was not statistically significant. The absolute risk for CE/MPA was 4.2 versus 2.7 cases per 10,000 women-years. 3. Dementia In the estrogen plus progestin Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to daily conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE/MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE/MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and PRECAUTIONS, Geriatric Use.) 4. Visual Abnormalities Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be permanently discontinued. PRECAUTIONS A. General 1. Addition of a progestin when a woman has not had a hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (lowering HDL, raising LDL) and impairment of glucose tolerance. 2. Undiagnosed abnormal vaginal bleeding In cases of undiagnosed abnormal vaginal bleeding, adequate diagnostic measures are indicated. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3. Elevated blood pressure Blood pressure should be monitored at regular intervals with estrogen plus progestin therapy. 4. Hypertriglyceridemia In patients with pre-existing hypertriglyceridemia, estrogen plus progestin therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. 5. Impaired liver function and past history of cholestatic jaundice Estrogens plus progestins may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued. 6. Fluid Retention Progestins may cause some degree of fluid retention. Patients who have conditions which might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogen plus progestin are prescribed. 7. Hypocalcemia Estrogen plus progestin therapy should be used with caution in individuals with severe hypocalcemia. 8. Exacerbation of other conditions Estrogen plus progestin therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. B. Patient Information Physicians are advised to discuss the Patient Information leaflet with patients for whom they prescribe PROVERA. There may be an increased risk of minor birth defects in children whose mothers are exposed to progestins during the first trimester of pregnancy. The possible risk to the male baby is hypospadias, a condition in which the opening of the penis is on the underside rather than the tip of the penis. This condition occurs naturally in approximately 5 to 8 per 1000 male births. The risk may be increased with exposure to PROVERA. Enlargement of the clitoris and fusion of the labia may occur in female babies. However, a clear association between hypospadias, clitoral enlargement and labial fusion with use of PROVERA has not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Inform the patient of the importance of reporting exposure to PROVERA in early pregnancy. C. Drug/Laboratory Test Interactions The following laboratory results may be altered by the use of estrogen plus progestin therapy: 1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta- thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 2. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay, T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG) leading to increased circulating corticosteroid and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). 4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels. 5. Impaired glucose metabolism. D. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term intramuscular administration of PROVERA has been shown to produce mammary tumors in beagle dogs. There was no evidence of a carcinogenic effect associated with the oral administration of PROVERA to rats and mice. Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays. Medroxyprogesterone acetate at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment. Long-term continuous administration of estrogen plus progestin therapy, has shown an increased risk of breast cancer and ovarian cancer. (See WARNINGS and PRECAUTIONS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda E. Pregnancy Pregnancy Category X: PROVERA should not be used during pregnancy. (See CONTRAINDICATIONS.) There may be increased risks for hypospadias, clitoral enlargement and labial fusion in children whose mothers are exposed to PROVERA during the first trimester of pregnancy. However, a clear association between these conditions with use of PROVERA has not been established. F. Nursing Mothers PROVERA should not be used during lactation. Detectable amounts of progestin have been identified in the milk of nursing mothers receiving progestins. G. Pediatric Use PROVERA is not intended for pediatric use and no clinical data has been collected in children. H. Geriatric Use Of the total number of subjects in the estrogen plus progestin substudy of the Women’s Health Initiative (WHI), 44 percent (n = 7,320) were 65 years and older, while 6.6 percent (n = 1,095) were 75 years and older. In women 75 and older compared to women less than 75 years of age, there was a higher relative risk of non-fatal stroke and invasive breast cancer in the estrogen plus progestin group versus placebo. In women greater than 75 years of age, the increased risk of non-fatal stroke and invasive breast cancer observed in the estrogen plus progestin group compared to placebo was 75 versus 24 per 10,000 women-years and 52 versus 12 per 10,000 women-years, respectively. In the estrogen plus progestin Women’s Health Iniative Memory Study (WHIMS), a substudy of WHI, a population of 4,532 postmenopausal women, aged 65 to 70 years, was randomized to receive daily CE 0.625 mg/MPA 2.5 mg or placebo. In the estrogen plus progestin group, after an average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of probable dementia was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of developing probable dementia with CE/MPA was 45 versus 22 cases per 10,000 women-years compared with placebo. Eighty-two percent of the cases of probable dementia occurred in women that were older than 70 in the CE/MPA group. The most common classification of probable dementia in the estrogen plus progestin and placebo groups was Alzheimer’s disease. When data from the estrogen alone and estrogen plus progestin WHIMS substudies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS See BOXED WARNINGS, WARNINGS, and PRECAUTIONS. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following adverse reactions have been reported in women taking progestins, including PROVERA tablets, without concomitant estrogens treatment: 1. Genitourinary system Abnormal uterine bleeding (irregular, increase, decrease), change in menstrual flow, breakthrough bleeding, spotting, amenorrhea, changes in cervical erosion and cervical secretions. 2. Breasts Breast tenderness, mastodynia or galactorrhea has been reported. 3. Cardiovascular Thromboembolic disorders including thrombophlebitis and pulmonary embolism have been reported. 4. Gastrointestinal Nausea, cholestatic jaundice. 5. Skin Sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash have occurred. Acne, alopecia and hirsutism have been reported. 6. Eyes Neuro-ocular lesions, for example, retinal thrombosis, and optic neuritis. 7. Central nervous system Mental depression, insomnia, somnolence, dizziness, headache, nervousness. 8. Miscellaneous Hypersensitivity reactions (for example, anaphylaxis and anaphylactoid reactions, angioedema), rash (allergic) with and without pruritus, change in weight (increase or decrease), pyrexia, edema/fluid retention, fatigue, decreased glucose tolerance. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The following additional adverse reactions have been reported with estrogen and/or progestin therapy. 1. Genitourinary system Abnormal uterine bleeding/spotting, or flow; breakthrough bleeding; spotting; dysmenorrheal/pelvic pain; increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer. 2. Breasts Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer. 3. Cardiovascular Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure. 4. Gastrointestinal Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis; enlargement of hepatic hemangiomas. 5. Skin Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash. 6. Eyes Retinal vascular thrombosis, intolerance to contact lenses. 7. Central nervous system Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia. 8. Miscellaneous Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthalgias; leg cramps; changes in libido; urticaria, angioedema, anaphylactoid/anaplylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides. OVERDOSAGE Overdosage of estrogen plus progestin therapy may cause nausea and vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda occur in women. Treatment of overdose consists of discontinuation of CE/MPA together with institution of appropriate symptomatic care. DOSAGE AND ADMINISTRATION Secondary Amenorrhea PROVERA tablets may be given in dosages of 5 or 10 mg daily for 5 to 10 days. A dose for inducing an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen is 10 mg of PROVERA daily for 10 days. In cases of secondary amenorrhea, therapy may be started at any time. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing PROVERA therapy. Abnormal Uterine Bleeding Due to Hormonal Imbalance in the Absence of Organic Pathology Beginning on the calculated 16th or 21st day of the menstrual cycle, 5 or 10 mg of PROVERA may be given daily for 5 to 10 days. To produce an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen, 10 mg of PROVERA daily for 10 days beginning on the 16th day of the cycle is suggested. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing therapy with PROVERA. Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with PROVERA. Reduction of Endometrial Hyperplasia in Postmenopausal Women Receiving Daily 0.625 mg Conjugated Estrogens When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate (for example, 3-month to 6-month intervals) to determine if treatment is still necessary (see WARNINGS). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. PROVERA tablets may be given in dosages of 5 or 10 mg daily for 12 to 14 consecutive days per month, in postmenopausal women receiving daily 0.625 mg conjugated estrogens, either beginning on the 1st day of the cycle or the 16th day of the cycle. Patients should be started at the lowest dose. The lowest effective dose of PROVERA has not been determined. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED PROVERA Tablets are available in the following strengths and package sizes: 2.5 mg (scored, round, orange) Bottles of 30 NDC 0009-0064-06 Bottles of 100 NDC 0009-0064-04 5 mg (scored, hexagonal, white) Bottles of 100 NDC 0009-0286-03 10 mg (scored, round, white) Bottles of 100 NDC 0009-0050-02 Bottles of 500 NDC 0009-0050-11 Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. “Keep out of reach of children” Rx only LAB-0144- 5.0 Revised September 2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PATIENT INFORMATION PROVERA® (medroxyprogesterone acetate tablets, USP) Read this PATIENT INFORMATION before you start taking PROVERA and read the patient information each time you refill your PROVERA prescription. There may be new information. This information does not take the place of talking to your health care provider about your medical condition or your treatment. WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT PROVERA (A PROGESTIN HORMONE)? * Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your health care provider should check any unusual vaginal bleeding to find out the cause. * Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes. Using estrogens with or without progestins may increase your chance of getting heart attacks, strokes, breast cancer, and blood clots. * Using estrogens with or without progestins may increase your risk of dementia, based on a study of women age 65 years or older. You and your health care provider should talk regularly about whether you still need treatment with PROVERA. What is PROVERA? PROVERA is a medicine that contains medroxyprogesterone acetate, a progestin hormone. What is PROVERA used for? PROVERA is used to: • Treat menstrual periods that have stopped or to treat abnormal uterine bleeding. Women with a uterus who are not pregnant, who stop having regular menstrual periods or who begin to have irregular menstrual periods may have a drop in their progesterone level. Talk with your health care provider about whether PROVERA is right for you. • Reduce your chances of getting cancer of the uterus. In postmenopausal women with a uterus who use estrogens, taking progestin in combination with estrogen will reduce your chances of getting cancer of the uterus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Who should not take PROVERA? Do not start taking PROVERA if you: • Have undiagnosed vaginal bleeding • Currently have or have had certain cancers. Estrogen plus progestin may increase your chance of getting certain cancers, including cancer of the breast. If you have or have had cancer, talk with your health care provider about whether you should use PROVERA. • Had a stroke or heart attack in the past year • Currently have or have had blood clots • Currently have or have had liver problems • Think you may be pregnant Tell you health care provider if you think that you may be pregnant or having a miscarriage. There may be an increased risk of minor birth defects in children whose mothers take this drug during the first 4 months of pregnancy. If you take PROVERA and later find out you were pregnant when you took it, be sure to discuss this with your doctor as soon as possible. PROVERA should not be used as a test for pregnancy. • Are allergic to any of the ingredients in PROVERA See the list of ingredients in PROVERA at the end of this leaflet. Tell your health care provider: • If you are breastfeeding. The hormone in PROVERA can pass into your breast milk. • About all of your medical problems. Your health care provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing); epilepsy (seizures); migraine headaches; endometriosis (severe pelvic pain); lupus; problems with your heart, liver, thyroid, or kidneys; or if you have high calcium levels in your blood. • About all the medicines you take. This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how PROVERA works. PROVERA may also affect how other medicines work. • If you are going to have surgery or will be on bed rest. If you are taking estrogen in addition to PROVERA, you may need to stop taking estrogen and PROVERA. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda How should I take PROVERA? Start at the lowest dose and talk to your health care provider about how well that dose is working for you. The lowest effective dose of PROVERA has not been determined. You and your health care provider should talk regularly (every 3-6 months) about the dose you are taking and whether you still need treatment with PROVERA. 1. Absence of menstrual period: PROVERA may be given in doses ranging from 5 to 10 mg daily for 5 to 10 days. 2. Abnormal Uterine Bleeding: PROVERA may be given in doses ranging from 5 to 10 mg daily for 5 to 10 days. 3. Overgrowth of the lining of the uterus: When used in combination with oral conjugated estrogens in postmenopausal women with a uterus, PROVERA may be given in doses ranging from 5 or 10 mg daily for 12 to 14 straight days per month. What are the possible side effects of PROVERA? The following side effects have been reported with the use of PROVERA alone: • Breast tenderness • Breast milk secretion • Breakthrough bleeding • Spotting (minor vaginal bleeding) • Irregular periods • Amenorrhea (absence of menstrual periods) • Vaginal secretions • Headaches • Nervousness • Dizziness • Depression • Insomnia, sleepiness, fatigue • Premenstrual syndrome-like symptoms • Thrombophlebitis (inflamed veins) • Blood clot This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Itching, hives, skin rash • Acne • Hair loss, hair growth • Abdominal discomfort • Nausea • Bloating • Fever • Increase in weight • Swelling • Changes in vision and sensitivity to contact lenses The following side effects have been reported with the use of PROVERA with an estrogen. Side effects are grouped by how serious they are and how often they happen when you are treated: Serious but less common side effects of estrogen include: • Breast cancer • Cancer of the uterus • Stroke • Heart attack • Blood clots • Dementia • Gallbladder disease • Ovarian cancer • High blood pressure • Liver problems • High blood sugar • Enlargement of benign tumors of the uterus (“fibroids”) Some of the warning signs of these serious side effects include: • Breast lumps • Unusual vaginal bleeding • Dizziness and faintness • Changes in speech • Severe headaches • Chest pain This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Shortness of breath • Pains in your legs • Changes in vision • Vomiting • Yellowing of the skin, eyes or nail beds Call your health care provider right away if you get any of these warning signs, or any other unusual symptom that concerns you. Less serious but common side effects include: • Headache • Breast pain • Irregular vaginal bleeding or spotting • Stomach/abdominal cramps, bloating • Nausea and vomiting • Hair loss • Fluid retention • Vaginal yeast infection These are not all the possible side effects of PROVERA with or without estrogen. For more information, ask your health care provider or pharmacist. What can I do to lower my chances of a serious side effect with PROVERA? • Talk with your health care provider regularly about whether you should continue taking PROVERA. The addition of a progestin is generally recommended for women with a uterus to reduce the chance of getting cancer of the uterus. • See your health care provider right away if you get vaginal bleeding while taking PROVERA. • Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your health care provider tells you otherwise. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. • If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have a higher chance of getting heart disease. Ask your health care provider for ways to lower your chance of getting heart disease. General information about safe and effective use of PROVERA • Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. • Do not take PROVERA for conditions for which it was not prescribed. • Do not give PROVERA to other people, even if they have the same symptoms you have. It may harm them. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Keep PROVERA out of the reach of children. This leaflet provides a summary of the most important information about PROVERA. If you would like more information, talk with your health care provider or pharmacist. You can ask for information about PROVERA that is written for health professionals. You can get more information by calling the toll-free number, 1-800-438-1985. What are the ingredients in PROVERA? Each PROVERA tablet for oral administration contains 2.5 mg, 5 mg or 10 mg of medroxyprogesterone acetate. Inactive ingredients: calcium stearate, corn starch, lactose, mineral oil, sorbic acid, sucrose, talc. The 2.5 mg tablet contains FD&C Yellow No. 6. LAB-0365-4.0 Revised September 2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:46.633052	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011839s071lbl.pdf', 'application_number': 11839, 'submission_type': 'SUPPL ', 'submission_number': 71}

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