DISKETS

6 ADVERSE REACTIONS The following serious adverse reactions and/or conditions are described, or described in greater detail, in other sections: • Respiratory Depression [see Warnings and Precautions ( 5.1 )] • Interactions with Benzodiazepines and other CNS Depressants [see Warnings and Precautions ( 5.2 )] • QT Prolongation [see Warnings and Precautions ( 5.3 )] • Serotonin Syndrome [see Warnings and Precautions ( 5.9 )] • Adrenal Insufficiency [see Warnings and Precautions ( 5.10 )] • Severe Hypotension [see Warnings and Precautions ( 5.11 )] • Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.13 )] • Seizures [see Warnings and Precautions ( 5.14 )] • Withdrawal [see Warnings and Precautions ( 5.15 )] • Hypoglycemia [see Warnings and Precautions ( 5.17 )] The following adverse reactions have been identified during post-approval use of methadone. 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 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 included lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seemed to be more prominent in ambulatory patients and in those who are not suffering severe pain. 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, torsade de pointes , ventricular fibrillation, ventricular tachycardia. Central Nervous System: agitation, confusion, disorientation, dysphoria, euphoria, insomnia, hallucinations, seizures, visual disturbances, congenital oculomotor disorders (nystagmus, strabismus) 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 Musculoskeletal: decreased muscle mass and strength, osteoporosis and fractures 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 DISKETS Dispersible Tablets. Serotonin Syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in DISKETS. Androgen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2 )] . Hypoglycemia: Cases of hypoglycemia have been reported in patients taking methadone [see Warnings and Precautions ( 5.17 )] . Most Common Adverse Reactions Are : lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS DISKETS Dispersible Tablets are contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions ( 5.1 )]. • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.8 )]. • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.13 )]. • Hypersensitivity (e.g. anaphylaxis) to methadone or any other ingredient in DISKETS Dispersible Tablets [see Adverse Reactions ( 6 )]. • Significant respiratory depression ( 4 ) • Acute or severe bronchial asthma ( 4 ) • Known or suspected paralytic ileus ( 4 ) • Known hypersensitivity to methadone ( 4 )

11 DESCRIPTION DISKETS Dispersible Tablets (Methadone Hydrochloride Tablets for Oral Suspension USP), contain methadone, an opioid agonist, available as 40 mg dispersible tablets for oral administration. Methadone hydrochloride is chemically described as 6-(dimethylamino)-4,4-diphenyl-3-heptanone hydrochloride. Methadone hydrochloride USP is a fine white powder. It is very soluble in water, soluble in isopropanol and in chloroform, and practically insoluble in ether and in glycerine. It is present in DISKETS Dispersible Tablets as the racemic mixture. Methadone hydrochloride has a melting point of 235°C, a pKa of 8.25 in water at 20°C, a solution (1 part per 100) pH between 4.5 and 6.5, a partition coefficient of 117 at pH 7.4 in octanol/water and a molecular weight of 345.91. Its molecular formula is C 21 H 27 NO•HCl and its structural formula is: Each DISKETS Dispersible Tablet contains 40 mg of methadone hydrochloride USP and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, orange lake blend, orange/pineapple flavor, potassium phosphate monobasic, pregelatinized starch and stearic acid. DISKETS Dispersible Tablets are cross-scored, allowing for flexible dosage adjustment. Each tablet may be broken or cut in half to yield two 20 mg doses, or in quarters to yield four 10 mg doses. DISKETS Dispersible Tablets (Methadone Hydrochloride Tablets for Oral Suspension USP), are for oral administration following dispersion in a liquid. DISKETS Dispersible Tablets contain insoluble excipients and must not be injected. chem.jpg

2 DOSAGE AND ADMINISTRATION • Strongly consider prescribing naloxone at the time DISKETS is initiated or renewed because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose. ( 2.3 ) • Initiation of Detoxification and Maintenance Treatment: A single dose of 20 to 30 mg may be sufficient to suppress withdrawal syndrome. ( 2.5 ) • Maintenance Treatment: Clinical stability is most commonly achieved at doses between 80 to 120 mg/day. ( 2.6 ) • Do not abruptly discontinue DISKETS Dispersible Tablets in a physically dependent patient. ( 2.7 , 5.15 ) 2.1 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)). 2.2 Important Dosage and Administration Information DISKETS Dispersible Tablets are for oral administration only. The preparation must not be injected. Methadone should be kept out of reach of children to prevent accidental ingestion. Consider the following important factors that differentiate methadone from other opioids: • The peak respiratory depressant effect of methadone occurs later and persists longer than its peak pharmacologic 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 other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other opioid agonists. • There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based conversion ratios between methadone and other opioids are not accurate when applied to individuals. • With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity. • Steady-state plasma concentrations are not attained until 3 to 5 days after initiation of dosing. DISKETS have a narrow therapeutic index, especially when combined with other drugs. 2.3 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with DISKETS Dispersible Tablets. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Warnings and Precautions ( 5.1 )] . Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with DISKETS Dispersible Tablets itself [see Overdosage ( 10 )] . Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Patient Counseling Information ( 17 )] . 2.4 Dosing Instructions DISKETS are intended for dispersion in a liquid immediately prior to oral administration of the prescribed dose. The tablets should not be chewed or swallowed before dispersing in liquid. DISKETS are cross-scored, allowing for flexible dosage adjustment. Each cross-scored tablet may be broken or cut in half to yield two 20-mg doses, or in quarters to yield four 10-mg doses. Prior to administration, the desired dose of DISKETS should be dispersed in approximately 120 mL (4 ounces) of water, orange juice, or other acidic fruit beverage prior to taking. Methadone hydrochloride is very soluble in water, but there are some insoluble excipients that will not entirely dissolve. If residue remains in the cup after initial administration, a small amount of liquid should be added and the resulting mixture administered to the patient. 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 methadone 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 methadone if withdrawal symptoms have not been suppressed or if symptoms reappear. The total daily dose of methadone 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 (i.e., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Because DISKETS can be administered only in 10 mg increments, DISKETS may not be the appropriate product for initial dosing in many patients. 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. Also consider concurrent medications and the general condition and medical status of the patient when selecting the initial dose. During the induction phase of methadone maintenance treatment, patients are being withdrawn from opioids and may have opioid withdrawal symptoms. Monitor patients for signs and symptoms of opioid withdrawal 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. 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 methadone. Decrease the dose of methadone on a daily basis or at 2-day intervals, keeping the amount of methadone 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. Because DISKETS can be administered only in 10 mg increments, DISKETS may not be the appropriate product for gradual dose reduction in many patients. 2.6 Titration and Maintenance Treatment of Opioid Dependence 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. During prolonged administration of methadone, monitor patients for persistent constipation and manage accordingly. 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. Because DISKETS can be administered only in 10 mg increments, it may not be the appropriate product for gradual dose reduction in many patients. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment. Do not abruptly discontinue DISKETS Dispersible tablets in a physically dependent patient [see Warnings and Precautions ( 5.15 )] . 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 [see Use in Specific Populations ( 8.1 )].

1 INDICATIONS AND USAGE DISKETS Dispersible Tablets contain methadone, an opioid agonist indicated for the: • 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. Limitations of Use Methadone products used for the treatment of opioid addiction in detoxification or maintenance programs are subject to the conditions for distribution and use required under 42 CFR 8.12 [see Dosage and Administration ( 2.1 )] . DISKETS Dispersible Tablets are an opioid agonist indicated for the: • Detoxification treatment of opioid addiction (heroin or other morphine-like drugs). ( 1 ) • Maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services. ( 1 ) Limitations of Use • Methadone products used for the treatment of opioid addiction in detoxification or maintenance programs are subject to the conditions for distribution and use required under 21 CFR, Title 42, Sec 8. ( 1 , 2.1 )

9.2 Abuse DISKETS contain methadone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, and tapentadol. DISKETS can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions ( 5.5 )] . Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: 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 persons with substance use disorders. 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 healthcare provider(s). “Doctor shopping” (visiting multiple prescribers 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. Healthcare providers 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. DISKETS, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity and frequency as required by state and federal law, is strongly advised. 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. Risks Specific to DISKETS: Abuse of methadone poses a risk of overdose and death. This risk is increased with concurrent abuse of methadone with alcohol and other substances. DISKETS are intended 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. DISKETS Dispersible Tablets, when used for the treatment of opioid addiction in detoxification or maintenance programs, may be dispensed only by opioid treatment programs certified by the Substance Abuse and Mental Health Services Administration (and agencies, practitioners, and institutions by formal agreements with the program sponsor).

9.1 Controlled Substance DISKETS contain methadone, a Schedule II controlled substance.

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 (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 significant dose reduction of a drug. Withdrawal is also precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene) or mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Physical dependence is expected during opioid agonist therapy of opioid addiction. DISKETS Dispersible Tablets should not be abruptly discontinued [see Dosage and Administration ( 2.6 , 2.7 )] . If DISKETS Dispersible Tablets are abruptly discontinued in a physically dependent patient, a withdrawal 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. Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions ( 5.6 )] .

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance DISKETS contain methadone, a Schedule II controlled substance. 9.2 Abuse DISKETS contain methadone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, and tapentadol. DISKETS can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions ( 5.5 )] . Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: 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 persons with substance use disorders. 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 healthcare provider(s). “Doctor shopping” (visiting multiple prescribers 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. Healthcare providers 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. DISKETS, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity and frequency as required by state and federal law, is strongly advised. 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. Risks Specific to DISKETS: Abuse of methadone poses a risk of overdose and death. This risk is increased with concurrent abuse of methadone with alcohol and other substances. DISKETS are intended 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. DISKETS Dispersible Tablets, when used for the treatment of opioid addiction in detoxification or maintenance programs, may be dispensed only by opioid treatment programs certified by the Substance Abuse and Mental Health Services Administration (and agencies, practitioners, and institutions by formal agreements with the program sponsor). 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 (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 significant dose reduction of a drug. Withdrawal is also precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene) or mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Physical dependence is expected during opioid agonist therapy of opioid addiction. DISKETS Dispersible Tablets should not be abruptly discontinued [see Dosage and Administration ( 2.6 , 2.7 )] . If DISKETS Dispersible Tablets are abruptly discontinued in a physically dependent patient, a withdrawal 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. Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions ( 5.6 )] .

10 OVERDOSAGE Clinical Presentation: Acute overdosage with methadone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology ( 12.2 )] . In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. Methadone overdosage is associated with rhabdomyolysis. Seek medical attention, especially if abuse/misuse results in prolonged immobilization. Acute toxic leukoencephalopathy has been reported after methadone overdose, often weeks after apparent recovery from the initial intoxication. Hearing loss has been reported after methadone overdose, in some cases permanent. 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. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist. Because the duration of reversal would be expected to be less than the duration of action of methadone, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to opioid antagonists is suboptimal or not sustained, administer additional antagonist as directed in the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced 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 initiated with care and by titration with smaller than usual doses of the antagonist.

7 DRUG INTERACTIONS Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Intervention: Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate. Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments [see Warnings and Precautions ( 5.2 )]. If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder [see Warnings and Precautions ( 5.1 )]. Examples: Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids. Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 Clinical Impact: Methadone undergoes hepatic N-demethylation by several cytochrome P450 (CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. The concomitant use of DISKETS Dispersible Tablets and CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors can increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects, and may result in a fatal overdose, particularly when an inhibitor is added after a stable dose of DISKETS Dispersible Tablets is achieved. These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes listed above. After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor, as the effects of the inhibitor decline, the methadone plasma concentration can decrease [see Clinical Pharmacology ( 12.3 )] , resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone. Intervention: If concomitant use is necessary, consider dosage reduction of DISKETS Dispersible Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, follow patients for signs of opioid withdrawal and consider increasing the DISKETS Dispersible Tablets dosage until stable drug effects are achieved. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), fluconazole, fluvoxamine, some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine). Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9 Clinical Impact: The concomitant use of DISKETS Dispersible Tablets and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone [see Clinical Pharmacology ( 12.3 )] , resulting in decreased efficacy or onset of withdrawal symptoms in patients physically dependent on methadone. These effects could be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes. After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects of the inducer decline, the methadone plasma concentration can increase [see Clinical Pharmacology ( 12.3 )] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, sedation, or death. Intervention: If concomitant use is necessary, consider increasing the DISKETS Dispersible Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider DISKETS Dispersible Tablets dosage reduction and monitor for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin, St. John’s Wort, phenobarbital. Potentially Arrhythmogenic Agents Clinical Impact: Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia). Intervention: Monitor patients closely for cardiac conduction changes. Examples: Drugs known to have potential to prolong QT interval: Class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Drugs capable of inducing electrolyte disturbances: Diuretics, laxatives, and, in rare cases, mineralocorticoid hormones. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions ( 5.9 )] . Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DISKETS if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.1 , 5.9 )] . Intervention: The use of DISKETS is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: Phenelzine, tranylcypromine, linezolid. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: Patients maintained on methadone may experience withdrawal symptoms when given opioid antagonists, mixed agonist/antagonists, and partial agonists. Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine. Muscle Relaxants Clinical Impact: Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DISKETS and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, strongly consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 , 5.2 )]. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when DISKETS are used concomitantly with anticholinergic drugs. Paradoxical Effects of Antiretroviral Agents on Methadone: Concurrent use of certain protease inhibitors with CYP3A4 inhibitory activity, alone and in combination, such as abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, and tipranavir+ritonavir, has resulted in increased clearance or decreased plasma levels of methadone. This may result in reduced efficacy of DISKETS Dispersible Tablets and could precipitate a withdrawal syndrome. Monitor patients receiving DISKETS Dispersible Tablets and any of these anti-retroviral therapies closely for evidence of withdrawal effects and adjust the DISKETS Dispersible Tablets dose accordingly. Effects of Methadone 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. Effects of Methadone on Antidepressants: Desipramine: Blood levels of desipramine have increased with concurrent methadone administration. • Potentially Arrhythmogenic Agents: Monitor patients closely for cardiac conduction changes. ( 7 ) • Interactions with CNS Depressants: Consider dose reduction of one or both drugs because of additive effects. ( 7 ) • Mixed Agonist/Antagonist and Partial Agonist Opioids : Avoid concomitant use with DISKETS because it may precipitate withdrawal symptoms. ( 5.15 , 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methadone hydrochloride is a mu-agonist; a synthetic opioid 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 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. 12.2 Pharmacodynamics Effects on the Central Nervous System: Methadone produces respiratory depression by 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. Methadone causes 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 origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Some NMDA receptor antagonists have been shown to produce neurotoxic effects in animals. Effects on the Gastrointestinal Tract and Other Smooth Muscle: Methadone causes 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 is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System: Methadone produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Effects on the Endocrine System: Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6 )] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6 )] . Effects on the 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. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Adverse Reaction Relationships: There is a relationship between increasing methadone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.5 , 2.6 , 2.7 )]. 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 1,255 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 to 8 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. Elimination: 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, CYP2C19, 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. Drug Interaction Studies: Cytochrome P450 Interactions: Methadone undergoes hepatic N-demethylation by cytochrome P450 (CYP) isoforms, principally CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. Co-administration 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 )] . Cytochrome P450 Inducers: The following drug interactions were reported following co-administration 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: Voriconazole: Voriconazole can inhibit the activity of CYP3A4, CYP2C9, and CYP2C19. 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 co-administration. Dose reduction of methadone may be needed [see Drug Interactions ( 7 )] . 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, tipranavir+ritonavir combination : Co-administration of these anti-retroviral agents resulted in increased clearance or decreased plasma levels of methadone [see Drug Interactions ( 7 )] . 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 )] . Zidovudine: Methadone increased the AUC of zidovudine which could result in toxic effects [see Drug Interactions ( 7 )] .

12.1 Mechanism of Action Methadone hydrochloride is a mu-agonist; a synthetic opioid 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 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.

12.2 Pharmacodynamics Effects on the Central Nervous System: Methadone produces respiratory depression by 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. Methadone causes 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 origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Some NMDA receptor antagonists have been shown to produce neurotoxic effects in animals. Effects on the Gastrointestinal Tract and Other Smooth Muscle: Methadone causes 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 is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System: Methadone produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Effects on the Endocrine System: Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6 )] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6 )] . Effects on the 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. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Adverse Reaction Relationships: There is a relationship between increasing methadone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.5 , 2.6 , 2.7 )].

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 1,255 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 to 8 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. Elimination: 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, CYP2C19, 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. Drug Interaction Studies: Cytochrome P450 Interactions: Methadone undergoes hepatic N-demethylation by cytochrome P450 (CYP) isoforms, principally CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. Co-administration 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 )] . Cytochrome P450 Inducers: The following drug interactions were reported following co-administration 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: Voriconazole: Voriconazole can inhibit the activity of CYP3A4, CYP2C9, and CYP2C19. 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 co-administration. Dose reduction of methadone may be needed [see Drug Interactions ( 7 )] . 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, tipranavir+ritonavir combination : Co-administration of these anti-retroviral agents resulted in increased clearance or decreased plasma levels of methadone [see Drug Interactions ( 7 )] . 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 )] . Zidovudine: Methadone increased the AUC of zidovudine which could result in toxic effects [see Drug Interactions ( 7 )] .

20231201

14

3 DOSAGE FORMS AND STRENGTHS 40 mg dispersible tablet for oral administration following dispersion in a liquid: pillow-shaped, light-pinkish orange, cross-scored compressed dispersible tablet. Tablets Intended for Dispersion in a Liquid Immediately Prior to Oral Administration: 40 mg. ( 3 )

DISKETS Methadone Hydrochloride METHADONE HYDROCHLORIDE METHADONE SILICON DIOXIDE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE MONOBASIC POTASSIUM PHOSPHATE STARCH, CORN STEARIC ACID FD&C YELLOW NO. 6 Light Pinkish 54;883

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 (HDD). 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 the HDD. 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 the HDD. 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 decreased sexual activity (mating) of male rats at 10 mg/kg/day (corresponding to 0.3 times the human daily oral dose of 120 mg/day based on body surface area). Methadone also produces a significant regression of sex accessory organs and testes of male mice and rats at 0.2 and 0.8 times the HDD, respectively. Methadone treatment of pregnant rats from Gestation Day 14 to 19 reduced fetal blood testosterone and androstenedione in males. Decreased serum levels of testosterone were observed in male rats that were treated with methadone (1.3 to 3.3 mg/kg/day for 14 days, corresponding to 0.1 to 0.3 times the HDD) or 10 to 15 mg/kg/day for 10 days (0.8 to 1.2 times the HDD).

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 (HDD). 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 the HDD. 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 the HDD. 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 decreased sexual activity (mating) of male rats at 10 mg/kg/day (corresponding to 0.3 times the human daily oral dose of 120 mg/day based on body surface area). Methadone also produces a significant regression of sex accessory organs and testes of male mice and rats at 0.2 and 0.8 times the HDD, respectively. Methadone treatment of pregnant rats from Gestation Day 14 to 19 reduced fetal blood testosterone and androstenedione in males. Decreased serum levels of testosterone were observed in male rats that were treated with methadone (1.3 to 3.3 mg/kg/day for 14 days, corresponding to 0.1 to 0.3 times the HDD) or 10 to 15 mg/kg/day for 10 days (0.8 to 1.2 times the HDD).

NDA017058

DISKETS

Methadone Hydrochloride

0054-4538

HUMAN PRESCRIPTION DRUG

ORAL

Package/Label Display Panel NDC 0054- 4538 -25 Rx only bottlelabel

Warnings and Precautions ( 5.17 ) 12/2023

17 PATIENT COUNSELING INFORMATION Provide the following information to patients receiving DISKETS Dispersible Tablets or to their caregivers: Life-Threatening Respiratory Depression: Discuss the risk of respiratory depression with patients, explaining that the risk is greatest when starting DISKETS Dispersible Tablets or when the dose is increased. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions ( 5.1 )]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose: Because patients being treated for opioid use disorder are at risk for relapse, discuss the importance of having access to naloxone with the patient and caregiver. Also discuss the importance of having access to naloxone if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers of the options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize the signs and symptoms of an opioid overdose. Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered. Repeat administration may be necessary, particularly for overdose involving DISKETS Dispersible Tablets, because naloxone is often not effective at the doses available for patient access [ Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 ), Overdosage ( 10 ) ]. If naloxone is prescribed, also advise patients and caregivers: • How to treat with naloxone in the event of an opioid overdose • To tell family and friends about their naloxone and to keep it in a place where family and friends can easily access it in an emergency • To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Interactions with Benzodiazepines and Other CNS Depressants: Inform patients and caregivers that potentially fatal additive effects may occur if DISKETS Dispersible Tablets are used with benzodiazepines or other CNS depressants, including alcohol. Counsel patients that such medications should not be used concomitantly unless supervised by a healthcare provider [see Warnings and Precautions ( 5.2 )] . 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 DISKETS Dispersible Tablets [see Warnings and Precautions ( 5.3 )] . Accidental Ingestion: Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions ( 5.4 )] . Instruct patients to take steps to store DISKETS Dispersible Tablets securely. Advise patients to dispose of unused DISKETS Dispersible Tablets by flushing the tablets down the toilet. Abuse Potential: Inform patients that DISKETS Dispersible Tablets contain methadone, a Schedule II controlled substance that is subject to abuse [see Warnings and Precautions ( 5.5 )] . Instruct patients not to share DISKETS Dispersible Tablets with others and to take steps to protect DISKETS Dispersible Tablets from theft or misuse. Important Administration Instructions [see Dosage and Administration ( 2 )]: Instruct patients how to properly take DISKETS Dispersible Tablets, including the following: • DISKETS Dispersible Tablets are for oral administration only and must be initially dispersed in liquid before use. After dispersion in liquid, the preparation must not be injected . • Inform patients that DISKETS Dispersible Tablets should be taken only as directed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression), and the dose should not be adjusted without consulting a physician or other healthcare professional. • Reassure patients initiating treatment with DISKETS Dispersible Tablets for opioid dependence that the dose of methadone will “hold” for longer periods of time as treatment progresses. • Apprise patients seeking to discontinue treatment with methadone for opioid dependence of the high risk of relapse to illicit drug use associated with discontinuation of DISKETS Dispersible Tablets maintenance treatment. • Advise patients not to discontinue DISKETS Dispersible Tablets without first discussing the need for a tapering regimen with the prescriber. Serotonin Syndrome: Inform patients that DISKETS could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see Warnings and Precautions ( 5.9 ), Drug Interactions ( 7 )] . MAOI Interaction: Inform patients to avoid taking DISKETS while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking DISKETS [see Drug Interactions ( 7 )]. Adrenal Insufficiency: Inform patients that DISKETS could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions ( 5.10 )] . Hypotension: Inform patients that DISKETS Dispersible Tablets may cause orthostatic hypotension and syncope. Instruct patients on 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) [see Warnings and Precautions ( 5.11 )] . Anaphylaxis: Inform patients that anaphylaxis has been reported with ingredients contained in DISKETS Dispersible Tablets. Advise patients how to recognize such a reaction and when to seek medical attention [see Adverse Reactions ( 6 )]. Neonatal Opioid Withdrawal: Advise women that if they are pregnant while being treated with DISKETS, the baby may have signs of withdrawal at birth and that withdrawal is treatable [see Warnings and Precautions ( 5.6 ), Specific Populations ( 8.1 )] . Lactation: Advise women who are breastfeeding to monitor the infant for increased sleepiness (more than usual), difficulty breathing or limpness. Instruct nursing mothers using DISKETS Dispersible Tablets 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 their 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) [see Use in Specific Populations ( 8.2 )]. Infertility: Advise patients that chronic use of opioids, such as DISKETS Dispersible Tablets, may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations ( 8.3 )]. Driving or Operating Heavy Machinery: Inform patients that DISKETS Dispersible Tablets may impair the ability to perform potentially hazardous activities such as driving or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions ( 5.16 )] . Constipation: Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions ( 6 ), Clinical Pharmacology ( 12.2 )] . Hypoglycemia: Inform patients that methadone may cause hypoglycemia. Instruct patients how to recognize that symptoms of low blood glucose and to contact their healthcare provider if these symptoms occur [see Warnings and Precautions ( 5.17 )] . Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07992 C50000737/03 Revised December 2023

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 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. Methadone is known to be substantially excreted by the kidney, and the risk of adverse 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.

8.4 Pediatric Use The safety, effectiveness, and pharmacokinetics of methadone in pediatric patients below the age of 18 years have not been established.

8.1 Pregnancy Risk Summary The majority of available data from clinical trials, observational studies, case series, and case reports on methadone use in pregnancy do not indicate an increased risk of major malformations specifically due to methadone. Pregnant women involved in methadone maintenance programs have been reported to have improved prenatal care leading to 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 in these studies appears to occur after the first trimester of pregnancy ( see Data ). Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions ( 5.6 )]. In published animal reproduction studies, methadone administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) in the hamster at doses 2 times the human daily oral dose of 120 mg/day on a mg/m 2 basis (HDD) and in mice at doses equivalent to the HDD. Administration of methadone to pregnant animals during organogenesis and through lactation resulted decreased litter size, increased pup mortality, decreased pup body weights, developmental delays, and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD. Administration of methadone to male rodents prior to mating with untreated females resulted in increased neonatal mortality and significant differences in behavioral tests in the offspring at exposures comparable to and less than the HDD ( see Data ). Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 Disease-associated Maternal and Embryo-fetal Risk : Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use. Dosage Adjustment During Pregnancy : Dosage adjustment using higher doses or administering the daily dose in divided doses may be necessary in pregnant women treated with DISKETS. Pregnant women appear to have significantly lower trough plasma methadone concentrations, increased plasma methadone clearance, and shorter methadone half-life than after delivery [see Dosage and Administration ( 2.10 ) and Clinical Pharmacology ( 12.3 )] . Withdrawal signs and symptoms should be closely monitored and the dose adjusted as necessary. Fetal/Neonatal Adverse Reactions : Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with DISKETS. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.6 )]. Labor or Delivery : Opioid-dependent women on methadone maintenance therapy may require additional analgesia during labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data The majority of available data from clinical trials, observational studies, case series, and case reports on methadone use in pregnancy do not indicate an increased risk of major malformations specifically due to methadone. Findings regarding specific major malformations, decreased fetal growth, premature birth and Sudden Infant Death Syndrome have been inconsistent. Children prenatally exposed to methadone have been reported to demonstrate mild but persistent deficits in performance on psychometric and behavioral tests and visual abnormalities. In a multicenter, double-blind, randomized, controlled trial [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups. A total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy. Among women who remained in treatment until delivery, there was no difference between methadone-treated and buprenorphine-treated groups in the number of neonates requiring NOWS treatment or in the peak severity of NOWS. Buprenorphine-exposed neonates required less morphine (mean total dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10.0 days vs. 17.5 days), and shorter duration of treatment for NOWS (4.1 days vs. 9.9 days) compared to the methadone-exposed group. There were no differences between groups in other primary outcomes (neonatal head circumference), or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1-minute and 5-minute Apgar scores), or in the rates of maternal or neonatal adverse events. The outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known. Because of the imbalance in discontinuation rates between the methadone and buprenorphine groups, the study findings are difficult to interpret. Animal Data Formal reproductive and developmental toxicology studies for methadone have not been conducted. Exposure margins for the following published study reports are based on a human daily dose (HDD) of 120 mg methadone using a body surface area comparison. In a published study in pregnant hamsters, a single subcutaneous dose of methadone ranging from 31 mg/kg (2 times the HDD) to 185 mg/kg on Gestation Day 8 resulted in a decrease in the number of fetuses per litter and an increase in the percentage of fetuses exhibiting neural tube defects including exencephaly, cranioschisis, and “various other lesions.” The majority of the doses tested also resulted in maternal death. In a study in pregnant JBT/Jd mice, a single subcutaneous dose of 22 to 24 mg/kg methadone (approximately equivalent to the HDD) administered on Gestation Day 9 produced exencephaly in 11% of the embryos. In another study in pregnant mice, subcutaneous doses up to 28 mg/kg/day methadone (equivalent to the HDD) administered from Gestation Day 6 to 15 resulted in no malformations, but there were increased post-implantation loss and decreased live fetuses at 10 mg/kg/day or greater (0.4 times the HDD) and decreased ossification and fetal body weight at 20 mg/kg/day or greater (0.8 times the HDD). In a second study of pregnant mice dosed with subcutaneous doses up to 28 mg/kg/day methadone from Gestation Day 6 to 15, there was decreased pup viability, delayed onset of development of negative phototaxis and eye opening, increased righting reflexes at 5 mg/kg/day or greater (0.2 times the HDD), and decreased number of live pups at birth and decreased pup weight gain at 20 mg/kg/day or greater (0.8 times the HDD). No effects were reported in a study of pregnant rats and rabbits at oral doses up to 40 mg/kg (3 and 6 times, respectively, the HDD) administered from Gestation Days 6 to 15 and 6 to 18, respectively. When pregnant rats were treated with intraperitoneal doses of 2.5, 5, or 7.5 mg/kg methadone from one week prior to mating, through gestation until the end of lactation period, 5 mg/kg or greater (0.4 times the HDD) methadone resulted in decreases in litter size and live pups born and 7.5 mg/kg (0.6 times the HDD) resulted in decreased birth weights. Furthermore, decreased pup viability and pup body weight gain at 2.5 mg/kg or greater (0.2 times the HDD) were noted during the preweaning period. Additional animal data demonstrate evidence for neurochemical changes in the brains of offspring from methadone-treated pregnant rats, including changes to the cholinergic, dopaminergic, noradrenergic and serotonergic systems at doses below the HDD. Other animal studies have reported that prenatal and/or postnatal exposure to opioids including methadone alters neuronal development and behavior in the offspring including alterations in learning ability, motor activity, thermal regulation, nociceptive responses, and sensitivity to drugs at doses below the HDD. Treatment of pregnant rats subcutaneously with 5 mg/kg methadone from Gestation Day 14 to 19 (0.4 times the HDD) reduced fetal blood testosterone and androstenedione in males. Published animal data have reported increased neonatal mortality in the offspring of male rodents that were treated with methadone at doses comparable to and less than the HDD for 1 to 12 days before and/or during mating (with more pronounced effects in the first 4 days). 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. Examination of uterine contents of methadone-naïve female mice bred to methadone-treated male mice (once a day for three consecutive days) indicated that methadone treatment produced an increase in the rate of preimplantation deaths in all post-meiotic states at 1 mg/kg/day or greater (0.04 times the HDD). Chromosome analysis revealed a dose-dependent increase in the frequency of chromosomal abnormalities at 1 mg/kg/day or greater. 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.

8 USE IN SPECIFIC POPULATIONS • Lactation : Monitor breastfed infants for increased drowsiness and breathing difficulties. ( 8.2 ) 8.1 Pregnancy Risk Summary The majority of available data from clinical trials, observational studies, case series, and case reports on methadone use in pregnancy do not indicate an increased risk of major malformations specifically due to methadone. Pregnant women involved in methadone maintenance programs have been reported to have improved prenatal care leading to 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 in these studies appears to occur after the first trimester of pregnancy ( see Data ). Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions ( 5.6 )]. In published animal reproduction studies, methadone administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) in the hamster at doses 2 times the human daily oral dose of 120 mg/day on a mg/m 2 basis (HDD) and in mice at doses equivalent to the HDD. Administration of methadone to pregnant animals during organogenesis and through lactation resulted decreased litter size, increased pup mortality, decreased pup body weights, developmental delays, and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD. Administration of methadone to male rodents prior to mating with untreated females resulted in increased neonatal mortality and significant differences in behavioral tests in the offspring at exposures comparable to and less than the HDD ( see Data ). Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 Disease-associated Maternal and Embryo-fetal Risk : Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use. Dosage Adjustment During Pregnancy : Dosage adjustment using higher doses or administering the daily dose in divided doses may be necessary in pregnant women treated with DISKETS. Pregnant women appear to have significantly lower trough plasma methadone concentrations, increased plasma methadone clearance, and shorter methadone half-life than after delivery [see Dosage and Administration ( 2.10 ) and Clinical Pharmacology ( 12.3 )] . Withdrawal signs and symptoms should be closely monitored and the dose adjusted as necessary. Fetal/Neonatal Adverse Reactions : Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with DISKETS. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.6 )]. Labor or Delivery : Opioid-dependent women on methadone maintenance therapy may require additional analgesia during labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data The majority of available data from clinical trials, observational studies, case series, and case reports on methadone use in pregnancy do not indicate an increased risk of major malformations specifically due to methadone. Findings regarding specific major malformations, decreased fetal growth, premature birth and Sudden Infant Death Syndrome have been inconsistent. Children prenatally exposed to methadone have been reported to demonstrate mild but persistent deficits in performance on psychometric and behavioral tests and visual abnormalities. In a multicenter, double-blind, randomized, controlled trial [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups. A total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy. Among women who remained in treatment until delivery, there was no difference between methadone-treated and buprenorphine-treated groups in the number of neonates requiring NOWS treatment or in the peak severity of NOWS. Buprenorphine-exposed neonates required less morphine (mean total dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10.0 days vs. 17.5 days), and shorter duration of treatment for NOWS (4.1 days vs. 9.9 days) compared to the methadone-exposed group. There were no differences between groups in other primary outcomes (neonatal head circumference), or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1-minute and 5-minute Apgar scores), or in the rates of maternal or neonatal adverse events. The outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known. Because of the imbalance in discontinuation rates between the methadone and buprenorphine groups, the study findings are difficult to interpret. Animal Data Formal reproductive and developmental toxicology studies for methadone have not been conducted. Exposure margins for the following published study reports are based on a human daily dose (HDD) of 120 mg methadone using a body surface area comparison. In a published study in pregnant hamsters, a single subcutaneous dose of methadone ranging from 31 mg/kg (2 times the HDD) to 185 mg/kg on Gestation Day 8 resulted in a decrease in the number of fetuses per litter and an increase in the percentage of fetuses exhibiting neural tube defects including exencephaly, cranioschisis, and “various other lesions.” The majority of the doses tested also resulted in maternal death. In a study in pregnant JBT/Jd mice, a single subcutaneous dose of 22 to 24 mg/kg methadone (approximately equivalent to the HDD) administered on Gestation Day 9 produced exencephaly in 11% of the embryos. In another study in pregnant mice, subcutaneous doses up to 28 mg/kg/day methadone (equivalent to the HDD) administered from Gestation Day 6 to 15 resulted in no malformations, but there were increased post-implantation loss and decreased live fetuses at 10 mg/kg/day or greater (0.4 times the HDD) and decreased ossification and fetal body weight at 20 mg/kg/day or greater (0.8 times the HDD). In a second study of pregnant mice dosed with subcutaneous doses up to 28 mg/kg/day methadone from Gestation Day 6 to 15, there was decreased pup viability, delayed onset of development of negative phototaxis and eye opening, increased righting reflexes at 5 mg/kg/day or greater (0.2 times the HDD), and decreased number of live pups at birth and decreased pup weight gain at 20 mg/kg/day or greater (0.8 times the HDD). No effects were reported in a study of pregnant rats and rabbits at oral doses up to 40 mg/kg (3 and 6 times, respectively, the HDD) administered from Gestation Days 6 to 15 and 6 to 18, respectively. When pregnant rats were treated with intraperitoneal doses of 2.5, 5, or 7.5 mg/kg methadone from one week prior to mating, through gestation until the end of lactation period, 5 mg/kg or greater (0.4 times the HDD) methadone resulted in decreases in litter size and live pups born and 7.5 mg/kg (0.6 times the HDD) resulted in decreased birth weights. Furthermore, decreased pup viability and pup body weight gain at 2.5 mg/kg or greater (0.2 times the HDD) were noted during the preweaning period. Additional animal data demonstrate evidence for neurochemical changes in the brains of offspring from methadone-treated pregnant rats, including changes to the cholinergic, dopaminergic, noradrenergic and serotonergic systems at doses below the HDD. Other animal studies have reported that prenatal and/or postnatal exposure to opioids including methadone alters neuronal development and behavior in the offspring including alterations in learning ability, motor activity, thermal regulation, nociceptive responses, and sensitivity to drugs at doses below the HDD. Treatment of pregnant rats subcutaneously with 5 mg/kg methadone from Gestation Day 14 to 19 (0.4 times the HDD) reduced fetal blood testosterone and androstenedione in males. Published animal data have reported increased neonatal mortality in the offspring of male rodents that were treated with methadone at doses comparable to and less than the HDD for 1 to 12 days before and/or during mating (with more pronounced effects in the first 4 days). 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. Examination of uterine contents of methadone-naïve female mice bred to methadone-treated male mice (once a day for three consecutive days) indicated that methadone treatment produced an increase in the rate of preimplantation deaths in all post-meiotic states at 1 mg/kg/day or greater (0.04 times the HDD). Chromosome analysis revealed a dose-dependent increase in the frequency of chromosomal abnormalities at 1 mg/kg/day or greater. 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. 8.2 Lactation Risk Summary Based on two small clinical studies, methadone was present in low levels in human milk, but the exposed infants in these studies did not show adverse reactions. 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. There have been rare case reports of sedation and respiratory depression in infants exposed to methadone through breast milk ( see Data ). Monitor infants exposed to DISKETS through breastmilk for excess sedation and respiratory depression. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methadone and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. Data In a study of ten breastfeeding women maintained on oral methadone doses of 10 to 80 mg/day, methadone concentrations from 50 to 570 mcg/L in milk were 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. In a study of twelve breastfeeding women maintained on oral methadone doses of 20 to 80 mg/day, methadone concentrations from 39 to 232 mcg/L in milk were reported. 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. 8.3 Females and Males of Reproductive Potential Infertility The effect of DISKETS on fertility is unknown. Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6 ), Clinical Pharmacology ( 12.2 ), Nonclinical Pharmacology ( 13.1 )]. Reproductive function in human males may be decreased by methadone treatment. Reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. In addition, reductions in serum testosterone levels and sperm motility, and abnormalities in sperm morphology have been reported. In published animal studies, methadone produces a significant regression of sex accessory organs and testes of male mice and rats and administration of methadone to pregnant rats reduced fetal blood testosterone and androstenedione in male offspring [see Nonclinical Toxicology ( 13 )]. 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 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. Methadone is known to be substantially excreted by the kidney, and the risk of adverse 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. 8.6 Hepatic Impairment Methadone pharmacokinetics have 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. 8.7 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.

16 HOW SUPPLIED/STORAGE AND HANDLING DISKETS Dispersible Tablets (Methadone Hydrochloride Tablets for Oral Suspension USP) 40 mg supplied as light pinkish orange, pillow shaped, compressed dispersible tablet with product identification “54 883” debossed on one side and cross scored on the other side. NDC 0054-4538-25: Bottle of 100 Dispersible Tablets DISKETS Dispersible Tablets, if dispensed, must be packaged in child-resistant containers. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Store DISKETS Dispersible Tablets securely and dispose of properly [see Patient Counseling Information ( 17 )] .

WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION, LIFE-THREATENING QT PROLONGATION, ACCIDENTAL INGESTION, ABUSE POTENTIAL, INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES and TREATMENT FOR OPIOID ADDICTION Life-Threatening Respiratory Depression Respiratory depression, including fatal cases, have been reported during initiation and conversion of patients to methadone, and even when the drug has been used as recommended and not misused or abused [see Warnings and Precautions ( 5.1 )]. Proper dosing and titration are essential and DISKETS Dispersible Tablets should only be prescribed by healthcare professionals who are knowledgeable in the use of methadone for detoxification and maintenance treatment of opioid addiction. Monitor for respiratory depression, especially during initiation of DISKETS Dispersible Tablets or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak pharmacologic effect, especially during the initial dosing period. Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants Concomitant use with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, is a risk factor for respiratory depression and death [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7 )] . • Reserve concomitant prescribing of benzodiazepines or other CNS depressants in patients in methadone treatment to those for whom alternatives to benzodiazepines or other CNS depressants are inadequate. • Follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation and consider delaying or omitting daily methadone dosing. Life-Threatening QT Prolongation QT interval prolongation and serious arrhythmia ( torsades de pointes ) have occurred during treatment with methadone [see Warnings and Precautions ( 5.3 )]. 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 with risk factors for development of prolonged QT interval, a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction for changes in cardiac rhythm during initiation and titration of DISKETS Dispersible Tablets. Accidental Ingestion Accidental ingestion of DISKETS Dispersible Tablets, especially by children, can result in fatal overdose of methadone [see Warnings and Precautions ( 5.4 )]. Misuse, Abuse, and Diversion of Opioids DISKETS Dispersible Tablets contain methadone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit [see Warnings and Precautions ( 5.5 )]. Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The concomitant use of DISKETS with all cytochrome P450 3A4, 2B6, 2C19, 2C9 or 2D6 inhibitors may result in an increase in methadone plasma concentrations, which could cause potentially fatal respiratory depression. In addition, discontinuation of concomitantly used cytochrome P450 3A4, 2B6, 2C19, or 2C9 inducers may also result in an increase in methadone plasma concentration. Follow patients closely for respiratory depression and sedation, and consider dosage reduction with any changes of concomitant medications that can result in an increase in methadone levels [see Warnings and Precautions ( 5.7 ), Drug Interactions ( 7 )]. 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 Dosage and Administration ( 2.1 )]. WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION, LIFE-THREATENING QT PROLONGATION, ACCIDENTAL INGESTION, ABUSE POTENTIAL, INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES and TREATMENT FOR OPIOID ADDICTION See full prescribing information for complete boxed warning. • Fatal respiratory depression may occur, with highest risk at initiation and with dose increases. Instruct patients on proper administration of DISKETS Dispersible Tablets to reduce the risk. ( 5.1 ) • Concomitant use with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, and death. ( 5.2 , 7 ) • QT Interval prolongation and serious arrhythmia ( torsades de pointes ) have occurred with treatment with methadone. ( 5.3 ) • Accidental ingestion of DISKETS Dispersible Tablets can result in fatal overdose of methadone, especially in children. ( 5.4 ) • DISKETS Dispersible Tablets contain methadone, a Schedule II controlled substance and can be abused and criminally diverted. ( 5.5 ) • Concomitant use with CYP3A4, 2B6, 2C19, 2C9 or 2D6 inhibitors or discontinuation of concomitantly used CYP3A4, 2B6, 2C19, or 2C9 inducers can result in a fatal overdose of methadone. ( 5.7 , 7 ) • 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. ( 2.1 )