METHADONE HYDROCHLORIDE

Each mL for oral administration contains 10 mg methadone hydrochloride USP. Methadone hydrochloride is chemically described as 6-(dimethylamino)-4,4-diphenyl-3-hepatanone hydrochloride. Methadone hydrochloride USP is a white powder that is water soluble. Its molecular formula is C 21 H 27 NO•HCl and it has a molecular weight of 345.91. Methadone hydrochloride has a melting point of 235°C, and a pKa of 8.25 in water at 20°C. Its octanol/water partition coefficient at pH 7.4 is 117. A solution (1:100) in water has a pH between 4.5 and 6.5. It has the following structural formula: Each mL of the unflavored liquid concentrate, for oral administration, contains 10 mg of methadone hydrochloride USP. The inactive ingredients are: citric acid, sodium benzoate and water. Each mL of the cherry flavored liquid concentrate, for oral administration, contains 10 mg of methadone hydrochloride USP. The inactive ingredients are: citric acid, cherry pistachio flavor, D&C Red #33, FD&C Red #40, glycerin, propylene glycol, saccharin sodium, sodium benzoate, sorbitol solution, sucrose and water. CHEMICAL STRUCTURAL

For detoxification treatment of opioid addiction (heroin or other morphine-like drugs). For 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 21 CFR, Title 42, Sec 8 (see DOSAGE AND ADMINISTRATION ).

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 21 CFR 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 21 CFR 1306.07(b)). Important General Information 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. Methadone has a narrow therapeutic index, especially when combined with other drugs. Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction For detoxification and maintenance of opiate dependence, methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration. The initial methadone dose should be administered, under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. Initially, a 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. If same-day dosing adjustments are to be made, the patient should be asked to wait 2 to 4 hours for further evaluation, when peak levels have been reached. An additional 5 to 10 mg of methadone may be provided 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. Dose adjustments should be made over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). Dose adjustment should be cautious; deaths have occurred in early treatment due to the cumulative effects of the first several days’ dosing. Patients should be reminded that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate. Initial doses should be lower for patients whose tolerance is expected to be low at treatment entry. Loss of tolerance should be considered in any patient who has not taken opioids for more than 5 days. Initial doses should not be determined by previous treatment episodes or dollars spent per day on illicit drug use. During the induction phase of methadone maintenance treatment, patients may show typical withdrawal symptoms, which should be differentiated from methadone-induced side effects. They may exhibit some or all of the following signs and symptoms associated with acute withdrawal from heroin or other opiates: lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose-flesh, fever, chilliness 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. Short-Term Detoxification For patients preferring a brief course of stabilization followed by a period of medically supervised withdrawal, it is generally recommended that the patient be titrated to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. Stabilization can be continued for 2 to 3 days, after which the dose of methadone should be gradually decreased. The rate at which methadone is decreased should be determined separately for each patient. The dose of methadone can be decreased on a daily basis or at 2-day intervals, but the amount of intake should remain sufficient to keep withdrawal symptoms at a tolerable level. In hospitalized patients, a daily reduction of 20% of the total daily dose may be tolerated. In ambulatory patients, a somewhat slower schedule may be needed. Titration and Maintenance Treatment of Opioid Dependence Patients in maintenance treatment should be titrated to a dose at which opioid symptoms are prevented for 24 hours, drug hunger or craving is reduced, the euphoric effects of self-administered opioids are blocked or attenuated, and 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. Medically Supervised Withdrawal After a Period of Maintenance Treatment There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. It is generally suggested that dose reductions should be less than 10% of the established tolerance or maintenance dose, and that 10 to 14-day intervals should elapse between dose reductions. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment. 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 ). Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients. 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. Dosage Adjustment During Pregnancy Methadone clearance may be increased during pregnancy. During pregnancy, a woman’s methadone dose may need to be increased or the dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus (see CLINICAL PHARMACOLOGY , Pharmacokinetics , Specific Populations, and PRECAUTIONS , Pregnancy ).

Methadone is contraindicated in patients with: Significant respiratory depression Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment Known or suspected gastrointestinal obstruction, including paralytic ileus Hypersensitivity (e.g. anaphylaxis) to methadone or any other ingredient in methadone

The major hazards of methadone are respiratory depression and, to a lesser degree, systemic hypotension. Respiratory arrest, shock, cardiac arrest, and death have occurred. The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients. In such individuals, lower doses are advisable. Other adverse reactions include the following: (listed alphabetically under each subsection) Body as a Whole: Asthenia (weakness), edema, headache Cardiovascular (see WARNINGS , Cardiac Conduction Effects): 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 Digestive: Abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis Hematologic and Lymphatic: Reversible thrombocytopenia has been described in opioid addicts with chronic hepatitis Metabolic and Nutritional: Hypokalemia, hypomagnesemia, weight gain Nervous: Agitation, confusion, disorientation, dysphoria, euphoria, insomnia, seizures Respiratory: Pulmonary edema, respiratory depression (see WARNINGS , Respiratory Depression) Skin and Appendages: Pruritus, urticaria, other skin rashes, and rarely, hemorrhagic urticarial Special Senses: Hallucinations, visual disturbances Urogenital: Amenorrhea, antidiuretic effect, reduced libido and/or potency, urinary retention or hesitancy Postmarketing Experience The following adverse reactions have been identified during post-approval use of methadone. Serotonin Syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs (see WARNINGS and PRECAUTIONS , Drug Interactions ). Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use (see WARNINGS ). Anaphylaxis: Anaphylactic reaction has been reported with ingredients contained in methadone (see CONTRAINDICATIONS ). Androgen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids (see CLINICAL PHARMACOLOGY ).

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 ). Examples: Alcohol, benzodiazepines, and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, 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 methadone 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 methadone 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, resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone. Intervention: If concomitant use is necessary, consider dosage reduction of methadone 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 methadone 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 methadone and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone, 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, 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 methadone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider methadone 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, mineralocortocoid 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 ). Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue methadone 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), 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 ). Intervention: The use of methadone 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 methadone and/or the muscle relaxant as necessary. 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 methadone is 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 tipranvir+ritonavir, has resulted in increased clearance or decreased plasma levels of methadone. This may result in reduced efficacy of methadone and could precipitate a withdrawal syndrome. Monitor patients receiving methadone and any of these antiretroviral therapies closely for evidence of withdrawal effects and adjust the methadone 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. Desipramine: Plasma levels of desipramine have increased with concurrent methadone administration.