FDA label e471506d-cd02-4fcc-acbd-bb881d13561a

Deaths, cardiac and respiratory, have been reported during initiation and conversion of pain patients to methadone treatment from treatment with other opioid agonists. It is critical to understand the pharmacokinetics of methadone when converting patients from other opioids ( see DOSAGE AND ADMINISTRATION ). Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose titration. Respiratory depression is the chief hazard associated with methadone hydrochloride administration. Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, particularly in the early dosing period. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. In addition, cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Methadone treatment for analgesic therapy in patients with acute or chronic pain should only be initiated if the potential analgesic or palliative care benefit of treatment with methadone is considered and outweighs the risks. 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)).

WARNINGS Respiratory Depression, Incomplete Cross-Tolerance, and Iatrogenic Overdose Respiratory depression is the chief hazard associated with methadone hydrochloride administration. Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, particularly during the initial dosing period. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation or dose titration. Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross-tolerance is of particular concern for patients tolerant to other mu-opioid agonists who are being converted to treatment with methadone, thus making determination of dosing during opioid treatment conversion complex. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. Therefore, it is critical to understand the pharmacokinetics of methadone when converting patients from other opioids ( see DOSAGE AND ADMINISTRATION , Table 1, for appropriate conversion schedules). A high degree of "opioid tolerance" does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Respiratory depression is of particular concern in elderly or debilitated patients as well as in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation. Methadone should be administered with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, and CNS depression or coma. In these patients, even usual therapeutic doses of methadone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Alternative, non-opioid analgesics should be considered, and methadone should be used at the lowest effective dose and only under careful medical supervision. Cardiac Conduction Effects Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200 mg/day). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In most of the cases seen at typical maintenance doses, concomitant medications and/or clinical conditions such as hypokalemia were noted as contributing factors. However, the evidence strongly suggests that methadone possesses the potential for adverse cardiac conduction effects in some patients. Methadone should be administered with particular caution to patients already at risk for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia). Careful monitoring is recommended when using methadone in patients with a history of cardiac conduction abnormalities, those taking medications affecting cardiac conduction, and in other cases where history or physical exam suggest an increased risk of dysrhythmia. QT prolongation has also been reported in patients with no prior cardiac history who have received high doses of methadone. Patients developing QT prolongation while on methadone treatment should be evaluated for the presence of modifiable risk factors, such as concomitant medications with cardiac effects, drugs which might cause electrolyte abnormalities, and drugs which might act as inhibitors of methadone metabolism. For use of methadone to treat pain, the risk of QT prolongation and development of dysrhythmias should be weighed against the benefit of adequate pain management and the availability of alternative therapies. Methadone treatment for analgesic therapy in patients with acute or chronic pain should only be initiated if the potential analgesic or palliative care benefit of treatment with methadone has been considered to outweigh the risk of QT prolongation that has been reported with high doses of methadone. The use of methadone in patients already known to have a prolonged QT interval has not been systematically studied. In using methadone an individualized benefit to risk assessment should be carried out and should include evaluation of patient presentation and complete medical history. For patients judged to be at risk, careful monitoring of cardiovascular status, including QT prolongation and dysrhythmias and those described previously should be performed. Misuse, Abuse, and Diversion of Opioids Methadone is a mu-agonist opioid with an abuse liability similar to that of morphine and is a Schedule II controlled substance. Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is subject to criminal diversion. Methadone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing methadone hydrochloride tablets in situations where the clinician is concerned about an increased risk of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Interactions with Other CNS Depressants Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics or other CNS depressants (including alcohol) concomitantly with methadone may experience respiratory depression, hypotension, profound sedation, or coma ( see PRECAUTIONS ). Interactions with Alcohol and Drugs of Abuse Methadone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Deaths associated with illicit use of methadone frequently have involved concomitant benzodiazepine abuse. Head Injury and Increased Intracranial Pressure The respiratory depressant effects of opioids and their capacity to elevate cerebrospinal-fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids produce effects which may obscure the clinical course of patients with head injuries. In such patients, methadone must be used with caution, and only if it is deemed essential. Acute Abdominal Conditions The administration of opioids may obscure the diagnosis or clinical course of patients with acute abdominal conditions. Hypotensive Effect The administration of methadone may result in severe hypotension in patients whose ability to maintain normal blood pressure is compromised (e.g., severe volume depletion).

ADVERSE REACTIONS Heroin Withdrawal During the induction phase of methadone maintenance treatment, patients are being withdrawn from heroin and may therefore 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. Initial Administration The initial methadone dose should be carefully titrated to the individual. Too rapid titration for the patient's sensitivity is more likely to produce adverse effects. The major hazards of methadone are respiratory depression and, to a lesser degree, systemic hypotension. Respiratory arrest, shock, cardiac arrest, and death have occurred. The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not suffering severe pain. In such individuals, lower doses are advisable. Other adverse reactions include the following: Body as a Whole – asthenia (weakness), edema, headache Cardiovascular – arrhythmias, bigeminal rhythms, bradycardia, cardiomyopathy, ECG abnormalities, extrasystoles, flushing, heart failure, hypotension, palpitations, phlebitis, QT interval prolongation, syncope, T-wave inversion, tachycardia, 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 Skin and Appendages – pruritis, urticaria, other skin rashes, and rarely, hemorrhagic urticaria Special Senses – hallucinations, visual disturbances Urogenital – amenorrhea, antidiuretic effect, reduced libido and/or potency, urinary retention or hesitancy Maintenance on a Stabilized Dose – During prolonged administration of methadone, as in a methadone maintenance treatment program, there is usually a gradual, yet progressive, disappearance of side effects over a period of several weeks. However, constipation and sweating often persist.