Methadone Hydrochloride (5 brand names, 9 dosage forms, 3 routes)
Available dosage forms: TABLET, TABLET, EFFERVESCENT, CONCENTRATE, TABLET, FOR SUSPENSION, SOLUTION, TABLET, DISPERSIBLE, INJECTABLE, SYRUP, POWDER.
Routes of administration: ORAL, INJECTION, FOR RX COMPOUNDING.
Brand Names
- DOLOPHINE HYDROCHLORIDE
- METHADONE HYDROCHLORIDE
- METHADONE HYDROCHLORIDE INTENSOL
- METHADOSE
- WESTADONE
Boxed Warning
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 Methadone Hydrochloride Intensol™ 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 Methadone Hydrochloride Intensol™ 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. Managing 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)]. • 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. • Limit dosages and durations to the minimum required for patients being treated for pain. • 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 opi
Indications and Usage
Methadone Hydrochloride Oral Concentrate (Intensol™) contains methadone, an opioid agonist indicated for the: •Management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Use oBecause of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with long-acting opioids [see Warnings and Precautions (5.5)], reserve Methadone Hydrochloride Intensol™ for use in patients for whom alternative analgesic treatment options (e.g., non-opioid analgesics or immediate-release opioid analgesics) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. oMethadone Hydrochloride Intensol™ are not indicated as an as-needed (prn) analgesic. •Detoxification treatment of opioid addiction (heroin or other morphine-like drugs). •Maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services. 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 (2.1)].
Contraindications
Methadone Hydrochloride Intensol™ is 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 Methadone Hydrochloride Intensol™ [see Adverse Reactions (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 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. Other adverse reactions include the following: Body as a Whole: asthenia (weakness), edema, headache Cardiovascular: arrhythmias, bigeminal rhythms, bradycardia, cardiomyopathy, ECG abnormalities, extrasystoles, flushing, heart failure, hypotension, palpitations, phlebitis, QT interval prolongation, syncope, T-wave inversion, tachycardia, torsades de pointes, ventricular fibrillation, ventricular tachycardia Central Nervous System: agitation, confusion, disorientation, dysphoria, euphoria, insomnia, hallucinations, seizures, visual disturbances, congenit
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: For Patients Being Treated for Pain Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.2)]. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Warnings and Precautions (5.1, 5.2, 5.5)]. For Patients Being Treated for Opioid Addiction 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 recommending or prescribing an opioid overdose reversal agent, 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, gabapentinoids (gabapentin or pregabalin), other opioids. Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 Clinical Impact: Methadone undergoes hepatic N-demethylation by several cytochrome P450 (CYP) isoforms, including CY
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. Other NMDA receptor antagonists have been shown to produce neurotoxic effects in animals.
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. Toxic leukoencephalopathy has been reported after opioid overdose, and can present hours, days, or weeks after apparent recovery from the initial intoxication. Hearing loss has been reported after methadone overdose, in some cases permanent. Treatment of Overdose In the case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. Because the duration of opioid reversal is expected to be less than the duration of action of methadone, carefully monitor the patient until spontaneous respiration is reliably established. If the response to an opioid overdose reversal agent is suboptimal or not sustained, administer additional reversal agent as directed in the product’s prescribing information. In an individual physically dependent on opioids, the administration of th