Methadone

Mechanism of Action Methadone hydrochloride is a mu-agonist; a synthetic opioid analgesic with multiple actions qualitatively similar to those of morphine, the most prominent of which involve the central nervous system and organs composed of smooth muscle. The principal therapeutic uses for methadone are for analgesia and for detoxification or maintenance in opioid addiction. The methadone abstinence 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.

INDICATIONS AND USAGE 1. Methadone Hydrochloride Injection is indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids. Limitations of Use • Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration (see WARNINGS ), and persist over the course of therapy, reserve opioid analgesics, including Methadone Hydrochloride Injection, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. • Methadone Hydrochloride Injection is not indicated as an as-needed (prn) analgesic. 2. For use in temporary treatment of opioid dependence in patients unable to take oral medication. Limitations of Use • Injectable methadone products are not approved for the outpatient treatment of opioid dependence. In this patient population, parenteral methadone is to be used only for patients unable to take oral medication, such as hospitalized patients. 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 requ

DOSAGE AND ADMINISTRATION 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. It is safer to underestimate a patient’s 24-hour methadone dosage and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour methadone dosage and manage an adverse reaction due to an overdose. While useful tables of opioid equivalents are readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. Frequently reevaluate patients for signs and symptoms of opioid withdrawal and for signs of oversedation/toxicity after converting patients to methadone. Methadone Hydrochloride Injection for Management of Pain Methadone Hydrochloride Injection should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. Consider the following important factors that differentiate methadone from other opioid analgesics: • There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals. • The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma elimination half-life is 8 to 59 hours. • With repeated dosing, the potency of methadone increases due to systemic accumulation. • Steady-state plasma concentrations, and full analgesic effects, are not attained until at least 3 to 5 days on a dose and may take longer in some patients. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals (see WARNINGS ). Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Methadone Hydrochloride Injection for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse (see WARNINGS ). Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Methadone Hydrochloride Injection. Consider this risk when selecting an initial dose and when making dose adjustments (see WARNINGS ). Methadone Hydrochloride Injection multiple-dose vials may be administered intravenously, subcutaneously or intramuscularly. The absorption of subcutaneous and intramuscular methadone has not been well characterized and appears to be unpredictable. Local tissue reactions may occur. Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use of Parenteral Methadone in Patients who are not Opioid Tolerant When parenteral methadone is used in patients who are not tolerant to opioids, the usual intravenous methadone starting dose is 2.5 mg to 10 mg every 8 to 12 hours, slowly titrated to effect. More frequent administration may be required during methadone initiation in order to maintain adequate analgesia, and extreme caution is necessary to avoid overdosage, taking into account methadone's long elimination half-life. Conversion from Oral Methadone to Parenteral Methadone Conversion from oral methadone to parenteral methadone should initially use a 2:1 dose ratio (e.g., 10 mg oral methadone to 5 mg parenteral methadone). Conversion from other Opioid Analgesics to Parenteral Methadone Switching a patient from another opioid analgesic to methadone requires caution due to the uncertainty of dose conversion ratios and incomplete

ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse (see WARNINGS ) • Life Threatening Respiratory Depression (see WARNINGS ) • QT Prolongation (see WARNINGS ) • Neonatal Opioid Withdrawal Syndrome (see WARNINGS ) • Interactions with CNS Depressants (see WARNINGS ) • Serotonin Syndrome (see WARNINGS ) • Adrenal Insufficiency (see WARNINGS ) • Severe Hypotension (see WARNINGS ) • Gastrointestinal Adverse Reactions (see WARNINGS ) • Seizures (see WARNINGS ) • Withdrawal (see WARNINGS ) • Hypoglycemia (see WARNINGS ) The following adverse reactions associated with the use of methadone were identified in clinical studies or post-marketing reports. Because some of these reactions were 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. In such individuals, lower doses of methadone are advisable. Other adverse reactions that have been reported in patients (including opioid addicts taking methadone for detoxification or maintenance) receiving methadone include the following: Body as a Whole : asthenia (weakness), edema, headache Cardiovascular: Arrhythmias, bigeminal rhythms, bradycardia, extrasystoles, tachycardia, Torsade de Pointes, ventricular fibrillation, ventricular tachycardia. ECG abnormalities, prolonged QT interval, T-wave inversion, cardiomyopathy, flushing, heart failure, hypotension, palpitations, phlebitis, syncope 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 Central Nervous System: Agitation, confusion, seizures, disorientation, dysphoria, euphoria, insomnia, hallucinations, seizures, visual disturbances, congenital oculomotor disorders (nystagmus, strabismus) Respiratory: Pulmonary edema Skin and Appendages: Intramuscular and Subcutaneous: Local tissue reactions (pain, erythema, swelling), particularly with continuous subcutaneous infusion Intravenous: Pruritis, urticaria, other skin rashes, and rarely, hemorrhagic urticaria Special Senses: Visual disturbances Urogenital: Antidiuretic effect, amenorrhea, urinary retention or hesitancy, reduced libido and/or potency 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 Methadone Hydrochloride Injection. Androgen Deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time. Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration (see WARNINGS ). Hypoglycemia: Cases of hypoglycemia have been reported in patients taking methadone (see WARNINGS ). Opioid-Induced Esophageal Dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term (see WARNINGS). Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n = 978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n = 1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: • approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and • app

Drug Interactions Table 1: Clinically Significant Drug Interactions with Methadone Hydrochloride Injection 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 Hydrochloride Injection 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 Hydrochloride Injection 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 ), 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 Hydrochloride Injection 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 Hydrochloride Injection 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 Hydrochloride Injection and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone (see CLINICAL PHARMACOLOGY ), 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 ), 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 Hydrochloride Injection 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 Hydrochloride Injection dosage reduction and monitor for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin, St. John’s Wort, Phenobarbital 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, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death (see WARNINGS ). Intervention: 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. Monitor patients closely for signs of respiratory depression and sedation (see WARNINGS , PRECAUTIONS ). Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol. 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 , PRECAUTIONS ). Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Methadone Hydrochloride Injection if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs),