Methadone Hydrochloride

Boxed Warning....................................................................................12/2023 Indications and Usage (1) ........................................................................12/2023 Dosage and Administration (2.1 , 2.3, 2.5) ...........................12/2023 Warnings and Precautions (5.9 , 5.19) ....................................12/2023

1 INDICATIONS AND USAGE Methadone Hydrochloride Oral Solution is indicated for the: Management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. Limitations of Use: Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions (5.2)], reserve Methadone Hydrochloride Oral Solution for use in patients for whom alternative analgesic treatment options (e.g., non-opioid analgesics or opioid combination products): Have not been tolerated or are not expected to be tolerated, Have not provided adequate analgesia or are not expected to provide adequate analgesia. Methadone Hydrochloride Oral Solution is 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 42 CFR 8.12 [see Dosage and Administration (2.1) ] . • Methadone Hydrochloride Oral Solution is indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. Limitations of Use: Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration (5.2), and because of the greater risks of overdose and death with extended-release/long-acting opioids, reserve Methadone Hydrochloride Oral Solution for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): o Have not been tolerated or are not expected to be tolerated, o Have not provided adequate analgesia or are not expected to provide adequate analgesia (1) Methadone Hydrochloride Oral Solution is not indicated as an as-needed (prn) analgesic. (1) • 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. (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 42 CFR 8.12. (2.1)

2 DOSAGE AND ADMINISTRATION Consider prescribing naloxone based on the patient's risk factors for overdose ( 2.3 , 5.2 , 5.4 , 5.8 ). Management of Pain: Methadone Hydrochloride Oral Solution 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. ( 2.1 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of Methadone Hydrochloride Oral Solution 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. ( 2.1 , 5 ) 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 ( 5.2 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Methadone Hydrochloride Oral Solution. Consider this risk when selecting an initial dose and making dose adjustments ( 2.1 , 5.4 ) For opioid naïve patients, initiate methadone hydrochloride treatment with 2.5 mg every 8 to 12 hours. ( 2.4 ) To convert to methadone hydrochloride from another opioid, use available conversion factors to obtain estimated dose. ( 2.4 ) Titrate slowly with dose increases no more frequent than every 3 to 5 days. ( 2.5 ) Do not abruptly discontinue methadone in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.6 , 5.17 ) Initiation of Detoxification and Maintenance Treatment: A single dose of 20 to 30 mg may be sufficient to suppress withdrawal syndrome. ( 2.7 ) 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 General Information Ensure accuracy when prescribing, dispensing, and administering Methadone Hydrochloride Oral Solution to avoid dosing errors due to confusion between mg and mL, and with other methadone hydrochloride oral solutions of different concentrations, which could result in accidental overdose and death. Ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume. When administering Methadone Hydrochloride Oral Solution ensure t …

3 DOSAGE FORMS AND STRENGTHS Each 5 mL of clear or nearly clear orange colored Methadone Hydrochloride Oral Solution USP contains methadone hydrochloride USP 5 mg or 10 mg. The concentration of the 5 mg per 5 mL solution is 1 mg/mL and the concentration of the 10 mg per 5 mL solution is 2 mg/mL. Oral Solution: Each 5 mL contains 5 mg or 10 mg of Methadone Hydrochloride Oral Solution. ( 3 )

4 CONTRAINDICATIONS Methadone Hydrochloride Oral Solution is contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions ( 5.4 )] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.9 )] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.14 )] • Hypersensitivity (e.g., anaphylaxis) to methadone [see Adverse Reactions ( 6 )] • Significant respiratory depression ( 4 ) • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment ( 4 ) • Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 ) • Hypersensitivity to methadone ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.2 )] • Life Threatening Respiratory Depression [see Warnings and Precautions ( 5.4 )] • QT Prolongation [see Warnings and Precautions ( 5.5 )] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.6 )] • Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions ( 5.8 )] • Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.9 )] • Serotonin Syndrome [see Warnings and Precautions ( 5.10 )] • Adrenal Insufficiency [see Warnings and Precautions ( 5.11 )] • Severe Hypotension [see Warnings and Precautions ( 5.12 )] • Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.14 )] • Seizures [see Warnings and Precautions ( 5.15 )] • Withdrawal [see Warnings and Precautions ( 5.16 )] The following adverse reactions associated with the use of methadone were identified in clinical studies or postmarketing 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 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, torsades 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, decreased testosterone 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 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 Methadone Hydrochloride Oral Solution. 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. Androgen Deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )]. Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.9 )] . Hypoglycemia: Cases of hypoglycemia have been reported in patients taking methadone [see Warnings and Precautions ( 5.19 )] . Opioid-induced esophageal dysfunction (OIED) Cases o …

7 DRUG INTERACTIONS 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 Oral Solution 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 Oral Solution 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 Methadone Hydrochloride Oral Solution until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, consider increasing the Methadone Hydrochloride Oral Solution dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. 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 Oral Solution 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 Methadone Hydrochloride Oral Solution dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider Methadone Hydrochloride Oral Solution dose reduction and evaluate patients at frequent intervals 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. 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. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.2 , 5.3 , 5.4 )] . For Patients Being Treated for Opioid Addiction Cessation of b …

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 use of opioids for an extended period of time 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/m2 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 methadone. 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 (2.9 ) 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 methadone. 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. …

12.1 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 involves 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 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.

11 DESCRIPTION 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 5 mL of methadone hydrochloride oral solution contains 5 mg or 10 mg of methadone hydrochloride USP and the following inactive ingredients: artificial raspberry flavor, citric acid anhydrous, FD&C Red #40, FD&C Yellow #6, glycerin, propylene glycol, purified water, saccharin sodium, sodium benzoate, sorbitol solution, and sucrose. May contain sodium citrate to adjust pH. Chemical Structure

10 OVERDOSAGE Clinical Presentation : Acute overdosage of 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 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 measures. 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 in Methadone Hydrochloride Oral Solution, carefully monitor the patient until spontaneous respiration is reliably re-established. 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 antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experience 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 begun with care and by titration with smaller than usual doses of the antagonist.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Storage and Handling Methadone is a controlled substance. Like fentanyl, morphine, oxycodone, hydromorphone, and oxymorphone, methadone is controlled under Schedule II of the Federal Controlled Substances Act. Methadone may be targeted for theft and diversion by criminals [ see Warnings and Precautions ( 5.1 ) ]. Dispense in a tight, light-resistant container as defined in the USP. Store at controlled room temperature 20° to 25°C (68° to 77°F); excursions are permitted to 15° to 30°C (59° -to 86°F) . [See USP Controlled Room Temperature.] 16.2 How Supplied Methadone Hydrochloride Oral Solution, USP Methadone Hydrochloride Oral Solution, USP 5 mg and 10 mg per 5 mL is a pinkish to red, cherry-flavored solution, available in two strengths as follows: 5 mg per 5 mL (1 mg/mL) Oral Solution NDC 66689-711-16: Bottles of 500 mL Solution NDC 66689-711-05: 5 mL unit dose cup NDC 66689-711-30: Case contains 30 unit dose cups of 5 mL (66689-711-05) packaged in 3 trays of 10 unit dose cups each. 10 mg per 5 mL (2 mg/mL) Oral Solution NDC 66689-712-16: Bottles of 500 mL Solution DEA order form required. Store Methadone Hydrochloride Oral Solution securely and dispose of properly [see Patient Counseling Information ( 17 ) ].