Methadone Hydrocloride
methadone hydrochloride · Concentrate · Oral
Uses
Methadone Hydrochloride contains methadone, an opioid agonist indicated for the: 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 )] . Methadone Hydrochloride is an opioid agonist indicated for the: Detoxification treatment of opioid addiction (heroin or other morphine-like drugs). ( 1 ) 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 21 CFR, Title 42, Sec. 8. ( 1 , 2.1 )
Dosage and administration
Strongly consider recommending or prescribing an opioid overdose reversal agent (e.g., naloxone, nalmefene) at the time Methadone Hydrochloride is initiated or renewed because patients being treated with methadone may be at risk for opioid overdose during initiation or titration, or in the case of relapse to illicit use. ( 2.3 ) Initiation of Detoxification and Maintenance Treatment : A single dose of 20 to 30 mg may be sufficient to suppress withdrawal syndrome. ( 2.4 ) Maintenance Treatment : Clinical stability is most commonly achieved at doses between 80 to 120 mg/day. ( 2.5 ) Do not rapidly reduce or abruptly discontinue Methadone Hydrochloride in a physically-dependent patient. ( 2.6 , 5.15 ) 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 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)). 2.2 Important Dosage and Administration Information Methadone Hydrochloride is for oral administration only. The preparation must not be injected. Package in child-resistant containers and inform patients that Methadone Hydrochloride should be kept out of reach of children to prevent accidental ingestion. 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 Hydrochloride has a narrow therapeutic index, especially when combined with other drugs. 2.3 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent. Because patients being treated with methadone may be at risk for opioid overdose during initiation or titration, or in the case of relapse to illicit use, strongly consider recommending or prescribing an overdose reversal agent for the emergency treatment of opioid overdose, both when initiating and renewing treatment with Methadone Hydrochloride. Also consider recommending or prescribing such an agent if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Warnings and Precautions ( 5.1 )] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions ( 5.1 )] . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Advise patients and caregivers that opioid overdose reversal agents, such as naloxone or nalmefene may also be administered for a known or suspected overdose with Methadone Hydrochloride itself [see Overdosage ( 10 )] . 2.4 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. Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. An initial 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.
Dosage forms and strengths
Oral Concentrate: 10 mg methadone hydrochloride (equivalent to 8.95 mg of methadone) per mL (10 mg/mL) as a dye-free, sugar-free, unflavored, clear liquid concentrate in 30 mL or 1-liter bottles Oral concentrate: 10 mg/mL in 30 mL or 1-Liter bottle ( 3 )
Contraindications
Methadone Hydrochloride 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 [see Adverse Reactions ( 6 )] Significant respiratory depression ( 4 ) Acute or severe bronchial asthma ( 4 ) Known or suspected paralytic ileus ( 4 ) Known hypersensitivity to methadone ( 4 )
Warnings and precautions
Neonatal Opioid Withdrawal Syndrome : Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. ( 5.6 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Monitor closely, particularly during initiation and titration. ( 5.8 ) Serotonin Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue Methadone Hydrochloride if serotonin syndrome is suspected. ( 5.9 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.10 ) Severe Hypotension : Monitor during dose initiation and titration. ( 5.11 ) Risks of Use in Patients with Head Injury and Increased Intracranial Pressure : Monitor for sedation and respiratory depression. Avoid use of methadone in patients with impaired consciousness or coma susceptible to intracranial effects of CO2 retention. ( 5.12 ) 5.1 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of methadone, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents, depending on the patient’s clinical status [see Overdosage ( 10 )] . While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Methadone Hydrochloride, the risk is greatest during the initiation of therapy 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. Monitor patients closely for respiratory depression, when initiating therapy with Methadone Hydrochloride and following dose increases. Instruct patients against use by individuals other than the patient for whom methadone was prescribed and to keep methadone out of the reach of children, as such inappropriate use may result in fatal respiratory depression [see Patient Counseling Information ( 17 )] . To reduce the risk of respiratory depression, proper dosing and titration of methadone are essential [see Dosage and Administration ( 2.4 )] . Overestimating the methadone dosage when initiating treatment can result in fatal overdose with the first dose. To further reduce the risk of respiratory depression, consider the following: 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. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. Follow induction directions closely to avoid inadvertent overdose [see Dosage and Administration ( 2.4 )] . Proper dosing and titration are essential and methadone should be overseen only by healthcare professionals who are knowledgeable in the pharmacokinetics and pharmacodynamics of methadone. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information ( 17 )] . Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2 )] . Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent. Because patients being treated with methadone may be at risk for opioid overdose during initiation or titration, or in the case of relapse to illicit use, strongly consider recommending or prescribing an opioid overdose reversal agent for the emergency treatment of an opioid overdose, both when initiating and renewing treatment with Methadone Hydrochloride. Also consider recommending or prescribing such an agent if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Dosage and Administration ( 2.3 )] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Advise patients and caregivers that an opioid overdose reversal agent, such as naloxone or nalmefene, may also be administered for a known or suspected overdose with Methadone Hydrochloride itself [see Overdosage ( 10 )] . Educate patients and caregivers on how to recognize respiratory depression and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose.
Side effects
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, torsade 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 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 Musculoskeletal : decreased muscle mass and strength, osteoporosis and fractures 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. 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 chronic use of opioids [see Clinical Pharmacology ( 12.2 )] . Hypoglycemia : Cases of hypoglycemia have been reported in patients taking methadone [see Warnings and Precautions ( 5.17 )] . 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 and Precautions ( 5.13 )] . Most Common Adverse Reactions Are : lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Lannett Company, Inc. at 1-844-834-0530 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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: 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 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 [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 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 [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 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, mineralocorticoid 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 and Precautions ( 5.9 )] . Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Methadone Hydrochloride 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 affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), 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 and Precautions ( 5.1 , 5.9 )] .
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 prolonged use of opioids 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/m 2 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 Hydrochloride. 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 ), 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 Hydrochloride. 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. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.6 )] . Labor or Delivery Opioid-dependent women on methadone maintenance therapy may require additional analgesia during labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data 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. Findings regarding specific major malformations, decreased fetal growth, premature birth and Sudden Infant Death Syndrome have been inconsistent. Children prenatally exposed to methadone have been reported to demonstrate mild but persistent deficits in performance on psychometric and behavioral tests and visual abnormalities. In a multicenter, double-blind, randomized, controlled trial [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups. A total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy. Among women who remained in treatment until delivery, there was no difference between methadone-treated and buprenorphine-treated groups in the number of neonates requiring NOWS treatment or in the peak severity of NOWS. Buprenorphine-exposed neonates required less morphine (mean total dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10.0 days vs. 17.5 days), and shorter duration of treatment for NOWS (4.1 days vs. 9.9 days) compared to the methadone-exposed group.
Pregnancy
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 prolonged use of opioids 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/m 2 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 Hydrochloride. 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 ), 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 Hydrochloride. 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. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.6 )] . Labor or Delivery Opioid-dependent women on methadone maintenance therapy may require additional analgesia during labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data 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. Findings regarding specific major malformations, decreased fetal growth, premature birth and Sudden Infant Death Syndrome have been inconsistent. Children prenatally exposed to methadone have been reported to demonstrate mild but persistent deficits in performance on psychometric and behavioral tests and visual abnormalities. In a multicenter, double-blind, randomized, controlled trial [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups. A total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy. Among women who remained in treatment until delivery, there was no difference between methadone-treated and buprenorphine-treated groups in the number of neonates requiring NOWS treatment or in the peak severity of NOWS. Buprenorphine-exposed neonates required less morphine (mean total dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10.0 days vs. 17.5 days), and shorter duration of treatment for NOWS (4.1 days vs. 9.9 days) compared to the methadone-exposed group.
Pediatric use
8.4 Pediatric Use The safety, effectiveness, and pharmacokinetics of methadone in pediatric patients below the age of 18 years have not been established.
Geriatric use
8.5 Geriatric Use Clinical studies of methadone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, start elderly patients at the low end of the dosing range, taking into account the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Closely monitor elderly patients for signs of respiratory and central nervous system depression. Methadone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
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 the usual dose of an opioid overdose reversal agent will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the reversal agent administered. If a decision is made treat serious respiratory depression in the physically dependent patient, administration of the reversal agent should be initiated with care and by titration with smaller than usual doses of the reversal agent.
Description
Methadone Hydrochloride Oral Concentrate, USP dye-free, sugar-free, unflavored contains methadone, an opioid agonist, and is available as a dye-free, sugar-free, unflavored liquid concentrate of methadone hydrochloride for oral administration. Methadone hydrochloride is chemically described as 6-(dimethylamino)-4,4-diphenyl-3-heptone hydrochloride. Methadone hydrochloride, USP is a fine white powder. It is very soluble in water, soluble in isopropanol and in chloroform, and practically insoluble in ether and in glycerine. It is present in Methadone Hydrochloride as the racemic mixture. Methadone hydrochloride has a melting point of 235°C, a pKa of 8.25 in water at 20°C, a solution (1 part per 100) pH between 4.5 and 6.5, a partition coefficient of 117 at pH 7.4 in octanol/water and a molecular weight of 345.91. Its structural formula is C 21 H 27 NO
• HCl. This liquid concentrate contains 10 mg of methadone hydrochloride (equivalent to 8.95 mg of methadone) per mL and the following inactive ingredients: citric acid anhydrous, purified water, sodium benzoate. Structural Formula
Mechanism of action
12.1 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.
How supplied
Methadone Hydrochloride Oral Concentrate, USP dye-free, sugar-free, unflavored 10 mg per mL is supplied as a dye-free, sugar-free, unflavored clear colorless liquid concentrate. NDC 0527-1927-36 30 mL bottle in a carton with a calibrated dropper [graduations of 0.25 mL (2.5 mg), 0.5 mL (5 mg), 0.75 mL (7.5 mg), and 1 mL (10 mg) on the dropper]. NDC 0527-1927-39 1 Liter bottle Dispense in tight containers, protected from light. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Store Methadone Hydrochloride securely and dispose of properly [see Patient Counseling Information ( 17 )] .
Patient information
Life-Threatening Respiratory Depression Discuss the risk of respiratory depression with patients, explaining that the risk is greatest when starting Methadone Hydrochloride or when the dose is increased. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions ( 5.1 )] . Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent. Because patients being treated with methadone may be at risk for opioid overdose during initiation or titration, or in the case of relapse to illicit use, discuss the importance of having access to an opioid overdose reversal agent. Also discuss the importance of having access to an opioid overdose reversal agent if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter (some products), or as part of a community-based program) [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 )] . There are important differences among the opioid overdose reversal agents. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize the signs and symptoms of an opioid overdose. Explain to patients and caregivers that effects of opioid overdose reversal agents like naloxone and nalmefene are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if an opioid overdose reversal agent is administered. Repeat administration may be necessary, particularly for overdose involving Methadone Hydrochloride [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 ), Overdosage ( 10 )] . Advise patients and caregivers: how to treat with an opioid overdose reversal agent in the event of an opioid overdose. to tell family and friends about their opioid overdose reversal agent, and to keep it in a place where family and friends can access it in an emergency. to read the Patient Information (or other educational material) that will come with their opioid overdose reversal agent. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if Methadone Hydrochloride is used with benzodiazepines or other CNS depressants (e.g., alcohol, non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids), and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7 )] . Symptoms of Arrhythmia Instruct patients to seek medical attention immediately if they experience symptoms suggestive of an arrhythmia (such as palpitations, near syncope, or syncope) when taking Methadone Hydrochloride [see Warnings and Precautions ( 5.3 )] . Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions ( 5.4 )] . Instruct patients to take steps to store Methadone Hydrochloride securely. Advise patients to dispose of unused Methadone Hydrochloride by flushing down the toilet. Abuse Potential Inform patients that Methadone Hydrochloride contains methadone, a Schedule II controlled substance that is subject to abuse [see Warnings and Precautions ( 5.5 )] . Instruct patients not to share Methadone Hydrochloride with others and to take steps to protect Methadone Hydrochloride from theft or misuse. Important Administration Instructions [see Dosage and Administration ( 2 )] Instruct patients how to properly take Methadone Hydrochloride, including the following: Methadone Hydrochloride is for oral administration only. The preparation must not be injected . Inform patients that Methadone Hydrochloride should be taken only as directed to reduce the risk of life- threatening adverse reactions (e.g., respiratory depression), and the dose should not be adjusted without consulting a physician or other healthcare professional. Reassure patients initiating treatment with Methadone Hydrochloride for opioid dependence that the dose of methadone will “hold” for longer periods of time as treatment progresses. Apprise patients seeking to discontinue treatment with methadone for opioid dependence of the high risk of relapse to illicit drug use associated with discontinuation of Methadone Hydrochloride maintenance treatment. Advise patients not to discontinue Methadone Hydrochloride without first discussing the need for a tapering regimen with the prescriber. Serotonin Syndrome Inform patients that Methadone Hydrochloride could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take, serotonergic medications [see Warnings and Precautions ( 5.9 ), Drug Interactions ( 7 )] . MAOI Interaction Inform patients to avoid taking Methadone Hydrochloride while using any drugs that inhibit monoamine oxidase.
Label text from the FDA structured product label by Lannett Company, Inc. (revised Jan 12, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Methadone Hydrochloride in 4 products
Methadone Hydrocloride NDC products (4)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 17856-1927 | Methadone Hydrochloride 10 mg/mL Concentrate | Atlantic Biologicals Corp. | ANDA · DEA CII |
| 63629-2098 | Methadone Hydrochloride 10 mg/mL Concentrate | Bryant Ranch Prepack | ANDA · DEA CII |
| 72162-1085 | Methadone Hydrochloride 10 mg/mL Concentrate | Bryant Ranch Prepack | ANDA · DEA CII |
| 0527-1927 | Methadone Hydrochloride 10 mg/mL Concentrate | Lannett Company, Inc. | ANDA · DEA CII |
Frequently asked questions
What is Methadone Hydrocloride used for?
Methadone Hydrochloride contains methadone, an opioid agonist indicated for the: 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…
What are the side effects of Methadone Hydrocloride?
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 )]… See the full label for the complete list.
Who makes Methadone Hydrocloride?
Methadone Hydrocloride is listed by 3 labelers in the FDA NDC directory, including Atlantic Biologicals Corp., Bryant Ranch Prepack, Lannett Company, Inc..