methadone hydrochloride

Methadone hydrochloride tablets are indicated for the: 1. 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 and persist over the course of therapy [see Warnings and Precautions ] , reserve opioid analgesics, including methadone hydrochloride tablets for use in patients for whom alternative analgesic treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
• Methadone hydrochloride tablets are not indicated as an as-needed (prn) analgesic. 2. Detoxification treatment of opioid addiction (heroin or other morphine-like drugs). 3. 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. Methadone hydrochloride tablets are 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 and persist over the course of therapy, reserve opioid analgesics, including methadone hydrochloride tablets 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 tablets are not indicated as an as-needed (prn) analgesic. 3. Detoxification treatment of opioid addiction (heroin or other morphine-like drugs). 4. 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 .

• Consider recommending or prescribing an opioid overdose reversal agent (e.g., naloxone, nalmefene) based on the patient’s risk factors for overdose . Management of Pain
• Methadone hydrochloride tablets 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.
• 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 tablets 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
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with methadone hydrochloride tablets. Consider this risk when selecting an initial dose and when making dose adjustments
• To convert to methadone hydrochloride tablets from another opioid, use available conversion factors to obtain estimated dose.
• Periodically reassess patients receiving methadone hydrochloride tablets to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse.
• Titrate slowly with dose increases no more frequent than every 3 to 5 days.
• Do not rapidly reduce or abruptly discontinue methadone hydrochloride tablets in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Initiation of Detoxification and Maintenance Treatment A single dose of 20 to 30 mg may be sufficient to suppress withdrawal syndrome.
• A single dose of 20 to 30 mg may be sufficient to suppress withdrawal syndrome. 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)).

Important General Information

• The peak respiratory depressant effect of methadone occurs later and persists longer than its peak therapeutic 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 agonists.
• With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity.
• Methadone 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 [ see Warnings and Precautions Overdosage ]. For Patients Being Treated for Pain Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. [see Warnings and Precautions ]. For Patients Being Treated for Opioid Addiction Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, 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 tablets. 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 tablets itself [see Overdosage ]. For patients being treated with methadone (regardless of indication), also consider recommending or prescribing such as agent if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. 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 ]. 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. 2.4 Methadone hydrochloride tablets for Management of Pain Important Dosage and Administration Information Methadone hydrochloride tablets 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 of methadone. 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 and Precautions ]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of methadone hydrochloride tablets 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 and Precautions ]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with methadone hydrochloride tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ]. Conversion from Other Oral Opioids to Methadone Hydrochloride Tablets : When methadone hydrochloride tablets therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate. The potency of methadone relative to other opioid analgesics is nonlinear and increases with increasing dose. Table 1 provides an estimated conversion factor for use when converting patients from another opioid to methadone. Because of the high inter-patient variability in absorption, metabolism, and relative potency, it is critical to avoid overestimating the methadone dose which can lead to fatal respiratory depression. 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. Consider the following when using the information in Table 1:
• This is not a table of equianalgesic doses.
• The conversion factors in this table are only for the conversion from another oral opioid analgesic to methadone hydrochloride tablets.
• The table cannot be used to convert from methadone hydrochloride tablets to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose. Table 1: Conversion Factors to Methadone Hydrochloride Tablets Total Daily Baseline Oral Morphine Equivalent Dose Estimated Daily Oral Methadone Requirement as Percent of Total Daily Morphine Equivalent Dose 1000 mg < 5 % To calculate the estimated methadone hydrochloride tablets dose using Table 1:
• For patients on a single opioid, sum the current total daily dose of the opioid, convert it to a Morphine Equivalent Dose according to specific conversion factor for that specific opioid, then multiply the Morphine Equivalent Dose by the corresponding percentage in the above table to calculate the approximate oral methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3).
• For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and sum the totals to obtain the approximate total methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3).
• For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion. Always round the dose down, if necessary, to the appropriate methadone hydrochloride tablets strength(s) available. Example conversion from a single opioid to methadone hydrochloride tablets: Step 1: Sum the total daily dose of the opioid (in this case, Morphine Extended Release Tablets 50 mg twice daily) 50 mg Morphine Extended Release Tablets 2 times daily = 100 mg total daily dose of Morphine Step 2: Calculate the approximate equivalent dose of methadone hydrochloride tablets based on the total daily dose of Morphine using Table 1. 100 mg total daily dose of Morphine x 15% (10% to 20% per Table 1) = 15 mg methadone hydrochloride tablets daily Step 3: Calculate the approximate starting dose of methadone hydrochloride tablets to be given every 12 hours. Round down, if necessary, to the appropriate methadone hydrochloride tablets strengths available. 15 mg daily / 2 = 7.5 mg methadone hydrochloride tablets every 12 hours Then 7.5 mg is rounded down to 5 mg methadone hydrochloride tablets every 12 hours Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to methadone hydrochloride tablets. Conversion from Parenteral Methadone to Methadone Hydrochloride Tablets: Use a conversion ratio of 1:2 mg for parenteral to oral methadone (e.g., 5 mg parenteral methadone to 10 mg oral methadone). 2.5 Titration and Maintenance of Therapy for Pain Individually titrate methadone hydrochloride tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving methadone hydrochloride tablets to assess the maintenance of pain control , signs and symptoms of opioid withdrawal, and other adverse reactions, as well as reassessing for the development of addiction, abuse, or misuse [see Warnings and Precautions ]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for the use of opioid analgesics. Patients who experience breakthrough pain may require a dose increase of methadone hydrochloride tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the methadone hydrochloride tablets dosage. Because of individual variability in the pharmacokinetic profile (i.e., terminal half-life (T 1/2 ) from 8 to 59 hours in different studies [see Clinical Pharmacology ], titrate methadone hydrochloride tablets slowly, with dose increases no more frequent than every 3 to 5 days. However, because of this high variability, some patients may require substantially longer periods between dose increases (up to 12 days). Monitor patients closely for the development of potentially life-threatening adverse reactions (e.g., CNS and respiratory depression). If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions ]. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.6 Safe Reduction or Discontinuation of Methadone Hydrochloride Tablets for Pain Do not rapidly reduce or abruptly discontinue methadone hydrochloride tablets in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking methadone hydrochloride tablets, there are a variety of factors that should be considered, including the total daily dose of opioid (including methadone hydrochloride tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on methadone hydrochloride tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions , Drug Abuse and Dependence ]. 2.7 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction For detoxification and maintenance of opioid 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 hydrochloride tablets will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg. To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have been reached. Provide an additional 5 to 10 mg of methadone hydrochloride tablets if withdrawal symptoms have not been suppressed or if symptoms reappear. The total daily dose of methadone hydrochloride tablets on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone levels will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Instruct patients that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate. Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment episodes or dollars spent per day on illicit drug use. During the induction phase of methadone maintenance treatment, patients are being withdrawn from opioids and may have opioid withdrawal symptoms. Monitor patients for signs and symptoms of opioid withdrawal including: lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose-flesh, fever, chilling alternating with flushing, restlessness, irritability, weakness, anxiety, depression, dilated pupils, tremors, tachycardia, abdominal cramps, body aches, involuntary twitching and kicking movements, anorexia, nausea, vomiting, diarrhea, intestinal spasms, and weight loss and consider dose adjustment as indicated. Short-term Detoxification For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization, gradually decrease the dose of methadone hydrochloride tablets. Decrease the dose of methadone hydrochloride tablets on a daily basis or at 2-day intervals, keeping the amount of methadone hydrochloride tablets sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule. 2.8 Titration and Maintenance Treatment of Opioid Dependence Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day. During prolonged administration of methadone, monitor patients for persistent constipation and manage accordingly. 2.9 Medically Supervised Withdrawal after a Period of Maintenance Treatment for Opioid Addiction There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment. 2.10 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms [see Drug Abuse and Dependence ]. Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients. 2.11 Considerations for Management of Acute Pain during Methadone Maintenance Treatment Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone. 2.12 Dosage Adjustment during Pregnancy Methadone clearance may be increased during pregnancy. During pregnancy, a woman’s methadone dose may need to be increased or the dosing interval decreased [see Use in Specific Populations ] .

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 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.

The following serious adverse reactions are described, or described in greater detail, in other sections:

• Addiction, Abuse, and Misuse [see Warnings and Precautions ].
• Life Threatening Respiratory Depression [see Warnings and Precautions ]
• Interactions with Benzodiazepines and other CNS Depressants [see Warnings and Precautions ]
• QT Prolongation [see Warnings and Precautions ]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ]
• Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ]
• Serotonin Syndrome [see Warnings and Precautions ]
• Adrenal Insufficiency [see Warnings and Precautions ]
• Severe Hypotension [see Warnings and Precautions ]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions ]
• Seizures [see Warnings and Precautions ]
• Withdrawal [see Warnings and Precautions ] 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: hypoglycemia, 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 tablets. 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 ]. Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ] Hypoglycemia : Cases of hypoglycemia have been reported in patients taking methadone [see Warnings and Precautions ]. 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 ] . 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
• approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ] , respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies. Most common adverse reactions are: lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. To report SUSPECTED ADVERSE REACTIONS, contact Epic Pharma, LLC at 1-888-374-2791 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 tablets 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 tablets 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 tablets until stable drug effects are achieved. Regularly 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 dosage until stable drug effects are achieved. Assess 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 tablets 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 tablets dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider methadone hydrochloride tablets dosage reduction and regularly 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 and Warnings and Precautions ]. For Patients Being Treated for Opioid Addiction Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate. Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments. 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 ] . 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, 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 ]. Intervention: If concomitant use is warranted, frequently monitor the patient, particularly during treatment initiation and dose adjustment. Discontinue methadone hydrochloride tablets 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 effect 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 [see Warnings and Precautions ] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ]. Intervention: The use of methadone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of methadone hydrochloride tablets and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression may be greater than otherwise expected, decrease the dosage of methadone hydrochloride tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration and Warnings and Precautions ]. Examples: Cyclobenzaprine, metaxalone. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when Methadone hydrochloride tablets are used concomitantly with anticholinergic drugs. Paradoxical Effects of Antiretroviral Agents on methadone hydrochloride tablets Concurrent use of certain antiretroviral agents with CYP3A4 inhibitory activity, alone and in combination, such as abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ ritonavir, saquinavir+ ritonavir, and tipranavir+ ritonavir, has resulted in increased clearance or decreased plasma levels of methadone. This may result in reduced efficacy of methadone hydrochloride tablets and could precipitate a withdrawal syndrome. Monitor methadone-maintained patients receiving any of these anti-retroviral therapies closely for evidence of withdrawal effects and adjust the methadone dose accordingly. Effects of methadone hydrochloride tablets on Antiretroviral Agents Didanosine and Stavudine: Experimental evidence demonstrated that methadone decreased the area under the concentration-time curve (AUC) and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered. Zidovudine: Experimental evidence demonstrated that methadone increased the AUC of zidovudine, which could result in toxic effects. Effects of methadone hydrochloride tablets on Antidepressants Desipramine: Blood levels of desipramine have increased with concurrent methadone administration.

• Anti-Retroviral Agents : May result in decreased efficacy or, in certain cases, increased toxicity.
• Potentially Arrhythmogenic Agents : Pharmacodynamic interactions may occur. Regularly evaluate patients closely for cardiac conduction changes.
• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with methadone hydrochloride tablets because they may reduce analgesic effect of methadone hydrochloride tablets or precipitate withdrawal symptoms.
• Monoamine Oxidase Inhibitors (MAOIs) : Can potentiate the effects of methadone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI.

• Lactation: Monitor breastfed infants for increased drowsiness and breathing difficulties. 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 ]. 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 hydrochloride tablets. 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 and Clinical Pharmacology ]. 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 tablets. 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 ] . 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. There were no differences between groups in other primary outcomes (neonatal head circumference), or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1minute and 5-minute Apgar scores), or in the rates of maternal or neonatal adverse events. The outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known. Because of the imbalance in discontinuation rates between the methadone and buprenorphine groups, the study findings are difficult to interpret. Animal Data: Formal reproductive and developmental toxicology studies for methadone have not been conducted. Exposure margins for the following published study reports are based on a human daily dose (HDD) of 120 mg methadone using a body surface area comparison. In a published study in pregnant hamsters, a single subcutaneous dose of methadone ranging from 31 mg/kg (2 times the HDD) to 185 mg/kg on Gestation Day 8 resulted in a decrease in the number of fetuses per litter and an increase in the percentage of fetuses exhibiting neural tube defects including exencephaly, cranioschisis, and “various other lesions.” The majority of the doses tested also resulted in maternal death. In a study in pregnant JBT/Jd mice, a single subcutaneous dose of 22 to 24 mg/kg methadone (approximately equivalent to the HDD) administered on Gestation Day 9 produced exencephaly in 11% of the embryos. In another study in pregnant mice, subcutaneous doses up to 28 mg/kg/day methadone (equivalent to the HDD) administered from Gestation Day 6 to 15 resulted in no malformations, but there were increased post-implantation loss and decreased live fetuses at 10 mg/kg/day or greater (0.4 times the HDD) and decreased ossification and fetal body weight at 20 mg/kg/day or greater (0.8 times the HDD). In a second study of pregnant mice dosed with subcutaneous doses up to 28 mg/kg/day methadone from Gestation Day 6 to 15, there was decreased pup viability, delayed onset of development of negative phototaxis and eye opening, increased righting reflexes at 5 mg/kg/day or greater (0.2 times the HDD), and decreased number of live pups at birth and decreased pup weight gain at 20 mg/kg/day or greater (0.8 times the HDD). No effects were reported in a study of pregnant rats and rabbits at oral doses up to 40 mg/kg (3 and 6 times, respectively, the HDD) administered from Gestation Days 6 to 15 and 6 to 18, respectively. When pregnant rats were treated with intraperitoneal doses of 2.5, 5, or 7.5 mg/kg methadone from one week prior to mating, through gestation until the end of lactation period, 5 mg/kg or greater (0.4 times the HDD) methadone resulted in decreases in litter size and live pups born and 7.5 mg/kg (0.6 times the HDD) resulted in decreased birth weights. Furthermore, decreased pup viability and pup body weight gain at 2.5 mg/kg or greater (0.2 times the HDD) were noted during the preweaning period. Additional animal data demonstrate evidence for neurochemical changes in the brains of offspring from methadone-treated pregnant rats, including changes to the cholinergic, dopaminergic, noradrenergic and serotonergic systems at doses below the HDD. Other animal studies have reported that prenatal and/or postnatal exposure to opioids including methadone alters neuronal development and behavior in the offspring including alterations in learning ability, motor activity, thermal regulation, nociceptive responses, and sensitivity to drugs at doses below the HDD. Treatment of pregnant rats subcutaneously with 5 mg/kg methadone from Gestation Day 14 to 19 (0.4 times the HDD) reduced fetal blood testosterone and androstenedione in males. Published animal data have reported increased neonatal mortality in the offspring of male rodents that were treated with methadone at doses comparable to and less than the HDD for 1 to 12 days before and/or during mating (with more pronounced effects in the first 4 days). In these studies, the female rodents were not treated with methadone, indicating paternally-mediated developmental toxicity. Specifically, methadone administered to the male rat prior to mating with methadone-naïve females resulted in decreased weight gain in progeny after weaning. The male progeny demonstrated reduced thymus weights, whereas the female progeny demonstrated increased adrenal weights. Behavioral testing of these male and female progeny revealed significant differences in behavioral tests compared to control animals, suggesting that paternal methadone exposure can produce physiological and behavioral changes in progeny in this model. Examination of uterine contents of methadone-naïve female mice bred to methadone-treated male mice (once a day for three consecutive days) indicated that methadone treatment produced an increase in the rate of preimplantation deaths in all post-meiotic states at 1 mg/kg/day or greater (0.04 times the HDD). Chromosome analysis revealed a dose-dependent increase in the frequency of chromosomal abnormalities at 1 mg/kg/day or greater. Studies demonstrated that methadone treatment of male rats for 21 to 32 days prior to mating with methadone-naïve females did not produce any adverse effects, suggesting that prolonged methadone treatment of the male rat resulted in tolerance to the developmental toxicities noted in the progeny. Mechanistic studies in this rat model suggest that the developmental effects of “paternal” methadone on the progeny appear to be due to decreased testosterone production. These animal data mirror the reported clinical findings of decreased testosterone levels in human males on methadone maintenance therapy for opioid addiction and in males receiving chronic intraspinal opioids. 8.2 Lactation Risk Summary Based on two small clinical studies, methadone was present in low levels in human milk, but the exposed infants in these studies did not show adverse reactions. Based on an average milk consumption of 150 mL/kg/day, an infant would consume approximately 17.4 mcg/kg/day which is approximately 2% to 3% of the oral maternal dose. There have been rare case reports of sedation and respiratory depression in infants exposed to methadone through breast milk (see Data). Monitor infants exposed to methadone hydrochloride tablets through breast milk for excess sedation and respiratory depression. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methadone and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. Data In a study of ten breastfeeding women maintained on oral methadone doses of 10 to 80 mg/day, methadone concentrations from 50 to 570 mcg/L in milk were reported, which, in the majority of samples, were lower than maternal serum drug concentrations at steady state. Peak methadone levels in milk occur approximately 4 to 5 hours after an oral dose. In a study of twelve breastfeeding women maintained on oral methadone doses of 20 to 80 mg/day, methadone concentrations from 39 to 232 mcg/L in milk were reported. Based on an average milk consumption of 150 mL/kg/day, an infant would consume approximately 17.4 mcg/kg/day which is approximately 2% to 3% of the oral maternal dose. Methadone has been detected in very low plasma concentrations in some infants whose mothers were taking methadone. 8.3 Females and Males of Reproductive Potential Infertility The effect of methadone hydrochloride tablets on fertility is unknown. Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions , Clinical Pharmacology , Nonclinical Pharmacology ]. Reproductive function in human males may be decreased by methadone treatment. Reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. In addition, reductions in serum testosterone levels and sperm motility, and abnormalities in sperm morphology have been reported. In published animal studies, methadone produces a significant regression of sex accessory organs and testes of male mice and rats and administration of methadone to pregnant rats reduced fetal blood testosterone and androstenedione in male offspring [see Nonclinical Toxicology ]. 8.4 Pediatric Use The safety, effectiveness, and pharmacokinetics of methadone in pediatric patients below the age of 18 years have not been established. 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. Elderly patients (aged 65 years or older) may have increased sensitivity to methadone. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of methadone hydrochloride tablets slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ]. 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 regularly evaluate renal function. 8.6 Hepatic Impairment Methadone pharmacokinetics have not been extensively evaluated in patients with hepatic insufficiency. Methadone is metabolized by hepatic pathways; therefore, patients with liver impairment may be at risk of increased systemic exposure to methadone after multiple dosing. Start these patients on lower doses and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression. 8.7 Renal Impairment Methadone pharmacokinetics have not been extensively evaluated in patients with renal insufficiency. Since unmetabolized methadone and its metabolites are excreted in urine to a variable degree, start these patients on lower doses and with longer dosing intervals and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression.