METHADOSE

2 DOSAGE AND ADMINISTRATION Strongly consider recommending or prescribing an opioid overdose reversal agent (e.g., naloxone, nalmefene) at the time METHADOSE 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 METHADOSE 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 METHADOSE is for oral administration only. The preparation must not be injected. Package in child-resistant containers and inform patients that METHADOSE 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. METHADOSE 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 METHADOSE. 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 METHADOSE 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. 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 if withdrawal symptoms have not been suppressed or if symptoms reappear. The total daily dose of methadone 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 (i.e., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone 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. Also consider concurrent medications and the general condition and medical status of the patient when selecting the initial dose. During the induction phase of methadone maintenance treatment, patients are being withdrawn from other opioids and may show typical withdrawal symptoms. Monitor patients for signs and symptoms of opioid withdrawal including: lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose-flesh, fever, chilliness 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. Decrease the dose of methadone on a daily basis or at 2-day intervals, keeping the amount of methadone 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. 2.5 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. 2.6 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. Do not rapidly reduce or abruptly discontinue METHADOSE in patients who may be physically dependent on opioids [see Warnings and Precautions ( 5.15 )] . 2.7 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 ( 9.3 )] . Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients. 2.8 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. 2.9 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 ( 8.1 )] .

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1 INDICATIONS AND USAGE METHADOSE contains methadone, an opioid agonist indicated for the: detoxification treatment of opioid addiction (heroin or other morphine-like drugs).