METHADOSE Tablet Ref.[10872] Active ingredients: Methadone

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©), 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 tablets for oral suspension are for oral administration only. The preparation must not be injected. Methadone 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 tablets for oral suspension have a narrow therapeutic index, especially when combined with other drugs.

2.3 Dosing Instructions

Methadone hydrochloride tablets for oral suspension are intended for dispersion in a liquid immediately prior to oral administration of the prescribed dose. The tablets should not be chewed or swallowed before dispersing in liquid.

Methadone hydrochloride tablets for oral suspension are cross-scored, allowing for flexible dosage adjustment. Each cross-scored tablet may be broken or cut in half to yield two 20-mg doses, or in quarters to yield four 10-mg doses.

Prior to administration, the desired dose of methadone hydrochloride tablets for oral suspension should be dispersed in approximately 120 mL (4 ounces) of water, orange juice, or other acidic fruit beverage prior to taking. Methadone hydrochloride is very soluble in water, but there are some insoluble excipients that will not entirely dissolve. If residue remains in the cup after initial administration, a small amount of liquid should be added and the resulting mixture administered to the patient.

2.4 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 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. Because methadone hydrochloride tablets for oral suspension can be administered only in 10 mg increments, methadone hydrochloride tablets for oral suspension may not be the appropriate product for initial dosing in many patients. 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 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. 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. Because methadone hydrochloride tablets for oral suspension can be administered only in 10 mg increments, methadone hydrochloride tablets for oral suspension may not be the appropriate product for gradual dose reduction in many patients.

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. Because methadone hydrochloride tablets for oral suspension can be administered only in 10 mg increments, it may not be the appropriate product for gradual dose reduction in many patients. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.

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. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].

Clinical Symptoms

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, 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.

Treatment of Overdose

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

The opioid antagonists, such as naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to methadone overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to methadone overdose.

Because the duration of reversal would be expected to be less than the duration of action of methadone, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to opioid antagonists is suboptimal or not sustained, administer additional antagonist as directed in the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist 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 antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Store methadone hydrochloride tablets for oral suspension securely and dispose of properly [see Patient Counseling Information (17)].