A narcotic analgesic - It is used to treat severe pain
FDA Alerts
Conditions for Distribution and Use for the Treatment of Opiate Dependence
When used for the treatment of opiate dependence in detoxification or maintenance programs, methadone should be dispensed only by programs certified by the Substance Abuse and Mental Health Services Administration (SAMHSA) and approved by the designated state authority (consult Federal Standards for regulatory exceptions). Certified treatment programs should dispense only oral methadone products as outlined in the Federal Opioid Treatment Standards (42 CFR 8.12).
Failure to follow the requirements outlined in the regulations may result in criminal prosecution, seizure of the drug supply, revocation of the program certification, and injunction precluding operation of the program.
Serious Adverse Effects
Death and life-threatening adverse effects (i.e., respiratory depression, cardiac arrhythmias) reported in patients receiving methadone. These events have been reported in patients initiating methadone therapy for pain and in patients transferring to methadone from other opiate therapy; death reported in patients initiating methadone therapy for opiate dependence. Interactions with other drugs (legal and illicit), respiratory and cardiac effects of methadone, or rapid dose titration may have contributed to these events. Consider pharmacokinetic and pharmacologic properties of methadone when initiating therapy, transferring patients from other opiate therapy, and during dose titration. (See Pharmacokinetics.)
Respiratory depression is the major toxicity associated with methadone. Peak respiratory depressant effect occurs later and persists longer than peak analgesic effect, particularly during the early dosing period. These properties can contribute to inadvertent overdosage, especially during treatment initiation and dose titration. (See Respiratory Depression under Cautions.)
Possible prolongation of the QT interval and serious cardiac arrhythmias, including torsades de pointes. Most cases have occurred in patients receiving relatively high dosages (>200 mg daily) for the treatment of chronic pain, but also reported in patients receiving lower dosages for maintenance treatment of opiate dependence. (See Cardiac Effects under Cautions.)
For pain management, initiate only if potential benefits outweigh risks of methadone therapy.
A strong analgesic used for the relief of moderate to severe pain that has not responded to nonopiate analgesics.
For relief of chronic pain in both opiate-naive patients and in individuals being switched to methadone therapy from other opiate agonists because of inadequate pain relief or adverse effects from the previous drug (opiate rotation).
Although considered by some clinicians to be second-line therapy in the management of chronic malignant pain, clinical studies suggest that efficacy may be similar to that of morphine and other opiates in this population.
Benefits associated with use for management of chronic pain include the commercial availability of multiple dosage forms of the drug, good oral bioavailability, rapid onset of action, reduced dosing frequency (because of the drug’s long half-life), low cost, and lack of active metabolites.
Disadvantages associated with use include increased potential for accumulation with repeated doses (which may result in toxicity), considerable interindividual variability in pharmacokinetic parameters, potential for drug interactions, challenges associated with dosage titration and with the transfer of patients from therapy with other opiate agonists, and commercial availability and relative ease of use of extended-release preparations of other opiate agonists.
Detoxification and Maintenance of Opiate Dependence
Used in detoxification treatment and maintenance treatment as an oral substitute for heroin or other morphine-like drugs to suppress the opiate-agonist abstinence syndrome in patients who are dependent on these drugs.
Success of treatment is dependent on the selection of properly motivated patients and on availability of social, psychologic, vocational, and educational as well as medical supportive services.
Dosage and Administration
General
Individualize dosage carefully; repeated doses may result in substantial accumulation of the drug, prolonging its duration of action and possibly resulting in adverse effects. There is considerable interindividual variability in absorption, metabolism, and relative analgesic potency of the drug.
Carefully monitor patients during initiation of therapy, dosage titration, and conversion from one opiate agonist to another.
Consider the specific characteristics of methadone (i.e., half-life is longer than duration of analgesic effect, peak respiratory depressant effects occur later and persist longer than peak analgesic effects, full analgesic effect not attained for several days) when making treatment decisions regarding use of the drug.
Conversion from Other Opiate Analgesic Therapy
Consider the daily dosage, potency, and specific characteristics (e.g., elimination half-life) of the previously administered opiate; adverse effects of and response to the previous regimen; degree of opiate tolerance; and the relative potency estimate used to calculate an equianalgesic dosage of methadone.
A high degree of opiate tolerance does not preclude the possibility of unintended methadone overdosage.Failure to individualize dosage has resulted in serious adverse effects, including death, in opiate-tolerant patients during conversion to methadone therapy.
Select dosage carefully when transferring patients from chronic therapy with another oral or parenteral opiate to therapy with oral or parenteral methadone, since cross-tolerance between methadone and other opiate agonists is incomplete, dosage conversion ratios are imprecise, and substantial interindividual variability exists. (See Conversion from Other Opiate Therapy under Dosage.)
Published equianalgesic dosage conversion ratios between methadone and other opiate agonists generally are based on single-dose studies in patients who are not opiate tolerant. These single-dose equivalency tables may overestimate dosage requirements during chronic therapy, since methadone may accumulate with repeated doses secondary to the long elimination half-life (see Elimination under Pharmacokinetics). Therefore, estimates of methadone dosage that are based on single-dose studies should not be used for conversion in patients receiving chronic opiate therapy.
Detoxification and Maintenance Treatment
Administer or dispense only in an oral form (e.g., tablet, dispersible tablet, liquid) that is formulated and packaged in such a way as to reduce potential for parenteral abuse and accidental ingestion.
Hospitalized patients unable to take oral medication may receive parenteral methadone on a temporary basis. If at any time during detoxification or maintenance treatment the patient cannot tolerate oral medication because of nausea or vomiting associated with acute complicating illness, hospitalize the patient and continue methadone by the parenteral route.
Short-term detoxification: Administer in decreasing doses under close observation over a period of ≤30 days to alleviate physical and psychologic effects of opiate withdrawal and to reach a drug-free state.
Long-term detoxification: Administer in decreasing doses over a period of >30 but ≤180 days to alleviate physical and psychologic effects of opiate withdrawal and to reach a drug-free state.
Maintenance treatment: Administer at a stable dosage for >21 days in the treatment of opiate dependence.
Patients with ≥2 unsuccessful detoxification episodes within a 12-month period should be assessed for alternative forms of treatment. An opiate treatment program may not admit a patient for >2 detoxification treatments within 1 year.
Patients undergoing short-term detoxification are not eligible for unsupervised administration.
Any patient in a comprehensive maintenance treatment program, including long-term detoxification treatment, may receive 1 dose to take at home for a day that the clinic is closed. Decisions to allow additional unsupervised administration by these patients should be based on the following factors: absence of recent abuse of drugs (including alcohol), regularity of clinic attendance, absence of serious behavioral problems at the clinic, absence of known recent criminal activity, stability of the patient’s home environment and social relationships, length of time in the program (see below), assurance that the drug can be safely stored in the patient’s home, and assessment of whether the rehabilitative benefit derived from decreased clinic attendance outweighs potential risks of diversion.
Patients meeting these criteria may be permitted to receive additional supplies of the drug to take at home each week, in the following amounts: 1-day supply during the 1st 90 days of treatment, 2-day supply during the 2nd 90 days, and 3-day supply during the 3rd 90 days (each in addition to the 1 dose allowed for clinic closure). All other doses must be administered while the patient is closely observed.
During the remainder of the 1st year of treatment, the patient may receive a maximum 6-day supply of the drug and must visit the clinic once weekly.
After 1 year of continuous treatment, the patient may receive a maximum 2-week supply and must make twice monthly visits. After 2 years of continuous treatment, the patient may receive a maximum 1-month supply of the drug and must make monthly visits.
Substantial deviations from the FDA-approved labeling for methadone (e.g., concerning dose, frequency of administration, or conditions of use) must be documented in the patient’s medical record.
Restricted Distribution
Distribution of 40-mg dispersible tablets restricted to authorized opiate-dependency treatment programs and to hospitals. Distribution restricted in response to reports of serious adverse effects (see Serious Adverse Effects in Boxed Warning).
Administration
Administer orally or by sub-Q, IM, or IV injection.
Oral Administration
Tablets, dispersible tablets, and oral concentrate solution are for oral administration only and must not be injected.
Dispersible Tablets
Disperse in 120 mL of a liquid (e.g., water, orange juice, citrus Tang®, citrus flavors of Kool-Aid®, other acidic fruit beverages) prior to oral administration. Complete tablet dispersion occurs within 1 minute; dispersion time is slightly increased when a cold and/or acidic vehicle is used.
Each 40-mg dispersible tablet can be divided in half to yield two 20-mg doses or into quarters to yield four 10-mg doses.
The 40-mg dispersible tablets are used in detoxification and maintenance of opiate dependence; this preparation should not be used for the treatment of pain.
Dispersible tablets contain insoluble excipients and must not be used to prepare solutions for injection.
Oral Concentrate Solution
Dilute the dose with water or other suitable liquid (e.g., Kool-Aid®, Tang®, apple juice, Crystal Light® [with aspartame]) to ≥30 mL prior to administration.
IM or Sub-Q Administration
Absorption following sub-Q or IM injection may be unpredictable and has not been fully characterized; local tissue reactions may occur.
IV Administration
Administer by IV injection.
For solution and drug compatibility information, see Compatibility under Stability.
When selecting an initial dosage, consider the type, severity, and expected duration of the patient’s pain; the age, general condition, and medical status of the patient; concurrent drug therapy (see Interactions); and the acceptable balance between pain relief and adverse effects.
Give the smallest effective dose in order to minimize development of tolerance and physical dependence.
Oral
Opiate-naive patients: Initially, 2.5–10 mg every 8–12 hours. Titrate dosage to provide adequate analgesia; increase dosage slowly to avoid accumulation and potential toxicity.
Dosage interval may range from 4–12 hours, since the duration of analgesia is relatively short during the first days of therapy but increases substantially with continued administration. Use caution to avoid overdosage.
Patients being switched from parenteral methadone: Initiate oral methadone at a parenteral:oral dosage ratio of 1:2 (e.g., 10 mg of oral methadone hydrochloride in patients previously receiving 5 mg of parenteral methadone hydrochloride).
IV
Opiate-naive patients: Initially, 2.5–10 mg every 8–12 hours. Titrate dosage to provide adequate analgesia; increase slowly to avoid accumulation and potential toxicity. More frequent administration may be required during initiation of therapy to maintain adequate analgesia; however, use caution to avoid overdosage.
Patients being switched from oral methadone: Initiate parenteral methadone at an oral:parenteral dosage ratio of 2:1 (e.g., 5 mg of parenteral methadone hydrochloride in patients previously receiving 10 mg of oral methadone hydrochloride).
Conversion from Other Opiate Therapy
For patients being transferred from therapy with other opiate agonists, dosage may be estimated based on comparisons with morphine sulfate. Select dosage carefully (see General: Conversion from Other Opiate Analgesic Therapy under Dosage and Administration).
For patients being transferred from therapy with opiate agonists other than morphine, a comparative opiate agonist dosage table may be consulted to determine the equivalent morphine dosage.
Oral
Dosage estimates obtained from Table 1 must be individualized (e.g., based on prior opiate use, medical condition, concurrent drug therapy, anticipated use of analgesics for breakthrough pain).
Administer the total daily dosage in divided doses (e.g., at 8-hour intervals) based on individual patient requirements.
Table 1. Conversion from Oral Morphine Sulfate to Oral Methadone Hydrochloride (for Chronic Administration)
Baseline Total Daily Oral Morphine Sulfate Dosage
Estimated Daily Oral Methadone Hydrochloride Dosage (as % of Total Daily Morphine Sulfate Dosage)
<100 mg
20–30%
100–300 mg
10–20%
300–600 mg
8–12%
600–1000 mg
5–10%
>1000 mg
<5%
IV
Dosage estimates obtained from Table 2 and Table 3 must be individualized (e.g., based on prior opiate use, medical condition, concurrent drug therapy, anticipated use of analgesics for breakthrough pain).
Administer the total daily dosage in divided doses (e.g., at 8-hour intervals) based on individual patient requirements.
Table 2. Conversion from Oral Morphine Sulfate to IV Methadone Hydrochloride (for Chronic Administration)
Baseline Total Daily Oral Morphine Sulfate Dosage
Estimated Daily IV Methadone Hydrochloride Dosage (as % of Total Daily Morphine Sulfate Dosage)
<100 mg
10–15%
100–300 mg
5–10%
300–600 mg
4–6%
600–1000 mg
3–5%
>1000 mg
<3%
Table 3. Conversion from Parenteral Morphine Sulfate to IV Methadone Hydrochloride (for Chronic Administration)
Baseline Total Daily Parenteral Morphine Sulfate Dosage
Estimated Daily IV Methadone Hydrochloride Dosage (as % of Total Daily Morphine Sulfate Dosage)
10–30 mg
40–66%
30–50 mg
27–66%
50–100 mg
22–50%
100–200 mg
15–34%
200–500 mg
10–20%
Derived from Table 2 assuming a 3:1 oral:parenteral morphine ratio.
Detoxification and Maintenance of Opiate Dependence
Detoxification
Oral
Initiate when there are substantial opiate-agonist abstinence symptoms.
A single dose of 20–30 mg will often suppress withdrawal symptoms. Initial dose should not exceed 30 mg; use lower initial dose in patients whose tolerance is expected to be low. Additional doses may be necessary if withdrawal symptoms are not suppressed or if they reappear. If same-day dosage adjustments are to be made, reevaluate the patient 2–4 hours after the previous dose. If an additional dose is needed to suppress withdrawal symptoms, administer an additional 5–10 mg. Total daily dose for the first day generally should not exceed 40 mg unless it is documented that this total dose does not suppress withdrawal symptoms.
During the first week, adjust dosage based on control of withdrawal symptoms at times of expected peak activity of methadone (2–4 hours after a dose). Use caution to avoid overdosage.
Usual stabilizing dosage is 40 mg daily in divided doses. When the patient has been stabilized (i.e., substantial symptoms of withdrawal are absent) for 2 or 3 days, gradually decrease dosage daily or at 2-day intervals. Individualize and adjust dosage to keep withdrawal symptoms at a tolerable level. In hospitalized patients, reduce dosage by 20% daily; a more gradual reduction may be required in ambulatory patients.
Parenteral
Patients unable to receive methadone orally: Hospitalize patient and convert oral dose to parenteral dose using accepted criteria. Patients being switched from oral methadone usually initiate parenteral methadone at an oral:parenteral dosage ratio of 2:1 (e.g., 5 mg of parenteral methadone hydrochloride in patients previously receiving 10 mg of oral methadone hydrochloride).
Maintenance
Oral
A single dose of 20–30 mg will often suppress withdrawal symptoms. Initial dose should not exceed 30 mg; use lower initial dose in patients whose tolerance is expected to be low. Additional doses may be necessary if withdrawal symptoms are not suppressed or if they reappear. If same-day dosage adjustments are to be made, reevaluate the patient 2–4 hours after the previous dose. If an additional dose is needed to suppress withdrawal symptoms, administer an additional 5–10 mg. Total daily dose for the first day generally should not exceed 40 mg unless it is documented that this total dose does not suppress withdrawal symptoms.
During the first week, adjust dosage based on control of withdrawal symptoms at times of expected peak activity of methadone (2–4 hours after a dose). Use caution to avoid overdosage.
Titrate dosage to a level at which opiate withdrawal symptoms are prevented for 24 hours, drug craving is reduced, euphoric effects of self-administered opiates are blocked or attenuated, and patient is able to tolerate the sedative effects of methadone. Usual stabilizing dosage is 80–120 mg daily. Review maintenance dosage requirements regularly and reduce as indicated.
Once-daily dosing usually is adequate; there generally is no apparent advantage to divided doses. However, rapid metabolizers may not maintain adequate plasma concentrations with usual dosing regimens.
Withdrawal from methadone maintenance: Considerable variability in appropriate rate of dosage reduction; one regimen involves reducing the dose by <10% of established tolerance or maintenance dosage at intervals of 10–14 days. All patients in a maintenance program should be given careful consideration for discontinuance of methadone therapy, especially after reaching a dosage of 10–20 mg daily.
Parenteral
Patients unable to receive methadone orally: Hospitalize patient and convert oral dose to parenteral dose using accepted criteria. Patients being switched from oral methadone usually initiate parenteral methadone at an oral:parenteral dosage ratio of 2:1 (e.g., 5 mg of parenteral methadone hydrochloride in patients previously receiving 10 mg of oral methadone hydrochloride).
Special Populations
Hepatic Impairment
Reduce initial dosage in patients with severe hepatic impairment.
Renal Impairment
Reduce initial dosage in patients with severe renal impairment.
Geriatric and Debilitated Patients
Reduce dosage in poor-risk and in very old patients.
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