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Methadone Hydrochloride

Methadone Hydrochloride

Pronunciation Pronunciation: METH-a-done HYE-droe-KLOR-ide

Class: Opioid analgesic

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Trade Names

Diskets

– Tablets, dispersible 40 mg

Dolophine Hydrochloride

– Tablets 5 mg

– Tablets 10 mg

Methadone Hydrochloride

– Injection 10 mg/mL

– Solution, oral 5 mg per 5 mL

– Solution, oral 10 mg per 5 mL

Methadone Hydrochloride Intensol

– Liquid concentrate, oral 10 mg/mL

Methadose

– Tablets 5 mg

– Tablets 10 mg

– Tablets, dispersible 40 mg

– Concentrate, oral 10 mg/mL

Metadol (Canada)

Pharmacology

Relieves pain by stimulating opiate receptors in CNS; also causes respiratory depression, peripheral vasodilation, inhibition of intestinal peristalsis, sphincter of Oddi spasm, stimulation of chemoreceptors that cause vomiting and increased bladder tone.

Pharmacokinetics

Absorption

Following oral administration, bioavailability ranges from 36% to 100%. T max ranges from 1 to 7.5 h. After administration of oral daily doses of 10 to 225 mg, the steady-state plasma concentrations ranged from 65 to 630 ng/mL and C max ranged from 124 to 1,255 ng/mL.

Distribution

Vd at steady state ranges from 1 to 8 L/kg. Protein binding is 85% to 90%, primarily to alpha-1 acid glycoprotein. Methadone is secreted in amniotic fluid, breast milk, saliva, and umbilical cord plasma.

Metabolism

Methadone is primarily metabolized to inactive metabolites by the CYP3A4, CYP2B6, and CYP2C19 isozymes, and to a lesser extent by CYP2C9 and CYP2D6 isozymes.

Elimination

The primary route of excretion is in the urine. Apparent plasma Cl ranges from 1.4 to 126 L/h, and the terminal half-life is highly variable, ranging from 8 to 59 h. Because it is lipophilic, methadone persists in the liver and tissue. The slow release from these sites may prolong the duration of methadone action despite low plasma concentrations.

Duration

Analgesia: 4 to 8 h.

Special Populations

Renal Function Impairment

The pharmacokinetics have not been extensively evaluated in patients with renal insufficiency.

Hepatic Function Impairment

The pharmacokinetics have not been extensively evaluated in patients with hepatic insufficiency. However, methadone is metabolized by hepatic pathways; therefore, there is a risk of drug accumulation after multiple dosing in patients with hepatic function impairment.

Elderly

Pharmacokinetics have not been evaluated.

Children

Pharmacokinetics have not been evaluated.

Gender

Pharmacokinetics have not been evaluated.

Race

Pharmacokinetics have not been evaluated.

Indications and Usage

Detoxification treatment of opioid addiction; maintenance treatment of opioid addiction, in conjunction with appropriate social and medical services.

Dolophine , Intensol , methadone injection, methadone oral solution, Methadose For the treatment of moderate to severe pain not responsive to non-narcotic analgesics. Methadone injection: Temporary treatment of opioid dependence in patients unable to take oral medication.

Contraindications

Any situation in which opioids are contraindicated (eg, respiratory depression in the absence of resuscitative equipment or in unmonitored settings); patients with acute bronchial asthma or hypercarbia; patients who have or are suspected of having a paralytic ileus; hypersensitivity to any component of the product.

Dosage and Administration

Conversion From Parenteral Methadone to Oral Methadone

Adults PO Start with 1:2 dose ratio (eg, parenteral methadone 5 mg to oral methadone 10 mg).

Detoxification and Maintenance Treatment of Opiate Dependence

Adults IV/IM/Subcutaneous/PO For detoxification and maintenance of opiate dependence, methadone should be administered in accordance with the treatment standards cited in the Code of Federal Regulation, Title 42, Section 8.12, including limitations on unsupervised administrations.

Induction

Adults PO Start with 20 to 30 mg to suppress withdrawal symptoms. For same-day dosing adjustments, wait 2 to 4 h for further evaluation when peak levels are reached. An additional 5 to 10 mg may be administered if withdrawal symptoms have not been suppressed or if symptoms reappear (max, 40 mg the first day). Dose adjustments should be made over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (eg, 2 to 4 h after dosing). Initial doses should be lower for patients whose tolerance is expected to be low at the beginning of treatment.

Initiation of Therapy in Opioid Nontolerant Patients

Adults IV/IM/Subcutaneous/PO When used as the first analgesic in patients who are not already being treated with, and tolerant to, opioids, start with 2.5 to 10 mg every 8 to 12 h. Slowly titrate to effect. More frequent administration may be required during initiation in order to maintain adequate analgesia.

Maintenance

Adults PO Most commonly, clinical stability is achieved at dosages between 80 and 120 mg/day. Titrate to a dose at which opioid symptoms are prevented for 24 h, drug hunger or craving is reduced, the euphoric effects of self-administered opioids are blocked or attenuated, and the patient is tolerant to the sedative effects of methadone.

Medically Supervised Withdrawal After a Period of Maintenance Treatment

Adults PO It is generally suggested that the dose reductions should be less than 10% of the established tolerance or maintenance dose, and that 10- to 14-day intervals should elapse between dose reductions.

Short-Term Detoxification

Adults PO Titrate patients to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilization level. Continue stabilization for 2 to 3 days, after which the dose should be gradually decreased. The rate of decrease should be determined for each patient. The dose can be decreased on a daily basis or at 2-day intervals, but the amount of intake should remain sufficient to keep withdrawal symptoms at a tolerable level. In hospitalized patients, a daily reduction of 20% of the total daily dose may be tolerated. In ambulatory patients, a somewhat slower schedule may be needed.

Switching Patients to Methadone From Other Chronic Opioids

Adults IV/PO Use the following guidelines for oral morphine to methadone conversion:

Total daily baseline oral morphine dose Morphine less than 100 mg The estimated daily oral methadone requirement as a percent of total daily oral morphine dose is 20% to 30% (IV, 10% to 15%).

Morphine 100 to 300 mg The estimated daily oral methadone requirement as a percent of total daily oral morphine dose is 10% to 20% (IV, 5% to 10%).

Morphine 300 to 600 mg The estimated daily oral methadone requirement as a percent of total daily oral morphine dose is 8% to 12% (IV, 4% to 6%).

Morphine 600 to 1,000 mg The estimated daily oral methadone requirement as a percent of total daily oral morphine dose is 5% to 10% (IV, 3% to 5%).

Morphine more than 1,000 mg The estimated daily oral methadone requirement as a percent of total daily oral morphine dose is less than 5% (IV, less than 3%). Published conversion guidelines to determine the equivalent morphine dose for patients converting from other opioids should be consulted.

Total daily baseline parenteral morphine dose Morphine 10 to 30 mg The estimated daily parenteral methadone requirement as percent of total daily morphine dose is 40% to 66%.

Morphine 30 to 50 mg The estimated daily parenteral methadone requirement as percent of total daily morphine dose is 27% to 66%.

Morphine 50 to 100 mg The estimated daily parenteral methadone requirement as percent of total daily morphine dose is 22% to 50%.

Morphine 100 to 200 mg The estimated daily parenteral methadone requirement as percent of total daily morphine dose is 15% to 34%.

Morphine 200 to 500 mg The estimated daily parenteral methadone requirement as percent of total daily morphine dose is 10% to 20%.

General Advice

  • Dose adjustment should be cautious; deaths have occurred in early treatment because of the cumulative effects of the first several days dosing. Extreme caution is necessary when titrating the dose to avoid overdosage, taking into account the long elimination half-life of methadone.
  • Loss of tolerance should be considered in any patient who has not taken opioids for more than 5 days.
  • Methadone Diskets and tablets for oral suspension are intended for dispersion in a liquid immediately prior to oral ingestion of the prescribed dose.
  • Methadone Diskets and tablets for oral suspension should not be chewed or swallowed before dispersing in liquid.
  • Methadone Diskets and tablets for oral suspension are cross-scored, allowing for flexible dosage adjustment in 10 mg increments.
  • Because Methadone Diskets and tablets for oral suspension can only be administered in 10 mg increments, they may not be appropriate for initial dosing or gradual dose reduction.
  • Prior to administration, the desired dose of the Diskets or tablet for oral suspension should be dispersed in approximately 120 mL of water, orange juice, Tang , citrus flavors of Kool-Aid , or other acidic fruit beverage. If residue remains in the cup after initial administration, a small amount of liquid should be added and the resulting mixture should be ingested by the patient.

Storage/Stability

Dolophine , Intensol , methadone injection, methadone oral solution Store at 59° to 86°F. Protect from light.

Methadone Diskets Store at 59° to 86°F.

Methadose dispersible tablets Store at 68° to 77°F.

Methadose oral solution, Methadose oral tablets Store at 68° to 77°F. Protect from light.

Drug Interactions

Agents that prolong the QT interval (eg, cisapride, class I antiarrhythmic agents [eg, procainamide, quinidine], class III antiarrhythmic agents [eg, dofetilide, sotalol], isradipine, nicardipine, pimozide, thioridazine, ziprasidone) The risk of life-threatening cardiac arrhythmias, including torsades de pointes, may be increased.

CNS depressants (alcohol, benzodiazepines [eg, alprazolam, diazepam], general anesthetics, hypnotics, opioid analgesics, phenothiazines, sedatives, tranquilizers) Risk of coma, hypotension, profound sedation, and respiratory depression may be increased. Deaths have been reported.

Desipramine Plasma concentrations may be elevated by methadone, increasing efficacy.

Didanosine, stavudine Plasma concentrations of these drugs may be reduced by methadone, decreasing their efficacy.

Inducers of CYP3A4, CYP2B6, CYP2C19, and, to a lesser degree, CYP2C9 and CYP2D6 (examples of agents in these classes include barbiturates [eg, phenobarbital], carbamazepine, NNRTIs [eg, efavirenz, nevirapine], phenytoin, protease inhibitors [eg, lopinavir, nelfinavir, ritonavir], rifampin, St. John’s wort) May reduce methadone plasma concentrations, decreasing the efficacy, possibly resulting in opioid withdrawal symptoms. Adjust the methadone dose as needed.

Inhibitors of CYP3A4, CYP2B6, CYP2C19, and, to a lesser degree, CYP2C9 and CYP2D6 (examples of agents in these classes include azole antifungals [eg, ketoconazole, voriconazole], fluvoxamine, grapefruit juice, macrolide antibiotics [eg, erythromycin]) May increase methadone plasma concentrations, increasing the pharmacologic effects and the risk of toxicity. Adjust the methadone dose as needed.

Opioid antagonists, mixed agonists/antagonists, and partial agonists (examples of these agents include buprenorphine, butorphanol, nalbuphine, naloxone, naltrexone, pentazocine) Opioid withdrawal symptoms may occur.

Quinolone antibiotics (eg, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, norfloxacin) Inhibition of methadone metabolism by ciprofloxacin and norfloxacin may elevate methadone plasma concentrations, increasing pharmacologic effects and adverse reactions. Gatifloxacin, levofloxacin, and moxifloxacin may increase the risk of life-threatening cardiac arrhythmias, including torsades de pointes.

Zidovudine Plasma concentrations may be elevated by methadone, increasing the risk of toxicity.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Arrhythmias, bigeminal rhythms, bradycardia, cardiac arrest, cardiomyopathy, ECG abnormalities, edema, flushing, heart failure, hypotension, palpitations, phlebitis, QT interval prolongation, shock, syncope, T-wave inversion, tachycardia, torsades de pointes, ventricular fibrillation, ventricular tachycardia.

CNS

Agitation; asthenia; confusion; disorientation; dizziness; dysphoria; euphoria; hallucinations; headache; insomnia; light-headedness; sedation; seizures.

Dermatologic

Hemorrhagic urticaria (rare), pruritus, skin rash, sweating, urticaria.

EENT

Visual disturbances.

GI

Abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis, nausea, vomiting.

Genitourinary

Amenorrhea, antidiuretic effect, reduced libido and/or potency, urinary retention or hesitancy.

Hematologic-Lymphatic

Reversible thrombocytopenia.

Metabolic-Nutritional

Hypokalemia, hypomagnesemia, weight gain.

Respiratory

Pulmonary edema, respiratory arrest and depression.

Miscellaneous

Edema.

Precautions

Warnings

Cardiac effects QT interval prolongation and serious arrhythmia (eg, torsades de pointes) have occurred with methadone treatment. Most cases involve treatment with large, multiple daily methadone doses; however, cases have been reported in patients receiving commonly used doses for maintenance treatment of opioid addiction.

Distribution and use Methadone products, used for treatment of opioid addiction in detoxification or maintenance programs, are to be dispensed only by opioid treatment programs certified by the Substance Abuse and Mental Health Service Administration and approved by the designated state authority, except: 1) during inpatient care, when the patient is admitted for conditions other than concurrent opioid addiction, to facilitate the treatment of the primary admitting diagnosis; and 2) during an emergency period of no longer than 3 days while definitive care for the addiction is being sought in an appropriately licensed facility.

Fatalities Deaths have been reported during initiation of methadone treatment for opioid dependence. Deaths appear to be due to drug interactions with licit and illicit drugs, or the respiratory or cardiac effects of methadone, and too-rapid titration without appreciation for the accumulation of methadone over time.

Respiratory depression Respiratory depression is the chief hazard associated with methadone administration. Peak respiratory depressant effects of methadone occur later and persist longer than peak analgesic effects, particularly during the early dosing period.

Monitor

Monitor for evidence of withdrawal when treatment with a CYP3A4 inducer is started.

Pregnancy

Category C . Methadone Cl is increased during pregnancy. It may be necessary to increase the dose or dosing interval during pregnancy.

Lactation

Excreted in breast milk.

Children

Not recommended for children; dosage is not well defined.

Elderly

Use with caution, usually starting at the low end of the dosage range, because of the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapy.

Renal Function

May need to decrease dose in patients with renal function impairment.

Hepatic Function

May need to decrease dose in patients with hepatic impairment.

Special Risk Patients

Use with caution in patients with myxedema, acute alcoholism, acute abdominal conditions, ulcerative colitis, decreased respiratory reserve, head injury or increased intracranial pressure, hypoxia, superventricular tachycardia, depleted blood volume, circulatory shock, hypothyroidism, Addison disease, prostatic hypertrophy, or urethral stricture.

Abuse

Methadone abuse poses risk of overdose and death. Methadone is a mu-agonist opioid and has abuse liability similar to morphine and other opioid agonists and is subject to criminal diversion.

Acute pain

Maintenance patients on a stable dose of methadone who experience physical trauma, postoperative pain, or other acute pain do not derive analgesia from their existing dose of methadone; treat these patients with analgesics, including opioids, in doses indicated for non–methadone-treated patients with similar painful conditions.

Debilitated patients

Use with caution because comorbidity or concurrent medications may predispose debilitated patients to dysrhythmia or reduced ventilatory drive.

Heroin withdrawal

During the induction phase of methadone maintenance treatment, patients are being withdrawn from heroin and may therefore show typical symptoms, which should be differentiated from methadone-induced side effects.

Hypotension

Severe hypotension may occur in patients whose ability to maintain normal BP is compromised (eg, severe volume depletion).

Incomplete cross-tolerance

Patients tolerant to other opioids may be incompletely tolerant to methadone, which is a concern when converting patients tolerant to other mu-opioid agonists to methadone. This makes determination of dosing conversion complex. Deaths have occurred during conversion.

Nonteratogenic effects

Babies born to mothers who have been taking opioids regularly prior to delivery may be physically dependent. Onset of withdrawal symptoms in infants is usually in the first days after birth. Duration of withdrawal signs may vary from a few days to weeks or even months. There is no consensus on the appropriate management of infant withdrawal.

Obstetrical analgesia

Do not use methadone for obstetrical analgesia. Its long duration of action increases the probability of neonatal respiratory depression.

Physical dependence

Physical dependence manifested by withdrawal symptoms may occur after abrupt discontinuation or administration of an antagonist.

Treatment of drug addiction

Methadone for detoxification should not be given for more than 21 days and treatment should not be repeated within 4 wk. More than 3 wk of methadone treatment for narcotic dependence is considered maintenance therapy; only approved programs can provide this therapy.

Overdosage

Symptoms

Apnea, bradycardia, cardiac arrest, circulatory collapse, cold and clammy skin, death, extreme somnolence progressing to stupor or coma, hypotension, maximally constricted pupils, respiratory depression, skeletal muscle flaccidity.

Patient Information

  • Tell patient to take methadone regularly, as prescribed. If dose is missed, tell patient to take as soon as possible. If close to next dose, wait and take next regularly scheduled dose.
  • Advise patient that drug may cause dizziness, drowsiness, or blurred vision, and to use caution while driving or performing other hazardous tasks.
  • Instruct patients to seek medical attention immediately if they experience symptoms suggestive of an arrhythmia (eg, dizziness, light-headedness, palpitations, syncope).
  • Caution patient to avoid intake of alcoholic beverages or other CNS depressants.
  • If constipation occurs, tell patient to increase fluids and fiber or to use fiber laxative.
  • Explain that use of methadone before pain becomes acute will allow it to alleviate pain better.
  • Caution patient to avoid sudden position changes to prevent orthostatic hypotension.
  • Explain types and potential significance of sympathomimetic side effects.

Copyright © 2009 Wolters Kluwer Health.

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Methadone Hydrochloride

Methadone Hydrochloride

Pronunciation Class: Opiate Agonists

VA Class: CN101

CAS Number: 1095-90-5

Brands: Dolophine, Methadose

For ProfessionalsSide EffectsInteractionsMore…

Warning(s)

  • 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).222 263 269 b Certified treatment programs should dispense only oral methadone products as outlined in the Federal Opioid Treatment Standards (42 CFR 8.12).222 263 269 b d
  • 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.222 269 b
  • Serious Adverse Effects
  • Death and life-threatening adverse effects (i.e., respiratory depression, cardiac arrhythmias) reported in patients receiving methadone.269 270 b These events have been reported in patients initiating methadone therapy for pain and in patients transferring to methadone from other opiate therapy; 269 death reported in patients initiating methadone therapy for opiate dependence.b Interactions with other drugs (legal and illicit), respiratory and cardiac effects of methadone, or rapid dose titration may have contributed to these events.269 b Consider pharmacokinetic and pharmacologic properties of methadone when initiating therapy, transferring patients from other opiate therapy, and during dose titration.269 b (See Pharmacokinetics.)
  • Respiratory depression is the major toxicity associated with methadone.269 b Peak respiratory depressant effect occurs later and persists longer than peak analgesic effect, particularly during the early dosing period.269 b These properties can contribute to inadvertent overdosage, especially during treatment initiation and dose titration.269 b (See Respiratory Depression under Cautions.)
  • Possible prolongation of the QT interval and serious cardiac arrhythmias, including torsades de pointes.222 223 234 269 b 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.222 233 234 269 b (See Cardiac Effects under Cautions.)
  • For pain management, initiate only if potential benefits outweigh risks of methadone therapy.269

Introduction

Opiate agonist; a synthetic diphenylheptane derivative.222 a

Uses for Methadone Hydrochloride

Pain (Acute or Chronic)

A strong analgesic used for the relief of moderate to severe pain that has not responded to nonopiate analgesics.222 224 225 226 269

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).228 232 254

Although considered by some clinicians to be second-line therapy in the management of chronic malignant pain,229 232 235 254 clinical studies suggest that efficacy may be similar to that of morphine and other opiates in this population.228 232

Benefits associated with use for management of chronic pain include the commercial availability of multiple dosage forms of the drug,232 good oral bioavailability,228 229 rapid onset of action,228 229 reduced dosing frequency (because of the drug’s long half-life),228 232 low cost,228 229 232 235 and lack of active metabolites.228 229 232

Disadvantages associated with use include increased potential for accumulation with repeated doses (which may result in toxicity),228 254 269 considerable interindividual variability in pharmacokinetic parameters,228 229 269 potential for drug interactions,228 232 269 challenges associated with dosage titration and with the transfer of patients from therapy with other opiate agonists,228 269 and commercial availability and relative ease of use of extended-release preparations of other opiate agonists.228

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.212 213 216 217 226 263 269

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.a

Methadone Hydrochloride 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.222 232 269 d There is considerable interindividual variability in absorption, metabolism, and relative analgesic potency of the drug.222 232 269 d

  • Carefully monitor patients during initiation of therapy, dosage titration, and conversion from one opiate agonist to another.222 269 d
  • 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.269 270 d

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.222 236 259 269 d

  • A high degree of opiate tolerance does not preclude the possibility of unintended methadone overdosage.222 269 d Failure to individualize dosage has resulted in serious adverse effects, including death, in opiate-tolerant patients during conversion to methadone therapy.222 236 269 d
  • 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.222 235 269 (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.222 d 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).222 227 d Therefore, estimates of methadone dosage that are based on single-dose studies should not be used for conversion in patients receiving chronic opiate therapy.222

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.214 261 262 263 264

  • Hospitalized patients unable to take oral medication may receive parenteral methadone on a temporary basis.d 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.222 a
  • 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.201 213 263
  • 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.201 213 263
  • Maintenance treatment: Administer at a stable dosage for >21 days in the treatment of opiate dependence.212 213 216 263 267
  • Patients with ≥2 unsuccessful detoxification episodes within a 12-month period should be assessed for alternative forms of treatment.263 An opiate treatment program may not admit a patient for >2 detoxification treatments within 1 year.263
  • Patients undergoing short-term detoxification are not eligible for unsupervised administration.263 264
  • 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.263 264 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.263
  • 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).263 264 265 All other doses must be administered while the patient is closely observed.263
  • 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.263 265
  • After 1 year of continuous treatment, the patient may receive a maximum 2-week supply and must make twice monthly visits.263 265 After 2 years of continuous treatment, the patient may receive a maximum 1-month supply of the drug and must make monthly visits.263 265
  • 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.263

Restricted Distribution

  • Distribution of 40-mg dispersible tablets restricted to authorized opiate-dependency treatment programs and to hospitals.271 272 273 Distribution restricted in response to reports of serious adverse effects (see Serious Adverse Effects in Boxed Warning).270 272 273

Administration

Administer orally or by sub-Q, IM, or IV injection.222 224 225 226

Oral Administration

Tablets, dispersible tablets, and oral concentrate solution are for oral administration only and must not be injected.224 225 262

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.262 b Complete tablet dispersion occurs within 1 minute; dispersion time is slightly increased when a cold and/or acidic vehicle is used.a

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.b

The 40-mg dispersible tablets are used in detoxification and maintenance of opiate dependence;271 this preparation should not be used for the treatment of pain.270 271

Dispersible tablets contain insoluble excipients and must not be used to prepare solutions for injection.262

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.255 256

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.222

IV Administration

Administer by IV injection.222

For solution and drug compatibility information, see Compatibility under Stability.

Dosage

Available as methadone hydrochloride; dosage expressed in terms of the salt.222 224 225 226 263 269

Adults

Pain

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.222 269

Give the smallest effective dose in order to minimize development of tolerance and physical dependence.a

Oral

Opiate-naive patients: Initially, 2.5–10 mg every 8–12 hours.269 Titrate dosage to provide adequate analgesia; increase dosage slowly to avoid accumulation and potential toxicity.269

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.223 227 269 Use caution to avoid overdosage.269

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).269

IV

Opiate-naive patients: Initially, 2.5–10 mg every 8–12 hours.222 Titrate dosage to provide adequate analgesia; increase slowly to avoid accumulation and potential toxicity.222 More frequent administration may be required during initiation of therapy to maintain adequate analgesia; however, use caution to avoid overdosage.222

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).222

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.222 269 Select dosage carefully (see General: Conversion from Other Opiate Analgesic Therapy under Dosage and Administration).222 269

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.222 269

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).222 269

Administer the total daily dosage in divided doses (e.g., at 8-hour intervals) based on individual patient requirements.222 269

Table 1. Conversion from Oral Morphine Sulfate to Oral Methadone Hydrochloride (for Chronic Administration)222269
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).222

Administer the total daily dosage in divided doses (e.g., at 8-hour intervals) based on individual patient requirements.222

Table 2. Conversion from Oral Morphine Sulfate to IV Methadone Hydrochloride (for Chronic Administration)222
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%

Derived from Table 2 assuming a 3:1 oral:parenteral morphine ratio.222

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%

Detoxification and Maintenance of Opiate Dependence
Detoxification

Oral Initiate when there are substantial opiate-agonist abstinence symptoms.224 269 b

A single dose of 20–30 mg will often suppress withdrawal symptoms.224 269 b Initial dose should not exceed 30 mg;263 269 b use lower initial dose in patients whose tolerance is expected to be low.269 b Additional doses may be necessary if withdrawal symptoms are not suppressed or if they reappear.224 269 b If same-day dosage adjustments are to be made, reevaluate the patient 2–4 hours after the previous dose.269 b If an additional dose is needed to suppress withdrawal symptoms, administer an additional 5–10 mg.269 b Total daily dose for the first day generally should not exceed 40 mg263 269 b unless it is documented that this total dose does not suppress withdrawal symptoms.263

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).269 b Use caution to avoid overdosage.269 b

Usual stabilizing dosage is 40 mg daily in divided doses.269 b 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.224 269 b Individualize and adjust dosage to keep withdrawal symptoms at a tolerable level.224 269 b In hospitalized patients, reduce dosage by 20% daily; a more gradual reduction may be required in ambulatory patients.224 269 b

Parenteral Patients unable to receive methadone orally: Hospitalize patient and convert oral dose to parenteral dose using accepted criteria.d 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).222

Maintenance

Oral A single dose of 20–30 mg will often suppress withdrawal symptoms.224 269 b Initial dose should not exceed 30 mg;263 269 b use lower initial dose in patients whose tolerance is expected to be low.269 b Additional doses may be necessary if withdrawal symptoms are not suppressed or if they reappear.224 269 b If same-day dosage adjustments are to be made, reevaluate the patient 2–4 hours after the previous dose.269 b If an additional dose is needed to suppress withdrawal symptoms, administer an additional 5–10 mg.269 b Total daily dose for the first day generally should not exceed 40 mg263 269 b unless it is documented that this total dose does not suppress withdrawal symptoms.263

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).269 b Use caution to avoid overdosage.269 b

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.269 Usual stabilizing dosage is 80–120 mg daily.269 b Review maintenance dosage requirements regularly and reduce as indicated.a

Once-daily dosing usually is adequate; there generally is no apparent advantage to divided doses.a However, rapid metabolizers may not maintain adequate plasma concentrations with usual dosing regimens.206 207 208 210

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.269 b 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.a

Parenteral Patients unable to receive methadone orally: Hospitalize patient and convert oral dose to parenteral dose using accepted criteria.d 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).222

Special Populations

Hepatic Impairment

Reduce initial dosage in patients with severe hepatic impairment.222 269

Renal Impairment

Reduce initial dosage in patients with severe renal impairment.222 269

Geriatric and Debilitated Patients

Reduce dosage in poor-risk and in very old patients.a

Cautions for Methadone Hydrochloride

Contraindications

  • Known hypersensitivity to methadone or any ingredient in the formulation.222 224 225 226 269 b

  • Respiratory depression in the absence of resuscitative equipment or in unmonitored settings.222 269 b
  • Acute asthma or hypercarbia (hypercapnia).269 b d
  • Known or suspected paralytic ileus.269 b

Warnings/Precautions

Warnings

Respiratory Depression

The major toxicity associated with methadone.269 b d (See Boxed Warning.)

Geriatric or debilitated patients and those with conditions accompanied by hypoxia or hypercapnia are at increased risk.222 269 b

Use with extreme caution in patients with asthma, COPD or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, CNS depression or coma, hypoxia, hypercapnia, or preexisting respiratory depression and in others with substantially decreased respiratory reserve.222 224 225 226 269 b

Cardiac Effects

Possible prolongation of the QT interval and serious cardiac arrhythmias, including torsades de pointes.222 223 234 269 b (See Boxed Warning.)

Use with caution and careful monitoring in patients who may be at risk for development of prolonged QT syndrome (e.g., those with cardiac hypertrophy, hypokalemia, or hypomagnesemia; those receiving relatively high methadone dosages or receiving concomitant therapy with a drug that may cause electrolyte disturbances or prolong the QT interval [see Specific Drugs under Interactions]).222 269 b

Use in patients with known prolongation of the QT interval not systematically evaluated.269 b

If prolongation of the QT interval occurs, evaluate the patient’s drug regimen to identify drugs that may prolong the QT interval, cause electrolyte abnormalities, or inhibit metabolism of methadone.222 269 b

Use for the treatment of acute or chronic pain only when the potential benefits outweigh the possible risk of QT-interval prolongation reported with higher methadone dosage.222 269

Incomplete Cross-Tolerance

Patients who are tolerant to other opiate agonists may have incomplete tolerance to methadone.222 253 269 b Overdosage (including fatalities) reported when dosage has not been carefully adjusted in patients being transferred from chronic, high-dose therapy with other opiate agonists to therapy with methadone.222 269

Use methadone with caution and at appropriately adjusted dosages in patients being transferred from other opiate therapy.222 253 269 b Carefully consider pharmacokinetic parameters during initiation and titration of methadone therapy in patients who previously received chronic opiate agonist therapy.222 269 b (See General: Conversion from Other Opiate Analgesic Therapy and also see Dosage: Conversion from Other Opiate Therapy, under Dosage and Administration.)

Drug Abuse and Dependence

Abuse liability similar to that of morphine.222 224 225 226 262 269 Clinicians should consider abuse potential when prescribing or dispensing methadone in situations where they are concerned about an increased risk of misuse, abuse, or diversion.269 b However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain.222 269

Physical and psychic dependence and tolerance may develop with repeated administration; use with caution.222 224 225 226 262 269

Abrupt cessation of therapy or sudden reduction in dosage after prolonged use may result in withdrawal symptoms.222 224 225 226 262 269 After prolonged exposure to opiate analgesics, if withdrawal is necessary, it must be undertaken gradually.222 224 225 226 262 269

Contact the state professional licensing board or controlled substance authority for information about prevention and detection of abuse or diversion.269 b

Increased Intracranial Pressure or Head Trauma

Potential for increased respiratory depressant effects and elevation of CSF pressure in patients with increased intracranial pressure, head trauma, or other intracranial lesions.222 224 225 226 262 269

Adverse effects of opiates may obscure the existence, extent, or course of intracranial pathology.222 224 225 226 262 269

Use with caution, if at all, in patients with head trauma.269 b d

Acute Abdominal Conditions

Administration may complicate assessment of patients with acute abdominal conditions.222 224 225 226 262 269

Contraindicated in patients with known or suspected paralytic ileus.269 b

Hypotensive Effects

Like all opiate analgesics, may cause severe hypotension in individuals whose ability to maintain their BP is compromised by depleted blood volume or concomitant drugs (e.g., phenothiazines, general anesthetics).222 224 225 226 262 269

May produce orthostatic hypotension in ambulatory patients.222 224 225 226

CNS Effects

May impair mental and/or physical abilities needed to perform potentially hazardous activities such as driving or operating machinery.222 224 225 226 262 Individuals who perform hazardous tasks requiring mental alertness or physical coordination should be warned about possible adverse CNS effects of opiate agonists.222 224 225 226 269

Concomitant use with other CNS depressants may cause profound sedation, coma, respiratory depression, or hypotension.222 269 b Deaths associated with illicit methadone use frequently have involved concomitant benzodiazepine abuse.222 269 b

General Precautions

Acute Pain Management in Patients Receiving Maintenance Treatment

Patients maintained on a stable dose of methadone who experience trauma or acute (e.g., postoperative) pain should not be expected to derive adequate analgesia from their stable methadone regimen.222 269

Such patients should receive analgesics, including opiates, appropriate for other patients experiencing similar nociceptive stimulation.222 269 Opiate doses may be somewhat higher or dosing intervals somewhat shorter than those in nontolerant patients.222 269

Anxiety

Anxiety in a patient receiving methadone maintenance treatment should not be confused with withdrawal syndrome and should not be treated with an increase in methadone dosage.222 269

Hypothyroidism

Use with caution and in reduced dosage in patients with hypothyroidism.222 269

Prostatic Hypertrophy or Urethral Stricture

Use with caution and in reduced dosage in patients with prostatic hypertrophy or urethral stricture.222 269

Addison’s Disease

Use with caution and in reduced dosage in patients with Addison’s disease.222 269

Specific Populations

Pregnancy

Category C.222 269 b

Use for obstetric analgesia is not recommended, since neonate may be at increased risk of respiratory depression because of the long duration of effect.222

Short- or long-term detoxification treatment is not recommended during pregnancy.201 However, pregnant women, regardless of age, are eligible for admission into a comprehensive maintenance treatment program if they have a history of documented opiate dependence and are considered at risk of possibly returning to such dependence (and all its attendant risks) during pregnancy.201 213

If methadone maintenance treatment is deemed necessary during pregnancy, undertake such treatment with caution and at the lowest possible effective dosage.201

Clearance may be increased during 2nd and 3rd trimesters, resulting in the need for higher doses or shorter dosing intervals in order to avoid withdrawal symptoms.222 269 b

Lactation

Distributed into milk.222 269 b Discontinue nursing or the drug.222 269 b

Women receiving high-dose maintenance therapy who are already nursing should be instructed to discontinue nursing gradually to prevent withdrawal (neonatal abstinence syndrome) in the infant.222 269 b

Pediatric Use

Safety and efficacy as analgesic not established in children <18 years of age.222 224 225 226 262 269 b

Short- or long-term detoxification treatment using methadone is not subject to any age limitation.201 263 However, the effects of prolonged use on the physiologic and psychologic development of children are not known; therefore, do not initiate maintenance treatment with the drug indiscriminately in children <18 years of age.201 213

Children <18 years of age are eligible to receive maintenance treatment provided they have undergone ≥2 documented attempts at detoxification or drug-free treatment in a 12-month period and the program physician has documented that the child continues to be, or is again, physiologically dependent on opiates.263 Signed informed consent must be obtained from a parent, legal guardian, or responsible adult designated by the appropriate local (e.g., state) authority (e.g., via emancipated minor laws).263

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger adults.222 269 b

Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, use with caution in this age group and select dosage at the lower end of the dosage range.222 269 b

Hepatic Impairment

Not studied extensively in patients with hepatic impairment.222 269 b However, risk of accumulation with multiple doses because the drug is metabolized in the liver.222 269 b Use with caution and in reduced dosage in patients with severe hepatic impairment.222 269 b

Renal Impairment

Not studied extensively in patients with renal impairment.222 269 b Use with caution and in reduced dosage in patients with severe renal impairment.222 269 b

Common Adverse Effects

Lightheadedness, dizziness, sedation, nausea, vomiting, sweating.222 224 269 b

Interactions for Methadone Hydrochloride

Metabolized principally by CYP3A4, CYP2B6, and CYP2C19, although other isoenzymes, including CYP2C9, and CYP2D6, also may be involved.269 b

Drugs Affecting Hepatic Microsomal Enzymes

Possible pharmacokinetic interaction with drugs that are inhibitors or inducers of CYP3A4 and other CYP isoenzymes (i.e., 2B6, 2C19, 2C9, 2D6) with possible alteration of the metabolism of methadone.269 b

Drugs that Prolong the QT Interval

Potential pharmacologic interaction (prolongation of the QT interval; potential for severe and/or life-threatening cardiac arrhythmias).222 269 b Use with extreme caution.222 269 b

Drugs that May be Associated with Electrolyte Abnormalities

Potential pharmacologic interaction (potential for electrolyte disorders that may cause severe and/or life-threatening cardiac arrhythmias).222 269 b Use with caution.222 269 b

Specific Drugs

Drug

Interaction

Comments

Abacavir

Possible decreased plasma methadone concentrations269 b e

Monitor for signs of opiate withdrawal; adjust methadone dosage as needed269 b

Alcohol

Chronic consumption: Increased methadone metabolism and reduced serum concentrations of the drug235

Acute consumption: Increased AUC of methadone235

Amphetamines

Dextroamphetamine may enhance opiate agonist analgesiac

Antiarrhythmic agents (class I or III)

Potential for severe and potentially life-threatening cardiac arrhythmias222 269 b

Use concomitantly with extreme caution222 269 b

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Increased methadone metabolism;222 232 235 269 b withdrawal symptoms reported222 235 269 b

Antidepressants, MAO inhibitors

Severe reactions (e.g., agitation, bizarre behavior, headache, hypertension, hypotension, rigidity, convulsions, hyperpyrexia, coma) reported in some patients receiving MAO inhibitors with meperidine; similar reactions not reported with methadone222 224 225 226 262 269 b c

If concomitant use is necessary, administer methadone in small, incremental doses over several hours with careful monitoring222 224 225 226 262 269 b

Antidepressants, SSRI (fluoxetine, fluvoxamine, sertraline)

Increased serum methadone concentrations and increased opiate effects secondary to inhibition of methadone metabolism222 235 269 b

Antidepressants, tricyclic

Potential for severe and/or life-threatening cardiac arrhythmias222 269 b

Methadone may potentiate effects of tricyclic antidepressants222

Desipramine: Increased serum desipramine concentrations222 235 269 b

Use concomitantly with extreme caution222 269 b

Antifungals, azoles (fluconazole, itraconazole, ketoconazole, voriconazole)

Decreased methadone clearance;222 232 235 potential for increased or prolonged opiate agonist effects222 269 b

Monitor carefully and adjust dosage as necessary222 269 b

Antipsychotic agents

Potential for severe and/or life-threatening cardiac arrhythmias with agents that prolong the QT interval222 269 b

Use concomitantly with extreme caution222 269 b

Atazanavir

Pharmacokinetic interaction unlikely243

Calcium-channel blocking agents

Potential for severe and/or life-threatening cardiac arrhythmias with agents that prolong the QT interval222 269 b

Use concomitantly with extreme caution222 269 b

CNS depressants (other opiates, general anesthetics, tranquilizers, sedatives and hypnotics, alcohol)

May potentiate the effects of other CNS depressants; possible coma, severe respiratory depression, cyanosis, or hypotension222 269 b c

Some tranquilizers, especially phenothiazines, may antagonize opiate agonist analgesiac

Use concomitantly with great caution and in reduced dosagea c

Corticosteroids (mineralocorticoid)

Potential for electrolyte disorders that may cause severe and/or life-threatening cardiac arrhythmias 222 269 b

Use concomitantly with caution222 269 b

Darunavir

Possible decreased methadone concentrations with ritonavir-boosted darunavir243

Monitor for signs of opiate withdrawal; increase methadone dosage if needed243

Delavirdine

Possible increased methadone concentrations; no change in delavirdine concentrations243

Monitor for methadone toxicity; consider need for reduction of methadone dosage243

Didanosine

Buffered didanosine preparations: Decreased serum didanosine concentrations; no apparent effect on serum methadone concentrations249

Didanosine delayed-release capsules: No change in the pharmacokinetics of didanosine243

Didanosine delayed-release capsules: Dosage adjustment not needed243

Diuretics

Potential for electrolyte disorders that may cause severe and/or life-threatening cardiac arrhythmias:222 269 b

Opiate agonists may decrease effects of diuretics used in CHFc

Use concomitantly with caution222 269 b

Efavirenz

Decreased plasma methadone concentrations; possible manifestations of opiate withdrawal222 232 243 246

Monitor closely for signs of opiate withdrawal; increased maintenance dosage of methadone may be necessary232 243 246 247

Etravirine

Pharmacokinetic interaction unlikely243

Dosage adjustment not needed; monitor patient and adjust methadone dosage if necessary243

Fosamprenavir

Possible decreased plasma concentrations of amprenavir and methadone243

Monitor patient; adjust methadone dosage as needed243 269 b

Indinavir

Pharmacokinetic interaction unlikely243 f

Laxatives

Potential for electrolyte disorders that may cause severe and/or life-threatening cardiac arrhythmias 222 269 b

Use concomitantly with caution222 269 b

Lopinavir

Decreased plasma methadone concentrations with lopinavir/ritonavir; withdrawal symptoms reported243 269 b

Monitor closely for signs of opiate withdrawal; increased maintenance dosage of methadone may be necessary243 269 b

Macrolide antibiotics (i.e., erythromycin)

Possible decreased methadone clearance222 232 269 b

Monitor patients carefully; adjust methadone dosage as necessary222 269 b

Maraviroc

Data not available243

Some clinicians suggest that use of maraviroc with methadone is potentially safe243

Nelfinavir

Possible decreased methadone concentrations; withdrawal symptoms reported rarely243 269

Monitor closely for signs of opiate withdrawal; increased maintenance dosage of methadone may be necessary243 269

Nevirapine

Decreased serum methadone concentrations; possible withdrawal symptoms following initiation of nevirapine 222 232 242 243 244 245

Monitor closely for signs of opiate withdrawal; increased maintenance dosage of methadone may be necessary222 232 242 243 244 245

If methadone dosage is increased during nevirapine therapy, monitor patients for methadone overdosage when nevirapine is discontinued244

Opiate antagonists (e.g., naloxone, naltrexone)

Precipitation of withdrawal symptoms222 269 b

Opiate partial agonists (e.g., buprenorphine, butorphanol, nalbuphine, pentazocine)

Precipitation of withdrawal symptoms; reduction of analgesic effect222 269 b

Avoid opiate partial agonists in patients who have received or are receiving opiate agonists222

Rifampin

Reduced serum methadone concentrations; possible withdrawal symptoms222 232 235 269 b

Risperidone

Possible withdrawal symptoms following initiation of risperidone therapy235 250

Ritonavir

Possible withdrawal symptoms and decreased serum methadone concentrations following initiation of ritonavir therapy222 232 235 241 243

Use with caution, especially in patients receiving other drugs that may decrease plasma concentrations of methadone222

Monitor patients closely for manifestations of opiate withdrawal; increased maintenance dosage of methadone may be necessary240 241 243

If methadone dosage is increased during ritonavir therapy, monitor patients for methadone overdosage when ritonavir is discontinued241

Saquinavir

Decreased plasma methadone concentrations with ritonavir-boosted saquinavir243

Monitor for opiate withdrawal; adjustment in the maintenance dosage of methadone may be necessary243

Skeletal muscle relaxants

Potential for enhanced neuromuscular blocking actionc

Smoking

Plasma methadone concentrations may be reduced secondary to increased CYP1A2 activity235

Stavudine

Decreased bioavailability222 232 249 and serum concentrations of stavudine249 243

Some clinicians suggest that dosage adjustment is not necessary243

St. John’s wort (Hypericum perforatum)

Increased metabolism of methadone; possible manifestations of opiate withdrawal222 269 b

Tenofovir

Pharmacokinetic interaction unlikely243

Tipranavir

Decreased plasma concentrations of methadone with ritonavir-boosted tipranavir266

Increased maintenance dosage of methadone may be necessary243 266

Zidovudine

Increased zidovudine AUC222 232 239 243 253

Maintenance dosage of methadone probably does not need to be adjusted when zidovudine therapy is initiated in patients receiving long-term methadone treatment;237 239 monitor patients for dose-related zidovudine toxicity237 239 243

Methadone Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Well absorbed from the GI tract.a

Following oral administration, bioavailability is approximately 80% ;223 232 235 however, there is considerable interindividual variability in oral bioavailability (range: 36–100%).269 b

Onset

Full analgesic effects generally are not achieved until completion of 3–5 days of therapy.222 269 b

Peak respiratory depressant effects occur later than analgesic effects, particularly during the early dosing period.269 b

Duration

Approximately 4–8 hours after a single dose.269 270 a b d

Approximately 22–48 hours following oral administration in patients on methadone maintenance.a

Respiratory depressant effects persist longer than analgesic effects, particularly during the early dosing period.269 b

Food

Effect of food on bioavailability not established.269 b

Plasma Concentrations

Trough plasma methadone concentrations exceeding 100–200 ng/mL may be necessary to optimize the success of methadone maintenance,205 206 207 208 209 particularly during the first 6 months of treatment.203

Distribution

Extent

Highly lipophilic and is widely distributed in body tissues.222 232 235 269 b With repeated administration, methadone is stored in the liver and other tissues and is slowly released, prolonging the duration of effect despite low plasma concentrations.269 b

Methadone crosses the placenta and is distributed into milk.222 235 269 b

Plasma Protein Binding

85–90% (mainly α1-acid glycoprotein).222 232 235 269 b

Elimination

Metabolism

Extensively metabolized, principally by CYP3A4, CYP2B6, and CYP2C19 in the liver and/or intestine, although other isoenzymes, including CYP2C9 and CYP2D6, also may be involved.222 232 235 251 269 b

Undergoes N-demethylation to an inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP)and other metabolites with little or no pharmacologic activity.222 232 269 b

Elimination Route

Excreted to varying degrees in urine and feces as metabolites and unchanged drug.222 232 235 269 b

Half-life

Considerable interindividual variability in terminal elimination half-life;222 269 b d generally reported as 8–59 hours,222 269 b d but values have ranged from 9–87 hours in postoperative patients, from 8.5–75 hours in opiate-dependent patients, and up to 120 hours in outpatients receiving therapy for chronic malignant pain.232

Special Populations

Elimination half-life is decreased during 2nd and 3rd trimesters of pregnancy.222 269 b

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).224 269

Tablets, Dispersible

15–30°C.262

Oral Solution and Concentrate Solution

15–30°C.225 226

Parenteral

Injection

25°C (may be exposed to 15–30°C).222

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID
Compatible

Sodium chloride 0.9%

Drug Compatibility
Y-Site CompatibilityHID
Compatible

Atropine sulfate

Dexamethasone sodium phosphate

Diazepam

Diphenhydramine HCl

Haloperidol lactate

Hydroxyzine HCl

Ketorolac tromethamine

Lorazepam

Metoclopramide HCl

Midazolam HCl

Phenobarbital sodium

Scopolamine HBr

Incompatible

Phenytoin sodium

Actions

  • A potent analgesic; shares the actions of the opiate agonists.262 269 b d

  • Opiate agonists alter perception of and emotional response to pain.c
  • Precise mechanism of action has not been fully elucidated; opiate agonists act at several CNS sites, involving several neurotransmitter systems to produce analgesia.c
  • Pain perception is altered in the spinal cord and higher CNS levels (e.g., substantia gelatinosa, spinal trigeminal nucleus, periaqueductal gray, periventricular gray, medullary raphe nuclei, hypothalamus).c
  • Opiate agonists do not alter the threshold or responsiveness of afferent nerve endings to noxious stimuli, nor peripheral nerve impulse conduction.c
  • Opiate agonists act at specific receptor binding sites in the CNS and other tissues; opiate receptors are concentrated in the limbic system, thalamus, striatum, hypothalamus, midbrain, and spinal cord.c
  • Agonist activity at the opiate μ- or κ-receptor can result in analgesia, miosis, and/or decreased body temperature.c
  • Agonist activity at the μ-receptor can also result in suppression of opiate withdrawal (and antagonist activity can result in precipitation of withdrawal).c
  • Respiratory depression may be mediated by μ-receptors, possibly μ2-receptors (which may be distinct from μ1-receptors involved in analgesia); κ- and δ-receptors may also be involved in respiratory depression.c
  • May also act as antagonist at N-methyl-D-aspartate (NMDA) receptors.269 b Not known whether NMDA antagonism contributes to efficacy of methadone.269 b Other NMDA antagonists have produced neurotoxic effects in animals.269 b
  • May depress the cough reflex by a direct effect on the cough centers in the medulla.c

Advice to Patients

  • Potential for drug to impair mental alertness or physical coordination; use caution when driving or operating machinery until effects on individual are known.222 224 225 226 262 269 b

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.222 224 225 226 262 269 b
  • Importance of informing patients that methadone should not be combined with alcohol or other CNS depressants (e.g., sleep medications, tranquilizers).222 224 225 226 262 269 b
  • Importance of advising patients to seek immediate medical attention if symptoms suggestive of an arrhythmia (e.g., palpitations, dizziness, lightheadedness, syncope) occur.222
  • Importance of informing patients that the duration of analgesia will increase with repeated dosing.269 b Importance of patients taking the drug only as prescribed and of not increasing the dose or abruptly discontinuing therapy without consulting a clinician.269 b
  • Importance of informing patients that this is a drug of potential abuse and should also be protected from theft.224 225 226 262 269 b
  • Importance of informing patients that this medication should never be given to anyone other than the individual for whom it was prescribed.224 225 226 262 269 b
  • Importance of informing patients to keep this and all medications in a secure location and out of the reach of children.224 225 226 262 269 b
  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.222 224 225 226 262 269 b
  • Importance of informing patients of other important precautionary information.222 224 225 226 262 269 b (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug; also subject to the Substance Abuse and Mental Health Services Administration (SAMHSA) regulations (42 CFR 8) for drugs that require special studies, records, and reports when used for detoxification and maintenance of opiate dependence.

Distribution of 40-mg dispersible tablets is restricted.271 (See Restricted Distribution under Dosage and Administration.)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Methadone Hydrochloride
Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

5 mg/5 mL*

Methadone Hydrochloride Oral Solution (C-II)

10 mg/5 mL*

Methadone Hydrochloride Oral Solution (C-II)

Solution, concentrate

10 mg/mL*

Methadone Hydrochloride Oral Concentrate (C-II)

Methadose Oral Concentrate (C-II)

Mallinckrodt

Tablets

5 mg*

Dolophine Hydrochloride (C-II)

Roxane

Methadone Hydrochloride Tablets (C-II; scored)

Methadose (C-II)

Mallinckrodt

10 mg*

Dolophine Hydrochloride (C-II)

Roxane

Methadone Hydrochloride Tablets (C-II; scored)

Methadose (C-II)

Mallinckrodt

Tablets, dispersible

40 mg*

Methadone Hydrochloride Diskets (C-II; scored)

Methadose (C-II)

Mallinckrodt

Parenteral

Injection

10 mg/mL*

Methadone Hydrochloride Injection (C-II)

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Methadone HCl 10MG Tablets (ROXANE): 20/$11.99 or 30/$16.99

Methadone HCl 5MG Tablets (ROXANE): 20/$11.99 or 30/$17.99

Methadone HCl Diskets 40MG Tablets (CEBERT PHARMACEUTICALS): 20/$16.66 or 30/$24.99

Methadose 10MG Tablets (MALLINCKRODT PHARM): 20/$13.99 or 30/$18.99

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug’s actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2013, Selected Revisions April 1, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

Only references cited for selected revisions after 1984 are available electronically.

200. Food and Drug Administration. National Institute on Drug Abuse; methadone in maintenance and detoxification; joint proposed revision of conditions for use. Fed Regist. 1987; 52:37046-61.

201. Food and Drug Administration. National Institute on Drug Abuse; methadone in maintenance and detoxification; joint revision of conditions for use. Fed Regist. 1989; 54:8954-72.

202. Food and Drug Administration. National Institute on Drug Abuse; methadone in maintenance treatment of narcotic addicts; joint proposed revision of conditions for use. Fed Regist. 1989; 54:8973-9.

203. Cooper JR. Methadone treatment and acquired immunodeficiency syndrome. JAMA. 1989; 262:1664-8. [IDIS 259344] [PubMed 2491420]

204. Ball JC, Lange WR, Myers CP et al. Reducing the risk of AIDS through methadone maintenance treatment. J Health Soc Behav. 1988; 29:214-26. [PubMed 3241064]

205. Dole VP. Methadone treatment and the acquired immunodeficiency syndrome epidemic. JAMA. 1989; 262:1681-2. [IDIS 259345] [PubMed 2769924]

206. Bell J, Seres V, Bowron P et al. The use of serum methadone levels in patients receiving methadone maintenance. Clin Pharmacol Ther. 1988; 43:623-9. [IDIS 243521] [PubMed 3378383]

207. Tennant FS Jr. Inadequate plasma concentrations in some high-dose methadone maintenance patients. Am J Psychiatry. 1987; 144:1349-50. [IDIS 234558] [PubMed 3661772]

208. Dole VP. Implications of methadone maintenance for theories of narcotic addiction. JAMA. 1988; 260:3025-9. [IDIS 247725] [PubMed 2846900]

209. Holmstrand J, Anggard E, Gunne LM. Methadone maintenance: plasma levels and therapeutic outcome. Clin Pharmacol Ther. 1978; 23:175-80. [IDIS 93091] [PubMed 620477]

210. Walton RG. Divided dose for methadone maintenance patients. Am J Psychiatry. 1988; 145:904. [PubMed 2898216]

211. Food and Drug Administration. Methadone in maintenance treatment of narcotic addicts; proposed interim maintenance treatment; public hearing. Fed Regist. 1989; 54:50226-8.

212. Substance Abuse and Mental Health Services Administration and Food and Drug Administration. Methadone in maintenance treatment of narcotic addicts; joint revision of conditions for use; interim maintenance treatment; human immunodeficiency virus disease counseling. 21 CFR 291. Final Rule. [Docket No. 88N-0444] Fed Regist. 1993; 58:495-9.

213. US Food and Drug Administration. Drugs used for treatment of narcotic addicts. [21 CFR Parts 200-299]. 1993(Apr 1):124-45.

214. Food and Drug Administration Levo-ALPHA-Acetyl-Methadol (LAAM) in maintenance; Revision of conditions for use in the treatment of narcotic addiction. Fed Regist. 1993; 58:38704-11.

215. Levomethadyl acetate hydrochloride prescribing information. In: 2002 Mosby’s drug consult. St. Louis, MO: Mosby, Inc; 2002; 111:1690-4.

216. Reckitt Benckiser Pharmaceuticals, Inc. Suboxone (buprenorphine hydrochloride and naloxone hydrochloride dihydrate) sublingual tablets and Subutex (buprenorphine hydrochloride) sublingual tablets prescribing information. Richmond, VA.

217. Methadone hydrochloride prescribing information. In: 2002 Mosby’s drug consult. St. Louis, MO: Mosby, Inc; 2002:III-1839-41.

218. Raisch DW, Fye CL, Boardman KD et al. Opioid dependence treatment, including buprenorphine/naloxone. Ann Pharmacother. 2002; 36:312-21. [IDIS 476846] [PubMed 11847954]

219. Boatwright DE. Buprenorphine and addiction: challenges for the pharmacist. J Am Pharm Assoc. 2002; 42:432-8.

220. Fiellin DA, O’Connor PG. New federal initiatives to enhance the medical treatment of opioid dependence. Ann Intern Med. 2002; 137: 688-92.

221. Schobelock MJ. Dear healthcare professional letter: Product discontinuation notice—Orlaam (levomethadyl hydrochloride acetate) oral solution, 10 mg/mL, CII. Columbus, OH: Roxane Laboratories; 2003 Apr 23.

222. aaiPharma, Inc. Methadone hydrochloride injection prescribing information. Wilmington, NC. 2004 Feb.

223. Anderson R, Saiers JH, Abram S et al. Accuracy in equianalgesic dosing: conversion dilemmas. J Pain Symptom Manage. 2001; 21:397-406. [IDIS 463769] [PubMed 11369161]

224. Roxane Laboratories, Inc. Methadone hydrochloride tablets prescribing information. Columbus, OH. 2000 Dec.

225. Roxane Laboratories, Inc. Methadone hydrochloride IntensolTM, (oral concentrate) prescribing information. Columbus, OH. 1998 Feb.

226. Roxane Laboratories, Inc. Methadone hydrochloride oral solution prescribing information. Columbus, OH. 2000 Oct.

227. Anon. Principles of analgesic use in the treatment of acute pain and cancer pain. 5th ed. Glenview, IL: American Pain Society; 2003.28-31.

228. Nicholson AB. Methadone for cancer pain. Cochrane Database Syst Rev. 2004; 3:CD003971.

229. Mercadante S. Methadone in cancer pain. Eur J Pain. 1997;1:77-83.

230. Gagnon B, Almahrezi A, Schreier G. Methadone in the treatment of neuropathic pain. Pain Res Manage. 2003; 8:149-54.

231. Moulin D. Use of methadone for neuropathic pain. Pain Res Manage. 2003; 8:131-2.

232. Layson-Wolf C, Goode JV, Small RE. Clinical use of methadone. J Pain Palliat Care Pharmacother. 2002; 16:29-59. [PubMed 14650449]

233. Kornick CA, Kilborn MJ, Santiago-Palma J et al. QTc interval prolongation associated with intravenous methadone. Pain. 2003; 105:499-506. [PubMed 14527710]

234. Krantz MJ, Kutinsky IB, Robertson AD et al. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy. 2003; 23:802-5. [IDIS 498498] [PubMed 12820821]

235. Davis MP, Walsh D. Methadone for relief of cancer pain: a review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Support Care Cancer. 2001; 9:73-83. [PubMed 11305074]

236. Pereira J, Lawlor P, Vigano A et al. Equianalgesic dose ratios for opioids: a critical review and proposals for long-term dosing. J Pain Symptom Manage. 2001; 22:672-87. [IDIS 468093] [PubMed 11495714]

237. McCance-Katz EF, Rainey PM, Jatlow P. Methadone effects on zidovudine disposition (AIDS clinical trials group 262) J Acquir Immune Defic Syndr Hum Retrovirol. 1998;18:435-43.

238. GlaxoSmithKline. Retrovir (zidovudine) IV infusion for intravenous infusion only prescribing information. Research Triangle Park, NC. 2003 Aug.

239. Schwartz EL, Brechbuhl AB, Kahl P et al Pharmacokinetic interactions of zidovudine and methadone in intravenous drug-using patients with HIV infection. J Acquir Immune Def Syndr. 1992; 5:619-26.

240. Abbott Laboratories. Norvir (ritonavir) soft gelatin capsules and oral solution prescribing information. North Chicago, IL; 2001 Sept.

241. Geletko SM, Erickson AD. Decreased methadone effect after ritonavir initiation. Pharmacotherapy. 2000; 20:93-4. [IDIS 439281] [PubMed 10641980]

242. Boehringer Ingelheim. Viramune (nevirapine) tablets and oral suspension prescribing information. Ridgefield, CT; 2002 Dec 20

243. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (January 29, 2008). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

244. Altice FL, Friedland GH, Cooney EL. Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone. AIDS. 1999; 13:957-62. [PubMed 10371177]

245. Heelon MW, Meade LB. Methadone withdrawal when starting an antiretroviral regimen including nevirapine. Pharmacotherapy. 1999; 19:471-2 [IDIS 423886] [PubMed 10212021]

246. Bristol-Myers Squibb Company. Sustiva (efavirenz) capsules and tablets prescribing information. Princeton, NJ; 2003 Apr

247. Tashima K, Bose T, Gormley J et al. The potential impact of efavirenz on methadone maintenance. Abstracts of 9th European Congress of Clinical Microbiology and Infectious Diseases, Berlin, Germany: 1999. Abstract No. P0552.

248. Bristol-Myers Squibb. Videx (didanosine) chewable/dispersible buffered tablets and pediatric powder for oral solution prescribing information. Princeton, NJ; 2006 Jul.

249. Rainey PM, Friedland G, McCance-Katz EF. Interaction of methadone with didanosine and stavudine. J Acquir Immune Defic Syndr. 2000; 24:241-8.

250. Wines JD, Weiss RD. Opioid withdrawal during risperidone treatment. J Clin Psychopharmacol. 1999; 19:265-7. [IDIS 428397] [PubMed 10350033]

251. Kharasch ED, Hoffer C, Whittington D et al. Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone. Clin Pharmacol Ther. 2004; 76:250-69. [IDIS 521156] [PubMed 15371986]

252. Dale O, Sheffels P, Kharasch ED. Bioavailabilities of rectal and oral methadone in healthy subjects. Br J Clin Pharmacol. 2004; 58:156-62. [IDIS 520428] [PubMed 15255797]

253. GlaxoSmithKline. Retrovir (zidovudine) tablets, capsules, syrup prescribing information. Research Triangle Park, NC. 2003 Apr.

254. Ballantyne JC, Ma J. Opioid therapy for chronic pain. N Engl J Med. 2003; 349:1943-53. [IDIS 506512] [PubMed 14614170]

255. USPDI: drug information for the health care professional. Greenwood Village, CO: Thomson/Micromedex; 2004:2149-50.

256. Lauriault G, LeBelle MJ, Lodge BA et al. Stability of methadone in four vehicles for oral administration. Am J Hosp Pharm. 1991; 48:1252-6. [PubMed 1858805]

257. Lawlor PG, Turner KS, Hanson J et al. Dose ratio between morphine and methadone in patients with cancer pain. Cancer. 1998; 82:1167-73. [IDIS 404009] [PubMed 9506365]

258. Ripamonti C, Groff L, Brunelli C et al. Switching from morphine to oral methadone in treating cancer pain: what is the equianalgesic dose ratio? J Clin Oncol. 1998; 16:3216-21.

259. Reviewers’ comments (personal observations).

260. Ripamonti C, Zecca E, Bruera E. An update on the clinical use of methadone for cancer pain. Pain. 1997; 70:109-15. [PubMed 9150283]

261. Cebert Pharmaceuticals. Diskets (methadone hydrochloride dispersible tablets) prescribing information. Birmingham, AL; 2002 Apr.

262. Mallinckrodt Inc. Methadose (methadone hydrochloride) dispersible tablets prescribing information. St. Louis, MO; 1998 Sep.

263. Department of Health and Human Services, Public Health Service. Certification of opioid treatment programs. (42 *CFR* Part 8). 2004; 42:62-70. From Government Printing Office website via GPO Access. Accessed 2005 May 3.

264. Substance Abuse and Mental Health Services Administration. Opioid treatment program frequently asked questions. Washington, DC; 2002 Jul 31. From SAMHSA website. Accessed 2005 May 4.

265. Substance Abuse and Mental Health Services Administration. Methadone patient support and community education project: About the new SAMHSA regulations for methadone treatment. Washington, DC. From SAMHSA website. Accessed 2005 May 5.

266. Boehringer Ingelheim. Aptivus (tipranavir) capsules prescribing information. Ridgefield, CT; 2006 Jun 27.

267. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. Opioid drugs in maintenance and detoxification treatment of opiate addiction. Final rule. [Docket No. 98N 0617] Fed Regist. 2001; 66:4075-9.

268. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. Opioid drugs in maintenance and detoxification treatment of opiate addiction; repeal of current regulations and issuance of new regulations: delay of effective date and resultant ammendments to the final rule. [Docket No. 85N 0617] Fed Regist. 2001; 66:15347-8.

269. Roxane Laboratories. Dolophine hydrochloride (methadone hydrochloride) tablets prescribing information. Columbus, OH. 2006 Oct.

270. Food and Drug Administration. FDA alert for healthcare professionals on methadone hydrochloride: death, narcotic overdose, and serious cardiac arrhythmias. From FDA website. Accessed 2006 Nov 30.

271. U.S. Department of Justice, Drug Enforcement Administration, Office of Diversion Control. Advisory: Methadone hydrochloride tablets USP 40 mg (dispersible). From the Department of Justice website. Accessed 22 Sep 2008.

272. American Pharmacists Association. Distribution of 40-mg methadone voluntarily limited to addiction facilities, hospitals. 10 Dec 2007. From American Pharmacists Association website. Accessed 22 Sep 2008.

273. Chianta M. Dear valued Mallinckrodt customer letter regarding methadone. Hazelwood, MO; Covidien Mallinckrodt. From Mallinckrodt website. Accessed 22 Sep 2008.

a. AHFS Drug Information 2007. McEvoy GK, ed. Methadone. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2139-45.

b. Cebert Pharmaceuticals. Diskets (methadone hydrochloride dispersible tablets) prescribing information. Birmingham, AL; 2006 Oct.

c. AHFS Drug Information 2007. McEvoy GK, ed. Opiate agonists general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2123-8.

d. Xanodyne. Methadone hydrochloride injection prescribing information. Charleston, SC; 2006 Mar.

e. GlaxoSmithKline. Ziagen (abacavir sulfate) tablets and oral solution prescribing information. Research Triangle Park, NC; 2002 Jul.

f. Merck & Company Inc. Crixivan (indinavir sulfate) capsules prescribing infomation. West Point, PA; 2006 Apr.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1079-80.

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