Methadone Hydrochloride

Pronunciation

Class: Opiate Agonists
VA Class: CN101
CAS Number: 1095-90-5
Brands: Dolophine, Methadose

Warning(s)

  • Abuse Potential
  • Abuse potential similar to that of other opiates.217

  • Assess patient's risk for abuse and addiction (e.g., personal or family history of substance abuse or mental illness) prior to prescribing.217 Routinely monitor all patients receiving methadone for signs of misuse, abuse, and addiction.217 (See Drug Abuse and Dependence under Cautions.)

  • 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).217 222 263 Certified treatment programs should dispense only oral methadone products as outlined in the Federal Opioid Treatment Standards (42 CFR 8.12).217 222 263

  • 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.217 222

  • Respiratory Depression
  • Fatal respiratory depression reported during initiation of therapy or transfer from other opiate therapy, even when used as recommended and not misused or abused.217 (See Respiratory Depression under Cautions.)

  • Peak respiratory depressant effect occurs later and persists longer than peak analgesic effect, particularly during the early dosing period.217

  • Appropriate dosage selection and titration are essential.217 (See Dosage and Administration.) Should be prescribed only by clinicians who are knowledgeable in the use of potent opiates for chronic pain management.217

  • Monitor for respiratory depression, especially during initiation of therapy and following dosage increases.217

  • QT-Interval Prolongation
  • QT-interval prolongation and serious cardiac arrhythmias (e.g., torsades de pointes) reported, usually in patients receiving large, multiple-daily doses (>200 mg daily) for chronic pain management, but also in patients receiving lower dosages for maintenance treatment of opiate dependence.217 233 234 (See Cardiac Effects under Cautions.)

  • Closely monitor for changes in cardiac rhythm during initiation of therapy and dosage adjustment.217

  • Inadvertent Exposure
  • Inadvertent exposure, especially in children, may result in fatal overdosage.217

REMS:

FDA approved a shared system REMS for extended-release and long-acting opiate analgesics to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of methadone hydrochloride and consists of the following: medication guide and elements to assure safe use. (See Risk Management Program under Dosage and Administration.) Also see the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Opiate agonist; a synthetic diphenylheptane derivative.217 222 a

Uses for Methadone Hydrochloride

Pain

Used parenterally for the relief of moderate to severe pain that has not responded to nonopiate analgesics.222

Used orally for the relief of moderate to severe pain when a continuous, around-the-clock analgesic is needed for an extended period of time.217 225 226 Oral preparations are not indicated for relief of acute (e.g., postoperative) pain, for relief of pain that is mild or is not expected to persist for an extended period of time, or for use on an as-needed (“prn”) basis.217 225 226

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

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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),217 228 254 considerable interindividual variability in pharmacokinetic parameters,217 228 229 potential for drug interactions,217 228 232 challenges associated with dosage titration and with the transfer of patients from therapy with other opiate agonists,217 228 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

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.217 222 232 There is considerable interindividual variability in absorption, metabolism, and relative analgesic potency of the drug.217 222 232

  • Carefully monitor patients during initiation of therapy, dosage titration, and conversion from one opiate agonist to another.217 222

  • 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, potential for drug interactions) when making treatment decisions regarding use of the drug.217 222 270

Risk Management Program

  • REMS has been developed for extended-release and long-acting opiate analgesics, including oral methadone preparations indicated for use as an analgesic (see REMS).282

  • REMS does not apply to use for detoxification and maintenance treatment of opiate dependence; does not alter current prescribing and dispensing requirements for methadone in opiate-dependency treatment programs.283

  • Goals are to reduce occurrence of addiction, unintentional overdosage, and death resulting from inappropriate prescribing, misuse, and abuse of extended-release and long-acting opiate analgesics, while maintaining patient access to these analgesics.282

  • Program consists of educational programs for prescribers, information that prescribers can use when counseling patients about risks and benefits of extended-release and long-acting opiate analgesics, and a product-specific medication guide that must be dispensed with every prescription.282

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.217 222 236 259

  • A high degree of opiate tolerance does not preclude the possibility of unintended methadone overdosage.217 222 Failure to individualize dosage has resulted in serious adverse effects, including death, in opiate-tolerant patients during conversion to methadone therapy.217 222 236

  • 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.217 222 235 (See Conversion from Other Opiate Therapy under Dosage.) Overestimation of dosage when transferring patients from other opiate therapy to methadone therapy can result in fatal overdosage with the first dose.217

  • 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.217 222 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).217 222 227 Therefore, estimates of methadone dosage that are based on single-dose studies should not be used for conversion in patients receiving chronic opiate therapy.217 222

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.222 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 Boxed Warning).270 272 273

Administration

Administer orally or by sub-Q, IM, or IV injection.217 222 225 226 261 262

Oral Administration

Tablets, dispersible tablets, oral solution, and oral concentrate solution are for oral administration only and must not be injected.217 225 226 261 262

Dispersible Tablets

Disperse dose in 120 mL of water, orange juice, Tang, citrus-flavored Kool-Aid, or other acidic fruit beverage immediately prior to oral administration.261 262 Complete tablet dispersion occurs within 1 minute; dispersion time is slightly increased when a cold and/or acidic vehicle is used.a If any residue remains in cup after initial administration, add a small amount of liquid and administer the resulting mixture.261 262

The 40-mg dispersible tablets are used in detoxification and maintenance of opiate dependence;261 262 271 this preparation should not be used for the treatment of pain.261 262 270 271

Dispersible tablets contain insoluble excipients and must not be used to prepare solutions for injection.261 262

Each 40-mg dispersible tablet can be divided in half or in quarters.261 262

Because dispersible tablets can be administered only in 10-mg increments, this dosage form may be inappropriate in many patients for initial dosing during detoxification and maintenance treatment or for gradual dosage reduction following detoxification or a period of maintenance treatment.261 262

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.217 222 225 226 261 262 263

Careful dosage selection and titration are essential to avoid overdosage.217

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.217 222

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

Oral

Opiate-naive patients: Initially, no more than 2.5–10 mg every 8–12 hours.217 Titrate dosage to provide adequate analgesia; increase dosage slowly to avoid accumulation and potential toxicity.217

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.217 223 227 Use caution to avoid overdosage.217

Patients being switched from parenteral methadone: Initiate oral methadone at an oral-to-parenteral dosage ratio of 2:1 (e.g., 10 mg of oral methadone hydrochloride in patients previously receiving 5 mg of parenteral methadone hydrochloride).217

Adjust dosage at intervals of 1–2 days with close monitoring.217 If breakthrough pain occurs, adjust dosage or administer small dose of rescue (immediate-release) analgesic.217 If adverse effects are excessive, reduce the next dose; if adverse effects are intolerable, adjust dose or dosing interval.217

If discontinuance of opiates is required, taper dosage every 2–4 days to avoid manifestations of abrupt withdrawal.217

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 a parenteral-to-oral dosage ratio of 1:2 (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.217 222 Select dosage carefully (see General: Conversion from Other Opiate Analgesic Therapy under Dosage and Administration).217 222

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.217 222

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).217 222

Administer the total daily dosage in divided doses (e.g., at 8-hour intervals) based on individual patient requirements.217 222

Table 1. Conversion from Oral Morphine Sulfate to Oral Methadone Hydrochloride (for Chronic Administration)217222

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-to-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.217

A single dose of 20–30 mg will often suppress withdrawal symptoms.217 Initial dose should not exceed 30 mg;217 263 use lower initial dose in patients whose tolerance is expected to be low.217 Additional doses may be necessary if withdrawal symptoms are not suppressed or if they reappear.217 If same-day dosage adjustments are to be made, reevaluate the patient 2–4 hours after the previous dose.217 If an additional dose is needed to suppress withdrawal symptoms, administer an additional 5–10 mg.217 Total daily dose for the first day generally should not exceed 40 mg217 263 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).217 Use caution to avoid overdosage.217 With continued dosing, symptoms are suppressed for a longer time.217

Usual stabilizing dosage is 40 mg daily in divided doses.217 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.217 Individualize and adjust dosage to keep withdrawal symptoms at a tolerable level.217 In hospitalized patients, reduce dosage by 20% daily; a more gradual reduction may be required in ambulatory patients.217

Parenteral

Patients unable to receive methadone orally: Hospitalize patient and convert oral dose to parenteral dose using accepted criteria.217 222 a Patients being switched from oral methadone usually initiate parenteral methadone at a parenteral-to-oral dosage ratio of 1:2 (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.217 Initial dose should not exceed 30 mg;217 263 use lower initial dose in patients whose tolerance is expected to be low.217 Additional doses may be necessary if withdrawal symptoms are not suppressed or if they reappear.217 If same-day dosage adjustments are to be made, reevaluate the patient 2–4 hours after the previous dose.217 If an additional dose is needed to suppress withdrawal symptoms, administer an additional 5–10 mg.217 Total daily dose for the first day generally should not exceed 40 mg217 263 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).217 Use caution to avoid overdosage.217 With continued dosing, symptoms are suppressed for a longer time.217

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.217 Usual stabilizing dosage is 80–120 mg daily.217 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.217 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.217 222 a Patients being switched from oral methadone usually initiate parenteral methadone at a parenteral-to-oral dosage ratio of 1:2 (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;217 222 titrate dosage slowly while monitoring for respiratory and CNS depression.217

Renal Impairment

Use smaller initial doses and longer dosing intervals;217 222 titrate dosage slowly while monitoring for respiratory and CNS depression.217

Geriatric and Debilitated Patients

In geriatric patients, select dosage at the lower end of the dosage range.217 222 Reduce dosage in poor-risk and in very old patients.a

Cautions for Methadone Hydrochloride

Contraindications

  • Known hypersensitivity (e.g., anaphylaxis) to methadone or any ingredient in the formulation.217 222

  • Oral therapy: Substantial respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.217

  • Parenteral therapy: Respiratory depression in the absence of resuscitative equipment or in unmonitored settings, acute asthma or hypercarbia (hypercapnia).222

  • Known or suspected paralytic ileus.217

Warnings/Precautions

Warnings

Respiratory Depression

The major toxicity associated with methadone.217 222 (See Respiratory Depression in Boxed Warning.)

Serious, life-threatening, or fatal respiratory depression can occur at any time during therapy, but risk is greatest during initiation of therapy and following dosage increases.217

Deaths reported during transfer to methadone from chronic high-dose therapy with other opiate analgesics and during initiation of maintenance treatment for opiate dependence in individuals previously taking high doses of other opiates.217

Geriatric, cachectic, or debilitated patients and those with conditions accompanied by hypoxia or hypercapnia are at increased risk.217 222 (See Contraindications, Other Warnings/Precautions, and Geriatric Use, under Cautions.)

Appropriate dosage selection and titration are essential to prevent overdosage.217 (See General and also Dosage, under Dosage and Administration.) Should be prescribed only by clinicians knowledgeable about methadone's pharmacokinetic and pharmacodynamic properties and use of potent opiates for chronic pain management.217

Cardiac Effects

Possible prolongation of the QT interval and serious cardiac arrhythmias, including torsades de pointes.217 222 223 234 (See QT-Interval Prolongation in Boxed Warning.)

Closely monitor for changes in cardiac rhythm during initiation of therapy and dosage adjustment.217

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]).217 222

Use in patients with known prolongation of the QT interval not systematically evaluated.217 222

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.217 222

Use for pain management only when the potential benefits outweigh the possible risk of QT-interval prolongation reported with higher methadone dosage.217 222

Drug Abuse and Dependence

Abuse liability similar to that of other opiates.217 222 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.217 However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain.217 222

Increased risk for abuse in patients with a personal or family history of substance abuse (e.g., drug or alcohol abuse or addiction) or mental illness (e.g., major depression).217 Intensive monitoring for signs of misuse, abuse, and addiction required in those at increased risk for abuse.217

Methadone abuse in combination with other CNS depressants may result in serious risk.217 222 (See CNS Effects under Cautions.)

Dependence and tolerance may develop with repeated administration; use with caution.217 222

Abrupt cessation of therapy or sudden reduction in dosage after prolonged use may result in withdrawal symptoms.217 222 After prolonged exposure to opiate analgesics, if withdrawal is necessary, it must be undertaken gradually.217 222

In patients receiving methadone maintenance treatment for opiate dependence, abrupt discontinuance can result in withdrawal symptoms and may increase risk of relapse to illicit drug use.217 222

Contact the state professional licensing board or controlled substance authority for information about prevention and detection of abuse or diversion.217 222

Inadvertent Exposure

Inadvertent ingestion, especially by children, may result in fatal overdosage.217

Other Warnings/Precautions

Shares the toxic potentials of the opiate agonists; observe the usual precautions of opiate agonist therapy.a

Incomplete Cross-Tolerance

Patients who are tolerant to other opiate agonists may have incomplete tolerance to methadone.217 222 253 Overdosage (including fatalities) reported in patients being transferred to methadone from chronic high-dose therapy with other opiate analgesics and during initiation of maintenance treatment for opiate dependence in individuals previously taking high doses of other opiates.217 222

Use methadone with caution and at appropriately adjusted dosages in patients being transferred from other opiate therapy.217 222 253 Carefully consider pharmacokinetic parameters during initiation and titration of methadone therapy in patients who previously received chronic opiate agonist therapy.217 222 (See General: Conversion from Other Opiate Analgesic Therapy and also see Dosage: Conversion from Other Opiate Therapy, under Dosage and Administration.)

Chronic Pulmonary Disease

Even usual therapeutic doses may decrease respiratory drive to the point of apnea in patients with COPD, cor pulmonale, substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression.217 222

Closely monitor these patients for respiratory depression, particularly during initiation of therapy and dosage titration.217 222 Consider use of nonopiate analgesics if possible.217 222

Cachectic or Debilitated Patients

Increased risk of respiratory depression, since methadone clearance may be decreased and reduced fat stores or muscle wasting may alter the drug’s pharmacokinetics.217

Closely monitor for respiratory depression, especially when other respiratory depressants are used concomitantly and during initiation of therapy and dosage titration.217

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.217 222 Monitor susceptible patients for sedation and respiratory depression, particularly during initiation of therapy.217

Adverse effects of opiates may obscure the clinical course of intracranial pathology.217 222

Use with caution, if at all, in patients with head trauma.222 Avoid use in patients with impaired consciousness or coma.217

Acute Abdominal Conditions

Administration may complicate assessment of patients with acute abdominal conditions.222

May cause spasm of the sphincter of Oddi.217 Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.217 Opiates may increase serum amylase.217

Contraindicated in patients with known or suspected paralytic ileus.217 Avoid use in patients with other GI obstruction.217

Hypotensive Effects

May cause severe hypotension (e.g., orthostatic hypotension and syncope) in ambulatory patients.217 222

Increased risk in patients whose ability to maintain their BP is compromised by reduced blood volume or concomitant drugs (e.g., phenothiazines, general anesthetics).217 222 Monitor these patients for hypotension during initiation of therapy and dosage titration.217

CNS Effects

May impair mental and/or physical abilities needed to perform potentially hazardous activities such as driving or operating machinery.217 222 Individuals who perform hazardous tasks requiring mental alertness or physical coordination should be warned about possible adverse CNS effects of opiate agonists.217 222

Concomitant use with other CNS depressants may cause profound sedation, coma, respiratory depression, or hypotension.217 222 (See Specific Drugs under Interactions.) Deaths associated with illicit methadone use frequently have involved concomitant benzodiazepine abuse.217 222

Seizures

May aggravate preexisting seizure disorder.217 Monitor for worsened seizure control.217

May induce seizures in some clinical settings.217

Acute Pain Management in Patients Receiving Maintenance Treatment

Patients receiving methadone maintenance treatment who experience physical trauma or acute (e.g., postoperative) pain should not be expected to derive adequate analgesia from their stable methadone regimen.217 222

Such patients should receive analgesics, including opiates, appropriate for other patients experiencing similar nociceptive stimulation.217 222 Opiate doses may be somewhat higher or dosing intervals somewhat shorter than those in nontolerant patients.217 222

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

Hypothyroidism

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

Prostatic Hypertrophy or Urethral Stricture

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

Addison’s Disease

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

Specific Populations

Pregnancy

Category C.217 222

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

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.217 222

Pregnant women in methadone maintenance programs receive better prenatal care, with fewer obstetric and fetal complications and reduced neonatal morbidity and mortality, compared with women using illicit drugs.217 222 Maternal use of methadone during pregnancy as part of a supervised therapeutic regimen is considered unlikely to pose a substantial teratogenic risk; however, data are insufficient to fully exclude such risk.217 222 280

Use in opiate-dependent women during pregnancy results in decreased fetal growth (reduced birth weight, length, and/or head circumference), but growth deficit does not appear to persist into later childhood.217 222 280 281

Mild but persistent deficits in psychometric and behavioral test performance observed in children exposed to methadone in utero.217 222

Possible increased risk of visual developmental anomalies in children born to opiate-dependent women who received methadone during pregnancy.217

Unclear whether maternal use during pregnancy is associated with higher incidence of sudden infant death syndrome.217 222

Lactation

Distributed into milk.217 222 280 285 Peak concentrations in milk reportedly occur approximately 4–5 hours after an oral dose.217 222 Based on average milk consumption of 150 mL/kg daily, dose ingested by infant would be about 2–3.5% of oral maternal dose.217 222 285

Detected in very low plasma concentrations in some infants whose mothers were receiving methadone.217 222 Sedation and respiratory depression reported in some infants exposed to methadone through breast milk.217

Discontinuance of nursing should be gradual (not abrupt) to prevent withdrawal (neonatal abstinence syndrome) in the infant.217 222

AAP states that methadone is usually compatible with breast-feeding.279

Manufacturers of oral methadone recommend that the drug be used with caution.217 (See Advice to Patients.)

Manufacturer of methadone injection recommends discontinuing nursing or the drug, since information on parenteral use and on safety of high-dose therapy for chronic pain in nursing women is lacking.222

Pediatric Use

Manufacturers state that safety, efficacy, and pharmacokinetics not established in pediatric patients <18 years of age.217 222

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;217 222 however, geriatric patients may be at greater risk for respiratory depression217 222

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.217 222

Closely monitor for respiratory and CNS depression, especially during initiation of therapy and dosage titration and when used concomitantly with other respiratory depressants.217

Hepatic Impairment

Not studied extensively in patients with hepatic impairment.217 222 However, risk of accumulation with multiple doses because the drug is metabolized in the liver.217 222 Use with caution and in reduced dosage.217 222 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Not studied extensively in patients with renal impairment.217 222 Use with caution and in reduced dosage.217 222 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Lightheadedness, dizziness, sedation, nausea, vomiting, sweating.217 222

Interactions for Methadone Hydrochloride

Metabolized principally by CYP isoenzymes 3A4, 2B6, and 2C19 and to a lesser extent by 2C9 and 2D6.217 222 232 235 251 .

Appears to be a P-glycoprotein substrate, but pharmacokinetics not substantially altered by P-glycoprotein inhibition.217

Drugs Affecting Hepatic Microsomal Enzymes

CYP inducers: Possible increased metabolism and decreased plasma concentrations of methadone.217 222 232 235 Use with caution and careful monitoring.217 222 232 235

CYP3A4 and/or CYP2C9 inhibitors: Possible decreased metabolism and increased plasma concentrations of methadone.217 222 232 235 Use with caution and careful monitoring.217 222 232 235

Drugs that Prolong the QT Interval

Potential pharmacologic interaction (prolongation of the QT interval; potential for severe and/or life-threatening cardiac arrhythmias).217 222 Use with extreme caution.217 222

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).217 222 Use with caution.217 222

Specific Drugs

Drug

Interaction

Comments

Abacavir

Increased methadone clearance243

Some experts state dosage adjustment not needed243

Manufacturer recommends close monitoring for opiate withdrawal and adjustment of methadone dosage as needed217

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 arrhythmias217 222

Use concomitantly with extreme caution and close monitoring217 222

Anticholinergics

Possible increased risk of urinary retention, severe constipation, and paralytic ileus217

Monitor for urinary retention and reduced gastric motility217

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Increased methadone metabolism;217 222 232 235 withdrawal symptoms reported217 222 235

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 methadone217 222 c

If concomitant use is necessary, administer methadone in small, incremental doses over several hours with careful monitoring217 222

Antidepressants, SSRI (fluoxetine, fluvoxamine, sertraline)

Increased serum methadone concentrations and increased opiate effects secondary to inhibition of methadone metabolism217 222 235

Antidepressants, tricyclic

Potential for severe and/or life-threatening cardiac arrhythmias217 222

Methadone may potentiate effects of tricyclic antidepressants222

Desipramine: Increased serum desipramine concentrations217 222 235

Use concomitantly with extreme caution and close monitoring217 222

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

Decreased methadone clearance;217 222 232 235 278 potential for increased or prolonged opiate agonist effects217 222

Monitor carefully and adjust dosage as necessary217 222 278

Antipsychotic agents

Potential for severe and/or life-threatening cardiac arrhythmias with agents that prolong the QT interval217 222

Use concomitantly with extreme caution and close monitoring217 222

Atazanavir

Atazanavir: Pharmacokinetic interaction unlikely243

Ritonavir-boosted atazanavir: Decreased concentrations of R-methadone (active isomer); opiate withdrawal is unlikely but may occur243

Atazanavir: No dosage adjustment needed243

Ritonavir-boosted atazanavir: Monitor for opiate withdrawal; adjust methadone dosage as needed243

Boceprevir

Possible decreased concentrations of R-methadone277

Not considered clinically important and dosage adjustment not recommended, but some patients may require methadone dosage adjustment on initiation or discontinuance of boceprevir277

Calcium-channel blocking agents

Potential for severe and/or life-threatening cardiac arrhythmias with agents that prolong the QT interval217 222

Use concomitantly with extreme caution and close monitoring217 222

Chlorpromazine

May produce false-positive results for urine screening tests for methadone217

Clomipramine

May produce false-positive results for urine screening tests for methadone217

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

May potentiate the effects of other CNS depressants; possible coma, severe respiratory depression, or hypotension217 222 c

Some tranquilizers, especially phenothiazines, may antagonize opiate agonist analgesiac

In patients already receiving a CNS depressant, assess response and duration of use, including degree of tolerance to CNS depression, prior to initiating methadone; also consider any alcohol or illicit drug use217

Use concomitantly with great caution; a c reduce dosage of one or both drugs; monitor for sedation and respiratory depression217

Avoid alcohol use217

Corticosteroids (mineralocorticoid)

Potential for electrolyte disorders that may cause severe and/or life-threatening cardiac arrhythmias 217 222

Use concomitantly with caution and close monitoring217 222

Darunavir

Ritonavir-boosted darunavir: Decreased AUC of methadone; opiate withdrawal is unlikely but may occur243

Monitor closely for opiate withdrawal; increase methadone dosage as needed217 243 274

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 concentrations217 249

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

Didanosine delayed-release capsules: Dosage adjustment not needed243

Diphenhydramine

May produce false-positive results for urine screening tests for methadone217

Diuretics

Potential for electrolyte disorders that may cause severe and/or life-threatening cardiac arrhythmias217 222

Opiate agonists may decrease effects of diuretics used in CHFc

Use concomitantly with caution and close monitoring217 222

Doxylamine

May produce false-positive results for urine screening tests for methadone217

Efavirenz

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

Monitor closely for opiate withdrawal; increased methadone maintenance dosage frequently is necessary217 232 243 246 247

Elvitegravir/cobicistat/tenofovir/emtricitabine

Pharmacokinetic interaction unlikely243

No dosage adjustment needed243

Etravirine

Pharmacokinetic interaction unlikely243

Dosage adjustment not needed243

Fosamprenavir

Decreased trough concentrations of R-methadone but no substantial change in AUC of methadone reported with amprenavir (active metabolite of fosamprenavir)243

Ritonavir-boosted fosamprenavir: Decreased AUC of R-methadone;243 275 opiate withdrawal is unlikely but may occur243

Fosamprenavir: Monitor patient; adjust methadone dosage as needed217 243 275

Ritonavir-boosted fosamprenavir: Monitor closely for opiate withdrawal; increase methadone dosage as needed243

Indinavir

Pharmacokinetic interaction unlikely284

Laxatives

Potential for electrolyte disorders that may cause severe and/or life-threatening cardiac arrhythmias217 222

Use concomitantly with caution and close monitoring217 222

Lopinavir

Lopinavir/ritonavir: Decreased AUC of methadone; withdrawal symptoms reported222 243

Monitor closely for opiate withdrawal; increase methadone dosage as needed217 243

Macrolide antibiotics (clarithromycin, erythromycin, telithromycin)

Possible decreased methadone clearance217 222 232

Monitor patients carefully; adjust methadone dosage as necessary217 222

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

Monitor closely for opiate withdrawal; increased maintenance dosage of methadone may be necessary217 243

Nevirapine

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

Monitor closely for opiate withdrawal; increased methadone maintenance dosage frequently is needed217 222 232 242 243 244 245

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 symptoms217 222

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

Precipitation of withdrawal symptoms; reduction of analgesic effect217 222

Avoid opiate partial agonists in patients who have received or are receiving opiate agonists217 222

Quetiapine

May produce false-positive results for urine screening tests for methadone217

Raltegravir

Pharmacokinetic interaction unlikely243

Dosage adjustment not needed243

Rifampin

Reduced serum methadone concentrations; possible withdrawal symptoms217 222 232 235

Rilpivirine

Possible decreased AUC of methadone243

Dosage adjustment not recommended, but monitor for opiate withdrawal243

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

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

Monitor patients closely for opiate withdrawal; increased maintenance dosage of methadone may be necessary217 240 241

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

Saquinavir

Ritonavir-boosted saquinavir: Decreased AUC of R-methadone; opiate withdrawal is unlikely but may occur243

Monitor closely for opiate withdrawal; increase methadone dosage as needed217 243

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 stavudine217 243 249

Dosage adjustment not necessary243

St. John’s wort (Hypericum perforatum)

Increased metabolism of methadone; possible manifestations of opiate withdrawal217 222

Telaprevir

Decreased peak concentrations and AUC of R-methadone276

Initial dosage adjustment not needed; closely monitor patient and adjust methadone dosage as needed217 276

Tenofovir

Pharmacokinetic interaction unlikely243

Thioridazine

May produce false-positive results for urine screening tests for methadone217

Tipranavir

Ritonavir-boosted tipranavir: Decreased plasma concentrations of R-methadone243 266

Monitor closely for opiate withdrawal; increase methadone dosage as needed217 243 266

Verapamil

May produce false-positive results for urine screening tests for methadone217

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%).217 Peak concentrations occur 1–7.5 hours after oral administration.217

Onset

Full analgesic effects generally are not achieved until completion of 3–5 days of therapy.217 222

Peak respiratory depressant effects occur later than analgesic effects, particularly during the early dosing period.217 222

Duration

Approximately 4–8 hours after a single dose.217 222 270 a

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.217 222

Food

Effect of food on bioavailability not established.217

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.217 222 232 235 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.217 222

Methadone crosses the placenta and is distributed into milk.217 222 235

Plasma Protein Binding

85–90% (mainly α1-acid glycoprotein).217 222 232 235

Elimination

Metabolism

Extensively metabolized, principally by CYP isoenzymes 3A4, 2B6, and 2C19 and to a lesser extent by 2C9 and 2D6.217 222 232 235 251

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.217 222 232

Appears to be a P-glycoprotein substrate, but pharmacokinetics not substantially altered by P-glycoprotein polymorphism or inhibition.217

Elimination Route

Excreted to varying degrees in urine and feces as metabolites and unchanged drug.217 222 232 235

Half-life

Considerable interindividual variability in terminal elimination half-life;217 222 generally reported as 8–59 hours,217 222 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.217 222

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).217

Tablets, Dispersible

25°C (may be exposed to 15–30°C).261 262

Oral Solution and Concentrate Solution

25°C (may be exposed to 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.217 222 262

  • 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.217 222 Not known whether NMDA antagonism contributes to efficacy of methadone.217 222 Other NMDA antagonists have produced neurotoxic effects in animals.217 222

  • May depress the cough reflex by a direct effect on the cough centers in the medulla.c

  • Inhibits cardiac potassium channels and prolongs the QT interval.217 222

Advice to Patients

  • Importance of providing patient a copy of the manufacturer's patient information (medication guide) if required.217 (See REMS.)

  • Risk of respiratory depression, particularly following initiation of therapy and dosage increases.217 Importance of recognizing respiratory depression and seeking immediate medical attention if breathing difficulty occurs.217

  • Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.217 222

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.217 222

  • Importance of advising patients to avoid alcohol (alcoholic beverages, alcohol-containing drug products); also avoid other CNS depressants (e.g., sleep medications, tranquilizers) unless use is supervised by a clinician.217 222

  • Importance of advising patients to seek immediate medical attention if symptoms suggestive of an arrhythmia (e.g., palpitations, dizziness, lightheadedness, syncope) occur.217 222

  • Importance of informing patients that the duration of analgesia will increase with repeated dosing.217 Importance of patients taking the drug only as prescribed and of not increasing the dose without consulting a clinician.217

  • Risk of orthostatic hypotension and syncope.217 Importance of rising slowly from a seated or supine position.217

  • Importance of not abruptly discontinuing methadone following prolonged opiate therapy.217 222

  • Importance of informing patients that this is a drug of potential abuse and should also be protected from theft.217

  • Importance of informing patients that methadone should never be given to anyone other than the individual for whom it was prescribed.217

  • Importance of storing methadone in a secure location and of properly disposing of any unused drug.217 Accidental exposure, especially in children, may result in serious harm or death.217

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.217 222 Advise women who are breast-feeding or wish to breast-feed that the drug distributes into milk, instruct them to recognize respiratory depression and sedation in infants and to know when to seek medical care, and advise them to discontinue nursing gradually (not abruptly) to prevent withdrawal symptoms in the infant.217 222

  • Importance of informing clinician of any breakthrough pain or adverse effects (e.g., constipation) that occur during therapy, so that therapy may be adjusted based on individual patient requirements.217

  • Potential for severe constipation.217

  • Importance of seeking immediate medical attention if anaphylaxis occurs.217

  • Importance of informing patients of other important precautionary information.217 222 (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 Intensol (C-II)

Roxane

Methadone Hydrochloride Oral Concentrate (C-II)

Methadose Oral Concentrate (C-II)

Mallinckrodt

Tablets

5 mg*

Dolophine Hydrochloride (C-II; scored)

Roxane

Methadone Hydrochloride Tablets (C-II)

Methadose (C-II; scored)

Mallinckrodt

10 mg*

Dolophine Hydrochloride (C-II; scored)

Roxane

Methadone Hydrochloride Tablets (C-II)

Methadose (C-II; scored)

Mallinckrodt

Tablets, dispersible

40 mg*

Methadone Hydrochloride Diskets (C-II; scored)

Roxane

Methadose (C-II; scored)

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 02/2014. 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

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions June 10, 2013. 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.

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