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Methadone

Medically reviewed by Drugs.com. Last updated on Apr 14, 2020.

Pronunciation

(METH a done)

Index Terms

  • Methadone Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Concentrate, Oral, as hydrochloride:

Methadone HCl Intensol: 10 mg/mL (30 mL) [unflavored flavor]

Methadose: 10 mg/mL (1000 mL) [contains fd&c red #40, methylparaben, propylene glycol, propylparaben; cherry flavor]

Methadose Sugar-Free: 10 mg/mL (1000 mL) [dye free, sugar free; unflavored flavor]

Generic: 10 mg/mL (30 mL, 1000 mL)

Solution, Injection, as hydrochloride:

Generic: 10 mg/mL (20 mL)

Solution, Oral, as hydrochloride:

Generic: 5 mg/5 mL (500 mL); 10 mg/5 mL (500 mL)

Tablet, Oral, as hydrochloride:

Dolophine: 5 mg, 10 mg [scored]

Generic: 5 mg, 10 mg

Tablet Soluble, Oral, as hydrochloride:

Methadose: 40 mg [scored; contains fd&c yellow #5 aluminum lake, fd&c yellow #6 (sunset yellow), fd&c yellow #6 aluminum lake]

Generic: 40 mg

Brand Names: U.S.

  • Dolophine
  • Methadone HCl Intensol
  • Methadose
  • Methadose Sugar-Free

Pharmacologic Category

  • Analgesic, Opioid

Pharmacology

Binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depression. Methadone has also been shown to have N-methyl-D-aspartate (NMDA) receptor antagonism.

Distribution

Lipophilic

Vd: Neonates PNA: <72 hours: 2.53 L/kg (Wiles 2015)

Vd: Children and Adolescents: 7.1 ± 2.5 L/kg (Berde 1987)

Vd: Adults: 1 to 8 L/kg

Metabolism

Hepatic; N-demethylation primarily via CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6 to inactive metabolites

Excretion

Urine (<10% as unchanged drug); increased with urine pH <6; Note: Methadone may persist in the liver and other tissues; slow release from tissues may prolong the pharmacologic effect despite low serum concentrations

Onset of Action

Oral: Analgesic: 0.5 to 1 hour; Parenteral: 10 to 20 minutes; Peak effect: Parenteral: 1 to 2 hours; Oral: Continuous dosing: 3 to 5 days

Time to Peak

1 to 7.5 hours

Duration of Action

Analgesia: Oral: 4 to 8 hours (single-dose studies), increases to 22 to 48 hours with repeated doses; slow release from the liver and other tissues may prolong duration of action

Half-Life Elimination

Terminal:

Children and Adolescents: 19.2 ± 13.6 hours (range: 3.8 to 62 hours) (Berde 1987)

Adults: 8 to 59 hours; may be prolonged with alkaline pH

Protein Binding

85% to 90% primarily to alpha-1 acid glycoprotein

Special Populations: Hepatic Function Impairment

Methadone is metabolized by hepatic pathways; therefore, there is a risk of drug accumulation after multiple dosing in patients with hepatic impairment.

Use: Labeled Indications

Opioid use disorder: Medically supervised withdrawal and maintenance treatment of opioid use disorder, in conjunction with appropriate social and medical services; injection is only for temporary treatment in patients unable to take oral medication.

Limitations of use: Injection: Not approved for outpatient treatment of opioid use disorder; only use in patients unable to take oral medication (eg, hospitalized patients).

Pain, chronic:

Injection: Management of pain severe enough to require an opioid analgesic and for which alternative treatment options are inadequate.

Oral (Dolophine only): Management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of use: Reserve for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Dolophine is not indicated for use as an as-needed analgesic.

Contraindications

Hypersensitivity (eg, anaphylaxis) to methadone or any component of the formulation; significant respiratory depression (in the absence of resuscitative equipment or in unmonitored settings); acute or severe bronchial asthma (in the absence of resuscitative equipment or in an unmonitored setting); hypercarbia; GI obstruction, including paralytic ileus (known or suspected)

Documentation of allergenic cross-reactivity for opioids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Contraindications may vary per product labeling; refer also to product labels: Diarrhea associated with pseudomembranous colitis or caused by poisoning until toxic material has been eliminated from the GI tract; concurrent use or use within 14 days of an MAOI; obstructive airway; mild, intermittent, or short duration pain that can be managed with other pain medications; management of acute pain; patients naive to opioids; diseases/conditions affecting bowel transit (known or suspected); suspected surgical abdomen (eg, acute appendicitis or pancreatitis); status asthmaticus; cor pulmonale; acute alcohol intoxication; delirium tremens; convulsive disorders; severe CNS depression; increased cerebrospinal or intracranial pressure; head injury; breastfeeding, pregnancy and during labor/delivery

Dosing: Adult

Note: Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse. Methadone has high interpatient variability in absorption, metabolism, and relative analgesic potency and exposure accumulates with repeated dosing, resulting in increased methadone potency. Therefore, equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals and will vary depending on baseline opioid requirements. Deaths have occurred during conversion from chronic high-dose treatment with other opioids and in patients who previously abused high doses of other opioids. Special attention is required during treatment initiation, during conversion from one opioid to another, and during dose titration. Steady-state plasma concentrations and full analgesic effects are not attained until at least 3 to 5 days on a dose and methadone has a narrow therapeutic index, especially when combined with other drugs.

Opioid use disorder: Note: Diskets can be administered only in 10 mg increments; may not be appropriate product for initial dosing or dose reductions.

IV: Note: For use only in patients unable to take oral medication (such as during hospitalization). For dosing, convert patient's oral methadone dose to an equivalent parenteral dose using the conversions provided in Pain, chronic.

Oral:

Initial: 20 to 30 mg (as a single dose) when there are no signs of sedation or intoxication and patient shows symptoms of withdrawal; maximum initial dose: 30 mg. Lower doses (5 to 10 mg) and much slower titration should be considered in patients with no or low tolerance at initiation (eg, absence of opioids ≥5 days, do not take opioids daily, use of weaker opioids [eg, codeine]); observe patients for over-sedation and withdrawal symptoms for 2 to 4 hours after initial dose (SAMHSA 2018); an additional 5 to 10 mg may be provided if withdrawal symptoms have not been suppressed or if symptoms reappear after 2 to 4 hours; total daily dose on the first day should not exceed 40 mg. Do not increase dose without waiting for steady-state to be achieved. Levels will accumulate over the first few days; deaths have occurred in early treatment due to cumulative effects.

Maintenance: Titrate to a dosage which prevents opioid withdrawal symptoms for 24 hours, prevents craving, attenuates euphoric effect of self-administered opioids, and tolerance to sedative effects of methadone. Usual range: 80 to 120 mg/day (titration should occur cautiously).

Opioid use disorder (eg, medically supervised withdrawal) (short-term): Oral:

Initial: Titrate to ~40 mg/day in divided doses to achieve stabilization.

Maintenance: May continue 40 mg/day dose for 2 to 3 days.

Discontinuation of therapy: After 2 to 3 days of stabilization at 40 mg, gradually decrease the dose on a daily basis or at 2-day intervals. Keep dose at a level sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a total daily dose decrease of 20%; ambulatory patients may require a slower reduction.

Pain, chronic:

Opioid-naïve patients:

Oral: Initial: 2.5 to 5 mg every 8 to 12 hours; some patients may benefit from 2.5 to 5 mg every 6 hours to maintain analgesia during initiation.

IM, IV, SubQ: Note: For use only in patients unable to take oral medication (such as during hospitalization). Initial: 2.5 to 10 mg every 8 to 12 hours.

Titration and maintenance: May increase dose by 2.5 mg per dose no more often than every 5 to 7 days (gradual titration) or by 2.5 to 5 mg per dose every 3 days (faster titration in monitored setting). Once a stable dose is reached, the dosing interval may be extended to every 8 to 12 hours or longer (VA/DoD 2017). Because of high interpatient variability, substantially longer periods between dose increases may be necessary in some patients (up to 12 days). If unacceptable adverse reactions are observed, reduce dose and/or dosing interval (ie, every 8 to 12 hours). Breakthrough pain may require a dose increase or rescue medication with an IR analgesic. Some guidelines note that dose increases should not be >10 mg per day every 5 to 7 days (Chou 2014).

Discontinuation of therapy: When discontinuing methadone for pain management, reduce dose gradually by 15% to 50% every 2 to 4 days to prevent signs or symptoms of withdrawal. If patient displays withdrawal symptoms, increase dose to previous level and then reduce dose more slowly by increasing interval between dose reductions, decreasing amount of daily dose reduction, or both.

Conversion from oral morphine to oral methadone in opioid-tolerant patients: 1) There is not a linear relationship when converting to methadone from oral morphine. The higher the daily morphine-equivalent dose the more potent methadone is, and 2) conversion to methadone is more of a process than a calculation. In general, the starting methadone dose should not exceed 30 to 40 mg/day, even in patients on high doses of other opioids. Patient response to methadone needs to be monitored closely throughout the process of the conversion. There are several proposed ratios for converting from oral morphine to oral methadone (Ayonrinde 2000; Mercadente 2001; Ripamonti 1998). The estimated total daily methadone dose should then be divided to reflect the intended dosing schedule (eg, divide by 3 and administer every 8 hours). Patients who have not taken an opioid for 1 to 2 weeks should be considered opioid naïve (Chou 2014).

Manufacturer's labeling: Dosing in the prescribing information may not reflect current clinical practice. Discontinue all other around-the-clock opioids when methadone therapy is initiated; fatalities have occurred in opioid-tolerant patients during conversion to methadone. Substantial interpatient variability exists in relative potency. Therefore, it is safer to underestimate a patient's daily methadone requirement and provide breakthrough pain relief with rescue medication (eg, IR opioid) than to overestimate requirements. Patient response to methadone needs to be monitored closely throughout the process of the conversion. For patients on a single opioid, sum the current total daily dose of oral opioid, convert it to a morphine-equivalent dose according to conversion factor for that specific opioid, then multiply the morphine equivalent dose by the corresponding percentage to calculate the approximate oral methadone daily dose. Divide total daily methadone dose by intended dosing schedule (ie, divide by 3 for administration every 8 hours). Round down, if necessary, to the nearest strength available. For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and sum the totals to obtain the approximate total methadone daily dose, and divide the total daily methadone dose by the intended dosing schedule (ie, divide by 3 for administration every 8 hours). For patients on a regimen of fixed-ratio opioid/nonopioid analgesic medications, only the opioid component of these medications should be used in the conversion. Note: Conversion factors listed below are only for the conversion from another opioid analgesic to methadone and cannot be used to convert from methadone to another opioid (doing so may lead to fatal overdose due to overestimation of the new opioid). This does not provide equianalgesic doses.

Conversion from oral opioids to oral methadone:

Daily oral morphine dose <100 mg: Estimated daily oral methadone dose: 20% to 30% of total daily morphine dose.

Daily oral morphine dose 100 to 300 mg: Estimated daily oral methadone dose: 10% to 20% of total daily morphine dose.

Daily oral morphine dose 300 to 600 mg: Estimated daily oral methadone dose: 8% to 12% of total daily morphine dose.

Daily oral morphine dose 600 to 1,000 mg: Estimated daily oral methadone dose: 5% to 10% of total daily morphine dose.

Daily oral morphine dose >1,000 mg: Estimated daily oral methadone dose: <5% of total daily morphine dose.

Conversion from oral morphine to parenteral methadone:

Daily oral morphine dose <100 mg: Estimated daily IV methadone dose: 10% to 15% of total daily morphine dose.

Daily oral morphine dose 100 to 300 mg: Estimated daily IV methadone dose: 5% to 10% of total daily morphine dose.

Daily oral morphine dose 300 to 600 mg: Estimated daily IV methadone dose: 4% to 6% of total daily morphine dose.

Daily oral morphine dose 600 to 1,000 mg: Estimated daily IV methadone dose: 3% to 5% of total daily morphine dose.

Daily oral morphine dose >1,000 mg: Estimated daily IV methadone dose: <3% of total daily morphine dose.

Conversion from parenteral morphine to parenteral methadone:

Total daily parenteral morphine dose: 10 to 30 mg: Estimated daily parenteral methadone dose: 40% to 66%.

Total daily parenteral morphine dose: 30 to 50 mg: Estimated daily parenteral methadone dose: 27% to 66%.

Total daily parenteral morphine dose: 50 to 100 mg: Estimated daily parenteral methadone dose: 22% to 50%.

Total daily parenteral morphine dose: 100 to 200 mg: Estimated daily parenteral methadone dose: 15% to 34%.

Total daily parenteral morphine dose: 200 to 500 mg: Estimated daily parenteral methadone dose: 10% to 20%.

Conversion from parenteral methadone to oral methadone: Initial dose: Parenteral:Oral ratio: 1:2 (eg, 5 mg parenteral methadone equals 10 mg oral methadone).

Critically ill patients in the ICU (analgesia and sedation) (alternative agent) (off-label use):

Note: May be used to slow development of tolerance when escalation with other opioids is required or to help wean prolonged continuous opioid infusions. Unpredictable pharmacokinetics/pharmacodynamics in opioid-naive patients. Monitor adverse effects (eg, QTc) and drug-drug interactions (Al Qadheeb 2012; Elefritz 2016; SCCM [Barr 2013]; Wanzuita 2012).

Oral: 10 to 40 mg every 6 to 12 hours (SCCM [Barr 2013]).

IV: 2.5 to 10 mg every 8 to 12 hours (SCCM [Barr 2013]).

Note: When used to wean prolonged continuous opioid infusions, titrate no more than every 3 to 5 days and wean continuous opioid infusion to off as tolerated; once continuous opioid infusion is weaned off, methadone can be tapered down by 10% to 25% every 2 to 3 days; discontinue methadone once daily doses of 10 to 15 mg are reached (Elefritz 2016).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing. Use with caution; initiate at the low end of dosage range and titrate slowly. For treatment of opioid use disorder, a lower initial oral dose of 10 to 20 mg has been recommended for patients >60 years of age (SAMHSA 2018).

Dosing: Pediatric

Pain, severe: Limited data available: Note: Doses should be titrated to effect, the potency of methadone varies according to patient’s current exposure to opioids (APS 2016); use lower doses in opioid naïve patients. Methadone has high interpatient variability in absorption, metabolism, and relative analgesic potency and exposure accumulates with repeated dosing, resulting in increased methadone potency. Therefore, equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals and will vary depending on baseline opioid requirements. Methadone may accumulate due to its long half life; if sedation occurs, withhold doses until sedation resolves and consider reduction in dose and/or increasing the dosing interval (eg, every 8 to 12 hours).

Infants ≤6 months, nonventilated (Berde 2002):

IV, SubQ: 0.025 mg/kg/dose every 4 to 8 hours

Oral: 0.025 to 0.05 mg/kg/dose every 4 to 8 hours

Infants >6 months, Children, and Adolescents, nonventilated (Berde 2002):

IV, SubQ:

Patient weight <50 kg: 0.1 mg/kg/dose every 4 to 8 hours

Patient weight ≥50 kg: 5 to 8 mg every 4 to 8 hours

Oral:

Patient weight <50 kg: 0.1 to 0.2 mg/kg/dose every 4 to 8 hours

Patient weight ≥50 kg: 5 to 10 mg every 4 to 8 hours

Iatrogenic opioid dependency: Limited data available, optimal regimen not defined. Methadone dose and taper schedule must be individualized and will depend upon patient's previous opioid dose, length of time on opioids, and severity of opioid withdrawal.

Prevention: Children and Adolescents: Several reports have been published, varying in conversion equivalence factors, when to convert to oral, and how long the taper should be, none of which have been proven to be superior to another; follow institutional protocols as appropriate. Patients receiving opioids for >14 days are more likely to experience opioid withdrawal and usually require opioid doses to be weaned, which may require transition to methadone. Once methadone dose is stabilized, a weaning schedule of ~10% to 20% reduction of the original dose every 24 to 48 hours has been recommended (AAP [Galinkin 2014]).

Treatment: Infants and Children: Oral: Initial: 0.05 to 0.1 mg/kg/dose every 6 hours; increase by 0.05 mg/kg/dose until withdrawal symptoms are controlled; after 24 to 48 hours, the dosing interval can be lengthened to every 12 to 24 hours; to taper dose, wean as tolerated until a dose of 0.05 mg/kg/day, then discontinue (Anand 1994)

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Adjustment for Toxicity

Excessive opioid-related adverse events: Reduce next dose. Assess and reduce both the maintenance dose and dosing interval if necessary. Some guidelines recommend holding the dose if there is evidence of sedation (Chou 2014).

QTc prolongation (Chou 2014):

QTc >450 to 499 msec: Discuss potential risks and benefits. Evaluate and correct potential causes of QTc interval prolongation prior to initiating therapy. Consider alternative therapies or reduced methadone dose if QTc interval becomes ≥450 to 499 msec during treatment.

QTc ≥500 msec: Alternative therapies for opioid use disorder or chronic pain are recommended. If QTc ≥500 msec occurs during therapy, switch to an alternative therapy or immediately decrease the dose of methadone; correct any reversible causes of QTc interval prolongation and repeat ECG.

Administration

Oral: Tablets for oral suspension (for medically supervised withdrawal and maintenance): For oral administration only; do not inject (contains insoluble excipients). Disperse tablet in ~120 mL of water, orange juice, or other acidic fruit beverage prior to administration; if insoluble excipients remain and do not entirely dissolve, add a small amount of liquid to cup and administer remaining mixture. Do not chew or swallow tablet before dispersing in liquid.

Injection: Administer IM, SubQ, or IV; rate of IV administration not defined. Absorption of SubQ and IM appears to be unpredictable. Local tissue reactions may occur.

Storage

Injection: Store at 20°C to 25°C (68°F to 77°F). Protect from light. Store vials in carton until ready for use.

Oral concentrate, tablet for oral suspension: Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect oral concentrate from light.

Oral solution, tablet: Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Metadol [Canadian product], Metadol-D [Canadian product]: Store at 15°C to 30°C (59°F to 86°F). Protect tablets from light. Protect oral concentrate and oral solution from light and freezing. After dilution of oral concentrate in compatible diluent, may store at 2°C to 8°C (35.6°F to 46.4°F) for 7 or 14 days (refer to manufacturer labeling for specific recommendations)

Drug Interactions

Abacavir: Methadone may diminish the therapeutic effect of Abacavir. Abacavir may decrease the serum concentration of Methadone. Monitor therapy

Abametapir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Abametapir: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Avoid combination

Alcohol (Ethyl): May enhance the CNS depressant effect of Methadone. Avoid combination

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Alvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Consider therapy modification

Amiodarone: May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Amisulpride (Oral): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Amisulpride (Oral). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even greater risk. Consider therapy modification

Amphetamines: May enhance the analgesic effect of Opioid Agonists. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Aromatase Inhibitors: May increase the serum concentration of Methadone. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Azithromycin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Azithromycin (Systemic). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Benzodiazepines: May enhance the CNS depressant effect of Methadone. Management: Clinicians should generally avoid concurrent use of methadone and benzodiazepines when possible; any combined use should be undertaken with extra caution. Consider therapy modification

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Cannabidiol: May enhance the CNS depressant effect of Methadone. Cannabidiol may increase the serum concentration of Methadone. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Methadone. Monitor therapy

Ceritinib: May enhance the QTc-prolonging effect of Methadone. Ceritinib may increase the serum concentration of Methadone. Management: Consider alternatives to this combination. Methadone dose reduction may be necessary when used with ceritinib. With any concurrent use, monitor closely for evidence of methadone toxicities such as QT-prolongation or respiratory depression. Consider therapy modification

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chloroquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Chloroquine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Citalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Citalopram. Avoid combination

Clarithromycin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clarithromycin. Avoid combination

Clofazimine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clofazimine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

CloZAPine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of CloZAPine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

CNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Cobicistat: May increase the serum concentration of Methadone. Management: No increased monitoring appears necessary if the cobicistat regimen also contains elvitegravir. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination. Some combinations are specifically contraindicated by manufacturers; others may have recommended dose adjustments. If combined, monitor for increased substrate effects. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Darunavir: May decrease the serum concentration of Methadone. More specifically, the combination of Darunavir and Ritonavir may decrease Methadone serum concentrations. Monitor therapy

Dasatinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Dasatinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Desmopressin: Opioid Agonists may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Didanosine: Methadone may decrease the serum concentration of Didanosine. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Monitor therapy

Domperidone: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Domperidone. Avoid combination

Doxepin-Containing Products: May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of Methadone. Droperidol may enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives. If combined, dose reductions are recommended. Monitor for additive toxicities such as QTc interval prolongation, ventricular arrhythmias, and CNS depression. Patients with additional risk factors are at even higher risk. Consider therapy modification

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Avoid combination

Encorafenib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Entrectinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Escitalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Escitalopram. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Etravirine: May decrease the serum concentration of Methadone. Monitor therapy

Fexinidazole [INT]: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Avoid combination

Fingolimod: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias (including TdP) with a continuous overnight ECG when fingolimod is combined with QT prolonging drugs. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Flecainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flecainide. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Consider therapy modification

Flupentixol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flupentixol. Avoid combination

FluvoxaMINE: Methadone may enhance the serotonergic effect of FluvoxaMINE. This could result in serotonin syndrome. FluvoxaMINE may increase the serum concentration of Methadone. Management: Monitor for increased methadone effects/toxicities if combined with fluvoxamine. Also monitor for signs and symptoms of serotonin syndrome/serotonin toxicity if these agents are combined. Monitor therapy

Fosamprenavir: Methadone may decrease serum concentrations of the active metabolite(s) of Fosamprenavir. Specifically, amprenavir concentrations may be reduced. This effect has been demonstrated with Amprenavir alone but not with Fosamprenavir / Ritonavir. The potential impact on Fosamprenavir alone has not been investigated. Fosamprenavir may decrease the serum concentration of Methadone. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosphenytoin: May decrease the serum concentration of Methadone. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Gadobenate Dimeglumine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Gadobenate Dimeglumine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Gemifloxacin: May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk Consider therapy modification

Gilteritinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. If use is necessary, monitor for QTc interval prolongation and arrhythmias. Consider therapy modification

Halofantrine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Halofantrine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Haloperidol: May enhance the CNS depressant effect of Methadone. Haloperidol may enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation or those taking IV haloperidol may be at even higher risk. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Inotuzumab Ozogamicin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Inotuzumab Ozogamicin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Interferons (Alfa): May increase the serum concentration of Methadone. Monitor therapy

Isavuconazonium Sulfate: May decrease the serum concentration of Methadone. Monitor therapy

Itraconazole: May increase the serum concentration of Methadone. Avoid combination

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Methadone. Avoid combination

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lefamulin: May enhance the QTc-prolonging effect of QT-prolonging CYP3A4 Substrates. Management: Do not use lefamulin tablets with QT-prolonging CYP3A4 substrates. Lefamulin prescribing information lists this combination as contraindicated. Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Levofloxacin-Containing Products (Systemic): May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Lofexidine: May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Lopinavir: May enhance the QTc-prolonging effect of Methadone. Lopinavir may decrease the serum concentration of Methadone. More specifically, the combination of Lopinavir and Ritonavir may decrease Methadone serum concentrations. Monitor therapy

Lubiprostone: Methadone may diminish the therapeutic effect of Lubiprostone. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mequitazine: Methadone may enhance the arrhythmogenic effect of Mequitazine. Management: Consider alternatives to methadone or mequitazine when possible. While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Consider therapy modification

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Midostaurin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Midostaurin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Monoamine Oxidase Inhibitors: Methadone may enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Avoid combination

Moxifloxacin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Moxifloxacin (Systemic). Avoid combination

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of nalmefene and opioid agonists. Discontinue nalmefene 1 week prior to any anticipated use of opioid agonistss. If combined, larger doses of opioid agonists will likely be required. Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

Nefazodone: Opioid Agonists (metabolized by CYP3A4) may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase the serum concentration of Opioid Agonists (metabolized by CYP3A4). Management: If concomitant use of opioid agonists that are metabolized by CYP3A4 and nefazodone is necessary, consider dose reduction of the opioid until stable drug effects are achieved. Monitor for increased opioid effects and serotonin syndrome/serotonin toxicity. Consider therapy modification

Nelfinavir: May decrease the serum concentration of Methadone. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Nilotinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Nilotinib. Avoid combination

OLANZapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of OLANZapine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Ondansetron: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ondansetron. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Osimertinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Osimertinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interupt oxybate salt treatment during short-term opioid use. Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Monitor therapy

Pentamidine (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pentamidine (Systemic). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

PHENobarbital: May decrease the serum concentration of Methadone. Monitor therapy

Phenytoin: May decrease the serum concentration of Methadone. Monitor therapy

Pilsicainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pilsicainide. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Pimozide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pimozide. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Avoid combination

Piperaquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Piperaquine. Avoid combination

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Posaconazole: May enhance the QTc-prolonging effect of Methadone. Posaconazole may increase the serum concentration of Methadone. Avoid combination

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Primidone: May decrease the serum concentration of Methadone. Monitor therapy

Probucol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Probucol. Avoid combination

Propafenone: May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Agents (Indeterminate Risk - Avoid): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Agents (Indeterminate Risk - Caution): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Class IA Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Class III Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Miscellaneous Agents (Highest Risk): Methadone may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): Methadone may enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Nilotinib; Ribociclib. Consider therapy modification

QUEtiapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of QUEtiapine. Avoid combination

Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Monitor therapy

Reverse Transcriptase Inhibitors (Non-Nucleoside): May increase the metabolism of Methadone. Management: Methadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Exceptions: Delavirdine; Etravirine. Monitor therapy

Ribociclib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ribociclib. Avoid combination

Rifamycin Derivatives: May decrease the serum concentration of Methadone. Management: Seek alternatives when possible. If used concomitantly, monitor closely for symptoms of methadone withdrawal upon rifamycin derivative initiation, and for excess sedation upon rifamycin derivative discontinuation. Exceptions: Rifabutin. Consider therapy modification

RisperiDONE: QT-prolonging Agents (Highest Risk) may enhance the CNS depressant effect of RisperiDONE. QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of RisperiDONE. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Ritonavir: May decrease the serum concentration of Methadone. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Saquinavir: May enhance the QTc-prolonging effect of Methadone. Saquinavir may decrease the serum concentration of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation, ventricular arrhythmias, and opioid withdrawal symptoms. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Serotonergic Agents (High Risk): Methadone may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: FluvoxaMINE; Isocarboxazid; Linezolid; Methylene Blue; Moclobemide; Nefazodone; Phenelzine; Tranylcypromine. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Consider therapy modification

Sodium Stibogluconate: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sodium Stibogluconate. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Sparfloxacin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sparfloxacin. Avoid combination

Stavudine: Methadone may decrease the serum concentration of Stavudine. Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Thioridazine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Thioridazine. Avoid combination

Thiotepa: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Monitor therapy

Tipranavir: May decrease the serum concentration of Methadone. More specifically, the combination of Tipranavir and Ritonavir may decrease Methadone serum concentrations. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Vemurafenib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Vemurafenib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Voriconazole: May enhance the QTc-prolonging effect of Methadone. Voriconazole may increase the serum concentration of Methadone. Management: Consider alternatives to this combination. Methadone dose reduction may be necessary when used with voriconazole. With any concurrent use, monitor closely for evidence of methadone toxicities such as QT-prolongation or respiratory depression. Consider therapy modification

Zidovudine: Methadone may increase the serum concentration of Zidovudine. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Test Interactions

Some quinolones may produce a false-positive urine screening result for opioids using commercially-available immunoassay kits. This has been demonstrated most consistently for levofloxacin and ofloxacin, but other quinolones have shown cross-reactivity in certain assay kits. Confirmation of positive opioid screens by more specific methods should be considered. False-positive urine methadone screens have been reported in patients taking medications, including diphenhydramine, doxylamine, clomipramine, chlorpromazine, thioridazine, quetiapine, and verapamil.

Adverse Reactions

Frequency not defined:

Cardiovascular: Bigeminy, bradycardia, cardiac arrhythmia, cardiac failure, cardiomyopathy, ECG changes, edema, extrasystoles, flushing, hypotension, inversion T wave on ECG, palpitations, phlebitis, prolonged QT interval on ECG, shock, syncope, tachycardia, torsades de pointes, ventricular fibrillation, ventricular tachycardia

Central nervous system: Agitation, confusion, disorientation, dizziness, drug dependence (physical dependence), dysphoria, euphoria, hallucination, headache, insomnia, sedation, seizure

Dermatologic: Diaphoresis, hemorrhagic urticaria (rare), pruritus, skin rash, urticaria

Endocrine & metabolic: Adrenocortical insufficiency, altered hormone level (androgen deficiency; chronic opioid use), amenorrhea, antidiuretic effect, decreased libido, decreased plasma testosterone, hypokalemia, hypomagnesemia, weight gain

Gastrointestinal: Abdominal pain, anorexia, biliary tract spasm, constipation, glossitis, nausea, vomiting, xerostomia

Genitourinary: Asthenospermia, decreased ejaculate volume, male genital disease (reduced seminal vesicle secretions), prostatic disease (reduced prostate secretions), spermatozoa disorder (morphologic abnormalities), urinary hesitancy, urinary retention

Hematologic: Thrombocytopenia (reversible, reported in patients with chronic hepatitis)

Local: Erythema at injection site (intramuscular/subcutaneous), local pain (intramuscular/subcutaneous), local swelling (intramuscular/subcutaneous)

Neuromuscular & skeletal: Amyotrophy, bone fracture, osteoporosis, weakness

Ophthalmic: Visual disturbance

Respiratory: Pulmonary edema, respiratory depression

<1%, postmarketing, and/or case reports: Hypoglycemia (dosage >40 mg/day [Flory 2016]), hypogonadism, increased serum prolactin (transient increase with chronic use; Molitch 2008)

ALERT: U.S. Boxed Warning

Addiction, abuse, and misuse:

Methadone is an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit. Methadone exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing methadone, and monitor all patients regularly for the development of these behaviors and conditions.

Opioid analgesic risk evaluation and mitigation strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the FDA has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to health care providers. Health care providers are strongly encouraged to complete a REMS-compliant education program and counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist; and consider other tools to improve patient, household, and community safety.

Life-threatening respiratory depression:

Respiratory depression, including fatal cases, has been reported during initiation and conversion of patients to methadone, and even when the drug has been used as recommended and not misused or abused. Proper dosing and titration are essential and methadone should only be prescribed by health care providers who are knowledgeable in the use of methadone for detoxification and maintenance treatment of opioid addiction. Monitor for respiratory depression, especially during initiation of methadone or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing period.

Life-threatening QT prolongation:

QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred during treatment with methadone. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Closely monitor patients with risk factors for development of prolonged QT interval, a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction for changes in cardiac rhythm during initiation and titration of methadone.

Accidental ingestion (oral formulations):

Accidental ingestion of even one dose of methadone, especially by children, can result in a fatal overdose of methadone.

Neonatal opioid withdrawal syndrome:

Neonatal opioid withdrawal syndrome is an expected and treatable outcome of use of methadone during pregnancy. Neonatal opioid withdrawal syndrome may be life-threatening if not recognized and treated in the neonate. The balance between the risks of neonatal opioid withdrawal syndrome and the benefits of maternal methadone use may differ based on the risks associated with the mother's underlying condition, pain, or addiction. Advise the patient of the risk of neonatal opioid withdrawal syndrome so that appropriate planning for management of the neonate can occur.

Conditions for distribution and use of methadone products for the treatment of opioid addiction:

For detoxification and maintenance of opioid dependence, methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8, including limitations on unsupervised administration.

Cytochrome P450 interaction:

The concomitant use of methadone with all cytochrome P450 (CYP-450) 3A4, 2B6, 2C19, 2C9, or 2D6 inhibitors may result in an increase in methadone plasma concentrations, which could cause potentially fatal respiratory depression. In addition, discontinuation of concomitantly used CYP450 3A4, 2B6, 2C19, or 2C9 inducers may also result in an increase in methadone plasma concentration. Follow patients closely for respiratory depression and sedation, and consider dosage reduction with any changes of concomitant medications that can result in an increase in methadone levels.

Risks from concomitant use with benzodiazepines or other CNS depressants:

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, is a risk factor for respiratory depression and death. Reserve concomitant prescribing of methadone and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation and consider delaying or omitting daily methadone dosing.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

• Constipation: May cause constipation, which may be problematic in patients with unstable angina and patients post-myocardial infarction (MI). Consider preventive measures (eg, stool softener, increased fiber) to reduce the potential for constipation.

• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.

• QT prolongation: [US Boxed Warning]: QT interval prolongation and serious arrhythmias (torsades de pointes) have occurred during treatment. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Closely monitor patients with risk factors for development of QT interval (eg, cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia), a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction for changes in cardiac rhythm during initiation and titration of methadone. QT interval prolongation and torsades de pointes may be more commonly associated with, but not limited to, higher dose treatment >200 mg/day. QT prolongation has been reported in patients with no prior cardiac history who have received high doses of methadone. Only initiate therapy in patients for whom anticipated benefit outweighs the risk of QT prolongation and development of dysrhythmias. Other agents should be used in patients with a baseline QTc interval ≥500 msec (Chou 2014).

• Respiratory depression: [US Boxed Warning]: Respiratory depression, including fatal cases, has been reported during initiation and conversion of patients to methadone, and even when the drug has been used as recommended and not misused or abused. Proper dosing and titration are essential and methadone should only be prescribed by healthcare professionals who are knowledgeable in the use of methadone for detoxification and maintenance treatment of opioid addiction. Monitor for respiratory depression, especially during initiation of methadone or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing period. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

• Serotonin syndrome: May occur with concomitant use of serotonergic agents (eg, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, triptans, tricyclic antidepressants), lithium, St. John's wort, agents that impair metabolism of serotonin (eg, monoamine oxidase inhibitors), or agents that impair metabolism of tramadol (eg, CYP2D6 and 3A4 inhibitors). Monitor patients for serotonin syndrome such as mental status changes (eg, agitation, hallucinations, coma); autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia); neuromuscular changes (eg, hyperreflexia, incoordination); and/or GI symptoms (eg, nausea, vomiting, diarrhea).

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions. Avoid use in patients with obstruction.

• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).

• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; may cause constriction of sphincter of Oddi.

• CNS depression/coma: Avoid use in patients with impaired consciousness or coma, because these patients are susceptible to intracranial effects of CO2 retention.

• Delirium tremens: Use with caution in patients with delirium tremens.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, suicidal tendencies, anxiety disorders, posttraumatic stress disorder) due to increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (Dowell [CDC 2016]). Methadone is ineffective for the relief of anxiety.

• Obesity: Use with caution in patients who are morbidly obese.

• Opioid use disorder: [US Boxed Warning]: When used for detoxification and maintenance of opioid addiction, methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8, including limitations on unsupervised administration. When used for the treatment of opioid addiction in detoxification or maintenance programs, methadone should be dispensed only by opioid treatment programs (and agencies, or practitioners or institutions by formal agreement with the program sponsor) certified by the substance abuse and mental health services administration and approved by the designated state authority. Certified treatment programs shall dispense and use methadone in oral form only and according to the treatment requirements stipulated in the Federal Opioid Treatment Standards. Failure to abide by the requirements in these regulations may result in criminal prosecution, seizure of drug supply, revocation of program approval, and injunction precluding program operation. Regulatory exceptions to the general requirements for certification to provide opioid agonist treatment include inpatient treatment of other conditions and emergency period (not >3 days) while definitive substance use disorder treatment is being sought.

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Psychosis: Use with caution in patients with toxic psychosis.

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Seizure disorders: Use with caution in patients with seizure disorders; may cause or exacerbate seizures.

• Sleep-related disorders: Opioid use increases the risk for sleep-related disorders (eg, central sleep apnea [CSA], hypoxemia) in a dose-dependent fashion. Use with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing (eg, heart failure, obesity). Consider dose reduction in patients presenting with CSA. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• Benzodiazepines or other CNS depressants: [US Boxed Warning]: Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, is a risk factor for respiratory depression and death. Reserve concomitant prescribing of methadone and benzodiazepines or other CNS depressants for use in patients for whom alternatives to benzodiazepines or other CNS depressants are inadequate. Limit dosages and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation and consider delaying or omitting daily methadone dosing.

• Cytochrome P450 interaction: [US Boxed Warning]: The concomitant use of methadone with all cytochrome P450 (CYP450) 3A4, 2B6, 2C19, 2C9, or 2D6 inhibitors may result in an increase in methadone plasma concentrations, which could cause potentially fatal respiratory depression. In addition, discontinuation of concomitantly used CYP450 3A4, 2B6, 2C19, or 2C9 inducers may also result in an increase in methadone plasma concentration. Follow patients closely for respiratory depression and sedation, and consider dosage reduction with any changes of concomitant medications that can result in an increase in methadone levels.

Special populations:

• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Elderly: Use with caution in elderly patients; may be more sensitive to adverse effects. Decrease initial dose and monitor closely when initiating and titrating. Use opioids for chronic pain with caution in this age group; monitor closely due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory depression or overdose (Dowell [CDC 2016]). Consider the use of alternative nonopioid analgesics in these patients.

• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Neonatal opioid withdrawal syndrome is an expected and treatable outcome of use of methadone during pregnancy. Neonatal opioid withdrawal syndrome may be life-threatening if not recognized and treated in the neonate. The balance between the risks of neonatal opioid withdrawal syndrome and the benefits of maternal methadone use may differ based on the risks associated with the mother's underlying condition, pain, or addiction. Advise the patient of the risk of neonatal opioid withdrawal syndrome so that appropriate planning for management of the neonate can occur. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

Other warnings/precautions:

• Abrupt discontinuation/withdrawal: Abrupt discontinuation in patients who are physically dependent on opioids has been associated with serious withdrawal symptoms, uncontrolled pain, attempts to find other opioids (including illicit), and suicide. Use a collaborative, patient-specific taper schedule that minimizes the risk of withdrawal, considering factors such as current opioid dose, duration of use, type of pain, and physical and psychological factors. Monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances and provide care as needed. Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may also precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists.

• Abuse/misuse/diversion: [US Boxed Warning]: Methadone exposes patients and other users to the risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing; monitor all patients regularly for development of these behaviors and conditions. Use with caution in patients with a history of substance use disorder; potential for opioid use disorder exists. Other factors associated with increased risk include younger age, concomitant depression (major), and psychotropic medication use.

• Accidental ingestion: Oral formulations: [US Boxed Warning]: Accidental ingestion of even one dose, especially in children, can result in a fatal overdose of methadone.

• Discontinuation of therapy: There is no maximum recommended duration for maintenance treatment of opioid use disorder with methadone; patients may continue treatment indefinitely as long as treatment is beneficial. Increased duration of therapy is associated with better treatment outcomes. Advise patients who are not yet stable of the potential to relapse to illicit drug use following discontinuation of methadone medication-assisted treatment (SAMHSA 2018).

• Opioid use disorder: When switching patients from methadone to buprenorphine, patients should preferably be on low doses of oral methadone (<30 to 40 mg/day) prior to the switch to lessen discomfort. Patients switching from methadone to naltrexone (oral or extended release IM) require complete withdrawal from methadone or other opioids before naltrexone initiation (typically achieved in 7 days but up to 14 days may be necessary). A naloxone challenge test may be helpful to confirm patient is opioid-free prior to therapy (Kampman [ASAM 2015]).

• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder) in outpatient setting in adults: Opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg. nonsteroidal anti-inflammatory drugs, acetaminophen, certain anticonvulsants and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when increasing dosage to ≥50 morphine milligram equivalents (MME)/day orally; dosages ≥90 MME/day orally should be avoided unless carefully justified (Dowell [CDC 2016]). Should only be prescribed by health care professionals who are knowledgeable in the use of potent opioids for chronic pain management.

• Incomplete cross-tolerance: Use caution in converting patients from other opioids to methadone. Follow appropriate conversion schedules. Patients tolerant to other mu opioid agonists may not be tolerant to methadone and at risk for severe respiratory depression when converted to methadone.

• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.

• REMS program: [US Boxed Warning]: To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, a REMS is required. Drug companies with approved opioid analgesic products must make REMS-compliant education programs available to health care providers. Health care providers are encouraged to complete a REMS-compliant education program; counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products. Emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and consider other tools to improve patient, household, and community safety.

• Surgery: Opioids decrease bowel motility; monitor for decrease bowel motility in postop patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.

Monitoring Parameters

Pain relief, respiratory and mental status, blood pressure; signs of misuse, abuse, and dependence; liver function (baseline and during treatment); hepatitis and HIV testing, particularly for patients with opioid use disorder (prior to initiation) (SAMHSA 2018); signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013). Consider monitoring blood glucose for doses at or exceeding 40 mg/day (Flory 2016). Consider methadone serum concentrations in patients with opioid dependence on a stable methadone dose that develop symptoms of increased sedation (drowsiness 2 to 4 hours following a dose) but also develop cravings or withdrawal symptoms before the next scheduled dose (SAMHSA 2018).

Obtain baseline ECG (evaluate QTc interval) prior to therapy in patients with risk factors for QTc interval prolongation, a prior ECG with a QTc >450 msec, or a history suggesting prior ventricular arrhythmia. If an ECG was obtained within the previous 3 months and it showed a QTc interval <450 msec, it can be used as a baseline for patients without new risk factors. Repeat ECG 2 to 4 weeks after initiating therapy and after significant dose increases; follow-up ECG should also be done if new risk factors present or signs/symptoms of arrhythmia occur. Repeat ECG when the methadone dose reaches 30 to 40 mg per day (when started at lower doses) and again at 100 mg per day (Chou 2014).

Critically ill: The Numeric Rating Scale should be used in patients who are able to self-report pain. In patients who are unable to self-report pain, the Behavioral Pain Scale and the Critical-Care Pain Observational Tool can be used in intubated or nonintubated patients (SCCM [Devlin 2018]).

Alternate recommendations: Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and re-checking should be considered at least yearly (includes controlled prescription medications and illicit drugs of abuse). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (Dowell [CDC 2016]).

Reproductive Considerations

Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility in men and women (Brennan 2013). In males, reduced ejaculate volume, reduced seminal vesicle and prostate secretions, decreased serum testosterone, and abnormalities in sperm motility and morphology have been reported during treatment. Amenorrhea has been reported in females during treatment but may also develop secondary to substance abuse; pregnancy may occur following the initiation of methadone maintenance treatment. Contraception counseling is recommended to prevent unplanned pregnancies (Dow 2012).

Pregnancy Considerations

Methadone crosses the placenta and can be detected in cord blood, amniotic fluid, and newborn urine.

Data are available related to fetal/neonatal outcomes following maternal use of methadone during pregnancy. Information collected by the Teratogen Information System is complicated by maternal use of illicit drugs, nutrition, infection, and psychosocial circumstances. However, pregnant women in methadone treatment programs are reported to have improved fetal outcomes compared to pregnant women using illicit drugs. Fetal growth, birth weight, length, and/or head circumference may be decreased in infants born to mothers with opioid use disorder treated with methadone during pregnancy. Growth deficits do not appear to persist; however, decreased performance on psychometric and behavioral tests has been found to continue into childhood. Abnormal fetal nonstress tests have also been reported.

[US Boxed Warning]: Neonatal opioid withdrawal syndrome is an expected and treatable outcome of use of methadone during pregnancy. Neonatal opioid withdrawal syndrome may be life-threatening if not recognized and treated in the neonate. The balance between the risks of neonatal opioid withdrawal syndrome and the benefits of maternal methadone use may differ based on the risks associated with the mother's underlying condition, pain, or dependence. Advise the patient of the risk of neonatal opioid withdrawal syndrome so that appropriate planning for management of the neonate can occur. Symptoms following opioid exposure may present as autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, increased muscle tone, irritability, seizure, tremor) symptoms (Dow 2012; Hudak 2012). Monitoring is recommended for neonates born to mothers receiving methadone for neonatal abstinence syndrome (Chou 2014).

Opioid agonist pharmacotherapy using methadone is an option when treating opioid use disorder in pregnant women (ACOG 711 2017). Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of methadone may be altered (clearance may be increased and half-life may be decreased); dosing adjustment may be required. Women receiving methadone for the treatment of opioid use disorder should also be maintained on their daily dose of methadone in addition to receiving the same pain management options during labor and delivery as opioid-naive women; maintenance doses of methadone will not provide adequate pain relief. Opioid agonist-antagonists should be avoided for the treatment of labor pain in women maintained on methadone due to the risk of precipitating acute withdrawal (ACOG 711 2017; Dow 2012).

Patient Education

What is this drug used for?

• It is used to ease very bad pain.

• It is used to treat addiction problems.

• It may be given to you for other reasons. Talk with the doctor.

If taking this drug for pain:

• It is only to be used when around-the-clock (continuous) care is needed for a long time. It is also only to be used when other pain drugs do not treat your pain well enough or you cannot take them.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Nausea

• Vomiting

• Headache

• Loss of strength and energy

• Sweating a lot

• Lack of appetite

• Injection site irritation

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Trouble breathing

• Slow breathing

• Shallow breathing

• Abnormal heartbeat

• Adrenal gland problems like severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss

• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat

• Low magnesium like mood changes; muscle pain or weakness; muscle cramps or spasms; seizures; tremors; lack of appetite; severe nausea or vomiting; or an abnormal heartbeat

• Serotonin syndrome like dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea

• Severe dizziness

• Passing out

• Chest pain

• Fast heartbeat

• Slow heartbeat

• Noisy breathing

• Sleep apnea

• Confusion

• Severe constipation

• Sexual dysfunction (males)

• No menstrual periods

• Decreased sex drive

• Trouble getting pregnant

• Sensing things that seem real but are not

• Mood changes

• Seizures

• Severe abdominal pain

• Shortness of breath

• Excessive weight gain

• Swelling of arms or legs

• Trouble sleeping

• Trouble urinating

• Bruising

• Bleeding

• Vision changes

• Severe fatigue

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine’s uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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