methadone (Rx)

Pain Management

Indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

Opioid-naive patients: 2.5 mg PO q8-12hr; titrate slowly with dose increases no more frequent than every 3-5 days

Conversion from parenteral methadone to oral methadone

• 1:2 Parenteral-to-PO ratio: 5 mg parenteral = 10 mg PO

Conversion from other oral opioids to oral or intravenous methadone

• Total daily baseline oral estimated daily oral and intravanous methadone requirement as percent of morphine equivalent dose
• < 100 mg morphine equivalent dose: Administer 20% to 30% oral methadone or 10-15% IV methdone as percent of morphine equivalent dose
• 100-300 mg morphine equivalent dose: Administer 10% to 20% oral methadone or 5-10% IV methadone as percent of morphine equivalent dose
• 300-600 mg morphine equivalent dose: administer 8% to 12% oral methadone or 4-6% IV methadone as percent of morphine equivalent dose
• 600-1,000 mg morphine equivalent dose: administer 5% to 10% oral methadone or 3-5% IV methadone as percent of morphine equivalent dose
• > 1,000 mg morphine equivalent dose: Administer < 5 % oral methadone or <3% IV methadone as percent of morphine equivalent dose
• For patients on a single opioid, sum the current total daily dose of the opioid, convert it to a morphine equivalent dose according to specific conversion factor for that specific opioid, then multiply the Morphine equivalent dose by the corresponding percentage in the above conversion description to calculate the approximate oral and IV methadone daily dose; divide the total daily methadone dose derived from the conversion description above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3)
• 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. Divide the total daily methadone dose derived from the conversion description above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3)

Parenteral morphine to intravenous methadone conversion for chronic administration

• Total daily baseline parenteral estimated daily parenteral methadone requirement as percent of total daily morphine dose
• 10-30 mg total daily baseline parenteral morphine dose: Administer 40-66% parenteral methadone as percent of morphine dose
• 30-50 mg total daily baseline parenteral morphine dose: Administer 27-66% parenteral methadone as percent of morphine dose
• 50-100 mg total daily baseline parenteral morphine dose: Administer 22-50% parenteral methadone as percent of morphine dose
• 100-200 mg total daily baseline parenteral morphine dose: Administer 15-34% parenteral methadone as percent of morphine dose
• 200-500 mg total daily baseline parenteral morphine dose: Administer 10% to 20% parenteral methadone as percent of morphine dose
• The total daily methadone dose derived from the conversion calculations above may be divided to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3)
• Methadone dosing should not be based solely on these methadone conversion calculations; dose titration methods should always be individualized to account for the patient's prior opioid exposure, general medical condition, concomitant medication, and anticipated breakthrough medication use; the endpoint of titration is achievement of adequate pain relief, balanced against tolerability of opioid side effects; if a patient develops intolerable opioid related side effects, the methadone dose, or dosing interval, may need to be decreased; for patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion; always round the dose down, if necessary, to the appropriate methadone tablet or IV formulation strength(s) available

Opioid-tolerant patients

• Discontinue all other around-the-clock opioids
• Substantial interpatient variability, see prescribing information for guidance

Opioid-tolerant definition

• Patients who are opioid tolerant are those receiving, for 1 week or longer, at least 60 mg/day PO morphine, 25 mcg/hr transdermal fentanyl, 30 mg/day PO oxycodone, 8 mg/day PO hydromorphone, 25 mg/day PO oxymorphone, or an equianalgesic dose of another opioid
• Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

Detoxification

20-30 mg PO once daily or minimum dosage necessary to suppress withdrawal; may be titrated to 40 mg/day in divided doses and continued for 2-3 days, then decreased 20% daily as tolerated

Dosing Modifications

Renal impairment (CrCl <10mL/min): 50-75% of normal dose

Hepatic impairment: Not recommended in severe liver disease:

Dosing Considerations

Do not abruptly discontinue methadone in a physically dependent patient

Limitations of use

• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve for patients whom alternative treatment options (eg, nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain
• Not indicated for acute pain or as a PRN analgesic

Access to naloxone for opioid overdose

• Assess need for naloxone upon initiating and renewing treatment

• Consider prescribing naloxone

  • Based on patient’s risk factors for overdose (eg, concomitant use of CNS depressants, a history of opioid use disorder, prior opioid overdose); presence of risk factors should not prevent proper pain management
  • Household members (including children) or other close contacts at risk for accidental ingestion or overdose

• Consult patients and caregivers on the following:

  • Availability of naloxone for emergency treatment of opioid overdose
  • Ways differ on how to obtain naloxone as permitted by individual state dispensing and prescribing requirements or guidelines (eg, by prescription, directly from a pharmacist, as part of a community-based program)

Pain (Off-label)

0.7 mg/kg/day PO/SC/IV/IM divided q6hr PRN; not to exceed 10 mg/dose  

Opiate Withdrawal (Off-label)

Neonates: 0.05-0.2 mg/kg PO q12-24hr; reduce dose by 10-20% per week over 4-6 weeks; adjust tapering on signs and symptoms of withdrawal

Pain

2.5 mg PO/IM q8-12hr; titrate slowly with dose increases no more frequent than every 3-5 days

Detoxification

20-30 mg PO once daily or minimum dosage necessary to suppress withdrawal; may be titrated to 40 mg/day in divided doses and continued for 2-3 days, then decreased 20% daily as tolerated

Contraindicated (11)

• alvimopan

  alvimopan, methadone. receptor binding competition. Contraindicated. Alvimopan is contraindicated in opioid tolerant patients (ie, those who have taken therapeutic doses of opioids for >7 consecutive days immediately prior to taking alvimopan). Patients recently exposed to opioids are expected to be more sensitive to the effects of alvimopan and therefore may experience abdominal pain, nausea and vomiting, and diarrhea. No significant interaction is expected with concurrent use of opioid analgesics and alvimopan in patients who received opioid analgesics for 7 or fewer consecutive days prior to alvimopan.

• eliglustat

  methadone increases levels of eliglustat by affecting hepatic enzyme CYP2D6 metabolism. Contraindicated. If coadministered with strong or moderate CYP2D6 inhibitors, reduce eliglustat dose from 84 mg BID to 84 mg once daily in extensive and intermediate metabolizers; eliglustat is contraindiated if strong or moderate CYP2D6 inhibitors are given concomitantly with strong or moderate CYP3A inhibitors.

• itraconazole

  itraconazole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred in patients using methadone concomitantly with oral itraconazole and/or other CYP3A4 inhibitors.

• ketoconazole

  ketoconazole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
  
  ketoconazole and methadone both increase QTc interval. Contraindicated.

• lefamulin

  lefamulin will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Lefamulin is contraindicated with CYP3A substrates know to prolong the QT interval.

• levoketoconazole

  levoketoconazole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
  
  levoketoconazole and methadone both increase QTc interval. Contraindicated.

• olanzapine/samidorphan

  olanzapine/samidorphan will decrease the level or effect of methadone by pharmacodynamic antagonism. Contraindicated. Samidorphan elicits opioid antagonistic effects and increases risk of precipitating acute opioid withdrawal in patients dependent on opioids. Prescribing information recommends at least a 7-day opioid-free interval for short-acting opioids and at least a 14-day opioid-free interval for long-acting opioids before starting olanzapine/samidorphan.

• rasagiline

  rasagiline increases toxicity of methadone by unknown mechanism. Contraindicated. Risk of hypotension, hyperpyrexia, somnolence, or death.

• ribociclib

  ribociclib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• safinamide

  methadone, safinamide. Either increases toxicity of the other by serotonin levels. Contraindicated. Concomitant use could result in life-threatening serotonin syndrome.

• selegiline

  selegiline increases toxicity of methadone by unknown mechanism. Contraindicated. At least 14 days should elapse between discontinuation of selegiline and initiation of analgesic.

Serious - Use Alternative (137)

• acrivastine

  acrivastine and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• adagrasib

  adagrasib, methadone. Either increases effects of the other by QTc interval. Avoid or Use Alternate Drug. Each drug prolongs the QTc interval, which may increased the risk of Torsade de pointes, other serious arryhthmias, and sudden death. If coadministration unavoidable, more frequent monitoring is recommended for such patients.

• alfuzosin

  alfuzosin and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• amiodarone

  amiodarone and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• amisulpride

  amisulpride and methadone both increase QTc interval. Avoid or Use Alternate Drug. ECG monitoring is recommended if coadministered.
  
  amisulpride and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• anagrelide

  anagrelide and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• apalutamide

  apalutamide will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.

• apomorphine

  apomorphine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• aripiprazole

  aripiprazole and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• arsenic trioxide

  arsenic trioxide and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• artemether

  artemether and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• asenapine

  asenapine and methadone both increase QTc interval. Avoid or Use Alternate Drug.
  
  asenapine and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• asenapine transdermal

  asenapine transdermal and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• atomoxetine

  atomoxetine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• avapritinib

  avapritinib and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• benzhydrocodone/acetaminophen

  benzhydrocodone/acetaminophen, methadone. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.
  
  benzhydrocodone/acetaminophen and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• bremelanotide

  bremelanotide will decrease the level or effect of methadone by Other (see comment). Avoid or Use Alternate Drug. Bremelanotide may slow gastric emptying and potentially reduces the rate and extent of absorption of concomitantly administered oral medications. Avoid use when taking any oral drug that is dependent on threshold concentrations for efficacy. Interactions listed are representative examples and do not include all possible clinical examples.

• brexpiprazole

  brexpiprazole and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• brimonidine

  brimonidine and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• brivaracetam

  brivaracetam and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• buprenorphine

  buprenorphine, methadone. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.
  
  buprenorphine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• buprenorphine buccal

  buprenorphine buccal, methadone. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.
  
  buprenorphine buccal and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• buprenorphine subdermal implant

  buprenorphine subdermal implant and methadone both increase QTc interval. Avoid or Use Alternate Drug.
  
  buprenorphine subdermal implant and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• buprenorphine transdermal

  buprenorphine transdermal and methadone both increase QTc interval. Avoid or Use Alternate Drug.
  
  buprenorphine transdermal and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• buprenorphine, long-acting injection

  buprenorphine, long-acting injection and methadone both increase QTc interval. Avoid or Use Alternate Drug.
  
  buprenorphine, long-acting injection and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• butorphanol

  butorphanol, methadone. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

• calcium/magnesium/potassium/sodium oxybates

  methadone, calcium/magnesium/potassium/sodium oxybates. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• carbamazepine

  carbamazepine will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• cariprazine

  cariprazine and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• ceritinib

  ceritinib and methadone both increase QTc interval. Avoid or Use Alternate Drug.
  
  ceritinib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• chloroquine

  chloroquine increases toxicity of methadone by QTc interval. Avoid or Use Alternate Drug.

• cimetidine

  cimetidine will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
  
  cimetidine increases effects of methadone by decreasing metabolism. Avoid or Use Alternate Drug.

• clarithromycin

  clarithromycin will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• clonidine

  clonidine, methadone. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration enhances CNS depressant effects.

• clozapine

  clozapine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• crizotinib

  crizotinib and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• degarelix

  degarelix and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• diazepam intranasal

  diazepam intranasal, methadone. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• disopyramide

  disopyramide and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• donepezil

  donepezil and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• efavirenz

  efavirenz and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• eliglustat

  eliglustat and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• eluxadoline

  methadone, eluxadoline. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Avoid coadministration with other drugs that cause constipation. Increases risk for constipation related serious adverse reactions. .

• encorafenib

  encorafenib and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• entrectinib

  methadone and entrectinib both increase QTc interval. Avoid or Use Alternate Drug.

• enzalutamide

  enzalutamide will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• eribulin

  eribulin and methadone both increase QTc interval. Avoid or Use Alternate Drug. Potential for enhanced QTc-prolonging effects; if concurrent use is necessary then ECG monitoring is recommended.

• erythromycin base

  erythromycin base will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• erythromycin ethylsuccinate

  erythromycin ethylsuccinate will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• erythromycin lactobionate

  erythromycin lactobionate will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• erythromycin stearate

  erythromycin stearate will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• escitalopram

  escitalopram increases toxicity of methadone by QTc interval. Avoid or Use Alternate Drug.

• ethotoin

  ethotoin decreases levels of methadone by increasing metabolism. Contraindicated.

• fentanyl

  fentanyl, methadone. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.
  
  fentanyl and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• fentanyl intranasal

  fentanyl intranasal, methadone. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.
  
  fentanyl intranasal and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• fentanyl iontophoretic transdermal system

  fentanyl iontophoretic transdermal system and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• fentanyl transdermal

  fentanyl transdermal, methadone. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.
  
  fentanyl transdermal and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• fentanyl transmucosal

  fentanyl transmucosal, methadone. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.
  
  fentanyl transmucosal and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• fexinidazole

  fexinidazole and methadone both increase QTc interval. Avoid or Use Alternate Drug. Avoid coadministration of fexinidazole with drugs known to block potassium channels and/or prolong QT interval.
  
  fexinidazole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.

• fingolimod

  fingolimod and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• fosphenytoin

  fosphenytoin decreases levels of methadone by increasing metabolism. Contraindicated.

• gadobenate

  gadobenate and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• gemifloxacin

  gemifloxacin and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• gilteritinib

  gilteritinib and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• givinostat

  methadone and givinostat both increase QTc interval. Avoid or Use Alternate Drug. If unable to avoid coadministration, obtain ECGs when initiating, during concomitant use, and as clinically indicated. Withhold if QTc interval >500 ms or a change from baseline >60 ms.

• glasdegib

  methadone and glasdegib both increase QTc interval. Avoid or Use Alternate Drug. If coadministration unavoidable, monitor for increased risk of QTc interval prolongation.

• granisetron

  granisetron and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• hydrocodone

  hydrocodone, methadone. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• hydroxychloroquine sulfate

  hydroxychloroquine sulfate and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• ibutilide

  ibutilide and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• idelalisib

  idelalisib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Idelalisib is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates

• indapamide

  indapamide and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• inotuzumab

  inotuzumab and methadone both increase QTc interval. Avoid or Use Alternate Drug. If unable to avoid concomitant use, obtain ECGs and electrolytes before and after initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during treatment.

• isocarboxazid

  isocarboxazid increases toxicity of methadone by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

• isoflurane

  isoflurane and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• ivosidenib

  ivosidenib and methadone both increase QTc interval. Avoid or Use Alternate Drug. Avoid coadministration of QTc prolonging drugs with ivosidenib or replace with alternate therapies. If coadministration of a QTc prolonging drug is unavoidable, monitor for increased risk of QTc interval prolongation.
  
  ivosidenib will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP3A4 substrates with ivosidenib or replace with alternative therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.

• levetiracetam

  levetiracetam and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• linezolid

  linezolid increases toxicity of methadone by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

• lithium

  lithium and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• lonafarnib

  methadone will increase the level or effect of lonafarnib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of lonafarnib (a sensitive CYP3A substrate) with weak CYP3A inhibitors is unavoidable, reduce to, or continue lonafarnib at starting dose. Closely monitor for arrhythmias and events (eg, syncope, heart palpitations) since lonafarnib effect on QT interval is unknown.

• lopinavir

  lopinavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• macimorelin

  macimorelin and methadone both increase QTc interval. Avoid or Use Alternate Drug. Macimorelin causes an increase of ~11 msec in the corrected QT interval. Avoid coadministration with drugs that prolong QT interval, which could increase risk for developing torsade de pointes-type ventricular tachycardia. Allow sufficient washout time of drugs that are known to prolong the QT interval before administering macimorelin.

• methohexital

  methohexital and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• methylene blue

  methylene blue and methadone both increase serotonin levels. Avoid or Use Alternate Drug. If drug combination must be administered, monitor for evidence of serotonergic or opioid-related toxicities

• metoclopramide intranasal

  methadone, metoclopramide intranasal. Either increases effects of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Avoid use of metoclopramide intranasal or interacting drug, depending on importance of drug to patient.

• mifepristone

  mifepristone will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• mirtazapine

  mirtazapine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• mobocertinib

  mobocertinib and methadone both increase QTc interval. Avoid or Use Alternate Drug. If coadministration unavoidable, reduce mobocertinib dose and monitor QTc interval more frequently.

• nalbuphine

  nalbuphine, methadone. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

• nefazodone

  nefazodone will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• olanzapine

  olanzapine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• olopatadine intranasal

  methadone and olopatadine intranasal both increase sedation. Avoid or Use Alternate Drug. Coadministration increases risk of CNS depression, which can lead to additive impairment of psychomotor performance and cause daytime impairment.

• ondansetron

  methadone and ondansetron both increase QTc interval. Avoid or Use Alternate Drug. Avoid with congenital long QT syndrome; ECG monitoring recommended with concomitant medications that prolong QT interval, electrolyte abnormalities, CHF, or bradyarrhythmias.

• oxaliplatin

  oxaliplatin and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• ozanimod

  ozanimod and methadone both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Avoid or Use Alternate Drug. Because the active metabolite of ozanimod inhibits MAO-B in vitro, there is a potential for serious adverse reactions, including hypertensive crisis. Therefore, coadministration of ozanimod with drugs that can increase norepinephrine or serotonin is not recommended. Monitor for hypertension with concomitant use.

• panobinostat

  methadone and panobinostat both increase QTc interval. Avoid or Use Alternate Drug. Panobinostat is known to significantly prolong QT interval. Panobinostat prescribing information states use with drugs known to prolong QTc is not recommended.

• pentamidine

  methadone and pentamidine both increase QTc interval. Avoid or Use Alternate Drug.

• pentazocine

  pentazocine, methadone. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

• phenelzine

  phenelzine increases toxicity of methadone by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

• phenytoin

  phenytoin decreases levels of methadone by increasing metabolism. Contraindicated.

• pimozide

  methadone and pimozide both increase QTc interval. Avoid or Use Alternate Drug.

• pitolisant

  methadone and pitolisant both increase QTc interval. Avoid or Use Alternate Drug.

• ponesimod

  ponesimod, methadone. Either increases effects of the other by QTc interval. Avoid or Use Alternate Drug. Consult cardiologist if considering treatment. Generally, should not be initiated in patients who are concurrently taking QT prolonging drugs with known arrhythmogenic properties, such as HR-lowering calcium channel blockers (eg, verapamil, diltiazem).

• primaquine

  primaquine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• procainamide

  methadone and procainamide both increase QTc interval. Avoid or Use Alternate Drug.

• procarbazine

  procarbazine increases toxicity of methadone by unknown mechanism. Avoid or Use Alternate Drug. MAOIs may potentiate CNS depression and hypotension. Do not use within 14 days of MAOI use. .

• quinidine

  quinidine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• ribociclib

  ribociclib and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• rifabutin

  rifabutin will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• rifampin

  rifampin will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• romidepsin

  methadone and romidepsin both increase QTc interval. Avoid or Use Alternate Drug.

• ropeginterferon alfa 2b

  ropeginterferon alfa 2b and methadone both increase Other (see comment). Avoid or Use Alternate Drug. Narcotics, hypnotics or sedatives can produce additive neuropsychiatric side effects. Avoid use and monitor patients receiving the combination for effects of excessive CNS toxicity.

• saquinavir

  saquinavir, methadone. Either increases toxicity of the other by QTc interval. Avoid or Use Alternate Drug. Increased risk of PR prolongation and cardiac arrhythmias.
  
  saquinavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• selegiline transdermal

  selegiline transdermal increases toxicity of methadone by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death.

• selinexor

  selinexor, methadone. unspecified interaction mechanism. Avoid or Use Alternate Drug. Patients treated with selinexor may experience neurological toxicities. Avoid taking selinexor with other medications that may cause dizziness or confusion.

• sertraline

  sertraline and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• sevoflurane

  sevoflurane and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• siponimod

  siponimod and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• sodium oxybate

  methadone, sodium oxybate. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• solifenacin

  solifenacin and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• sotalol

  methadone and sotalol both increase QTc interval. Avoid or Use Alternate Drug.

• St John's Wort

  St John's Wort will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• sufentanil SL

  sufentanil SL, methadone. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration may result in hypotension, profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• sunitinib

  sunitinib and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• tacrolimus

  tacrolimus and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• tetrabenazine

  tetrabenazine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• tramadol

  tramadol, methadone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• tranylcypromine

  tranylcypromine increases toxicity of methadone by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

• tucatinib

  tucatinib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.

• umeclidinium bromide/vilanterol inhaled

  methadone increases toxicity of umeclidinium bromide/vilanterol inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.

• valerian

  valerian and methadone both increase sedation. Avoid or Use Alternate Drug.

• vandetanib

  methadone, vandetanib. Either increases toxicity of the other by QTc interval. Avoid or Use Alternate Drug. Avoid coadministration with drugs known to prolong QT interval; if a drug known to prolong QT interval must be used, more frequent ECG monitoring is recommended.

• vemurafenib

  vemurafenib and methadone both increase QTc interval. Avoid or Use Alternate Drug. Concomitant use of vemurafenib with drugs that prolong QT interval is not recommended.

• vilanterol/fluticasone furoate inhaled

  methadone increases toxicity of vilanterol/fluticasone furoate inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.

• vorinostat

  vorinostat and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• voxelotor

  voxelotor will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.

• zuranolone

  methadone, zuranolone. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration of zuranolone with other CNS depressants may increase impairment of psychomotor performance or CNS depressant effects. If unavoidable, consider dose reduction. .

Monitor Closely (345)

• abacavir

  abacavir will decrease the level or effect of methadone by unknown mechanism. Use Caution/Monitor. Monitor for opioid withdrawal symptoms.

• albuterol

  methadone increases and albuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.
  
  albuterol and methadone both increase QTc interval. Use Caution/Monitor.

• alfentanil

  alfentanil and methadone both increase sedation. Use Caution/Monitor.

• alfuzosin

  methadone and alfuzosin both increase QTc interval. Use Caution/Monitor.

• alprazolam

  alprazolam and methadone both increase sedation. Use Caution/Monitor.

• amitriptyline

  amitriptyline and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and amitriptyline both increase sedation. Use Caution/Monitor.

• amobarbital

  amobarbital will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  amobarbital and methadone both increase sedation. Use Caution/Monitor.

• amoxapine

  amoxapine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and amoxapine both increase sedation. Use Caution/Monitor.

• apomorphine

  methadone and apomorphine both increase sedation. Use Caution/Monitor.

• aprepitant

  aprepitant will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• arformoterol

  methadone increases and arformoterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.
  
  arformoterol and methadone both increase QTc interval. Use Caution/Monitor.

• aripiprazole

  methadone and aripiprazole both increase sedation. Use Caution/Monitor.
  
  methadone, aripiprazole. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• armodafinil

  armodafinil will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  methadone increases and armodafinil decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• artemether/lumefantrine

  artemether/lumefantrine will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  artemether/lumefantrine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• asenapine

  methadone, asenapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• asenapine transdermal

  asenapine transdermal and methadone both increase sedation. Use Caution/Monitor.

• atazanavir

  atazanavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• atogepant

  methadone will increase the level or effect of atogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• avapritinib

  methadone will increase the level or effect of avapritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• axitinib

  methadone increases levels of axitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• azelastine

  azelastine and methadone both increase sedation. Use Caution/Monitor.

• baclofen

  baclofen and methadone both increase sedation. Use Caution/Monitor.

• bedaquiline

  methadone and bedaquiline both increase QTc interval. Modify Therapy/Monitor Closely. ECG should be monitored closely

• belladonna and opium

  methadone and belladonna and opium both increase sedation. Use Caution/Monitor.

• benperidol

  methadone and benperidol both increase sedation. Use Caution/Monitor.

• benzphetamine

  methadone increases and benzphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• bosentan

  bosentan will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• bosutinib

  bosutinib and methadone both increase QTc interval. Use Caution/Monitor.

• brexanolone

  brexanolone, methadone. Either increases toxicity of the other by sedation. Use Caution/Monitor.

• brexpiprazole

  methadone will increase the level or effect of brexpiprazole by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Administer a quarter of brexpiprazole dose if coadministered with a moderate CYP2D6 inhibitor PLUS a strong/moderate CYP3A4 inhibitor.

• brompheniramine

  brompheniramine and methadone both increase sedation. Use Caution/Monitor.

• budesonide

  budesonide will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• buprenorphine

  buprenorphine and methadone both increase sedation. Use Caution/Monitor.

• buprenorphine buccal

  buprenorphine buccal and methadone both increase sedation. Use Caution/Monitor.

• buprenorphine, long-acting injection

  methadone increases toxicity of buprenorphine, long-acting injection by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of buprenorphine and benzodiazepines or other CNS depressants increases risk of adverse reactions including overdose, respiratory depression, and death. Cessation of benzodiazepines or other CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering CNS depressants may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

• butabarbital

  butabarbital will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  butabarbital and methadone both increase sedation. Use Caution/Monitor.

• butalbital

  butalbital will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  butalbital and methadone both increase sedation. Use Caution/Monitor.

• butorphanol

  butorphanol and methadone both increase sedation. Use Caution/Monitor.

• caffeine

  methadone increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• cannabidiol

  cannabidiol will increase the level or effect of methadone by decreasing metabolism. Modify Therapy/Monitor Closely. Cannabidiol may potentially inhibit CYP2C8 activity. Consider reducing the dose when concomitantly using CYP2C8 substrates.

• capecitabine

  capecitabine and methadone both increase QTc interval. Use Caution/Monitor.

• carbinoxamine

  carbinoxamine and methadone both increase sedation. Use Caution/Monitor.

• cariprazine

  methadone, cariprazine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• carisoprodol

  carisoprodol and methadone both increase sedation. Use Caution/Monitor.

• cenobamate

  cenobamate will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase dose of CYP3A4 substrate, as needed, when coadministered with cenobamate.

• chloral hydrate

  chloral hydrate and methadone both increase sedation. Use Caution/Monitor.

• chlordiazepoxide

  chlordiazepoxide and methadone both increase sedation. Use Caution/Monitor.

• chlorpheniramine

  chlorpheniramine and methadone both increase sedation. Use Caution/Monitor.

• chlorpromazine

  chlorpromazine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and chlorpromazine both increase sedation. Use Caution/Monitor.

• chlorzoxazone

  chlorzoxazone and methadone both increase sedation. Use Caution/Monitor.

• cinnarizine

  cinnarizine and methadone both increase sedation. Use Caution/Monitor.

• ciprofloxacin

  ciprofloxacin and methadone both increase QTc interval. Use Caution/Monitor. Ciprofloxacin elicits minimal effects on QT interval. Caution if used in combination with other drugs known to affect QT interval or in patients with other risk factors.

• citalopram

  methadone and citalopram both increase QTc interval. Use Caution/Monitor. Combination may increase risk of serotonin syndrome or neuroleptic malignant syndrome like reactions. ECG monitoring is recommended, along with drugs that may prolong the QT interval.

• clarithromycin

  clarithromycin and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• clemastine

  clemastine and methadone both increase sedation. Use Caution/Monitor.

• clobazam

  methadone, clobazam. Other (see comment). Use Caution/Monitor. Comment: Concomitant administration can increase the potential for CNS effects (e.g., increased sedation or respiratory depression).

• clomipramine

  clomipramine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and clomipramine both increase sedation. Use Caution/Monitor.

• clonazepam

  clonazepam and methadone both increase sedation. Use Caution/Monitor.

• clorazepate

  clorazepate and methadone both increase sedation. Use Caution/Monitor.

• clozapine

  methadone and clozapine both increase sedation. Use Caution/Monitor.
  
  methadone, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• cobicistat

  cobicistat will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Methadone dose may require an adjustment

• codeine

  codeine and methadone both increase sedation. Use Caution/Monitor.

• conivaptan

  conivaptan will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• cortisone

  cortisone will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• crizotinib

  crizotinib increases levels of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A. ECG monitoring is recommended, along with drugs that may prolong the QT interval.

• crofelemer

  crofelemer increases levels of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Crofelemer has the potential to inhibit CYP3A4 at concentrations expected in the gut; unlikely to inhibit systemically because minimally absorbed.

• cyclizine

  cyclizine and methadone both increase sedation. Use Caution/Monitor.

• cyclobenzaprine

  cyclobenzaprine and methadone both increase sedation. Use Caution/Monitor.

• cyclosporine

  cyclosporine will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• cyproheptadine

  cyproheptadine and methadone both increase sedation. Use Caution/Monitor.

• dabrafenib

  dabrafenib will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

• danazol

  danazol will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• dantrolene

  dantrolene and methadone both increase sedation. Use Caution/Monitor.

• daridorexant

  methadone and daridorexant both increase sedation. Modify Therapy/Monitor Closely. Coadministration increases risk of CNS depression, which can lead to additive impairment of psychomotor performance and cause daytime impairment.

• darifenacin

  darifenacin will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• darunavir

  darunavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Carefully titrate dose when initiating buprenorphine, buprenorphine/naloxone, or methadone with patients taking darunavir/cobicstat. When initiating cobicistat in patients taking buprenorphine, buprenorphine/naloxone, or methadone, adjust dose for buprenorphine, buprenorphine/naloxone, or methadone and monitor clinical signs and symptoms.

• dasatinib

  dasatinib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  dasatinib and methadone both increase QTc interval. Use Caution/Monitor.

• deferasirox

  deferasirox will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• desflurane

  desflurane and methadone both increase sedation. Use Caution/Monitor. Opioids may decrease MAC requirements, less inhalation anesthetic may be required.

• desipramine

  desipramine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and desipramine both increase sedation. Use Caution/Monitor.

• deutetrabenazine

  methadone and deutetrabenazine both increase sedation. Use Caution/Monitor.
  
  deutetrabenazine and methadone both increase QTc interval. Use Caution/Monitor. At the maximum recommended dose, deutetrabenazine does not prolong QT interval to a clinically relevant extent. Certain circumstances may increase risk of torsade de pointes and/or sudden death in association with drugs that prolong the QTc interval (eg, bradycardia, hypokalemia or hypomagnesemia, coadministration with other drugs that prolong QTc interval, presence of congenital QT prolongation).

• dexamethasone

  dexamethasone will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• dexchlorpheniramine

  dexchlorpheniramine and methadone both increase sedation. Use Caution/Monitor.

• dexfenfluramine

  methadone increases and dexfenfluramine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dexmedetomidine

  dexmedetomidine and methadone both increase sedation. Use Caution/Monitor.

• dexmethylphenidate

  methadone increases and dexmethylphenidate decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dextroamphetamine

  methadone increases and dextroamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dextromoramide

  dextromoramide and methadone both increase sedation. Use Caution/Monitor.

• DHEA, herbal

  DHEA, herbal will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• diamorphine

  diamorphine and methadone both increase sedation. Use Caution/Monitor.

• diazepam

  diazepam and methadone both increase sedation. Use Caution/Monitor.

• dichlorphenamide

  dichlorphenamide and methadone both decrease serum potassium. Use Caution/Monitor.

• didanosine

  methadone decreases levels of didanosine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

• diethylpropion

  methadone increases and diethylpropion decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• difelikefalin

  difelikefalin and methadone both increase sedation. Use Caution/Monitor.

• difenoxin hcl

  difenoxin hcl and methadone both increase sedation. Use Caution/Monitor.

• diltiazem

  diltiazem will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• dimenhydrinate

  dimenhydrinate and methadone both increase sedation. Use Caution/Monitor.

• diphenhydramine

  diphenhydramine and methadone both increase sedation. Use Caution/Monitor.

• diphenoxylate hcl

  diphenoxylate hcl and methadone both increase sedation. Use Caution/Monitor.

• dipipanone

  dipipanone and methadone both increase sedation. Use Caution/Monitor.

• dobutamine

  methadone increases and dobutamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dofetilide

  dofetilide and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• dolasetron

  dolasetron and methadone both increase QTc interval. Use Caution/Monitor.

• dopamine

  methadone increases and dopamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dopexamine

  methadone increases and dopexamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dosulepin

  methadone and dosulepin both increase sedation. Use Caution/Monitor.

• doxepin

  doxepin and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and doxepin both increase sedation. Use Caution/Monitor.

• doxylamine

  doxylamine and methadone both increase sedation. Use Caution/Monitor.

• dronedarone

  dronedarone will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  dronedarone and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• droperidol

  droperidol and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and droperidol both increase sedation. Use Caution/Monitor.

• duvelisib

  duvelisib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration with duvelisib increases AUC of a sensitive CYP3A4 substrate which may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the coadministered sensitive CYP3A substrate.

• efavirenz

  efavirenz will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• elagolix

  elagolix decreases levels of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.

• eltrombopag

  eltrombopag increases levels of methadone by decreasing metabolism. Use Caution/Monitor. UGT inhibition; significance of interaction unclear.

• elvitegravir

  elvitegravir decreases levels of methadone by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Dosage of methadone may need to be increased.

• elvitegravir/cobicistat/emtricitabine/tenofovir DF

  elvitegravir/cobicistat/emtricitabine/tenofovir DF increases levels of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Cobicistat is a CYP3A4 inhibitor; contraindicated with CYP3A4 substrates for which elevated plasma concentrations are associated with serious and/or life-threatening events.

• encorafenib

  encorafenib, methadone. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Encorafenib both inhibits and induces CYP3A4 at clinically relevant plasma concentrations. Coadministration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.

• ephedrine

  methadone increases and ephedrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• epinephrine

  epinephrine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone increases and epinephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• epinephrine racemic

  epinephrine racemic and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone increases and epinephrine racemic decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• erythromycin base

  erythromycin base and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• erythromycin ethylsuccinate

  erythromycin ethylsuccinate and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• erythromycin lactobionate

  erythromycin lactobionate and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• erythromycin stearate

  erythromycin stearate and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• esketamine intranasal

  esketamine intranasal, methadone. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely.

• eslicarbazepine acetate

  eslicarbazepine acetate will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• estazolam

  estazolam and methadone both increase sedation. Use Caution/Monitor.

• ethanol

  methadone and ethanol both increase sedation. Use Caution/Monitor.

• etomidate

  etomidate and methadone both increase sedation. Use Caution/Monitor.

• etrasimod

  etrasimod, methadone. Either increases effects of the other by QTc interval. Modify Therapy/Monitor Closely. Transient decrease in heart rate and AV conduction delays may occur when initiating etrasimod. Owing to potential of additive effect on heart rate, etrasimod may increase risk of QT prolongation and Torsades de Pointes when coadministered with Class Ia or Class III antiarrhythmic drugs, or other drugs that prolong the QT interval. .

• etravirine

  etravirine will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• ezogabine

  ezogabine, methadone. Either increases toxicity of the other by QTc interval. Use Caution/Monitor. Slight and transient QT-prolongation observed with ezogabine, particularly when dose titrated to 1200 mg/day. QT interval should be monitored when ezogabine is prescribed with agents known to increase QT interval.

• fedratinib

  fedratinib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.

• fenfluramine

  methadone increases and fenfluramine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• finerenone

  methadone will increase the level or effect of finerenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor serum potassium during initiation and dosage adjustment of either finererone or weak CYP3A4 inhibitors. Adjust finererone dosage as needed.

• flecainide

  flecainide and methadone both increase QTc interval. Use Caution/Monitor.

• flibanserin

  methadone and flibanserin both increase sedation. Modify Therapy/Monitor Closely. Risk for sedation increased if flibanserin is coadministration with other CNS depressants.
  
  methadone will increase the level or effect of flibanserin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Increased flibanserin adverse effects may occur if coadministered with multiple weak CYP3A4 inhibitors.

• floxuridine

  floxuridine and methadone both increase QTc interval. Use Caution/Monitor.

• fluconazole

  fluconazole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  fluconazole and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• fludrocortisone

  fludrocortisone will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• fluoxetine

  fluoxetine and methadone both increase QTc interval. Use Caution/Monitor.

• fluphenazine

  fluphenazine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and fluphenazine both increase sedation. Use Caution/Monitor.
  
  methadone, fluphenazine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• flurazepam

  flurazepam and methadone both increase sedation. Use Caution/Monitor.

• fluvoxamine

  fluvoxamine and methadone both increase QTc interval. Use Caution/Monitor.

• formoterol

  formoterol and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone increases and formoterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• fosamprenavir

  fosamprenavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• fosaprepitant

  fosaprepitant will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• foscarnet

  foscarnet and methadone both increase QTc interval. Use Caution/Monitor.

• fosphenytoin

  fosphenytoin will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• gabapentin

  gabapentin, methadone. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

• gabapentin enacarbil

  gabapentin enacarbil, methadone. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

• ganaxolone

  methadone and ganaxolone both increase sedation. Use Caution/Monitor.

• gemtuzumab

  methadone and gemtuzumab both increase QTc interval. Use Caution/Monitor.

• gepirone

  gepirone and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• goserelin

  goserelin increases toxicity of methadone by QTc interval. Use Caution/Monitor. Increases risk of torsades de pointes.

• grapefruit

  grapefruit will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• griseofulvin

  griseofulvin will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• haloperidol

  haloperidol and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and haloperidol both increase sedation. Use Caution/Monitor.
  
  methadone, haloperidol. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• histrelin

  histrelin increases toxicity of methadone by QTc interval. Use Caution/Monitor. Increases risk of torsades de pointes.

• hydrocortisone

  hydrocortisone will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• hydromorphone

  hydromorphone and methadone both increase sedation. Use Caution/Monitor.

• hydroxyzine

  hydroxyzine and methadone both increase sedation. Use Caution/Monitor.
  
  hydroxyzine increases toxicity of methadone by QTc interval. Use Caution/Monitor. Increases risk of torsades de pointes.

• iloperidone

  iloperidone and methadone both increase QTc interval. Use Caution/Monitor.
  
  methadone and iloperidone both increase sedation. Use Caution/Monitor.
  
  iloperidone increases levels of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Iloperidone is a time-dependent CYP3A inhibitor and may lead to increased plasma levels of drugs predominantly eliminated by CYP3A4.
  
  methadone, iloperidone. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• imipramine

  imipramine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and imipramine both increase sedation. Use Caution/Monitor.

• indacaterol, inhaled

  indacaterol, inhaled, methadone. QTc interval. Use Caution/Monitor. Drugs that are known to prolong the QTc interval may have an increased the risk of ventricular arrhythmias.

• indinavir

  indinavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• isavuconazonium sulfate

  methadone will increase the level or effect of isavuconazonium sulfate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• isoniazid

  isoniazid will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• isoproterenol

  methadone increases and isoproterenol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• istradefylline

  istradefylline will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.

• ketamine

  ketamine and methadone both increase sedation. Use Caution/Monitor.

• ketotifen, ophthalmic

  methadone and ketotifen, ophthalmic both increase sedation. Use Caution/Monitor.

• lapatinib

  lapatinib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  lapatinib and methadone both increase QTc interval. Use Caution/Monitor.

• larotrectinib

  larotrectinib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• lasmiditan

  lasmiditan, methadone. Either increases effects of the other by sedation. Use Caution/Monitor. Coadministration of lasmiditan and other CNS depressant drugs, including alcohol have not been evaluated in clinical studies. Lasmiditan may cause sedation, as well as other cognitive and/or neuropsychiatric adverse reactions.

• lemborexant

  methadone will increase the level or effect of lemborexant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Lower nightly dose of lemborexant recommended if coadministered with weak CYP3A4 inhibitors. See drug monograph for specific dosage modification.
  
  lemborexant, methadone. Either increases effects of the other by sedation. Modify Therapy/Monitor Closely. Dosage adjustment may be necessary if lemborexant is coadministered with other CNS depressants because of potentially additive effects.

• lenacapavir

  lenacapavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When initiating methadone while on lenacapavir, use lowest feasible initial or maintenance dose of methadone and carefully titrate dose to desired effect. When initiating lenacapavir while taking methadone, consider adjusting dose for methadone. Monitor clinical signs and symptoms.

• lenvatinib

  methadone and lenvatinib both increase QTc interval. Use Caution/Monitor. Lenvatinib prescribing information recommends monitoring ECG closely when coadministered with QT prolonging drugs.

• letermovir

  letermovir increases levels of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• leuprolide

  leuprolide increases toxicity of methadone by QTc interval. Use Caution/Monitor. Increases risk of torsades de pointes.

• levalbuterol

  methadone increases and levalbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• levofloxacin

  levofloxacin and methadone both increase QTc interval. Use Caution/Monitor.

• levorphanol

  levorphanol and methadone both increase sedation. Use Caution/Monitor.

• lisdexamfetamine

  methadone increases and lisdexamfetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• lofepramine

  lofepramine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and lofepramine both increase sedation. Use Caution/Monitor.

• lofexidine

  methadone and lofexidine both increase sedation. Use Caution/Monitor.
  
  methadone and lofexidine both increase QTc interval. Use Caution/Monitor. ECG monitoring is recommended.

• lomitapide

  methadone increases levels of lomitapide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Lomitapide dose should not exceed 30 mg/day.

• loprazolam

  loprazolam and methadone both increase sedation. Use Caution/Monitor.

• lorazepam

  lorazepam and methadone both increase sedation. Use Caution/Monitor.

• lorlatinib

  lorlatinib will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• lormetazepam

  lormetazepam and methadone both increase sedation. Use Caution/Monitor.

• loxapine

  methadone and loxapine both increase sedation. Use Caution/Monitor.
  
  methadone, loxapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• loxapine inhaled

  methadone and loxapine inhaled both increase sedation. Use Caution/Monitor.
  
  methadone, loxapine inhaled. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• lumefantrine

  lumefantrine will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  lumefantrine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• lurasidone

  lurasidone, methadone. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.
  
  methadone, lurasidone. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• maprotiline

  maprotiline and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and maprotiline both increase sedation. Use Caution/Monitor.

• maraviroc

  maraviroc increases levels of methadone by QTc interval. Use Caution/Monitor. Potential for increased toxicity. Increased risk of QT prolongation and cardiac arrhythmias.

• marijuana

  marijuana will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  methadone and marijuana both increase sedation. Use Caution/Monitor.

• melatonin

  methadone and melatonin both increase sedation. Use Caution/Monitor.

• meperidine

  meperidine and methadone both increase sedation. Use Caution/Monitor.

• meprobamate

  methadone and meprobamate both increase sedation. Use Caution/Monitor.

• metaproterenol

  methadone increases and metaproterenol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• metaxalone

  metaxalone and methadone both increase sedation. Use Caution/Monitor.

• methamphetamine

  methadone increases and methamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• methocarbamol

  methocarbamol and methadone both increase sedation. Use Caution/Monitor.

• methylenedioxymethamphetamine

  methadone increases and methylenedioxymethamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• methylprednisolone

  methylprednisolone will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• metronidazole

  metronidazole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• miconazole vaginal

  miconazole vaginal will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• midazolam

  midazolam and methadone both increase sedation. Use Caution/Monitor.

• midazolam intranasal

  methadone will increase the level or effect of midazolam intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration of mild CYP3A4 inhibitors with midazolam intranasal may cause higher midazolam systemic exposure, which may prolong sedation.
  
  midazolam intranasal, methadone. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of benzodiazepines and opioids increases risk of respiratory depression. Use only in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required.

• midodrine

  methadone increases and midodrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• mifepristone

  mifepristone will increase the level or effect of methadone by Other (see comment). Modify Therapy/Monitor Closely. Inhibits CYP2C8/2C9; use smallest recommended doses for substrates and monitor; combination may increase QT interval. Use alternatives if available

• mirtazapine

  methadone and mirtazapine both increase sedation. Use Caution/Monitor.

• mitotane

  mitotane decreases levels of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Mitotane is a strong inducer of cytochrome P-4503A4; monitor when coadministered with CYP3A4 substrates for possible dosage adjustments.

• modafinil

  methadone increases and modafinil decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• molindone

  methadone, molindone. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• morphine

  methadone and morphine both increase sedation. Use Caution/Monitor.

• motherwort

  methadone and motherwort both increase sedation. Use Caution/Monitor.

• moxifloxacin

  methadone and moxifloxacin both increase QTc interval. Modify Therapy/Monitor Closely.

• moxonidine

  methadone and moxonidine both increase sedation. Use Caution/Monitor.

• nabilone

  methadone and nabilone both increase sedation. Use Caution/Monitor.

• nafcillin

  nafcillin will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• nalbuphine

  methadone and nalbuphine both increase sedation. Use Caution/Monitor.

• nelfinavir

  nelfinavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• nevirapine

  nevirapine will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• nifedipine

  nifedipine will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• nilotinib

  nilotinib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  methadone and nilotinib both increase QTc interval. Modify Therapy/Monitor Closely.

• nirmatrelvir

  nirmatrelvir will decrease the level or effect of methadone by affecting hepatic enzyme CYP2B6 metabolism. Use Caution/Monitor. Methadone is metabolized by CYP2B6 and CYP3A4. Ritonavir may decrease AUC and peak plasma concentration by CYP2B6 induction. This may be partially offset by ritonavir inhibiting CYP3A4.

• nirmatrelvir/ritonavir

  nirmatrelvir/ritonavir will decrease the level or effect of methadone by affecting hepatic enzyme CYP2B6 metabolism. Use Caution/Monitor. Methadone is metabolized by CYP2B6 and CYP3A4. Ritonavir may decrease AUC and peak plasma concentration by CYP2B6 induction. This may be partially offset by ritonavir inhibiting CYP3A4.

• norepinephrine

  methadone increases and norepinephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• nortriptyline

  nortriptyline and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and nortriptyline both increase sedation. Use Caution/Monitor.

• octreotide

  methadone and octreotide both increase QTc interval. Modify Therapy/Monitor Closely.

• octreotide (Antidote)

  methadone and octreotide (Antidote) both increase QTc interval. Modify Therapy/Monitor Closely.

• ofloxacin

  methadone and ofloxacin both increase QTc interval. Use Caution/Monitor.

• olanzapine

  methadone and olanzapine both increase sedation. Use Caution/Monitor.
  
  methadone, olanzapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• oliceridine

  methadone will increase the level or effect of oliceridine by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. If concomitant use is necessary, may require less frequent oliceridine dosing. Closely monitor for respiratory depression and sedation and titrate subsequent doses accordingly. If inhibitor is discontinued, consider increase oliceridine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
  
  oliceridine, methadone. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• olodaterol inhaled

  methadone and olodaterol inhaled both increase QTc interval. Use Caution/Monitor. Drugs that prolong the QTc interval and may potentiate the effects of beta2 agonists on the cardiovascular system; increased risk of ventricular arrhythmias

• omaveloxolone

  omaveloxolone will decrease the level or effect of methadone by Other (see comment). Use Caution/Monitor. Omaveloxolone may reduce systemic exposure of sensitive CYP2C8 substrates. Check prescribing information of substrate if dosage modification is needed.

• opium tincture

  methadone and opium tincture both increase sedation. Use Caution/Monitor.

• orphenadrine

  orphenadrine and methadone both increase sedation. Use Caution/Monitor.

• osilodrostat

  osilodrostat and methadone both increase QTc interval. Use Caution/Monitor.

• osimertinib

  osimertinib and methadone both increase QTc interval. Use Caution/Monitor. Conduct periodic monitoring with ECGs and electrolytes in patients taking drugs known to prolong the QTc interval.

• oxaliplatin

  oxaliplatin will increase the level or effect of methadone by Other (see comment). Use Caution/Monitor. Monitor for ECG changes if therapy is initiated in patients with drugs known to prolong QT interval.

• oxazepam

  oxazepam and methadone both increase sedation. Use Caution/Monitor.

• oxcarbazepine

  oxcarbazepine will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• oxycodone

  methadone and oxycodone both increase sedation. Use Caution/Monitor.

• oxymorphone

  methadone and oxymorphone both increase sedation. Use Caution/Monitor.

• ozanimod

  ozanimod and methadone both increase QTc interval. Modify Therapy/Monitor Closely. The potential additive effects on heart rate, treatment with ozanimod should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties.

• paliperidone

  methadone and paliperidone both increase QTc interval. Use Caution/Monitor.
  
  methadone and paliperidone both increase sedation. Use Caution/Monitor.
  
  methadone, paliperidone. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• papaveretum

  methadone and papaveretum both increase sedation. Use Caution/Monitor.

• papaverine

  methadone and papaverine both increase sedation. Use Caution/Monitor.

• paroxetine

  methadone and paroxetine both increase QTc interval. Use Caution/Monitor.

• pasireotide

  methadone and pasireotide both increase QTc interval. Modify Therapy/Monitor Closely.

• peginterferon alfa 2b

  peginterferon alfa 2b will increase the level or effect of methadone by unknown mechanism. Use Caution/Monitor. Methadone levels may be elevated, increasing the pharmacologic effects and adverse reactions. Monitor patients for signs and symptoms of increased narcotic effects and adjust methadone dose as needed.

• pegvisomant

  methadone decreases effects of pegvisomant by unknown mechanism. Use Caution/Monitor.

• pentazocine

  methadone and pentazocine both increase sedation. Use Caution/Monitor.

• pentobarbital

  pentobarbital will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  pentobarbital and methadone both increase sedation. Use Caution/Monitor.

• perampanel

  perampanel and methadone both decrease sedation. Use Caution/Monitor.

• perphenazine

  perphenazine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and perphenazine both increase sedation. Use Caution/Monitor.
  
  methadone, perphenazine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• phendimetrazine

  methadone increases and phendimetrazine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• phenobarbital

  phenobarbital will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  phenobarbital and methadone both increase sedation. Use Caution/Monitor.

• phentermine

  methadone increases and phentermine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• phenylephrine

  methadone increases and phenylephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• phenylephrine PO

  methadone increases and phenylephrine PO decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor. .

• phenytoin

  phenytoin will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• pholcodine

  methadone and pholcodine both increase sedation. Use Caution/Monitor.

• pimavanserin

  methadone, pimavanserin. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• pimozide

  methadone and pimozide both increase sedation. Use Caution/Monitor.
  
  methadone, pimozide. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• pirbuterol

  methadone increases and pirbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• posaconazole

  posaconazole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  methadone and posaconazole both increase QTc interval. Use Caution/Monitor.

• prednisone

  prednisone will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• pregabalin

  pregabalin, methadone. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

• primidone

  primidone will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  primidone and methadone both increase sedation. Use Caution/Monitor.

• prochlorperazine

  prochlorperazine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and prochlorperazine both increase sedation. Use Caution/Monitor.

• promazine

  promazine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• promethazine

  promethazine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  promethazine and methadone both increase sedation. Use Caution/Monitor.

• propofol

  propofol and methadone both increase sedation. Use Caution/Monitor.

• propylhexedrine

  methadone increases and propylhexedrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• protriptyline

  protriptyline and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and protriptyline both increase sedation. Use Caution/Monitor.

• quazepam

  quazepam and methadone both increase sedation. Use Caution/Monitor.

• quetiapine

  methadone and quetiapine both increase sedation. Use Caution/Monitor.
  
  quetiapine, methadone. Either increases toxicity of the other by QTc interval. Use Caution/Monitor. Avoid use with drugs that prolong QT and in patients with risk factors for prolonged QT interval. Postmarketing cases show QT prolongation with overdose in patients with concomitant illness or with drugs known to cause electrolyte imbalance or prolong QT.
  
  methadone, quetiapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• quinine

  methadone and quinine both increase QTc interval. Use Caution/Monitor.

• quinupristin/dalfopristin

  quinupristin/dalfopristin will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• quizartinib

  quizartinib, methadone. Either increases effects of the other by QTc interval. Modify Therapy/Monitor Closely. Monitor patients more frequently with ECG if coadministered with QT prolonging drugs.

• ramelteon

  methadone and ramelteon both increase sedation. Use Caution/Monitor.

• ranolazine

  methadone and ranolazine both increase QTc interval. Use Caution/Monitor.

• remimazolam

  remimazolam, methadone. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely. Coadministration may result in profound sedation, respiratory depression, coma, and/or death. Continuously monitor vital signs during sedation and recovery period if coadministered. Carefully titrate remimazolam dose if administered with opioid analgesics and/or sedative/hypnotics.

• rifampin

  rifampin decreases levels of methadone by increasing metabolism. Use Caution/Monitor.

• rifapentine

  rifapentine will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• rilpivirine

  rilpivirine, methadone. Other (see comment). Use Caution/Monitor. Comment: No dose adjustments are required when initiating co-administration of methadone with rilpivirine. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.
  
  rilpivirine increases toxicity of methadone by QTc interval. Use Caution/Monitor. Rilpivirine should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.

• risperidone

  methadone and risperidone both increase QTc interval. Use Caution/Monitor.
  
  methadone and risperidone both increase sedation. Use Caution/Monitor.
  
  methadone, risperidone. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• ritonavir

  ritonavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  ritonavir decreases effects of methadone by Other (see comment). Use Caution/Monitor. Comment: Ritonavir may induce the metabolism of methadone and/or induce the p glycoprotein pathway that pumps drugs out of the CNS.

• rucaparib

  rucaparib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP3A4 substrates, if clinically indicated.

• rufinamide

  rufinamide will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• salmeterol

  methadone increases and salmeterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• schisandra

  schisandra will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• scullcap

  methadone and scullcap both increase sedation. Use Caution/Monitor.

• secobarbital

  secobarbital will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  secobarbital and methadone both increase sedation. Use Caution/Monitor.

• selpercatinib

  selpercatinib increases toxicity of methadone by QTc interval. Use Caution/Monitor.

• sevoflurane

  sevoflurane and methadone both increase sedation. Use Caution/Monitor.

• shepherd's purse

  methadone and shepherd's purse both increase sedation. Use Caution/Monitor.

• sodium sulfate/?magnesium sulfate/potassium chloride

  sodium sulfate/?magnesium sulfate/potassium chloride increases toxicity of methadone by QTc interval. Use Caution/Monitor. Consider predose and post-colonoscopy ECGs in patients at increased risk of serious cardiac arrhythmias. .

• sodium sulfate/potassium sulfate/magnesium sulfate

  sodium sulfate/potassium sulfate/magnesium sulfate increases toxicity of methadone by QTc interval. Use Caution/Monitor. Consider predose and post-colonoscopy ECGs in patients at increased risk of serious cardiac arrhythmias. .

• sorafenib

  sorafenib and methadone both increase QTc interval. Use Caution/Monitor.

• stiripentol

  stiripentol, methadone. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.
  
  stiripentol will increase the level or effect of methadone by Other (see comment). Modify Therapy/Monitor Closely. Stiripentol is a CYP2C8 inhibitor. Consider dosage reduction for CYP2C8 substrates if adverse effects are experienced when coadministered.
  
  stiripentol, methadone. Either increases effects of the other by sedation. Use Caution/Monitor. Concomitant use stiripentol with other CNS depressants, including alcohol, may increase the risk of sedation and somnolence.

• sufentanil

  methadone and sufentanil both increase sedation. Use Caution/Monitor.

• sulfamethoxazole

  sulfamethoxazole and methadone both increase QTc interval. Use Caution/Monitor.

• suvorexant

  suvorexant and methadone both increase sedation. Modify Therapy/Monitor Closely. Dosage adjustments of suvorexant and concomitant CNS depressants may be necessary

• tamsulosin

  methadone increases levels of tamsulosin by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

• tapentadol

  methadone and tapentadol both increase sedation. Use Caution/Monitor.

• tazemetostat

  tazemetostat will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  methadone will increase the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• tecovirimat

  tecovirimat will increase the level or effect of methadone by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. Tecovirimat is a weak inhibitor of CYP2C8 and CYP2C19. Monitor for adverse effects if coadministered with sensitive substrates of these enzymes.
  
  tecovirimat will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.

• telavancin

  methadone and telavancin both increase QTc interval. Use Caution/Monitor.

• temazepam

  temazepam and methadone both increase sedation. Use Caution/Monitor.

• terbutaline

  methadone increases and terbutaline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• teriflunomide

  teriflunomide increases levels of methadone by Other (see comment). Use Caution/Monitor. Comment: Teriflunomide inhibits CYP2C8; caution when coadministered with CYP2C8 substrates.

• thioridazine

  thioridazine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and thioridazine both increase sedation. Use Caution/Monitor.

• thiothixene

  methadone and thiothixene both increase sedation. Use Caution/Monitor.
  
  methadone, thiothixene. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• tinidazole

  methadone will increase the level or effect of tinidazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• tipranavir

  tipranavir decreases levels of methadone by increasing metabolism. Use Caution/Monitor.
  
  tipranavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• topiramate

  topiramate will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  methadone and topiramate both increase sedation. Modify Therapy/Monitor Closely.

• tramadol

  methadone and tramadol both increase sedation. Use Caution/Monitor.

• trazodone

  trazodone and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and trazodone both increase sedation. Use Caution/Monitor.

• triazolam

  triazolam and methadone both increase sedation. Use Caution/Monitor.

• triclabendazole

  triclabendazole and methadone both increase QTc interval. Use Caution/Monitor.

• triclofos

  triclofos and methadone both increase sedation. Use Caution/Monitor.

• trifluoperazine

  trifluoperazine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and trifluoperazine both increase sedation. Use Caution/Monitor.
  
  methadone, trifluoperazine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• trimethoprim

  methadone and trimethoprim both increase QTc interval. Use Caution/Monitor.

• trimipramine

  trimipramine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and trimipramine both increase sedation. Use Caution/Monitor.

• triprolidine

  triprolidine and methadone both increase sedation. Use Caution/Monitor.

• triptorelin

  triptorelin increases toxicity of methadone by QTc interval. Use Caution/Monitor. Increases risk of torsades de pointes.

• tropisetron

  methadone and tropisetron both increase QTc interval. Use Caution/Monitor.

• valbenazine

  valbenazine and methadone both increase QTc interval. Use Caution/Monitor.

• venlafaxine

  methadone and venlafaxine both increase QTc interval. Use Caution/Monitor.

• verapamil

  verapamil will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• voclosporin

  voclosporin, methadone. Either increases effects of the other by QTc interval. Use Caution/Monitor.

• voriconazole

  voriconazole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed.
  
  methadone and voriconazole both increase QTc interval. Use Caution/Monitor.

• xylometazoline

  methadone increases and xylometazoline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• yohimbine

  methadone increases and yohimbine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• zafirlukast

  zafirlukast will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• ziconotide

  methadone and ziconotide both increase sedation. Use Caution/Monitor.

• ziprasidone

  methadone and ziprasidone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and ziprasidone both increase sedation. Use Caution/Monitor.
  
  methadone, ziprasidone. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• zotepine

  methadone and zotepine both increase sedation. Use Caution/Monitor.

Minor (17)

• acetazolamide

  acetazolamide will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• anastrozole

  anastrozole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• azithromycin

  azithromycin and methadone both increase QTc interval. Minor/Significance Unknown.

• brimonidine

  brimonidine increases effects of methadone by pharmacodynamic synergism. Minor/Significance Unknown. Increased CNS depression.

• cyclophosphamide

  cyclophosphamide will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• dextroamphetamine

  dextroamphetamine increases effects of methadone by unspecified interaction mechanism. Minor/Significance Unknown.

• drospirenone

  drospirenone will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• eucalyptus

  methadone and eucalyptus both increase sedation. Minor/Significance Unknown.

• lidocaine

  lidocaine increases toxicity of methadone by pharmacodynamic synergism. Minor/Significance Unknown. Risk of increased CNS depression.

• octreotide

  octreotide decreases levels of methadone by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

• octreotide (Antidote)

  octreotide (Antidote) decreases levels of methadone by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

• pazopanib

  methadone and pazopanib both increase QTc interval. Minor/Significance Unknown.

• ruxolitinib

  methadone will increase the level or effect of ruxolitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• ruxolitinib topical

  methadone will increase the level or effect of ruxolitinib topical by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• sage

  methadone and sage both increase sedation. Minor/Significance Unknown.

• ziconotide

  ziconotide, methadone. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Additive decreased GI motility. Additive analgesia. Ziconotide does NOT potentiate opioid induced respiratory depression.

• zidovudine

  methadone increases levels of zidovudine by decreasing renal clearance. Minor/Significance Unknown.

• abacavir

  Monitor Closely (1)abacavir will decrease the level or effect of methadone by unknown mechanism. Use Caution/Monitor. Monitor for opioid withdrawal symptoms.

• acetazolamide

  Minor (1)acetazolamide will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• acrivastine

  Serious - Use Alternative (1)acrivastine and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• adagrasib

  Serious - Use Alternative (1)adagrasib, methadone. Either increases effects of the other by QTc interval. Avoid or Use Alternate Drug. Each drug prolongs the QTc interval, which may increased the risk of Torsade de pointes, other serious arryhthmias, and sudden death. If coadministration unavoidable, more frequent monitoring is recommended for such patients.

• albuterol

  Monitor Closely (2)methadone increases and albuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.
  
  albuterol and methadone both increase QTc interval. Use Caution/Monitor.

• alfentanil

  Monitor Closely (1)alfentanil and methadone both increase sedation. Use Caution/Monitor.

• alfuzosin

  Monitor Closely (1)methadone and alfuzosin both increase QTc interval. Use Caution/Monitor.Serious - Use Alternative (1)alfuzosin and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• alprazolam

  Monitor Closely (1)alprazolam and methadone both increase sedation. Use Caution/Monitor.

• alvimopan

  Contraindicated (1)alvimopan, methadone. receptor binding competition. Contraindicated. Alvimopan is contraindicated in opioid tolerant patients (ie, those who have taken therapeutic doses of opioids for >7 consecutive days immediately prior to taking alvimopan). Patients recently exposed to opioids are expected to be more sensitive to the effects of alvimopan and therefore may experience abdominal pain, nausea and vomiting, and diarrhea. No significant interaction is expected with concurrent use of opioid analgesics and alvimopan in patients who received opioid analgesics for 7 or fewer consecutive days prior to alvimopan.

• amiodarone

  Serious - Use Alternative (1)amiodarone and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• amisulpride

  Serious - Use Alternative (2)amisulpride and methadone both increase QTc interval. Avoid or Use Alternate Drug. ECG monitoring is recommended if coadministered.
  
  amisulpride and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• amitriptyline

  Monitor Closely (2)amitriptyline and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and amitriptyline both increase sedation. Use Caution/Monitor.

• amobarbital

  Monitor Closely (2)amobarbital will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  amobarbital and methadone both increase sedation. Use Caution/Monitor.

• amoxapine

  Monitor Closely (2)amoxapine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and amoxapine both increase sedation. Use Caution/Monitor.

• anagrelide

  Serious - Use Alternative (1)anagrelide and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• anastrozole

  Minor (1)anastrozole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• apalutamide

  Serious - Use Alternative (1)apalutamide will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.

• apomorphine

  Monitor Closely (1)methadone and apomorphine both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)apomorphine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• aprepitant

  Monitor Closely (1)aprepitant will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• arformoterol

  Monitor Closely (2)methadone increases and arformoterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.
  
  arformoterol and methadone both increase QTc interval. Use Caution/Monitor.

• aripiprazole

  Monitor Closely (2)methadone, aripiprazole. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).
  
  methadone and aripiprazole both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)aripiprazole and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• armodafinil

  Monitor Closely (2)armodafinil will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  methadone increases and armodafinil decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• arsenic trioxide

  Serious - Use Alternative (1)arsenic trioxide and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• artemether

  Serious - Use Alternative (1)artemether and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• artemether/lumefantrine

  Monitor Closely (2)artemether/lumefantrine will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  artemether/lumefantrine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• asenapine

  Monitor Closely (1)methadone, asenapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).Serious - Use Alternative (2)asenapine and methadone both increase QTc interval. Avoid or Use Alternate Drug.
  
  asenapine and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• asenapine transdermal

  Monitor Closely (1)asenapine transdermal and methadone both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)asenapine transdermal and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• atazanavir

  Monitor Closely (1)atazanavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• atogepant

  Monitor Closely (1)methadone will increase the level or effect of atogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• atomoxetine

  Serious - Use Alternative (1)atomoxetine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• avapritinib

  Monitor Closely (1)methadone will increase the level or effect of avapritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.Serious - Use Alternative (1)avapritinib and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• axitinib

  Monitor Closely (1)methadone increases levels of axitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• azelastine

  Monitor Closely (1)azelastine and methadone both increase sedation. Use Caution/Monitor.

• azithromycin

  Minor (1)azithromycin and methadone both increase QTc interval. Minor/Significance Unknown.

• baclofen

  Monitor Closely (1)baclofen and methadone both increase sedation. Use Caution/Monitor.

• bedaquiline

  Monitor Closely (1)methadone and bedaquiline both increase QTc interval. Modify Therapy/Monitor Closely. ECG should be monitored closely

• belladonna and opium

  Monitor Closely (1)methadone and belladonna and opium both increase sedation. Use Caution/Monitor.

• benperidol

  Monitor Closely (1)methadone and benperidol both increase sedation. Use Caution/Monitor.

• benzhydrocodone/acetaminophen

  Serious - Use Alternative (2)benzhydrocodone/acetaminophen, methadone. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.
  
  benzhydrocodone/acetaminophen and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• benzphetamine

  Monitor Closely (1)methadone increases and benzphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• bosentan

  Monitor Closely (1)bosentan will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• bosutinib

  Monitor Closely (1)bosutinib and methadone both increase QTc interval. Use Caution/Monitor.

• bremelanotide

  Serious - Use Alternative (1)bremelanotide will decrease the level or effect of methadone by Other (see comment). Avoid or Use Alternate Drug. Bremelanotide may slow gastric emptying and potentially reduces the rate and extent of absorption of concomitantly administered oral medications. Avoid use when taking any oral drug that is dependent on threshold concentrations for efficacy. Interactions listed are representative examples and do not include all possible clinical examples.

• brexanolone

  Monitor Closely (1)brexanolone, methadone. Either increases toxicity of the other by sedation. Use Caution/Monitor.

• brexpiprazole

  Monitor Closely (1)methadone will increase the level or effect of brexpiprazole by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Administer a quarter of brexpiprazole dose if coadministered with a moderate CYP2D6 inhibitor PLUS a strong/moderate CYP3A4 inhibitor.Serious - Use Alternative (1)brexpiprazole and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• brimonidine

  Serious - Use Alternative (1)brimonidine and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequateMinor (1)brimonidine increases effects of methadone by pharmacodynamic synergism. Minor/Significance Unknown. Increased CNS depression.

• brivaracetam

  Serious - Use Alternative (1)brivaracetam and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• brompheniramine

  Monitor Closely (1)brompheniramine and methadone both increase sedation. Use Caution/Monitor.

• budesonide

  Monitor Closely (1)budesonide will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• buprenorphine

  Monitor Closely (1)buprenorphine and methadone both increase sedation. Use Caution/Monitor.Serious - Use Alternative (2)buprenorphine, methadone. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.
  
  buprenorphine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• buprenorphine buccal

  Monitor Closely (1)buprenorphine buccal and methadone both increase sedation. Use Caution/Monitor.Serious - Use Alternative (2)buprenorphine buccal, methadone. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.
  
  buprenorphine buccal and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• buprenorphine subdermal implant

  Serious - Use Alternative (2)buprenorphine subdermal implant and methadone both increase QTc interval. Avoid or Use Alternate Drug.
  
  buprenorphine subdermal implant and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• buprenorphine transdermal

  Serious - Use Alternative (2)buprenorphine transdermal and methadone both increase QTc interval. Avoid or Use Alternate Drug.
  
  buprenorphine transdermal and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• buprenorphine, long-acting injection

  Monitor Closely (1)methadone increases toxicity of buprenorphine, long-acting injection by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of buprenorphine and benzodiazepines or other CNS depressants increases risk of adverse reactions including overdose, respiratory depression, and death. Cessation of benzodiazepines or other CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering CNS depressants may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.Serious - Use Alternative (2)buprenorphine, long-acting injection and methadone both increase QTc interval. Avoid or Use Alternate Drug.
  
  buprenorphine, long-acting injection and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• butabarbital

  Monitor Closely (2)butabarbital will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  butabarbital and methadone both increase sedation. Use Caution/Monitor.

• butalbital

  Monitor Closely (2)butalbital will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  butalbital and methadone both increase sedation. Use Caution/Monitor.

• butorphanol

  Monitor Closely (1)butorphanol and methadone both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)butorphanol, methadone. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

• caffeine

  Monitor Closely (1)methadone increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• calcium/magnesium/potassium/sodium oxybates

  Serious - Use Alternative (1)methadone, calcium/magnesium/potassium/sodium oxybates. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• cannabidiol

  Monitor Closely (1)cannabidiol will increase the level or effect of methadone by decreasing metabolism. Modify Therapy/Monitor Closely. Cannabidiol may potentially inhibit CYP2C8 activity. Consider reducing the dose when concomitantly using CYP2C8 substrates.

• capecitabine

  Monitor Closely (1)capecitabine and methadone both increase QTc interval. Use Caution/Monitor.

• carbamazepine

  Serious - Use Alternative (1)carbamazepine will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• carbinoxamine

  Monitor Closely (1)carbinoxamine and methadone both increase sedation. Use Caution/Monitor.

• cariprazine

  Monitor Closely (1)methadone, cariprazine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).Serious - Use Alternative (1)cariprazine and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• carisoprodol

  Monitor Closely (1)carisoprodol and methadone both increase sedation. Use Caution/Monitor.

• cenobamate

  Monitor Closely (1)cenobamate will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase dose of CYP3A4 substrate, as needed, when coadministered with cenobamate.

• ceritinib

  Serious - Use Alternative (2)ceritinib and methadone both increase QTc interval. Avoid or Use Alternate Drug.
  
  ceritinib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• chloral hydrate

  Monitor Closely (1)chloral hydrate and methadone both increase sedation. Use Caution/Monitor.

• chlordiazepoxide

  Monitor Closely (1)chlordiazepoxide and methadone both increase sedation. Use Caution/Monitor.

• chloroquine

  Serious - Use Alternative (1)chloroquine increases toxicity of methadone by QTc interval. Avoid or Use Alternate Drug.

• chlorpheniramine

  Monitor Closely (1)chlorpheniramine and methadone both increase sedation. Use Caution/Monitor.

• chlorpromazine

  Monitor Closely (2)chlorpromazine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and chlorpromazine both increase sedation. Use Caution/Monitor.

• chlorzoxazone

  Monitor Closely (1)chlorzoxazone and methadone both increase sedation. Use Caution/Monitor.

• cimetidine

  Serious - Use Alternative (2)cimetidine will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
  
  cimetidine increases effects of methadone by decreasing metabolism. Avoid or Use Alternate Drug.

• cinnarizine

  Monitor Closely (1)cinnarizine and methadone both increase sedation. Use Caution/Monitor.

• ciprofloxacin

  Monitor Closely (1)ciprofloxacin and methadone both increase QTc interval. Use Caution/Monitor. Ciprofloxacin elicits minimal effects on QT interval. Caution if used in combination with other drugs known to affect QT interval or in patients with other risk factors.

• citalopram

  Monitor Closely (1)methadone and citalopram both increase QTc interval. Use Caution/Monitor. Combination may increase risk of serotonin syndrome or neuroleptic malignant syndrome like reactions. ECG monitoring is recommended, along with drugs that may prolong the QT interval.

• clarithromycin

  Monitor Closely (1)clarithromycin and methadone both increase QTc interval. Modify Therapy/Monitor Closely.Serious - Use Alternative (1)clarithromycin will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• clemastine

  Monitor Closely (1)clemastine and methadone both increase sedation. Use Caution/Monitor.

• clobazam

  Monitor Closely (1)methadone, clobazam. Other (see comment). Use Caution/Monitor. Comment: Concomitant administration can increase the potential for CNS effects (e.g., increased sedation or respiratory depression).

• clomipramine

  Monitor Closely (2)clomipramine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and clomipramine both increase sedation. Use Caution/Monitor.

• clonazepam

  Monitor Closely (1)clonazepam and methadone both increase sedation. Use Caution/Monitor.

• clonidine

  Serious - Use Alternative (1)clonidine, methadone. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration enhances CNS depressant effects.

• clorazepate

  Monitor Closely (1)clorazepate and methadone both increase sedation. Use Caution/Monitor.

• clozapine

  Monitor Closely (2)methadone, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).
  
  methadone and clozapine both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)clozapine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• cobicistat

  Monitor Closely (1)cobicistat will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Methadone dose may require an adjustment

• codeine

  Monitor Closely (1)codeine and methadone both increase sedation. Use Caution/Monitor.

• conivaptan

  Monitor Closely (1)conivaptan will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• cortisone

  Monitor Closely (1)cortisone will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• crizotinib

  Monitor Closely (1)crizotinib increases levels of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A. ECG monitoring is recommended, along with drugs that may prolong the QT interval.Serious - Use Alternative (1)crizotinib and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• crofelemer

  Monitor Closely (1)crofelemer increases levels of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Crofelemer has the potential to inhibit CYP3A4 at concentrations expected in the gut; unlikely to inhibit systemically because minimally absorbed.

• cyclizine

  Monitor Closely (1)cyclizine and methadone both increase sedation. Use Caution/Monitor.

• cyclobenzaprine

  Monitor Closely (1)cyclobenzaprine and methadone both increase sedation. Use Caution/Monitor.

• cyclophosphamide

  Minor (1)cyclophosphamide will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• cyclosporine

  Monitor Closely (1)cyclosporine will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• cyproheptadine

  Monitor Closely (1)cyproheptadine and methadone both increase sedation. Use Caution/Monitor.

• dabrafenib

  Monitor Closely (1)dabrafenib will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

• danazol

  Monitor Closely (1)danazol will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• dantrolene

  Monitor Closely (1)dantrolene and methadone both increase sedation. Use Caution/Monitor.

• daridorexant

  Monitor Closely (1)methadone and daridorexant both increase sedation. Modify Therapy/Monitor Closely. Coadministration increases risk of CNS depression, which can lead to additive impairment of psychomotor performance and cause daytime impairment.

• darifenacin

  Monitor Closely (1)darifenacin will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• darunavir

  Monitor Closely (1)darunavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Carefully titrate dose when initiating buprenorphine, buprenorphine/naloxone, or methadone with patients taking darunavir/cobicstat. When initiating cobicistat in patients taking buprenorphine, buprenorphine/naloxone, or methadone, adjust dose for buprenorphine, buprenorphine/naloxone, or methadone and monitor clinical signs and symptoms.

• dasatinib

  Monitor Closely (2)dasatinib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  dasatinib and methadone both increase QTc interval. Use Caution/Monitor.

• deferasirox

  Monitor Closely (1)deferasirox will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• degarelix

  Serious - Use Alternative (1)degarelix and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• desflurane

  Monitor Closely (1)desflurane and methadone both increase sedation. Use Caution/Monitor. Opioids may decrease MAC requirements, less inhalation anesthetic may be required.

• desipramine

  Monitor Closely (2)desipramine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and desipramine both increase sedation. Use Caution/Monitor.

• deutetrabenazine

  Monitor Closely (2)methadone and deutetrabenazine both increase sedation. Use Caution/Monitor.
  
  deutetrabenazine and methadone both increase QTc interval. Use Caution/Monitor. At the maximum recommended dose, deutetrabenazine does not prolong QT interval to a clinically relevant extent. Certain circumstances may increase risk of torsade de pointes and/or sudden death in association with drugs that prolong the QTc interval (eg, bradycardia, hypokalemia or hypomagnesemia, coadministration with other drugs that prolong QTc interval, presence of congenital QT prolongation).

• dexamethasone

  Monitor Closely (1)dexamethasone will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• dexchlorpheniramine

  Monitor Closely (1)dexchlorpheniramine and methadone both increase sedation. Use Caution/Monitor.

• dexfenfluramine

  Monitor Closely (1)methadone increases and dexfenfluramine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dexmedetomidine

  Monitor Closely (1)dexmedetomidine and methadone both increase sedation. Use Caution/Monitor.

• dexmethylphenidate

  Monitor Closely (1)methadone increases and dexmethylphenidate decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dextroamphetamine

  Monitor Closely (1)methadone increases and dextroamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.Minor (1)dextroamphetamine increases effects of methadone by unspecified interaction mechanism. Minor/Significance Unknown.

• dextromoramide

  Monitor Closely (1)dextromoramide and methadone both increase sedation. Use Caution/Monitor.

• DHEA, herbal

  Monitor Closely (1)DHEA, herbal will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• diamorphine

  Monitor Closely (1)diamorphine and methadone both increase sedation. Use Caution/Monitor.

• diazepam

  Monitor Closely (1)diazepam and methadone both increase sedation. Use Caution/Monitor.

• diazepam intranasal

  Serious - Use Alternative (1)diazepam intranasal, methadone. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• dichlorphenamide

  Monitor Closely (1)dichlorphenamide and methadone both decrease serum potassium. Use Caution/Monitor.

• didanosine

  Monitor Closely (1)methadone decreases levels of didanosine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

• diethylpropion

  Monitor Closely (1)methadone increases and diethylpropion decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• difelikefalin

  Monitor Closely (1)difelikefalin and methadone both increase sedation. Use Caution/Monitor.

• difenoxin hcl

  Monitor Closely (1)difenoxin hcl and methadone both increase sedation. Use Caution/Monitor.

• diltiazem

  Monitor Closely (1)diltiazem will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• dimenhydrinate

  Monitor Closely (1)dimenhydrinate and methadone both increase sedation. Use Caution/Monitor.

• diphenhydramine

  Monitor Closely (1)diphenhydramine and methadone both increase sedation. Use Caution/Monitor.

• diphenoxylate hcl

  Monitor Closely (1)diphenoxylate hcl and methadone both increase sedation. Use Caution/Monitor.

• dipipanone

  Monitor Closely (1)dipipanone and methadone both increase sedation. Use Caution/Monitor.

• disopyramide

  Serious - Use Alternative (1)disopyramide and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• dobutamine

  Monitor Closely (1)methadone increases and dobutamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dofetilide

  Monitor Closely (1)dofetilide and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• dolasetron

  Monitor Closely (1)dolasetron and methadone both increase QTc interval. Use Caution/Monitor.

• donepezil

  Serious - Use Alternative (1)donepezil and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• dopamine

  Monitor Closely (1)methadone increases and dopamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dopexamine

  Monitor Closely (1)methadone increases and dopexamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dosulepin

  Monitor Closely (1)methadone and dosulepin both increase sedation. Use Caution/Monitor.

• doxepin

  Monitor Closely (2)doxepin and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and doxepin both increase sedation. Use Caution/Monitor.

• doxylamine

  Monitor Closely (1)doxylamine and methadone both increase sedation. Use Caution/Monitor.

• dronedarone

  Monitor Closely (2)dronedarone will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  dronedarone and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• droperidol

  Monitor Closely (2)droperidol and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and droperidol both increase sedation. Use Caution/Monitor.

• drospirenone

  Minor (1)drospirenone will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• duvelisib

  Monitor Closely (1)duvelisib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration with duvelisib increases AUC of a sensitive CYP3A4 substrate which may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the coadministered sensitive CYP3A substrate.

• efavirenz

  Monitor Closely (1)efavirenz will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.Serious - Use Alternative (1)efavirenz and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• elagolix

  Monitor Closely (1)elagolix decreases levels of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.

• eliglustat

  Contraindicated (1)methadone increases levels of eliglustat by affecting hepatic enzyme CYP2D6 metabolism. Contraindicated. If coadministered with strong or moderate CYP2D6 inhibitors, reduce eliglustat dose from 84 mg BID to 84 mg once daily in extensive and intermediate metabolizers; eliglustat is contraindiated if strong or moderate CYP2D6 inhibitors are given concomitantly with strong or moderate CYP3A inhibitors.Serious - Use Alternative (1)eliglustat and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• eltrombopag

  Monitor Closely (1)eltrombopag increases levels of methadone by decreasing metabolism. Use Caution/Monitor. UGT inhibition; significance of interaction unclear.

• eluxadoline

  Serious - Use Alternative (1)methadone, eluxadoline. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Avoid coadministration with other drugs that cause constipation. Increases risk for constipation related serious adverse reactions. .

• elvitegravir

  Monitor Closely (1)elvitegravir decreases levels of methadone by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Dosage of methadone may need to be increased.

• elvitegravir/cobicistat/emtricitabine/tenofovir DF

  Monitor Closely (1)elvitegravir/cobicistat/emtricitabine/tenofovir DF increases levels of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Cobicistat is a CYP3A4 inhibitor; contraindicated with CYP3A4 substrates for which elevated plasma concentrations are associated with serious and/or life-threatening events.

• encorafenib

  Monitor Closely (1)encorafenib, methadone. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Encorafenib both inhibits and induces CYP3A4 at clinically relevant plasma concentrations. Coadministration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.Serious - Use Alternative (1)encorafenib and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• entrectinib

  Serious - Use Alternative (1)methadone and entrectinib both increase QTc interval. Avoid or Use Alternate Drug.

• enzalutamide

  Serious - Use Alternative (1)enzalutamide will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• ephedrine

  Monitor Closely (1)methadone increases and ephedrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• epinephrine

  Monitor Closely (2)epinephrine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone increases and epinephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• epinephrine racemic

  Monitor Closely (2)epinephrine racemic and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone increases and epinephrine racemic decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• eribulin

  Serious - Use Alternative (1)eribulin and methadone both increase QTc interval. Avoid or Use Alternate Drug. Potential for enhanced QTc-prolonging effects; if concurrent use is necessary then ECG monitoring is recommended.

• erythromycin base

  Monitor Closely (1)erythromycin base and methadone both increase QTc interval. Modify Therapy/Monitor Closely.Serious - Use Alternative (1)erythromycin base will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• erythromycin ethylsuccinate

  Monitor Closely (1)erythromycin ethylsuccinate and methadone both increase QTc interval. Modify Therapy/Monitor Closely.Serious - Use Alternative (1)erythromycin ethylsuccinate will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• erythromycin lactobionate

  Monitor Closely (1)erythromycin lactobionate and methadone both increase QTc interval. Modify Therapy/Monitor Closely.Serious - Use Alternative (1)erythromycin lactobionate will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• erythromycin stearate

  Monitor Closely (1)erythromycin stearate and methadone both increase QTc interval. Modify Therapy/Monitor Closely.Serious - Use Alternative (1)erythromycin stearate will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• escitalopram

  Serious - Use Alternative (1)escitalopram increases toxicity of methadone by QTc interval. Avoid or Use Alternate Drug.

• esketamine intranasal

  Monitor Closely (1)esketamine intranasal, methadone. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely.

• eslicarbazepine acetate

  Monitor Closely (1)eslicarbazepine acetate will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• estazolam

  Monitor Closely (1)estazolam and methadone both increase sedation. Use Caution/Monitor.

• ethanol

  Monitor Closely (1)methadone and ethanol both increase sedation. Use Caution/Monitor.

• ethotoin

  Serious - Use Alternative (1)ethotoin decreases levels of methadone by increasing metabolism. Contraindicated.

• etomidate

  Monitor Closely (1)etomidate and methadone both increase sedation. Use Caution/Monitor.

• etrasimod

  Monitor Closely (1)etrasimod, methadone. Either increases effects of the other by QTc interval. Modify Therapy/Monitor Closely. Transient decrease in heart rate and AV conduction delays may occur when initiating etrasimod. Owing to potential of additive effect on heart rate, etrasimod may increase risk of QT prolongation and Torsades de Pointes when coadministered with Class Ia or Class III antiarrhythmic drugs, or other drugs that prolong the QT interval. .

• etravirine

  Monitor Closely (1)etravirine will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• eucalyptus

  Minor (1)methadone and eucalyptus both increase sedation. Minor/Significance Unknown.

• ezogabine

  Monitor Closely (1)ezogabine, methadone. Either increases toxicity of the other by QTc interval. Use Caution/Monitor. Slight and transient QT-prolongation observed with ezogabine, particularly when dose titrated to 1200 mg/day. QT interval should be monitored when ezogabine is prescribed with agents known to increase QT interval.

• fedratinib

  Monitor Closely (1)fedratinib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.

• fenfluramine

  Monitor Closely (1)methadone increases and fenfluramine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• fentanyl

  Serious - Use Alternative (2)fentanyl, methadone. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.
  
  fentanyl and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• fentanyl intranasal

  Serious - Use Alternative (2)fentanyl intranasal, methadone. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.
  
  fentanyl intranasal and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• fentanyl iontophoretic transdermal system

  Serious - Use Alternative (1)fentanyl iontophoretic transdermal system and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• fentanyl transdermal

  Serious - Use Alternative (2)fentanyl transdermal, methadone. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.
  
  fentanyl transdermal and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• fentanyl transmucosal

  Serious - Use Alternative (2)fentanyl transmucosal, methadone. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.
  
  fentanyl transmucosal and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• fexinidazole

  Serious - Use Alternative (2)fexinidazole and methadone both increase QTc interval. Avoid or Use Alternate Drug. Avoid coadministration of fexinidazole with drugs known to block potassium channels and/or prolong QT interval.
  
  fexinidazole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.

• finerenone

  Monitor Closely (1)methadone will increase the level or effect of finerenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor serum potassium during initiation and dosage adjustment of either finererone or weak CYP3A4 inhibitors. Adjust finererone dosage as needed.

• fingolimod

  Serious - Use Alternative (1)fingolimod and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• flecainide

  Monitor Closely (1)flecainide and methadone both increase QTc interval. Use Caution/Monitor.

• flibanserin

  Monitor Closely (2)methadone will increase the level or effect of flibanserin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Increased flibanserin adverse effects may occur if coadministered with multiple weak CYP3A4 inhibitors.
  
  methadone and flibanserin both increase sedation. Modify Therapy/Monitor Closely. Risk for sedation increased if flibanserin is coadministration with other CNS depressants.

• floxuridine

  Monitor Closely (1)floxuridine and methadone both increase QTc interval. Use Caution/Monitor.

• fluconazole

  Monitor Closely (2)fluconazole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  fluconazole and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• fludrocortisone

  Monitor Closely (1)fludrocortisone will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• fluoxetine

  Monitor Closely (1)fluoxetine and methadone both increase QTc interval. Use Caution/Monitor.

• fluphenazine

  Monitor Closely (3)methadone, fluphenazine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).
  
  fluphenazine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and fluphenazine both increase sedation. Use Caution/Monitor.

• flurazepam

  Monitor Closely (1)flurazepam and methadone both increase sedation. Use Caution/Monitor.

• fluvoxamine

  Monitor Closely (1)fluvoxamine and methadone both increase QTc interval. Use Caution/Monitor.

• formoterol

  Monitor Closely (2)formoterol and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone increases and formoterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• fosamprenavir

  Monitor Closely (1)fosamprenavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• fosaprepitant

  Monitor Closely (1)fosaprepitant will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• foscarnet

  Monitor Closely (1)foscarnet and methadone both increase QTc interval. Use Caution/Monitor.

• fosphenytoin

  Monitor Closely (1)fosphenytoin will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.Serious - Use Alternative (1)fosphenytoin decreases levels of methadone by increasing metabolism. Contraindicated.

• gabapentin

  Monitor Closely (1)gabapentin, methadone. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

• gabapentin enacarbil

  Monitor Closely (1)gabapentin enacarbil, methadone. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

• gadobenate

  Serious - Use Alternative (1)gadobenate and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• ganaxolone

  Monitor Closely (1)methadone and ganaxolone both increase sedation. Use Caution/Monitor.

• gemifloxacin

  Serious - Use Alternative (1)gemifloxacin and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• gemtuzumab

  Monitor Closely (1)methadone and gemtuzumab both increase QTc interval. Use Caution/Monitor.

• gepirone

  Monitor Closely (1)gepirone and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• gilteritinib

  Serious - Use Alternative (1)gilteritinib and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• givinostat

  Serious - Use Alternative (1)methadone and givinostat both increase QTc interval. Avoid or Use Alternate Drug. If unable to avoid coadministration, obtain ECGs when initiating, during concomitant use, and as clinically indicated. Withhold if QTc interval >500 ms or a change from baseline >60 ms.

• glasdegib

  Serious - Use Alternative (1)methadone and glasdegib both increase QTc interval. Avoid or Use Alternate Drug. If coadministration unavoidable, monitor for increased risk of QTc interval prolongation.

• goserelin

  Monitor Closely (1)goserelin increases toxicity of methadone by QTc interval. Use Caution/Monitor. Increases risk of torsades de pointes.

• granisetron

  Serious - Use Alternative (1)granisetron and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• grapefruit

  Monitor Closely (1)grapefruit will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• griseofulvin

  Monitor Closely (1)griseofulvin will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• haloperidol

  Monitor Closely (3)methadone, haloperidol. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).
  
  haloperidol and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and haloperidol both increase sedation. Use Caution/Monitor.

• histrelin

  Monitor Closely (1)histrelin increases toxicity of methadone by QTc interval. Use Caution/Monitor. Increases risk of torsades de pointes.

• hydrocodone

  Serious - Use Alternative (1)hydrocodone, methadone. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• hydrocortisone

  Monitor Closely (1)hydrocortisone will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• hydromorphone

  Monitor Closely (1)hydromorphone and methadone both increase sedation. Use Caution/Monitor.

• hydroxychloroquine sulfate

  Serious - Use Alternative (1)hydroxychloroquine sulfate and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• hydroxyzine

  Monitor Closely (2)hydroxyzine increases toxicity of methadone by QTc interval. Use Caution/Monitor. Increases risk of torsades de pointes.
  
  hydroxyzine and methadone both increase sedation. Use Caution/Monitor.

• ibutilide

  Serious - Use Alternative (1)ibutilide and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• idelalisib

  Serious - Use Alternative (1)idelalisib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Idelalisib is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates

• iloperidone

  Monitor Closely (4)methadone, iloperidone. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).
  
  iloperidone and methadone both increase QTc interval. Use Caution/Monitor.
  
  methadone and iloperidone both increase sedation. Use Caution/Monitor.
  
  iloperidone increases levels of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Iloperidone is a time-dependent CYP3A inhibitor and may lead to increased plasma levels of drugs predominantly eliminated by CYP3A4.

• imipramine

  Monitor Closely (2)imipramine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and imipramine both increase sedation. Use Caution/Monitor.

• indacaterol, inhaled

  Monitor Closely (1)indacaterol, inhaled, methadone. QTc interval. Use Caution/Monitor. Drugs that are known to prolong the QTc interval may have an increased the risk of ventricular arrhythmias.

• indapamide

  Serious - Use Alternative (1)indapamide and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• indinavir

  Monitor Closely (1)indinavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• inotuzumab

  Serious - Use Alternative (1)inotuzumab and methadone both increase QTc interval. Avoid or Use Alternate Drug. If unable to avoid concomitant use, obtain ECGs and electrolytes before and after initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during treatment.

• isavuconazonium sulfate

  Monitor Closely (1)methadone will increase the level or effect of isavuconazonium sulfate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• isocarboxazid

  Serious - Use Alternative (1)isocarboxazid increases toxicity of methadone by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

• isoflurane

  Serious - Use Alternative (1)isoflurane and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• isoniazid

  Monitor Closely (1)isoniazid will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• isoproterenol

  Monitor Closely (1)methadone increases and isoproterenol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• istradefylline

  Monitor Closely (1)istradefylline will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.

• itraconazole

  Contraindicated (1)itraconazole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred in patients using methadone concomitantly with oral itraconazole and/or other CYP3A4 inhibitors.

• ivosidenib

  Serious - Use Alternative (2)ivosidenib and methadone both increase QTc interval. Avoid or Use Alternate Drug. Avoid coadministration of QTc prolonging drugs with ivosidenib or replace with alternate therapies. If coadministration of a QTc prolonging drug is unavoidable, monitor for increased risk of QTc interval prolongation.
  
  ivosidenib will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP3A4 substrates with ivosidenib or replace with alternative therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.

• ketamine

  Monitor Closely (1)ketamine and methadone both increase sedation. Use Caution/Monitor.

• ketoconazole

  Contraindicated (2)ketoconazole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
  
  ketoconazole and methadone both increase QTc interval. Contraindicated.

• ketotifen, ophthalmic

  Monitor Closely (1)methadone and ketotifen, ophthalmic both increase sedation. Use Caution/Monitor.

• lapatinib

  Monitor Closely (2)lapatinib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  lapatinib and methadone both increase QTc interval. Use Caution/Monitor.

• larotrectinib

  Monitor Closely (1)larotrectinib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• lasmiditan

  Monitor Closely (1)lasmiditan, methadone. Either increases effects of the other by sedation. Use Caution/Monitor. Coadministration of lasmiditan and other CNS depressant drugs, including alcohol have not been evaluated in clinical studies. Lasmiditan may cause sedation, as well as other cognitive and/or neuropsychiatric adverse reactions.

• lefamulin

  Contraindicated (1)lefamulin will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Lefamulin is contraindicated with CYP3A substrates know to prolong the QT interval.

• lemborexant

  Monitor Closely (2)methadone will increase the level or effect of lemborexant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Lower nightly dose of lemborexant recommended if coadministered with weak CYP3A4 inhibitors. See drug monograph for specific dosage modification.
  
  lemborexant, methadone. Either increases effects of the other by sedation. Modify Therapy/Monitor Closely. Dosage adjustment may be necessary if lemborexant is coadministered with other CNS depressants because of potentially additive effects.

• lenacapavir

  Monitor Closely (1)lenacapavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When initiating methadone while on lenacapavir, use lowest feasible initial or maintenance dose of methadone and carefully titrate dose to desired effect. When initiating lenacapavir while taking methadone, consider adjusting dose for methadone. Monitor clinical signs and symptoms.

• lenvatinib

  Monitor Closely (1)methadone and lenvatinib both increase QTc interval. Use Caution/Monitor. Lenvatinib prescribing information recommends monitoring ECG closely when coadministered with QT prolonging drugs.

• letermovir

  Monitor Closely (1)letermovir increases levels of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• leuprolide

  Monitor Closely (1)leuprolide increases toxicity of methadone by QTc interval. Use Caution/Monitor. Increases risk of torsades de pointes.

• levalbuterol

  Monitor Closely (1)methadone increases and levalbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• levetiracetam

  Serious - Use Alternative (1)levetiracetam and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• levofloxacin

  Monitor Closely (1)levofloxacin and methadone both increase QTc interval. Use Caution/Monitor.

• levoketoconazole

  Contraindicated (2)levoketoconazole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
  
  levoketoconazole and methadone both increase QTc interval. Contraindicated.

• levorphanol

  Monitor Closely (1)levorphanol and methadone both increase sedation. Use Caution/Monitor.

• lidocaine

  Minor (1)lidocaine increases toxicity of methadone by pharmacodynamic synergism. Minor/Significance Unknown. Risk of increased CNS depression.

• linezolid

  Serious - Use Alternative (1)linezolid increases toxicity of methadone by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

• lisdexamfetamine

  Monitor Closely (1)methadone increases and lisdexamfetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• lithium

  Serious - Use Alternative (1)lithium and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• lofepramine

  Monitor Closely (2)lofepramine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and lofepramine both increase sedation. Use Caution/Monitor.

• lofexidine

  Monitor Closely (2)methadone and lofexidine both increase QTc interval. Use Caution/Monitor. ECG monitoring is recommended.
  
  methadone and lofexidine both increase sedation. Use Caution/Monitor.

• lomitapide

  Monitor Closely (1)methadone increases levels of lomitapide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Lomitapide dose should not exceed 30 mg/day.

• lonafarnib

  Serious - Use Alternative (1)methadone will increase the level or effect of lonafarnib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of lonafarnib (a sensitive CYP3A substrate) with weak CYP3A inhibitors is unavoidable, reduce to, or continue lonafarnib at starting dose. Closely monitor for arrhythmias and events (eg, syncope, heart palpitations) since lonafarnib effect on QT interval is unknown.

• lopinavir

  Serious - Use Alternative (1)lopinavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• loprazolam

  Monitor Closely (1)loprazolam and methadone both increase sedation. Use Caution/Monitor.

• lorazepam

  Monitor Closely (1)lorazepam and methadone both increase sedation. Use Caution/Monitor.

• lorlatinib

  Monitor Closely (1)lorlatinib will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• lormetazepam

  Monitor Closely (1)lormetazepam and methadone both increase sedation. Use Caution/Monitor.

• loxapine

  Monitor Closely (2)methadone, loxapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).
  
  methadone and loxapine both increase sedation. Use Caution/Monitor.

• loxapine inhaled

  Monitor Closely (2)methadone, loxapine inhaled. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).
  
  methadone and loxapine inhaled both increase sedation. Use Caution/Monitor.

• lumefantrine

  Monitor Closely (2)lumefantrine will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  lumefantrine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• lurasidone

  Monitor Closely (2)lurasidone, methadone. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.
  
  methadone, lurasidone. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• macimorelin

  Serious - Use Alternative (1)macimorelin and methadone both increase QTc interval. Avoid or Use Alternate Drug. Macimorelin causes an increase of ~11 msec in the corrected QT interval. Avoid coadministration with drugs that prolong QT interval, which could increase risk for developing torsade de pointes-type ventricular tachycardia. Allow sufficient washout time of drugs that are known to prolong the QT interval before administering macimorelin.

• maprotiline

  Monitor Closely (2)maprotiline and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and maprotiline both increase sedation. Use Caution/Monitor.

• maraviroc

  Monitor Closely (1)maraviroc increases levels of methadone by QTc interval. Use Caution/Monitor. Potential for increased toxicity. Increased risk of QT prolongation and cardiac arrhythmias.

• marijuana

  Monitor Closely (2)marijuana will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  methadone and marijuana both increase sedation. Use Caution/Monitor.

• melatonin

  Monitor Closely (1)methadone and melatonin both increase sedation. Use Caution/Monitor.

• meperidine

  Monitor Closely (1)meperidine and methadone both increase sedation. Use Caution/Monitor.

• meprobamate

  Monitor Closely (1)methadone and meprobamate both increase sedation. Use Caution/Monitor.

• metaproterenol

  Monitor Closely (1)methadone increases and metaproterenol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• metaxalone

  Monitor Closely (1)metaxalone and methadone both increase sedation. Use Caution/Monitor.

• methamphetamine

  Monitor Closely (1)methadone increases and methamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• methocarbamol

  Monitor Closely (1)methocarbamol and methadone both increase sedation. Use Caution/Monitor.

• methohexital

  Serious - Use Alternative (1)methohexital and methadone both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate

• methylene blue

  Serious - Use Alternative (1)methylene blue and methadone both increase serotonin levels. Avoid or Use Alternate Drug. If drug combination must be administered, monitor for evidence of serotonergic or opioid-related toxicities

• methylenedioxymethamphetamine

  Monitor Closely (1)methadone increases and methylenedioxymethamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• methylprednisolone

  Monitor Closely (1)methylprednisolone will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• metoclopramide intranasal

  Serious - Use Alternative (1)methadone, metoclopramide intranasal. Either increases effects of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Avoid use of metoclopramide intranasal or interacting drug, depending on importance of drug to patient.

• metronidazole

  Monitor Closely (1)metronidazole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• miconazole vaginal

  Monitor Closely (1)miconazole vaginal will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• midazolam

  Monitor Closely (1)midazolam and methadone both increase sedation. Use Caution/Monitor.

• midazolam intranasal

  Monitor Closely (2)methadone will increase the level or effect of midazolam intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration of mild CYP3A4 inhibitors with midazolam intranasal may cause higher midazolam systemic exposure, which may prolong sedation.
  
  midazolam intranasal, methadone. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of benzodiazepines and opioids increases risk of respiratory depression. Use only in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required.

• midodrine

  Monitor Closely (1)methadone increases and midodrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• mifepristone

  Monitor Closely (1)mifepristone will increase the level or effect of methadone by Other (see comment). Modify Therapy/Monitor Closely. Inhibits CYP2C8/2C9; use smallest recommended doses for substrates and monitor; combination may increase QT interval. Use alternatives if availableSerious - Use Alternative (1)mifepristone will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• mirtazapine

  Monitor Closely (1)methadone and mirtazapine both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)mirtazapine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• mitotane

  Monitor Closely (1)mitotane decreases levels of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Mitotane is a strong inducer of cytochrome P-4503A4; monitor when coadministered with CYP3A4 substrates for possible dosage adjustments.

• mobocertinib

  Serious - Use Alternative (1)mobocertinib and methadone both increase QTc interval. Avoid or Use Alternate Drug. If coadministration unavoidable, reduce mobocertinib dose and monitor QTc interval more frequently.

• modafinil

  Monitor Closely (1)methadone increases and modafinil decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• molindone

  Monitor Closely (1)methadone, molindone. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• morphine

  Monitor Closely (1)methadone and morphine both increase sedation. Use Caution/Monitor.

• motherwort

  Monitor Closely (1)methadone and motherwort both increase sedation. Use Caution/Monitor.

• moxifloxacin

  Monitor Closely (1)methadone and moxifloxacin both increase QTc interval. Modify Therapy/Monitor Closely.

• moxonidine

  Monitor Closely (1)methadone and moxonidine both increase sedation. Use Caution/Monitor.

• nabilone

  Monitor Closely (1)methadone and nabilone both increase sedation. Use Caution/Monitor.

• nafcillin

  Monitor Closely (1)nafcillin will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• nalbuphine

  Monitor Closely (1)methadone and nalbuphine both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)nalbuphine, methadone. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

• nefazodone

  Serious - Use Alternative (1)nefazodone will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• nelfinavir

  Monitor Closely (1)nelfinavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• nevirapine

  Monitor Closely (1)nevirapine will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• nifedipine

  Monitor Closely (1)nifedipine will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• nilotinib

  Monitor Closely (2)nilotinib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  methadone and nilotinib both increase QTc interval. Modify Therapy/Monitor Closely.

• nirmatrelvir

  Monitor Closely (1)nirmatrelvir will decrease the level or effect of methadone by affecting hepatic enzyme CYP2B6 metabolism. Use Caution/Monitor. Methadone is metabolized by CYP2B6 and CYP3A4. Ritonavir may decrease AUC and peak plasma concentration by CYP2B6 induction. This may be partially offset by ritonavir inhibiting CYP3A4.

• nirmatrelvir/ritonavir

  Monitor Closely (1)nirmatrelvir/ritonavir will decrease the level or effect of methadone by affecting hepatic enzyme CYP2B6 metabolism. Use Caution/Monitor. Methadone is metabolized by CYP2B6 and CYP3A4. Ritonavir may decrease AUC and peak plasma concentration by CYP2B6 induction. This may be partially offset by ritonavir inhibiting CYP3A4.

• norepinephrine

  Monitor Closely (1)methadone increases and norepinephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• nortriptyline

  Monitor Closely (2)nortriptyline and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and nortriptyline both increase sedation. Use Caution/Monitor.

• octreotide

  Monitor Closely (1)methadone and octreotide both increase QTc interval. Modify Therapy/Monitor Closely.Minor (1)octreotide decreases levels of methadone by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

• octreotide (Antidote)

  Monitor Closely (1)methadone and octreotide (Antidote) both increase QTc interval. Modify Therapy/Monitor Closely.Minor (1)octreotide (Antidote) decreases levels of methadone by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

• ofloxacin

  Monitor Closely (1)methadone and ofloxacin both increase QTc interval. Use Caution/Monitor.

• olanzapine

  Monitor Closely (2)methadone, olanzapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).
  
  methadone and olanzapine both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)olanzapine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• olanzapine/samidorphan

  Contraindicated (1)olanzapine/samidorphan will decrease the level or effect of methadone by pharmacodynamic antagonism. Contraindicated. Samidorphan elicits opioid antagonistic effects and increases risk of precipitating acute opioid withdrawal in patients dependent on opioids. Prescribing information recommends at least a 7-day opioid-free interval for short-acting opioids and at least a 14-day opioid-free interval for long-acting opioids before starting olanzapine/samidorphan.

• oliceridine

  Monitor Closely (2)methadone will increase the level or effect of oliceridine by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. If concomitant use is necessary, may require less frequent oliceridine dosing. Closely monitor for respiratory depression and sedation and titrate subsequent doses accordingly. If inhibitor is discontinued, consider increase oliceridine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
  
  oliceridine, methadone. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• olodaterol inhaled

  Monitor Closely (1)methadone and olodaterol inhaled both increase QTc interval. Use Caution/Monitor. Drugs that prolong the QTc interval and may potentiate the effects of beta2 agonists on the cardiovascular system; increased risk of ventricular arrhythmias

• olopatadine intranasal

  Serious - Use Alternative (1)methadone and olopatadine intranasal both increase sedation. Avoid or Use Alternate Drug. Coadministration increases risk of CNS depression, which can lead to additive impairment of psychomotor performance and cause daytime impairment.

• omaveloxolone

  Monitor Closely (1)omaveloxolone will decrease the level or effect of methadone by Other (see comment). Use Caution/Monitor. Omaveloxolone may reduce systemic exposure of sensitive CYP2C8 substrates. Check prescribing information of substrate if dosage modification is needed.

• ondansetron

  Serious - Use Alternative (1)methadone and ondansetron both increase QTc interval. Avoid or Use Alternate Drug. Avoid with congenital long QT syndrome; ECG monitoring recommended with concomitant medications that prolong QT interval, electrolyte abnormalities, CHF, or bradyarrhythmias.

• opium tincture

  Monitor Closely (1)methadone and opium tincture both increase sedation. Use Caution/Monitor.

• orphenadrine

  Monitor Closely (1)orphenadrine and methadone both increase sedation. Use Caution/Monitor.

• osilodrostat

  Monitor Closely (1)osilodrostat and methadone both increase QTc interval. Use Caution/Monitor.

• osimertinib

  Monitor Closely (1)osimertinib and methadone both increase QTc interval. Use Caution/Monitor. Conduct periodic monitoring with ECGs and electrolytes in patients taking drugs known to prolong the QTc interval.

• oxaliplatin

  Monitor Closely (1)oxaliplatin will increase the level or effect of methadone by Other (see comment). Use Caution/Monitor. Monitor for ECG changes if therapy is initiated in patients with drugs known to prolong QT interval.Serious - Use Alternative (1)oxaliplatin and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• oxazepam

  Monitor Closely (1)oxazepam and methadone both increase sedation. Use Caution/Monitor.

• oxcarbazepine

  Monitor Closely (1)oxcarbazepine will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• oxycodone

  Monitor Closely (1)methadone and oxycodone both increase sedation. Use Caution/Monitor.

• oxymorphone

  Monitor Closely (1)methadone and oxymorphone both increase sedation. Use Caution/Monitor.

• ozanimod

  Monitor Closely (1)ozanimod and methadone both increase QTc interval. Modify Therapy/Monitor Closely. The potential additive effects on heart rate, treatment with ozanimod should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties.Serious - Use Alternative (1)ozanimod and methadone both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Avoid or Use Alternate Drug. Because the active metabolite of ozanimod inhibits MAO-B in vitro, there is a potential for serious adverse reactions, including hypertensive crisis. Therefore, coadministration of ozanimod with drugs that can increase norepinephrine or serotonin is not recommended. Monitor for hypertension with concomitant use.

• paliperidone

  Monitor Closely (3)methadone, paliperidone. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).
  
  methadone and paliperidone both increase QTc interval. Use Caution/Monitor.
  
  methadone and paliperidone both increase sedation. Use Caution/Monitor.

• panobinostat

  Serious - Use Alternative (1)methadone and panobinostat both increase QTc interval. Avoid or Use Alternate Drug. Panobinostat is known to significantly prolong QT interval. Panobinostat prescribing information states use with drugs known to prolong QTc is not recommended.

• papaveretum

  Monitor Closely (1)methadone and papaveretum both increase sedation. Use Caution/Monitor.

• papaverine

  Monitor Closely (1)methadone and papaverine both increase sedation. Use Caution/Monitor.

• paroxetine

  Monitor Closely (1)methadone and paroxetine both increase QTc interval. Use Caution/Monitor.

• pasireotide

  Monitor Closely (1)methadone and pasireotide both increase QTc interval. Modify Therapy/Monitor Closely.

• pazopanib

  Minor (1)methadone and pazopanib both increase QTc interval. Minor/Significance Unknown.

• peginterferon alfa 2b

  Monitor Closely (1)peginterferon alfa 2b will increase the level or effect of methadone by unknown mechanism. Use Caution/Monitor. Methadone levels may be elevated, increasing the pharmacologic effects and adverse reactions. Monitor patients for signs and symptoms of increased narcotic effects and adjust methadone dose as needed.

• pegvisomant

  Monitor Closely (1)methadone decreases effects of pegvisomant by unknown mechanism. Use Caution/Monitor.

• pentamidine

  Serious - Use Alternative (1)methadone and pentamidine both increase QTc interval. Avoid or Use Alternate Drug.

• pentazocine

  Monitor Closely (1)methadone and pentazocine both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)pentazocine, methadone. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

• pentobarbital

  Monitor Closely (2)pentobarbital will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  pentobarbital and methadone both increase sedation. Use Caution/Monitor.

• perampanel

  Monitor Closely (1)perampanel and methadone both decrease sedation. Use Caution/Monitor.

• perphenazine

  Monitor Closely (3)methadone, perphenazine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).
  
  perphenazine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and perphenazine both increase sedation. Use Caution/Monitor.

• phendimetrazine

  Monitor Closely (1)methadone increases and phendimetrazine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• phenelzine

  Serious - Use Alternative (1)phenelzine increases toxicity of methadone by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

• phenobarbital

  Monitor Closely (2)phenobarbital will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  phenobarbital and methadone both increase sedation. Use Caution/Monitor.

• phentermine

  Monitor Closely (1)methadone increases and phentermine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• phenylephrine

  Monitor Closely (1)methadone increases and phenylephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• phenylephrine PO

  Monitor Closely (1)methadone increases and phenylephrine PO decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor. .

• phenytoin

  Monitor Closely (1)phenytoin will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.Serious - Use Alternative (1)phenytoin decreases levels of methadone by increasing metabolism. Contraindicated.

• pholcodine

  Monitor Closely (1)methadone and pholcodine both increase sedation. Use Caution/Monitor.

• pimavanserin

  Monitor Closely (1)methadone, pimavanserin. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

• pimozide

  Monitor Closely (2)methadone, pimozide. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).
  
  methadone and pimozide both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)methadone and pimozide both increase QTc interval. Avoid or Use Alternate Drug.

• pirbuterol

  Monitor Closely (1)methadone increases and pirbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• pitolisant

  Serious - Use Alternative (1)methadone and pitolisant both increase QTc interval. Avoid or Use Alternate Drug.

• ponesimod

  Serious - Use Alternative (1)ponesimod, methadone. Either increases effects of the other by QTc interval. Avoid or Use Alternate Drug. Consult cardiologist if considering treatment. Generally, should not be initiated in patients who are concurrently taking QT prolonging drugs with known arrhythmogenic properties, such as HR-lowering calcium channel blockers (eg, verapamil, diltiazem).

• posaconazole

  Monitor Closely (2)posaconazole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  methadone and posaconazole both increase QTc interval. Use Caution/Monitor.

• prednisone

  Monitor Closely (1)prednisone will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• pregabalin

  Monitor Closely (1)pregabalin, methadone. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

• primaquine

  Serious - Use Alternative (1)primaquine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• primidone

  Monitor Closely (2)primidone will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  primidone and methadone both increase sedation. Use Caution/Monitor.

• procainamide

  Serious - Use Alternative (1)methadone and procainamide both increase QTc interval. Avoid or Use Alternate Drug.

• procarbazine

  Serious - Use Alternative (1)procarbazine increases toxicity of methadone by unknown mechanism. Avoid or Use Alternate Drug. MAOIs may potentiate CNS depression and hypotension. Do not use within 14 days of MAOI use. .

• prochlorperazine

  Monitor Closely (2)prochlorperazine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and prochlorperazine both increase sedation. Use Caution/Monitor.

• promazine

  Monitor Closely (1)promazine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

• promethazine

  Monitor Closely (2)promethazine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  promethazine and methadone both increase sedation. Use Caution/Monitor.

• propofol

  Monitor Closely (1)propofol and methadone both increase sedation. Use Caution/Monitor.

• propylhexedrine

  Monitor Closely (1)methadone increases and propylhexedrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• protriptyline

  Monitor Closely (2)protriptyline and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and protriptyline both increase sedation. Use Caution/Monitor.

• quazepam

  Monitor Closely (1)quazepam and methadone both increase sedation. Use Caution/Monitor.

• quetiapine

  Monitor Closely (3)methadone, quetiapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).
  
  methadone and quetiapine both increase sedation. Use Caution/Monitor.
  
  quetiapine, methadone. Either increases toxicity of the other by QTc interval. Use Caution/Monitor. Avoid use with drugs that prolong QT and in patients with risk factors for prolonged QT interval. Postmarketing cases show QT prolongation with overdose in patients with concomitant illness or with drugs known to cause electrolyte imbalance or prolong QT.

• quinidine

  Serious - Use Alternative (1)quinidine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• quinine

  Monitor Closely (1)methadone and quinine both increase QTc interval. Use Caution/Monitor.

• quinupristin/dalfopristin

  Monitor Closely (1)quinupristin/dalfopristin will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• quizartinib

  Monitor Closely (1)quizartinib, methadone. Either increases effects of the other by QTc interval. Modify Therapy/Monitor Closely. Monitor patients more frequently with ECG if coadministered with QT prolonging drugs.

• ramelteon

  Monitor Closely (1)methadone and ramelteon both increase sedation. Use Caution/Monitor.

• ranolazine

  Monitor Closely (1)methadone and ranolazine both increase QTc interval. Use Caution/Monitor.

• rasagiline

  Contraindicated (1)rasagiline increases toxicity of methadone by unknown mechanism. Contraindicated. Risk of hypotension, hyperpyrexia, somnolence, or death.

• remimazolam

  Monitor Closely (1)remimazolam, methadone. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely. Coadministration may result in profound sedation, respiratory depression, coma, and/or death. Continuously monitor vital signs during sedation and recovery period if coadministered. Carefully titrate remimazolam dose if administered with opioid analgesics and/or sedative/hypnotics.

• ribociclib

  Contraindicated (1)ribociclib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.Serious - Use Alternative (1)ribociclib and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• rifabutin

  Serious - Use Alternative (1)rifabutin will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• rifampin

  Monitor Closely (1)rifampin decreases levels of methadone by increasing metabolism. Use Caution/Monitor.Serious - Use Alternative (1)rifampin will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• rifapentine

  Monitor Closely (1)rifapentine will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• rilpivirine

  Monitor Closely (2)rilpivirine, methadone. Other (see comment). Use Caution/Monitor. Comment: No dose adjustments are required when initiating co-administration of methadone with rilpivirine. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.
  
  rilpivirine increases toxicity of methadone by QTc interval. Use Caution/Monitor. Rilpivirine should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.

• risperidone

  Monitor Closely (3)methadone, risperidone. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).
  
  methadone and risperidone both increase QTc interval. Use Caution/Monitor.
  
  methadone and risperidone both increase sedation. Use Caution/Monitor.

• ritonavir

  Monitor Closely (2)ritonavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  ritonavir decreases effects of methadone by Other (see comment). Use Caution/Monitor. Comment: Ritonavir may induce the metabolism of methadone and/or induce the p glycoprotein pathway that pumps drugs out of the CNS.

• romidepsin

  Serious - Use Alternative (1)methadone and romidepsin both increase QTc interval. Avoid or Use Alternate Drug.

• ropeginterferon alfa 2b

  Serious - Use Alternative (1)ropeginterferon alfa 2b and methadone both increase Other (see comment). Avoid or Use Alternate Drug. Narcotics, hypnotics or sedatives can produce additive neuropsychiatric side effects. Avoid use and monitor patients receiving the combination for effects of excessive CNS toxicity.

• rucaparib

  Monitor Closely (1)rucaparib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP3A4 substrates, if clinically indicated.

• rufinamide

  Monitor Closely (1)rufinamide will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• ruxolitinib

  Minor (1)methadone will increase the level or effect of ruxolitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• ruxolitinib topical

  Minor (1)methadone will increase the level or effect of ruxolitinib topical by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• safinamide

  Contraindicated (1)methadone, safinamide. Either increases toxicity of the other by serotonin levels. Contraindicated. Concomitant use could result in life-threatening serotonin syndrome.

• sage

  Minor (1)methadone and sage both increase sedation. Minor/Significance Unknown.

• salmeterol

  Monitor Closely (1)methadone increases and salmeterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• saquinavir

  Serious - Use Alternative (2)saquinavir, methadone. Either increases toxicity of the other by QTc interval. Avoid or Use Alternate Drug. Increased risk of PR prolongation and cardiac arrhythmias.
  
  saquinavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• schisandra

  Monitor Closely (1)schisandra will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• scullcap

  Monitor Closely (1)methadone and scullcap both increase sedation. Use Caution/Monitor.

• secobarbital

  Monitor Closely (2)secobarbital will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  secobarbital and methadone both increase sedation. Use Caution/Monitor.

• selegiline

  Contraindicated (1)selegiline increases toxicity of methadone by unknown mechanism. Contraindicated. At least 14 days should elapse between discontinuation of selegiline and initiation of analgesic.

• selegiline transdermal

  Serious - Use Alternative (1)selegiline transdermal increases toxicity of methadone by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death.

• selinexor

  Serious - Use Alternative (1)selinexor, methadone. unspecified interaction mechanism. Avoid or Use Alternate Drug. Patients treated with selinexor may experience neurological toxicities. Avoid taking selinexor with other medications that may cause dizziness or confusion.

• selpercatinib

  Monitor Closely (1)selpercatinib increases toxicity of methadone by QTc interval. Use Caution/Monitor.

• sertraline

  Serious - Use Alternative (1)sertraline and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• sevoflurane

  Monitor Closely (1)sevoflurane and methadone both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)sevoflurane and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• shepherd's purse

  Monitor Closely (1)methadone and shepherd's purse both increase sedation. Use Caution/Monitor.

• siponimod

  Serious - Use Alternative (1)siponimod and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• sodium oxybate

  Serious - Use Alternative (1)methadone, sodium oxybate. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• sodium sulfate/?magnesium sulfate/potassium chloride

  Monitor Closely (1)sodium sulfate/?magnesium sulfate/potassium chloride increases toxicity of methadone by QTc interval. Use Caution/Monitor. Consider predose and post-colonoscopy ECGs in patients at increased risk of serious cardiac arrhythmias. .

• sodium sulfate/potassium sulfate/magnesium sulfate

  Monitor Closely (1)sodium sulfate/potassium sulfate/magnesium sulfate increases toxicity of methadone by QTc interval. Use Caution/Monitor. Consider predose and post-colonoscopy ECGs in patients at increased risk of serious cardiac arrhythmias. .

• solifenacin

  Serious - Use Alternative (1)solifenacin and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• sorafenib

  Monitor Closely (1)sorafenib and methadone both increase QTc interval. Use Caution/Monitor.

• sotalol

  Serious - Use Alternative (1)methadone and sotalol both increase QTc interval. Avoid or Use Alternate Drug.

• St John's Wort

  Serious - Use Alternative (1)St John's Wort will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• stiripentol

  Monitor Closely (3)stiripentol, methadone. Either increases effects of the other by sedation. Use Caution/Monitor. Concomitant use stiripentol with other CNS depressants, including alcohol, may increase the risk of sedation and somnolence.
  
  stiripentol, methadone. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.
  
  stiripentol will increase the level or effect of methadone by Other (see comment). Modify Therapy/Monitor Closely. Stiripentol is a CYP2C8 inhibitor. Consider dosage reduction for CYP2C8 substrates if adverse effects are experienced when coadministered.

• sufentanil

  Monitor Closely (1)methadone and sufentanil both increase sedation. Use Caution/Monitor.

• sufentanil SL

  Serious - Use Alternative (1)sufentanil SL, methadone. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration may result in hypotension, profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• sulfamethoxazole

  Monitor Closely (1)sulfamethoxazole and methadone both increase QTc interval. Use Caution/Monitor.

• sunitinib

  Serious - Use Alternative (1)sunitinib and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• suvorexant

  Monitor Closely (1)suvorexant and methadone both increase sedation. Modify Therapy/Monitor Closely. Dosage adjustments of suvorexant and concomitant CNS depressants may be necessary

• tacrolimus

  Serious - Use Alternative (1)tacrolimus and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• tamsulosin

  Monitor Closely (1)methadone increases levels of tamsulosin by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

• tapentadol

  Monitor Closely (1)methadone and tapentadol both increase sedation. Use Caution/Monitor.

• tazemetostat

  Monitor Closely (2)tazemetostat will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  methadone will increase the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• tecovirimat

  Monitor Closely (2)tecovirimat will increase the level or effect of methadone by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. Tecovirimat is a weak inhibitor of CYP2C8 and CYP2C19. Monitor for adverse effects if coadministered with sensitive substrates of these enzymes.
  
  tecovirimat will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.

• telavancin

  Monitor Closely (1)methadone and telavancin both increase QTc interval. Use Caution/Monitor.

• temazepam

  Monitor Closely (1)temazepam and methadone both increase sedation. Use Caution/Monitor.

• terbutaline

  Monitor Closely (1)methadone increases and terbutaline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• teriflunomide

  Monitor Closely (1)teriflunomide increases levels of methadone by Other (see comment). Use Caution/Monitor. Comment: Teriflunomide inhibits CYP2C8; caution when coadministered with CYP2C8 substrates.

• tetrabenazine

  Serious - Use Alternative (1)tetrabenazine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• thioridazine

  Monitor Closely (2)thioridazine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and thioridazine both increase sedation. Use Caution/Monitor.

• thiothixene

  Monitor Closely (2)methadone, thiothixene. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).
  
  methadone and thiothixene both increase sedation. Use Caution/Monitor.

• tinidazole

  Monitor Closely (1)methadone will increase the level or effect of tinidazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• tipranavir

  Monitor Closely (2)tipranavir decreases levels of methadone by increasing metabolism. Use Caution/Monitor.
  
  tipranavir will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• topiramate

  Monitor Closely (2)topiramate will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  methadone and topiramate both increase sedation. Modify Therapy/Monitor Closely.

• tramadol

  Monitor Closely (1)methadone and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, methadone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• tranylcypromine

  Serious - Use Alternative (1)tranylcypromine increases toxicity of methadone by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

• trazodone

  Monitor Closely (2)trazodone and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and trazodone both increase sedation. Use Caution/Monitor.

• triazolam

  Monitor Closely (1)triazolam and methadone both increase sedation. Use Caution/Monitor.

• triclabendazole

  Monitor Closely (1)triclabendazole and methadone both increase QTc interval. Use Caution/Monitor.

• triclofos

  Monitor Closely (1)triclofos and methadone both increase sedation. Use Caution/Monitor.

• trifluoperazine

  Monitor Closely (3)methadone, trifluoperazine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).
  
  trifluoperazine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and trifluoperazine both increase sedation. Use Caution/Monitor.

• trimethoprim

  Monitor Closely (1)methadone and trimethoprim both increase QTc interval. Use Caution/Monitor.

• trimipramine

  Monitor Closely (2)trimipramine and methadone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and trimipramine both increase sedation. Use Caution/Monitor.

• triprolidine

  Monitor Closely (1)triprolidine and methadone both increase sedation. Use Caution/Monitor.

• triptorelin

  Monitor Closely (1)triptorelin increases toxicity of methadone by QTc interval. Use Caution/Monitor. Increases risk of torsades de pointes.

• tropisetron

  Monitor Closely (1)methadone and tropisetron both increase QTc interval. Use Caution/Monitor.

• tucatinib

  Serious - Use Alternative (1)tucatinib will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.

• umeclidinium bromide/vilanterol inhaled

  Serious - Use Alternative (1)methadone increases toxicity of umeclidinium bromide/vilanterol inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.

• valbenazine

  Monitor Closely (1)valbenazine and methadone both increase QTc interval. Use Caution/Monitor.

• valerian

  Serious - Use Alternative (1)valerian and methadone both increase sedation. Avoid or Use Alternate Drug.

• vandetanib

  Serious - Use Alternative (1)methadone, vandetanib. Either increases toxicity of the other by QTc interval. Avoid or Use Alternate Drug. Avoid coadministration with drugs known to prolong QT interval; if a drug known to prolong QT interval must be used, more frequent ECG monitoring is recommended.

• vemurafenib

  Serious - Use Alternative (1)vemurafenib and methadone both increase QTc interval. Avoid or Use Alternate Drug. Concomitant use of vemurafenib with drugs that prolong QT interval is not recommended.

• venlafaxine

  Monitor Closely (1)methadone and venlafaxine both increase QTc interval. Use Caution/Monitor.

• verapamil

  Monitor Closely (1)verapamil will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• vilanterol/fluticasone furoate inhaled

  Serious - Use Alternative (1)methadone increases toxicity of vilanterol/fluticasone furoate inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.

• voclosporin

  Monitor Closely (1)voclosporin, methadone. Either increases effects of the other by QTc interval. Use Caution/Monitor.

• voriconazole

  Monitor Closely (2)voriconazole will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed.
  
  methadone and voriconazole both increase QTc interval. Use Caution/Monitor.

• vorinostat

  Serious - Use Alternative (1)vorinostat and methadone both increase QTc interval. Avoid or Use Alternate Drug.

• voxelotor

  Serious - Use Alternative (1)voxelotor will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.

• xylometazoline

  Monitor Closely (1)methadone increases and xylometazoline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• yohimbine

  Monitor Closely (1)methadone increases and yohimbine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• zafirlukast

  Monitor Closely (1)zafirlukast will increase the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• ziconotide

  Monitor Closely (1)methadone and ziconotide both increase sedation. Use Caution/Monitor.Minor (1)ziconotide, methadone. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Additive decreased GI motility. Additive analgesia. Ziconotide does NOT potentiate opioid induced respiratory depression.

• zidovudine

  Minor (1)methadone increases levels of zidovudine by decreasing renal clearance. Minor/Significance Unknown.

• ziprasidone

  Monitor Closely (3)methadone, ziprasidone. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).
  
  methadone and ziprasidone both increase QTc interval. Modify Therapy/Monitor Closely.
  
  methadone and ziprasidone both increase sedation. Use Caution/Monitor.

• zotepine

  Monitor Closely (1)methadone and zotepine both increase sedation. Use Caution/Monitor.

• zuranolone

  Serious - Use Alternative (1)methadone, zuranolone. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration of zuranolone with other CNS depressants may increase impairment of psychomotor performance or CNS depressant effects. If unavoidable, consider dose reduction. .