Drug interactions
Methadone + Phenytoin
Severity: Major
Methadone and Phenytoin: major interaction.
Last updated Sources: US FDA label
For healthcare professionals — reference only. This page is a brief summary, not medical advice and not a substitute for official labeling or clinical judgement. Always verify before prescribing or dispensing.
Summary
Phenytoin induces hepatic metabolism of methadone, which lowers methadone concentrations and can precipitate opioid withdrawal in dependent patients. Pain control may also be lost. Withdrawal can be severe, and stopping phenytoin may later cause methadone levels to rise.
What this interaction means in plain words
Methadone and Phenytoin can interact in a way that may be serious. Using them together is sometimes necessary, but it needs a deliberate decision by the prescriber, a plan for monitoring, and clear advice on the warning signs to watch for.
Methadone belongs to Musculoskeletal; Phenytoin belongs to Central Nervous System.
Why it happens
Induction of CYP3A4 and CYP2B6 by phenytoin accelerates methadone clearance.
What to do
Monitor for withdrawal symptoms and titrate the methadone dose upward as needed. Lower the methadone dose again if phenytoin is discontinued.
What to ask your pharmacist
- Does the benefit of taking both outweigh the risk in my case?
- Do I need any blood test, ECG or other check while on both?
- What early warning signs should I watch for, and what should I do if they appear?
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References
Other interactions of Methadone
- Alvimopan + Methadone Contraindicated
- Calcium / magnesium / potassium / sodium oxybates + Methadone Contraindicated
- Droperidol + Methadone Contraindicated
- Ibutilide + Methadone Contraindicated
- Isocarboxazid + Methadone Contraindicated
- Lefamulin + Methadone Contraindicated
Other interactions of Phenytoin
- Artemether / lumefantrine + Phenytoin Contraindicated
- Bictegravir + Phenytoin Contraindicated
- Cabotegravir + Phenytoin Contraindicated
- Doravirine + Phenytoin Contraindicated
- Elbasvir / grazoprevir + Phenytoin Contraindicated
- Elvitegravir / cobicistat / emtricitabine / tenofovir df + Phenytoin Contraindicated
Frequently asked questions
Can I take Methadone with Phenytoin?
MediHelp rates the interaction as major. Methadone and Phenytoin can interact in a way that may be serious. Using them together is sometimes necessary, but it needs a deliberate decision by the prescriber, a plan for monitoring, and clear advice on the warning signs to watch for. Phenytoin induces hepatic metabolism of methadone, which lowers methadone concentrations and can precipitate opioid withdrawal in dependent patients. Pain control may also be lost. Withdrawal can be severe, and stopping phenytoin may later cause methadone levels to rise.
How serious is the interaction between Methadone and Phenytoin?
MediHelp rates it major, on a four-level scale (minor, moderate, major, contraindicated) based on published labels and references. What to do, in brief: Monitor for withdrawal symptoms and titrate the methadone dose upward as needed. Lower the methadone dose again if phenytoin is discontinued.
What other medicines interact with Methadone?
MediHelp also lists interactions of Methadone with, for example, Alvimopan, Calcium / magnesium / potassium / sodium oxybates, Droperidol. The full list is on the Methadone page.
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