Drug Interaction Report

Disulfiram and Phenytoin: Interaction Details

A pharmacist-reviewed analysis of the Disulfiram and Phenytoin interaction: the documented clinical effects, severity rating, onset, mechanism, and management considerations, with cited references throughout.

AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature

Phenytoin

Dilantin Phenytek
+

Disulfiram

Antabuse Antabuse®
Dr. Brian Staiger, PharmD, BCPS
Medically reviewed by
Dr. Brian Staiger, PharmD, BCPS
Updated Aug 8, 2026
Editorial policy · Data sources
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Interaction severity
Major
Potentially serious — often needs a change or close monitoring.
How we grade severity & evidence

Severity levels

  • Contraindicated: These should generally not be used together.
  • Major: Potentially serious — often needs a change or close monitoring.
  • Moderate: Can be significant — usually manageable with monitoring.
  • Minor: Usually limited clinical impact.

Evidence grades

  • Established: Well documented — supported by controlled studies or strong clinical data.
  • Probable: Good supporting evidence, though not definitively proven.
  • Suspected: Some evidence suggests this interaction, but it is not well established.
  • Possible: Limited or conflicting evidence; the interaction may occur.
  • Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.

Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.

Of 45 documented Disulfiram interactions, 25 are rated major — including this one.
Worried about symptoms right now? Contact your pharmacist or prescriber, or call Poison Control at 1-800-222-1222 (US). Call 911 for an emergency.
Onset
delayed
Evidence
probable
Severity
Major

What happens

Increased phenytoin or fosphenytoin (prodrug of phenytoin) exposure and an increased risk of phenytoin or fosphenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremors)

Interaction Deep Dive

Concurrent use of phenytoin or fosphenytoin (prodrug of phenytoin) and disulfiram (CYP2C9 inhibitor) may increase exposure of phenytoin or fosphenytoin and which will lead to toxicity. Monitor patients for signs of phenytoin or fosphenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremor) when receiving disulfiram concurrently. Consider phenytoin or fosphenytoin dose adjustments to achieve optimal clinical response when disulfiram is added to or withdrawn from a patient's regimen. Monitor phenytoin or fosphenytoin serum drug level during concurrent use of disulfiram and phenytoin or fosphenytoin123. In clinical studies and case reports, the concurrent use of these drugs resulted in significant increases of phenytoin exposure. There was a reported increase in half-life and a significant decrease in phenytoin clearance 6.

Why it happens (mechanism)

Inhibition of CYP2C9-mediated metabolism of phenytoin

Literature reports

2 reports — tap to read

a) The administration of phenytoin, with usual therapeutic doses of disulfiram, for a duration of 4 to 9 days can result in significant increases in serum phenytoin. The elevated serum concentrations may persist for 3 to 4 days after disulfiram is discontinued. Disulfiram appears to reduce the metabolic clearance of phenytoin, increasing the volume of distribution and half-life 45.

b) Delirium from combined disulfiram and phenytoin administration was reported in a 54-year-old man. Both drugs were administered in recommended doses and the phenytoin level was 63 mg/L when delirium was diagnosed. Disulfiram can inhibit the biotransformation of phenytoin and produce toxic serum concentrations with associated behavioral and psychiatric changes 6. There was a reported increase in half-life and a significant decrease in phenytoin clearance 674.

Common questions

Can I take Disulfiram and Phenytoin together?

Increased phenytoin or fosphenytoin (prodrug of phenytoin) exposure and an increased risk of phenytoin or fosphenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremors) Always confirm with your pharmacist or prescriber before making any change.

How serious is the Disulfiram and Phenytoin interaction?

It is rated major. Potentially serious — often needs a change or close monitoring.

How quickly could this interaction happen?

The documented onset is "delayed". Effects tend to build up gradually over days to weeks.

How strong is the evidence for this interaction?

The evidence is graded "probable". Good supporting evidence, though not definitively proven.

From our Q&A

Real reader questions about these medications, each personally answered by our pharmacist:

Questions for your pharmacist

  • Does my dose of Disulfiram or Phenytoin need adjusting while I take them together?
  • What symptoms should prompt me to call you or my prescriber right away?
  • Does the timing of my doses matter for this combination?
  • Is there a safer alternative to one of these medications for me?

References (7)

  1. Product Information: FOSPHENYTOIN SODIUM intravenous and intramuscular injection, fosphenytoin sodium intravenous and intramuscular injection. SAGENT Pharmaceuticals (per Dailymed), Schaumburg, IL, 2024. DailyMed
  2. Product Information: PHENYTOIN SODIUM intravenous and intramuscular injection, phenytoin sodium intravenous and intramuscular injection. Acella Pharmaceuticals, LLC (per Dailymed), Alpharetta, GA, 2024. DailyMed
  3. Product Information: PHENYTOIN SODIUM oral extended-release capsules, phenytoin sodium oral extended-release capsules. Sun Pharmaceutical Industries, Inc. (per Dailymed), Cranbury, NJ, 2023. DailyMed
  4. Svendsen TL, Kristenson MB, Hansen JM, et al: The influence of disulfiram on the half-life and metabolic clearance rate of diphenylhydantoin and tolbutamide in man. Eur J Clin Pharmacol 1976; 9:439-441. DOI
  5. Olesen OV: The influence of disulfiram and calcium carbimide on the serum diphenylhydantoin. Excretion of HPPH in the urine. Arch Neurol 1967; 16:642. DOI
  6. Brown CG, Kaminsky MJ, & Feroli ER: Delirium with phenytoin and disulfiram administration. Ann Emerg Med 1983; 12:310-313. PubMed
  7. Taylor JW, Alexander B, Kathol RG, et al: Pharmacokinetic analysis of the phenytoin-disulfiram interaction (abstract). Drug Intell Clin Pharm 1984; 18:499.
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Phenytoin

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Disulfiram

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Beyond drug–drug

These medications also interact with supplements

Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:

Phenytoin + 1,4-butanediol Activated Charcoal Beer Gamma-hydroxybutyrate (ghb) Kava L-tryptophan Siberian Cocklebur St. John's Wort + 216 more
Disulfiram + Activated Charcoal Bach Flower Remedies Beer Wine Biofeedback Black Tea Caffeine Cannabinol (cbn) + 37 more

major · moderate · minor — check everything you take with our drug–supplement interaction checker.

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This information is for education, not a substitute for professional medical advice. Do not start, stop, or change any medication without talking to your pharmacist or prescriber.