Drug Interaction Report

Phenytoin and Felbamate: Interaction Details

A pharmacist-reviewed analysis of the Phenytoin and Felbamate 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
+

Felbamate

Felbatol Felbatol®
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 237 documented Phenytoin interactions, 191 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

An increased risk of phenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremors), reduced felbamate exposure and reduced efficacy of felbamate

Interaction Deep Dive

Concurrent administration of phenytoin and felbamate may result in reduced felbamate exposure12. Concurrent administration of phenytoin and felbamate may increase exposure of phenytoin. Monitor patients for signs of phenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremor) when receiving felbamate concurrently. Consider phenytoin dose adjustments to achieve optimal clinical response when felbamate is added to or withdrawn from a patient's regimen. Monitor phenytoin serum drug level during concurrent use of felbamate and phenytoin 1314.

Why it happens (mechanism)

Inhibition of CYP2C19-mediated metabolism of phenytoin

Literature reports

4 reports — tap to read

a) Four patients who were receiving carBAMazepine, phenytoin, and felbamate have been described. Following discontinuation of phenytoin, felbamate clearance decreased 21%. CarBAMazepine dosage was reduced, resulting in an additional felbamate clearance of 16.5% 2.

b) Felbamate clearance doubles, and a 45% decrease in felbamate's steady-state trough concentration occurs when phenytoin is added to felbamate therapy. Additionally, felbamate causes an increase in the steady-state phenytoin plasma concentration 10.

c) Felbamate appears to be a competitive inhibitor of phenytoin metabolism. Increased serum phenytoin levels in two patients who exhibited symptomatic phenytoin intoxication have been noted 11. Both patients required at least a 20% reduction in daily phenytoin dosage while receiving felbamate 38 to 40 mg/kg/day. When the dose was tapered to less than 20 mg/kg/day, serum phenytoin concentrations declined. This interaction was corroborated by other investigators, who found similar increases in phenytoin levels (approximately 20%) when felbamate was added to the anticonvulsant regimen. Phenytoin dosage modification may be required in patients receiving felbamate and phenytoin concurrently 31.

d) Phenytoin, carBAMazepine, or their prodrugs during pregnancy significantly increase the risk of teratogenicity, especially when combined with other anticonvulsants. The risk is linked to the levels of reactive epoxide metabolites 456. which rise when these drugs are paired with others that induce cytochrome P450 enzymes (eg, barbiturates, felbamate) or inhibit epoxide hydrolase (eg, valproic acid, lamoTRIgine). Such combinations increase the risk of major birth defects by 3 to 4 times over monotherapy and 10 times over baseline rates 789.

Common questions

Can I take Phenytoin and Felbamate together?

An increased risk of phenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremors), reduced felbamate exposure and reduced efficacy of felbamate Always confirm with your pharmacist or prescriber before making any change.

How serious is the Phenytoin and Felbamate 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.

Questions for your pharmacist

  • Does my dose of Phenytoin or Felbamate 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 (14)

  1. Leppik IE, Dreifuss FE, Pledger GW, et al: Felbamate for partial seizures: results of a controlled clinical trial. Neurology 1991; 41:1785-1789. DOI
  2. Wagner ML, Graves NM, Marienau K, et al: Discontinuation of phenytoin and carbamazepine in patients receiving felbamate. Epilepsia 1991; 32:398-406. PubMed
  3. Graves NM, Holmes GB, & Fuerst RH: Effect of felbamate on phenytoin and carbamazepine serum concentrations. Epilepsia 1989; 30:225-229. PubMed
  4. Buehler BA, Delimont D, Van Waes M, et al: Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med 1990; 322:1567-1572. DOI
  5. Van Dyke DC, Berg MJ, & Olson CH: Differences in phenytoin biotransformation and susceptibility to congenital malformations: a review. Drug Intell Clin Pharm 1991; 25:987-992. PubMed
  6. Finnell RH, Buehler BA, Kerr BM, et al: Clinical and experimental studies linking oxidative metabolism to phenytoin-induced teratogenesis. Neurology 1992; 42(4 suppl 5):25-31.
  7. Bianchetti G, Padovani P, Thenot JP, et al: Pharmacokinetic interactions of progabide with other antiepileptic drugs. Epilepsia 1987; 28:68-73. PubMed
  8. Ramsay RE, McManus DQ, Guterman A, et al: Carbamazepine metabolism in humans: effect of concurrent anticonvulsant therapy. Ther Drug Monit 1990; 12:235-241. PubMed
  9. Spina E, Pisani F, & Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: An update. Clin Pharmacokinet 1996; 31:198-214. PubMed
  10. Product Information: Felbatol(R), felbamate. Wallace Laboratories, Cranbury, NJ, 2000. DailyMed
  11. Fuerst RH, Graves NM, & Leppik IE: Felbamate increases phenytoin but decreases carbamazepine concentrations. Epilepsia 1988; 29:488-491. PubMed
  12. Product Information: FELBATOL(R) oral tablet, oral suspension, felbamate oral tablet, oral suspension. MedPointe Pharmaceuticals MedPointe Healthcare Inc, Somerset, NJ, 2003. DailyMed
  13. Product Information: PHENYTOIN SODIUM intravenous and intramuscular injection, phenytoin sodium intravenous and intramuscular injection. Acella Pharmaceuticals, LLC (per Dailymed), Alpharetta, GA, 2024. DailyMed
  14. Product Information: PHENYTOIN SODIUM oral extended-release capsules, phenytoin sodium oral extended-release capsules. Sun Pharmaceutical Industries, Inc. (per Dailymed), Cranbury, NJ, 2023. DailyMed
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Phenytoin

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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
Felbamate + 1,4-butanediol Activated Charcoal American Hellebore Arsenic Beer Cesium Ephedra Gamma-hydroxybutyrate (ghb) + 164 more

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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.