Drug Interaction Report

Phenytoin and Leucovorin: Interaction Details

Name: Phenytoin and Leucovorin Interaction
Creator: Dr. Brian Staiger, PharmD, BCPS

A pharmacist-reviewed analysis of the Phenytoin and Leucovorin 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

Leucovorin

Vykoura Wellcovorin

Medically reviewed by

Dr. Brian Staiger, PharmD, BCPS

Updated Aug 8, 2026

Editorial policy · Data sources

Interaction severity

Moderate

Can be significant — usually manageable with monitoring.

Minor

Moderate

Major

Contraindicated

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, 38 are rated moderate — including this one.

Onset

unspecified

Evidence

theoretical

Severity

Moderate

What happens

Reduced efficacy phenytoin or fosphenytoin (prodrug of phenytoin) and an increased risk or frequency of seizures

Interaction Deep Dive

Concomitant use of leucovorin with phenytoin or fosphenytoin (prodrug of phenytoin) may reduce phenytoin or fosphenytoin (antiepileptic drug) exposure and thereby increase the frequency of seizures¹. Monitor the patient for seizure control if high doses of leucovorin are administered concurrently with phenytoin or fosphenytoin ².

Why it happens (mechanism)

Interference of leucovorin (folinic or folic acid) in phenytoin or fosphenytoin (prodrug of phenytoin) absorption

Common questions

Can I take Phenytoin and Leucovorin together?

Reduced efficacy phenytoin or fosphenytoin (prodrug of phenytoin) and an increased risk or frequency of seizures Always confirm with your pharmacist or prescriber before making any change.

How serious is the Phenytoin and Leucovorin interaction?

It is rated moderate. Can be significant — usually manageable with monitoring.

How quickly could this interaction happen?

The documented onset is "unspecified". The timing of this interaction is not well characterized.

How strong is the evidence for this interaction?

The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.

Questions for your pharmacist

Does my dose of Phenytoin or Leucovorin 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 anything you'd monitor while I'm on both?

References (2)

Product Information: VYKOURA™ intramuscular, intravenous injection, leucovorin calcium intramuscular, intravenous injection. Avyxa Pharma LLC (per FDA), Denville, NJ, 2026.
Product Information: leucovorin calcium oral tablets, leucovorin calcium oral tablets. Roxane Laboratories Inc, Columbus, OH, 2005. DailyMed

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Phenytoin

Keep reading about Phenytoin

All Phenytoin interactions (237)

Also serious with: Doravirine Lurasidone Cabotegravir Fostemsavir

Leucovorin

Keep reading about Leucovorin

All Leucovorin interactions (13) Leucovorin drug information

Also serious with: Capecitabine Fluorouracil Fluorouracil Injection Fluorouracil Topical

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

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

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A message from HelloPharmacist

About our interaction database: depth, not breadth

HelloPharmacist doesn't license one of the big commercial interaction databases, so what you'll find here is not a complete list of every known drug interaction. Instead, each entry is researched, analyzed, and written up individually — documented from the published literature, reviewed by a pharmacist, and cited so you can check every source yourself.

If a combination isn't listed here, it means we haven't documented it yet — never that it's safe. For screening a full medication list, we recommend pairing this site with a comprehensive tool like the Drugs.com Interaction Checker and, most importantly, a review by your own pharmacist. For a deep, plain-English, fully sourced explanation of a specific documented interaction — that's exactly what we built this for.

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.