Phenytoin and Metronidazole: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Phenytoin
Metronidazole
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.
What happens
An increased risk of phenytoin toxicity or reduced metroNIDAZOLE exposure
Interaction Deep Dive
A pharmacokinetic study of concurrent use of metroNIDAZOLE and phenytoin resulted in a small decrease in phenytoin clearance and an increase in half-life3. However, drugs which induce microsomal liver enzymes, such as phenytoin, may increase the elimination of metroNIDAZOLE, resulting in reduced plasma levels of metroNIDAZOLE 21.
Why it happens (mechanism)
Inhibition of phenytoin metabolism ; induction of CYP450 liver enzymes-mediated metabolism of metroNIDAZOLE
Literature reports
2 reports — tap to read
a) Concomitant administration of oral metroNIDAZOLE and IV phenytoin was reported to result in prolongation of the half-life and reduction in the clearance of phenytoin. In this study, phenytoin 300 mg IV was given to volunteers who had been receiving oral metroNIDAZOLE 250 mg 3 times daily for 4 days. The total clearance of phenytoin was reduced from 24 to 20 mL/min with combined therapy, whereas the half-life was increased from 16 to 23 hours. It is speculated that effects on clearance are related to impairment of aromatic hydroxylation of phenytoin by metroNIDAZOLE. The kinetics of oral ALPRAZolam (metabolized by aliphatic hydroxylation) and intravenous LORazepam (metabolized by glucuronide conjugation) were unimpaired with concurrent metroNIDAZOLE in this study. As previous reports have indicated that metroNIDAZOLE can impair the clearance of warfarin (metabolized by aliphatic hydroxylation), it is speculated that there is no apparent way to predict which drugs will be influenced by metroNIDAZOLE administration, despite its capacity to impair the clearance of certain oxidatively metabolized drugs 3.
b) In a pharmacokinetic study in healthy subjects, a single oral dose of phenytoin 300 mg was administered before and after 5 days of metroNIDAZOLE 400 mg twice daily. There were no changes in phenytoin half-life, volume of distribution, or elimination 4.
Common questions
Can I take Phenytoin and Metronidazole together?
An increased risk of phenytoin toxicity or reduced metroNIDAZOLE exposure Always confirm with your pharmacist or prescriber before making any change.
How serious is the Phenytoin and Metronidazole 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 "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Phenytoin or Metronidazole 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 (4)
- Product Information: LIKMEZ(TM) oral suspension, metronidazole oral suspension. Saptalis Pharmaceuticals LLC (per FDA), Hauppauge, NY, 2023. DailyMed
- Product Information: FLAGYL ER(R) oral extended-release tablets, metronidazole oral extended-release tablets. Pfizer (per FDA), New York, NY, 2023. DailyMed
- Blyden GT, Scavone JM, & Greenblatt DJ: Metronidazole impairs clearance of phenytoin but not alprazolam or lorazepam. J Clin Pharmacol 1988; 28:240-245.
- Jensen JC & Gugler R: Interaction between metronidazole and drugs eliminated by oxidative metabolism. Clin Pharmacol Ther 1985; 37:407-410. PubMed
Keep reading about Phenytoin
Keep reading about Metronidazole
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:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
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