Acyclovir and Phenytoin: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Jul 10, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Phenytoin
Acyclovir
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
Decreased phenytoin plasma concentrations and potential increased seizure activity
Interaction Deep Dive
A case report documented a reduction in plasma levels of both phenytoin and valproic acid when combined with acyclovir treatment. This reduction resulted in significantly increased seizure activity from approximately 1 per month to 25 in one day1.
Why it happens (mechanism)
Increased gastrointestinal transit or change in gastrointestinal fluid pH
Literature reports
1 report — tap to read
a) According to a case report from the University of Bologna in Italy, a 7-year-old boy with a history of epilepsy experienced increased seizure activity after being treated with acyclovir in addition to his antiepileptic medications. The patient's trough plasma levels of phenytoin and valproic acid were 17 mcg/mL and 32 mcg/mL, respectively, 10 days before starting acyclovir treatment for viral throat and mouth lesions. Four days after initiation of acyclovir treatment, the trough levels were 5 mcg/mL and 22 mcg/mL, respectively. Acyclovir treatment was discontinued after 6 days. Three and 6 days after acyclovir withdrawal, phenytoin and valproic acid plasma levels were still low, and the patient experienced 25 serial partial seizures 5 days after discontinuation. Phenytoin dosage was increased to reach therapeutic plasma levels and the frequency of seizures was reduced to 2 or 3 per week. The authors suggest that further study of this possible interaction is warranted 1.
Common questions
Can I take Acyclovir and Phenytoin together?
Decreased phenytoin plasma concentrations and potential increased seizure activity Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acyclovir and Phenytoin interaction?
It is rated moderate. Can be significant — usually manageable with 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 Acyclovir 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 anything you'd monitor while I'm on both?
References (1)
- Parmeggiani A, Riva R, Posar A, et al: Possible interaction between acyclovir and antiepileptic treatment. Ther Drug Monit 1995; 17:312-315.
Keep reading about Phenytoin
Keep reading about Acyclovir
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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