Phenytoin and Simvastatin: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 4, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Phenytoin
Simvastatin
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.
Phenytoin can make your simvastatin work less well. Phenytoin (Dilantin) speeds up the liver enzymes that break down simvastatin (Zocor). When those enzymes work faster, more of your simvastatin gets cleared out before it can do its job, so less of it is available to lower your cholesterol.
This doesn't happen overnight, it builds up over time. The good news is that this is very manageable. Your care team can check your cholesterol numbers and, if needed, adjust your simvastatin dose so it still works for you. Please don't change either medicine on your own, just bring it up with your pharmacist or doctor.
Effect: Reduced simvastatin exposure via phenytoin (and its prodrug fosphenytoin) inducing CYP3A4-mediated hepatic metabolism of simvastatin.
- Direction: Enzyme induction lowers simvastatin AUC/Cmax, potentially reducing lipid-lowering efficacy.
- Onset: Delayed (induction develops and reverses over days to weeks).
- Evidence: Probable; severity rated major.
- Management: Monitor lipid panel for adequate response. Simvastatin dose may need to be adjusted and individualized when phenytoin/fosphenytoin is started or stopped, since withdrawal removes the induction and can raise simvastatin levels.
What happens
Reduced simvastatin exposure
Interaction Deep Dive
Giving phenytoin or fosphenytoin (the prodrug of phenytoin) together with simvastatin has been shown to lower simvastatin exposure. When phenytoin or fosphenytoin is either introduced into or removed from a patient's regimen, consider adjusting the simvastatin dose to attain an optimal clinical response123.
Why it happens (mechanism)
Induction of CYP3A4-mediated metabolism of simvastatin; induction of hepatic drug-metabolizing enzymes by phenytoin
How to manage this interaction
Keep taking both medications as prescribed unless your prescriber tells you otherwise. This interaction is manageable.
- Your care team may check your cholesterol (lipid panel) to confirm your simvastatin is still working well.
- Your simvastatin dose may need to be adjusted and individualized, especially whenever phenytoin (or fosphenytoin) is added to or removed from your regimen.
- Tell your pharmacist and doctor about any recent changes to your seizure medicine.
- Ask before starting or stopping either drug so your team can plan for the change.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) A 50-year-old woman was taking simvastatin 10 mg daily for familial hypercholesterolemia and had a total cholesterol of 9.4 mmol/L and a triglyceride level of 1.87 mmol/L. Her additional medications included sodium valproate 200 mg three times daily for epilepsy. Her anticonvulsant was changed to phenytoin 325 mg daily, and three months afterward her cholesterol had risen to 15.99 mmol/L. The serum activity of gamma-glutamyl transpeptidase, which had been within the normal range (5 Units/L to 50 Units/L) prior to phenytoin, was also raised at 175 Units/L. Simvastatin was raised to 40 mg in a step-wise manner, without resolution. Her lipid-lowering therapy was changed to fluvastatin 40 mg daily and eventually to atorvastatin, begun at 10 mg daily and increased step-wise to 80 mg daily. Her cholesterol remained above 10 mmol/L throughout these adjustments, while phenytoin concentrations stayed within the therapeutic range. Phenytoin was gradually stopped, and her total cholesterol fell to 6.24 mmol/L while gamma-glutamyl transpeptidase returned to normal values 4.
Common questions
Can I take Phenytoin and Simvastatin together?
Phenytoin speeds up how your body clears simvastatin, so your cholesterol medicine may work less well; your care team can check your lipids and adjust the simvastatin dose to keep it effective. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Phenytoin and Simvastatin 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 is the Phenytoin and Simvastatin interaction managed?
Keep taking both medications as prescribed unless your prescriber tells you otherwise. This interaction is manageable. Your care team may check your cholesterol (lipid panel) to confirm your simvastatin is still working well. Your simvastatin dose may need to be adjusted and individualized, especially whenever phenytoin (or fosphenytoin) is added to or removed from your regimen. Tell your pharmaci… Management is individual — always follow your own care team's guidance.
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 Phenytoin or Simvastatin 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: FOSPHENYTOIN SODIUM intravenous and intramuscular injection, fosphenytoin sodium intravenous and intramuscular injection. SAGENT Pharmaceuticals (per Dailymed), Schaumburg, IL, 2024. DailyMed
- Product Information: PHENYTOIN SODIUM intravenous and intramuscular injection, phenytoin sodium intravenous and intramuscular injection. Acella Pharmaceuticals, LLC (per Dailymed), Alpharetta, GA, 2024. DailyMed
- Product Information: PHENYTOIN SODIUM oral extended-release capsules, phenytoin sodium oral extended-release capsules. Sun Pharmaceutical Industries, Inc. (per Dailymed), Cranbury, NJ, 2023. DailyMed
- Murphy MJ & Dominiczak MH: Efficacy of statin therapy: possible effect of phenytoin. Postgrad Med 1999; 75:359-360. PubMed
Keep reading about Phenytoin
Keep reading about Simvastatin
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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