Atorvastatin and Fosphenytoin: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Jul 15, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Atorvastatin
Fosphenytoin
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
Reduced atorvastatin exposure and reduced efficacy of atorvastatin
Interaction Deep Dive
Concomitant use of atorvastatin and phenytoin or fosphenytoin (prodrug of phenytoin) may result in reduced atorvastatin exposure and reduced therapeutic effect due to induction of CYP3A4-mediated atorvastatin metabolism. In a pharmacokinetic study (n=44) of the concomitant administration of atorvastatin and phenytoin, the AUC and Cmax of atorvastatin was reduced by 54% and 24%, respectively, compared with administration of atorvastatin alone. Monitor patients receiving concomitant atorvastatin and phenytoin or fosphenytoin (prodrug of phenytoin) for atorvastatin efficacy and atorvastatin dosage adjustment may be necessary1, to achieve optimal clinical response when phenytoin or fosphenytoin is added to or withdrawn from a patient's regimen 345.
Why it happens (mechanism)
Induction of CYP3A4-mediated metabolism of atorvastatin; induction of hepatic drug-metabolizing enzymes by phenytoin
Literature reports
2 reports — tap to read
a) In an open-label pharmacokinetic study, coadministration of atorvastatin and phenytoin reduced atorvastatin AUC and Cmax by 54% and 24%, respectively, compared with administration of atorvastatin alone. Healthy subjects (n=44) received atorvastatin 40 mg once daily for 7 days, then on days 8 to 28 all participants received daily atorvastatin 40 mg plus oral phenytoin at a target dose of 4 mg/kg/day. On days 7 and 28, the mean atorvastatin AUC was 63.4 nanogram(ng) x hr/mL (95% CI, 54.3 to 74 ng x hr/mL) and 29.2 ng x hr/mL (95% CI, 24.4 to 35 ng x hr/mL), respectively. The mean atorvastatin Cmax was 12.1 nanogram/mL (21.7 nanomol/L) on day 7, compared with 9.2 nanogram/mL (16.5 nanomol/L) on day 28. When atorvastatin is coadministered with phenytoin, atorvastatin dosage may need to be increased to maintain its exposure 1.
b) A 50-year-old woman was receiving simvastatin 10 mg daily for familial hypercholesterolemia and had a total cholesterol level of 9.4 mmol/L and a triglyceride level of 1.87 mmol/L. Other medications included sodium valproate 200 mg 3 times daily for epilepsy. Her anticonvulsant medication was switched to phenytoin 325 mg daily, and 3 months later her cholesterol had increased to 15.99 mmol/L. Serum activity of gamma-glutamyl transpeptidase, which was in the normal range (5 units/L to 50 units/L) before phenytoin, was also elevated at 175 units/L. Simvastatin was increased to 40 mg in a step-wise manner, with no resolution. Anti-lipidemic therapy was switched to fluvastatin 40 mg daily and finally to atorvastatin, starting at 10 mg daily and increasing in a step-wise fashion to 80 mg daily. Her cholesterol stayed in excess of 10 mmol/L throughout these changes, while phenytoin levels remained within the therapeutic range. Phenytoin was slowly discontinued, and her total cholesterol decreased to 6.24 mmol/L while gamma-glutamyl transpeptidase returned to normal values 2.
Common questions
Can I take Atorvastatin and Fosphenytoin together?
Reduced atorvastatin exposure and reduced efficacy of atorvastatin Always confirm with your pharmacist or prescriber before making any change.
How serious is the Atorvastatin and Fosphenytoin 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 "established". Well documented — supported by controlled studies or strong clinical data.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Atorvastatin or Fosphenytoin 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 (5)
- Bullman J, Nicholls A, Van Landingham K, et al: Effects of lamotrigine and phenytoin on the pharmacokinetics of atorvastatin in healthy volunteers. Epilepsia 2011; 52(7):1351-1358. PubMed
- Murphy MJ & Dominiczak MH: Efficacy of statin therapy: possible effect of phenytoin. Postgrad Med 1999; 75:359-360. PubMed
- 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
Keep reading about Atorvastatin
Keep reading about Fosphenytoin
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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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