Drug Interaction Report

Phenytoin and Aspirin Rectal: Interaction Details

A pharmacist-reviewed analysis of the Phenytoin and Aspirin Rectal interaction: the documented clinical effects, severity rating, onset, mechanism, and management considerations, with cited references throughout.

AI-assisted, pharmacist-reviewed · Source data updated Jul 11, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature

Phenytoin

Dilantin Phenytek
+

Aspirin Rectal

Aspirin
Dr. Brian Staiger, PharmD, BCPS
Medically reviewed by
Dr. Brian Staiger, PharmD, BCPS
Updated Jul 11, 2026
Editorial policy · Data sources
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Interaction severity
Major
Potentially serious — often needs a change or close monitoring.
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, 191 are rated major — including this one.
Worried about symptoms right now? Contact your pharmacist or prescriber, or call Poison Control at 1-800-222-1222 (US). Call 911 for an emergency.
Onset
delayed
Evidence
theoretical
Severity
Major

What happens

Altered phenytoin or fosphenytoin (prodrug of phenytoin) exposure and an increased risk of phenytoin or fosphenytoin toxicity

Interaction Deep Dive

Use caution while using aspirin and phenytoin or fosphenytoin (prodrug of phenytoin) concomitantly. During coadministration, aspirin can displace protein-bound phenytoin and may result in reduced exposure of phenytoin or fosphenytoin1. Concurrent administration of phenytoin or fosphenytoin and aspirin (salicylate) have resulted in increased exposure of phenytoin or fosphenytoin and lead to toxicity. Monitor patients for signs of phenytoin or fosphenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremor) when receiving aspirin concurrently. Consider phenytoin or fosphenytoin dose adjustments to achieve optimal clinical response when aspirin is added to or withdrawn from a patient's regimen. Monitor phenytoin or fosphenytoin serum drug level during concurrent use of aspirin and phenytoin or fosphenytoin 234.

Why it happens (mechanism)

Unknown; displacement of phenytoin from protein-binding sites

Literature reports

3 reports — tap to read

a) Early reports indicated that concomitant aspirin and phenytoin therapy has been reported to result in possible elevations in phenytoin serum concentrations 5. This interaction is presumably a result of displacement of phenytoin from plasma protein binding sites 6.

b) A study has shown that aspirin reduces total serum phenytoin concentration but does not change salivary phenytoin concentration, indicating free (unbound) phenytoin concentration does not change significantly. Similar results in terms of total and unbound phenytoin concentrations have been reported by 7. Similar results in terms of lower total phenytoin concentrations and relatively constant salivary (free) phenytoin concentrations are reported when patients on chronic phenytoin therapy were given 600 mg aspirin four times daily for 2 days 89.

c) Concomitant phenytoin and aspirin therapy has been reported to result in decreases in total serum phenytoin concentrations with high doses of aspirin (975 mg every 4 hours) but not with lower doses (325 mg or 650 mg every 4 hours), indicating that protein binding displacement of phenytoin by aspirin occurs only at the highest salicylate dose level. Although total serum phenytoin concentrations may decrease during aspirin therapy, free serum phenytoin concentrations appear to be unaffected, thus the phenytoin dose need not be altered in most patients 10.

Common questions

Can I take Phenytoin and Aspirin Rectal together?

Altered phenytoin or fosphenytoin (prodrug of phenytoin) exposure and an increased risk of phenytoin or fosphenytoin toxicity Always confirm with your pharmacist or prescriber before making any change.

How serious is the Phenytoin and Aspirin Rectal 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.

Questions for your pharmacist

  • Does my dose of Phenytoin or Aspirin Rectal 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 (10)

  1. Product Information: CARISOPRODOL, ASPIRIN, CODEINE PHOSPHATE oral tablets, carisoprodol, aspirin, codeine phosphate oral tablets. Ingenus Pharmaceuticals LLC (per DailyMed), Orlando, FL, 2021. DailyMed
  2. Product Information: FOSPHENYTOIN SODIUM intravenous and intramuscular injection, fosphenytoin sodium intravenous and intramuscular injection. SAGENT Pharmaceuticals (per Dailymed), Schaumburg, IL, 2024. DailyMed
  3. Product Information: PHENYTOIN SODIUM intravenous and intramuscular injection, phenytoin sodium intravenous and intramuscular injection. Acella Pharmaceuticals, LLC (per Dailymed), Alpharetta, GA, 2024. DailyMed
  4. Product Information: PHENYTOIN SODIUM oral extended-release capsules, phenytoin sodium oral extended-release capsules. Sun Pharmaceutical Industries, Inc. (per Dailymed), Cranbury, NJ, 2023. DailyMed
  5. Toakley JG: Dilantin overdosage. Med J Aust 1968; 2:640.
  6. Gilman AG, Rall TW, Nies AS, et alGilman AG, Rall TW, Nies AS, et al (Eds): Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th. Macmillan Publishing Co, New York, NY, 1990.
  7. Fraser DG, Ludden TM, Evens RP, et al: Displacement of phenytoin from plasma binding sites by salicylate. Clin Pharmacol Ther 1980; 27:165-169. PubMed
  8. Olanow CW, Finn AL, & Prussak C: The effects of salicylate on the pharmacokinetics of phenytoin. Neurology 1981; 31:341-342. DOI
  9. Paxton JW: Effects of aspirin on salivary and serum phenytoin kinetics in healthy subjects. Clin Pharmacol Ther 1980; 27:170-178. PubMed
  10. Leonard RJ, Knott PJ, Rankin GO, et al: Phenytoin-salicylate interaction. Clin Pharmacol Ther 1981; 29:56-60. DOI
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Phenytoin

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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:

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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.