Omeprazole and Fosphenytoin: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 2, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Fosphenytoin
Omeprazole
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.
You've been prescribed fosphenytoin (which your body turns into phenytoin, a seizure medicine) along with omeprazole (Prilosec) for stomach acid. Here's the concern: omeprazole may slow down how your body breaks down phenytoin, so the phenytoin can build up higher than expected. Phenytoin has a narrow safe range, so even a small increase can cause side effects like unsteady walking, tremor, or jerky eye movements. At the same time, the phenytoin may make the omeprazole work a bit less.
This is based mostly on theory, not lots of real-world cases, so please don't worry. Keep taking both exactly as prescribed and let your care team know. They can check blood levels and adjust things easily.
Direction: Omeprazole inhibits CYP2C19-mediated metabolism of phenytoin (the active moiety from the prodrug fosphenytoin), potentially increasing phenytoin exposure and toxicity risk. Phenytoin may also induce CYP2C19, reducing omeprazole exposure.
- Effect: Elevated phenytoin levels (ataxia, nystagmus, hyperreflexia, tremor); diminished omeprazole efficacy.
- Onset: Delayed. Evidence: Theoretical.
- NTI drug: Phenytoin has a narrow therapeutic index; small AUC changes are clinically meaningful.
Management: Monitor serum phenytoin levels and clinical signs of toxicity; individualize/adjust phenytoin dosing. Consider an H2-receptor antagonist for GI protection instead of a PPI, particularly where CYP2C9/2C19 polymorphism status is unknown.
What happens
Increased phenytoin exposure or fosphenytoin (prodrug of phenytoin), an increased risk of phenytoin or fosphenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremor) and reduced omeprazole exposure
Interaction Deep Dive
When omeprazole is given together with phenytoin or fosphenytoin (the prodrug of phenytoin), the exposure to phenytoin or fosphenytoin may rise2. In addition, taking phenytoin or fosphenytoin alongside omeprazole (a CYP2C19 substrate) may lower omeprazole exposure. In patients receiving omeprazole at the same time, watch for indications of phenytoin or fosphenytoin toxicity such as ataxia, hyperreflexia, nystagmus, and tremor 34. Serum levels of phenytoin or fosphenytoin should be checked, and a dose adjustment of phenytoin or fosphenytoin may be required 15; when CYP2C9 polymorphisms have not been determined, an alternative to a proton pump inhibitor, namely a histamine-2 (H2) receptor antagonist, can be considered for gastrointestinal protection 6.
Why it happens (mechanism)
Inhibition of CYP2C19-mediated metabolism of phenytoin; induction of CYP2C19-mediated metabolism of omeprazole
How to manage this interaction
Good news: this is manageable, and you should keep taking both medicines as prescribed unless your prescriber tells you otherwise.
- Your team may check your phenytoin blood level and watch for toxicity signs (unsteadiness, tremor, jerky eye movements, overactive reflexes).
- Your phenytoin dose may need to be adjusted and individualized by your care team based on those levels.
- Your team may consider a different acid-reducing medicine, such as an H2 blocker (like famotidine), instead of omeprazole.
Tell your pharmacist or prescriber that you take both, and report any new dizziness, tremor, or unsteadiness promptly.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) A 5-year-old child who was homozygous for the CYP2C9*3 variant developed phenytoin toxicity after receiving phenytoin along with omeprazole following a severe head injury. On admission, phenytoin 5 mg/kg twice daily and omeprazole 0.8 mg/kg daily were started, and during the first 3 days intracranial pressure remained normal with no neurological deficits. On day 3, an MRI showed multiple small hemorrhagic contusions within the white matter of the frontal, parietal, and temporal lobes. On day 8, phenytoin was stopped after the patient had 2 failed extubations associated with worsening respiratory distress accompanied by psychomotor agitation and tachypnea. By day 10, the patient was awake but had loss of awareness, horizontal nystagmus, central neurological hyperventilation, positive bilateral Babinski signs, and prolonged I to V interpeak latency on brainstem auditory evoked potentials. EEG evaluation showed frontal intermittent rhythmic delta activity. Phenytoin concentrations stayed abnormally elevated (greater than 35 mcg/mL) 5 days after the drug was withdrawn. Once omeprazole was discontinued, phenytoin levels fell markedly over the next 3 days. The patient's neurological findings and breathing returned to normal. Sequencing analysis identified impaired CYP2C9 metabolism as the cause of the phenytoin intoxication 6.
Common questions
Can I take Omeprazole and Fosphenytoin together?
Omeprazole can raise phenytoin (from fosphenytoin) levels toward the toxic range while phenytoin may weaken omeprazole, so ask your care team about checking phenytoin levels or switching to an H2 blocker for acid protection. Keep taking both as prescribed until they advise you. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Omeprazole 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 is the Omeprazole and Fosphenytoin interaction managed?
Good news: this is manageable, and you should keep taking both medicines as prescribed unless your prescriber tells you otherwise. Your team may check your phenytoin blood level and watch for toxicity signs (unsteadiness, tremor, jerky eye movements, overactive reflexes). Your phenytoin dose may need to be adjusted and individualized by your care team based on those levels. Your team may consider… Management is individual — always follow your own care team's guidance.
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 Omeprazole 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 (6)
- Product Information: PRILOSEC(R) oral delayed-release capsules, omeprazole oral delayed-release capsules. AstraZeneca Pharmaceuticals LP (per FDA), Wilmington, DE, 2018. DailyMed
- Product Information: KONVOMEP(TM) powder for oral suspension, omeprazole sodium bicarbonate powder for oral suspension. Azurity Pharmaceuticals Inc (per manufacturer), Woburn, MA, 2022. DailyMed
- 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
- Marano M, Nicoletti F, Pro S, et al: Phenytoin intoxication associated with omeprazole administration in a child with defective CYP2C9. Eur J Clin Pharmacol 2020; 76(5):731-732. PubMed
Keep reading about Fosphenytoin
Keep reading about Omeprazole
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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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