Acetazolamide and Phenytoin: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Jul 10, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Phenytoin
Acetazolamide
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
An increased risk of osteomalacia
Interaction Deep Dive
Coadministration of acetaZOLAMIDE with phenytoin may increase serum levels of phenytoin as acetaZOLAMIDE modifies phenytoin metabolism. This may increase or enhance the occurrence of osteomalacia in some patients receiving chronic phenytoin therapy. Use caution with the coadministration of acetaZOLAMIDE and chronic phenytoin therapy1. Coadministration of acetaZOLAMIDE and phenytoin may produce osteomalacia if these medications are used on a long-term basis 3425. Significant, immediate reductions in calcium excretion rates were noted when patients with osteomalacia discontinued use of acetaZOLAMIDE.2.
Why it happens (mechanism)
Additive adverse effects including excessive urinary excretion of calcium and phosphate, systemic acidosis, and/or hypophosphatemia
Literature reports
1 report — tap to read
a) Two female patients were treated for seven to 12 years with acetaZOLAMIDE 750 mg/day, in addition to phenytoin or primidone and phenobarbital, for atypical seizures. Severe osteomalacia with multiple pseudofractures, hypocalcemia, and increased alkaline phosphatase were found in both cases. Additionally, the patients were noted to have marked hyperchloremic acidosis with high urinary calcium excretion in relation to blood concentrations of calcium. Discontinuation of acetaZOLAMIDE resulted in resolution of the hyperchloremic acidosis and reduction of calcium excretion. In one patient, the rate of urinary calcium excretion fell from 170 mg/day to 56 mg/day after acetaZOLAMIDE was withdrawn. In the other patient, urinary calcium excretion dropped from 114 mg/day to 30 mg/day with cessation of acetaZOLAMIDE 2.
Common questions
Can I take Acetazolamide and Phenytoin together?
An increased risk of osteomalacia Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetazolamide 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 Acetazolamide 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 (5)
- Product Information: Acetazolamide oral extended-release capsules, acetazolamide oral extended-release capsules. Micro Labs USA Inc (per DailyMed), Somerset, NJ, 2022. DailyMed
- Mallette LE: Acetazolamide-accelerated anticonvulsant osteomalacia. Arch Intern Med 1977; 137:1013-1017. DOI
- Mallette LE: Anticonvulsants, acetazolamide and osteomalacia (letter). N Engl J Med 1975; 293:668. DOI
- Matsuda I, Takekoshi Y, Shida N, et al: Renal tubular acidosis and skeletal demineralization in patients on long-term anticonvulsant therapy. J Pediatr 1975; 87:202-205. DOI
- Lifshitz F & MacLaren NK: Vitamin D-dependent rickets in institutionalized, mentally retarded children receiving long-term anticonvulsant therapy: I. a survey of 288 patients. J Pediatr 1973; 83:613-621. PubMed
Keep reading about Phenytoin
Keep reading about Acetazolamide
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:
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