Drug Interaction Report

Folic Acid and Phenytoin: Interaction Details

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

AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature

Phenytoin

Dilantin Phenytek
+

Folic Acid

Folacin Folicet® Folvite® Quiofic
Dr. Brian Staiger, PharmD, BCPS
Medically reviewed by
Dr. Brian Staiger, PharmD, BCPS
Updated Aug 8, 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 94 documented Folic Acid interactions, 14 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
probable
Severity
Major

What happens

Reduced folic acid exposure and reduce phenytoin or fosphenytoin (prodrug of phenytoin) exposure

Interaction Deep Dive

Concurrent use of folic acid and phenytoin or fosphenytoin (prodrug of phenytoin) has resulted in increased seizure frequency in some epileptic patients on phenytoin or fosphenytoin therapy who received supplemental oral folic acid. Reduced phenytoin levels were observed in folate-deficient patients who received 5 mg or 15 mg of folic acid daily1. Monitor patients for signs of phenytoin or fosphenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremor) when receiving folic acid concurrently. Consider phenytoin or fosphenytoin dose adjustments to achieve optimal clinical response when folic acid is added to or withdrawn from a patient's regimen. Monitor phenytoin or fosphenytoin serum drug level during concurrent use of folic acid and phenytoin or fosphenytoin 234.

Why it happens (mechanism)

Reduced folate absorption; increased phenytoin metabolism

Literature reports

6 reports — tap to read

a) Subnormal serum folate concentrations occur in 27% to 91% of patients receiving long-term phenytoin 56. Progression to megaloblastic anemia occurs in less than 1% of patients 768, although macrocytosis is common 910116.

b) Reduced folate concentrations in RBCs and cerebrospinal fluid (CSF) have also been identified in patients receiving chronic phenytoin therapy. The development of subnormal folate levels in this patient population does not appear related to dose, duration of therapy, or serum levels 1213141516.

c) Several studies have addressed the effect of folic acid supplementation on the serum concentrations of phenytoin. In 5 subjects receiving phenytoin 300 mg daily, blood phenytoin levels were measured for 10 days, then patients were started on folic acid 10 mg daily for 15 days. Phenytoin blood levels decreased by 15% to 45% within 10 days 17. A similar study found a mean decrease in serum phenytoin levels of 16% 18. Two studies reported significant decreases in phenytoin blood levels in a total of 62 epileptic patients receiving folic acid 5 to 15 mg daily. One study showed 11 of 12 patients had decreases in serum phenytoin levels up to 20%, with one patient experiencing a drop of 50% 5. Reports have described a patient receiving folic acid 5 mg daily who had increased frequency and severity of seizures after 10 days of therapy 19.

d) Case studies have also described decreased phenytoin concentrations and subsequent loss of seizure control as a result of folic acid supplementation 2021. Some uncontrolled studies have also reported a loss of seizure control 8. However, numerous large controlled studies, mostly double-blind, have found no significant difference in mean seizure frequency when a group of folate-deficient epileptic patients treated with folic acid was compared with a similar group receiving placebo 62223242526.

e) It may be possible that both indirect effects upon phenytoin's pharmacokinetic disposition and direct effects on seizure frequency are involved in folate's interaction with phenytoin. Several studies indicate that folic acid supplementation increases phenytoin liver metabolism; two studies suggest increased phenytoin parahydroxylation 2725, and another suggests increased O-methylation of the catechol metabolite 17. One study concluded that folic acid does not stimulate phenytoin metabolism, but that change in the rates of different elimination pathways was responsible 28. Evidence of a direct effect includes animal data which demonstrates strong seizure-evoking potential of folic acid, especially when injected directly into the third ventricle of the brain 293031.

f) Although several controlled studies with folate showed no significant effect on seizure frequency in patients controlled with phenytoin, one author theorized that the studies may not have been conducted over a sufficient period of time, since cerebrospinal fluid (CSF) folate concentrations may take several months to rise. However, this does not explain why short-term folate therapy can markedly increase seizure frequency in some patients previously stabilized on phenytoin 8.

Common questions

Can I take Folic Acid and Phenytoin together?

Reduced folic acid exposure and reduce phenytoin or fosphenytoin (prodrug of phenytoin) exposure Always confirm with your pharmacist or prescriber before making any change.

How serious is the Folic Acid and Phenytoin 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 "probable". Good supporting evidence, though not definitively proven.

Questions for your pharmacist

  • Does my dose of Folic Acid 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 a safer alternative to one of these medications for me?

References (31)

  1. Product Information: folic acid oral tablets, folic acid oral tablets. Trimarc Laboratories, Oklahoma City, OK, 2006. 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. Reynolds EH: Diphenylhydantoin: Hematologic aspects of toxicity In: Woodbury DM, Penry JK, & Schmidt RP (Eds): Antiepileptic drugs, Raven Press, New York, NY, 1972, pp 247-262.
  6. Rivey MP, Schottelius DD, & Berg MJ: Phenytoin-folic acid: a review. Drug Intell Clin Pharm 1984; 18:292-301. PubMed
  7. Flexner JM & Hartmann RC: Megaloblastic anemia associated with anticonvulsant drugs. Am J Med 1960; 28:386-396. DOI
  8. MacCosbe PE & Toomey K: Interaction of phenytoin and folic acid. Clin Pharm 1983; 2:362-369.
  9. Reynolds EH, Milner G, Matthew DM, et al: Anticonvulsant therapy, megaloblastic haemopoiesis and folic acid metabolism. Q J Med 1966; 35:521-537. DOI
  10. Klipstein FA: Subnormal serum folate and macrocytosis associated with anticonvulsant drug therapy. Blood 1964; 23:68-85. DOI
  11. Ibbotson RN, Dilena BA, & Horwood JM: Studies on deficiency and absorption of folates in patients on anticonvulsant drugs. Aust Ann Med 1967; 16:144-150. DOI
  12. Dahike MB & Mertens-Roesler E: Malabsorption of folic acid due to diphenyihydantoin. Blood 1967; 30:341-351.
  13. Preece J, Reynolds EH, & Johnson AL: Relation of serum to red cell folate concentrations in drug treated epileptic patients. Epilepsia 1971; 12:335-340. PubMed
  14. Wells DG & Casey HJ: Lactobacillus casei CSF folate activity. Br Med J 1967; 3:834-836.
  15. Reynolds EH, Preece J, & Chanarin I: Folic acid and anticonvulsants. Lancet 1969; 1:1264-1265. DOI
  16. Reizenstein P & Lund L: Effect of anticonvulsive drugs in folate absorption and the cerebrospinal folate pump. Scand J Haematol 1973; 11:158-165.
  17. Glazko AJ: Antiepileptic drugs: biotransformation, metabolism, and serum half-life. Epilepsia 1975; 16:367-391. PubMed
  18. Furlanut M, Benetello P, Avogaro A, et al: Effects of folic acid on phenytoin kinetics in healthy subjects. Clin Pharmacol Ther 1978; 24:294-297.
  19. Baylis EM, Crowley JM, Preece JM, et al: Influence of folic acid on blood-phenytoin levels. Lancet 1971; 1:62-64. PubMed
  20. Strauss RG & Bernstein R: Folic acid and dilantin antagonism in pregnancy. Obstet Gynecol 1974; 44:45-48.
  21. Arellano-Isaac C & Rivera-Calimlim L: Phenytoin neurotoxicity. Drug Ther 1978; 8:152-163.
  22. Houben PF, Hommes OR, & Knaven PJ: Anticonvulsant drugs and folic acid in young mentally retarded epileptic patients. A study of serum folate, fit frequency, and IQ. Epilepsia 1971; 21:235-247. DOI
  23. Norris JW & Pratt RF: A controlled study of folic acid in epilepsy. Neurology 1971; 21:659-664. DOI
  24. Ralston AJ, Snaith RP, & Hinley JB: Effects of folic acid on fit-frequency and behavior in epileptics on anticonvulsants. Lancet 1970; 1:867-868.
  25. Makki KA, Perucca E, & Richens A: Metabolic effects of folic acid replacement therapy in folate-deficient epileptic patients In: Johannessen SI, Morselli PI, & Pippenger CE (Eds): Antiepileptic therapy: advances in drug monitoring, Raven Press, New York, NY, 1980, pp 391-396. DOI
  26. Mattson RH, Gallagher BB, Reynolds EH, et al: Folate therapy in epilepsy. Arch Neurol 1973; 29:78-81. DOI
  27. Kutt H, Winters W, & McDowell FH: Depression of parahydroxylation of diphenylhydantoin by antituberculosis chemotherapy. Neurology 1966; 16:594-602. DOI
  28. Andreason PB, Hansen JM, Skovsted L, et al: Folic acid and the half-life of diphenylhydantoin in man. Acta Neurol Scand 1971; 47:117-119. PubMed
  29. Hommes OR, Obbens EAMT, & Wijffels CCB: Epileptogenic activity of sodium-folate and the blood-brain barrier in the rat. J Neurol Sci 1973; 19:63-71. DOI
  30. Hommes OR & Obbens EAMT: The epileptogenic action of Na-folate in the rat. J Neurol Sci 1972; 16:271-281. PubMed
  31. Noell WK, Magoss MS, Cohen LH, et al: Cerebral effects of folic acid, pyrimidines, amino acids and their antimetabolites. EEGJ 1960; 12:238.
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Beyond drug–drug

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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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