Pyrimethamine and Folic Acid: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Folic Acid
Pyrimethamine
No brand names on record
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 efficacy of folic acid
Interaction Deep Dive
Concomitant use of pyrimethamine and folic acid may increase the risk of bone marrow suppression2. The mode of action of pyrimethamine is inhibition of dihydrofolic acid reductase in disease-causing parasites. If folic acid is given with pyrimethamine to prevent bone marrow depression in HIV-positive or other patients, the folic acid can cause a pharmacodynamic antagonism of the antiparasitic effect of pyrimethamine. Pyrimethamine with leucovorin (folinic acid) is recommended for the treatment of toxoplasmic encephalitis in HIV-infected patients. Leucovorin is administered to lessen the bone marrow suppression and other toxicities associated with pyrimethamine therapy 7. Concomitant use of folic acid with antifolate agents, including pyrimethamine, directly inhibit dihydrofolate reductase, reducing the formation of active folate derivatives. If coadministered, monitor for reduced efficacy and adjust the dose of folic acid as needed 1.
Why it happens (mechanism)
Pharmacodynamic antagonism
Literature reports
2 reports — tap to read
a) Leucovorin (folinic acid) does not antagonize pyrimethamine and may be given as folate supplementation in pyrimethamine-treated patients with toxoplasmosis or Pneumocystis pneumonia 34. Neither folic acid nor leucovorin antagonizes pyrimethamine in the treatment of malaria due to specific factors related to the microorganism Plasmodium falciparum 5. One report suggests that leucovorin should not be used with pyrimethamine for the treatment of toxoplasmosis or Pneumocystis infection in patients with leukemia as it may induce hematologic relapse of the leukemia 6.
b) The mode of action of pyrimethamine is inhibition of dihydrofolic acid reductase in disease-causing parasites. If folic acid is given with pyrimethamine to prevent bone marrow depression in HIV-positive or other patients, the folic acid can cause a pharmacodynamic antagonism of the antiparasitic effect of pyrimethamine. Pyrimethamine with leucovorin (folinic acid) is recommended for the treatment of toxoplasmic encephalitis in HIV-infected patients. Leucovorin is administered to lessen the bone marrow suppression and other toxicities associated with pyrimethamine therapy 7.
Common questions
Can I take Pyrimethamine and Folic Acid together?
Reduced efficacy of folic acid Always confirm with your pharmacist or prescriber before making any change.
How serious is the Pyrimethamine and Folic Acid 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 Pyrimethamine or Folic Acid 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 (7)
- Product Information: QUIOFIC™ oral solution, folic acid oral solution. Solubiomix, LLC (per Dailymed), Madisonville, LA, 2026. DailyMed
- Product Information: Daraprim(R), pyrimethamine. GlaxoSmithKline, Research Triangle Park, NC, 2002. DailyMed
- Van Delden C & Hirschel B: Folinic acid supplements to pyrimethamine-sulfadiazine for Toxoplasma encephalitis are associated with better outcomes. J Infect Dis 1996; 173:1294-1295. PubMed
- Kirby HB, Kenamore B, & Guckian JC: Pneumocystis carinii pneumonia treated with pyrimethamine and sulfadiazine. Ann Intern Med 1971; 75:505-509.
- Tong MJ, Strickland GT, Botteri BA, et al: Supplemental folates in the therapy of Plasmodium falciparum malaria. JAMA 1970; 214:2330-2333. DOI
- Helmer RE III: Hazard of folinic acid with pyrimethamine and sulfadiazine (letter). Ann Intern Med 1975; 82:124-125. PubMed
- Richards F, Kovac J, & Luft B: Preventing toxoplasmic encephalitis in persons infected with human immunodeficiency virus. Clin Infect Dis 1995; 21(suppl 1):S49-S56. DOI
Keep reading about Folic Acid
Keep reading about Pyrimethamine
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