PYRIMETHAMINE
Clinical safety rating: avoid
Positive evidence of fetus risks but benefits may outweigh risks in some cases
Pyrimethamine inhibits dihydrofolate reductase (DHFR) in the parasite, blocking the conversion of dihydrofolate to tetrahydrofolate, thereby inhibiting nucleic acid synthesis.
| Metabolism | Primarily hepatic, via involvement of CYP450 enzymes (not definitively characterized). Partially metabolized by CYP2C8 and CYP3A4. |
| Excretion | Primarily renal (approximately 30% unchanged and 20-30% as metabolites); additional biliary/fecal elimination (20-30% as metabolites). Total urinary excretion of parent drug and metabolites accounts for 60-80% of dose. |
| Half-life | Terminal elimination half-life is approximately 96 hours (range 80-123 hours) in adults with normal renal function; prolonged in renal impairment (up to 200 hours). This long half-life supports weekly dosing regimens. |
| Protein binding | Approximately 87% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Apparent volume of distribution is 2.3 L/kg (range 1.7-3.0 L/kg), indicating extensive tissue distribution (e.g., kidneys, liver, spleen). |
| Bioavailability | Oral: Well absorbed with absolute bioavailability of 95-100%. |
| Onset of Action | Oral: Onset of antimalarial effect is within 1-2 hours; for toxoplasmosis, clinical response may take 24-48 hours. |
| Duration of Action | Oral: Antimalarial prophylaxis persists for 1 week after a single dose due to long half-life; for toxoplasmosis, treatment duration is typically 4-6 weeks based on clinical response. |
For toxoplasmosis: 200 mg orally once, then 50-75 mg orally once daily for 4-6 weeks, plus sulfadiazine and folinic acid. For malaria prophylaxis: 25 mg orally once weekly.
| Dosage form | TABLET |
| Renal impairment | CrCl <50 mL/min: not recommended; CrCl 50-90 mL/min: no adjustment needed. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: contraindicated. |
| Pediatric use | For toxoplasmosis: 1 mg/kg/day orally divided twice daily (max 25 mg/day) for 2 days, then 1 mg/kg/day once daily (max 25 mg/day) followed by 0.5 mg/kg/day (max 25 mg/day) for 4-6 weeks; plus sulfadiazine and folinic acid. For malaria prophylaxis: <1 year: 6.25 mg once weekly; 1-3 years: 12.5 mg once weekly; 4-8 years: 25 mg once weekly; >8 years: 50 mg once weekly. |
| Geriatric use | Start at lowest adult dose; monitor for folate deficiency and renal function; consider dose adjustment based on renal function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Other drugs that cause folate deficiency can have additive effects Can cause megaloblastic anemia and blood dyscrasias.
| Breastfeeding | Pyrimethamine is excreted into breast milk. Milk-to-plasma ratio (M/P) approximately 0.6-0.8. Concentrations are higher in colostrum. Low oral bioavailability in infants, but risk of hemolysis in G6PD-deficient infants. Use with caution, especially in first month postpartum. Monitor infant for jaundice, pallor, and poor feeding. |
| Teratogenic Risk | Pyrimethamine is a folic acid antagonist and is teratogenic in animals (cleft palate, hydrocephalus). Human data limited but may cause neural tube defects, cardiovascular anomalies, and oral clefts if used in first trimester. Risk may be mitigated by concurrent folinic acid supplementation (not folic acid). Avoid in first trimester unless essential for life-threatening toxoplasmosis. Second and third trimester: risk lower but evidence of potential effects on fetal hematopoiesis (megaloblastic anemia) and growth restriction. All trimesters: monitor fetal growth and amniotic fluid index. |
■ FDA Black Box Warning
Pyrimethamine may cause bone marrow suppression, including pancytopenia, especially with prolonged use or high doses. Concomitant use with sulfonamides may increase risk of severe adverse reactions.
| Common Effects | toxoplasmosis |
| Serious Effects |
Hypersensitivity to pyrimethamine or any component; megaloblastic anemia secondary to folate deficiency; severe hepatic or renal impairment (relative).
| Precautions | Bone marrow suppression (monitor CBC), folic acid supplementation recommended to prevent hematologic toxicity; hepatotoxicity; hypersensitivity reactions; renal impairment; pregnancy (may cause fetal harm); lactation. |
Loading safety data…
| Fetal Monitoring | Maternal: CBC with differential and platelet count weekly (risk of megaloblastic anemia and neutropenia); serum folate and vitamin B12 levels; renal and hepatic function tests. Fetal: Ultrasound for structural anomalies (especially if used in first trimester); serial growth scans for intrauterine growth restriction (IUGR). Neonatal: CBC at birth for cytopenias; assess for hemolysis if G6PD screen positive. |
| Fertility Effects | No direct human studies on fertility. Animal studies suggest reversible suppression of spermatogenesis at high doses. Folate antagonism may theoretically impair ovulation and implantation; concurrent folinic acid is recommended to mitigate. No evidence of permanent infertility. |