DARAPRIM
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DARAPRIM (DARAPRIM).
Daraprim (pyrimethamine) is a folic acid antagonist that inhibits dihydrofolate reductase (DHFR) in susceptible protozoa, thereby interfering with folate synthesis and blocking DNA synthesis and cell replication. It is synergistic with sulfonamides, which inhibit dihydropteroate synthase in the folate pathway.
| Metabolism | Pyrimethamine is extensively metabolized in the liver via multiple pathways, including N-oxidation and N-dealkylation. The primary enzyme involved is cytochrome P450 3A4 (CYP3A4), with minor contributions from other CYP isoforms. Metabolites are excreted in urine and feces. |
| Excretion | Primarily hepatic metabolism; renal excretion accounts for approximately 30% of elimination as unchanged drug and metabolites. Fecal excretion is minimal (<5%). |
| Half-life | Terminal elimination half-life is approximately 111 hours (range 54-148 hours) in adults. The long half-life allows weekly dosing for toxoplasmosis treatment. |
| Protein binding | Approximately 87% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution is approximately 3.3 L/kg (range 1.8-5.5 L/kg), indicating extensive tissue distribution with accumulation in erythrocytes and tissues. |
| Bioavailability | Oral bioavailability is well absorbed, estimated at >95% (no parenteral formulation available). |
| Onset of Action | Oral: Clinical effect observed within 24-48 hours after the first dose for treatment of toxoplasmosis. |
| Duration of Action | Duration of action is prolonged due to long half-life; therapeutic levels persist for 2-3 weeks after discontinuation. Weekly dosing maintains steady-state for prophylaxis. |
50 mg orally once daily for 2 days, then 25 mg orally once daily for 4 weeks; for toxoplasmosis, a loading dose of 200 mg orally once daily for 1 day, followed by 50-75 mg orally once daily for 4-6 weeks, with folinic acid 10-25 mg daily.
| Dosage form | TABLET |
| Renal impairment | No specific dosage adjustment provided; use with caution in severe renal impairment (CrCl < 15 mL/min) due to potential accumulation. |
| Liver impairment | No specific dosage adjustment provided for Child-Pugh classification; use with caution in severe hepatic impairment. |
| Pediatric use | For toxoplasmosis: 2 mg/kg/day orally divided every 12 hours for 2 days, then 1 mg/kg/day orally once daily for 4-6 weeks; maximum adult dose; concomitant folinic acid 5-20 mg daily. |
| Geriatric use | No specific dose adjustment; use with caution due to age-related renal impairment and increased risk of folate deficiency and myelosuppression; consider folinic acid supplementation. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for DARAPRIM (DARAPRIM).
| Breastfeeding | Contraindicated during breastfeeding due to potential for severe adverse effects in the infant (e.g., myelosuppression). M/P ratio unknown. |
| Teratogenic Risk | First trimester: High risk of neural tube defects, craniofacial anomalies, and cardiovascular malformations due to folate antagonism. Second and third trimesters: Risk of myelosuppression and growth restriction. Advised to avoid unless maternal benefit outweighs risk. |
| Fetal Monitoring |
■ FDA Black Box Warning
None (Leucovorin must be administered with pyrimethamine to prevent hematologic toxicity; however, this is not a black box warning but a standard of care. No formal FDA black box warning exists.)
| Serious Effects |
["Absolute: Hypersensitivity to pyrimethamine or any component of the formulation.","Absolute: Severe megaloblastic anemia due to folate deficiency.","Absolute: Pregnancy (particularly first trimester) unless no alternative therapy is available; potential fetal harm.","Relative: Lactation (pyrimethamine is excreted in breast milk; avoid if possible)","Relative: G6PD deficiency (may increase risk of hemolytic anemia, especially with concurrent sulfonamide use)","Relative: Pre-existing bone marrow suppression (unless leucovorin is used and benefits outweigh risks)"]
| Precautions | ["Hematologic toxicity: Bone marrow suppression (leukopenia, thrombocytopenia, megaloblastic anemia) due to folic acid antagonism; leucovorin (folinic acid) must be co-administered to prevent these effects.","Teratogenicity: Pyrimethamine is teratogenic in animals and is generally avoided in pregnancy unless benefit outweighs risk; use with caution in women of childbearing potential.","Hypersensitivity reactions: Severe allergic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported, especially when used with sulfonamides.","Hepatic impairment: Caution in patients with hepatic disease; monitor liver function tests.","Renal impairment: Caution in patients with renal dysfunction; dose adjustment may be required.","Drug interactions: Potential for increased toxicity with methotrexate, trimethoprim, and other folic acid antagonists."] |
Loading safety data…
| Maternal: Complete blood count weekly, including platelets and reticulocytes, serum folate levels, liver function tests. Fetal: Ultrasound for structural anomalies, growth scans every 4-6 weeks. |
| Fertility Effects | No direct reproductive toxicity data, but folate antagonism may impair oocyte and sperm quality. Use folate supplementation if pregnancy is planned. |