Clinical safety rating
cautionCombination used for Intermittent Preventive Treatment in Pregnancy (IPTp) — a WHO-recommended malaria prevention strategy for sub-Saharan Africa. Given at each ANC visit from 13 weeks onward (not T1) at least 4 weeks apart. Reduces risk of maternal anaemia, LBW, and perinatal mortality in malaria-endemic settings. Pyrimethamine is a folate antagonist — co-administer with folic acid 5 mg/day. Avoid in T1 (folate antagonism during organogenesis). Sulfadoxine carries sulfonamide risk at term.
Pyrimethamine inhibits dihydrofolate reductase, blocking tetrahydrofolate synthesis. Sulfadoxine inhibits dihydropteroate synthase, blocking folate synthesis. Sequential blockade of folate metabolism.
| Metabolism | Pyrimethamine is metabolized in the liver via CYP450 isoenzymes (minor). Sulfadoxine is primarily excreted unchanged in urine, with some hepatic metabolism (acetylation). |
| Excretion | Renal: ~60% unchanged sulfadoxine, ~5% unchanged pyrimethamine; fecal: ~10% pyrimethamine. Biliary excretion minimal. |
| Half-life | Pyrimethamine: ~80-120 hours; Sulfadoxine: ~100-200 hours. Long half-lives allow single-dose therapy for malaria. |
| Protein binding | Pyrimethamine: ~87% (albumin); Sulfadoxine: ~90% (albumin). |
| Volume of Distribution | Pyrimethamine: 2.3-3.6 L/kg (wide tissue distribution, crosses blood-brain barrier); Sulfadoxine: 0.14-0.2 L/kg (limited to plasma and interstitial fluid). |
| Bioavailability | Oral: ~90-100% for both components, with high and consistent absorption. |
| Onset of Action | Oral: Clinical response within 2-3 days for malaria; therapeutic levels reached in ~4 hours. |
| Duration of Action | Single dose provides therapeutic effect for ~7-10 days for sensitive malaria. Prophylactic action lasts up to 4 weeks with weekly dosing. |
| Molecular Weight | Pyrimethamine: 248.71 Da; Sulfadoxine: 310.33 Da |
Pyrimethamine 25 mg plus sulfadoxine 500 mg per tablet; typical adult dose for acute uncomplicated malaria is 3 tablets (pyrimethamine 75 mg, sulfadoxine 1500 mg) orally as a single dose. For toxoplasmosis in immunocompromised patients: loading dose pyrimethamine 200 mg orally once, then pyrimethamine 50-75 mg orally once daily plus sulfadoxine 1000-1500 mg orally once daily (dosing based on sulfadoxine component) for 4-6 weeks, then reduce to half.
| Renal impairment | Contraindicated in severe renal impairment (GFR <30 mL/min). For GFR 30-50 mL/min: reduce dose by 50% or extend interval to every 48-72 hours. For GFR >50 mL/min: no adjustment needed. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh class C). For Child-Pugh class B: reduce dose by 50% and monitor liver function. For Child-Pugh class A: no adjustment typically required, but caution advised. |
| Pediatric use | For acute uncomplicated malaria: weight-based single dose as follows: 5-6 kg: 125 mg sulfadoxine/6.25 mg pyrimethamine (¼ tablet); 7-10 kg: 250 mg/12.5 mg (½ tablet); 11-20 kg: 500 mg/25 mg (1 tablet); 21-30 kg: 750 mg/37.5 mg (1.5 tablets); 31-45 kg: 1000 mg/50 mg (2 tablets); >45 kg: adult dose (3 tablets). For congenital toxoplasmosis: pyrimethamine 1-2 mg/kg/day plus sulfadoxine 50-100 mg/kg/day orally divided every 12-24 hours for 6-12 months. |
| Geriatric use | Use with caution due to increased risk of sulfonamide adverse reactions (e.g., severe cutaneous reactions, renal toxicity). Dose adjustment per renal function; consider lower end of dosing range. Monitor renal function and electrolytes. Avoid in patients with significant hepatic impairment or glucose-6-phosphate dehydrogenase deficiency. |
| 1st trimester | Avoid due to teratogenicity (folate antagonism). Associated with neural tube defects and cardiovascular malformations. Use only if benefit outweighs risk. |
| 2nd trimester | Use with caution. Monitor for folate deficiency and megaloblastic anemia. Consider folic acid supplementation. |
| 3rd trimester | Avoid near term due to risk of kernicterus (sulfadoxine competes for bilirubin binding sites) and hemolytic anemia in G6PD-deficient neonates. |
Clinical note
Combination used for Intermittent Preventive Treatment in Pregnancy (IPTp) — a WHO-recommended malaria prevention strategy for sub-Saharan Africa. Given at each ANC visit from 13 weeks onward (not T1) at least 4 weeks apart. Reduces risk of maternal anaemia, LBW, and perinatal mortality in malaria-endemic settings. Pyrimethamine is a folate antagonist — co-administer with folic acid 5 mg/day. Avoid in T1 (folate antagonism during organogenesis). Sulfadoxine carries sulfonamide risk at term.
| Placental transfer | Both components cross the placenta. Pyrimethamine achieves fetal concentrations 30-60% of maternal; sulfadoxine crosses freely due to lipophilicity and low protein binding. |
| Breastfeeding | Both pyrimethamine and sulfadoxine are excreted into breast milk in low amounts. In healthy, full-term infants, exposure is unlikely to cause adverse effects. However, caution in G6PD-deficient infants or those with hyperbilirubinemia. Consider folic acid supplementation for the mother. |
| Lactation Rating | L2 (Limited data - compatible) |
| Teratogenic Risk | First trimester: Avoid due to antifolate effect; sulfonamides may cause kernicterus if used near term. FDA Category C; pyrimethamine is teratogenic in animal studies. Second/third trimester: Use only if benefit outweighs risk; monitor for neonatal hyperbilirubinemia. |
| Fetal Monitoring | Maternal: CBC, folate levels, liver and renal function. Fetal: Ultrasound for neural tube defects (first trimester), growth monitoring. Neonatal: Observe for jaundice, hemolytic anemia if G6PD deficient. |
| Fertility Effects | Pyrimethamine may reduce folate levels affecting spermatogenesis and ovulation. Sulfonamides are not known to impair fertility. Folate supplementation recommended to mitigate antifolate effects. |
■ FDA Black Box Warning
Fatalities due to severe adverse reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported with sulfonamide-containing products. Discontinue at first sign of rash or any sign of adverse reaction.
| Serious Effects |
Hypersensitivity to pyrimethamine, sulfonamides, or sulfadoxineMegaloblastic anemia due to folate deficiencySevere hepatic or renal impairmentPorphyriaG6PD deficiency (relative, but absolute in hemolytic risk)Concomitant folic acid antagonists (e.g., methotrexate)
| Precautions | Hypersensitivity reactions (including severe cutaneous adverse reactions), hematologic toxicity (folate deficiency, megaloblastic anemia), sulfonamide hypersensitivity (including anaphylaxis), glucose-6-phosphate dehydrogenase deficiency (hemolysis risk), photosensitivity, renal impairment (accumulation), hepatic impairment, caution in pregnancy (antifolate effect - use with leucovorin when indicated), caution in lactation. |
| Food/Dietary | No significant food interactions. May be taken with or without food. Maintain adequate hydration to prevent crystalluria. |
| Clinical Pearls | Always administer with folinic acid (leucovorin) to reduce hematologic toxicity. Monitor for severe cutaneous adverse reactions (e.g., Stevens-Johnson syndrome) especially in first 8 weeks. Contraindicated in patients with sulfonamide allergy. Not recommended for prophylaxis in pregnancy; alternative antimalarials preferred. |
| Patient Advice | Take exactly as prescribed; do not skip doses. · Report any skin rash, blistering, or mouth sores immediately (signs of severe allergic reaction). · Complete full course even if feeling better. · Avoid alcohol during treatment. · Use effective contraception during and for 1 month after treatment if female of childbearing potential. |
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