Sulfadoxine Pyrimethamine

Sulfadoxine with pyrimethamine is an oral fixed-dose antifolate combination used in malaria prevention: intermittent preventive treatment in pregnancy, perennial malaria chemoprevention in young children, and, with amodiaquine, seasonal malaria chemoprevention in the Sahel. Widespread resistance has removed it as a treatment for falciparum malaria on its own, though it still protects pregnant women and infants. Severe skin reactions are the main safety concern.

Class. Antimalarial; sequential antifolate combination.

Mechanism. Sulfadoxine inhibits dihydropteroate synthase and pyrimethamine inhibits dihydrofolate reductase, blocking parasite folate synthesis in sequence. Mutations in dhfr and dhps (especially the dhps 581G mutation) cause resistance.

Pharmacokinetics. Well absorbed orally. Half life of sulfadoxine about 7 to 9 days and of pyrimethamine about 3 to 4 days, giving prolonged post-treatment protection. Excreted by the kidney.

Intermittent preventive treatment in pregnancy. 3 tablets (each sulfadoxine 500 mg with pyrimethamine 25 mg; total 1500/75 mg) as a single dose from 13 weeks of gestation, repeated at each scheduled visit at least 1 month apart until delivery. Doses are given under observation.

Perennial malaria chemoprevention in young children (where adopted). Single dose by age at set visits: under 1 year half a 500/25 mg tablet; 1 year and over one tablet.

Seasonal malaria chemoprevention (with amodiaquine, Sahel). Single SP dose on day 1 with amodiaquine for 3 days each month in the rainy season: 3 to 11 months half a 500/25 mg tablet; 12 to 59 months one tablet.

Treatment of uncomplicated falciparum malaria (with artesunate, where still effective). Sulfadoxine 25 mg/kg with pyrimethamine 1.25 mg/kg as a single dose.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 3 tablets (1500/75 mg) in a single dose.

Main alternatives. Dihydroartemisinin with piperaquine for chemoprevention in some programmes.

Contraindications. Hypersensitivity to sulphonamides or pyrimethamine; first trimester of pregnancy; infants under 2 months; severe kidney or liver impairment; daily co-trimoxazole prophylaxis in HIV (do not combine); severe haematological disease.

Serious adverse effects. Stevens-Johnson syndrome and toxic epidermal necrolysis, hepatotoxicity, bone marrow suppression and megaloblastic anaemia, and haemolysis in G6PD deficiency.

Common adverse effects. Nausea, vomiting, headache, rash and pruritus.

Interactions. - Co-trimoxazole (sulphonamide plus trimethoprim) given together adds toxicity and removes the benefit of SP; do not give both. - Folic acid at 5 mg daily lowers SP efficacy; use 0.4 mg daily during IPTp. - Methotrexate and other antifolates add toxicity.

Common prescribing errors. Starting before 13 weeks, giving to women taking co-trimoxazole, giving a weekly folic acid dose of 5 mg, and using in sulphonamide allergy.

Special groups. - Pregnancy: used from the second trimester only; avoid in the first trimester. - Breastfeeding: compatible after the first weeks; avoid if the infant is under 2 months or has G6PD deficiency. - Children: from 2 months for chemoprevention. - Older adults: usual dose. - Kidney impairment: avoid in severe impairment. - Liver impairment: avoid in severe impairment.

Regional points. The dhps 581G mutation reduces efficacy of IPTp in parts of East Africa (northern Tanzania, Uganda), but IPTp-SP still lowers low birth weight and maternal anaemia and remains in use; women with HIV on daily co-trimoxazole get co-trimoxazole alone and not SP.

Formulations. Tablets sulfadoxine 500 mg with pyrimethamine 25 mg; dispersible tablets for children.

Administration. Single observed dose with or without food, with clean water.

Baseline. Gestational age, HIV status and co-trimoxazole use, sulphonamide allergy, folic acid dose.

Monitoring. Rash and mucosal symptoms in the days after dosing; haemoglobin at antenatal visits.

Stopping thresholds. Do not give further doses after any rash with mucosal involvement, fever or blistering; stop for severe hypersensitivity.

Referral and escalation. Admission for suspected Stevens-Johnson syndrome or hepatitis.