Atovaquone Proguanil

Atovaquone with proguanil is an oral fixed-dose combination for treatment of uncomplicated falciparum malaria and for daily prophylaxis, mainly in travellers. It is well tolerated and can be started 1 to 2 days before travel and stopped 7 days after return. It is expensive and rarely used in programmes.

Class. Antimalarial; naphthoquinone with a dihydrofolate reductase inhibitor.

Mechanism. Atovaquone inhibits the parasite cytochrome bc1 complex, collapsing mitochondrial membrane potential. Proguanil (via cycloguanil) inhibits dihydrofolate reductase and enhances atovaquone’s effect.

Pharmacokinetics. Absorption of atovaquone increases with fat. Half life of atovaquone 2 to 3 days and of proguanil 12 to 21 hours. Atovaquone is excreted in faeces; proguanil in urine.

Treatment of uncomplicated falciparum malaria. Adults and children 40 kg or more: 4 adult tablets (atovaquone 1000 mg with proguanil 400 mg) once daily with food for 3 days. - 5 to under 9 kg: 2 paediatric tablets daily; 9 to under 11 kg: 3 paediatric tablets daily. - 11 to under 21 kg: 1 adult tablet; 21 to under 31 kg: 2 adult tablets; 31 to under 40 kg: 3 adult tablets daily.

Prophylaxis. One adult tablet (250/100 mg) daily with food, starting 1 to 2 days before travel, continued during travel and for 7 days after return. Children: weight-banded paediatric or adult tablets.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 4 adult tablets daily.

Main alternative. Artemether with lumefantrine for treatment; doxycycline for prophylaxis.

Contraindications. Hypersensitivity; CrCl under 30 mL/min for prophylaxis.

Serious adverse effects. Hepatitis (rare), Stevens-Johnson syndrome (rare), anaphylaxis, and pancytopenia in severe kidney impairment.

Common adverse effects. Abdominal pain, nausea, vomiting, headache, diarrhoea, mouth ulcers and cough.

Interactions. - Rifampicin, rifabutin, tetracycline, metoclopramide, efavirenz and boosted protease inhibitors lower atovaquone levels. - Warfarin effect may rise. - Etoposide and indinavir levels rise.

Common prescribing errors. Taking without food, vomiting soon after a dose, and prescribing with rifampicin.

Special groups. - Pregnancy: limited data; avoid unless benefit outweighs risk. - Breastfeeding: avoid if infant is under 5 kg. - Children: from 5 kg for treatment; prophylaxis from 11 kg. - Older adults: usual dose. - Kidney impairment: avoid prophylaxis at CrCl under 30 mL/min. - Liver impairment: caution in severe disease.

Formulations. Tablets 250 mg/100 mg (adult) and 62.5 mg/25 mg (paediatric).

Administration. Once daily with fatty food or milk; repeat the dose if vomiting occurs within 1 hour.

Baseline. Malaria diagnosis (treatment), weight, creatinine, pregnancy test, drug history.

Monitoring. Symptoms and parasite clearance; liver tests if symptomatic.

Stopping thresholds. Stop for severe skin reaction, hepatitis or anaphylaxis.

Referral and escalation. Admission for severe malaria or treatment failure.