Artemether Lumefantrine

Artemether with lumefantrine is an oral fixed-dose artemisinin combination for uncomplicated falciparum malaria and mixed infections, and the first-line treatment in most of East Africa. Artemether clears parasites quickly and lumefantrine removes the remainder over days. It needs fat for lumefantrine absorption and a full six-dose course. It is not used for severe malaria.

Class. Antimalarial; artemisinin combination therapy.

Mechanism. Artemether (via dihydroartemisinin) generates free radicals from its endoperoxide bridge after activation by haem iron, damaging parasite proteins. Lumefantrine is thought to inhibit haem detoxification within the parasite food vacuole.

Pharmacokinetics. Absorption of lumefantrine increases several-fold with fatty food or milk. Half life of artemether 1 to 3 hours and of lumefantrine 3 to 6 days. Both are metabolised by CYP3A4; artemether induces CYP3A4.

Uncomplicated falciparum malaria (and mixed infections). Six doses over 3 days, given at 0, 8, 24, 36, 48 and 60 hours. Each tablet contains artemether 20 mg and lumefantrine 120 mg. - 5 kg to under 15 kg: 1 tablet in each dose. - 15 kg to under 25 kg: 2 tablets in each dose. - 25 kg to under 35 kg: 3 tablets in each dose. - 35 kg or more: 4 tablets in each dose.

Vomiting. If vomiting occurs within 30 minutes of a dose, repeat the dose.

Persistent treatment failure. Use a different artemisinin combination or oral quinine with a second drug.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 24 tablets over 3 days.

Main alternatives. Dihydroartemisinin with piperaquine, or artesunate with amodiaquine.

Contraindications. Hypersensitivity; severe malaria; congenital QT prolongation or family history of sudden death; uncorrected hypokalaemia; co-prescription with drugs that prolong the QT interval; strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John’s wort).

Serious adverse effects. QT prolongation (uncommon), hypersensitivity and severe skin reactions (rare), and hepatotoxicity (rare).

Common adverse effects. Headache, dizziness, weakness, nausea, abdominal pain, vomiting, arthralgia and palpitations.

Interactions. - Efavirenz and nevirapine lower levels of both drugs and may reduce cure; monitor, and consider an alternative combination. - Rifampicin: avoid. - Ritonavir-boosted protease inhibitors raise lumefantrine levels. - Other QT-prolonging drugs (macrolides, quinolones, antipsychotics) add risk.

Common prescribing errors. Dosing by age instead of weight, giving without fat or milk, missing a dose, and treating severe malaria with oral drugs.

Special groups. - Pregnancy: used in the second and third trimesters; artemisinin combinations are now also used in the first trimester when benefit is clear. - Breastfeeding: compatible. - Children: weight-banded from 5 kg; tablets may be crushed in water. - Older adults: usual dose; check QT drugs. - Kidney impairment: no adjustment. - Liver impairment: caution in severe disease; monitor.

Regional points. It is first-line for uncomplicated falciparum malaria in Kenya, Uganda and Tanzania. Partial artemisinin resistance has been confirmed in parts of Uganda, Tanzania, Rwanda and Eritrea, so cure is checked and treatment failure leads to a different combination under local rules.

Formulations. Tablets 20 mg/120 mg; dispersible tablets 20 mg/120 mg.

Administration. With fatty food or milk (a cup of milk is enough); crush or disperse in water for infants.

Baseline. Malaria diagnosis by rapid test or microscopy, weight, pregnancy status, drug history for QT drugs, ECG if risk factors.

Monitoring. Symptoms and parasite clearance at day 3 and day 28 (where available); haemoglobin in children with anaemia.

Stopping thresholds. Stop for severe skin reaction, hypersensitivity, or symptomatic arrhythmia.

Referral and escalation. Admission for severe malaria (impaired consciousness, convulsions, respiratory distress, jaundice, anaemia with haemoglobin under 50 g/L, hypoglycaemia, shock, inability to take oral therapy), treatment failure and vomiting that persists.