Artemisinin Based Combination Therapy

Artemisinin-based combination therapy pairs a fast-acting artemisinin derivative with a longer-acting partner drug. The artemisinin clears most parasites within 3 days, and the partner removes the remainder, protecting against resistance. A 3-day course cures more than 95% of uncomplicated falciparum malaria where partner drugs remain effective.

Pharmacokinetics. Artemisinins have half-lives under 1 hour and are converted to dihydroartemisinin. Lumefantrine absorption rises with fat, and piperaquine has a half-life of several weeks.

• Artemether with lumefantrine (20 mg/120 mg tablets): six doses over 3 days at 0, 8, 24, 36, 48 and 60 hours. Tablets for each dose: 5 to under 15 kg, 1; 15 to under 25 kg, 2; 25 to under 35 kg, 3; 35 kg and over, 4. Take with fatty food.
• Artesunate with amodiaquine: artesunate 4 mg/kg and amodiaquine 10 mg/kg once daily for 3 days.
• Dihydroartemisinin with piperaquine: dihydroartemisinin 4 mg/kg and piperaquine 18 mg/kg once daily for 3 days, on an empty stomach.
• Artesunate with pyronaridine: weight-banded fixed-dose tablets (pyronaridine 180 mg with artesunate 60 mg) once daily for 3 days.
• Artesunate with mefloquine: used mainly outside Africa.

First-line. Artemether with lumefantrine in most African national policies. Alternatives are used when it fails, or when a rotation or multiple first-line policy is adopted.

Dose checks. Repeat the full dose if vomiting occurs within 30 minutes; give half the dose if within 30 to 60 minutes. Observe the first dose in children.

Special situations.

• Pregnancy: first trimester, artemether with lumefantrine; quinine with clindamycin is an alternative.
• HIV treatment: efavirenz, nevirapine and rifampicin lower lumefantrine and artemether levels, and extended treatment or close follow-up is used; protease inhibitors raise lumefantrine levels.
• Severe malaria: after intravenous artesunate, complete a full 3-day course.
• Infants under 5 kg: limited data; use weight-based dosing under specialist direction.

Region. In East Africa, artemisinin partial resistance has been reported in some areas. Follow-up at day 3 and day 28 identifies treatment failure; report failures to the malaria programme.

Contraindications. Hypersensitivity; dihydroartemisinin with piperaquine in congenital long QT or drugs that prolong QT; artesunate with pyronaridine in significant liver disease.

Serious adverse effects. QT prolongation with piperaquine, lumefantrine and amodiaquine; delayed haemolysis after intravenous artesunate; amodiaquine liver toxicity and neutropenia with repeated use; pyronaridine transaminase rise.

Interactions. Strong CYP3A4 inducers lower artemether and lumefantrine; QT-prolonging drugs (macrolides, fluoroquinolones, antipsychotics, ondansetron) add risk.

Monitoring. Fever and parasite clearance at day 3 and day 28; haemoglobin; ECG if QT risk.

Special groups.

• Breastfeeding: compatible.
• Kidney and liver impairment: no dose change for most; avoid pyronaridine in significant liver disease.
• Older adults: review QT-prolonging medicines.

Referral and escalation. Refer vomiting that persists, deterioration within 48 hours, parasitaemia at day 3, or recurrence within 28 days.