An integrated assessment of the clinical safety of artemether-lumefantrine: a new oral fixed-dose combination antimalarial drug.

Artemether-lumefantrine (A-L), a new fixed-dose oral antimalarial drug, combines the fast onset of action of artemether (an artemisinin derivative) in terms of parasite clearance with the high cure rate of lumefantrine in the treatment of acute uncomplicated Plasmodium falciparum malaria. The extensive clinical trial database of A-L has allowed a comprehensive evaluation of its tolerability and safety in a total of 1869 patients (including 243 children aged 5-12 years and 368 children aged < 5 years). The most commonly reported and possibly related adverse effects following A-L therapy involved the gastro-intestinal (abdominal pain, anorexia, nausea, vomiting, diarrhoea) and central nervous (headache, dizziness) systems. Pruritus and rash were reported by < 2% of patients. More than 90% of the reported adverse events, many of which overlapped considerably with the clinical symptomatology or evolution of acute malaria, were rated mild to moderate in intensity. Compared to A-L, significantly higher incidences of vomiting and pruritus were observed with chloroquine, dizziness, nausea and vomiting with mefloquine, somnolence with pyrimethamine + sulfadoxine, and vomiting and dizziness with quinine. There were no serious or persistent neurological side-effects related to A-L administration. A-L did not lead to any clinically relevant alterations of the laboratory parameters. Serial electrocardiographic data were available for 713 patients. The frequency of QT interval prolongations was similar to or lower than that observed with chloroquine, mefloquine, or artesunate + mefloquine; these changes were considerably less frequent than with quinine or halofantrine. All patients with QT prolongation remained asymptomatic and no adverse clinical cardiac events were reported. Artemether-lumefantrine can thus be expected to show, both in children and in adults, a favourable safety profile for the treatment of acute, uncomplicated, P. falciparum malaria; it could as well be a reserve treatment option for travellers to endemic countries.