HALOFANTRINE & LUMEFANTRINE
Halofantrine hydrochloride, a phenanthrene-methanol, is effec-tive against erythrocytic (but not other) stages of all four human malaria species. Oral absorption is variable and is enhanced with food. Because of toxicity concerns, it should not be taken with meals. Plasma levels peak 16 hours after dosing, and the half-life is about 4 days. Excretion is mainly in the feces. The mechanism of action of halofantrine is unknown. The drug is not available in the USA (although it has been approved by the FDA), but it is widely available in malaria-endemic countries.
Halofantrine (three 500-mg doses at 6-hour intervals, repeated in 1 week for nonimmune individuals) is rapidly effective against most strains of P falciparum, but its use is limited by irregular absorption and cardiac toxicity. It should not be used for chemopro-phylaxis. Halofantrine is generally well tolerated. The most com-mon adverse effects are abdominal pain, diarrhea, vomiting, cough, rash, headache, pruritus, and elevated liver enzymes. Of greater concern, the drug alters cardiac conduction, with dose-related pro-longation of QT and PR intervals. This effect is seen with standard doses and is worsened by prior mefloquine therapy. Rare instances of dangerous arrhythmias and deaths have been reported. The drug is contraindicated in patients who have cardiac conduction defects or who have recently taken mefloquine. Halofantrine is embryo-toxic in animals and therefore contraindicated in pregnancy.
Lumefantrine, an aryl alcohol related to halofantrine, is avail-able only as a fixed-dose combination with artemether (Coartem), which is now the first-line therapy for uncomplicated falciparum malaria in many countries. In addition, Coartem is approved in many nonendemic countries, including the USA. The half-life of lumefantrine, when used in combination, is approximately 4 days. Drug levels may be altered by interactions with other drugs, including those that affect CYP3A4 metabolism, but this area has not been well studied. As with halofantrine, oral absorption is highly variable and improved when the drug is taken with food.
Since lumefantrine does not engender the dangerous toxicity con-cerns of halofantrine, Coartem should be administered with fatty food to maximize antimalarial efficacy. Coartem is highly effective in the treatment of falciparum malaria when administered twice daily for 3 days. Coartem can cause minor prolongation of the QT interval, but this appears to be clinically insignificant, and the drug does not carry the risk of dangerous arrhythmias seen with halofantrine and quinidine. Indeed, Coartem is very well toler-ated. The most commonly reported adverse events in drug trials have been gastrointestinal disturbances, headache, dizziness, rash, and pruritus, and in many cases these toxicities may have been due to underlying malaria or concomitant medications rather than to Coartem.