Halofantrine with mefloquine

Early laboratory studies suggested cross-resistance of halofantrine with mefloquine. In rats, parasites that are resistant to mefloquine, quinine, chloroquine, and amodiaquine are also markedly resistant to halofantrine (13). 

For uncomplicated falciparum malaria there are several options (with the major drawback in brackets) halofantrine (arrhytmia), mefloquine (neurotoxicity), quinine (vomiting, tinnitus), artemether (recrudescence), atovaquone-proguanil (possible fast development of resistance). 

Halofantrine prolongs the QT interval and therefore should not be used with other drugs that can prolong the QT interval because of the increased risk of cardiac arrhythmias. The concurrent and sequential use of halofantrine and mefloquine markedly increased the risk of clinically important increases in the QT interval... 

Sporadic resistance to mefloquine has been reported from many areas. At present, resistance appears to be uncommon except in regions of Southeast Asia with high rates of multidrug resistance (especially border areas of Thailand). Mefloquine resistance appears to be associated with resistance to quinine and halofantrine but not with resistance to chloroquine. 

In parallel, extensive studies on P. falciparum field isolates in Gabon [140-142], Senegal [143], Cambodia [118, 119, 144], and the Thailand Burmese border [145] corroborated the efficacy of FQ on the parasite whatever its resistance level to chloroquine or to other commonly used antimalarials mefloquine, quinine, halofantrine, and artemisinin derivatives [146, 147]. The cross reactivity observed in some studies with CQ was limited and it was demonstrated that it was caused by differences in initial parasitemia among isolates at the start of the assays [141]. Independance of susceptibility of P. falciparum with phenotypic variation of pfcrt gene, responsible for CQ resistance, could be suspected from these results, but this was demonstrated at the molecular level on Cambodia isolates [148] and extended further on other genes currently involved in resistance to aminoquinoline antimalarials [89, 90]. 

Instances of mefloquine resistance were reported in Tanzania in 1983, in Thailand in 1989, and in Africa (Malawi) in 1991. Resistance to combinations of mefloquine with sulfadoxine and pyrimethamine was reported in 1985 (SEDA-13, 808) (40 4). The possibility of crossresistance between mefloquine and halofantrine was raised in 1990 (SEDA-13, 808) (45). Currently there are extensive areas, including Thailand, Cambodia, Laos, Papua New Guinea, and Myanmar, where P. falciparum... 

Pyrimethamine/sulfadoxine and tetracycline have been shown to increase halofantrine levels, and may therefore increase its toxicity. Diltiazem, erythromycin, ketoconazole, mefloquine, quinine, and quinidine might also increase the toxicity of halofantrine because they have been shown to inhibit its metabolism in vitro. The manufacturer has therefore recommended caution with the concurrent use of potent CYP3A4 inhibitors. Fatty food markedly increases halofantrine levels, consequently it is recommended that halofantrine is taken on an empty stomach. Grapefruit juice has a similar effect Note that halofantrine is no longer widely marketed. 

A study in animals found that ketoconazole roughly doubled the AUC of halofantrine and inhibited its metabolism to the equipotent metabolite, desbutylhalofantrine. In in vitro studies, ketoconazole markedly inhibited the metabolism of halofantrine by CYP3A4. It has been suggested that the rise in halofantrine levels could reasonably be expected to increase toxicity. Other CYP3A4 inhibitors, diltiazem and erythromycin, also inhibited the metabolism of halofantrine in vitro, and might therefore do so clinically. The manufacturer recommended caution with the concurrent use of potent CYP3A4 inhibitors. Further study is needed of these potential pharmacokinetic interactions. Mefloquine, quinine and quinidine may also inhibit the metabolism of halofantrine by CYP3A4, see (b) below. 

In addition to possible additive QT-prolonging effects, quinidine and quinine have been shown in vitro to inhibit the metabolism of halofantrine by CYP3A4, and so may increase halofantrine levels, which could reasonably be expected to increase XoxxcxXy Animal studies found that although mefloquine alone did not significantly alter the QTc interval, it enhanced the effects of halofantrine by increasing blood levels. Similarly, a study in patients with malaria found that the risk of clinically relevant QT prolongation was increased twofold when halofantrine was used after mefloquine failure (7 of 10 patients) when compared with use as primary... 

Lightbown ID, Lambert JP, Edwards G, Coker SI Potentiation of halofantrine-induced QTc prolongation by mefloquine correlation with blood concentrations of halofantrine. Br J Pharmacol 200V) 132,197-204. 

An isolated report describes cardiopulmonary arrest in a patient taking mefloquine with propranolol. The WHO have issued a warning about the concurrent use of mefloquine with an-tiarrhythmics, beta blockers, calcium-channel blockers, antihistamines, phenothiazines, and some related antimalarials. For mention that halofantrine should not be used with or after mefloquine, because of a clinically significant lengthening of the QT interval, see Halofantrine + Miscellaneous , p.229. 

An isolated report describes life-threatening hypoglycaemia in a 3-year-old boy, with uncomplicated malaria, 90 minutes after he took sulfadox-ine-pyrimethaniine (Fansidar). Mefloquine has been reported to reduce plasma glucose levels in healthy subjects. Artemisinin derivatives such as artemether may be associated with fewer episodes of hypoglycaemia than quinine in children with severe malaria. Chloroquine, amo-diaquine and halofantrine do not apparently stimulate the release of insulin. ... 

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