Prolonged QT interval with halofantrine

Castot, A; Rapoport, Priscila Bogar; Coz, Pierre Le; Monlun, É.; Pillet, O.; Cochard, J.F.; Garrigues, Jean‐Christophe; Bras, Michel Le

doi:10.1016/0140-6736(93)90685-a

Cited by 63 publications

(17 citation statements)

References 3 publications

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“…Ventricular arrhythmia and/or syncope in connection with QTc prolongation has been reported after standard [21][22][23][24] and high-dose (3 doses of 24 mg/kg) halofantrine treatment. 25 Such arrhythmia occurred mainly under conditions of preexisting QTc prolongation or in malaria patients pretreated with mefloquine.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the cardiac effects of the antimalarials co-artemether and halofantrine in healthy participants.

Bindschedler

Lefèvre²,

Degen³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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Abstract. Co-artemether (Coartem, Riamet) is a tablet containing 20 mg artemether and 120 mg lumefantrine for treatment of falciparum malaria. Lumefantrine has some chemical similarities to halofantrine (Halfan), an antimalarial known for QTc prolongation. Effects on the QTc interval of fed single oral doses of 500 mg halofantrine and 80/480 mg co-artemether were compared in 13 healthy males in a randomized double-blind crossover study. Electrocardiograms (ECGs) were recorded from 48 hours before dosing until 48 hours thereafter. The maximum QTc interval (QTc ‫ס‬ QT/√RR) was compared before and after treatment and between treatments, fitting a general linear model. Drug plasma concentrations were determined concomitantly. After halofantrine, all participants showed an increase in the QTc interval; the mean maximum increase was 28 ms. The length of the QTc interval was positively correlated to halofantrine exposure. The QTc interval remained unchanged after co-artemether. The difference between treatments was statistically significant. In conclusion, halofantrine caused a significant, exposure-dependent increase in the QTc interval. No such effect was seen with co-artemether.Malaria is the cause of considerable morbidity and mortality in the developing world, and there is a clear need for new treatments, particularly as resistance to available drugs is increasing. 1,2Co-artemether (Coartem, Riamet), which was developed in China for the treatment of falciparum malaria, is an oral preparation containing 20 mg artemether and 120 mg lumefantrine (previously known as benflumetol) per tablet. Artemether, an artemisinin derivative, is characterized by a rapid onset of schizontocidal action resulting in fast relief from fever and fast parasite clearance. However, recrudescence is frequent when provided as a single agent, unless given for at least 5-7 days.3-6 By contrast, lumefantrine has a high cure rate when administered as a short treatment course of 2-3 days duration, but parasite and fever clearance is much slower than with artemether. Co-artemether combines the treatment advantages of both drugs, providing a short and simple antimalarial treatment likely to improve compliance. In areas of multidrug resistance and in nonimmune patients, the recommended dose regimen is 6 doses of 4 tablets each (80 mg artemether and 480 mg lumefantrine per dose) given over 60 hours. Otherwise, the recommended dose regimen is 4 doses of 4 tablets over 2 days.Halofantrine (Halfan) is one of the antimalarial compounds causing QTc prolongation at standard therapeutic doses (3 doses of 500 mg given at 6-hour intervals). Because lumefantrine has some chemical similarities to halofantrine, and QTc prolongation was reported after high-dose intramuscular treatment with artemether in animal experiments 7 and in a clinical study in patients with severe malaria, 8 a careful evaluation of co-artemether with regard to cardiac effects, particularly on the QTc interval, was warranted.In the current study, the potential cardiac effects of coartemethe...

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Section: Discussionmentioning

confidence: 99%

Comparison of the cardiac effects of the antimalarials co-artemether and halofantrine in healthy participants.

Bindschedler

Lefèvre²,

Degen³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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“…This is also true in the Romano± Ward syndrome, in which histological abnormalities in conduction tissue and patches of myocardial ® brosis have been reported (James et al, 1978); these tissue changes probably explain the frequent occurrence of late ventricular potentials during this syndrom e, whose association with lengthening of the QT interval could theoretically lead to re-entry (Tobe et al, 1992). This mechanism could explain why serious halofantrine-induced ventricular arrhythmia might occur in patients with this syndrome (Castot et al, 1993;Monlun et al, 1993). The appearance of ECG abnormalities is directly correlated with serum levels of halofantrine but not of its metabolite, N-desbutyl-halofantrine (Karbwang and Na Bangchang, 1994).…”

Section: Cardioto Xicitymentioning

confidence: 93%

“…A few months later, Castot et al (1993) and then Monlun et al (1993) each reported a case of severe ventricular arrhythmia after administration of halofantrine at the standard dose of 24 mg/kg. Both patients presented constitutional prolongation of the QT interval (the Romano± Ward syndrome) and one had a ventricular arrhythmia which was a`torsade de pointe' .…”

Section: Cardioto Xicitymentioning

confidence: 99%

Is halofantrine still advisable in malaria attacks

Touze

Fourcade

Peyron

et al. 1997

Annals of Tropical Medicine And Parasitology

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Halofantrine is an antimalarial drug which is widely prescribed for the treatment of infections with chloroquine-resistant strains of Plasmodium falciparum. Chemically, it is a phenanthrene methanol, belonging to the aryl-amino-alcohol family. It has recently been recognized that this drug may induce rare but serious, cardiotoxic effects, including lengthening of the QTc interval, 'torsade de pointes' and induction of late ventricular potentials. These events are thought to be related to a quinidine-like action of the drug. In addition, severe haemolytic accidents have been reported, mimicking blackwater fever and indicating an immunological process. As a result of these side-effects, new guidelines for prescription and more cautious use of halofantrine, particularly as a stand-by treatment for febrile access among travellers, are required.

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“…A 1-day treatment has been shown to be efficacious in semi-immune patients, but unexplained relapses were observed in non-immune patients with imported malaria [4,12]. For this reason, some authors recommended a regimen with a repeated dose after 1 week despite reports of severe cardiological side-effects after treatment and, more recently, severe hepatic disorders [1,2,9]. The aim of the study was therefore to assess halofantrine efficacy (1-day regimen) in non-immune children and to define risk factors for relapse after halofantrine treatment.…”

Section: Introductionmentioning

confidence: 99%