Provocation of ventricular tachycardia by antimalarial drug halofantrine in congenital long QT syndrome

Toivonen, Lauri; Viitasalo, Matti; Pohjola-Sintonen, Sinikka; Siikamäki, Heli; Raatikka, Marja

doi:10.1002/clc.4960170711

Cited by 41 publications

(11 citation statements)

References 6 publications

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“…The magnitude of QTc prolongation was greater in patients whose HF treatment closely followed mefloquine. Since then several reports of HF-induced QTc prolongation, as well as severe ventricular arrhythmias and torsades de pointes, particularly in patients with congenital prolonged QT syndromes have been published [8-10,12,14,18,24,25]. In 1993, the discovery of electrocardiographic and possible clinical cardiac effects induced by HF has led the WHO and GSK, which produces HF, to recommend limitations on the prescribing of HF [21].…”

Section: Discussionmentioning

confidence: 99%

Fatal cardiotoxicity related to halofantrine: a review based on a worldwide safety data base

Bouchaud

Imbert

et al. 2009

Malar J

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BackgroundHalofantrine (HF) was considered an effective and safe treatment for multi-drug resistant falciparum malaria until 1993, when the first case of drug-associated death was reported. Since then, numerous studies have confirmed cardiac arrythmias, possibly fatal, in both adults and children. The aim of the study was to review fatal HF related cardiotoxicity.MethodsIn addition, to a systematic review of the literature, the authors have had access to the global safety database on possible HF related cardiotoxicity provided by GlaxoSmithKline.ResultsThirty-five cases of fatal cardiotoxicity related to HF, including five children, were identified. Females (70%) and patients from developing countries (71%) were over-represented in this series. Seventy-four percent of the fatal events occurred within 24 hours of initial exposure to HF. Twenty six patients (74%) had at least one predisposing factor for severe cardiotoxicity, e.g., underlying cardiac disease, higher than recommended doses, or presence of a concomitant QT-lengthening drug. All (100%) of the paediatric cases had either a contraindication to HF or an improper dose was given. In six cases there was no malaria.ConclusionA distinction should be made between common but asymptomatic QT-interval prolongation and the much less common ventricular arrhythmias, such as torsades de pointes, which can be fatal and seem to occur in a very limited number of patients. The majority of reported cardiac events occurred either in patients with predisposing factors or with an improper dose.Therefore, in the rare situations in which HF is the only therapeutic option, it can still be given after carefully checking for contraindications, such as underlying cardiac disease, bradycardia, metabolic disorders, personal or family history of long QT-interval or concomitant use of another QT-prolonging drug (e.g., mefloquine), especially in females.

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Section: Discussionmentioning

confidence: 99%

Fatal cardiotoxicity related to halofantrine: a review based on a worldwide safety data base

Bouchaud

Imbert

et al. 2009

Malar J

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“…The fact that artemether and arteether, given in high intramuscular doses, prolonged the QTc-interval in rats and dogs, 30 and that lumefantrine has structural similarities to halofantrine, an antimalarial associated with QTc prolongation, [31][32][33] have given rise to concern that similar effects could occur in clinical use with artemether-lumefantrine. Although there has never been evidence of any cardiotoxicity with artemether in humans, 34,35 extensive monitoring of electrocardiographic parameters was conducted in all clinical studies with artemether-lumefantrine.…”

Section: Discussionmentioning

confidence: 99%

A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand.

Lefèvre¹,

Looareesuwan²,

Treeprasertsuk³

et al. 2001

The American Journal of Tropical Medicine and Hygiene

160

130

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Abstract. The efficacy-safety and pharmacokinetics of the six-dose regimen of artemether-lumefantrine (Coartem/ Riamet; Novartis Pharma AG, Basel, Switzerland) were assessed in a randomized trial in 219 patients (Ն 12 years old) with acute, uncomplicated Plasmodium falciparum malaria in Thailand. One hundred and sixty-four patients received artemether-lumefantrine and 55 received the standard treatment combination of mefloquine-artesunate. Both drugs induced rapid clearance of parasites and malaria symptoms. The 28-day cure rates were 95.5% (90% confidence interval [CI] ϭ 91.7, 97.9%) for artemether-lumefantrine and 100% (90% CI ϭ 94.5, 100%) for mefloquine-artesunate. This high-dose regimen of artemether-lumefantrine was very well tolerated, with very good compliance. The most frequent adverse events were headache, dizziness, nausea, abdominal pain, dyspepsia, vomiting, and skin rash. Overall, only 2% of patients in both groups showed QTc prolongations but without any cardiac complication, and no differences were seen between patients with and without measurable baseline plasma levels of quinine or mefloquine. Plasma levels of artemether, dihydroartemisinin, and lumefantrine were consistent with historical data for the same dose regimen, and were higher, particularly for lumefantrine, than those previously observed with the four-dose regimen, explaining the greater efficacy of the six-dose regimen in a drug-resistant setting. These results confirm the excellent safety and efficacy of the six-dose regimen of artemether-lumefantrine in the treatment of multidrug-resistant P. falciparum malaria.

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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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Provocation of ventricular tachycardia by antimalarial drug halofantrine in congenital long QT syndrome

Cited by 41 publications

References 6 publications

Fatal cardiotoxicity related to halofantrine: a review based on a worldwide safety data base

Fatal cardiotoxicity related to halofantrine: a review based on a worldwide safety data base

A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand.

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

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