ral
ssBioMed CentMalaria Journal
Open AcceResearch
Fatal cardiotoxicity related to halofantrine: a review based on a 
worldwide safety data base
Olivier Bouchaud*1, Patrick Imbert2, Jean Etienne Touze3, Alex NO Dodoo4, 
Martin Danis5 and Fabrice Legros6
Address: 1Service des maladies infectieuses et tropicales, Hôpital Avicenne AP-HP et Université Paris 13, 125 rue de Stalingrad, 93009 Bobigny, 
France, 2Service des maladies infectieuses et tropicales, Hôpital d'Instruction des Armées Bégin, 69 avenue de Paris, 94160 Saint-Mandé, France, 
3Ecole de Santé des Armées du Val de Grâce, Place A. Laveran, Paris 75230, France, 4Centre for Tropical Clinical Pharmacology & Therapeutics, 
University of Ghana, Medical School Korle-Bu Teaching Hospital, Accra, Ghana, 5Service de Parasitologie Mycologie, Centre National de Référence 
du Paludisme, CHU Pitié-Salpêtrière, 47-83 boulevard de l Hôpital, 75651 Paris cedex 13, France and 6French Malaria National Reference Centre, 
Paris, France
Email: Olivier Bouchaud* - olivier.bouchaud@avc.aphp.fr; Patrick Imbert - patrick.imbert@santarm.fr; Jean Etienne Touze - jetouze@aol.com; 
Alex NO Dodoo - alexooo@yahoo.com; Martin Danis - martin.danis@psl.aphp.fr; Fabrice Legros - olivier.bouchaud@avc.aphp.fr
* Corresponding author    
Abstract
Background: Halofantrine (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.
Methods: In 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.
Results: Thirty-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.
Conclusion: A 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.
Published: 10 December 2009
Malaria Journal 2009, 8:289 doi:10.1186/1475-2875-8-289
Received: 17 July 2009
Accepted: 10 December 2009
This article is available from: http://www.malariajournal.com/content/8/1/289
© 2009 Bouchaud et al; licensee BioMed Central Ltd. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), 
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 8
(page number not for citation purposes)
Malaria Journal 2009, 8:289 http://www.malariajournal.com/content/8/1/289
Background
Halofantrine (HF), a phenanthrenemethanol derivative of
aminoalcohol, was first marketed in 1988. It was consid-
ered effective and safe for treating malaria, including
multidrug resistant P falciparum strains [1] until 1993,
when ter Kuile et al reported the first death related to HF
cardiotoxicity [2]. Of note is that HF was given at higher
doses than recommended (72 versus 25 mg/kg) to
increase efficacy on the Thai-Burma border, an area with
high level resistance [2]. This report led to a prospective
electrocardiographic study which consistently showed HF
dose related lengthening of the PR and QT intervals [3].
Since then numerous studies have confirmed cardiac tox-
icity in both adults and children, and several cases of
death or severe cardiac toxicity of HF have been reported
[4-15]. Due to these potentially severe side effects, and
despite a reliable and rapid efficacy, usage of HF decreased
dramatically in both malaria-endemic and industrialized
countries.
Since the majority of reported cardiac accidents appeared
to occur either in patients with predisposing factors or at
higher than recommended doses, the aim of the study was
to collect and carefully examine all reported fatal cases of
HF-related cardiotoxicity [15-18]. While there are cur-
rently safer and equally effective anti-malarial drugs avail-
able (e.g., artemisinin derivatives, atovaquone-
proguanil), the prospect of new drugs becoming available
over the next decade is limited due to financial con-
straints. Thus, it seems reasonable to carefully examine
the risk/benefit ratio of HF and either discard it altogether,
or better define that ratio for possible use should the need
for it arise, e.g. the occurrence of resistance or unexpected
side-effects of current anti-malarials.
Methods
In March 2005, the Regulatory Affairs Department of
GlaxoSmithKline (GSK)
(GlaxoSmithKline Research & Development Limited,
New Frontiers Sciences Park, Harlow, Essex, UK) provided
all mortality data of cardiac origin related to HF from the
GSK Worldwide Global Clinical Safety and Pharmacovig-
ilance Data base [19]. All spontaneous, post-marketing
surveillance and clinical trial serious adverse events
reports of fatal cardiac arrhythmia or death, where HF was
reported as the suspect drug, were considered for identifi-
cation of cases. To provide as comprehensive a report as
possible, relevant key words were used including the fol-
lowings: arrhythmia, atrioventricular block, bradycardia,
bundle branch block, cardiac arrest, cardiac failure, car-
dio-respiratory arrest, cardiovascular disorder, chest pain,
circulatory collapse, death and sudden death, electrocar-
QT prolonged, shock, tachycardia, torsade de pointes,
ventricular hypertrophy, ventricular fibrillation, ventricu-
lar tachycardia.
Reports were considered as unassessable when the details
of neither the event nor the patient were available. In
addition, reports were excluded when there was an alter-
native diagnosis much more likely to have caused the
death. In addition to this systematic review of all cases of
fatal cardiotoxicity possibly related to HF reported to the
GSK database, all similar cases reported in the literature
were reviewed. Doubles in both sources were identified by
comparing available data (date, age, sex, country, case
description, outcome).
Results
GSK has estimated that 17.9 million patients, mainly in
developing countries, were treated with HF between 1988
and 2005 (19). Of the 261 reports of severe HF related
side effects reported to the GSK safety database, 95 had a
cardiac explanation [19]. They were mainly reported from
France (41%), Pakistan (14.7%), Germany (8.4%), and
Kenya (6.3%). Fifty six cases were excluded because the
only information available was exposure to HF and death
in three cases and because of non-fatal outcome in 53
cases. Among the 39 remaining fatal cases, five were much
more likely due to an unrelated cause (details not shown,
available on demand), leaving 34 cases of cardiac fatalities
suspected to be related to HF (Figure 1). An additional
case published in the literature but not included in the
GSK data base was identified, resulting in a total number
of fatal cases of 35 [3].
Table 1 summarizes the main characteristics of these 35
patients and Table 2 displays the cumulative effect in
patients having more than one predisposing factors. In 26
patients (74%) at least one predisposing cardiac factor
(and up to three) was recorded including: concomitant
medication with possible cardiac effect (n = 20), underly-
ing cardiovascular disease or deleterious medical condi-
tion (n = 14), improper administration of HF (excess, n =
3, or drug taken with food, n = 2). One patient died from
a cardiac arrest following a seizure.
Autopsies were performed in eight cases including three
cases without an apparent cause of death appeared (in one
of these three cases, brain pathology findings suggested
cerebral malaria). In five cases cardiac abnormalities were
noted, including one case where HF was cited as responsi-
ble in a 27 year-old Kenyan patient who had an history of
cardiac arrhythmia and had received mefloquine for an
acute malaria shortly before HF. For the four other
patients pathologic findings were respectively, previouslyPage 2 of 8
(page number not for citation purposes)
diogram abnormal or change, extrasystoles, hypotension,
long QT syndrome, myocardial infarction, palpitations,
unknown right ventricular arrhythmogenic dysplasia (two
young French females); hypertrophic cardiomyopathy in
Malaria Journal 2009, 8:289 http://www.malariajournal.com/content/8/1/289
a 22 year-old patient from Togo (having taken meflo-
quine before HF); and a flabby myocardium and signs of
multi-organ failure (congested kidneys, pulmonary
oedema and congestion, and enlarged liver) in a 31 year-
old female from Ghana.
Halofantrine levels measured by HPLC were available in
three cases: two considered in the normal therapeutic
range for both halofantrine and N-desbutyl-halofantrine
[20] and one with high values (respectively 879 and 510
ng/mL) supporting a possible overdose [15,19]. Five cases
occurred in children less than 16 y (three males and two
females), living in a developing country (four) or in
France (one). Mean age was 9.6 y (range: 2-13). All had a
contraindication to halofantrine (including one case of
cerebral malaria) or a concomitant medication, which
Of the 35 cases, twenty-one (including one paediatric
case) have been published either as case reports or
included in a review published by Wesche et al from the
FDA Spontaneous Reporting System (containing fewer
details than those available in the GSK safety data base)
[3,7,9,13,15,18,21].
Discussion
Based on the analysis of the GSK Worldwide Global Clin-
ical Safety and Pharmacovigilance data base and a review
of the literature, it appears that 35 fatalities presumably
related to HF, including five children, were reported from
1988, when the drug first became available, to March
2005. No additional cases have been published since. No
cases were reported in clinical trials prior to marketing nor
during the post-marketing phase. Besides possible under-
reporting, another limitation is that reported cases often
lack essential information such as the exact dosage, body
weights, time course for development of arrhythmia or
death, description of concomitant morbidity (especially
heart diseases), usage of potentially complicating medica-
tions, electrocardiographic description, etc. With such
insufficient data, there are two main problems with
attempting to delineate cardiac risk with HF: first, other
causes or predilecting factors, including those related to
the malaria itself, may have not been reported. Indeed it
appears that HF was incorrectly given in at least three cases
of severe malaria (a case of clinical cerebral malaria and
two other cases of autopsy-proven cerebral malaria with
multi-organ failure). Second, in 15% of cases of sudden
cardiac death in the general population, no cause is found
despite extensive study, including autopsies [22,23].
Cardiac toxicity of HF was first reported in 1993 when a
Thai woman with a life-long history of tachyarrhythmias
died suddenly. She had received high-dose HF (72 mg/kg,
i.e approximately three times the standard dose recom-
mended) for a recrudescent falciparum malaria after fail-
ure of a mefloquine treatment [2]. As pre-marketing and
early post-marketing safety studies had not shown previ-
ously any HF cardiac effect, electrocardiograms were not
included in the high-dose halofantrine prospective study
performed to validate the 72 mg/kg regimen in this area
one year before that death [2]. A subsequent prospective
electrocardiographic study performed by the same team
showed that high-dose HF was associated with QTc inter-
val prolongation [3]. The lengthening was correlated to
HF and its metabolite plasma concentrations as reported
in another study [3,24]. The magnitude of QTc prolonga-
tion 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
Selection of 34 cases* of fatal outcome from cardiac origin presumably related to halof ntrine from the GSK Global Clinical Pharma ovigilance Da a Base [18]Figure 1
Selection of 34 cases* of fatal outcome from cardiac 
origin presumably related to halofantrine from the 
GSK Global Clinical Pharmacovigilance Data Base 
[18]. * an additional case not reported in the GSK data base 
was found in the literature.
261 cases of severe side effects 
related to halofantrine 
95 cases from cardiac origin 
3 unassessable cases 
53 cases with no fatal 
outcome 
5 fatal outcomes not 
related to halofantrine
39 fatal outcomes 
34 fatal outcomes  
from cardiac origin  
presumably related to 
halofantrinePage 3 of 8
(page number not for citation purposes)
could have been a predisposing factor for cardiac arryth-
mia (Table 3).
patients with congenital prolonged QT syndromes have
been published [8-10,12,14,18,24,25]. In 1993, the dis-
Malaria Journal 2009, 8:289 http://www.malariajournal.com/content/8/1/289covery of electrocardiographic and possible clinical car-
diac effects induced by HF has led the WHO and GSK,
which produces HF, to recommend limitations on the
Assuming there is no reason for an over-representation of
females receiving HF, it appears from the data shown here
that females (70%) seem inordinately sensitive to fatal
Table 1: main characteristics of 35 cases of fatal outcome from cardiac origin presumably related to halofantrine
patient agea (year) Median: 27; range: 2 - 53
sexb male: n = 9 (27%); female: n = 24 (70%)
geographic origin of patients developing world, n = 25; developed world, n = 10
type of report • spontaneous n = 34
 clinical trial n = 0
(GSK data base only)  post marketing survey n = 0
source of report health care professional n = 35
time from first dose to death (day) median: 1; range: 0 3
 same day as first dose: n = 13 (37%)
 1 day after first dose: n = 13 (37%)
 2 days after first dose: n = 2 (6%)
 3 days after first dose: n = 3 (8%)
 unknown: n = 4 (11%)
number of patients receiving 1 or 2 courses of halofantrive and number 
of doses taken by patientsc
 first course of halofantrine: n = 23
 1 dose: n = 1 (3%)
 2 doses: n = 9 (26%)
 3 doses: n = 10 (28%)
 other including pediatric formulation: n = 3
 second course of halofantrine: n = 6
 5 or 6 doses: n = 5 (14%)
 8 doses: n = 1 (3%)
malaria diagnosis and malaria  no diagnostic test performed: n = 8
speciesd  blood smear negative: n = 7
 P. falciparum: n = 8
 P. vivax: n = 1
 Plasmodium sp: n = 4
concomitant drugs with possible cardiac effect n = 20 (57%)
 anti-malarial: chloroquine: n = 7; mefloquine: n = 4; amodiaquine: n 
= 1;
 antibiotics: cyclines, n = 2; metronidazole, n = 1; ciprofloxacine, n = 
1; norfloxacine, n = 1
 drugs leading to electrolyte imbalance: diuretics, n = 2; potassium, n 
= 1
underlying medical condition n = 14 (40%)
 cardiovascular disease, n = 11
 obesity, n = 1
 epilepsy, n = 1
 severe anaemia, n = 1
missing data: a: n = 3; b: n = 2; c: 6; d: n = 7Page 4 of 8
(page number not for citation purposes)
prescribing of HF [21]. cardiac toxicity. There are, unfortunately, not enough
Malaria Journal 2009, 8:289 http://www.malariajournal.com/content/8/1/289
Page 5 of 8
(page number not for citation purposes)
Table 2: Classification of 35 patients with fatal outcome from cardiac origin presumably related to halofantrine (HF) according to the 
number of predisposing factors to cardiac complication and indication for halofantrine
Number of predisposing factor(s), 
number of patients (number of children)
Details on predisposing factors (underlying 
cardiac disease, concomitant medication, 
misuse of HF, etc)
Wrong or debatable indication for HF
no predisposing factors, n = 9 (0) Pt # 2, 11§ 12, 16, 17, 18, 20, 31, 33 a* = 1, b* = 2, c* = 1, d* = 2
1 predisposing factor, n = 16 (2) Pt # 1, 30: vibramycine b* = 3, c* = 2
Pt # 5, 8, 14, 19: chloroquine e* = 1
Pt # 7: bundle branch block¤
Pt # 9, 34: HF taken with food
Pt # 13: metronidazole
Pt # 21: potassium infusion
Pt # 23: unknown severe cardiac valve disease
Pt # 24: angina pectoris
Pt # 25: ciprofloxacine
Pt # 29: mefloquine
Pt # 32: HF overdose (45 mg/kg)
2 predisposing factors, n = 5 (2) Pt # 3: cardiomyopathy¤ + furosemide a* = 1; c* = 1
Pt # 4: obesity + chloroquine d* = 1; f* = 1
Pt # 6: tachycardia + mefloquine
Pt # 10: severe anaemia and dehydration + 
amodiaquine
Pt # 26: unknown right ventricular 
arrhythmogenic dysplasia + chloroquine
3 predisposing factors, n = 5 (1) Pt # 15: cardiac arrhythmia + chloroquine + 
amodiaquine
b*= 2; c* = 2
Pt # 22: arteriosclerosis and high blood pressure 
+ indapamide + HF taken with food
Pt # 27: unknown cardiomyopathy + mefloquine + 
erythromycin
Pt # 28: unknown right ventricular 
arrhythmogenic dysplasia + chloroquine + 
probable HF overdose°
Pt # 35: tachyarrhythmia¤ + mefloquine + HF 
overdose (72 mg/kg)
*: a = no certainty of malaria diagnosis/no blood smear performed (industrialised country);
b = no certainty of malaria diagnosis/no blood smear performed (developing country);
c = no malaria (blood smear negative); d = possible severe malaria; e = severe malaria;
f = P. vivax
¤: known prior to HF prescription; §actual exposure to HF unsure; ° high HF blood level (see text)
Table 3: Contraindication (and complicating drugs) to halofantrine in 5 children with fatal outcome of cardiac origin presumably 
related to halofantrine
patient #3 (13 y. old) known history of cardiomyopathy (treated by furosemide)
patient #10 (2 y. old) severe anaemia, dehydration (+ amodiaquine prior to halofantrine)
patient #15 (11 y. old) known history of cardiopathy with cardiac arrhythmia (+chloroquine and amodiaquine prior to halofantrine)
patient #21 (8 y. old) severe/cerebral malaria + bradycardia (+ potassium injection)
patient #32 (12 y. old) HF overdosing (45 mg/kg) (+ concomitant norfloxacine + possible intake of amodiaquine)
Malaria Journal 2009, 8:289 http://www.malariajournal.com/content/8/1/289
available data to enable an analysis of weight as a possible
risk factor of HF overdosing due to significant lower body
weight in females. Within the general population it is
known that QT interval is longer and QT prolongation
and torsades de pointes are more common among
females, who are more susceptible to torsades de pointes
from QT-prolonging drugs [26,27]. However, there is no
evidence for a greater risk of sudden death. On the con-
trary, the risk for females seems lower globally [26,27].
Twenty-five cases (71%) occurred in patients living in
developing countries. This is not surprising as the denom-
inator (malaria patients exposed to HF) is much higher
(200 fold) compared to industrialized countries [19]. In
addition, due to field conditions it is likely that side-
effects were underreported in contrast to the higher rate of
predisposing cardiac factors e.g., vitamin B1 deficiency
(inducing QT prolongation) due to nutritional insuffi-
ciency, electrolyte abnormalities or cardiac rheumatism
[28]. Thus, HF toxicity may have been underestimated in
tropical areas.
Indeed 74% of patients had at least one predisposing car-
diac factor and in five cases each, two and three factors
(Table 2). Such pre-existing or concomitant predisposing
factors have been highlighted by some authors to increase
the HF-cardio-toxicity and to contribute to the onset of
severe clinical manifestations of HF cardio-toxicity, HF-
induced QT prolongation being the initial step [2,15,18].
In addition, the role of malaria itself cannot be excluded
even if cardiac impairment in malaria is debated and
unlikely in non-severe forms. However, HF could exacer-
bate malaria-associated orthostatic hypotension, making
it a potentially predisposing factor [3,29,30]. While
acknowledging the limits of available data in this study, it
is interesting that no predisposing factors were observed
in nine cases (26%). Among these nine cases, the diagno-
sis of malaria was unproven in 3 cases (including one case
in a developed country), disproven in one case, and
according to available data, severe malaria was likely in 3
cases, which constituted a contraindication to the use of
HF. Of the 26 cases where at least one predisposing factor
was identified, the diagnosis of malaria was unproven in
six cases (including one in a developed country) and dis-
proven in five cases (Table 2).
Death occurred after two or three doses in 65% of docu-
mented cases and within the first twenty four hours fol-
lowing first dose of HF in 74% of the cases. This is
consistent with pharmacokinetic data on HF including the
fact that QT-prolongation, which reaches a maximum 12
hours after first dose, is related to the plasma concentra-
tion of the parent drug which appears, according to
The fatal event occurred during the first course of HF in
79% of the cases, assuming that, given the quality of data,
the event occurred after the first course unless explicitly
stated to have occurred during the second. This is not sur-
prising as a second course was only recommended in non-
immune patients, who represented only a small part of
the population exposed to HF. However, electrocardio-
graphic changes have been reported as greater during the
second course than the first due to higher HF plasma con-
centrations, leading to a probable higher risk of severe
outcome [24].
Paediatric HF cardiotoxicity has been documented, in the
form of asymptomatic electrocardiographic changes, in
almost half of treated children [10,14]. However the risk
of severe cardiac complications was considered very low
as, none of the numerous studies of HF when standard
recommendations were followed, have shown sympto-
matic cardiac manifestations in either developing and
industrialized countries [10,11,14,31-39]. In contrast, five
fatal paediatric cases are reported in this study, all of
which occurring in a context of contraindication or mis-
use of HF (Table 3). In addition, HF was given in one case
of vivax malaria and in another case (in a European coun-
try) without proven malaria [19].
Statements about the danger of using HF may be unwar-
ranted if they fail to discriminate between the frequent (as
for other common drugs) but asymptomatic electrocardi-
ographic changes limited to QT-interval prolongation and
potentially fatal ventricular arrhythmias or torsades de
pointes which occur in a very limited number of patients
with probable predisposing factors after a first step of QT-
prolongation [18,40,41]. HF has a high pro-arrhythmic
potency, inducing the same concentration-dependant
effects on QTc dispersion and variability as class-III anti-
arrhythmic agents, which are known for their pro-arrhyth-
mic action [18,30,42]. This pro-arrhythmic effect is due
largely to the fact that HF, like mefloquine and lumefan-
trine, acts upon cardiac myocytes to block the potassium
channels which initiate repolarization and determine the
QT interval under genetic regulation (LQT1 and HERG
genes) [16,17]. Although research in this area is relatively
new, it may well be as has been recently postulated by
Kannankeril that the ability for QT-prolonging drugs to
induce ventricular arrhythmias or torsades de pointes is
genetically determined [43,44]. An underlying cardiac
impairment would seem to be an additional risk factor for
a severe outcome [3,15]. Thus discerning how much of
the problem is due to the inherent properties of HF can be
difficult when there are multiple complicating factors. An
excellent example was the first reported death related to
HF, who was a female with a known pre-existing tachyar-Page 6 of 8
(page number not for citation purposes)
Wesche et al, more cardiotoxic than its N-desbutyl metab-
olite [1,3,18,24].
rhythmia, given an excessive dose of HF, and who had
Malaria Journal 2009, 8:289 http://www.malariajournal.com/content/8/1/289
also recently taken mefloquine, a long half-life QT-pro-
longing drug [2].
The 53 non-fatal cases of HF associated cardiotoxicity in
the sampled patients were not analysed as the data sources
on cardiotoxicity were variable and as several other stud-
ies and methodologies have yielded robust information
on HF associated cardiotoxicity. This study therefore
focused exclusively on fatal cases of HF cardiotoxicity
despite the obvious heterogeneity of the data sources and
the challenges that posed to the review and analysis.
This review of fatal HF cardiotoxicity focused on 35 cases
from the GSK Worldwide Global Clinical Safety and Phar-
macovigilance data base, plus a review of the literature.
This figure is very likely underestimated given that the vast
majority of HF treatments took place in the developing
world where pharmacovigilance activities are absent or
newly developed and where adverse events to all medi-
cines are poorly documented. It would be useful to com-
pare this with fatalities due to comparable drugs such as
mefloquine, but at the time of this review we were unable
to access the safety data base of Roche laboratories. In
contrast, no cardiac effects or deaths have been reported to
date following treatment using lumefantrine, a parent
drug of HF [30,45]. These major differences in cardiotox-
icity between HF and lumefantrine, which are very similar
drugs, are consistent with the known lesser cardiotoxicity
of HF racemic compound and/or the HF N-desbutyl
metabolite compared to HF itself [18].
HF is still used in countries such as Pakistan or parts of
West and Central Africa, despite the availability of much
safer options including the WHO recommended artemisi-
nin combination therapies. In these countries, physicians
should carefully check for contraindications, especially in
females, such as any underlying heart disease, bradycar-
dia, personal or family history of long QT-interval, con-
comitant use of another QT-prolonging drug (especially
mefloquine) and only prescribe HF at the recommended
dosage (25 mg/kg) to be taken on an empty stomach. In
addition, HF should be strictly restricted to non-severe P.
falciparum malaria in patients with no risk of severe elec-
trolytes imbalance. Following these guidelines would
greatly lessen the risk of cardiac side-effects [43]. In indus-
trialized countries, where other safer and efficient anti-
malarial agents are available, there is currently no real
need for HF apart from unusual cases.
Conclusion
The undoubted cardiotoxicity of HF should lead physi-
cians to use safer drugs when available. Nevertheless,
when there is no other choice, serious adverse outcomes
addition, HF may again be needed if the limited number
of new anti-malarial agents proves inadequate for future
needs. In that case, the development of the N-desbutyl-
metabolite or a racemic compound of HF would be pref-
erable, as they seem significantly less cardiotoxic than the
parent drug [18]. The development of pharmaco-genetic
tools would possibly allow a safer use of HF and other QT-
prolonging drugs by screening patients at particular risk
for severe complications. Routine genotyping of patients
appears unrealistic for the foreseeable future [43].
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
OB participated in the design of the study, performed the
analysis of data, wrote and reviewed the manuscript. PI
participated in the design of the study, contributed to the
analysis of data and reviewed the manuscript. JET partici-
pated in the design of the study and reviewed the manu-
script. ANOD reviewed the manuscript. MD participated
in the design of the study and reviewed the manuscript. FL
participated in the design of the study and was in charge
of contacts with the Regulatory Affairs Department of the
GlaxoSmithKline Laboratory. All authors read and
approved the final manuscript.
Acknowledgements
We are grateful to Dr Nesemann for his help in preparing the manuscript 
and especially for linguistic assistanceto and to Dr Duparc, from Medicines 
for Malaria Venture, former GlaxoSmithKline (GSK) employee, for facilitat-
ing contacts with the Global Clinical Safety and Pharmacovigilance Depart-
ment of GSK in the UK.
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Moreno JL, Engohan E, Blanc G, Dupasquier I, Iannascoli F: Efficacy,
safety and acceptability of halofantrine in the treatment of