Safety profile of Coartem®: the evidence base

This article reviews the comprehensive data on the safety and tolerability from over 6,300 patients who have taken artemether/lumefantrine (Coartem®) as part of Novartis-sponsored or independently-sponsored clinical trials. The majority of the reported adverse events seen in these studies are mild or moderate in severity and tend to affect the gastrointestinal or nervous systems. These adverse events, which are common in both adults and children, are also typical of symptoms of malaria or concomitant infections present in these patients. The wealth of safety data on artemether/lumefantrine has not identified any neurological, cardiac or haematological safety concerns. In addition, repeated administration is not associated with an increased risk of adverse drug reactions including neurological adverse events. This finding is especially relevant for children from regions with high malaria transmission rates who often receive many courses of anti-malarial medications during their lifetime. Data are also available to show that there were no clinically relevant differences in pregnancy outcomes in women exposed to artemether/lumefantrine compared with sulphadoxine-pyrimethamine during pregnancy. The six-dose regimen of artemether/lumefantrine is therefore well tolerated in a wide range of patient populations. In addition, post-marketing experience, based on the delivery of 250 million treatments as of July 2009, has not identified any new safety concerns for artemether/lumefantrine apart from hypersensitivity and allergies, known class effects of artemisinin derivatives.

and quality and is marketed as Coartem ® for use as a sixdose regimen in infants, children and adults with acute, uncomplicated infection due to P. falciparum or mixed infections including P. falciparum [3,4].
The efficacy of AL has been confirmed in many different patient populations around the world and is discussed elsewhere in this supplement [5]. This article reviews the comprehensive safety data on AL that has been reported in the scientific literature from Novartis-sponsored and independent clinical trials.

Novartis-sponsored studies
Six Novartis-sponsored clinical studies [6][7][8][9][10][11] have been conducted to assess efficacy and safety of the six-dose regimen of AL, with safety data from these summarized in Table 1. These studies were conducted in different regions of the world and so included patients who lived in areas with varying levels of drug resistant P. falciparum and malaria endemicity. Some of the studies included other anti-malarial drugs as active comparators [7,8], one allowed the inclusion of patients with mixed infections that included P. falciparum [10], and one utilized a dispersible paediatric formulation [11].
In all of these studies AL was well tolerated and most reported adverse events were of mild or moderate severity. Reported adverse events occurred mainly in the nervous system or gastrointestinal system and were considered typical of the symptomatology of malaria or concomitant infections. No cardiac, neurological or audiological safety issues were identified in the studies that assessed these safety parameters [6][7][8][9][10][11].

Comparative results from independent studies
Many independent trials on AL have also been published in the scientific literature. Results from the studies conducted in Africa  are summarized in Table 2 and the results from studies conducted in Asia [33][34][35][36][37][38][39] in Table 3. The safety findings from these trials confirm the results of the Novartis-sponsored studies, namely that the majority of adverse events were mild or moderate in severity, tended to affect the gastrointestinal or nervous system, and were consistent with the symptoms of malaria. Serious adverse events were infrequent and were unrelated or unlikely to be related to study medication.
Data have also been pooled to provide a more complete assessment of the safety and tolerability of AL in a large number (>1,900) of adult and paediatric patients. The results of two of these meta-analyses, Mueller Table 4 [40,41]. These pooled results confirm earlier data and show that AL is generally well tolerated with the majority of reported adverse events again affecting either the gastrointestinal or nervous systems and of mild or moderate severity [40,41]. Few adverse events were considered by the investigators to be drug-related -most were regarded as being related to the symptomatology of malaria. Serious adverse events occurred infrequently [40,41]. There were, however, some differences in the adverse event profile in children when different body weights were compared, but this is unlikely to be of clinical relevance. Instead, it is more likely to be related to the subjective nature of these adverse events and the differences in the ability of young infants and children to verbalize these complaints [41].

Special safety considerations
Neurological and audiological safety There have been case reports of neurological problems (including ataxia, nystagmus, tremor and slurred speech) occurring after administration of herbal artemisinin [42] or artesunate monotherapy [43,44]. However, it is questionable whether these neurological effects are related to artemisinin treatment [45][46][47]. Indeed, this is not supported by audiology case-control [48][49][50] or other audiology data [14,51], although additional analyses are often called for to investigate this fully. There were, however, no neurological or audiological safety concerns identified for AL in the Novartis-sponsored studies [6][7][8][9][10]52] as shown in Table 1. In addition, audiological data are currently being analysed from a Novartis-sponsored study in 265 patients treated with AL, malarone or mefloquine-artesunate. [Personal communication with Novartis, study A2417). A routine review of the data collected from the first 85 patients, however, did not raise any safety concerns. Neurological or audiological safety concerns have not been identified in the African studies by Bukirwa et al [12], Gürkov et al [14], and Adjei et al [20], as shown in Table 2, Asian studies by Krudsood et al [33], and Mayxay et al [35], as shown in Table 3, and in the pooled analyses reported by Mueller et al [40] or Makanga et al [41], which are summarized in Table 4.

Cardiac safety
Lumefantrine is chemically related to halofantrine, an anti-malarial known to be associated with significant prolongation of QTc interval. Indeed, QTc prolongation is a known class effect of many anti-malarial drugs. As such, cardiac safety has been thoroughly investigated during the preclinical and clinical development of AL.
The effects of lumefantrine and its major metabolite desbutyl-lumefantrine on wild-type hERG K + channels have been investigated in stably transfected human embryonic kidney cells (HEK293) using a whole cell patch-clamp technique [52]. This in vitro hERG channel assay showed that lumefantrine and desbutyl-lumefantrine have higher IC 50 values (approximately 200-fold) than halofantrine (see Table 5). In addition, the calculated  [9] (5 to 25 kg) Nigeria differences in AEs were seen in the different body weight groups but as these were generally mild, differences were not considered clinically relevant. Only one patient had a SAE (urticaria) that was considered to be related to study medication and this event resolved when treatment was withdrawn. No cardiac safety issues were identified and there were no significant abnormal laboratory values associated with AL treatment.

Hatz
Open-label Nil Adult, non-165 EU, Treatment was well tolerated and most AEs et al 2008 immune Colombia were mild or moderate in severity.The most [10] travellers frequently reported AEs were headache, insomnia, diarrhoea, nausea and vomiting and these AEs (along with anorexia, vertigo and chills) were most probably related to signs and symptoms of malaria. No allergic reactions were reported in any of the patients.There were few SAEs and none of these were considered related to AL. No significant effects were observed during ECGs and there were no significant effects seen with regard to laboratory parameters.

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cardiac safety indices, which are over 30 for lumefantrine, suggest that lumefantrine and its major metabolite pose an unlikely risk of cardiotoxocity compared with halofantrine [52]. A phase I, parallel group study with AL, moxifloxacin and placebo arms (n=42 per group) was conducted in healthy volunteers to assess cardiac safety [52]. As shown in Figure 1, this study demonstrated that the six-dose regimen of AL was associated with a mean maximum increase in QTc (Fridericia's formula) of 7.45 msec compared with placebo (90% CI: 4.4 to 10.5 msec) in healthy volunteers. By comparison, the effect on QTc (Fridericia's formula) was much greater after dosing with moxifloxacin, the positive control. A formal analysis of the relationship between the plasma concentration of lumefantrine and the change from mean baseline in QTc (Fridericia's formula) was conducted (see Figure 2). This shows that the 95% confidence limit for the mean lumefantrine plasma concentration does not cross the upper confidence band for the threshold of relevance for change in QTc (Fridericia's formula).
One possible explanation for the alterations in QTc seen with AL may be due to malaria itself and recovery from this disease, as well as to stress and anaemia. These conditions can affect cardiac electrophysiology and may lengthen the QT interval [53]. As QT correction formulae are based on a normal heart rate of 60 beats/minute, and patients with malaria tend to have elevated heart rates that decrease with successful treatment and defervescence, overcorrection of the QT interval can also occur. This is even more pronounced in small children, and heart rates higher than 60 beats/minute are routinely seen in healthy children. Despite the changes in QTc associated with malaria, no adverse events attributable to QTc prolongation (e.g. syncope or sudden death) have been reported in clinical trials with AL [6] as shown in

Haematological safety
Preclinical data suggested that repeated exposure to AL may affect blood cell counts and as such, particular attention was paid to haemoglobin levels and haematological adverse events reported during clinical trials. A published pooled analysis of 15 trials conducted in China, India, Thailand, The Gambia, Tanzania, France, The Netherlands and the UK confirmed these results [54]. Indeed, in this analysis, anaemia and thrombocytopaenia were frequently present at baseline, but returned to normal or improved considerably with the resolution of disease [54]. No haematological safety concerns were identified during the safety assessment presented in this review.

Safety of repeated administration
Most safety data on antimalarials are collected as part of clinical trials and these tend to evaluate the treatment of a single episode of malaria. In practice, however, children in areas of high malaria endemicity are likely to suffer from repeated episodes of malaria and this raises concerns over potential toxicity due to repeated shortterm exposure to the drugs.
Two longitudinal studies have therefore attempted to address this question by assessing the efficacy, safety and tolerability of amodiaquine-artesunate versus AL [55] and amodiaquine plus sulphadoxine-pyrimethamine versus artesunate-amodiaquine versus AL [56] after repeated use. Tanzania, Mali, seen in patients who received treatment with [11] blind of AL (5 to <35 kg) Benin, crushed AL tablets compared with those who Mozambique received the dispersible formulation. No new or unexpected AEs were identified and the most commonly reported AEs were also related to malaria.The most common drug-related AE was vomiting; this was more frequently reported in the lowest weight category.The number of SAEs was low (1-2% in both groups) and most of these were infections.There were no signs of ototoxicity.There were no clinically relevant findings or differences between study groups for ECG assessments, vital signs, or laboratory parameters. blind, single centre in ASAQ (n=204) intensity and there was no difference between the two treatment groups. SAEs [12] children (1-10 years) were uncommon with both regimens, with one occurring in each group and judged to be unrelated to study medication (ASAQ) or unlikely to be related to study medication (AL). No abnormalities in hearing or fine finger dexterity were detected.

Dorsey Uganda
Single-blind, AL (n=103 and All study regimens appeared to be safe and generally well tolerated. In the first et al 2007 randomized, single 202 treatments) 14 days, anorexia and weakness occurred more commonly in children treated with [13] centre in children AQSP (n=111 AQSP than those receiving ASAQ or AL. A total of 45 SAEs were reported in (1-10 years) and 253 38 patients, but none of these were considered probably or definitely related to treatments) study medication. ASAQ (n=113 and 232 treatments)

Gürkov
Ethiopia Single centre in AL (n=30) The first randomized clinical trial to directly compare ototoxicity of AL with other et al 2008 adults and children Quinine (n=35) anti-malarial drugs. Pure tone audiometry and distortion product otoacoustic [14] >5 years of age Atovaquone/ emission levels revealed transient significant cochlear hearing loss in patients proguanil (n=32) treated with quinine but not in those treated with AL or atovaquone/proguanil.
Transitory evoked otoacoustic emission could be elicited in all examinations, except for three patients in the quinine group on day 7, who suffered a transient hearing loss greater than 30 dB.There was no evidence of drug-induced brain stem lesions by brain stem evoked response audiometry.There was no detrimental effect of AL on peripheral hearing or brainstem auditory pathways; however, transient hearing loss is common after quinine therapy due to temporary outer hair cell dysfunction.

Kamya Uganda
Single-blind, AL (n=210) Both drugs were well tolerated and reported AEs were of mild or moderate et al 2007 randomized, single DP (n=211) severity and consistent with symptoms of malaria.There were 6 SAEs reported in [15] centre in children this study and all were judged unrelated to study medications. (6 months to 10 years)

Mårtensson Zanzibar
Multicenter, AL (n=200) Both drugs were well tolerated and most AEs were of mild severity. Similar et al 2005 randomized, open-ASAQ (n=208) proportions of moderate or severe AEs were reported by the two groups (10% [16] label in children for AL vs. 12% for ASAQ). All severe AEs were associated with malaria and were (6-59 months) not attributed to the study drugs. No significant differences were seen in the mean counts of white blood cells and neutrophils during follow-up. Significant and similar increases in mean haemoglobin levels from baseline to day 42 were seen in both groups. given AL (5 cases of gastric disturbance, 5 of excessive sleepiness and 1 of [17] and adults dizziness). All were mild and self-limited and no patients withdrew from the study because of an AE.

Yeka
Uganda Randomized , single AL (n=199) Most AEs were of mild or moderate severity and consistent with symptoms of et al 2008 centre, single-blinded DP (n=215) malaria.The most commonly reported AEs in both groups were cough, coryza, [18] study in children aged abdominal pain, anorexia, weakness, diarrhoea and pruritus and there were no 6 months to 10 years significant differences between groups. A total of 7 SAEs were reported (2.3% after DP and 1% after AL), but all were judged unrelated to study medication.

Mulenga Zambia
Randomized, open-AL (n=485) AL and SP were generally well tolerated. SAEs were observed in 2 patients treated et al 2006 label, multicentre SP (n=486) with SP and one patient treated with AL. Eleven patients (5 on AL and 6 on SP) [19] in adults had various symptoms possibly related to the study drugs but none were serious enough to interrupt the treatment. 11% in the CQSP and AL groups, respectively), anorexia (12% and 16%), diarrhoea [27] in children (1-10 years) (7% and 4%), abdominal pain (5% and 5%), and pruritus (1% and 1%). No SAEs occurred in either group, and there were no deaths among children in the study.

Zongo Burkina
Multicentre, AL (n=261) Both drugs were well tolerated. AEs did not differ between groups apart from et al Faso randomized, open-AQSP (n=260) pruritus, which was more common with AQSP than AL (16% vs. 3%, p<0·0001). 2007 [28] label in children Only 2 SAEs (both haemoglobin levels below 50 g/L) were reported; 1 SAE was (6 months to 10 years) due to early treatment failure after AQSP and 1 SAE was due to late clinical failure after AL.

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These studies in Ghanaian and Ugandan children indicated all treatments were efficacious, but the various treatments were associated with slightly different adverse event profiles. For example, treatment with amodiaquine plus sulphadoxine-pyrimethamine had a greater risk compared with AL of anorexia, weakness and subjective fever and a greater risk compared with artesunate-amodiaquine of weakness and subjective fever. Children treated with AL, however, had a higher risk of elevated temperature than those receiving artesunate-amodiaquine [56]. In both studies, repeated administration of AL did not seem to be associated with an increased risk of adverse drug reactions. The study in Ghanaian children also included neurological examinations for children treated with repeated artemisinin-based regimens. This did not identify any abnormal neurological signs that were considered related to artemisinin [55].

Comparison with other anti-malarial therapies
The safety of the six-dose regimen of AL has been compared with MAS in two Novartis-sponsored, openlabel randomized trials [7,8,52], as summarized in Table 1. In these two studies, 314 patients received AL and 105 patients received MAS. Overall, AL was at least as well tolerated as MAS, and had a similar safety profile (Table 6) [52]. Only one patient, who developed urticarial rash, experienced a serious adverse event that was thought to be treatment-related [52]. Independent studies have also compared AL with other anti-malarial therapies as shown in Table 2, Table 3 and Table 4  . These studies showed that AL was at least as well tolerated as the various comparators (AQSP, ASAQ, ASCD, ASSP, AS plus sulphamethoxypyrazine plus pyrimethamine, atovaquone/ proguanil, CQ, CQSP, DP, DNP, MAS, quinine, or SP) used in clinical trials.  in the AQSP and AL groups than in the DP group (24% and 20% vs. 9%, [29] label in children DP (n=187) respectively), headache was more common in the AL group than in the AQSP and (≥6 months) DP groups (21% vs. 14% and 10% respectively) and pruritus was more common in the AQSP group than in the AL and DP groups (18% vs. 6% and 3%, respectively). No SAEs were reported in this study.  with AL or DNP. Minor symptoms (nausea, headache, and dizziness) were seen in [33] adults both groups.These could not be differentiated from malaria signs and symptoms as they resolved simultaneously with fever 1-4 days after treatment.There were no SAEs or deaths, and no neurological or neuropsychiatric manifestations were seen during treatment or during the 28-day follow-up period.

Stohrer Laos
Randomized, open-AL (n=53) Most of the recorded treatment emergent symptoms/signs (TESS) on day 0 and et al 2004 label, hospital and MAS (n=55) day 3 were mild or moderate in severity, and were symptoms typical of malaria. [34] community-based There were no significant differences between treatment groups in the incidence study in adults and of gastrointestinal disorders like abdominal pain, nausea, vomiting, diarrhoea or children (≥10 kg) anorexia (12.8% for AL vs. 12.0% for MAS), or nervous system disorders like headache, dizziness, weakness, or sleep disorder (29.8% for AL vs. 41.5% for MAS). Apart from severe diarrhoea (1 patient in the AL group) and sleep disorder and dizziness (1 patient in the MAS group), no other potentially drug-related AEs were reported.

Mayxay Laos
Randomized, open-AL (n=110) The proportion of patients with symptoms and signs before treatment, which may et al 2004 label, single centre, MAS (n=110) subsequently be confused with drug-related AEs, did not differ significantly [35] in adolescents and CQSP (n=110) between the 3 groups.The proportion of patients with ≥1 potential side-effect adults (12-19 years) was higher in the MAS group (52%) than in the CQSP group (44%) or the AL group (27%).Three patients in the MAS group had serious neuropsychiatric effects following treatment, 1 patient developed fever and a Glasgow coma score of 8/15 due to the presence of gametocytes on day 15 after CQSP and 1 patient had hallucinations and uncharacteristic anxiety on day 20.

Ratcliff
Indonesia Randomized, open-AL (n=387) AEs were assessed in patients without the symptom at enrolment and were et al 2007 label, 2-centre in DP (n=387) similar between groups apart from a two-fold increased risk of diarrhoea on days [36] children (body weight 1 and 2 in more patients receiving DP compared with AL (95% CI 1·3-3·3; ≥10 kg) and adults p=0.003). By day 7, the risk of diarrhoea was 5% in both treatment groups. Although 35% of patients developed a headache on days 1 and 2 after DP compared with 23% of patients given AL, the difference was not significant as headache was a common symptom at presentation.

Hutagalung Thailand
Randomized, open-AL (n=245) AL and MAS were well tolerated.Vomiting of one or more doses of drug occurred 2005 [37] label, 2-centre, in MAS (n=245) in 2.1% in the AL group and 0.8% of the MAS group (relative risk, 2.5; 95% CI, children (>10 kg) 0.5-12.7; p=0.45).The rates of early vomiting (within one hour) of dosing were and adults very low (around 2%) and did not differ between groups.The most commonly reported and possibly drug-related AEs were effects on the gastrointestinal (abdominal pain, anorexia, nausea, diarrhoea and vomiting more than 1 hour after dosing) and central nervous system (headache, dizziness).There were fewer AEs in the AL group compared with the MAS group, although this was not statistically significant. No SAEs were reported.

van den
Bangladesh Randomized, open-AL (n=121) All treatments were well tolerated. Mild AEs reported during the 3 days of Broek et al label, single centre, MAS (n=121) treatment were headache, vomiting, nausea and dizziness.The frequency of these 2005 [38] in adults and children CQSP (n=122) AEs was generally higher after MAS compared with AL (p<0.05). After CQSP (≥1 year) treatment, complaints were of intermediate frequency, but vomiting occurred more in this group. Other AEs were anorexia, skin itching and deafness with CQSP, sleeplessness, anorexia, skin itching/rash, epigastric pain and excessive sweating with MAS and blurred vision and anorexia with AL. No severe AEs were observed.

Thapa Nepal
Randomized, open-AL (n=66) The most commonly reported symptoms at presentation apart from fever were et al 2007 label, single centre, in SP (n=33) headache (97% in the AL group and 88% in the SP groups), nausea (42% and 64%, [39] adults and children respectively), and vomiting (39% and 46%, respectively). Other gastrointestinal, (>5 years) neurological, musculoskeletal, respiratory, and dermatologic complaints were much less frequent. During treatment, <12.5% of patients reported one or more symptoms, with the majority of mild intensity, and no significant differences seen between groups.There were no group-specific differences in changes in pulse or blood pressure during initial therapy. ECGs were conducted in 10 patients in the AL group and 8 patients in the SP group and no changes in QTc were observed during treatment with either drug.
AL: artemether/lumefantrine; ECG: electrocardiogram; SP: sulphadoxine/pyrimethamine; CI: confidence interval; CQSP: Chloroquine/sulphadoxine/ pyrimethamine; DP: Dihydroartemisinin/piperaquine; DNP: dihydroartemisinin/napthoquine/trimethoprim; MAS: mefloquine/artesunate; vs.: versus exposed to artemisinin antimalarials. In this study, birth outcomes did not differ significantly from community rates of congenital malformations and stillbirth [57]. In addition, data from a prospective observational study to compare the safety of AL and SP in pregnant women treated for symptomatic falciparum malaria was   [40] conducted in Thailand, India, Europe, generally comparable between the 6-and four-dose groups. Most AEs were reported during the China, Bangladesh in adolescents first 3 days of treatment and were of mild or moderate severity. Severe AEs were infrequent and adults aged >12 years (5.9% for the six-dose group, 3.8% for the four-dose group).The most common AEs reported for AL included headache, asthenia, dizziness, myalgia, arthralgia, nausea, anorexia and fatigue; all Six-dose AL (n=598) of these could have been disease-related. Only a small proportion of patients reported AEs that Four-dose AL (n=770) were suspected to be drug-related and these occurred less frequently with the six-dose AL group than in the four-dose group. Drug-related AEs were more frequent for most comparator Comparators included: treatments than six-dose AL regimen, and for MAS, these were higher than the rates seen in Mefloquine (n=126) both the six-dose and four-dose groups. Quinine/SP (n=114) Chloroquine (n=90) SAEs were reported by 0.6% of patients in the six-dose group and 0.8% of patients in the MAS (n=335) four-dose group. No SAEs in patients in the six-dose group (dyspnoea, febrile coma, pulmonary Halofantrine (n=52) oedema, typhoid fever) were considered to be drug-related. SAEs in the four-dose group included (one each of) abnormal laboratory values, anaemia, falciparum malaria, malaria relapse, severe malaria, and two cases of hepatitis; only the reports of anaemia and malaria relapse were suspected to be drug-related. For the comparators, one SAE was reported in each of the MAS and chloroquine groups.
There was no difference in neurotoxicity between any of the groups, apart from paresthesia, which was only present in the four-dose AL group and the MAS group. Headache and dizziness were the most frequently reported neurological AEs. Decreased hearing (hypoacusis) was reported by 1.6% of patients in the four-dose group; there were no reports in the six-dose group. All cases of hypoacusis were mild, apart from one case of moderate severity and only two were considered to be drug-related. For the comparators, only patients in the MAS group reported hypoacusis (6.3%).

Makanga et al 8 clinical trials in Gambia,Tanzania,
The majority of patients reported at least one AE after dosing; these were generally mild or 2006 [41] Kenya, Nigeria and Thailand in moderate in severity. Severe AEs were infrequent (5.2% for the six-dose and 7.0% for the children (5-25 kg) four-dose AL groups).The most commonly reported AEs included cough, anaemia, anorexia, vomiting, hepato-/splenomegaly, headache, and diarrhoea, with most of these possibly related to Six-dose AL (n=343) malaria.The proportion of patients with AEs was similar between the 5 to <10, 10 to <15, and Four-dose AL (n=201) 15-25 kg body weight groups for both dosing groups.There were some differences between body weight groups for certain AEs such as headache and dizziness.These subjective AEs appeared less commonly in very small infants, but this may have been related to the patients' limited ability to verbalize symptoms and as such is not considered clinically relevant. Drug-related AEs were only reported for a small number of patients and occurred more frequently in the six-dose group.
Only three patients (0.9%) in the six-dose group reported SAEs (convulsion, urticaria, viral hepatitis) compared with one patient (0.5%) in the four-dose group (pneumonia). Of these SAEs, only the case of severe urticaria, which required hospitalisation, was considered drug-related. In addition to these SAEs, one patient died, but this was from causes unrelated to study treatment. Fewer patients in the six-dose than in the four-dose group reported AEs that were related to the central nervous system; headache (9.9% vs. 40.3%, respectively) and dizziness (3.8% vs. 16.4%, respectively) were the most commonly reported events. Other neurological AEs reported in the six-dose and four-dose groups included clonus (3.8% vs. 1.0%, respectively), hyperreflexia (1.7% vs. 0.5%, respectively), and convulsions (0.3% vs. 1.0%). Patients in the six-dose group failed to report the following AEs which were seen in the four-dose group: nystagmus, ataxia, and coordination abnormal (all 1.0-1.5%) and decreased hearing (1.5%).The cases of decreased hearing were not considered to be drug-related.
For cardiac safety assessments, the incidence of QTc changes within specific ranges was comparable between groups, and it is unlikely that there is an increased cardiac risk in the paediatric patients included in this analysis. Clinical laboratory parameters showed no major differences between the groups; findings were consistent with acute malaria. AE: adverse event; AL: artemether-lumefantrine; MAS: mefloquine plus artesunate; SAE: serious adverse event; SP: sulphadoxine plus pyrimethamine vs.: versus presented at ASTMH Annual Meeting in December 2008 [58]. This study analysed data from 1,001 pregnant women (AL: n=495; SP: n=506) and their foetuses/newborns (AL: n=470; SP: n=477). There were no clinically relevant differences in perinatal mortality, neonatal mortality, still births, preterm deliveries, gestational age-adjusted low birth weight or birth defects between the two groups.

Post-marketing experience
As of July 2009, 250 million AL treatments (70% of which were for children) have been delivered to malaria-

Conclusions
This review summarizes some of the safety and tolerability data on AL (Coartem ® ) from published Novartissponsored and independently-sponsored clinical trials. Data are available to support the use of a six-dose regimen of AL as a safe and well-tolerated treatment for P. falciparum malaria or malaria due to mixed infection including P. falciparum in adults, adolescents, children and infants. Indeed, the safety profile of this drug is similar in both adults and children, and many of the reported adverse events are typical of symptoms of malaria or concomitant infections that are commonly seen in these patient populations. Reported adverse events are mainly of mild or moderate severity, with very few serious adverse events reported and even fewer serious adverse events considered related to treatment. In addition, no notable neurological adverse events or cardiac safety concerns were identified in the many studies that examined the safety of AL. As patients (and especially children) often take repeated courses of treatment for malaria, it is reassuring to note that data are available that show repeated administration of AL is not associated with an increased risk of adverse drug reactions, in particular with regard to neurological adverse events. In addition, a thorough review of the clinical data for AL does not identify any potential cardiac safety issues. Data are also available to show that there were no clinically relevant differences in perinatal mortality, neonatal mortality, still birth, pre-term delivery, low birth weight and spontaneous abortion in women exposed to AL compared with SP during pregnancy.
In conclusion, AL is a safe and well-tolerated treatment for P. falciparum infections that should help fight malaria. Indeed, as of July 2009, 250 million AL (Coartem ® ) treatments have been delivered and post-marketing experience confirms the favourable safety and tolerability profile for this drug. In addition, this wealth of safety evidence has not identified any safety concerns for AL apart from rare type 1 hypersensitivity reactions, a recognized class effect of artemisinin derivatives [2].

Figure 2
Relationship between QTc (Fridericia's formula) and maximum plasma concentration (C max ) in healthy volunteers. [Data on file (study A2101), Novartis]. Note: the threshold of relevance for QTc change is 10 msec vs. placebo