Safety of a fixed-dose combination of artesunate and amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in real-life conditions of use in Côte d’Ivoire

Abstract

BackgroundIn many malaria-endemic, sub-Saharan African countries, existing pharmacovigilance systems are not sufficiently operational to document reliably the safety profile of anti-malarial drugs. This study describes the implantation of a community-based pharmacovigilance system in Côte d’Ivoire and its use to document the safety of ASAQ Winthrop® (artesunate–amodiaquine).MethodsThis prospective, longitudinal, descriptive, non-comparative, non-interventional study on the use of artesunate–amodiaquine in real-life conditions of use was conducted in seven Community Health Centres of the Agboville district in Côte d’Ivoire. Twenty trained Health Centre employees and 70 trained community health workers were involved in data collection in the field. All patients with suspected uncomplicated falciparum malaria, seeking treatment at one of the participating Health Centres, and treated with artesunate–amodiaquine could be enrolled. Two visits were planned, one for inclusion at the Health Centre and a second at home, performed by a community health worker 3–10 days after the inclusion visit. Administration of artesunate–amodiaquine was unsupervised. Adverse events (AEs) were documented at the home visit or during any unexpected visit to the Health Centre or to the hospital and coded and adjudicated by a local pharmacovigilance committee. Symptoms suggestive of hepatic failure, severe neutropaenia, extrapyramidal disorders and retinopathy were considered a priori as AEs of special interest.ResultsSome 15,228 malaria episodes in 12,198 patients were evaluated; 2545 AEs were documented during 1978 malaria episodes (13.0%). The most frequently observed events were asthenia (682 cases), vomiting (482 cases) and somnolence (174 cases). Most reported AEs were of mild or moderate intensity and resolved without corrective treatment. One-hundred and five (105) AEs reported during 100 episodes (0.7%) were considered as serious. Three serious cases of transient extrapyramidal disorders, identified as AEs of special interest were reported in three patients.ConclusionThe fixed dose artesunate–amodiaquine combination ASAQ Winthrop® for the unsupervised treatment of uncomplicated falciparum malaria under real-life conditions of care in Côte d’Ivoire is well tolerated. The study emphasizes the interest of involving properly trained community health workers to collect pharmacovigilance data in the field in order to document rare AEs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1655-1) contains supplementary material, which is available to authorized users.

Prescriber practices and patient adherence to artemisinin-based combination therapy for the treatment of uncomplicated malaria in Guinea, 2016

“…Patients diagnosed with uncomplicated malaria who reported adverse events had almost three times the odds of interrupting treatment than those who did not (holding age and region constant). The most common side effects of fatigue, drowsiness and nausea/vomiting associated with ASAQ were consistent with studies evaluating the safety of ASAQ [16–18]. Even if the adverse events were minor, it is important that prescribers consider potential adverse events when educating patients upon prescribing ACT.…”

Fixed dose drug combinations – are they pharmacoeconomically sound? Findings and implications especially for lower- and middle-income countries

“…There are also ongoing initiatives with DP combinations to improve their packaging to facilitate correct use to further improve their overall effectiveness and value, with published studies showing a single course treatment for uncomplicated falciparum malaria is well tolerated [269,270]. Assi et al (2017) have also demonstrated that the artesunate-amodiaquine FDC is well tolerated to treat uncomplicated PCP malaria under real-life conditions [271], with this combination now widely used. Banek et al (2018) have shown that co-formulated artemether-lumefantrine (AL) and fixed dose amodiaquine-artesunate (AQAS) have high self-reported adherence rates among children [272].…”

The cardiovascular effects of amodiaquine and structurally related antimalarials: An individual patient data meta-analysis

“…Life-threatening neutropenia [ 4 ] and hepatitis [ 5 ] stopped the use of amodiaquine in continuous antimalarial chemoprophylaxis, but there have not been significant adverse effects reported in intermittent prophylaxis. Other serious adverse reactions [ 6 ] such as extrapyramidal movement disorders [ 7 , 8 ] are rare [ 9 ] following standard regimens for treatment and use in SMC. By contrast, asthenia and asthenia-like reactions have been reported frequently (9% to 36.6%) and have a higher incidence with ASAQ than with other ACTs [ 8 , 10 , 11 ].…”

“…Other serious adverse reactions [ 6 ] such as extrapyramidal movement disorders [ 7 , 8 ] are rare [ 9 ] following standard regimens for treatment and use in SMC. By contrast, asthenia and asthenia-like reactions have been reported frequently (9% to 36.6%) and have a higher incidence with ASAQ than with other ACTs [ 8 , 10 , 11 ]. Metabolism of amodiaquine to toxic reactive quinoneimine intermediates [ 12 ] may contribute towards development of neutropenia, but the physiological mechanisms underlying its more common adverse drug reactions are not well understood.…”