WHO strongly recommends the continued use of injectable artesunate in the treatment of severe malaria. The need for continued use and further adoption of injectable artesunate as a life-saving treatment by malaria endemic countries should be emphasized and supported. However, healthcare professionals should be made aware of the potential for delayed haemolytic anaemia for up to one month post treatment. WHO/GMP INFORMATION NOTE ON DELAYED HAEMOLYTIC ANAEMIA FOLLOWING TREATMENT WITH ARTESUNATE Injectable artesunate is a life‐saving therapy for patients with severe Plasmodium falciparum malaria, providing a substantial reduction of mortality. In the two largest randomized controlled trials conducted in patients with severe malaria, parenteral artesunate treatment reduced deaths by 34.7% (in the Asian SEAQUAMAT trial) and by 22.5% (in the African AQUAMAT trial) compared with parenteral quinine.1,2 WHO currently recommends artesunate (intravenous or intramuscular) as the first line treatment for the initial management of severe malaria.3 A number of cases of delayed haemolytic anaemia have been identified following treatment of severe malaria with injectable artesunate. The Medicines for Malaria Venture (MMV), in March 2013, convened a meeting of experts to review the available evidence on delayed haemolytic anaemia following treatment with injectable artesunate. The full report of the MMV convened expert meeting is available on the MMV webpage (mmv.org/newsroom/events/expert-group-meeting-safety-profile-injectable-artesunate). This information note reflects the current WHO/GMP position based on the outcome of the review meeting and consultation with the Co-Chairs of the GMP Technical Expert Group on Malaria Chemotherapy . Summary Delayed haemolytic anaemia following treatment with injectable artesunate has been observed in non-immune travelers presenting with severe falciparum malaria and particularly in patients presenting with hyperparasitaemia. Post-treatment haemolytic anaemia is not specific to a particular injectable artesunate formulations, and has been described following use of injectable artesunate, intra‐muscular artemether and, also, oral artemether‐lumefantrine. Available data are mainly from case reports and retrospective studies, conducted with different study designs, case definitions and study endpoints, with delayed anaemia defined differently across the various studies. Definitions of severe malaria have also varied across studies. As a result the incidence and predisposing factors (other than hyperparasitaemia) remain uncertain. The mechanisms of delayed haemolytic anaemia following the treatment of severe malaria are multiple, and are not fully understood. Conditions such as blackwater fever (sudden massive haemolysis and haemoglobinuria associated with malaria), and severe haemolysis caused by malaria itself, may overlap with delayed haemolytic anaemia. Other mechanisms, such as delayed auto-immune haemolysis may contribute in some cases. Preliminary evidence suggests that the key pharmacodynamic advantage of artesunate over quinine, that it kills young circulating ring stage parasites before they sequester in the microcirculation, could explain the delayed haemolysis. This mechanism explains the rapid action of artesunate and its beneficial effect on mortality and other clinical outcomes. Most of the killed ring stage parasites are cleared rapidly by 1 Dondorp A, Nosten F, Stepniewska K, Day N, White N, 2005. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366: 717‐25. 2 Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K, Kivaya E, Agbenyega T, Nguah SB, Evans J, Gesase S, Kahabuka C, Mtove G, Nadjm B, Deen J, Mwanga‐Amumpaire J, Nansumba M, Karema C, Umulisa N, Uwimana A, Mokuolu OA, Adedoyin OT, Johnson WB, Tshefu AK, Onyamboko MA, Sakulthaew T, Ngum WP, Silamut K, Stepniewska K, Woodrow CJ, Bethell D, Wills B, Oneko M, Peto TE, von Seidlein L, Day NP, White NJ, 2010. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open‐label, randomised trial. Lancet 376: 1647‐57. 3 Guidelines for the treatment of malaria, Second Edition 2010. Geneva, World Health Organization, 2011, (whqlibdoc.who.int/publications/2010/9789241547925_eng.pdf. mmv.org/newsroom/events/expert-group-meeting-safety-profile-injectable-artesunate
Posted on: Tue, 01 Oct 2013 03:52:33 +0000
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