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`Organization
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`QSM/ MC/ IEA.117
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`4 March 2008
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`Information Exchange System
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`Alert No_ 117
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`Antimalarial chlorproguanil-dapsone (LapDapTJ\1) withdrawn following demonstration of
`post-treatment haemolytic anaemia in G6PD deficient patients in a Phase III trial of
`chlorproguanil-dapsone-artesunate (DacartTM) versus artemether-lumefantrine
`(Coartem®) and confirmation of findings in a comparative trial
`of LapDap™ versus Dacart T M
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`GlaxoSmithKline (GSK) and Medicines for Malaria Venture (MMV) have decided to tenninate the
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`fmther development ofDaca1t™, a fixed-dose combination antimalarial product of chlorproguanil,
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`dapsone and a1tesunate (CDA). GSK has also commenced a product recall process at pha1macy level in
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`Kenya, for LapDap™, another anti-malarial product containing chlorproguanil and dapsone (CD). These
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`decisions are based on data from two Phase III clinical trials assessing the efficacy and safety of CDA
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`(Daca1tTM) and CD (LapDapTM); significant reductions of haemoglobin levels in patients with G6PD
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`deficiency have been observed with both CDA and CD.
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`Background information
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`Chlorproguanil-dapsone (LapDapTJ\1)
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`This product was granted a marketing authorization in July 2003 by the United Kingdom Medicines and
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`Healthcare products Regulatory Agency (MHRA) for the treatment of uncomplicated falciparum malaria.
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`Chlorproguanil-dapsone (CD) was contraindicated in patients with known glucose-6-phosphate
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`dehydrogenase (G6PD) deficiency. In view of the potential widespread use of CD (LapDap™) in malaria
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`endemic sub-Saharan Africa, the high prevalence of G6PD deficiency in the region ( estimated to affect
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`around 10-25% of the population in sub-Saharan Africa) and the limited availability of screening tests for
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`this genetic condition in Africa, WHO had unde1taken a safety assessment of the product in 2004, to
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`provide recommendations on the safe use of CD (LapDap™) in Africa.
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`The WHO expe1t group cautioned against the use of the medicine in G6PD deficient patients and made
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`the following recommendations:
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`1. This medicine should be used only if a diagnosis of malaria is confiimed.
`2. CD should be used only after severe anaemia (haemoglobin concentration < 5 g/dl) and
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`G6PD deficiency have been excluded by appropriate tests. In patients with a haemoglobin
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`concentration of 7 g/dl, administration of CD should be considered with caution and should be
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`undertaken only under clinical supervision, with monitoring of the haemoglobin concentration. The
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`diagnosis of methaemoglobinaemia is less impo1tant.
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`3. In areas where G6PD deficiency is prevalent but appropriate tests are not available, an alternative
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`antimalarial medicine should be used.
`4. If there is no suitable alternative, CD should be used but in cognizance of the haematological risks
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`associated with this medicine.
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`The group also advised that these recommendations should be reconsidered when more data become
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`available from phaimacovigilance and active post-marketing smveillance.
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`The WHO safety assessment repo1t also provided a series of recommendations for ongoing and planned
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`clinical trials as well as phase IV studies to gather the necessary evidence on safety of CD (LapDap™),
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`including in malaria patients with G6PD deficiency. However, several CD (LapDapTM) phase IV studies
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`which sta1ted in African countries did not continue beyond April 2006 due to low utilization of this
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`medicine. Research on the safety aspects mainly continued as pait of the Medicines for Malaria Venture
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`(MMV)- sponsored studies on chlorproguanil-dapsone-aitesunate (CDA).
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`Chlorproguanil-dapsone-artesunate (Daca1i TM)
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`GSK's multi-center, double-blind Phase ill clinical trial of chlorproguanil-dapsone-a1tesunate (CDA)
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`versus the combination antimalarial lumefantrine-a1temether (Coaitem®) in Africa suggest a strong
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`association between haemolytic anaemia and CDA treatment for uncomplicated falciparum malai'ia in
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`G6PD deficient patients. The study included 1372 patients. Study results showed a significant reduction
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`in haemoglobin due to haemolytic anaemia in patients with G6PD deficiency, with lowest levels of
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`haemoglobin occun-ing seven days after treatment. At day 7, 35% of the patients with G6PD deficiency
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`treated with CDA had a reduction in haemoglobin of more than 2 g/dl compai·ed to 8% of patients treated
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`with Coa1tem®, and 10% of the patients with G6PD deficiency treated with CDA had a reduction in
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`haemoglobin of more than 4 g/dl compared to 0% of patients treated with Coa1tem®. 38% of the male
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`patients with G6PD deficiency had severe anaemia after treatment with CDA, compai·ed to 0% in the
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`group treated with Coaitem®. In total, 15 patients had severe post-treatment haemolysis requiring blood
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`transfusion in the study: all 15 were in the CDA treated group, 13 of whom were G6PD deficient.
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`References:
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`1. Press Release. GlaxoSmithKline and Medicines for Malai-ia Venture, 29 February 2008, London,
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`UK; Geneva, Switzerland.
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`2. Review of the safety of chlorproguanil-dapsone in the treatment of uncomplicated fakiparnm
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`malaria in Afi-ica: Repo1t of a Technical Consultation convened by the World Health
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`Organization. WHO, 2005, Switzerland (http://www.who.int/malaria/docs/LapDap.pdf).
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