World Health
`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`Antimalarial chlorproguanil-dapsone (LapDapTM) withdrawn following demonstration of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 LapDapTM versus Dacart TM
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`GlaxoSmithKline (GSK) and Medicines for Malaria Venture (MMV) have decided to terminate the
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`further development of DacartTM, a fixed-dose combination antimalarial product of chlorprognanil,
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`dapsone and artesunate (CDA). GSK has also commenced a product recall process at pharmacy level in
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`Kenya, for LapDapTM, another anti-malarial product containing chlorprognanil and dapsone (CD). These
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`decisions axe based on data from two Phase III clinical trials assessing the efficacy and safety of CDA
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`(DacartTM) 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 (LapDapTM)
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`This product was granted a marketing authorization in July 2003 by the United Kingdom Medicines and
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`Healthcoxe products Regulatory Agency (MHRA) for the treatment of uncomplicated falciparum malaria.
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`Chlorprognanil-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 (LapDapTM) 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 undertaken a safety assessment of the product in 2004, to
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`provide recommendations on the safe use of CD (LapDapTM) in Africa.
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`The WHO expert 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 confirmed.
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`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 important.
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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.
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`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 pharmacovigilance and active post-marketing surveillance.
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`The WHO safety assessment report 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 (LapDapTM),
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`including in malaria patients with G6PD deficiency. However, several CD (LapDapTM) phase IV studies
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`which started 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 part of the Medicines for Malaria Venture
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`(MMV)- sponsored studies on chlorprognanil-dapsone-artesunate (CDA).
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`Chlorproguanil-dapsone-artesunate (DacarffM)
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`GSK’s multi-center, double-blind Phase III clinical trial of chlorproguanil-dapsone-artesunate (CDA)
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`versus the combination antimalarial lumefantrine-artemether (Coartem®) in Africa suggest a strong
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`association between haemolytic anaemia and CDA treatment for uncomplicated falciparum malaria 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 occurring 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 compared to 8% of patients treated
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`with Coartem®, 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 Coartem®. 38% of the male
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`patients with G6PD deficiency had severe anaemia after treatment with CDA, compared to 0% in the
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`group treated with Coartem®. 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 Malaria Venture, 29 February 2008, London,
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`UK; Geneva, Switzerland.
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`2. Review of the safety of chlorprognanil-dapsone in the treatment of uncomplicated falciparum
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`malaria in Africa: Report 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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