Effectiveness and risk with LapDap A classic dilemma Personal views: I Ralph Edwards

What is LapDap Two very old drugs, combined for a new indication: Malaria Chlorproguanil An little used anti-malarial Dapsone An anti-leprotic and immunomodulator

Mystic Herbal balm ? Mystic Herbal balm ?

Is the combination effective in malaria? Yes, in studies of nearly 3000 African subjects (nearly all children) published in the Lancet and submitted to the UK MHRA, it is very effective Also in sulfadoxine-pyrimethamine resistance In Asia there is considerable resistance developed The time window for effective use in Africa may be limited It is also cheap: around the same price as chloroquine

Is it safe? Considerable inter-individual variability in plasma levels of both drugs ? Genetic polymorphisms No PK studies in elderly or diseased Limited previous experience in children Dapsone dose about 2x its use in leprosy, and close to toxic dose Limited experience with chlorproguanil, but no major problems

But….. Dapsone causes: Variably severe haemolysis in people with G6PD deficiency >20% of Africans have the deficiency to some extent They will not know they have it unless tested Methaemaglobinaemia, with reduced oxygen carryng capacity Malaria also causes haemolysis!!

Registration of LapDap First registered in UK, now in <20 African countries UK conditions are: Prescription only Contraindicated in G6PD There is no serious restriction on availability imposed in Africa About 50% of patients who treat themselves for malaria do not have the disease How will patients know they are G6PD deficient anyway

”Pull out, Bettyl Pull out...You’ve hit on artery”

Review of Safety of Chlorproguanil/Dapsone WHO Technical Consultation Geneva, 1-2July, 2004 Publ. March 2005 The executive summary only

Chlorproguanil/Dapsone Should be used only if the diagnosis of malaria is confirmed. Should only be used after anaemia have been excluded by a reliable clinical or laboratory test and G6PD deficiency by a reliable laboratory test. The diagnosis of methaemoglobinemia is less important

Chlorproguanil/Dapsone In areas where G6PD deficiency is prevalent, it is important before using CPG-DDS to know the level of anaemia and the G6PD status of the patient. If appropriate tests are not possible, an alternative antimalarial medicine should be used. If there is no suitable alternative, CPG-DDS should be used taking into account all the risks associated with this medicine.

Chlorproguanil/Dapsone These recommendations are to be reconsidered when more data becomes available from pharmacovigilance and active post-marketing surveillance. Safety studies have yet to be done!

Implications What is its safety on repeated use? Is this a good combination with artemesinin derivatives? For: Cheap and effective Against: Safety, as we assess it now