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

How will patients know they are G6PD deficient anyway

About 50% of patients who treat themselves for

malaria do not have the disease

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

Review of Safety of Chlorproguanil/Dapsone

WHO Technical Consultation

Geneva, 1-2July, 2004Publ. 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