Regulatory Decision Summary for Primaquine

Primaquine is the only anti-malarial agent effective in the radical cure (prevention of relapse) of malaria infection caused by Plasmodium vivax and Plasmodium ovale species. It has been marketed for more than four decades with an established benefit-risk profile. Malaria infection is a major public health issue associated with significant morbidity and mortality in endemic areas. Although considered less virulent than falciparum malaria, infection with P. vivax still carries the potential for significant morbidity. One of the major safety concerns of Primaquine is that administration of its standard 14-day course (0.25 mg/kg body weight per day) can induce dose-dependent, life-threatening hemolysis in patients with G6PD deficiency. Use of Primaquine is contraindicated in patients with severe G6PD deficiency.

A higher prevalence of G6PD deficiency across malaria endemic populations has limited the use of Primaquine and led to research in modified dosing regimens. Several studies have looked into optimising Primaquine dosing while maintaining its therapeutic activity against malaria infection in patients with G6PD deficiency. Some studies indicate that a weekly dose of 45 mg Primaquine administered for eight weeks is effective against P. vivaxinfections, yet did not produce clinically demonstrable haemolysis in Primaquine-sensitive adult males with G6PD deficiency. Current WHO treatment guidelines recommend that malaria infection in patients with mild-to-moderate G6PD deficiency may be treated with 8 weeks of 45 mg/week of Primaquine.

The proposed weekly dosing recommendation of Primaquine for malaria in patients with mild-to-moderate G6PD deficiency is considered safer as compared to daily administration. However, some cases of haemolysis could still develop in G6PD deficient patients treated with this modified weekly regimen of Primaquine. This uncertainty is addressed by adequate labelling in the Warnings section of the Product Monograph recommending that baseline hematocrit and hemoglobin must be checked before treatment and close hematological monitoring is required. Further, adequate medical support and follow-up to manage haemolytic risk should be available.

In conclusion, the proposed dosing recommendations for Primaquine in patients with mild-to-moderate G6PD deficiency are supported by the literature studies. The benefit-risk profile of Primaquine remains favorable under the conditions of use described in the approved Product Monograph.