Primaquine: the risks and the benefits

Abstract

Primaquine is the only generally available anti-malarial that prevents relapse in vivax and ovale malaria, and the only potent gametocytocide in falciparum malaria. Primaquine becomes increasingly important as malaria-endemic countries move towards elimination, and although it is widely recommended, it is commonly not given to malaria patients because of haemolytic toxicity in subjects who are glucose-6-phosphate dehydrogenase (G6PD) deficient (gene frequency typically 3-30% in malaria endemic areas; >180 different genetic variants). In six decades of primaquine use in approximately 200 million people, 14 deaths have been reported. Confining the estimate to reports with known denominators gives an estimated mortality of one in 621,428 (upper 95% CI: one in 407,807). All but one death followed multiple dosing to prevent vivax malaria relapse. Review of dose-response relationships and clinical trials of primaquine in G6PD deficiency suggests that the currently recommended WHO single low dose (0.25 mg base/kg) to block falciparum malaria transmission confers a very low risk of haemolytic toxicity.

Figure 1

Primaquine-induced haemolysis in adults with different G6PD variants during daily dosing. Primaquine was given daily for 14 days at a dose of 30 mg/day in individuals with Mediterranean and African A-variants [18, 21] and 15 mg/day for Mahidol or Viangchan variants [22, 23]. The effects of a 45-mg single primaquine dose in individuals with either Mahidol or Viangchan variants are shown for comparison [24]. This figure uses data derived from different studies as referenced.

Figure 2

G6PD-deficient red cell survival following daily primaquine dosing. G6PD-deficient red cell survival was assessed by ⁵¹Cr labelling and transfusion into G6PD-normal healthy recipients (15 mg/day or 45 mg single dose in Mahidol or Viengchan variants, 30 mg/day Mediterranean variant, and a range of doses in African A- variant). The corresponding haematocrit reductions following continuous dosing (or in the green bar, a single dose) in G6PD-deficient subjects are shown in the inset [, –24, 37].