Primaquine

Primaquine phosphate is an 8-aminoquinoline compound which eliminates tissue (exoerythrocytic) infection. Thereby, it prevents the development of the blood (erythrocytic) forms of the parasite which are responsible for relapses in vivax malaria. Primaquine phosphate is also active against gametocytes of Plasmodium falciparum.

Animal Pharmacology and/or Animal Toxicology

Literature data on reproductive toxicology identified embryo-fetal development toxicity. In studies in rats, teratogenic effects on fetus were observed.

In the first reproductive toxicity study primaquine was administered orally to rats between gestation day (GD) 6 and GD15 at dose levels of 10.3, 30.8 and 61.5 mg/kg/day (as base) (representing approximatively 7, 20 and 40 times the human dose [HD] on a body surface area comparison) when considering a human body weight of 60 kg). High dose levels induced death of pregnant females in almost all cases, while lower dose levels caused maternal toxicity. At cesarean section, embryo resorption, a decrease in fetal survival rate and body size, internal abnormalities (including hydrocephalia, heterotaxia), and an increase in skeletal variations were observed at the mid dose level. There were no fetal abnormalities at the low dose level providing a potential safety margin of at least 7 times the recommended clinical dose.

For the second reproductive toxicity study 6 to 10 animals per group were used. Dose levels of 0.57, 5.7, 11.4 and 34 mg/kg/day of primaquine (as base) (representing approximatively 0.4, 4, 7 and 22 times the HD on a body surface area comparison) were administered orally to Sprague Dawley rats between GD8 and GD16, or of 57 mg/kg only once on GD13 (representing more than 37 times the HD on a body surface area comparison). A total of 1/7 and 4/6 pregnant females at 34 mg/kg/day and at 57 mg/kg, respectively, died. Primaquine-associated teratogenic malformations (including cleft palate and small chin) were observed in 4/54 fetuses in the 57 mg/kg single-dose group.