Primaquine is fairly innocuous when given to most Caucasians in the usual therapeutic doses. Primaquine can cause mild-to-moderate abdominal distress, which can be alleviated by taking the drug with food. Mild anemia, cyanosis (methemoglobinemia), and leukocytosis are less common. High doses (60—240 mg/day) accentuate the abdominal symptoms and cause methemoglobinemia in most subjects. Methemoglobinemia can be severe in individuals with congenital deficiency of nicotinamide adenine dinucleotide (NADH) methemoglobin reductase. Chloroquine and dapsone may be synergistic with primaquine in producing methemoglobinemia in these patients. Granulocytopenia and agranulocytosis are rare complications of therapy and usually are associated with overdosage. Also rare are hypertension, arrhythmias, and symptoms referable to the CNS.
Therapeutic or higher doses of primaquine may cause hemolytic anemia in humans with G6PD deficiency. This condition affects >200 million people worldwide. About 11% of African Americans have a G6PD variant that makes them vulnerable to hemolysis caused by oxidant drugs such as primaquine. Erythrocyte sensitivity to primaquine can be more severe in Sardinians, Sephardic Jews, Greeks, and Iranians. Because primaquine sensitivity is X-linked, hemolysis is of intermediate severity in heterozygous females who have two red cell populations, one normal and the other deficient in G6PD.
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