Table 6.

Recommended therapeutic use of primaquine in relation to G6PD phenotype

Predicted G6PD phenotype based on genotype	Implications for phenotypic measures	Therapeutic recommendations	Classification of recommendationsa	Considerations
Normal	Low risk of acute hemolytic anemia	No reason to avoid primaquine based on G6PD status	Strong
Deficient	High risk of acute hemolytic anemia with standard (or higher than standard) anti-relapse dosages for Plasmodium vivax or Plasmodium ovale of 0.25–0.5 mg/kg daily for 14 days	Avoid primaquine, except in the following cases where established expert consensus guidelines for the treatment of malaria should be followed: (1) Treating Plasmodium vivax or Plasmodium ovale malaria for radical cure of liver-stage infections: 0.75 mg/kg once weekly x8 weeks (WHO) or 45 mg once weekly x8 weeks (CDC) - with close monitoring for hemolysis; (2) Treating Plasmodium falciparum malaria by using primaquine single dose as a gametocytocide at 0.25 mg/kg (WHO) - without need for monitoring for hemolysis.	Strong	Dosing recommendations for primaquine in patients with G6PD deficiency are derived from the malaria treatment guidelines issued by the World Health Organization (40) and the U.S. Centers for Disease Control and Prevention (41).
Deficient with CNSHA	High risk of acute exacerbation of chronic hemolysis	Avoid primaquine	Strong	The strength of evidence among patients with the G6PD Deficient phenotype provides strong rationale to also avoid primaquine in the setting of the more severe G6PD Deficient with CNSHA phenotype.
Variable	Variable risk of acute hemolytic anemia	To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.	Moderate	Due to X-linked mosaicism, individuals with more than one X chromosome (e.g., females, individuals with Klinefelter syndrome) and heterozygous for one nondeficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to guide treatment in such cases.
Indeterminate	Unknown risk of acute hemolytic anemia	To ascertain G6PD status, enzyme activity must be measured. Drug use should be guided per the recommendations based on the activity-based phenotype.	Moderate

CNSHA, chronic non-spherocytic hemolytic anemia; G6PD, glucose-6-phosphate dehydrogenase

^aRating scheme described in Supplement (see Strength of Recommendations material)