Table 3.

Recommended therapeutic use of high risk drugs^a in relation to G6PD phenotype

Predicted G6PD phenotype based on genotype	Implications for phenotypic measures	Therapeutic recommendations for high risk drugs	Classification of recommendationsb	Considerations
Normal	Low risk of acute hemolytic anemia	No reason to avoid high risk drugs based on G6PD status	Strong	Tafenoquine’s safety has been established for a G6PD enzyme activity ≥70% of normal.c
Deficient	High risk of acute hemolytic anemia	Avoid use of high risk drugs	See Table 2 for drug-specific strength of recommendations
Deficient with CNSHA	High risk of acute exacerbation of chronic hemolysis	Avoid use of high risk drugs	Strong	Although there are no published data in individuals with the G6PD Deficient with CNSHA phenotype, there is a strong rationale to avoid these drugs based on evidence in G6PD Deficient individuals.
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 non-deficient (class IV) and one deficient (class I–III) allele may display a normal or a deficient phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases. Tafenoquine’s safety has been established for a G6PD enzyme activity ≥70% of normal.c
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

^aDrugs are classified as high, medium, or low-to-no risk for acute hemolytic anemia based on evidence review and on assumptions of normal dosing regimens. Drug-induced hemolysis in G6PD deficiency is generally related to drug dosage (the higher the dose, the more the oxidative stress and the more likely anemia is to occur). Because primaquine has been well studied at high, medium and low dosages, see Table 6 for primaquine-specific recommendations.

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

^cInclusion criteria for clinical trials involving tafenoquine included G6PD activity ≥70% (51).