What is the alternative to primaquine (an antimalarial medication) for patients with severe Glucose-6-phosphate dehydrogenase (G6PD) deficiency?

Alternative to Primaquine in Severe G6PD Deficiency

In patients with severe G6PD deficiency requiring radical cure of P. vivax or P. ovale malaria, the safest alternative is weekly primaquine at 0.75 mg base/kg (maximum 45 mg) for 8 weeks with close monitoring, or alternatively, forgoing radical cure entirely and treating relapses as they occur. 1

Primary Alternative Strategies

Weekly Primaquine Regimen (Preferred Alternative)

• Administer primaquine 0.75 mg base/kg (maximum 45 mg) once weekly for 8 weeks rather than the standard 14-day daily regimen 1
• This regimen is specifically recommended for patients with intermediate G6PD deficiency but can be applied to those with severe deficiency who have non-Mediterranean variants 1
• Requires weekly methemoglobin monitoring throughout the treatment course 1
• This approach provides substantially lower hemolytic risk while still achieving radical cure 2

Tafenoquine (Limited Availability)

• A single 300 mg dose of tafenoquine may be considered as an alternative 1
• Only available in the United States and Australia, not in Europe 1
• Requires quantitative G6PD testing showing >70% enzyme activity before administration 1, 3
• This option is contraindicated in severe G6PD deficiency

No Radical Cure Strategy

• In non-endemic settings where reinfection risk is absent, forgoing radical cure and treating relapses as they occur may be the safest approach 1
• This is a reasonable strategy that prioritizes patient safety over complete parasite eradication 1

Critical Management Steps

Immediate Blood-Stage Treatment

• Continue chloroquine (or alternative blood-stage antimalarial) to complete treatment of the acute infection 1
• Chloroquine remains first-line for P. vivax at 1000 mg salt initially, then 500 mg at 6,24, and 48 hours 1
• Alternative blood-stage treatments include artemether-lumefantrine or dihydroartemisinin-piperaquine if chloroquine resistance is suspected 1

Essential Testing and Monitoring

• Retest for G6PD deficiency if not previously done, as G6PD deficiency increases risk of both hemolysis and methemoglobinemia 1
• Qualitative screening is recommended for initial assessment 3
• Quantitative G6PD testing is required before tafenoquine administration 3
• Baseline complete blood count with hemoglobin determination before initiating any treatment 3

Critical Caveats and Variant-Specific Considerations

Mediterranean Variant (Highest Risk)

• The Mediterranean G6PD variant (B-) has very high risk of severe complications with primaquine and should absolutely avoid standard primaquine regimens 1
• This variant can cause life-threatening hemolysis 3
• Asian populations may have higher rates of severe G6PD deficiency 1

African Variant (Lower Risk)

• Found in 10-15% of Black men and women 3
• Associated with milder hemolysis compared to Mediterranean variants 3
• May tolerate modified regimens better, though caution still required

Warning Signs Requiring Immediate Action

• Immediately discontinue any potentially hemolytic medication if signs of hemolysis occur, such as back or abdominal pain 3
• Monitor for clinically concerning declines in hemoglobin, as nearly one-third of patients may experience significant hemoglobin reductions 4

Historical Context on Standard Primaquine Contraindication

The older guidelines note that among populations where severe G6PD deficiency is common (notably among Asians), primaquine should not be administered for greater than 5 days as administration for longer periods may result in life-threatening hemolysis 5. This underscores why the weekly regimen or no radical cure approach represents the safest alternatives in severe G6PD deficiency.