What are the considerations for prescribing primaquine (an antimalarial drug) to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency?

From the Guidelines

Primaquine should be used with extreme caution or avoided entirely in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to the high risk of hemolytic anemia. Before prescribing primaquine, all patients should undergo G6PD testing, as the drug can trigger severe hemolysis in deficient individuals. In patients with mild G6PD deficiency, a reduced dosage regimen may be considered under close medical supervision - typically 45 mg weekly for 8 weeks rather than the standard 30 mg daily for 14 days, as suggested by the most recent study 1. For those with severe G6PD deficiency, primaquine is generally contraindicated. If treatment is absolutely necessary, hospitalization with close monitoring of hemoglobin levels, reticulocyte counts, and signs of hemolysis is essential. The hemolytic reaction occurs because primaquine causes oxidative stress in red blood cells, and G6PD-deficient cells cannot produce enough NADPH to counteract this oxidative damage, leading to cell destruction. The risk varies by G6PD variant, with Mediterranean and Asian variants typically causing more severe reactions than African variants, as noted in earlier studies 1. Alternative antimalarial medications should be considered for these patients, particularly when treating Plasmodium vivax or Plasmodium ovale infections that require radical cure of hypnozoites. It's also important to consider the guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children, which recommend verifying G6PD status before administering primaquine 1. Additionally, the management of adult patients with malaria in non-endemic settings should take into account the risk of hemolysis in G6PD-deficient individuals, as highlighted in a recent study 1. Overall, the use of primaquine in patients with G6PD deficiency requires careful consideration and monitoring to minimize the risk of hemolytic anemia.

From the FDA Drug Label

Due to the risk of hemolytic anemia in patients with G6PD deficiency, G6PD testing has to be performed before using primaquine. Primaquine should not be prescribed for patients with severe G6PD deficiency. In case of mild to moderate G6PD deficiency, a decision to prescribe primaquine must be based on an assessment of the risks and benefits of using primaquine. If primaquine administration is considered, baseline hematocrit and hemoglobin must be checked before treatment and close hematological monitoring (e. g. at day 3 and 8) is required. Adequate medical support to manage hemolytic risk should be available.

The main considerations for prescribing primaquine to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are:

• G6PD testing must be performed before using primaquine.
• Severe G6PD deficiency is a contraindication for primaquine use.
• For mild to moderate G6PD deficiency, the decision to prescribe primaquine should be based on an assessment of the risks and benefits.
• Close hematological monitoring is required if primaquine is prescribed.
• Adequate medical support should be available to manage hemolytic risk 2.

From the Research

Considerations for Prescribing Primaquine to Patients with G6PD Deficiency

• Primaquine is an antimalarial drug that can cause hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency 3, 4, 5.
• The risk of hemolysis is dose-dependent, with higher doses of primaquine resulting in a greater risk of hemolysis 3.
• Patients with G6PD deficiency may experience a greater fall in hemoglobin levels and a larger percentage fall from baseline to day 7 compared to those without G6PD deficiency 3.
• The use of primaquine in patients with G6PD deficiency requires careful consideration of the risks and benefits, and alternative treatment regimens may be necessary 4, 6.
• G6PD deficiency testing is not always available, and clinicians may need to make decisions based on an assessment of the risks and benefits of prescribing primaquine without testing 4.

Alternative Dosing Schedules for Primaquine

• Alternative dosing schedules for primaquine, such as 0.5 mg/kg/day for 7 days or 0.75 mg/kg/week for 8 weeks, may be safer and more effective for patients with G6PD deficiency 6.
• These alternative regimens may reduce the risk of hemolysis and improve treatment outcomes for patients with G6PD deficiency 6.
• However, more research is needed to determine the efficacy and safety of these alternative regimens in different populations and settings 6.

Pharmacogenomics and Primaquine

• Primaquine pharmacology is influenced by CYP 2D6 pharmacogenomics, which can affect the efficacy and safety of the drug 7.
• CYP 2D6 is highly polymorphic among different human populations, adding complexity to the understanding of primaquine pharmacology 7.
• Further research is needed to understand the relationship between CYP 2D6 and primaquine pharmacology, and to develop personalized treatment regimens based on genetic factors 7.