Medications to Avoid in G6PD Deficiency
Seven medications are definitively contraindicated in G6PD deficiency and must be avoided: dapsone, methylene blue (methylthioninium chloride), nitrofurantoin, phenazopyridine, primaquine, rasburicase, and tolonium chloride (toluidine blue). 1, 2, 3
Absolutely Contraindicated Medications
High-Risk Oxidant Drugs
- Dapsone is a potent oxidant that causes methemoglobinemia and red blood cell hemolysis by overwhelming the reductive capacity of G6PD-deficient patients and should never be used 1, 4
- Methylene blue (methylthioninium chloride) causes severe hemolytic anemia in G6PD-deficient patients and is absolutely contraindicated 1, 2
- Primaquine causes severe hemolysis in G6PD-deficient individuals and is contraindicated in severe G6PD deficiency (though may be used at reduced dosing in mild-moderate deficiency with close monitoring) 5, 1, 6
- Rasburicase is contraindicated in G6PD deficiency 2, 3
- Nitrofurantoin should be avoided as it causes hemolysis in G6PD-deficient patients 3
- Phenazopyridine is contraindicated in G6PD deficiency 3
- Tolonium chloride (toluidine blue) should be avoided 3
Additional High-Risk Medication
- Aspirin is explicitly contraindicated in G6PD deficiency as it can overwhelm the reduced antioxidant capacity in G6PD-deficient red blood cells 2
Medications Requiring Caution or Special Circumstances
Antimalarials with Conditional Use
- Primaquine may be considered in mild to moderate G6PD deficiency (>30% to <70% activity) at reduced dosing of 45 mg once weekly for 8 weeks, but only after G6PD testing and with close hematological monitoring 1, 7
- Tafenoquine is contraindicated during pregnancy regardless of G6PD status and requires quantitative G6PD testing before administration 1, 7
- Chloroquine/hydroxychloroquine in standard doses appears relatively safe in most G6PD-deficient patients, though hemolysis can occur and blood monitoring may be needed 1, 8
Relatively Safe Antimalarials
- Artemisinin-based combination therapies (ACTs) including artesunate, artemether-lumefantrine, and dihydroartemisinin-piperaquine can be used safely for malaria treatment in G6PD-deficient patients 1
Critical Pre-Treatment Requirements
Mandatory G6PD Testing
- Screen all patients with predisposing racial or ethnic backgrounds (Mediterranean, African, Indian, or Southeast Asian descent) before starting any oxidant drug 1, 7
- G6PD testing must be performed before using primaquine due to the risk of hemolytic anemia 6
- Quantitative G6PD testing is required before tafenoquine administration 7
- Qualitative screening is sufficient for initial assessment, but quantitative testing may be needed to determine the degree of deficiency in borderline cases 1, 7
Baseline Monitoring Before Treatment
- Check baseline hematocrit and hemoglobin before treatment with any potentially hemolytic drug 6
- Complete blood cell counts should be checked periodically if patients are given prolonged therapy with drugs that may cause hemolysis 8
Variant-Specific Risk Stratification
Mediterranean Variant (Higher Risk)
- The Mediterranean variant (Gdmed) typically causes more severe reactions and may experience life-threatening hemolysis 1, 2
- Found predominantly in men from Mediterranean regions, India, and Southeast Asia 1
- Requires stricter avoidance of oxidant medications 7
African Variant (Lower Risk)
- The African variant (GdA-) is found in 10-15% of Black men and women and typically causes milder, self-limited hemolysis 1, 7
- Patients with this variant may tolerate some medications better, but caution is still required 1
Monitoring During Treatment
Close Hematological Surveillance
- Monitor at day 3 and day 8 when using potentially hemolytic drugs in G6PD-deficient patients 6
- Blood examinations during therapy should include blood cell counts and hemoglobin 7
- Watch for signs of hemolysis including darkening of urine, marked fall of hemoglobin or erythrocyte count, back or abdominal pain, or jaundice 7, 2, 6
Immediate Action Required
- Discontinue immediately any potentially hemolytic medication if signs of hemolysis occur 7, 6
- Adequate medical support to manage hemolytic risk should be available when prescribing potentially hemolytic drugs 6
Common Pitfalls to Avoid
Testing Timing Issues
- Avoid testing during acute hemolytic episodes as G6PD levels can be falsely elevated because young reticulocytes have higher enzyme activity 2
- Avoid testing during or immediately post-transfusion as this will give falsely elevated results 2
- Repeat testing after 3 months may be necessary for accurate diagnosis if initial testing occurred during hemolysis 2
Drug Interaction Considerations
- Rifampin lowers dapsone levels 7 to 10-fold, though this interaction is less relevant given dapsone is contraindicated in G6PD deficiency 4
- Folic acid antagonists such as pyrimethamine may increase the likelihood of hematologic reactions when combined with potentially hemolytic drugs 4
Safe Alternatives
Medications NOT Contraindicated
- Penicillins (such as amoxicillin) are not among the contraindicated medications and can be used in normal therapeutic doses 2
- Benzodiazepines, codeine/codeine derivatives, propofol, fentanyl, and ketamine have not been shown to cause hemolytic crises in G6PD-deficient patients 9
- Paracetamol (acetaminophen) is safe even in the context of severe oxidative hemolysis 10
Special Populations
Pregnancy Considerations
- Primaquine and tafenoquine are contraindicated during pregnancy regardless of G6PD status 1
- Chloroquine may be used during pregnancy as it has not been found to have harmful effects on the fetus when used in recommended doses, though the fetus may be G6PD-deficient even if the mother is normal 5, 8
- Pregnancy testing should be performed in sexually-active females of reproductive potential prior to starting primaquine 6