What medications should a patient with Glucose-6-phosphate dehydrogenase (G6PD) deficiency avoid?

Medications to Avoid in G6PD Deficiency

Patients with G6PD deficiency must absolutely avoid seven definitively contraindicated medications: dapsone, methylene blue (methylthioninium chloride), primaquine (in severe deficiency), rasburicase, nitrofurantoin, phenazopyridine, and tolonium chloride (toluidine blue). 1, 2

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 erythrocytes 3, 4
• Methylene blue (methylthioninium chloride) causes severe hemolytic anemia and is completely contraindicated; if methemoglobinemia occurs, use ascorbic acid (0.2-1.0 g/day orally in divided doses) instead 3, 5, 2
• Rasburicase must be avoided in all G6PD-deficient patients 1, 2
• Nitrofurantoin is definitively contraindicated based on solid evidence of hemolytic risk 2
• Phenazopyridine should be avoided, though real-world data shows hundreds of G6PD-deficient patients have received it without major hemolysis 2, 6
• Tolonium chloride (toluidine blue) is contraindicated 2

Antimalarial Medications

• Primaquine is absolutely contraindicated in severe G6PD deficiency (activity <30%) 3, 7
• In mild to moderate deficiency (30-70% activity), primaquine may be used only at reduced dosing of 45 mg once weekly for 8 weeks with mandatory G6PD testing beforehand and close hematological monitoring at days 3 and 8 3, 7
• Tafenoquine is contraindicated during pregnancy regardless of G6PD status 3
• Standard 14-day primaquine regimens (0.25 mg/kg/day) carry significant risk of acute hemolytic anemia in populations with high G6PD deficiency prevalence, with nearly one-third experiencing clinically concerning hemoglobin declines 8

Medications Requiring Caution

Local Anesthetics

• Benzocaine, prilocaine, lidocaine, and tetracaine can precipitate methemoglobinemia and should be used with extreme caution 5

NSAIDs

• Aspirin is explicitly contraindicated as it overwhelms the reduced antioxidant capacity in G6PD-deficient red blood cells 1
• Ibuprofen and other NSAIDs present moderate hemolysis risk and should be used cautiously with hemoglobin monitoring 1

Sulfonamides

• Sulfamethoxazole/cotrimoxazole may pose theoretical risk, though recent real-world data from hundreds of G6PD-deficient patients suggests they may be safer than previously thought 5, 6
• Sulfasalazine has been prescribed safely to thousands of G6PD-deficient patients in real-world settings 6

Safe Medications (Evidence-Based)

Antimalarials

• Chloroquine/hydroxychloroquine in standard doses appears relatively safe in most G6PD-deficient patients and can be used during pregnancy 3, 6
• Artemisinin-based combination therapies (artesunate, artemether-lumefantrine, dihydroartemisinin-piperaquine) can be used safely for malaria treatment 3

Antibiotics

• Penicillins (including amoxicillin) are not contraindicated and can be used in normal therapeutic doses 1
• Ciprofloxacin and ofloxacin have been prescribed safely to thousands of G6PD-deficient patients 6

Anesthetics

• Benzodiazepines, codeine/codeine derivatives, propofol, fentanyl, and ketamine have not been shown to cause hemolytic crises 9
• Dexmedetomidine may be particularly useful due to its antioxidant properties 10

Critical Management Principles

Pre-Treatment Screening

• Mandatory G6PD testing before starting any oxidant drug in patients of Mediterranean, African, Indian, or Southeast Asian descent 3, 5
• Qualitative screening is sufficient initially, but quantitative testing may be needed for borderline cases (30-70% activity) 3, 1
• Avoid testing during acute hemolysis as G6PD levels can be falsely elevated due to young reticulocytes having higher enzyme activity 1
• Avoid testing during or immediately post-transfusion as this gives falsely elevated results 1

Variant-Specific Risk

• Mediterranean variant (Gdmed) causes more severe, potentially life-threatening hemolysis 3, 5
• African variant (GdA-) typically causes milder, self-limited hemolysis 3, 5
• Found in 10-15% of Black men and women 3

Monitoring Protocol

• Check baseline hematocrit and hemoglobin before treatment 7
• Close hematological monitoring at days 3 and 8 when using any potentially risky medication 7
• Monitor for signs of hemolysis: darkening of urine, marked fall in hemoglobin or erythrocyte count, jaundice 1, 4
• Consider transfusion if hemoglobin drops below 7-8 g/dL with symptoms 1
• Provide folic acid supplementation (1 mg daily) 1

Special Populations

• Pregnancy: Primaquine and tafenoquine are contraindicated regardless of maternal G6PD status because the fetus may be G6PD-deficient even if the mother is normal 3, 7
• Children: The same medication restrictions apply to children of any age, as they can develop hemolysis from contraindicated medications 3
• Mefloquine is not indicated for children <15 kg and doxycycline is contraindicated in children <8 years 3

Common Pitfall

The most critical error is assuming infection-related hemolysis is drug-induced—many compounds have been wrongly cited as causing hemolysis when they were administered during an infection-related hemolytic episode 2. Real-world evidence shows that many previously suspected medications have been prescribed safely to thousands of G6PD-deficient patients without major hemolysis 6.