What medications should be avoided in individuals with Glucose-6-phosphate dehydrogenase (G6PD) deficiency?

Medications to Avoid in G6PD Deficiency

Seven medications are definitively contraindicated in G6PD deficiency and must be avoided: dapsone, methylene blue (methylthioninium chloride), primaquine (in severe deficiency), rasburicase, nitrofurantoin, phenazopyridine, and tolonium chloride (toluidine blue). 1, 2, 3

Absolutely Contraindicated Medications (High-Risk)

Core Contraindications

• Dapsone: Potent oxidant causing methemoglobinemia and severe hemolysis by overwhelming G6PD reductive capacity 1
• Methylene blue (methylthioninium chloride): Causes severe hemolytic anemia 1, 2
• Rasburicase: Absolutely contraindicated per FDA labeling; causes hemolysis and methemoglobinemia 2, 4, 3
• Primaquine: Contraindicated in severe G6PD deficiency (<30% activity); may be used cautiously in mild-to-moderate deficiency (>30% to <70% activity) at reduced dosing of 45 mg once weekly for 8 weeks with close hematological monitoring 1, 5
• Nitrofurantoin: Solid evidence for causing hemolysis 3
• Phenazopyridine: Documented to cause hemolytic reactions 3
• Tolonium chloride (toluidine blue): Evidence-based contraindication 3

Additional High-Risk Considerations

• Aspirin: Explicitly contraindicated as it overwhelms reduced antioxidant capacity in G6PD-deficient red blood cells 2
• Tafenoquine: Contraindicated if G6PD activity is <70%; requires quantitative testing before use 1

Medium-Risk Medications (Use with Caution)

Antimalarials

• Chloroquine/Hydroxychloroquine: Appears relatively safe in standard doses for most G6PD-deficient patients 1
• Artemisinin-based combination therapies (ACTs): Including artesunate, artemether-lumefantrine, and dihydroartemisinin-piperaquine can be used safely for malaria treatment 1

Real-World Safety Data

A large Israeli study of 31,962 G6PD-deficient patients found only 3 medication-associated hemolysis cases out of 71 total hemolysis hospitalizations (4.2%), while hundreds to thousands safely received nitrofurantoin, ciprofloxacin, sulfamethoxazole/cotrimoxazole, sulfasalazine, hydroxychloroquine, and phenazopyridine 6. This suggests many traditionally "risky" medications may be safer than previously thought, though caution remains warranted.

Medications Safe to Use

Anesthetic Agents

• Benzodiazepines, codeine/codeine derivatives, propofol, fentanyl, and ketamine: No evidence of causing hemolytic crises 7
• Dexmedetomidine: May be particularly useful due to antioxidant properties 8

Antibiotics

• Penicillins (including amoxicillin): Not contraindicated; can be used in normal therapeutic doses 2

Variant-Specific Risk Stratification

Mediterranean Variant (Gdmed)

• Causes life-threatening hemolysis requiring strict oxidant drug avoidance 1, 2
• Found predominantly in men from Mediterranean regions, India, and Southeast Asia 1

African Variant (GdA-)

• Produces milder, self-limited hemolysis 1, 2
• Found in 10-15% of Black men and women 1

Critical Screening Recommendations

Who to Screen

• Mandatory screening before starting oxidant drugs in patients of Mediterranean, African, Indian, or Southeast Asian descent 1, 9
• Screen first-degree relatives of G6PD-deficient patients 9

Testing Approach

• Qualitative screening sufficient for initial assessment 1, 2
• Quantitative testing needed for borderline cases (30-70% activity) to determine specific variant and predict severity 1, 9
• Avoid testing during acute hemolysis as G6PD levels may be falsely elevated; repeat after 3 months if necessary 2, 9
• Wait 50-120 days post-transfusion before testing to avoid false-negative results 9

Management of Suspected Hemolysis

Immediate Actions

• Discontinue the offending medication immediately 9
• Monitor for darkening urine, marked fall in hemoglobin or erythrocyte count 5
• Use ascorbic acid (not methylene blue) for methemoglobinemia in G6PD-deficient patients 9
• Consider exchange transfusion for severe cases 9

Alternative Therapies

• For dermatologic conditions: Use mycophenolate, azathioprine, or methotrexate instead of dapsone 9
• For Pneumocystis prophylaxis: Use atovaquone or inhaled pentamidine instead of dapsone 9

Special Populations

Pregnancy

• Primaquine and tafenoquine are contraindicated during pregnancy regardless of maternal G6PD status, as the fetus may be G6PD-deficient even if the mother is normal 1, 5
• Chloroquine may be used during pregnancy as it has not shown harmful effects on the fetus 1
• Pregnancy testing required before starting primaquine in females of reproductive potential 5

Pediatrics

• Children of any age can develop hemolysis from contraindicated medications; same restrictions apply 1
• Mefloquine not indicated for children <15 kg 1
• Doxycycline contraindicated in children <8 years 1

Common Pitfalls to Avoid

• Do not assume all sulfonamides are equally dangerous: Real-world data suggests sulfamethoxazole/cotrimoxazole and sulfasalazine may be safer than historically believed 6
• Do not test during infections or acute illness: Many compounds have been wrongly cited as causing hemolysis when they were administered during infection-related hemolytic episodes 3
• Do not rely solely on ethnicity: G6PD deficiency is now a worldwide disease due to migration 7