What medications are contraindicated in patients with Glucose-6-phosphate dehydrogenase (G6PD) deficiency?

Medications Contraindicated in G6PD Deficiency

Absolutely Contraindicated Medications (High-Risk)

The following medications must be avoided in patients with G6PD deficiency due to high risk of severe hemolytic anemia: dapsone, methylene blue (methylthioninium chloride), primaquine (in severe deficiency), rasburicase, nitrofurantoin, phenazopyridine, and tolonium chloride (toluidine blue). 1, 2, 3, 4, 5

Definitive High-Risk Agents:

• Dapsone - A potent oxidant that causes methemoglobinemia and red blood cell hemolysis by overwhelming the reductive capacity of G6PD-deficient erythrocytes 1

• Methylene blue (methylthioninium chloride) - Causes severe hemolytic anemia and is absolutely contraindicated; if methemoglobinemia occurs, use ascorbic acid instead 1, 2, 3, 5

• Primaquine - Contraindicated in severe G6PD deficiency (<30% activity); may be used cautiously in mild-to-moderate deficiency (30-70% activity) at reduced dosing of 45 mg once weekly for 8 weeks with close hematological monitoring 1, 4, 5

• Rasburicase - Causes severe hemolytic anemia and is absolutely contraindicated 2, 3, 5

• Nitrofurantoin - Solid evidence supports prohibition; however, real-world data shows it has been prescribed safely to 1,366 G6PD-deficient patients, suggesting the risk may be lower than traditionally believed 5, 6

• Phenazopyridine - Should be avoided based on evidence, though one case report suggests association with hemolysis 5, 6

• Tolonium chloride (toluidine blue) - Solid evidence supports prohibition 5

Medications Requiring Caution (Medium-Risk)

• Tafenoquine - Contraindicated if G6PD activity is <70%; requires quantitative G6PD testing before use 3

• Chloroquine/Hydroxychloroquine - Appears relatively safe in standard doses for most G6PD-deficient patients, including during pregnancy, though use with caution 1, 6

Safe Medications (Low-to-No Risk)

Many medications previously suspected of causing hemolysis can be used safely in G6PD-deficient patients with standard precautions:

• Artemisinin-based combination therapies (ACTs) including artesunate, artemether-lumefantrine, and dihydroartemisinin-piperaquine are safe for malaria treatment 1

• Anesthetic agents - Benzodiazepines, codeine/codeine derivatives, propofol, fentanyl, ketamine, and dexmedetomidine have not been shown to cause hemolytic crises 7, 8

• Antibiotics - Real-world data demonstrates safe use of ciprofloxacin, ofloxacin, sulfamethoxazole/cotrimoxazole, sulfasalazine, and sulfacetamide in thousands of G6PD-deficient patients 6

• Other medications - Glibenclamide, glimepiride, and mesalazine have been prescribed safely 6

Critical Screening and Monitoring Recommendations

Screen for G6PD deficiency before starting any oxidant drug in patients of Mediterranean, African, Indian, or Southeast Asian descent. 1, 3

Testing Approach:

• Qualitative screening is sufficient for initial assessment in males and homozygous females with severe deficiency 1, 3

• Quantitative testing is required for tafenoquine use, heterozygous females, borderline cases, and determining degree of deficiency 1, 3

• Timing matters - Avoid testing during or immediately after acute hemolytic episodes, as reticulocytes may show near-normal enzyme levels; wait at least 50 days (ideally 120 days) after RBC transfusion 3

Monitoring Protocol When Using Medium-Risk Medications:

• Check baseline hemoglobin and hematocrit before treatment 4

• Perform close hematological monitoring at day 3 and day 8 4

• Monitor for signs of hemolysis: darkening of urine, jaundice, marked fall in hemoglobin, fatigue, and pallor 2, 4

• Discontinue medication promptly if hemolysis occurs 4

Variant-Specific Risk Stratification

The severity of hemolytic risk depends on the genetic variant:

• Mediterranean variant (Gdmed) - Causes life-threatening hemolysis requiring strict avoidance of all oxidant drugs; found predominantly in Mediterranean regions, India, and Southeast Asia 1, 2

• African variant (GdA-) - Produces milder, self-limited hemolysis; found in 10-15% of Black individuals; may tolerate some medications better 1, 2

Special Populations

Pregnancy:

• Primaquine and tafenoquine are absolutely contraindicated during pregnancy regardless of maternal G6PD status, as the fetus may be G6PD-deficient even if the mother is normal 1, 4

• Chloroquine may be used during pregnancy as it has not been found harmful to the fetus in recommended doses 1

• Sexually-active females of reproductive potential should have pregnancy testing before starting primaquine and use effective contraception during and after treatment 4

Pediatrics:

• Children of any age can develop hemolysis from contraindicated medications; the same restrictions apply 1

• Mefloquine is not indicated for children <15 kg 1

• Doxycycline is contraindicated in children <8 years of age 1

Alternative Therapies When High-Risk Medications Are Needed

• For Pneumocystis prophylaxis (instead of dapsone): Use atovaquone or inhaled pentamidine 3

• For dermatologic conditions (instead of dapsone): Use mycophenolate, azathioprine, or methotrexate 3

• For methemoglobinemia (instead of methylene blue): Use ascorbic acid 0.5-10 g, though this exceeds FDA-mandated RDA limits for G6PD-deficient patients; exchange transfusion may be needed for severe cases 3

Common Pitfalls to Avoid

• Do not rely on infection as the sole cause of hemolysis - Many medications have been wrongly implicated because they were administered during infection-related hemolytic episodes 5

• Real-world evidence contradicts some traditional warnings - A 2024 study showed only 0.2% of G6PD-deficient patients experienced major hemolysis requiring hospitalization, with 71.8% caused by fava beans, not medications 6

• Do not use quinacrine with primaquine - Quinacrine potentiates primaquine toxicity and is contraindicated 4