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

Medications Prohibited in G6PD Deficiency

Seven medications are definitively contraindicated in G6PD deficiency: dapsone, methylene blue (methylthioninium chloride), nitrofurantoin, phenazopyridine, primaquine, rasburicase, 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 in G6PD-deficient patients and must be avoided 3, 1
• Nitrofurantoin is definitively contraindicated based on evidence of hemolytic risk 1, 2
• Phenazopyridine should be avoided in all G6PD-deficient individuals 1, 2
• Rasburicase is contraindicated in G6PD deficiency 1, 2
• Tolonium chloride (toluidine blue) must not be used in G6PD-deficient patients 2

Antimalarials Requiring Special Consideration

• Primaquine is contraindicated in severe G6PD deficiency (activity <30%) and should never be used without prior G6PD testing 3, 5
• For mild to moderate G6PD deficiency (30-70% activity), primaquine may be considered only at reduced dosing of 45 mg once weekly for 8 weeks with close hematological monitoring 3, 5
• Primaquine is absolutely contraindicated during pregnancy regardless of G6PD status, as the fetus may be G6PD-deficient even if the mother is normal 3, 5
• Tafenoquine is contraindicated in pregnancy and requires quantitative G6PD testing before administration 3

Additional Contraindicated Medication

• Aspirin is explicitly contraindicated in G6PD deficiency as it overwhelms the reduced antioxidant capacity in G6PD-deficient red blood cells 1

Medications That Can Be Used Safely

Antimalarials

• Artemisinin-based combination therapies (ACTs) including artesunate, artemether-lumefantrine, and dihydroartemisinin-piperaquine can be used safely for malaria treatment in G6PD-deficient patients 3
• Chloroquine/hydroxychloroquine in standard doses appears relatively safe in most G6PD-deficient patients 3, 6
• Chloroquine may be used during pregnancy as it has not been found harmful to the fetus in recommended doses 3

Antibiotics

• Penicillins (such as amoxicillin) are not contraindicated and can be used in normal therapeutic doses 1
• Sulfamethoxazole/trimethoprim (Bactrim) can be used but requires caution, as hemolysis may occur and is frequently dose-related 7, 6
• Real-world data shows that ciprofloxacin, ofloxacin, sulfasalazine, and sulfacetamide have been prescribed safely to thousands of G6PD-deficient patients 6

Anesthetic Agents

• Benzodiazepines, codeine/codeine derivatives, propofol, fentanyl, and ketamine have not been shown to cause hemolytic crises in G6PD-deficient patients 8
• Dexmedetomidine may be particularly useful as it has antioxidant actions that could reduce hemolysis risk 9

Mandatory G6PD Testing Before Treatment

When Testing is Required

• G6PD testing must be performed before starting primaquine, tafenoquine, or dapsone therapy 10, 3, 5, 4
• Screening is strongly recommended before starting any oxidant drug in patients with predisposing racial or ethnic backgrounds (Mediterranean, African, Indian, or Southeast Asian descent) 10, 3

Testing Approach

• Qualitative screening is sufficient for initial assessment, but quantitative testing may be needed to determine the degree of deficiency in borderline cases 10, 3
• Avoid testing during acute hemolytic episodes, as G6PD levels can be falsely elevated because young reticulocytes have higher enzyme activity 1
• Avoid testing during or immediately post-transfusion, as this will give falsely elevated results 1
• If G6PD levels are borderline (30-70% of normal), consider genetic testing to determine specific variant and predict severity 1

Variant-Specific Risk Stratification

Mediterranean Variant (Gdmed)

• Found predominantly in men from Mediterranean regions, India, and Southeast Asia 3
• Causes more severe reactions and may result in life-threatening hemolysis 3, 1
• Requires stricter avoidance of oxidant medications 10

African Variant (GdA-)

• Found in 10-15% of Black men and women 10, 3
• Associated with milder, typically self-limited hemolysis 10, 3

Monitoring During Treatment with Potentially Hemolytic Drugs

Baseline Assessment

• Check baseline hematocrit and hemoglobin before treatment 5
• Obtain complete blood count with hemoglobin determination 10

Ongoing Monitoring

• Close hematological monitoring is required (e.g., at day 3 and 8) when using potentially hemolytic drugs 5
• Monitor blood cell counts and hemoglobin throughout therapy 10
• Adequate medical support to manage hemolytic risk must be available 5

Warning Signs Requiring Immediate Discontinuation

• Discontinue any potentially hemolytic medication immediately if signs of hemolysis occur: darkening of urine, marked fall in hemoglobin or erythrocyte count, back or abdominal pain, or jaundice 10, 1, 5

Critical Clinical Pitfalls

Common Errors to Avoid

• Do not assume infection-related hemolysis is drug-induced - many compounds have been wrongly cited as causing hemolysis when administered during infection-related hemolytic episodes 2
• Real-world data from over 31,000 G6PD-deficient patients showed that major hemolysis requiring hospitalization occurred in only 0.2%, with 71.8% caused by fava beans and only 4.2% potentially associated with medications 6
• Children of any age can develop hemolysis from contraindicated medications, and the same restrictions apply as in adults 3

Special Populations

• Pregnant women: Even if the mother is G6PD normal, the fetus may be G6PD-deficient 3, 5
• Patients with intermediate G6PD deficiency and non-Mediterranean variants: Weekly primaquine may be considered with close monitoring for hemolysis 10
• Patients with concurrent conditions: Those with renal dysfunction, liver disease, or malnutrition are at particularly high risk when receiving potentially hemolytic drugs 7