What are the management and treatment options for individuals with Glucose-6-phosphate dehydrogenase (G6PD) deficiency?

Management of G6PD Deficiency

The cornerstone of managing G6PD deficiency is strict avoidance of seven definitively contraindicated medications (dapsone, methylene blue, nitrofurantoin, phenazopyridine, primaquine, rasburicase, and tolonium chloride), mandatory G6PD testing before prescribing any oxidant drug, and immediate discontinuation of any medication if hemolysis occurs. 1, 2, 3

Mandatory Screening and Testing

Screen all patients with Mediterranean, African, Indian, or Southeast Asian ancestry before starting any oxidant medication. 1, 2

• Qualitative screening is sufficient for initial assessment in most clinical situations 1, 2
• Quantitative G6PD testing is required before administering tafenoquine or when enzymatic activity is borderline (30-70% of normal) 1, 2
• Avoid testing during acute hemolytic episodes as G6PD levels can be falsely elevated due to young reticulocytes having higher enzyme activity 4
• Avoid testing during or immediately after transfusion as this will give falsely elevated results 4
• Repeat testing after 3 months may be necessary if initial testing occurred during acute hemolysis 4

Absolutely Contraindicated Medications

These seven medications must never be used in G6PD deficiency: 3

1. Dapsone - potent oxidant causing methemoglobinemia and severe hemolysis 2
2. Methylthioninium chloride (methylene blue) - causes severe hemolytic anemia 2, 3
3. Nitrofurantoin 3
4. Phenazopyridine 3
5. Primaquine - contraindicated in severe G6PD deficiency 2, 5
6. Rasburicase 3
7. Tolonium chloride (toluidine blue) 3

Variant-Specific Risk Stratification

The Mediterranean variant (found in Mediterranean regions, India, Southeast Asia) causes life-threatening hemolysis and requires stricter precautions than the African variant (GdA-). 1, 2

• African variant (GdA-): Found in 10-15% of Black individuals, typically causes milder, self-limited hemolysis 1, 2
• Mediterranean variant (Gdmed): Causes more severe reactions requiring aggressive monitoring 1, 2

Special Considerations for Primaquine Use

Primaquine is absolutely contraindicated in severe G6PD deficiency and during pregnancy. 2, 5

• For mild to moderate G6PD deficiency (>30% to <70% activity): Modified dosing of 45 mg once weekly for 8 weeks may be considered with close hematological monitoring 2, 5
• Among Asian populations with severe G6PD deficiency: Primaquine should not be administered for greater than 5 days due to risk of life-threatening hemolysis 6
• G6PD testing is mandatory before any primaquine use 1, 5
• Both 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 2, 5

Safe Antimalarial Alternatives

Artemisinin-based combination therapies (ACTs) including artesunate, artemether-lumefantrine, and dihydroartemisinin-piperaquine can be used safely in G6PD-deficient patients. 2

• Chloroquine in standard doses is relatively safe in most G6PD deficient patients and is safe during pregnancy 6, 2
• Quinine is safe although pregnant women receiving IV quinine should be monitored for hypoglycemia 6

Baseline Testing Before Starting Potentially Hemolytic Drugs

If a potentially hemolytic medication must be used (after confirming it's not absolutely contraindicated): 1, 5

• Complete blood count with hemoglobin determination 1
• Baseline hematocrit and hemoglobin 5
• ECG monitoring when using primaquine in patients with cardiac disease, long QT syndrome, or concomitant QT-prolonging agents 5

Ongoing Monitoring During Treatment

Close hematological monitoring at day 3 and day 8 is required when using any potentially hemolytic medication. 5

• Monitor blood cell counts and hemoglobin regularly during therapy 1, 5
• Adequate medical support to manage hemolytic risk must be available 5

Warning Signs Requiring Immediate Drug Discontinuation

Discontinue any potentially hemolytic medication immediately if any of these occur: 1, 5

• Darkening of the urine (hemoglobinuria) 5
• Marked fall in hemoglobin or erythrocyte count 5
• Back or abdominal pain 1
• Jaundice 4

Medications That Can Be Used Safely

Despite widespread misconceptions, most medications can be used safely in normal therapeutic doses in G6PD-deficient patients. 3

• Penicillins (including amoxicillin) are safe 4
• Aspirin is explicitly contraindicated and should be avoided 4
• All other medications not on the seven-drug contraindicated list have no solid evidence contraindicating their use 3

Family Screening

Test first-degree relatives of patients with G6PD deficiency or hereditary methemoglobinemia. 1

Patient Education Priorities

Educate patients to: 4

• Avoid the seven absolutely contraindicated medications
• Inform all healthcare providers of their G6PD status before receiving any new medication
• Seek immediate medical attention for darkening urine, jaundice, back/abdominal pain, or sudden weakness
• Understand that children of any age can develop hemolysis from contraindicated medications 2

Common Pitfall to Avoid

Many compounds have been wrongly cited as causing hemolysis because they were administered during infection-related hemolytic episodes. 3 The infection itself, not the medication, was often the trigger. This has led to unnecessarily restrictive medication lists that cause patient distress and limit treatment options without evidence-based justification.