Medications Contraindicated in G6PD Deficiency

High-Risk Medications to Avoid

• Dapsone should be avoided as it is a potent oxidant that can cause methemoglobinemia and red blood cell hemolysis by overcoming the reductive capacity of G6PD in patients with G6PD deficiency 1
• Methylene blue (methylthioninium chloride) is contraindicated as it can cause severe hemolytic anemia in affected patients with G6PD deficiency 2

Risk Factors and Severity

• The severity of G6PD deficiency varies based on genetic variant, with the Mediterranean variant (Gdmed) typically causing more severe reactions than the African variant (GdA-) in patients with G6PD deficiency 3, 4
• The Mediterranean variant is found predominantly in men from Mediterranean regions, India, and Southeast Asia, while the GdA- variant is found in 10-15% of Black men and women with G6PD deficiency 3, 4
• Patients with the Mediterranean variant may experience life-threatening hemolysis, while those with the African variant typically have milder, self-limited hemolysis in the context of G6PD deficiency 3

Clinical Management

• Screening for G6PD deficiency is strongly recommended before starting therapy with oxidant drugs in patients with predisposing racial or ethnic backgrounds (Mediterranean, African, Indian, or Southeast Asian descent) by the Clinical Infectious Diseases society 3, 4
• Qualitative screening is sufficient for initial assessment, but quantitative testing may be needed to determine the degree of deficiency in patients with G6PD deficiency 4

Medium-Risk Medications (Use with Caution)

• Chloroquine/Hydroxychloroquine in standard doses appears to be relatively safe in most G6PD deficient patients, according to the Clinical Microbiology and Infection society 5

G6PD Testing Before Starting Dapsone

Guideline Recommendations

• The National Comprehensive Cancer Network recommends measurement of G6PD levels before starting dapsone therapy, noting that G6PD deficient patients may have an increased risk for hemolytic adverse reactions 6
• The American Academy of Dermatology notes that some subjects with G6PD deficiency developed changes suggestive of mild hemolysis with topical dapsone gel 5% and recommends observing for signs and symptoms 7

Clinical Rationale

• No cited facts are available for this section

Testing Approach

• Quantitative testing may be needed to determine the degree of deficiency in borderline cases, according to the National Comprehensive Cancer Network 6

Medications Contraindicated in G6PD Deficiency

Absolutely Contraindicated Medications

• Primaquine is contraindicated in severe G6PD deficiency and should only be used in mild to moderate deficiency (>30% to <70% activity) at reduced dosing (45 mg once weekly for 8 weeks) in patients, according to the Clinical Microbiology and Infection guideline 8
• Both primaquine and tafenoquine are contraindicated during pregnancy regardless of G6PD status, as recommended by the Clinical Microbiology and Infection guideline 8
• Artemisinin-based combination therapies (ACTs) including artesunate, artemether-lumefantrine, and dihydroartemisinin-piperaquine can be used safely for malaria treatment in G6PD-deficient patients, as stated in the Clinical Microbiology and Infection guideline 8

Medication Use in G6PD Deficiency

Contraindicated and Conditionally Used Medications

• The Centers for Disease Control and Prevention recommends that primaquine may be considered in mild to moderate G6PD deficiency (>30% to <70% activity) at reduced dosing of 45 mg once weekly for 8 weeks, but only after G6PD testing and with close hematological monitoring, and notes that children of any age can develop hemolysis from contraindicated medications, and the same restrictions apply 9
• The Centers for Disease Control and Prevention suggests that chloroquine may be used during pregnancy as it has not been found to have harmful effects on the fetus when used in recommended doses, though the fetus may be G6PD-deficient even if the mother is normal 9
• The Centers for Disease Control and Prevention recommends that mefloquine is not indicated for children less than 15 kg (30 lbs) and doxycycline is contraindicated in children less than 8 years of age 9

Contraindicated Oxidant Drugs and Hemolysis Monitoring in G6PD Deficiency

Contraindicated Oxidant Medications

• Dapsone is a potent oxidant that can cause methemoglobinemia and hemolysis and must be avoided in patients with G6PD deficiency (strong evidence from a 2019 review in Blood Advances) 10

Clinical Monitoring for Hemolysis

• Patients with G6PD deficiency should be educated to recognize early signs of hemolysis, which include dark urine, sudden fatigue or pallor, jaundice, and abdominal or back pain (clinical guidance based on the same 2019 evidence) 10

Management of Severe Hemolysis in G6PD Mediterranean Deficiency

Risk Assessment

• The Mediterranean G6PD variant (G6PD‑B⁻) carries a very high risk of severe, potentially life‑threatening hemolysis, requiring strict avoidance of oxidant medications. 11

Contraindicated Antimalarial

• Tafenoquine is contraindicated in individuals with G6PD activity < 70% because it can trigger hemolysis in the Mediterranean variant. 11

Acute Hemolytic Crisis Management

Supportive Care

• Provide aggressive intravenous hydration to maintain renal perfusion and reduce the risk of hemoglobin‑induced kidney injury during an acute hemolytic episode. 11
• Continuously monitor for complications, especially acute kidney injury resulting from hemoglobinuria, while the patient is in crisis. 11

Management of Primaquine‑Induced Hemolytic Anemia in G6PD Deficiency (Cited Evidence)

Renal Protection and Monitoring

• Maintain urine output of ≥ 100 mL hour⁻¹ in adults (or ≥ 3 mL kg⁻¹ hour⁻¹ for patients < 40 kg) during aggressive intravenous hydration to prevent hemoglobin‑induced acute kidney injury. Evidence level not specified. 12
• Record vital signs (heart rate, blood pressure, respiratory rate, temperature) every 4–6 hours during the initial 24–48 hours to detect tachycardia or hypotension associated with ongoing hemolysis. Evidence level not specified. 12

Transfusion Thresholds

• In a patient with hemoglobin ≈ 8.6 g/dL who is asymptomatic, transfusion is not indicated; supportive care and close observation are sufficient. Evidence level not specified. 13
• Initiate red‑cell transfusion when hemoglobin falls below 7 g/dL or when the patient develops signs of severe anemia (e.g., dyspnea, chest pain, altered mental status, hemodynamic instability), regardless of the absolute hemoglobin value. Evidence level not specified. 13
• The Korean Association for the Study of the Liver recommends considering discontinuation of hemolysis‑inducing drugs (e.g., ribavirin) when hemoglobin drops below 8.5 g/dL, providing a practical threshold for intervention in drug‑induced anemia. Evidence level not specified. 13

G6PD Variant–Specific Risk

• The Mediterranean G6PD variant (B⁻) is associated with a very high risk of severe, potentially life‑threatening hemolysis, whereas the African variant (A⁻) generally produces milder, self‑limited hemolysis. Evidence level not specified. 14

Alternative Antimalarial Options for G6PD‑Deficient Patients

• Artemisinin‑based combination therapies (ACTs)—including artesunate, artemether‑lumefantrine, and dihydroartemisinin‑piperaquine—are considered safe for treating malaria in individuals with G6PD deficiency. Evidence level not specified. 14
• Chloroquine and hydroxychloroquine at standard dosing are relatively safe for most G6PD‑deficient patients. Evidence level not specified. 14

Contraindicated Drugs and Conditional Use

• Primaquine and tafenoquine remain contraindicated in patients with severe G6PD deficiency. If radical cure is required, a weekly primaquine regimen (45 mg for 8 weeks) may be used only when measured G6PD activity exceeds 30 % and with intensive monitoring. Evidence level not specified. 14

Contraindicated Medications in G6PD Deficiency

Absolutely Contraindicated Medications

• The following five agents—rasburicase, primaquine, tafenoquine, dapsone, and methylene blue—are classified as absolutely contraindicated in individuals with glucose‑6‑phosphate dehydrogenase (G6PD) deficiency because they act as potent oxidants capable of precipitating life‑threatening hemolysis. 15

• Rasburicase must be avoided in all G6PD‑deficient patients, irrespective of the specific genetic variant, and should never be employed for the management of tumor lysis syndrome in this population. 15