Nitrofurantoin and Hemolysis Risk in G6PD Deficiency
Yes, nitrofurantoin can cause hemolytic anemia in G6PD-deficient patients, but the absolute risk is extremely low—approximately 1 in 100,000 courses of therapy—and the drug can be used cautiously with appropriate monitoring in most cases. 1, 2
Evidence-Based Risk Assessment
FDA-Confirmed Association
The FDA drug label explicitly warns that "cases of hemolytic anemia of the primaquine-sensitivity type have been induced by nitrofurantoin" and that "hemolysis appears to be linked to a glucose-6-phosphate dehydrogenase deficiency in the red blood cells of the affected patients." 1 The label states hemolysis is an indication for discontinuing nitrofurantoin and that hemolysis ceases when the drug is withdrawn. 1
Quantified Real-World Risk
Despite theoretical concerns, the actual clinical risk is remarkably low:
Out of approximately 245 million exposures worldwide, only 318 episodes of hemolytic anemia were reported, with just 42 cases (13%) in confirmed or highly probable G6PD-deficient individuals. 3
A retrospective analysis of 130 million courses of nitrofurantoin therapy in the U.S. identified only 127 hemolytic reactions total, yielding a worst-case incidence of 1 in 100,000 courses. 2
In a real-world Israeli cohort of 31,962 G6PD-deficient patients, nitrofurantoin was prescribed safely to 1,366 G6PD-deficient males and females, with only 2 out of 1,000 Egyptian G6PD-deficient patients experiencing hemolysis attributed to nitrofurantoin. 4, 5
Clinical Decision Algorithm
When Nitrofurantoin Can Be Used
For short-course (3-5 day) urinary tract infection treatment, a total daily dose of 200 mg nitrofurantoin may be used without G6PD screening when accompanied by appropriate patient counseling about warning signs. 3 This recommendation is particularly relevant in regions with high antimicrobial resistance where nitrofurantoin retains activity against drug-resistant uropathogens. 3
Contraindications and High-Risk Scenarios
Nitrofurantoin is absolutely contraindicated in:
Monitoring Requirements
If nitrofurantoin is prescribed to a G6PD-deficient patient, counsel them to watch for:
- Pallor, dark red/brown urine, jaundice, fatigue 6, 5
- Symptoms typically appear 24-72 hours after exposure 5
- Discontinue immediately if hemolysis occurs; recovery is complete in 87% of documented cases 2
Comparative Context
Severity Relative to Other Oxidant Drugs
Early erythrocyte survival studies suggest nitrofurantoin is less likely to cause oxidant hemolysis in G6PD-deficient individuals than primaquine. 3 While primaquine, rasburicase, and methylene blue are absolutely contraindicated in G6PD deficiency 7, 6, nitrofurantoin occupies a middle ground where cautious use is possible.
Variant-Specific Considerations
The Mediterranean G6PD variant (Gdmed) typically causes more severe hemolytic reactions than the African variant (GdA-). 8, 6 However, even in Mediterranean populations, the absolute risk remains low based on pharmacovigilance data. 3
Critical Caveats
The major limitation is that most hemolysis reports come from regions where G6PD deficiency is uncommon. 3 Enhanced pharmacovigilance is recommended in countries with high G6PD deficiency prevalence (Mediterranean, African, Indian, Southeast Asian populations) to better quantify risk. 3
Infections themselves can trigger hemolysis in G6PD-deficient patients 5, making it difficult to distinguish drug-induced from infection-induced hemolysis in urinary tract infection treatment scenarios. 9 This confounding factor may have historically led to overestimation of nitrofurantoin's hemolytic risk. 9