Dapsone-induced methemoglobinemia: a dose-related occurrence?

BACKGROUND: Dapsone, used for Pneumocystis jiroveci (PCP) prophylaxis, is associated with increased risk of methemoglobinemia. Absence of cytochrome b5 reductase enzyme activity causes congenital methemoglobinemia, but its role in dapsone-associated methemoglobinemia is unknown. The authors sought to elucidate drug-related risk factors for dapsone-associated methemoglobinemia in pediatric oncology patients, including contribution of cytochrome b5 reductase enzyme activity.
METHODS: Among 167 pediatric patients treated for hematologic malignancies or aplastic anemia who received dapsone for PCP prophylaxis, demographic and dapsone treatment data were retrospectively collected. Drug-related risk factors were evaluated by Cox proportional hazards, and in a cross-sectional subgroup of 40 patients, cytochrome b5 reductase enzyme activity was assessed.
RESULTS: Methemoglobinemia (median methemoglobin level = 9.0% [3.5-22.4]) was documented in 32 (19.8%) patients. There was a 73% risk reduction in methemoglobinemia with dosing ≥20% below the target dose of 2 mg/kg/d (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.09-0.78; P = .016), whereas methemoglobinemia risk was increased with dosing ≥20% above the target dose (HR, 6.25; 95% CI, 2.45-15.93; P < .001). Sex, body mass index, and age were not associated with increased risk. Cytochrome b5 reductase enzyme activity did not differ by methemoglobinemia status (median 8.6 IU/g hemoglobin [Hb]; [5.5-12.1] vs 9.1 IU/g Hb; [6.7-12.7]). No patient developed PCP on dapsone.
CONCLUSIONS: Methemoglobinemia occurred in almost 20% of pediatric oncology patients receiving dapsone for PCP prophylaxis. Higher dapsone dosing is associated with increased risk. A cross-sectionally acquired cytochrome b5 reductase enzyme activity level was not associated with methemoglobinemia risk. Studies are needed to define biologic correlates of methemoglobinemia and evaluate lower dapsone doses for PCP prophylaxis.