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.
Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr Children's Hospital at Vanderbilt, Nashville, TN 37232, USA. adam.esbenshade@vanderbilt.edu
Adam J
AJ
Esbenshade
Richard H
RH
Ho
Ayumi
A
Shintani
Zhiguo
Z
Zhao
Lesley-Ann
LA
Smith
Debra L
DL
Friedman
D000741:Anemia, Aplastic / Q000628:therapy*; D000890:Anti-Infective Agents / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003622:Dapsone / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D019337:Hematologic Neoplasms / Q000628:therapy*; D006801:Humans; D008297:Male; D008708:Methemoglobinemia / Q000139:chemically induced*; D015999:Multivariate Analysis; D011020:Pneumonia, Pneumocystis / Q000517:prevention & control; D016016:Proportional Hazards Models
D000890:Anti-Infective Agents; D003622:Dapsone
AIDS. 1990 Nov;4(11):1145-8
2282188
Pediatr Infect Dis J. 1996 Feb;15(2):183-4
8822303
Biochem Pharmacol. 1993 Mar 9;45(5):1027-33
8461032
Medicine (Baltimore). 2004 Sep;83(5):265-273
15342970
Eur J Pediatr. 2009 Jul;168(7):779-82
19263080
Blood Cells Mol Dis. 2008 Jul-Aug;41(1):50-5
18343696
Biol Blood Marrow Transplant. 2006 Feb;12(2):241-2
16443522
Antimicrob Agents Chemother. 1996 Dec;40(12):2743-8
9124833
Ann Pharmacother. 1998 May;32(5):549-53
9606476
Biol Blood Marrow Transplant. 2000;6(1):35-43
10707997
Antimicrob Agents Chemother. 1997 May;41(5):1077-81
9145873
Pediatr Blood Cancer. 2008 Apr;50(4):779-83
17635000
J Acquir Immune Defic Syndr (1988). 1992;5(4):341-7
1548570
Clin Infect Dis. 2002 Mar 15;34(6):730-51
11850858
Antimicrob Agents Chemother. 1995 May;39(5):1101-6
7625796
Am J Ther. 2007 Nov-Dec;14(6):585-7
18090884
Cancer. 2007 Apr 15;109(8):1654-8
17345613
Br J Dermatol. 1979 Apr;100(4):427-32
454569
Pediatr Infect Dis J. 1999 May;18(5):432-9
10353516
Control Clin Trials. 1990 Apr;11(2):116-28
2161310
J Pediatr Oncol Nurs. 2001 Sep-Oct;18(5):224-8
11588763
Pediatr Pulmonol Suppl. 1997;16:199-200
9443273
Pediatr Blood Cancer. 2008 Apr;50(4):896-8
17458875
Clin Infect Dis. 1998 Jul;27(1):191-204
9675476
Pediatr Blood Cancer. 2006 Nov;47(6):859-60
16568443
Tex Heart Inst J. 2008;35(1):76-7
18427660
Pediatr Blood Cancer. 2005 Jan;44(1):55-62
15390276
Pediatr Infect Dis J. 1997 May;16(5):523-4
9154550
Nucl Med Biol. 1997 May;24(4):327-32
9257331