Abstract
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect and one of the most common genetic disorders worldwide, with an estimated 400 million people worldwide carrying a mutation in the G6PD gene that causes deficiency of the enzyme. Although drug-induced haemolysis is considered the most common adverse clinical consequence of G6PD deficiency, significant confusion exists regarding which drugs can cause haemolytic anaemia in patients with G6PD deficiency. In the absence of consensus among physicians, patients are subject to conflicting advice, causing uncertainty and distress. In the current review we aimed, by thorough search of the medical literature, to collect evidence on which to base decisions either to prohibit or allow the use of various medications in patients with G6PD deficiency. A literature search was conducted during May 2009 for studies and case reports on medication use and G6PD deficiency using the following sources: MEDLINE (1966–May 2009), PubMed (1950–May 2009), the Cochrane database of systematic reviews (2009), and major pharmacology, internal medicine, haematology and paediatric textbooks. After assessing the literature, we divided medications into one of three groups: medications that should be avoided in individuals with G6PD deficiency, medications that were considered unsafe by at least one source, but according to our review can probably be given safely in normal therapeutic dosages to individuals with G6PD deficiency as evidence does not contravene their use, and medications where no evidence at all was found to contravene their use in G6PD-deficient patients. It is reasonable to conclude that, over time, many compounds have been wrongly cited as causing haemolysis because they were administered to patients experiencing an infection-related haemolytic episode. We found solid evidence to prohibit only seven currently used medications: dapsone, methylthioninium chloride (methylene blue), nitrofurantoin, phenazopyridine, primaquine, rasburicase and tolonium chloride (toluidine blue). Regarding all other medications, our review found no evidence to contravene their use in normal therapeutic doses to G6PD-deficient patients.
There is a need for evidence-based global consensus regarding medication use in G6PD-deficient patients.
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References
Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008; 5: 64–74
Beutler E. G6PD deficiency. Blood 1994; 843: 613–36
Alving AS, Carson PE, Flanagan CL, et al. Enzymatic deficiency in primaquine-sensitive erythrocytes. Science 1956; 124: 484–5
Beutler E. The hemolytic effect of primaquine and related compounds: a review. Blood 1959; 14: 103–39
Mason PJ. New insights into G6PD deficiency. Br J Haematol 1996; 94: 585–91
Burka ER. Infectious disease: a cause of hemolytic anemia in glucose-6 phosphate dehydrogenase deficiency. Ann Intern Med 1969; 70: 222–5
Beutler E. Glucose-6-phosphate dehydrogenase deficiency. N Engl J Med 1991; 324: 169–74
Lichtman MA, Beutler E, Kipps TJ, et al. Williams hematology. 7th ed. New York: McGraw-Hill, 2006
Kliegman RM, Behrman RE, Jenson HB, et al. Nelson textbook of pediatrics. 18th ed. Philadelphia (PA): WB Saunders Co., 2007
Fauci AS, Braunwald E, Kasper DL, et al. Harrison’s principles of internal medicine. 17th ed. New York: McGraw-Hill, 2008
Beutler E. Abnormalities of the hexose monophosphate shunt. Semin Hematol 1971; 8: 311–47
Rosen PJ, Johnson C, Mcgehee WG, et al. Failure of methylene blue treatment in toxic methemoglobinemia: association with glucose-6-phosphate dehydrogenase deficiency. Ann Intern Med 1971; 75: 83–6
Gauthier TW. Methylene blue-induced hyperbilirubinemia in neonatal glucose-6-phosphate dehydrogenase (G6PD) deficiency. J Matern Fetal Med 2000; 9: 252–4
Foltz LM, Dalal BI, Wadsworth LD, et al. Recognition and management of methemoglobinemia and hemolysis in a G6PD-deficient patient on experimental anticancer drug Triapine. Am J Hematol 2006; 81: 210–1
Mandi G, Witte S, Meissner P, et al. Safety of the combination of chloroquine and methylene blue in healthy adult men with G6PD deficiency from rural Burkina Faso. Trop Med Int Health 2005; 10: 32–8
Meissner PE, Mandi G, Witte S, et al. Safety of the methylene blue plus chloroquine combination in the treatment of uncomplicated falciparum malaria in young children of Burkina Faso [ISRCTN27290841]. Malar J 2005; 4: 45
Chan TK, Todd D, Tso SC. Red cell survival studies in glucose-6-phosphate dehydrogenase deficiency. Bull Hong Kong Med Assoc 1974; 26: 41–8
Chan TK, Todd D, Tso SC. Drug-induced haemolysis in glucose-6-phosphate dehydrogenase deficiency. BMJ 1976; 2: 1227–9
Lavelle KJ, Atkinson KF, Kleit SA. Hyperlactatemia and hemolysis in G6PD deficiency after nitrofurantoin ingestion. Am J Med Sci 1976; 272: 201–4
Herman J, Ben-Meir S. Overt hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency: a survey in general practice. Isr J Med Sci 1975; 11: 340–6
Powell RD, DeGowin RL, Alving AS. Nitrofurantoin-induced hemolysis. J Lab Clin Med 1963; 62: 1002–3
Mercieca JE, Clarke MF, Phillips ME, et al. Acute haemolytic anaemia due to phenazopyridine hydrochloride in G-6-PD deficiency subject [letter]. Lancet 1982; II: 564
Tishler M, Abramov A. Phenazopyridine-induced hemolytic anemia in a patient with G6PD deficiency. Acta Haematol 1983; 70(3): 208–9
Galun E, Oren R, Glikson M, et al. Phenazopyridine-induced hemolytic anemia in G-6-PD deficiency. Drug Intell Clin Pharm 1987; 21: 921–2
Jeffrey WH, Zelicoff AP, Hardy WR. Acquired methemoglobinemia and hemolytic anemia after usual doses of phenazopyridine. Drug Intell Clin Pharm 1982; 16: 157–9
Noonan HM, Kimbrell M, Ben Johnson WB, et al. Phenazopyridine-induced hemolytic anemia. Urology 1983; 21: 623–4
Nathan DM, Siegel AJ, Bunn HF. Acute methemoglobinemia and hemolytic anemia with phenazopyridine: possible relation to acute renal failure. Arch Internal Med 1977; 137: 1636–8
Fincher ME, Campbell HT. Methemoglobinemia and hemolytic anemia after phenazopyridine hydrochloride (pyridium) administration in end-stage renal disease. South Med J 1989; 82: 372–4
Charles LJ. Observations on the haemolytic effect of primaquine in 100 Ghanaian children. Ann Trop Med Parasitol 1960; 54: 460–70
Greenberg MS, Wong H. Studies on the destruction of glutathione-unstable red blood cells: the influence of fava beans and primaquine upon such cells in vivo. J Lab Clin Med 1961; 57: 733–46
George JN, Sears DA, McCurdy PR, et al. Primaquine sensitivity in Caucasians: hemolytic reactions induced by primaquine in G-6-PD deficient subjects. J Lab Clin Med 1967; 70: 80–93
Krudsood S, Wilairatana P, Tangpukdee N, et al. Safety and tolerability of elubaquine [bulaquine, CDRI 80/53] for treatment of Plasmodium vivax malaria in Thailand. Korean J Parasitol 2006; 44: 221–8
Degowin RL, Eppes RB, Powel RD, et al. The haemolytic effects of diaphenylsulfone [DDS] in normal subjects and in those with glucose-6-phosphate-dehydrogenase deficiency. Bull WHO 1966; 35: 165–79
Grossman S, Budinsky R, Jollow D. Dapsone-induced hemolytic anemia: role of glucose-6-phosphate dehydrogenase in the hemolytic response of rat erythrocytes to N-hydroxydapsone. J Pharmacol Exp Ther 1995; 273: 870–7
Sheehy TW. Supplemental sulfone (dapsone) therapy: use in treatment of chloroquine-resistant falciparum malaria. Arch Intern Med 1967; 119: 561–6
Fanello CI, Karema C, Avellino P, et al. High risk of severe anaemia after chlorproguanil-dapsone+artesunate anti-malarial treatment in patients with G6PD [A-] deficiency. PLoS ONE 2008; 3: e4031
Brant JM. Rasburicase: an innovative new treatment for hyperuricemia associated with tumor lysis syndrome. J Oncol Nurs 2002; 6: 12–6
Browning LA, Kruse JA. Hemolysis and methemoglobinemia secondary to Rasburicase administration. Ann Pharmacother 2005; 39: 1932–5
Marquez A, Todd M. Acute hemolytic anemia and agranulocytosis following intravenous administration of toluidine blue. Am Pract Dig Treat 1959; 10: 1548–50
Teunis BS, Leftwich EI, Pierce LE. Acute methemoglobinemia and hemolytic anemia due to toluidine blue. Arch Surg 1970; 101: 527–31
Cottafava F, Nieri S, Franzone G, et al. Double blind trial between placebo and paracetamol in children with G6PD deficiency. Ped Med Chir 1990; 12: 631–8
Sklar GE. Hemolysis as a potential complication of acetaminophen overdose in a patient with glucose-6-phosphate dehydrogenase deficiency. Pharmacotherapy 2002; 22: 656–8
Wright RO, Perry HE, Shannon NW. Hemolysis after acetaminophen overdose in a patient with glucose-6-phosphate dehydrogenase deficiency. J Toxicol Clin Toxicol 1996; 34: 731–4
Walz B, Riecken B. A young man with acute generalized jaundice and intermittent epigastric pain [abstract]. Dtsch Med Wochenschr 2008; 133: 129–32
Shahidi NT, Westring DW. Acetylsalicylic acid-induced hemolysis and its mechanism. J Clin Invest 1970; 49: 1334–40
Glader BE. Evaluation of hemolytic role of aspirin in glucose-6-phosphate dehydrogenase deficiency. J Pediatr 1976; 89: 1027–8
Stockman JA, Lubin B, Oski FA. Aspirin-induced hemolysis: the role of concomitant oxidant [H2O2] challenge. Pediatr Res 1978; 12: 927–31
Shalev O. Long-term low-dose aspirin is safe in glucose-6-phosphate dehydrogenase deficiency. DICP 1991; 25: 1074–5
Kanetaka T, Oda T. Toxic liver injuries. Acta Pathol Jpn 1973; 23: 617–27
Prankerd TAJ. Hemolytic effects of drugs and chemical agents. Clin Pharmacol Ther 1963; 4: 334–50
Campbell GD, Steinberg MH, Bower JD. Ascorbic acid induced hemolysis in G6PD deficiency [letter]. Ann Intern Med 1975; 82: 810
Udomratn T, Steinberg MH, Campbell Jr GD, et al. Effects of ascorbic acid on glucose-6-phosphate dehydrogenase-deficient erythrocytes: studies in an animal model. Blood 1977; 49: 471–5
Barkshi S, Singh J. Acute hemolytic anemia in typhoid fever. Indian J Pediatr 1972; 39: 270–3
McCaffrey RP, Halsted CH, Wahab MFA, et al. Chloramphenicol induced hemolysis in Caucasian glucose-6-phosphate dehydrogenase deficiency. Ann Intern Med 1971; 74: 722–6
Rajkondawar VL, Modi TH, Mishra SN. Drug induced acute haemolytic anaemia in glucose-6-phosphate dehydrogenase deficiency subjects. J Assoc Physicians India 1968; 16: 589–93
Chan TK, Chesterman CN, McFadzean AJ, et al. The survival of glucose-6-phosphate dehydrogenase-deficient erythrocytes in patients with typhoid fever on chloramphenicol therapy. J Lab Med 1971; 77: 177–84
Choudhry VP, Ghafary A, Zaher M, et al. Drug-induced haemolysis and renal failure in children with glucose-6-phosphate dehydrogenase deficiency in Afghanistan [abstract]. Ann Trop Paediatr 1990; 10: 335–8
Gaetani GD, Mareni C, Ravazzolo R, et al. Haemolytic effect of two sulphonamides evaluated by a new method. Br J Haematol 1976; 32: 183–91
Gerr F, Frumkin H, Hodgins P. Hemolytic anemia following succimer administration in glucose-6-phosphate dehydrogenase deficient patient. Clin Toxicol 1994; 32(5): 569–75
Graziano JH, Lolacono NJ, Moulton T, et al. Controlled study of meso-2,3-dimercaptosuccinic acid for the management of childhood lead intoxication. J Pediatr 1992; 120: 133–9
Abbate SL, Hoogwerf BJ. Hemolytic anemia associated with sulfonylurea use. Diabetes Care 1990; 13: 904–5
Meloni G, Meloni T. Glyburide-induced acute hemolysis in a G6PD-deficient patient with NIDDM. Br J Haematol 1996 Jan; 92: 159–60
Vinizo S, Andrès E, Perrin AE, et al. Glibenclamide-induced acute hemolytic anemia revealing a G6PD-deficiency. Diabetes Res Clin Pract 2004; 64: 181–3
Product information: oral tablets, glyburide oral tablets. New York: Pharmacia & Upjohn Company, 2009
McCurdy PR, Donohoe RF. Pyridoxine-responsive anemia conditioned by isonicotinic acid hydrazide. Blood 1966; 27: 352–62
Aderka D, Garfinkel D, Bograd H, et al. Isosorbide dinitrate-induced hemolysis in G6PD-deficient subjects. Acuta Haemat 1983; 69: 63–4
Mandal BK, Stevenson J. Hemolytic crisis caused by nalidixic acid [letter]. Lancet 1970; I: 614
Belton EM, Jones RV. Hemolytic anemia due to nalidixic acid [letter]. Lancet 1965; II: 691
Oh YR, Carr-Lopez SM, Probasco JM, et al. Levofloxacin-induced autoimmune hemolytic anemia. Ann Pharmacother 2003; 37: 1010–3
Lim S, Alam MG. Ciprofloxacin-induced acute interstitial nephritis and autoimmune hemolytic anemia. Ren Fail 2003; 25: 647–51
Carmoi T, Bordier L, Bonnefoy S, et al. Ofloxacin is contraindicated in case of G6PD deficiency: is it evidenced based? Rev Med Intern 2009; 30: 355–7
Product information: ciprofloxacin hydrochloride oral tablets. Wayne (NJ): Bayer HealthCare Pharmaceuticals Inc, 2009
Dern RJ, Beutler E, Alving AS. The hemolytic effect of primaquine. J Lab Clin Med 1955; 45: 30–9
Wood Jr WB. Anemia during sulfanilamide therapy. JAMA 1938; 11: 1916–9
Wintrobe M. Clinical hematology. Philadelphia (PA): Lea & Febringer, 1951: 434
Szeinberg A, Pras M, Sheba C, et al. The hemolytic effect of various sulfonamides on subjects with a deficiency of glucose-6-phosphate dehydrogenase of erythrocytes. Isr J Med Sci 1959; 18: 176
Cohen SM, Rosenthal DS, Karp PJ. Ulcerative colitis and erythrocyte G6PD deficiency: salicylazosulfapyridine-provoked hemolysis. JAMA 1968; 205: 528–30
Kaplinsky N, Frankl O. Salicylazosulphapyridine-induced Heinz body anemia. Acta Haematol 1978; 59: 310–4
Markowitz N, Saravolatz LD. Use of trimethoprim-sulfamethoxazole in a glucose-6-phosphate dehydrogenase deficient population. Rev Infect Dis 1987; 9 Suppl. 2: S218–25
Chan TK, McFadzean JS. Hemolytic effect of trimethoprim-sulfamethoxazole in G6PD deficiency. Trans R Soc Trop Med Hyg 1974; 68: 61–2
Shinohara K, Tanaka KR. The effects of adriamycin (doxorubicin HCl) on human red blood cells. Hemoglobin 1980; 4: 735–45
Gaetani G, Salvidio E, Pannacciulli I, et al. Absence of hemolytic effects of L-DOPA on transfused G6PD-deficient erythrocytes. Experientia 1970; 26: 785–6
Sansone G, Reali S, Sansone R, et al. Acute hemolytic anemia induced by a pyrazolonic drug in a child with glucose-6-phosphate dehydrogenase deficiency. Acta Haematol 1984; 72: 285–7
Khoo KK. The treatment of malaria in glucose-6-phosphate dehydrogenase deficient patients in Sabah [abstract]. Ann Trop Med 1981; 75: 591–5
Heinrich RA, Smith TC, Buchaman RA. A pharmacological study of a new sulfonamide in glucose-6-phosphate dehydrogenase deficient subjects. J Clin Pharmacol 1971 Nov–Dec; 11(6): 428–32
Eldad A, Neuman A, Weinberg A, et al. Silver sulphadiazine-induced hemolytic anemia in a glucose-6-phosphate dehydrogenase-deficient burn patient. Burns 1991; 17: 430–2
Brown AK, Cevik N. Hemolysis and jaundice in the newborn following maternal treatment with sulfamethoxypyridazine (kynex). Pediatrics 1965; 36: 742–4
Kellermeyer RW, Tarlov AR, Schrier SL, et al. Hemolytic effect of commonly used drugs on erythrocytes deficient in glucose-6-phosphate dehydrogenase. J Lab Clin Med 1958; 52: 827–8
Mela Q, Perpignano G, Ruggiero V, et al. Tolerability of tiaprofenic acid in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Drugs 1988; 35 Suppl. 1: 107–10
Zail SS, Charlton RW, Bothwell TH. The haemolytic effect of certain drugs in Bantu subjects with a deficiency of glucose-6-phosphate dehydrogenase. S Afr J Med Sci 1962; 27: 95–9
Zinkham W. Peripheral blood and bilirubin values in normal full-term primaquine-sensitive Negro infants: effect of vitamin K. Pediatrics 1963; 31: 983–95
Kulwichit W, Torranin P. Glucose-6-phosphate dehydrogenase deficiency, vitamin K, and ambiguity in medical textbooks. Acta Haematol 2004; 111: 173–4
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The authors state that no financial support or author involvement with organizations with financial interest in the subject matter exists, and that no actual or potential conflict of interest exists. The first two authors contributed equally to the design and implementation of the study.
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Youngster, I., Arcavi, L., Schechmaster, R. et al. Medications and Glucose-6-Phosphate Dehydrogenase Deficiency. Drug-Safety 33, 713–726 (2010). https://doi.org/10.2165/11536520-000000000-00000
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DOI: https://doi.org/10.2165/11536520-000000000-00000