Drug Safety

, Volume 33, Issue 9, pp 713–726 | Cite as

Medications and Glucose-6-Phosphate Dehydrogenase Deficiency

An Evidence-Based Review
  • Ilan YoungsterEmail author
  • Lidia Arcavi
  • Renata Schechmaster
  • Yulia Akayzen
  • Hen Popliski
  • Janna Shimonov
  • Svetlana Beig
  • Matitiahu Berkovitch
Review Article


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.


Haemolytic Anaemia Dapsone G6PD Deficiency Dipyrone Primaquine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



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.


  1. 1.
    Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008; 5: 64–74CrossRefGoogle Scholar
  2. 2.
    Beutler E. G6PD deficiency. Blood 1994; 843: 613–36Google Scholar
  3. 3.
    Alving AS, Carson PE, Flanagan CL, et al. Enzymatic deficiency in primaquine-sensitive erythrocytes. Science 1956; 124: 484–5PubMedGoogle Scholar
  4. 4.
    Beutler E. The hemolytic effect of primaquine and related compounds: a review. Blood 1959; 14: 103–39PubMedGoogle Scholar
  5. 5.
    Mason PJ. New insights into G6PD deficiency. Br J Haematol 1996; 94: 585–91PubMedGoogle Scholar
  6. 6.
    Burka ER. Infectious disease: a cause of hemolytic anemia in glucose-6 phosphate dehydrogenase deficiency. Ann Intern Med 1969; 70: 222–5PubMedGoogle Scholar
  7. 7.
    Beutler E. Glucose-6-phosphate dehydrogenase deficiency. N Engl J Med 1991; 324: 169–74PubMedCrossRefGoogle Scholar
  8. 8.
    Lichtman MA, Beutler E, Kipps TJ, et al. Williams hematology. 7th ed. New York: McGraw-Hill, 2006Google Scholar
  9. 9.
    Kliegman RM, Behrman RE, Jenson HB, et al. Nelson textbook of pediatrics. 18th ed. Philadelphia (PA): WB Saunders Co., 2007Google Scholar
  10. 10.
    Fauci AS, Braunwald E, Kasper DL, et al. Harrison’s principles of internal medicine. 17th ed. New York: McGraw-Hill, 2008Google Scholar
  11. 11.
    Beutler E. Abnormalities of the hexose monophosphate shunt. Semin Hematol 1971; 8: 311–47PubMedGoogle Scholar
  12. 12.
    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: 83–6PubMedGoogle Scholar
  13. 13.
    Gauthier TW. Methylene blue-induced hyperbilirubinemia in neonatal glucose-6-phosphate dehydrogenase (G6PD) deficiency. J Matern Fetal Med 2000; 9: 252–4PubMedCrossRefGoogle Scholar
  14. 14.
    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: 210–1PubMedCrossRefGoogle Scholar
  15. 15.
    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: 32–8PubMedCrossRefGoogle Scholar
  16. 16.
    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: 45PubMedCrossRefGoogle Scholar
  17. 17.
    Chan TK, Todd D, Tso SC. Red cell survival studies in glucose-6-phosphate dehydrogenase deficiency. Bull Hong Kong Med Assoc 1974; 26: 41–8Google Scholar
  18. 18.
    Chan TK, Todd D, Tso SC. Drug-induced haemolysis in glucose-6-phosphate dehydrogenase deficiency. BMJ 1976; 2: 1227–9PubMedCrossRefGoogle Scholar
  19. 19.
    Lavelle KJ, Atkinson KF, Kleit SA. Hyperlactatemia and hemolysis in G6PD deficiency after nitrofurantoin ingestion. Am J Med Sci 1976; 272: 201–4PubMedCrossRefGoogle Scholar
  20. 20.
    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: 340–6PubMedGoogle Scholar
  21. 21.
    Powell RD, DeGowin RL, Alving AS. Nitrofurantoin-induced hemolysis. J Lab Clin Med 1963; 62: 1002–3Google Scholar
  22. 22.
    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: 564CrossRefGoogle Scholar
  23. 23.
    Tishler M, Abramov A. Phenazopyridine-induced hemolytic anemia in a patient with G6PD deficiency. Acta Haematol 1983; 70(3): 208–9PubMedCrossRefGoogle Scholar
  24. 24.
    Galun E, Oren R, Glikson M, et al. Phenazopyridine-induced hemolytic anemia in G-6-PD deficiency. Drug Intell Clin Pharm 1987; 21: 921–2PubMedGoogle Scholar
  25. 25.
    Jeffrey WH, Zelicoff AP, Hardy WR. Acquired methemoglobinemia and hemolytic anemia after usual doses of phenazopyridine. Drug Intell Clin Pharm 1982; 16: 157–9Google Scholar
  26. 26.
    Noonan HM, Kimbrell M, Ben Johnson WB, et al. Phenazopyridine-induced hemolytic anemia. Urology 1983; 21: 623–4PubMedCrossRefGoogle Scholar
  27. 27.
    Nathan DM, Siegel AJ, Bunn HF. Acute methemoglobinemia and hemolytic anemia with phenazopyridine: possible relation to acute renal failure. Arch Internal Med 1977; 137: 1636–8CrossRefGoogle Scholar
  28. 28.
    Fincher ME, Campbell HT. Methemoglobinemia and hemolytic anemia after phenazopyridine hydrochloride (pyridium) administration in end-stage renal disease. South Med J 1989; 82: 372–4PubMedCrossRefGoogle Scholar
  29. 29.
    Charles LJ. Observations on the haemolytic effect of primaquine in 100 Ghanaian children. Ann Trop Med Parasitol 1960; 54: 460–70PubMedGoogle Scholar
  30. 30.
    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: 733–46PubMedGoogle Scholar
  31. 31.
    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: 80–93PubMedGoogle Scholar
  32. 32.
    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: 221–8PubMedCrossRefGoogle Scholar
  33. 33.
    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: 165–79PubMedGoogle Scholar
  34. 34.
    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: 870–7PubMedGoogle Scholar
  35. 35.
    Sheehy TW. Supplemental sulfone (dapsone) therapy: use in treatment of chloroquine-resistant falciparum malaria. Arch Intern Med 1967; 119: 561–6PubMedCrossRefGoogle Scholar
  36. 36.
    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: e4031PubMedCrossRefGoogle Scholar
  37. 37.
    Brant JM. Rasburicase: an innovative new treatment for hyperuricemia associated with tumor lysis syndrome. J Oncol Nurs 2002; 6: 12–6CrossRefGoogle Scholar
  38. 38.
    Browning LA, Kruse JA. Hemolysis and methemoglobinemia secondary to Rasburicase administration. Ann Pharmacother 2005; 39: 1932–5PubMedCrossRefGoogle Scholar
  39. 39.
    Marquez A, Todd M. Acute hemolytic anemia and agranulocytosis following intravenous administration of toluidine blue. Am Pract Dig Treat 1959; 10: 1548–50PubMedGoogle Scholar
  40. 40.
    Teunis BS, Leftwich EI, Pierce LE. Acute methemoglobinemia and hemolytic anemia due to toluidine blue. Arch Surg 1970; 101: 527–31PubMedCrossRefGoogle Scholar
  41. 41.
    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: 631–8Google Scholar
  42. 42.
    Sklar GE. Hemolysis as a potential complication of acetaminophen overdose in a patient with glucose-6-phosphate dehydrogenase deficiency. Pharmacotherapy 2002; 22: 656–8PubMedCrossRefGoogle Scholar
  43. 43.
    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: 731–4PubMedCrossRefGoogle Scholar
  44. 44.
    Walz B, Riecken B. A young man with acute generalized jaundice and intermittent epigastric pain [abstract]. Dtsch Med Wochenschr 2008; 133: 129–32PubMedCrossRefGoogle Scholar
  45. 45.
    Shahidi NT, Westring DW. Acetylsalicylic acid-induced hemolysis and its mechanism. J Clin Invest 1970; 49: 1334–40PubMedCrossRefGoogle Scholar
  46. 46.
    Glader BE. Evaluation of hemolytic role of aspirin in glucose-6-phosphate dehydrogenase deficiency. J Pediatr 1976; 89: 1027–8PubMedCrossRefGoogle Scholar
  47. 47.
    Stockman JA, Lubin B, Oski FA. Aspirin-induced hemolysis: the role of concomitant oxidant [H2O2] challenge. Pediatr Res 1978; 12: 927–31PubMedGoogle Scholar
  48. 48.
    Shalev O. Long-term low-dose aspirin is safe in glucose-6-phosphate dehydrogenase deficiency. DICP 1991; 25: 1074–5PubMedGoogle Scholar
  49. 49.
    Kanetaka T, Oda T. Toxic liver injuries. Acta Pathol Jpn 1973; 23: 617–27PubMedGoogle Scholar
  50. 50.
    Prankerd TAJ. Hemolytic effects of drugs and chemical agents. Clin Pharmacol Ther 1963; 4: 334–50PubMedGoogle Scholar
  51. 51.
    Campbell GD, Steinberg MH, Bower JD. Ascorbic acid induced hemolysis in G6PD deficiency [letter]. Ann Intern Med 1975; 82: 810PubMedGoogle Scholar
  52. 52.
    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: 471–5PubMedGoogle Scholar
  53. 53.
    Barkshi S, Singh J. Acute hemolytic anemia in typhoid fever. Indian J Pediatr 1972; 39: 270–3CrossRefGoogle Scholar
  54. 54.
    McCaffrey RP, Halsted CH, Wahab MFA, et al. Chloramphenicol induced hemolysis in Caucasian glucose-6-phosphate dehydrogenase deficiency. Ann Intern Med 1971; 74: 722–6PubMedGoogle Scholar
  55. 55.
    Rajkondawar VL, Modi TH, Mishra SN. Drug induced acute haemolytic anaemia in glucose-6-phosphate dehydrogenase deficiency subjects. J Assoc Physicians India 1968; 16: 589–93PubMedGoogle Scholar
  56. 56.
    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: 177–84Google Scholar
  57. 57.
    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: 335–8PubMedGoogle Scholar
  58. 58.
    Gaetani GD, Mareni C, Ravazzolo R, et al. Haemolytic effect of two sulphonamides evaluated by a new method. Br J Haematol 1976; 32: 183–91PubMedCrossRefGoogle Scholar
  59. 59.
    Gerr F, Frumkin H, Hodgins P. Hemolytic anemia following succimer administration in glucose-6-phosphate dehydrogenase deficient patient. Clin Toxicol 1994; 32(5): 569–75CrossRefGoogle Scholar
  60. 60.
    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: 133–9PubMedCrossRefGoogle Scholar
  61. 61.
    Abbate SL, Hoogwerf BJ. Hemolytic anemia associated with sulfonylurea use. Diabetes Care 1990; 13: 904–5PubMedGoogle Scholar
  62. 62.
    Meloni G, Meloni T. Glyburide-induced acute hemolysis in a G6PD-deficient patient with NIDDM. Br J Haematol 1996 Jan; 92: 159–60PubMedCrossRefGoogle Scholar
  63. 63.
    Vinizo S, Andrès E, Perrin AE, et al. Glibenclamide-induced acute hemolytic anemia revealing a G6PD-deficiency. Diabetes Res Clin Pract 2004; 64: 181–3CrossRefGoogle Scholar
  64. 64.
    Product information: oral tablets, glyburide oral tablets. New York: Pharmacia & Upjohn Company, 2009Google Scholar
  65. 65.
    McCurdy PR, Donohoe RF. Pyridoxine-responsive anemia conditioned by isonicotinic acid hydrazide. Blood 1966; 27: 352–62PubMedGoogle Scholar
  66. 66.
    Aderka D, Garfinkel D, Bograd H, et al. Isosorbide dinitrate-induced hemolysis in G6PD-deficient subjects. Acuta Haemat 1983; 69: 63–4CrossRefGoogle Scholar
  67. 67.
    Mandal BK, Stevenson J. Hemolytic crisis caused by nalidixic acid [letter]. Lancet 1970; I: 614CrossRefGoogle Scholar
  68. 68.
    Belton EM, Jones RV. Hemolytic anemia due to nalidixic acid [letter]. Lancet 1965; II: 691CrossRefGoogle Scholar
  69. 69.
    Oh YR, Carr-Lopez SM, Probasco JM, et al. Levofloxacin-induced autoimmune hemolytic anemia. Ann Pharmacother 2003; 37: 1010–3PubMedCrossRefGoogle Scholar
  70. 70.
    Lim S, Alam MG. Ciprofloxacin-induced acute interstitial nephritis and autoimmune hemolytic anemia. Ren Fail 2003; 25: 647–51PubMedCrossRefGoogle Scholar
  71. 71.
    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: 355–7CrossRefGoogle Scholar
  72. 72.
    Product information: ciprofloxacin hydrochloride oral tablets. Wayne (NJ): Bayer HealthCare Pharmaceuticals Inc, 2009Google Scholar
  73. 73.
    Dern RJ, Beutler E, Alving AS. The hemolytic effect of primaquine. J Lab Clin Med 1955; 45: 30–9PubMedGoogle Scholar
  74. 74.
    Wood Jr WB. Anemia during sulfanilamide therapy. JAMA 1938; 11: 1916–9CrossRefGoogle Scholar
  75. 75.
    Wintrobe M. Clinical hematology. Philadelphia (PA): Lea & Febringer, 1951: 434Google Scholar
  76. 76.
    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: 176PubMedGoogle Scholar
  77. 77.
    Cohen SM, Rosenthal DS, Karp PJ. Ulcerative colitis and erythrocyte G6PD deficiency: salicylazosulfapyridine-provoked hemolysis. JAMA 1968; 205: 528–30PubMedCrossRefGoogle Scholar
  78. 78.
    Kaplinsky N, Frankl O. Salicylazosulphapyridine-induced Heinz body anemia. Acta Haematol 1978; 59: 310–4PubMedCrossRefGoogle Scholar
  79. 79.
    Markowitz N, Saravolatz LD. Use of trimethoprim-sulfamethoxazole in a glucose-6-phosphate dehydrogenase deficient population. Rev Infect Dis 1987; 9 Suppl. 2: S218–25PubMedCrossRefGoogle Scholar
  80. 80.
    Chan TK, McFadzean JS. Hemolytic effect of trimethoprim-sulfamethoxazole in G6PD deficiency. Trans R Soc Trop Med Hyg 1974; 68: 61–2PubMedCrossRefGoogle Scholar
  81. 81.
    Shinohara K, Tanaka KR. The effects of adriamycin (doxorubicin HCl) on human red blood cells. Hemoglobin 1980; 4: 735–45PubMedCrossRefGoogle Scholar
  82. 82.
    Gaetani G, Salvidio E, Pannacciulli I, et al. Absence of hemolytic effects of L-DOPA on transfused G6PD-deficient erythrocytes. Experientia 1970; 26: 785–6PubMedCrossRefGoogle Scholar
  83. 83.
    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: 285–7PubMedCrossRefGoogle Scholar
  84. 84.
    Khoo KK. The treatment of malaria in glucose-6-phosphate dehydrogenase deficient patients in Sabah [abstract]. Ann Trop Med 1981; 75: 591–5Google Scholar
  85. 85.
    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): 428–32Google Scholar
  86. 86.
    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: 430–2PubMedCrossRefGoogle Scholar
  87. 87.
    Brown AK, Cevik N. Hemolysis and jaundice in the newborn following maternal treatment with sulfamethoxypyridazine (kynex). Pediatrics 1965; 36: 742–4PubMedGoogle Scholar
  88. 88.
    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: 827–8Google Scholar
  89. 89.
    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: 107–10PubMedCrossRefGoogle Scholar
  90. 90.
    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: 95–9Google Scholar
  91. 91.
    Zinkham W. Peripheral blood and bilirubin values in normal full-term primaquine-sensitive Negro infants: effect of vitamin K. Pediatrics 1963; 31: 983–95PubMedGoogle Scholar
  92. 92.
    Kulwichit W, Torranin P. Glucose-6-phosphate dehydrogenase deficiency, vitamin K, and ambiguity in medical textbooks. Acta Haematol 2004; 111: 173–4PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  • Ilan Youngster
    • 1
    • 2
    Email author
  • Lidia Arcavi
    • 3
  • Renata Schechmaster
    • 4
  • Yulia Akayzen
    • 5
    • 2
  • Hen Popliski
    • 5
    • 2
  • Janna Shimonov
    • 5
    • 2
  • Svetlana Beig
    • 5
    • 2
  • Matitiahu Berkovitch
    • 1
    • 2
  1. 1.Clinical Pharmacology UnitAssaf Harofeh Medical CenterZerifinIsrael
  2. 2.Sackler School of MedicineTel-Aviv UniversityTel-AvivIsrael
  3. 3.Clinical Pharmacology UnitKaplan Medical CenterRehovot
  4. 4.School of Medicinethe Hebrew UniversityJerusalemIsrael
  5. 5.Pharmacy DepartmentAssaf Harofeh Medical CenterZerifin

Personalised recommendations