title: Allopurinol Use and Risk of Fatal Hypersensitivity Reactions: A Nationwide Population-Based Study in Taiwan.
abstract: OBJECTIVE
  Allopurinol, a first-line drug used for treating gout, is increasingly prescribed worldwide to patients with asymptomatic hyperuricemia and comorbid renal or cardiovascular diseases. Nevertheless, allopurinol use has been associated with fatal hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The overall risks of allopurinol use remain unclear.
  
  
  OBJECTIVE
  To investigate the incidence of, risk factors for, and mortality associated with allopurinol hypersensitivity in new users of allopurinol.
  
  
  METHODS
  A retrospective nationwide population study was conducted using data from the Taiwan National Health Insurance Research Database, which includes detailed medical records of more than 23 million insured enrollees. Data were collected from January 1, 2005, through December 31, 2011, using the Anatomical Therapeutic Chemical classification system and International Classification of Diseases, Ninth Revision, Clinical Modification codes. Among 1,613,719 patients receiving allopurinol prescriptions, 495,863 were identified as new users.
  
  
  METHODS
  Allopurinol hypersensitivity was identified within 3 months since the first prescription. The period for measuring related hospitalizations was 1 month since the episode, and the period for measuring renal complications or mortality was 2 months since the episode. Poisson regression test and multivariable logistic regression analysis were performed, and P < .01 was considered statistically significant.
  
  
  RESULTS
  Among the more than 23 million insured enrollees, the annual incidence rates were 4.68 per 1000 new users for allopurinol hypersensitivity, 2.02 per 1000 new users for related hospitalization, and 0.39 per 1000 new users for related mortality. The annual incidence of allopurinol hypersensitivity rose statistically significantly during the study period (P < .001). Risk factors for allopurinol hypersensitivity included female sex, age 60 years or older, initial allopurinol dosage exceeding 100 mg/d, renal or cardiovascular comorbidities, and use for treating asymptomatic hyperuricemia. Patients with asymptomatic hyperuricemia and renal or cardiovascular diseases had statistically significantly increased risk of allopurinol hypersensitivity (odds ratio [OR], 1.61; 95% CI, 1.33-1.94; P < .001 for renal diseases and OR, 1.52; 95% CI, 1.19-1.93; P < .001 for cardiovascular diseases). They also had statistically significantly increased risk of mortality (OR, 5.59; 95% CI, 2.61-11.94; P < .001 for renal diseases and OR, 3.57; 95% CI, 2.31-5.51; P < .001 for cardiovascular diseases).
  
  
  CONCLUSIONS
  The use of allopurinol in patients with asymptomatic hyperuricemia accompanied by renal or cardiovascular diseases statistically significantly increased the risk of hypersensitivity reactions. Physicians should be cautious when prescribing allopurinol to high-risk populations and should consider the potential risks of fatal adverse reactions.
authors.affiliation: Division of Clinical Pharmacy, Department of Pharmacy, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Chien-Yi
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Division of Clinical Pharmacy, Department of Pharmacy, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Chi-Hua
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Division of Clinical Pharmacy, Department of Pharmacy, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Shin-Tarng
authors.initials: ST
authors.lastname: Deng
authors.affiliation: National Health Insurance Administration-Northern Division, Ministry of Health and Welfare, Taipei, Taiwan.
authors.forename: Chi-Shan
authors.initials: CS
authors.lastname: Huang
authors.affiliation: Statistical Center for Clinical Research, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Yu-Jr
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan5Department of Dermatology, Taichung Veterans General Hospital, China Medical University, Taichung, Taiwan.
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan6Division of Gastroenterology, Taichung Veterans General Hospital, China Medical University, Taichung, Taiwan7Department of Life Sciences, National Chung-Hsing Universit.
authors.forename: Chun-Ying
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shuen-Iu
authors.initials: SI
authors.lastname: Hung
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan10College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Chung
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000493:Allopurinol / Q000009:adverse effects*; D002318:Cardiovascular Diseases / Q000150:complications; D002648:Child; D002675:Child, Preschool; D004342:Drug Hypersensitivity / Q000209:etiology* / Q000401:mortality*; D005260:Female; D006074:Gout Suppressants / Q000009:adverse effects*; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D033461:Hyperuricemia / Q000150:complications / Q000188:drug therapy*; D015994:Incidence; D007223:Infant; D007674:Kidney Diseases / Q000150:complications; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D013624:Taiwan / Q000453:epidemiology; D055815:Young Adult
chemical_list: D006074:Gout Suppressants; D000493:Allopurinol