Allopurinol Use and Risk of Fatal Hypersensitivity Reactions: A Nationwide Population-Based Study in Taiwan

Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  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.

Allopurinol was approved by the US Food and Drug Administration in 1966 for treating gout and remains a cornerstone of the treatment of uric acid nephrolithiasis and hyperuricemia caused by cancer or chemotherapy.^1,2 Although it is generally well tolerated, allopurinol is one of the most common drugs associated with life-threatening hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms.^3-8 Stevens-Johnson syndrome and toxic epidermal necrolysis are variants of the same mucocutaneous blistering reaction disease and carry high morbidity and mortality.³ Drug rash with eosinophilia and systemic symptoms is a nonblistering cutaneous adverse reaction with systemic manifestations, including eosinophilia, leukocytosis, fever, hepatitis, and renal dysfunction.^8,9 In previous studies,^3,4,7 allopurinol hypersensitivity was found in 1 of 260 patients (approximately 0.4% of new users of allopurinol) and was a leading cause of severe cutaneous adverse reactions in several countries. Allopurinol hypersensitivity–related mortality was reported to be as high as 18% to 32%, and its long-term complications (eg, renal failure and eye sequelae) are frequently observed in survivors.^3,7,10,11

Although controversial, the use of allopurinol in patients with asymptomatic hyperuricemia has been increasing worldwide in recent years.^12-16 Prescriptions of allopurinol to patients having asymptomatic hyperuricemia with cardiovascular, renal, or metabolic diseases may be based on the assumption that high levels of serum uric acid contribute to the prognosis of these disorders.^12-16 However, the overall risks of allopurinol use in asymptomatic hyperuricemia remain unclear. We conducted a retrospective nationwide population-based study using the Taiwan National Health Insurance Research Database to analyze the incidence of, risk factors for, and mortality associated with allopurinol hypersensitivity in new users of allopurinol over a 7-year period.

Secondary data were collected from the Taiwan National Health Insurance Research Database from January 1, 2005, through December 31, 2011. The database is composed of detailed medical records of more than 23 million insured enrollees, representing more than 99% of the population of Taiwan, of which 98% are Han Chinese. The database includes enrollees’ demographic data, medical service providers and records, and expenditure claims for inpatients, ambulatory care, and contracted pharmacies. The diagnosis codes are from the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Data on all medications were collected using the Anatomical Therapeutic Chemical classification system codes of the World Health Organization. The accuracy of the diagnosis codes of diseases and data retrieved from the database have been validated and published.^17-19 The protocol for this study was approved by the Institutional Review Board of Chang Gung Memorial Hospital. We retrieved the data of patients receiving allopurinol prescriptions (Anatomical Therapeutic Chemical code M04AA01), defined new users as individuals who had not received the drug in the past 3 years, and collected the claims data, including medical orders, basic data files, and drug master files. If an individual appeared as a new user more than once during the study period, we used the information collected at the first instance.

The ICD-9-CM diagnosis codes of hypersensitivity reactions included dermatitis due to drugs and medicines (code 693.0); erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis (code 695.1); unspecified erythematous conditions (code 695.9); and other specified erythematous conditions (code 695.89). Because the symptoms and onset of allopurinol-induced or other drug-induced hypersensitivity reactions usually developed within the first 3 months after drug exposure,^20,21 we identified patients with allopurinol hypersensitivity if the new users had diagnosis codes (ICD-9-CM codes 693.0, 695.1, 695.9, and 695.89) within 3 months after receiving the first allopurinol prescription and no further use of the drug listed in the data set after the episode. Comedications were excluded as the cause if the drugs had been used for longer than 3 months or continued to be used after the hypersensitivity reaction. Allopurinol hypersensitivity–related hospitalization was defined as the patient being hospitalized within 1 month of the episode. Based on the survival analysis data of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis,^22,23 we defined allopurinol hypersensitivity–related mortality as the patient being deceased within 2 months after the episode. For allopurinol hypersensitivity–related renal complications, we excluded patients who had chronic renal diseases before the episode and included patients who experienced renal insufficiency (ICD-9-CM codes 580-586) within 2 months after the episode. To limit coding errors in the administrative data, the medical information of the patients with allopurinol hypersensitivity was reviewed by 2 dermatologists (W.-H.C. and another physician).

To ascertain the national database information, we retrieved the data on allopurinol hypersensitivity from the electronic medical records of the Chang Gung Memorial Hospital Health System, which is the largest health care system in Taiwan, covering approximately one-tenth of the health services nationwide. We collected clinical information, including photographs, pathology results (if available), and laboratory data, from January 1, 2009, through December 31, 2011. Two experienced dermatologists (W.-H.C. and another physician) reviewed the detailed clinical information of the patients from the Chang Gung Memorial Hospital Health System and compared the data set with that retrieved from the national database using a consensus definition of hypersensitivity reactions.^24-26

We examined several variables, including sex, age, initial allopurinol dosage (low if ≤100 mg/d or high if >100 mg/d), comedications, comorbidities, and use of allopurinol for gout prevention or the treatment of asymptomatic hyperuricemia. Comedications for analysis included antibiotics, anticonvulsants, thiazide diuretics, and angiotensin-converting enzyme inhibitors.^27,28 Comorbidities consisted of the following ICD-9-CM codes: (1) chronic renal diseases, which range from renal dysfunction to renal failure (codes 580-586) and unspecified small kidney disease (code 589); (2) diabetes mellitus (code 250); (3) cardiovascular diseases, which include ischemic heart disease (codes 410-414) and heart failure (code 428); and (4) cancer (codes 140-208 and 230-234). If a new user had been diagnosed as having any of these comorbid diseases within 3 years before the diagnosis of allopurinol hypersensitivity, the comorbidities were considered. Asymptomatic hyperuricemia was identified in patients with allopurinol prescriptions but without the diagnosis code for gout (ICD-9-CM code 274).

Statistical software was used for the analyses (SPSS, version 20; SPSS Inc and SAS, version 9.2; SAS Institute Inc). Descriptive statistics included the incidence analysis and basic characteristics of participants, given as a percentage or number per 1000 new users. Poisson regression test and multivariable logistic regression analysis were used to investigate the trends and associations among various risk factors, incidences, and odds ratios (ORs). The 95% CIs and P values were reported. P < .01 was considered statistically significant.

Based on the information retrieved from the national database, we identified 1 613 719 patients receiving 9 721 780 allopurinol prescriptions between 2005 and 2011 (Table 1). Among those, 495 863 were new users. The proportion of allopurinol new users with asymptomatic hyperuricemia increased from 36.7% in 2005 to 49.5% in 2011. The annual incidence of allopurinol hypersensitivity increased from 3.71 per 1000 new users in 2005 to 6.12 per 1000 new users in 2011 and showed an overall incidence of 4.68 per 1000 new users. The increased annual incidence of allopurinol hypersensitivity was statistically significant (P < .001, Poisson regression test) (Figure). The annual incidence of allopurinol hypersensitivity–related hospitalizations also statistically significantly rose from 1.63 per 1000 new users in 2005 to 2.35 per 1000 new users in 2011 (P = .001, Poisson regression test), with an overall incidence of 2.02 per 1000 new users (Table 1). The annual incidence of allopurinol hypersensitivity–related mortality increased from 0.36 per 1000 new users in 2005 to 0.39 per 1000 new users in 2011, accounting for 8.3% (193 of 2322 patients) of the total mortality among the patients during the 7-year period. In total, 2.8% (64 of 2322 patients) developed renal complications or injuries after the episode of allopurinol hypersensitivity. The ICD-9-CM diagnosis code 695.1 (erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis) was found in 28.3% of patients with allopurinol hypersensitivity, in 51.1% of hospitalized patients, and in 66.8% of deceased patients.

The national database reported 8817 new users and 33 cases of allopurinol hypersensitivity from the Chang Gung Memorial Hospital Health System between 2009 and 2011. The incidence was 3.74 per 1000 new users (33 of 8817 patients) in the medical records compared with 4.68 per 1000 new users (2322 of 495 863 patients) in the national database. All medical records of the 33 patients were reviewed by experienced dermatologists, and the diagnosis of allopurinol hypersensitivity was confirmed. Two of the 33 patients died of Stevens-Johnson syndrome and toxic epidermal necrolysis, and one patient died of drug rash with eosinophilia and systemic symptoms. The mortality rate was 9.1% (3 of 33 patients) in the medical records sample compared with 8.3% (193 of 2322 patients) in the national database.

Table 2 lists the numbers of new users and patients with allopurinol hypersensitivity and related hospitalizations and mortality. The incidences of allopurinol hypersensitivity and its related hospitalizations and mortality increased in individuals with the following characteristics: female sex, age 60 years or older, initial allopurinol dosage exceeding 100 mg/d, use of the drug to treat asymptomatic hyperuricemia, and comorbidities of chronic renal diseases, cardiovascular diseases, diabetes mellitus, or cancer. The use of allopurinol for asymptomatic hyperuricemia without gout indication accounted for 42.5% (210 817 of 495 863 patients) of new users. The incidences of allopurinol hypersensitivity and related hospitalizations and mortality were higher in patients receiving the drug to treat asymptomatic hyperuricemia accompanied by renal or cardiovascular diseases. The results of the multivariable logistic regression analysis of risk factors for allopurinol hypersensitivity and mortality are summarized in Table 3.

Females were at higher risk for allopurinol hypersensitivity (OR, 1.45; 95% CI, 1.35-1.56; P < .001) and related mortality (OR, 1.63; 95% CI, 1.28-2.08; P < .001) (Table 3). The incidence of allopurinol hypersensitivity increased statistically significantly in new users 60 years or older, particularly those 80 years or older (OR, 2.27; 95% CI, 1.97-2.60; P < .001). The risk of allopurinol hypersensitivity–related mortality was 12-fold higher in patients older than 80 years (OR, 12.37; 95% CI, 6.24-24.53; P < .001) compared with those 0 to 39 years old (Table 3). In addition, a high initial allopurinol dosage (>100 mg/d) increased the risk of allopurinol hypersensitivity (OR, 1.27; 95% CI, 1.18-1.37; P < .001) but not mortality (OR, 1.07; 95% CI, 0.83-1.38; P = .61). The use of comedications such as antibiotics, antiepileptic drugs, thiazide diuretics, and angiotensin-converting enzyme inhibitors was not associated with allopurinol hypersensitivity or mortality.

Multivariable logistic regression analysis showed that comorbid chronic renal diseases statistically significantly increased the risk of allopurinol hypersensitivity (OR, 1.49; 95% CI, 1.38-1.61; P < .001) and mortality (OR, 2.20; 95% CI, 1.69-2.87; P < .001) (Table 3). Comorbid cardiovascular diseases also increased the risk of allopurinol hypersensitivity (OR, 1.13; 95% CI, 1.04-1.22; P = .003) and mortality (OR, 1.79; 95% CI, 1.39-2.30; P < .001). However, neither diabetes mellitus nor cancer was associated with allopurinol hypersensitivity or mortality.

The use of allopurinol in asymptomatic hyperuricemia was statistically significantly associated with allopurinol hypersensitivity (OR, 2.08; 95% CI, 1.94-2.24; P < .001) and mortality (OR, 2.32; 95% CI, 1.79-3.01; P < .001) (Table 3). The subgroup analysis further demonstrated that the use of allopurinol in asymptomatic hyperuricemia accompanied by chronic renal diseases statistically significantly increased the risk of allopurinol hypersensitivity (OR, 1.61; 95% CI, 1.33-1.94; P < .001) and mortality (OR, 5.59; 95% CI, 2.61-11.94; P < .001) (Table 4). In addition, the use of allopurinol in asymptomatic hyperuricemia accompanied by cardiovascular diseases was statistically significantly associated with allopurinol hypersensitivity (OR, 1.52; 95% CI, 1.19-1.93; P < .001) and mortality (OR, 3.57; 95% CI, 2.31-5.51; P < .001). By comparison, asymptomatic hyperuricemia without comorbid renal or cardiovascular diseases showed no statistically significant association with allopurinol hypersensitivity or its mortality.

Allopurinol is generally well tolerated, but it can cause fatal adverse reactions in rare cases. In this study, we retrieved data from the Taiwan National Health Insurance Research Database and report that 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 HLA-B*58:01 is a genetic marker of allopurinol hypersensitivity, but it has a low positive predictive value, suggesting that other factors contribute to the reactions.^20,29-31 In the present study, we identified nongenetic risk factors for allopurinol hypersensitivity, including female sex, age 60 years or older, initial allopurinol dosage exceeding 100 mg/d, and renal or cardiovascular comorbidities. Because allopurinol is on the World Health Organization’s list of essential medicines and is still the main drug for treating hyperuricemia and gout, the data from this study suggest that physicians should be cautious when prescribing allopurinol to high-risk populations and should consider the potential risks of fatal hypersensitivity reactions.

Regarding the potential implications of our findings in other populations, allopurinol is a common drug that is associated with severe cutaneous adverse reactions in different ethnic groups, including Asians and Europeans.^{3-5,8,11,27,29-31} Epidemiological data, including the incidence and mortality of allopurinol hypersensitivity reported herein, are consistent with previous studies.^{3-5,7,10-12,32,33} Allopurinol hypersensitivity typically occurs in older patients with renal impairment in whom the dosage has not been appropriately reduced.^12,34,35 It has been suggested that the initial allopurinol dosage should be adjusted based on patients’ serum creatinine levels.^34,35 Guidelines published by the American College of Rheumatology and the Clinical Pharmacogenomics Implementation Consortium recommend that initiating allopurinol treatment at a lower dosage may decrease the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis.^36-38 In this study, we found that a high initial dosage (>100 mg/d) was associated with allopurinol hypersensitivity (OR, 1.27; 95% CI, 1.18-1.37; P < .001) but not mortality. By comparison, chronic renal diseases were strongly associated with allopurinol hypersensitivity (OR, 1.49; 95% CI, 1.38-1.61; P < .001) and mortality (OR, 2.20; 95% CI, 1.69-2.87; P < .001), suggesting that effective excretion of oxypurinol, an allopurinol metabolite, is important for preventing hypersensitivity reactions. Our group’s recent study²¹ on plasma levels of oxypurinol in patients with allopurinol hypersensitivity also noted that impaired renal function is associated with sustained high levels of plasma oxypurinol and correlates with a poor prognosis. Taken together, these data support that chronic renal disease is one of the most important factors contributing to allopurinol hypersensitivity.

Allopurinol has been increasingly used worldwide in patients with asymptomatic hyperuricemia in recent years.^12-16 However, studies^7,39 from Asia and Europe observed that a high proportion of patients with allopurinol hypersensitivity had received the drug without a clear indication of gout and that the prescriptions were unnecessary based on current guidelines. In this study, we found that the proportion of patients receiving allopurinol for treating asymptomatic hyperuricemia and the annual incidence of allopurinol hypersensitivity were statistically significantly increased in recent years. The increasing use of allopurinol in patients with cardiovascular diseases may be explained by attempts to control rising serum uric acid levels in patients with heart failure.^12-14 In addition, allopurinol has been reported to decrease serum uric acid and C-reactive protein levels, slow the progression of renal disease, and reduce the risk of cardiovascular events.¹⁵ However, a systematic review found that studies related to the safety and efficacy of allopurinol use in chronic renal diseases showed inconsistent results.¹⁶ Carnovale et al³⁹ further reinforced a need for caution related to increased use of allopurinol in patients with asymptomatic hyperuricemia and its consequences of potential hypersensitivity reactions. The present study further notes that the use of allopurinol in patients with asymptomatic hyperuricemia and renal or cardiovascular diseases statistically significantly increased the risk of allopurinol hypersensitivity and mortality.

There are limitations to this study. The national database contained diagnosis codes but did not provide detailed medical information such as the severity and phenotypes of allopurinol hypersensitivity. Moreover, the results relied exclusively on the claims data, and misclassification of diseases may occur in a registry-based data set. We could not ascertain whether the patients had continued exposure to allopurinol beyond the index prescription. In addition, data in the present study were not confirmed using a secondary database, nor were they validated in different ethnic populations. To examine the accuracy of the data, we retrieved the medical records of patients with allopurinol hypersensitivity from the largest medical center in Taiwan and confirmed the consistency of the results between the nationwide data set and the hospital system–based medical records. Furthermore, the epidemiological data reported in this study were correlated with those in the literature.^{3-5,7,10-12,32,33}

Potential strategies may be considered to reduce the incidence of allopurinol hypersensitivity. These include (1) HLA-B*58:01 genetic testing before prescribing allopurinol to individuals among populations with a high prevalence of the risk allele and (2) the use of alternative drugs in high-risk populations. The American College of Rheumatology and the Clinical Pharmacogenomics Implementation Consortium released guidelines on gout and recommended HLA-B*58:01 genetic testing for patients of Asian ethnicity to clarify their risk of allopurinol hypersensitivty.^36-38 In 2010, the Taiwan Food and Drug Administration relabeled the drug information for allopurinol to note the association between HLA-B*5801 and the risk of hypersensitivity. Many medical centers started to provide HLA-B*58:01 genetic testing in 2011. However, the cost of this test is not covered by the national health insurance, and the testing was unavailable in many regional hospitals and private clinics until recently. In this study, our data were collected between 2005 and 2011, so the incidence of allopurinol hypersensitivity was unaffected by the use of genetic testing. As an alternative to allopurinol in high-risk populations, febuxostat may be considered, which was approved in 2009 by the US Food and Drug Administration for the treatment of gout. The Scottish Medicines Consortium approved febuxostat as a cost-effective second-line option for urate-lowering therapy to treat patients with chronic hyperuricemia when treatment with allopurinol is inadequate, not tolerated, or contraindicated.⁴⁰ The Taiwan Food and Drug Administration has recently changed its policy for physicians regarding the prescription of febuxostat as an alternative first-line antihyperuricemic agent for patients with comorbid chronic renal failure. Further studies are needed to determine the overall clinical benefits and pharmacoeconomic outcomes of genetic testing and the use of alternative drugs to treat hyperuricemia and gout.

Allopurinol, a conventional first-line drug used for the treatment of hyperuricemia and gout, is generally well tolerated. However, its use has been associated with fatal hypersensitivity reactions in rare cases. In this nationwide population-based study of Taiwanese adults, we found 4.68 annual allopurinol hypersensitivity reactions per 1000 new users, with 2.02 related hospitalizations and a 0.39 incidence of related death per 1000 new users. Female sex, high initial dosage, age 60 years or older, and chronic renal or cardiovascular comorbidities were associated with increased risk, particularly among patients with asymptomatic hyperuricemia and renal or cardiovascular diseases, for whom the benefits of treatment are less clear. Physicians should be cautious when prescribing allopurinol to patients with advanced age, cardiovascular disease, or impaired renal function and should consider the risks of rare fatal adverse reactions compared with the drug’s potential benefits.

Accepted for Publication: May 4, 2015.

Corresponding Authors: Shuen-Iu Hung, PhD, Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, 155 Linong St, Section 2, Taipei, Taiwan 11221 (sihung@ym.edu.tw) and Wen-Hung Chung, MD, PhD, Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, 5 Fusing St, Taoyuan, Taiwan 33305 (chung1@cgmh.org.tw).

Published Online: July 20, 2015. doi:10.1001/jamainternmed.2015.3536.

Author Contributions: Drs Hung and Chung had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Hung, Chung.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Yang, Hung, Chung.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Yang, Lin, Y.-J. Chen, Wu.

Obtained funding: Hung, Chung.

Administrative, technical, or material support: All authors.

Study supervision: Hung, Chung.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported by grants NSC101-2321-B-182-008, NSC101-2628-B-182-001-MY3, NSC98-2314-B-182A-027-MY3, NSC101-2320-B-010-072-MY3, NSC101-2321-B-010-027, and NSC102-2314-B-010-014-MY3 from the National Science Council of Taiwan and by grants CMRPG-290051-3, OMRPG2C0011, and OMRPG2C0021 from the Chang-Gung Memorial Hospital.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Disclaimer: This study was based in part on National Health Insurance Research Database data provided by the Administration of National Health Insurance, Ministry of Health and Welfare, Taiwan. The interpretation and conclusions contained herein do not represent positions of the Administration of National Health Insurance.

Additional Contributions: We thank the National Health Insurance Administration, Ministry of Health and Welfare, Taiwan for its support.