Risk of cutaneous adverse reactions associated with allopurinol or febuxostat in real‐world patients: A nationwide study

Abstract

Summary Aims Allopurinol carries a well‐known risk of cutaneous adverse reactions (CARs). Although febuxostat, a xanthine‐oxidase inhibitor with different chemical structure, has been considered an alternative to allopurinol, post‐marketing case reports of life‐threatening febuxostat‐related CARs have been reported. We aimed to compare the risk of CARs between allopurinol and febuxostat in real‐world settings and to assess the impact of the market entry of febuxostat on allopurinol use and associated CARs. Methods A nationwide study was conducted using Taiwan's National Health Insurance Research Database. In the new‐user cohort study, patients who received their first prescriptions of allopurinol or febuxostat were included, and Poisson regression was used to estimate the incidence rate ratios (IRRs) of CARs. In the interrupted time series analysis, time series data on new users and incidence rate of CARs were divided into three periods based on the reimbursement scheme of febuxostat in Taiwan, and segmented regression models were used to estimate changes in both the level and trend in each period. Results We identified 526 cases of CARs with 487 among new users of allopurinol and 39 among new users of febuxostat (incidence rate: 15.37 vs 3.48 per 1000 person‐years). Allopurinol was associated with higher risk of CARs (adjusted IRR 5.55, 95% CI [3.97‐7.76]), mild CARs (1.86, [1.24‐2.81]), severe CARs (16.75, [8.87‐31.62]) and fatal CARs (16.18, [5.05‐51.83]) than febuxostat. The overall incidence rates of xanthine‐oxidase inhibitor‐related CARs decreased from 15.28 to 14.28 per 1000 person‐years after the initial reimbursement of febuxostat and further decreased to 9.46 after the reimbursement coverage of febuxostat expanded; however, the changes were not statistically significant. Conclusion Febuxostat can be considered an alternative for patients carrying risk factors for allopurinol‐related CARs. However, since there were fatal cases of febuxostat‐related CARs, the closely monitoring of symptoms of CARs during the initiation of febuxostat is still warranted.

Hypersensitivity reactions with allopurinol and febuxostat: a study using the Medicare claims data

“…In a Taiwanese population-based cohort, cutaneous adverse reaction incidence rates were higher in allopurinol versus febuxostat, 15.37 vs 3.48 per 1000 person-years 9. Although our HSR rates in allopurinol exposed were similar to those in the Taiwanese study at 24/1000 person-years, rates in febuxostat-exposed patients were much higher at 31/1000 person-years in our study.…”

“…Similar studies have not been conducted in populations from the USA or the European countries. Comparative studies of allopurinol versus febuxostat are limited to some ethnicities only 9…”

Risk factors for cutaneous reactions to allopurinol in Kinh Vietnamese: results from a case-control study

“…MCARs feature sparse maco-papular rash and no other organ involvement and quick resolution after drug discontinuation. In contrast, severe CARs (SCARs), characterized by widespread skin lesions, fever, organ involvement, and a mortality rate of 10 to 32% [3,10,11], are rare, although their frequency seems increased in Asians and some other non-Caucasian ethnicities [3,9,12,13]. Allopurinol-induced SCARs include Stevens-Johnson syndrome/toxic epidermal necrosis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis.…”

“…Previous studies found that the incidence of SCARs due to allopurinol was higher in Asian than Caucasian populations. The incidence was estimated at 0.16% per year in Thailand [16], and for patients with chronic renal insufficiency (CRI), 2% and 2.3% per year in Korea [17] and Taiwan [9], respectively. More recently, the incidence of SCARs between 2008 and 2015 in Taiwan has been estimated at 0.10% per year; older estimations based on 2001-2004 data were close to 0.30% per year [18].…”

“…Mild CARs (MCARs) are the most common. Their incidence has been estimated at 2 to 4% in Caucasian allopurinol initiators [ 7 , 8 ] and more than 15% in Taiwanese [ 9 ]. MCARs feature sparse maco-papular rash and no other organ involvement and quick resolution after drug discontinuation.…”