Safety profiles of two XOD and two URAT1 inhibitors in hyperuricemic patients: a real-world pharmacovigilance analysis based on the FAERS and JADER databases.

Hyperuricemia is a major risk factor of gout and other metabolic diseases. Allopurinol, febuxostat, dotinurad, and benzbromarone are commonly used clinically as uric acid-lowering drugs. Real-world pharmacovigilance studies of four drug-related adverse drug reactions (ADRs) were conducted in the Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Database of Adverse Reactions (JADER) to provide a reference for the safe clinical use of drugs. Adverse reaction data (Q1 2004 through Q3 2024) for data pertaining to the four drugs were retrieved from the FAERS and JADER databases. Four disproportionality analysis algorithms, including proportional reporting ratio (PRR), reporting ratio of ratios (ROR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM) methods, were used to analyze the signals of ADRs. A total of 14,125 ADR reports were included. Patients aged ≥ 65 years constituted the largest age group, and the proportion of reports was higher in males than in females. At the system organ class (SOC) level, positive signals for hepatobiliary disorders and renal and urinary disorders were detected for all four drugs. The predominant ADRs associated with allopurinol were drug reaction with eosinophilia and systemic symptoms and acute kidney injury, whereas those associated with febuxostat were primarily rash and nausea. Abnormal liver function and acute kidney injury were the main ADRs reported for benzbromarone and dotinurad. Several unexpected signals not previously documented in the literature were also identified, including allopurinol-associated sepsis, multiple organ dysfunction syndrome, and tubulointerstitial nephritis. Most ADRs associated with the four drugs occurred during the early stage of treatment, particularly within the first 30 days, although some were reported more than 1 year after treatment initiation. External validation using the JADER database showed that disproportionality analyses of allopurinol and febuxostat supported the findings obtained from the FAERS database. Sensitivity analyses further confirmed the robustness of the main results. This study compares ADR signaling differences between two XOD and two URAT1 inhibitors as well as high-risk signals, providing evidence for clinical monitoring of drug safety. However, large-scale prospective studies are still needed for future validation.