Sex-stratified disproportionality signals of adverse events with allopurinol and febuxostat: a retrospective pharmacovigilance analysis of FAERS and EudraVigilance.

BACKGROUND

Xanthine oxidase inhibitors (XOIs), including allopurinol, febuxostat, and topiroxostat, are widely used for the treatment of hyperuricemia and gout. While their efficacy is well established, sex-associated differences in adverse event (AE) profiles remain poorly understood, despite evidence suggesting that sex may influence drug safety and response.

AIM: This study aimed to systematically evaluate sex-associated differences in AE safety signals for XOIs using large-scale pharmacovigilance data from two international databases.

METHODS

AE reports of XOIs from the FDA Adverse Event Reporting System (FAERS) were extracted from the first quarter of 2004 to the fourth quarter of 2024. Reporting odds ratios (RORs) were calculated separately within female and male reports to assess drug event disproportionality for each sex. Selected findings from the FAERS analysis were further examined in EudraVigilance (EV) for directional consistency.

RESULTS

Analysis indicated notable sex-associated safety signals. In female reports, allopurinol showed strong disproportionality signals for haematological irregularities such as pancytopenia (ROR = 6.87, 95% CI: 6.09-7.75, cases = 271). In male reports, febuxostat showed strong disproportionality signals for rhabdomyolysis (ROR = 4.55, 95% CI: 3.64-5.68, cases = 79). Several of these sex-associated signals showed directionally consistent patterns in EV. For topiroxostat, only raw descriptive counts are provided in the supplementary material.

CONCLUSION

Notable sex associated safety signals for allopurinol and febuxostat showed directionally consistent patterns across two databases but should be interpreted as hypothesis generating. Allopurinol showed disproportionality signals for haematological irregularities in female reports, while febuxostat showed signals for rhabdomyolysis in male reports. Topiroxostat data were insufficient for analysis. The findings identify exploratory reporting patterns that require confirmation in studies with exposure denominators and adjustment for confounding.