Febuxostat Utilization Declines Following Label Change, Despite Favorable Benefit-Risk Profile

An overall decrease in the number of patients taking febuxostat was noted throughout the entire study period.

The number of new users of febuxostat (allopurinol-naïve) and prevalent new users (prior allopurinol use) decreased following a recent US Food and Drug Administration (FDA) warning for increased cardiovascular mortality risk with febuxostat vs allopurinol, according to study findings published in Rheumatology and Therapy.

A drug safety communication (DSC) was issued by the FDA in November 2017 citing increased risk for heart-related mortality with febuxostat compared with allopurinol, according to preliminary results of the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial (ClinicalTrials.gov Identifier: NCT01101035).

The FDA approved a revised indication for febuxostat, adding a boxed warning concerning cardiovascular mortality. The FDA maintained that the febuxostat benefit-risk profile remains favorable for treatment of hyperuricemia among certain patients with gout, based on available data.

Investigators aimed to assessed the impact of this label change on the use of febuxostat among patients with gout.

The results of this study do not change the benefit–risk profile of febuxostat.

A cross-sectional study was conducted to identify patients with gout who initiated febuxostat from June 2016 through June 2020.

Data were sourced from 2 administrative claims databases, IQVIA PharMetrics Plus and the Optum Research Database (ORD), and assessed according to 3 time periods: (1) the baseline period (18 months prior to the FDA’s DSC), (2) the intermediate period (DSC to the change in prescribing information), and (3) the post-labeling change period.

A total of 13,848 patients (43% new users; 57% prevalent new users) from the PharMetrics cohort and 10,198 (41% new users; 59% prevalent new users) from the ORD cohort were included in the study.

An overall decrease in the number of patients taking febuxostat was noted throughout the entire study period.

The proportion of new users of febuxostat decreased in the PharMetrics cohort from the baseline period (46.7%), to the intermediate period (39.5%), to the post-labeling change period (36.1%).

The proportion of new users decreased over time in the ORD cohort as well (baseline, 44.3%; intermediate, 35.8%; post-labeling change, 39.7%).  

During the 12 months prior to initiation of febuxostat, the most commonly reported cardiovascular disease morbidities among the PharMetrics cohort vs the ORD cohort included diabetes mellitus (28% vs 47%), ischemic heart disease (17% vs 33%), and heart failure/cardiomyopathy (13% vs 28%), respectively.

A higher proportion of new users with pre-existing heart failure/cardiomyopathy was noted in the post-labeling change period vs the baseline period (PharMetrics, 14.2% vs 10.4%; ORD, 32.9% vs 26.0%).

This study was limited by its cross-sectional design, which cannot be used to infer causality. Additional limitations included unaccounted-for changes in allopurinol utilization, confounding variables, differences in duration of the study periods, and lack of data on the impact of the COVID-19 pandemic on the post-labeling change period.

“The results of this study do not change the benefit–risk profile of febuxostat,” the study authors noted.

Disclosure: This research was supported by Takeda Pharmaceuticals Company Limited. One or more study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Sosinsky AZ, Song Y, Gunawardhana L, Phillips S, Page M. The impact of label changes (boxed warning) on real-world febuxostat utilization in patients with gout: a cross-sectional drug utilization study. Rheumatol Ther. Published online July 17, 2023. doi:10.1007/s40744-023-00581-x