The US Food and Drug Administration's (FDA's) Arthritis Advisory Committee (AAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee voted by a large margin to continue to recommend febuxostat (Uloric, Takeda) for some patients with gout-related hyperuricemia after a discussion of a postmarketing study showing possible  cardiovascular risk.

Treatment and prevention of gout include use of anti-inflammatories during acute attacks and urate-lowering medications to manage hyperuricemia . Medications used to manage hyperuricemia include xanthine oxidase inhibitors (XOIs), which lower uric acid production (allopurinol and febuxostat); uricosuric therapies (probenecid, sulfinpyrazone, and lesinurad), which increase uric acid excretion; and uricase products (pegloticase). Xanthine oxidase inhibitors, uricosuric therapies, and uricase products are first-line, second-line, and third-line treatments, respectively, for gout. 


Allopurinol  is currently the only other XOI approved in the United States for gout. Therapies for gout are in general limited, and there is an unmet need for gout treatments. "I do think there is a need for this drug in a certain patient population that has been intolerant to allopurinol or where the drug has had no effect," voting AAC member Alyce M. Oliver, MD, PhD, professor of medicine, Medical College of Georgia at Augusta University, said of her yes vote.

Postmarketing Safety Study

The FDA approved febuxostat for the treatment of gout on February 13, 2009, after declining to approve it twice for concerns about cardiovascular safety and death. As part of the approval, the FDA required the company to conduct a postmarketing safety study to determine whether febuxostat is linked to a moderately increased risk for serious adverse cardiovascular outcomes compared with allopurinol.

The vote follows consideration of results from the postmarketing study the Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities (CARES) trial published online March 12, 2018, in the New England Journal of Medicine and reported by Medscape Medical News. CARES was a multicenter, double-blind, noninferiority trial that randomly assigned 6190 patients with gout and cardiovascular disease (CVD) to receive febuxostat or allopurinol.

Doses were adjusted on the basis of kidney function. The study's primary composite endpoint was the first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization. Secondary endpoints included the individual components of the major cardiovascular event (MACE) composite as well as any-cause mortality.

Patients were followed for a median of 32 months and a maximum of 85 months. More than half (56.6%) of patients discontinued the treatment regimen, and 45% discontinued follow-up. Time and again during the meeting, the discussion returned to the high number of treatment and follow-up discontinuations, with members disagreeing at times about the importance of, and possible reasons for, these discontinuations.