The US Food and Drug Administration (FDA) has added a boxed warning to the label for gout drug febuxostat (Uloric, Takeda) on the basis of results of a large post marketing safety study.

The FDA has concluded that there is an increased risk for death with febuxostat compared to another gout medicine, allopurinol (multiple brands).

“This conclusion is based on our in-depth review of results from a safety clinical trial that found an increased risk of heart-related death and death from all causes with Uloric,” the FDA said in a safety communication February 21.

The FDA said febuxostat should be reserved for patients for whom allopurinol has failed or who do not tolerate allopurinol. Patients should be counseled about cardiovascular risk with febuxostat and should be advised to seek immediate medical attention if they experience chest pain, shortness of breath, rapid or irregular heartbeat, numbness or weakness on one side of the body, dizziness, trouble talking, or sudden, severe headache.

Gout is a chronic disease that affects roughly 8.3 million adults in the United States. The FDA approved febuxostat for gout in 2009. The number of medicines to treat gout is limited, and there is an unmet need for treatments for this disease, the agency notes.

In mid-January, as reported by Medscape Medical News, the FDA’s Arthritis Advisory Committee and its Drug Safety and Risk Management Advisory Committee voted by a large margin to continue to recommend febuxostat for some patients with gout-related hyperuricemia, despite the postmarketing study.

Since approval in 2009, the prescribing information for febuxostat has included a warning about possible cardiovascular events in patients treated with the drug. The FDA-required postmarketing safety study, known as CARES, included more than 6000 patients with gout who were treated with either febuxostat or allopurinol.

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 composite as well as any-cause mortality.

Overall, febuxostat did not increase the risk for these combined events compared with allopurinol. However, when the outcomes were evaluated separately, febuxostat was found to be associated with an increased risk for heart-related deaths and death from all causes.

Among patients taking febuxostat, 15 deaths from heart-related causes were observed for every 1000 patients treated for 1 year, compared to 11 heart-related deaths per 1000 patients treated with allopurinol for 1 year. In addition, there were 26 deaths from any cause per 1000 patients treated for 1 year with febuxostat, compared to 22 deaths per 1000 patients treated for 1 year with allopurinol.

In the modified intention-to-treat analysis, 335 patients (10.8%) in the febuxostat group and 321 patients (10.4%) in the allopurinol group experienced a primary endpoint event (hazard ratio [HR], 1.03; upper limit of the one-sided 98.5% confidence interval [CI], 1.23; P = .002 for noninferiority).

For those in the febuxostat group, rates of all-cause mortality and cardiovascular mortality were higher compared with those in the allopurinol group (HR for death from any cause, 1.22; 95% CI, 1.01 – 1.47; HR for cardiovascular death, 1.34; 95% CI, 1.03 – 1.73).

As a result, the FDA will update the febuxostat prescribing information with a boxed warning noting the increased risk and limit the approved use of the drug to certain patients for whom treatment with allopurinol is not effective or who experience severe side effects with allopurinol.

Healthcare professionals are encouraged to report adverse events or side effects related to the use of febuxostat to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.