Febuxostat (Uloric), a xanthine oxidase inhibitor that decreases serum uric acid levels, was approved to treat gout in 2009. In a postmarketing trial examining cardiovascular risk, patients with preexisting cardiovascular disease who were treated with febuxostat had a higher rate of cardiovascular death than those treated with the traditional gout medication allopurinol. The Food and Drug Administration (FDA) has upgraded the warning related to cardiovascular concerns in febuxostat's labeling to a black box warning, which now states that febuxostat should be limited to those who are nonresponsive or intolerant to allopurinol or not advised to take the drug.

The multicenter, randomized, double-blind cardiovascular outcomes trial, Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES), studied over 6,000 patients with gout who were given either febuxostat or allopurinol. Although there was no difference between the drugs in the primary outcome-a combination of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and unstable angina-separate analysis of each component found an increase in cardiovascular death in those receiving febuxostat, as well as in the secondary outcome of death from any cause.

Outcomes data from the CARES trial were discussed at the January 11 joint meeting of the FDA's Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee. The joint committee could not determine the biological cause of the increased cardiovascular mortality in patients treated with febuxostat, hypothesizing that it could be from platelet aggregation, the quick drop in serum urate levels, or some other mechanism. Despite failure to identify the root cause, the members agreed that this increased risk of cardiovascular death was associated with febuxostat. There was some discussion as to whether a Risk Evaluation and Mitigation Strategy should be instituted for febuxostat or if the drug should be withdrawn from the market. However, the committee members recognized that patients who were nonresponsive to allopurinol benefited from febuxostat and would be negatively affected if the drug was withdrawn. The committee's final decision (19 to two, with one abstaining) was to add the black box warning related to cardiovascular death to febuxostat's labeling, and to limit use of the drug to second-line therapy when allopurinol therapy is unsuccessful. (To read the minutes from the joint meeting, go to http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs.)

NPs should prescribe febuxostat only after allopurinol has failed to control gout or if the patient cannot tolerate allopurinol. The risks and benefits of febuxostat should be considered prior to prescribing it. Nurses and NPs should review with patients the signs and symptoms of cardiovascular adverse events (chest pain, shortness of breath, rapid or irregular heartbeat, numbness or weakness on one side of the body, dizziness, trouble talking, or a sudden severe headache) and tell them to seek immediate medical attention if any of these develop. Nurses should also tell patients to read the full medication guide that comes with each prescription for the most current information about adverse effects. For complete prescribing information for febuxostat, go to http://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021856s013lbl.pdf.