In February 2019, the U.S. Food and Drug Administration (FDA) has issued a warning regarding febuxostat, which has increased the risk of death from cardiovascular complications and death from any cause. This drug, known under the brand name Uloric, is widely used in long-term therapy for gout in the task of preventing its acute attacks.
The regulator insists that physicians should only prescribe febuxostat to patients who do not respond to allopurinol at the maximum appropriate dose, cannot tolerate it, or for whom allopurinol is contraindicated (for example, in severe renal failure). In addition, it is imperative to inform patients of the risk of cardiovascular complications when prescribing febuxostat.
The FDA advises patients to monitor for signs and symptoms of cardiovascular complications and to seek immediate medical attention for symptoms such as chest pain, shortness of breath, rapid or irregular heartbeat, numbness or weakness on one side of the body, dizziness, speech problems, and sudden severe headache.
A safety analysis of febuxostat from the CARES (NCT01101035) phase 3b postmarketing clinical trial (randomized, double-blind, active comparison group, multicenter) conducted by Takeda Pharmaceutical among patients (n=6190) aged 50 years and older, suffering from chronic gout, found that prescribing febuxostat was associated with an increased risk of mortality compared to allopurinol, another popular antigout drug known under the brand names Aloprim and Zyloprim.
Thus, after a median of 32 months of follow-up (maximum 85 months), febuxostat or allopurinol was found to have similar rates of serious adverse cardiovascular events (MACE), defined as the combined events of cardiovascular death, nonfatal myocardial infarction, non-fatal stroke, and unstable angina with emergency coronary revascularization. Such events were experienced by 10.8% and 10.4% of patients, respectively (hazard ratio [HR] 1.03 [97% CI: 0.87–1.23]; p=0.66).
Meanwhile, antigout therapy with febuxostat marked a statistically significant increase in the risk of death due to cardiovascular complications or any cause compared with allopurinol treatment, by 34% and 22%, respectively: HR 1.34 ([95% CI: 1.03–1.73]; p=0.03) and HR 1.22 ([95% CI: 1.01–1.47]; p=0.04).
This is true for gout patients with a history of serious cardiovascular or cerebrovascular disease, such as myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack followed by hospitalization, peripheral vascular disease, diabetes with signs of micro- or macrovascular complications.
The prescribing information for febuxostat received a corresponding boxed warning, indicating the seriousness of the risks.
Meanwhile, Public Citizen, a nonprofit organization that protects the rights of American consumers, prepared a petition calling for an immediate ban on sales of febuxostat. The drug, developed by Takeda and Abbott Laboratories, was twice rejected by the regulator (in 2005 and 2006) precisely because of safety profile claims before it was still approved in 2009. Allegedly, the seriousness of the risks outweighed any benefits of febuxostat, with no evidence that febuxostat does a better job than allopurinol at preventing acute gout attacks or other clinically important complications. Between 2012 and 2017, Takeda earned $1.9 billion from sales of febuxostat in the United States.
Gout is a form of chronic inflammatory arthritis characterized by recurrent attacks of severe pain and swelling in the joints and elbows. It is caused by deposits of uric acid crystals due to dietary habits, genetic predisposition or insufficient urate excretion.
Febuxostat is a strong, selective, non-purine xanthine oxidase (XO) inhibitor that works by non-competitive blocking of the molybdenum-pterine center, the active site of XO. Xanthine oxidase is an enzyme that catalyzes two steps of purine metabolism: oxidation of hypoxanthine to xanthine and then oxidation of xanthine to uric acid. Suppression of xanthine oxidase decreases serum uric acid concentration.
When comparing the effectiveness of febuxostat with allopurinol, a purine xanthine oxidase inhibitor, the former is more effective (stronger and faster) than the latter in reducing serum uric acid concentration, but this effectiveness appears to be similar when the allopurinol dose is increased. There is an opinion that suboptimal therapeutic effectiveness of allopurinol is due to its underdose: it is possible that the allopurinol dose should be increased to 800–1500 mg/day until the target serum uric acid level (<6 mg/dL) is reached.