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FDA Slaps a Boxed Warning on Febuxostat for CV Risk

The U.S. Food and Drug Administration (FDA) has reviewed data from the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial and concluded there is an increased risk of death with Uloric (febuxostat) compared with allopurinol, and has added this as a boxed warning to the drug’s product label.

This action follows the recommendations of the FDA Arthritis Advisory Commitee that met in January 2019.  That panel voted in favor of keeping febuxostat on the market, noting the benefit-risk profile for febuxostat is favorable for the treatment of hyperuricemia in gout patients. But the panel was concerned about the increase risk of CV death and death from all causes with Uloric.  They clearly expressed concerns that febuxostat use may pose a small CV risk to some gout patients, especially those with severe gout and those not receiving daily aspirin.

The FDA has responded by updating the febuxostat prescribing information that requires a Boxed Warning, most prominent safety warning, and changes to the patient Medication Guide.

Moreover, the FDA has limited the approved use of febuxostat to certain patients who are not treated effectively or experience severe side effects with allopurinol.

The new changes include: 

  • FDA’s review of a large safety clinical trial showed an increased risk of cardiovascular death and all-cause death with the gout medicine Uloric (febuxostat).
  • Reserve Uloric for use in patients who have failed or cannot tolerate maximally titrated allopurinol doses.
  • Monitor for cardiovascular signs and symptoms in patients who are taking Uloric.
  • Counsel patients to seek medical attention immediately 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 a sudden severe headache while taking Uloric.
  • Encourage patients to read the Medication Guide they receive with their Uloric prescriptions, which helps patients understand the cardiovascular safety risks and provides other important information.

Febuxostat was FDA-approved in 2009 to gout which affects approximately 8.3 million adults in the U.S.  At that time there were concerns about the cardiovascular risk that comes with gout and that such risk may be augmented by febuxostat. Thus with approval came the postmarketing committment to do a large safety clinical trial - the CARES trial.

The trial was conducted in more than 6,000 patients with gout treated with either Uloric or allopurinol. The primary outcome was a combination of CV death, non-fatal MI, non-fatal CVA and unstable angina requiring intervention. 

The results showed that overall, Uloric did not increase the risk of these combined events compared to allopurinol (See Data Summary). However, when the outcomes were evaluated separately, Uloric showed an increased risk of heart-related deaths and death from all causes. In patients treated with Uloric, 15 deaths from heart-related causes were observed for every 1,000 patients treated for a year compared to 11 deaths from heart-related causes per 1,000 patients treated with allopurinol for a year. In addition, there were 26 deaths from any cause per 1,000 patients treated for a year with Uloric compared to 22 deaths per 1,000 patients treated for a year with allopurinol.

The study design was a noninferiority trial with a noninferiority margin of 1.3. Results showed that although the study met the pre-specified noninferiority margin, there was a significant increase in cardiovascular death (See Table 1 below). In addition, there was a significant increase in overall mortality, which was driven by cardiovascular death.

Table 1. CARES Study Results

  N (%)Uloric
Hazard Ratio
(95% CI)
Primary Endpoint:
335 (10.8)321 (10.4)1.03 (0.89, 1.21)
Cardiovascular death134 (4.3)100 (3.2)1.34 (1.03, 1.73)
Nonfatal myocardial infarction111 (3.6)118 (3.8)0.93 (0.72, 1.21)
Nonfatal stroke71 (2.3)70 (2.3)1.01 (0.73, 1.41)
Unstable angina with urgent coronary revascularization49 (1.6)56 (1.8)0.86 (0.59, 1.26)
Additional Endpoint:
All-cause mortality243 (7.8)199 (6.4)1.22 (1.01, 1.47)
The author has received compensation as an advisor or consultant on this subject

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