Regulatory Decision Summary for Uloric

The purpose of this Supplemental New Drug Submission (SNDS) was to review the cardiovascular safety concerns of Uloric (febuxostat). During its development, Uloric was compared with placebo and allopurinol in clinical trials in patients without gout. These trials suggested a modestly higher rate of cardiovascular events with Uloric. To address the cardiovascular safety concerns, the sponsor was required to conduct a post-market trial of adequate size and duration to determine whether the use of Uloric is associated with an increased risk of serious adverse cardiovascular outcomes compared to allopurinol.

A randomized, double-blind, allopurinol-controlled cardiovascular (CV) outcomes study (CARES) was conducted to evaluate the CV risk of Uloric in patients with gout who had a history of major CV disease, cerebrovascular disease or diabetes mellitus with micro- and/or macrovascular disease. The primary endpoint of major adverse cardiovascular events (MACE) [a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, and unstable angina with urgent coronary revascularization] was similar for Uloric and allopurinol (Hazard Ratio: 1.03, 95% CI: 0.89, 1.21) confirming non-inferiority. The rates of nonfatal MI, stroke, and unstable angina with urgent coronary revascularization were also similar. However, there was a higher rate of CV deaths in patients treated with Uloric than in allopurinol-treated patients (Hazard Ratio: 1.34, 95% CI: 1.03, 1.73). All-cause mortality was also higher in the Uloric group than the allopurinol group (Hazard Ratio: 1.22, 95% CI: 1.01, 1.47), due to a higher rate of CV deaths. Sensitivity analysis censoring CV deaths or all-cause deaths that happened post-treatment or 30 days post-treatment were consistent with the uncensored data. The results from this study suggest that there may be an increased risk of CV death in patients treated with Uloric compared to allopurinol.

Despite the potential increased risk of CV death, Uloric is currently the only urate-lowering therapy (ULT) alternative to allopurinol in Canada. Uloric may provide benefits over allopurinol in certain subgroups of gout patients. There is some support that Uloric is more effective than allopurinol in reducing serum urate levels (sUA) in subjects with high disease burden (sUA ≥10 mg/dL or tophi), who are more difficult to treat. This is consistent with real world use data where Uloric users tend to have more severe gout than allopurinol users. In patients with renal impairment, optimal dosing for allopurinol is complicated because of its elimination via the kidneys. Patients with decreased renal function need to be prescribed lower doses of allopurinol than those with normal renal function, which would reduce its efficacy; these patients also require close monitoring. Uloric is almost entirely eliminated by liver metabolism; therefore, unlike allopurinol, a dose adjustment is not required for patients with mild to moderate renal impairment. The use of allopurinol is also limited by safety concerns, such as serious hypersensitivity reactions. Allopurinol also has many drug-drug interactions, including dicumarol, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin, and thiazide diuretics. Therefore, Uloric is an important therapy for some subgroups of gout patients where allopurinol is insufficient (e.g. more severe cases of gout or patients with renal impairment where further dose increase is not possible) or intolerable/inappropriate (hypersensitive or have drug interactions). In these patients, the healthcare practitioner should weigh whether the benefits outweigh the possible risks.

Although the risk of CV death is higher in the Uloric group than in the allopurinol group, the difference in risk is relatively small (though statistically significant); 134 out of 3098 subjects (4.3%) had CV death in the Uloric group compared to 100 out of 3,092 subjects (3.2%) in the allopurinol group. Based on an analysis done by another group the number needed to harm (NNH) for the population in the CARES study (i.e. high CV risk) is ~278 for CV death, meaning that 278 patient-years of exposure to Uloric are needed to observe one additional CV death relative to allopurinol.

Changes in the Product Monograph are considered sufficient to mitigate the risk identified in the CARES trial. These changes include:

• Narrowing the indication from "patients with gout" to "patients with gout who have an inadequate response or intolerance to allopurinol, or for whom treatment with allopurinol is inappropriate".
• Adding a Serious Warnings and Precautions box to highlight the increased risk of CV death.
• Updating the WARNINGS AND PRECAUTIONS, Cardiovascular section with the results from the CARES study.
• Describing in further detail the study design and results of CARES in the CLNICAL TRIALS section.