Febuxostat (Page 7 of 9)

14.2 Cardiovascular Safety Study

A randomized, double-blind, allopurinol-controlled CV outcomes study (CARES) was conducted to evaluate the CV risk of febuxostat tablets. The study compared the risk of MACE between patients treated with febuxostat tablets (N = 3098) and allopurinol-treated patients (N = 3092). The primary endpoint was the time to first occurrence of a MACE defined as the composite of CV death, nonfatal MI, nonfatal stroke, or unstable angina with urgent coronary revascularization. The study was designed to exclude a prespecified risk margin of 1.3 for the hazard ratio of MACE. An independent committee conducted a blinded evaluation of serious CV adverse events according to predefined criteria (adjudication) for determination of MACE. The study was event driven and patients were followed until a sufficient number of primary outcome events accrued. The median on-study follow-up time was 2.6 years.

Patients randomized to febuxostat tablets initially received 40 mg once daily which was increased to 80 mg once daily, if their sUA was ≥ 6 mg/dL at Week 2. For patients randomized to allopurinol, those who had normal renal function or mild renal impairment (estimated creatinine clearance (eClcr ) ≥ 60 to ˂ 90 mL/minute) initially received 300 mg once daily with 100 mg/day dose increments monthly until either sUA ˂ 6 mg/dL or an allopurinol dosage of 600 mg once daily was achieved; those who had moderate renal impairment (eClcr ≥ 30 to ˂ 60 mL/minute) initially received 200 mg once daily with 100 mg/day dose increments monthly until either a sUA ˂ 6 mg/dL or an allopurinol dosage of 400 mg once daily was achieved.

The mean age of the population was 65 years (range: 44 to 93 years). Most patients were male (84%) and Caucasian (69%). Patients had a diagnosis of gout for approximately 12 years, a mean baseline sUA of 8.7 mg/dL, and 90% had experienced at least one gout flare in the past year. CV history included MI (39%), hospitalization for unstable angina (28%), cardiac revascularization (37%), and stroke (14%). The most prevalent comorbid conditions were hypertension (92%), hyperlipidemia (87%), diabetes mellitus (55%), diabetes mellitus with micro- or macrovascular disease (39%), and renal impairment [92% with an eClcr 30 to 89 mL/minute]. The use of CV disease medication was balanced across treatment groups. Baseline CV disease medications included: ACE inhibitors or ARBs (70%), lipid modifying agents (74%), aspirin (62%), beta-blockers (59%), calcium channel blockers (26%), and nonaspirin antiplatelet medications (31%).

Table 5 shows the study results for the primary MACE composite endpoint and its individual components. For the composite primary endpoint, the febuxostat tablets group was non-inferior compared with the allopurinol group. The rates of nonfatal MI, stroke, and unstable angina with urgent coronary revascularization were similar. There was a higher rate of CV deaths in patients treated with febuxostat tablets (134 CV deaths; 1.5 per 100 PY) than in allopurinol-treated patients (100 CV deaths; 1.1 per 100 PY). Sudden cardiac death was the most common cause of adjudicated CV deaths in the febuxostat tablets group (83 of 3098; 2.7%) as compared to the allopurinol group (56 of 3092; 1.8%). The biological plausibility of CV death associated with febuxostat tablets is unclear.

All-cause mortality was higher in the febuxostat tablets group (243 deaths [7.8%]; 2.6 per 100 PY) than the allopurinol group (199 deaths [6.4%]; 2.2 per 100 PY) [Hazard Ratio: 1.22, 95% CI: 1.01, 1.47], due to a higher rate of CV deaths.

Table 5: Patients with MACE in CARES (Cardiovascular Outcomes Study in Patients with Gout)
*
Patient Years (PY)

Febuxostat Tablets

N = 3098

Allopurinol

N = 3092

Hazard Ratio

Number of Patients with Event (%)

Rate per 100 PY *

Number of Patients with Event (%)

Rate per 100 PY*

95% CI

Composite of primary endpoint

MACE

335 (10.8)

3.8

321 (10.4)

3.7

1.03 (0.89, 1.21)

Cardiovascular Death

134 (4.3)

1.5

100 (3.2)

1.1

1.34 (1.03, 1.73)

Nonfatal MI

111 (3.6)

1.2

118 (3.8)

1.3

0.93 (0.72, 1.21)

Nonfatal stroke

71 (2.3)

0.8

70 (2.3)

0.8

1.01 (0.73, 1.41)

Unstable angina with urgent coronary revascularization

49 (1.6)

0.5

56 (1.8)

0.6

0.86 (0.59, 1.26)

16 HOW SUPPLIED/STORAGE AND HANDLING

Febuxostat Tablets are available containing 40 mg or 80 mg of febuxostat.

The 40 mg tablets are white to off-white, film-coated, round, unscored tablets debossed with M on one side of the tablet and FX1 on the other side. They are available as follows:

NDC 0378-3925-93
bottles of 30 tablets

NDC 0378-3925-77
bottles of 90 tablets

NDC 0378-3925-05
bottles of 500 tablets

The 80 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with M on one side of the tablet and FX2 on the other side. They are available as follows:

NDC 0378-3926-93
bottles of 30 tablets

NDC 0378-3926-77
bottles of 90 tablets

NDC 0378-3926-05bottles of 500 tablets

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Medication Guide with each prescription.

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