Febuxostat (Page 6 of 8)

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 ≥6mg/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 ˂6mg/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 3,098; 2.7%) as compared to the allopurinol group (56 of 3,092; 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)
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 (32) 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)

* Patient Years (PY)

16 HOW SUPPLIED/STORAGE AND HANDLING

Febuxostat tablets are available in two strengths as 40 mg and 80 mg.

40 mg: Light green to green, round, biconvex, film-coated tablets debossed with L440 on one side and plain on other side. They are supplied as:

NDC 46708-190-30 bottle of 30 units

NDC 46708-190-31 bottle of 100 units

NDC 46708-190-91 bottle of 1000 units

NDC 46708-190-08 80 Tablets Carton of 80 (10 x 8) Unit-Dose Tablets

NDC 46708-190-10 100 Tablets Carton of 100 (10 x 10) Unit-Dose Tablets

80 mg: Light green to green, tear drop shaped, biconvex film coated tablets debossed with L441 on one side and plain on other side and supplied as:

NDC 46708-191-30 bottle of 30 units

NDC 46708-191-31 bottle of 100 units

NDC 46708-191-91 bottle of 1000 units

NDC 46708-191-06 60 Tablets Carton of 60 (10 x 6) Unit-Dose Tablets

NDC 46708-191-10 100 Tablets Carton of 100 (10 x 10) Unit-Dose Tablets

Protect from light. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

CV Death

Inform patients that gout patients with established CV disease treated with febuxostat tablets had a higher rate of CV death compared to those treated with allopurinol in a CV outcomes study. Inform all patients of the higher rate of CV death with febuxostat tablets compared to allopurinol. Instruct all patients (those with and without CV disease) to be alert for the development of signs and symptoms of CV events [see Warnings and Precautions (5.1)].

Gout Flares

Inform patients that after initiation of febuxostat tablets there was an increased frequency of gout flares. Instruct patients that it is recommended to initiate and continue gout prophylaxis therapy for six months while taking febuxostat tablets [see Warnings and Precautions (5.2)].

Hepatic Effects

Inform patients that hepatic effects have occurred in patients treated with febuxostat tablets and instruct them to inform their healthcare provider if they experience liver injury symptoms [see Warnings and Precautions (5.3)].

Serious Skin Reactions

Inform patients that serious skin and hypersensitivity reactions have occurred in patients treated with febuxostat tablets. Instruct patients to discontinue febuxostat tablets if they develop symptoms of these reactions [see Warnings and Precautions (5.4)].

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