Febuxostat (Page 6 of 9)

13.2 Animal Toxicology

A 12 month toxicity study in beagle dogs showed deposition of xanthine crystals and calculi in kidneys at 15 mg/kg (approximately 4 times the MRHD on an AUC basis). A similar effect of calculus formation was noted in rats in a six month study due to deposition of xanthine crystals at 48 mg/kg (approximately 31 and 40 times the MRHD on an AUC basis in males and females respectively).

14 CLINICAL STUDIES

A serum uric acid level of less than 6 mg/dL is the goal of antihyperuricemic therapy and has been established as appropriate for the treatment of gout.

14.1 Management of Hyperuricemia in Gout

The efficacy of febuxostat tablets was demonstrated in three randomized, double-blind, controlled trials in patients with hyperuricemia and gout. Hyperuricemia was defined as a baseline serum uric acid level ≥ 8 mg/dL.

Study 1 (ClinicalTrials.gov identifier NCT00430248) randomized patients to: febuxostat tablets 40 mg daily, febuxostat tablets 80 mg daily, or allopurinol (300 mg daily for patients with estimated creatinine clearance (Clcr ) ≥ 60 mL/min or 200 mg daily for patients with estimated Clcr ≥ 30 mL/min and ≤ 59 mL/min). The duration of Study 1 was six months.

Study 2 (ClinicalTrials.gov identifier NCT00174915) randomized patients to: placebo, febuxostat tablets 80 mg daily, febuxostat tablets 120 mg daily, febuxostat tablets 240 mg daily or allopurinol (300 mg daily for patients with a baseline serum creatinine ≤ 1.5 mg/dL or 100 mg daily for patients with a baseline serum creatinine greater than 1.5 mg/dL and ≤ 2 mg/dL). The duration of Study 2 was six months.

Study 3 (ClinicalTrials.gov identifier NCT00102440), a one year study, randomized patients to: febuxostat tablets 80 mg daily, febuxostat tablets 120 mg daily, or allopurinol 300 mg daily. Patients who completed Study 2 and Study 3 were eligible to enroll in a Phase 3 long-term extension study in which patients received treatment with febuxostat tablets for over three years.

In all three studies, patients received naproxen 250 mg twice daily or colchicine 0.6 mg once or twice daily for gout flare prophylaxis. In Study 1 the duration of prophylaxis was six months; in Study 2 and Study 3 the duration of prophylaxis was eight weeks.

The efficacy of febuxostat tablets was also evaluated in a four week dose ranging study which randomized patients to: placebo, febuxostat tablets 40 mg daily, febuxostat tablets 80 mg daily, or febuxostat tablets 120 mg daily. Patients who completed this study were eligible to enroll in a long-term extension study in which patients received treatment with febuxostat tablets for up to five years.

Patients in these studies were representative of the patient population for which febuxostat tablet use is intended. Table 2 summarizes the demographics and baseline characteristics for the patients enrolled in the studies.

Table 2: Patient Demographics and Baseline Characteristics in Study 1, Study 2, and Study 3

Male

95%

Race: Caucasian African American

80%

10%

Ethnicity: Hispanic or Latino

7%

Alcohol User

67%

Mild to Moderate Renal Insufficiency (percent with estimated Clcr less than 90 mL/min)

59%

History of Hypertension

49%

History of Hyperlipidemia

38%

BMI ≥ 30 kg/m2

63%

Mean BMI

33 kg/m2

Baseline sUA ≥ 10 mg/dL

36%

Mean baseline sUA

9.7 mg/dL

Experienced a gout flare in previous year

85%

Serum Uric Acid Level Less Than 6 mg/dL at Final Visit

Febuxostat tablets 80 mg were superior to allopurinol in lowering serum uric acid to less than 6 mg/dL at the final visit. Febuxostat tablets 40 mg daily, although not superior to allopurinol, were effective in lowering serum uric acid to less than 6 mg/dL at the final visit (Table 3).

Table 3: Proportion of Patients with Serum Uric Acid Levels Less Than 6 mg/dL at Final Visit
*
Randomization was balanced between treatment groups, except in Study 2 in which twice as many patients were randomized to each of the active treatment groups compared to placebo.

Study *

FebuxostatTablets 40 mg daily

FebuxostatTablets 80 mg daily

Allopurinol

Placebo

Difference in Proportion (95% CI)

FebuxostatTablets 40 mg vsAllopurinol

FebuxostatTablets 80 mg vsAllopurinol

Study 1 (6 months) (N = 2268)

45%

67%

42%

3% (-2%, 8%)

25% (20%, 30%)

Study 2 (6 months) (N = 643)

72%

39%

1%

33% (26%, 42%)

Study 3 (12 months) (N = 491)

74%

36%

38% (30%, 46%)

In 76% of febuxostat tablets 80 mg patients, reduction in serum uric acid levels to less than 6 mg/dL was noted by the Week 2 visit. Average serum uric acid levels were maintained at 6 mg/dL or below throughout treatment in 83% of these patients.

In all treatment groups, fewer patients with higher baseline serum urate levels (≥ 10 mg/dL) and/or tophi achieved the goal of lowering serum uric acid to less than 6 mg/dL at the final visit; however, a higher proportion achieved a serum uric acid less than 6 mg/dL with febuxostat tablets 80 mg than with febuxostat tablets 40 mg or allopurinol.

Study 1 evaluated efficacy in patients with mild to moderate renal impairment (i.e., baseline estimated Clcr less than 90 mL/min). The results in this subgroup of patients are shown in Table 4.

Table 4: Proportion of Patients with Serum Uric Acid Levels Less Than 6 mg/dL in Patients with Mild or Moderate Renal Impairment at Final Visit
*
Allopurinol patients (n = 145) with estimated Cl cr ≥ 30 mL/min and Cl cr ≤ 59 mL/min were dosed at 200 mg daily.

FebuxostatTablets 40 mg daily (N = 479)

FebuxostatTablets 80 mg daily (N = 503)

Allopurinol * 300 mg daily (N = 501)

Difference in Proportion (95% CI)

FebuxostatTablets 40 mg vs Allopurinol

FebuxostatTablets 80 mg vs Allopurinol

50%

72%

42%

7%

(1%, 14%)

29%

(23%, 35%)

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