Two year carcinogenicity studies were conducted in F344 rats and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of the urinary bladder was observed at 24 mg/kg (25 times the MHRD on an AUC basis) and 18.75 mg/kg (12.5 times the MHRD on an AUC basis) in male rats and female mice, respectively. The urinary bladder neoplasms were secondary to calculus formation in the kidney and urinary bladder.
Febuxostat showed a positive clastogenic response in a chromosomal aberration assay in a Chinese hamster lung fibroblast cell line with and without metabolic activation in vitro. Febuxostat was negative in the following genotoxicity assays: the in vitro Ames assay, in vitro chromosomal aberration assay in human peripheral lymphocytes, the L5178Y mouse lymphoma cell line assay, the in vivo mouse micronucleus assay, and the rat unscheduled DNA synthesis assay.
Fertility and reproductive performance were unaffected in male or female rats that received febuxostat at oral doses up to 48 mg/kg/day (approximately 31 and 40 times the MRHD on an AUC basis in males and females respectively).
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).
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.
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 studies 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 subjects received treatment with febuxostat tablets for up to five years.
Patients in these studies were representative of the patient population for which febuxostat tablets 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|
|Ethnicity: Hispanic or Latino||7%|
|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 was 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, was 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|
|Study*||Febuxostat tablets 40 mg daily||Febuxostat tablets 80 mg daily||allopurinol||Placebo||Difference in Proportion (95% CI)|
|Febuxostat tablets 40 mg vs allopurinol||Febuxostat tablets80 mg vs allopurinol|
|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%)|
*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.
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 tablet 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|
|Febuxostat tablets 40 mg daily (N=479)||Febuxostat tablets 80 mg daily (N=503)||allopurinol* 300 mg daily (N=501)||Difference in Proportion (95% CI)|
|Febuxostat tablets 40 mg daily vs allopurinol||Febuxostat tablets 80 mg daily vs allopurinol|
|50%||72%||42%||7% (1%, 14%)||29% (23%, 35%)|
*Allopurinol patients (n=145) with estimated Clcr ≥30 mL/min and Clcr ≤59 mL/min were dosed at 200 mg daily.
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 (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)|
* Patient Years (PY)
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