The recommended ULORIC dosage is 40 mg or 80 mg once daily.

The recommended starting dosage of ULORIC is 40 mg once daily. For patients who do not achieve a serum uric acid (sUA) less than 6 mg/dL after two weeks, the recommended ULORIC dosage is 80 mg once daily.

Testing for the target serum uric acid level of less than 6 mg/dL may be performed as early as two weeks after initiating ULORIC therapy.

Consider the risks and benefits of ULORIC when deciding to prescribe or continue patients on ULORIC. Consider use of prophylactic low-dose aspirin therapy in patients with a history of CV disease. Monitor patients for the development of CV events. Inform patients about the symptoms of serious CV events and the steps to take if they occur.

After initiation of ULORIC, an increase in gout flares is frequently observed. This increase is due to reduction in serum uric acid levels, resulting in mobilization of urate from tissue deposits.

Obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) as a baseline before initiating ULORIC.

Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient presents abnormal liver tests (ALT or AST greater than three times the upper limit of the reference range), interrupt ULORIC treatment while investigating the probable cause. Permanently discontinue ULORIC if liver injury is confirmed, and no alternate etiology can be found.

Permanently discontinue ULORIC in patients who have serum ALT or AST greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies because they are at risk for severe drug-induced liver injury. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with ULORIC can be used with close monitoring.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reactions have been identified during post approval use of ULORIC. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Drug interaction studies of ULORIC with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of ULORIC during cytotoxic chemotherapy.

Safety and effectiveness of ULORIC in pediatric patients have not been established.

No studies have been conducted in patients with secondary hyperuricemia (including organ transplant recipients); ULORIC is not recommended for use in patients whom the rate of urate formation is greatly increased (e.g., malignant disease and its treatment, Lesch-Nyhan syndrome). The concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract.

ULORIC, a xanthine oxidase inhibitor, achieves its therapeutic effect by decreasing serum uric acid. ULORIC is not expected to inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at therapeutic concentrations.

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 MRHD on an AUC basis and 18.75 mg/kg (12.5 times the MRHD 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.

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 6-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).

The efficacy of ULORIC 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 2 (NCT00174915) randomized patients to: placebo, ULORIC 80 mg daily, ULORIC 120 mg daily, ULORIC 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 (NCT00102440), a year study, randomized patients to: ULORIC 80 mg daily, ULORIC 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 ULORIC 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 ULORIC was also evaluated in a 4-week dose ranging study which randomized patients to: placebo, ULORIC 40 mg daily, ULORIC 80 mg daily, or ULORIC 120 mg daily. Patients who completed this study were eligible to enroll in a long-term extension study in which patients received treatment with ULORIC for up to five years.

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

A randomized, double-blind, allopurinol-controlled CV outcomes study (CARES) was conducted to evaluate the CV risk of ULORIC (NCT01101035). The study compared the risk of MACE between patients treated with ULORIC (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.

Table 5 shows the study results for the primary MACE composite endpoint and its individual components. For the composite primary endpoint, the ULORIC 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 ULORIC (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 ULORIC 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 ULORIC is unclear.

All-cause mortality was higher in the ULORIC 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.