General Information

Uloric (febuxostat) is a xanthine oxidase (XO) inhibitor and 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.

Uloric is specifically indicated for the chronic management of hyperuricemia in patients with gout.

Mechanism of Action

Uloric (febuxostat) is a xanthine oxidase (XO) inhibitor and 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.

Side Effects

Adverse events associated with the use of Uloric may include, but are not limited to, the following:

• liver function abnormalities
• nausea
• arthralgia
• rash
• dizziness

Dosing/Administration

Uloric is supplied as a 40 mg tablet designed for oral administration. The recommended initial dose of the drug is 40 mg once daily. For patients who do not achieve a serum uric acid less than 6 mg per dL after two weeks with 40 mg, Uloric 80 mg is recommended.

Clinical Trial Results

FDA approval of Uloric was based on three randomized, double-blind, controlled trials. In all three studies, subjects 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 6 months; in study 2 and study 3 the duration of prophylaxis was 8 weeks.

Study 1
This study randomized patients to: Uloric 40 mg daily, Uloric 80 mg daily, or allopurinol (300 mg daily for patients with estimated creatinine clearance (Clcr) ≥ 60 mL per min or 200 mg daily for patients with estimated Clcr ≥ 30 mL per min and ≤ 59 mL per min). The duration was six months.

Study 2
This study 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 per dL or 100 mg daily for patients with a baseline serum creatinine greater than 1.5 mg per dL and ≤ 2 mg per dL). The duration was six months.

Study 3
This was a one-year study and randomized patients to: Uloric 80 mg daily, Uloric 120 mg daily, or allopurinol 300 mg daily. Subjects who completed study 2 and study 3 were eligible to enroll in a phase 3 long-term extension study in which subjects received treatment with Uloric for over three years.

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

In all the studies, Uloric 80 mg was superior to allopurinol in lowering serum uric acid to less than 6 mg per dL at the final visit. Uloric 40 mg daily, although not superior to allopurinol, was effective in lowering serum uric acid to less than 6 mg per dL at the final visit in study 1. In 76 percent of Uloric 80 mg patients, reduction in serum uric acid levels to less than 6 mg per dL was noted by the week 2 visit. Average serum uric acid levels were maintained at 6 mg per dL or below throughout treatment in 83 percent of these patients. In all treatment groups, fewer subjects with higher baseline serum urate levels (≥ 10 mg per dL) and/or tophi achieved the goal of lowering serum uric acid to less than 6 mg per dL at the final visit; however, a higher proportion achieved a serum uric acid less than 6 mg per dL with Uloric 80 mg than with Uloric 40 mg or allopurinol. Study 1 also evaluated efficacy in patients with mild to moderate renal impairment (i.e., baseline estimated Clcr less than 90 mL per minute). The percentage of patients with serum uric acid levels less than 6 mg per dL was as follows: Uloric 40mg: 50 percent; Uloric 80mg: 72 percent; allopurinol 300mg: 42 percent.