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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.

Uloric is supplied as a 40 mg tablet designed for oral administration. The recommended initial dose of the drug is is 40 mg once daily. For patients who do not achieve a serum uric acid less than 6 mg per dL after 2 weeks with 40 mg, Uloric 80 mg is recommended.

Clinical Results

FDA Approval
FDA approval of Urolic 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 One
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 6 months.

Study Two
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 6 months.

Study Three
This was a 1-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 4 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 One. In 76% 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% 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%; Uloric 80mg: 72%; allopurinol 300mg: 42%.

Ongoing Study Commitments

Takeda has agreed to conduct a randomized, controlled trial of adequate size and duration to determine whether the use of Uloric is associated with a moderate increase in the risk of serious adverse cardiovascular outcomes as compared to allopurinol.
Final Protocol Submission Date: August 31, 2009
Trial Start Date: January 31, 2010
Trial Completion Date: January 31, 2014
Final Report Submission: January 31, 2015
Takeda has agreed to conduct a drug-drug interaction trial to evaluate the effect of Uloric on the pharmacokinetics of a single, oral dose of theophylline.
Final Protocol Submission Date: April 30, 2009
Trial Start Date: June 30, 2009
Trial Completion Date: July 31, 2009
Final Report Submission: May 31, 2010

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

Mechanism of Action

Literature References

Becker MA, Schumacher HR, Macdonald PA, Lloyd E, Lademacher C Clinical Efficacy and Safety of Successful Longterm Urate Lowering with Febuxostat or Allopurinol in Subjects with Gout. The Journal of Rheumatology 2009 Mar 13

Schumacher HR Jr, Becker MA, Lloyd E, MacDonald PA, Lademacher C Febuxostat in the treatment of gout: 5-yr findings of the FOCUS efficacy and safety study. Rheumatology (Oxford, England) 2009 Feb;48(2):188-94

Schumacher HR Jr, Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit J, Lademacher C, Joseph-Ridge N Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis and Rheumatism 2008 Nov 15;59(11):1540-8

Khosravan R, Grabowski BA, Wu JT, Joseph-Ridge N, Vernillet L Pharmacokinetics, pharmacodynamics and safety of febuxostat, a non-purine selective inhibitor of xanthine oxidase, in a dose escalation study in healthy subjects. Clinical Pharmacokinetics 2006;45(8):821-41

Khosravan R, Grabowski BA, Mayer MD, Wu JT, Joseph-Ridge N, Vernillet L The effect of mild and moderate hepatic impairment on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase. Journal of Clinical Pharmacology 2006 Jan;46(1):88-102

Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Palo WA, Eustace D, Vernillet L, Joseph-Ridge N Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis and Rheumatism 2005 Mar;52(3):916-23

Osada Y, Tsuchimoto M, Fukushima H, Takahashi K, Kondo S, Hasegawa M, Komoriya K Hypouricemic effect of the novel xanthine oxidase inhibitor, TEI-6720, in rodents. European Journal of Pharmacology 1993 Sep 14;241(2-3):183-8