Pharmacology Update
Febuxostat Tablets (Uloric®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.
The first new urate-lowering drug has been approved in more than 40 years. Febuxostat is a non-purine selective inhibitor of xanthine oxidase. It will be marketed by Takeda Pharmaceuticals America, Inc., as Uloric®.
Indication
Febuxostat is indicated for the chronic management of hyperuricemia in patients with gout.1
Dosage
The recommended starting dose is 40 mg once daily. If serum uric acid level < 6 mg/dL is not achieved after 2 weeks of therapy, then 80 mg once daily is recommended. No dosage adjustment is required in patients with mild-to-moderate renal or hepatic impairment. Febuxostat may be taken without regard to meals. Flare prophylaxis with a non-steroidal anti-inflammatory drug or colchicine is recommended upon initiation of febuxostat therapy for possibly up to 6 months.1
Febuxostat is supplied as 40 mg and 80 mg tablets.
Potential Advantages
Febuxostat (80 mg) is more effective in urate-lowering than allopurinol.1-3 It does not appear to be associated with hypersensitivity reactions (i.e., Steven-Johnson syndrome) seen with allopurinol. The drug does not appear to have any clinically important drug-drug interactions involving the cytochrome P450 isoenzyme system.1
Potential Disadvantages
A higher rate of thromboembolic events (cardiovascular death, non-fatal MI, and non-fatal strokes) was observed in clinical trials compared to allopurinol (0.74; 95% confidence interval [CI], 0.36-1.37) per 100 patient-years vs 0.60 (95% CI, 0.16-1.53) per 100 patient-years, respectively.1 Common adverse events include liver function abnormalities (4.6% -6.6%) vs 4.2% for allopurinol and 0.7% for placebo. As with allopurinol, concomitant administration with azathioprine, mercaptopurine, and theophylline is contraindicated.
Comments
Febuxostat is a selective xanthine oxidase inhibitor. In contrast to allopurinol, which inhibits the reduced form of xanthine oxidase, febuxostat binds to both the reduced and oxidized forms.4 Its efficacy was shown in two 6-month and one 1-year, randomized, double-blind, controlled trials in patients with hyperuricemia (serum uric acid level ≥ 8 mg/dL) and gout (n = 3402). Study participants were mostly male (~95%) with an approximate age of 52 years. The primary endpoint was serum uric acid < 6 mg/dL. The proportion of study participants that achieved the primary endpoint was 42%-50% for febuxostat 40 mg, 67%-74% for febuxostat 80 mg, and 38%-42% for allopurinol. Allopurinol was dosed from 100 mg to 300 mg daily based on renal function (i.e., Scr or estimated creatinine clearance).1 Febuxostat 80 mg was statistically better than allopurinol; however, the allopurinol dose was not adjusted to optimize urate-lowering effect. In patients who were assessed for tophi, there were no statistical differences among the study groups in the percent reduction in tophus area or in the number of tophi.3 In a long-term extension study, approximately two-thirds of patients who failed to achieve or maintain uric acid level ≤ 6 mg/dL on allopurinol were successfully treated with febuxostat.5 Liver function abnormalities occurred more frequently with febuxostat and were the most common adverse event that led to discontinuation of therapy.1
Clinical Implications
Febuxostat is the first antigout drug to be approved in over 40 years. It provides an option for patients who have not achieved desired uric acid levels with allopurinol, such as those with refractory gout, renal insufficiency, and allopurinol hypersensitivity.6 The long-term safety of febuxostat, particularly with thromboembolic events, remains to be established.
References
1. Uloric Product Information. Deerfield, IL: Takeda Pharmaceuticals, Inc.; February 2009.
2. Schumacher HR Jr, et al. 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 Rheum 2008;59:1540-1548.
3. Becker MA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353:2450-2461.
4. Takano Y, et al. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci 2005;76:1835-1847.
5. Hair PI, et al. Febuxostat. Drugs 2008;68:1865-1874.
6. Lee SJ, Terkeltaub RA. New developments in clinically relevant mechanisms and treatment of hyperuricemia. Curr Rheumatol Rep 2006;8:224-230.
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