New Drug Reviews
Febuxostat (Uloric) for Hyperuricemia and Gout
Am Fam Physician. 2010 May 15;81(10):1287-1289.
Allopurinol (Zyloprim), the most widely prescribed agent for gout in the United States, reduces uric acid levels by inhibiting the enzyme xanthine oxidase.1 Like allopurinol, febuxostat (Uloric) inhibits xanthine oxidase and is labeled for the management of hyperuricemia in patients with gout.2
|Drug||Starting dosage||Dose form||Approximate monthly cost*|
40 mg once per day; may increase dosage to 80 mg once per day if serum uric acid levels greater than 6 mg per dL (356.91 μmol per L) after two weeks of therapy
Immediate-release tablets, 40 mg or 80 mg
*— Estimated retail price of one month's treatment based on information obtained at http://www.drugstore.com. Accessed April 14, 2010.
The main safety issues of febuxostat involve the hepatic and cardiovascular systems. Liver function abnormalities requiring discontinuation of therapy are more common in patients treated with febuxostat than in those treated with allopurinol: 1.2 percent with 40-mg febuxostat, 1.8 percent with 80-mg febuxostat, and 0.9 percent with allopurinol. The manufacturer recommends liver function monitoring on initiation of therapy, at two and four months after initiation, and periodically thereafter.2
Although a direct causal relationship has not been established, a higher rate of cardiovascular thrombotic events has been observed with febuxostat compared with allopurinol (0.74 versus 0.60 per 100 patient-years, respectively; P = not significant).2 Patients should be monitored for signs and symptoms of myocardial infarction and stroke. As with allopurinol, febuxostat should not be combined with azathioprine (Imuran), mercaptopurine, or theophylline; these medications can reach toxic levels in the blood because xanthine oxidase is partially responsible for their metabolism.2 Febuxostat is U.S. Food and Drug Administration pregnancy category C.2
Adverse effects of febuxostat are mild and are similar to those reported with allopurinol or placebo. Nausea, arthralgias, and rash occur slightly more often with febuxostat than with placebo or allopurinol; however, these rates are still low (2 percent).2 About 25 to 30 percent of patients will experience a gout flare-up after starting therapy with febuxostat, which is similar to the rate found with allopurinol.3–6 In premarketing studies, the overall drop-out rate was approximately 34 percent in patients taking febuxostat compared with 24 percent in patients taking allo-purinol.3–6 During the initiation of febuxostat therapy, adverse effects from concurrent use of colchicine (nausea, vomiting, and, rarely, neutropenia) or nonsteroidal anti-inflammatory drugs (NSAIDs; gastrointestinal distress, ulcers, and renal dysfunction) are possible.
Febuxostat has been compared with placebo or allopurinol in five clinical studies enrolling more than 2,700 patients.3–7 The duration of these studies ranged from 28 days to five years. No research has compared febuxostat with probenecid. Febuxostat in a dosage of 80 mg once per day decreases serum uric acid levels by approximately 50 percent from baseline, compared with a 30 percent decrease in patients taking allopurinol. A dosage of 40 mg once per day produces a 30 to 40 percent reduction in serum uric acid levels after one month.7 About twice as many patients (approximately 63 percent) taking 80-mg febuxostat will achieve the goal serum uric acid level of less than 6 mg per dL (356.91 μmol per L) compared with those taking allopurinol (approximately 30 percent).5,7 The incidence of gout flare-up is highest within four to six months after initiating therapy, but it gradually decreases to nearly zero after one year of therapy with allopurinol or febuxostat.3,4 Patients who achieve serum uric acid levels of less than 6 mg per dL with either febuxostat or allopurinol will have similar decreases in size, number, and likelihood of resolution of palpable tophi.3,4 The effects on other clinical manifestations of gout (e.g., urolithiasis, gouty nephropathy) have not been studied.
A one-month supply of 40-mg febuxostat costs $160. This price far exceeds the cost of allopurinol, which is $14 (brand: $31) for a one-month supply.
Febuxostat is available in 40-mg and 80-mg tablets. The initial dosage is 40 mg once per day, increasing to 80 mg once per day if serum uric acid levels remain at 6 mg per dL or higher after two weeks of therapy. Dosage adjustments are unnecessary for mild to moderate renal or hepatic impairment. Prophylaxis with colchicine or an NSAID is recommended for up to six months after initiation of febuxostat to prevent acute flare-ups from mobilized uric acid.
Febuxostat more effectively lowers serum uric acid to goal levels than does allopurinol; however, this benefit is offset by a slightly higher incidence of adverse effects and treatment discontinuation. Until superiority for patient-oriented outcomes is shown in comparative trials with allopurinol, febuxostat should be reserved for symptomatic patients who do not obtain adequate reduction in serum uric acid levels or are intolerant of allopurinol.
1. Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, Herrero-Beites A, García-Erauskin G, Ruiz-Lucea E. Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout. Ann Rheum Dis. 1998;57(9):545–549.
2. Uloric (febuxostat) tablets [prescribing information]. Deerfield, Ill.: Takeda Pharmaceuticals North America; 2009. http://www.uloric.com. Accessed September 30, 2009.
3. 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. J Rheumatol. 2009;36(6):1273–1282.
4. 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). 2009;48(2):188–194.
5. Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353(23): 2450–2461.
6. Schumacher HR Jr, Becker MA, Wortmann RL, 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(11):1540–1548.
7. Becker MA, Schumacher HR Jr, Wortmann RL, et al. 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 Rheum. 2005;52(3):916–923.
STEPS new drug reviews cover Safety, Tolerability, Effectiveness, Price, and Simplicity. Each independent review is provided by authors who have no financial association with the drug manufacturer.
The series coordinator for AFP is Allen F. Shaughnessy, PharmD, Tufts University Family Medicine Residency Program at Cambridge Health Alliance, Malden, Mass.
A collection of STEPS published in AFP is available at http://www.aafp.org/afp/steps.
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