FDA Approves Febuxostat for Chronic Management of Hyperuricemia in Patients With Gout

Laurie Barclay, MD

February 17, 2009

February 17, 2009 — The US Food and Drug Administration (FDA) last week approved febuxostat (Uloric), 40 mg and 80 mg, administered orally once daily, for chronic management of hyperuricemia in patients with gout, according to an announcement by Takeda Pharmaceuticals North American. This is the first new treatment option available for gout in more than 40 years.

"The approval of Uloric offers clinicians and their patients who have hyperuricemia associated with gout a new treatment option that helps prevent uric acid production," Nancy Joseph-Ridge, MD, president of Takeda Global Research & Development Center, Inc, US, said in a news release. "...[G]out is a chronic disease that needs to be managed on a long-term, daily basis."

In multiple clinical trials enrolling more than 4000 participants for up to 5 years in some studies, the xanthine oxidase inhibitor safely and effectively reduced serum uric acid levels in patients with hyperuricemia associated with gout.

CONFIRMS, the largest, pivotal, phase 3 clinical trial, showed that febuxostat 80 mg was superior to febuxostat 40 mg and allopurinol 300/200 mg at achieving the main study outcome of serum uric acid less than 6.0 mg/dL at the final visit (67%, 45%, and 42%, respectively; P < .001 for both comparisons).

The safety profile of febuxostat is well established, with liver function abnormalities, nausea, joint pain, and rash being the most frequently reported adverse reactions, occurring in at least 1% of febuxostat-treated patients, and at a rate at least 0.5% greater than placebo. Mild to moderate renal or hepatic impairment does not necessitate dose adjustments.

The mechanism of action of febuxostat is to inhibit xanthine oxidase, an enzyme that breaks down hypoxanthine (a purine base) to xanthine and then to uric acid, thereby reducing elevated levels of serum uric acid. Febuxostat is indicated for the chronic management of hyperuricemia in patients with gout, but not for the treatment of asymptomatic hyperuricemia.

Contraindications include concomitant treatment with azathioprine, mercaptopurine, or theophylline. When treatment is started with antihyperuricemic agents, including febuxostat, an increase in gout flares may occur, but the drug does not have to be discontinued. Use of prophylactic treatment with a nonsteroidal anti-inflammatory drug or colchicine may be beneficial for up to 6 months.

In clinical trials, cardiovascular thromboembolic events were more common in patients treated with febuxostat (0.74/100 patient-years) than in patients treated with allopurinol (0.60/100 patient-years), but a causal relationship has not been established. Patients receiving febuxostat should be monitored for signs and symptoms of myocardial infarction and stroke, as well as with periodic liver function tests. Although transaminase elevations have been reported in patients receiving febuxostat, no dose-effect relationship was observed.

Gout results from an acute inflammatory response to crystallized uric acid in the affected joints, causing flares characterized by intense pain, redness, swelling, and heat. It is the most common inflammatory arthritis in men older than 40 years, affecting about 5.1 million Americans, according to the National Health and Nutrition Examination Survey III 1988–1994.

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