Febuxostat for Treatment of Chronic Gout

Charnelda L. Gray, Pharm.D., BCPS; Nafesa E. Walters-Smith, Pharm.D., BCPS

Disclosures

Am J Health Syst Pharm. 2011;68(5):389-398. 

In This Article

Short-term Studies

Febuxostat versus Placebo

In a randomized, double-blind, placebo-controlled trial with 153 patients age 23–80 years with gout and hyperuricemia, Becker et al.[10] compared the efficacy and safety of febuxostat 40 mg (n = 37), 80 mg (n = 40), and 120 mg (n = 38) once daily with placebo (n = 38) for 28 days with colchicine prophylaxis for 14 days before and after randomization. The efficacy analysis was based on an intent-to-treat population of 140 patients. Thirteen patients were excluded because their serum uric acid level was collected outside of the specified time frame. All 153 patients were analyzed for adverse effects and gout flares. The target serum uric acid concentration of <6.0 mg/dL at each visit was achieved by a greater percentage of patients in the febuxostat 40-mg group (50%, n = 19; 56%, n = 21; 59%, n = 22; and 56%, n = 21), 80-mg group (59%, n = 24; 68%, n = 27; 76%, n = 30; and 76%, n = 30), and 120-mg group (91%, n = 35; 94%, n = 36; 97%, n = 37; and 94%, n = 36) on days 7, 14, 21, and 28, respectively, compared with those in the placebo group (3%, n = 1; 0%; 0%; 0%; p < 0.001 for each comparison). Gout flares were similar in the placebo and febuxostat 40-mg/day groups (37% [n = 14] versus 35% [n = 13], respectively), with increasing flare frequency in the 80-mg (43%, n = 17) and 120-mg (55%, n = 21) groups. With colchicine prophylaxis, the rates of gout flares were 8% (n = 3), 8% (n = 3), 13% (n = 5), and 11% (n = 4) for febuxostat 40, 80, and 120 mg and placebo, respectively, versus 30% (n = 11), 40% (n = 16), 42% (n = 16), and 34% (n = 13) for febuxostat 40, 80, and 120 mg and placebo, respectively, when febuxostat or placebo was administered alone. Gout flares occurred more frequently in patients receiving the higher febuxostat dosages, implying that extended prophylaxis may be appropriate with more potent antihyperurecemic agents.[10] The number of adverse effects with febuxostat and placebo was similar, with diarrhea being the most common adverse effect, occurring in 0%, 10% (n = 4), 8% (n = 3), and 8% (n = 3) of patients receiving febuxostat 40, 80, and 120 mg and placebo, respectively.

Febuxostat versus Allopurinol

Febuxostat has been compared with allopurinol and has demonstrated increased efficacy in lowering serum uric acid levels.

Febuxostat versus Allopurinol Controlled Trial Becker et al.[35] conducted a randomized, double-blind, 52-week trial at 112 centers in the United States and Canada. This study, known as the Febuxostat versus Allopurinol Controlled Trial (FACT), compared the efficacy and safety of daily febuxostat 80 mg (n = 256) or 120 mg (n = 251) with allopurinol 300 mg daily (n = 253) in 760 adults with gout and hyperuricemia (serum uric acid concentration of ≥8.0 mg/dL). Before randomization, patients already receiving a uric-acid-lowering therapy underwent a two-week washout period. Prophylaxis with naproxen 250 mg twice daily or colchicine 0.6 mg once daily was administered to all patients during the washout period and the first eight weeks of double-blind treatment. The primary endpoint was the percentage of patients achieving a serum uric acid concentration of <6.0 mg/dL based on measurements during each of the preceding three months. Baseline characteristics, including mean serum uric acid concentration, history or presence of tophi, age, sex ratio, and racial distribution, were similar in all three groups. Most subjects were white men age 50 years or older who reported drinking alcohol. Subjects had gout for a mean ± S.D. 11.9 ± 9.6 years, 24% (n = 186) had tophi or a history of tophi, 16% (n = 123) had a history of urolithiasis, and 44% (n = 331) had previously taken a uric-acid-lowering therapy. A serum uric acid concentration of <6.0 mg/dL during the preceding three months was attained by 53% (n = 136), 62% (n = 154), and 21% (n = 53) of patients receiving febuxostat 80 mg, febuxostat 120 mg, and allopurinol, respectively (p < 0.001 for febuxostat groups versus allopurinol group). A significantly higher percentage of patients treated with febuxostat (80 mg: 80%, n = 196; and 120 mg: 88%, n = 211) achieved a serum uric acid concentration of <6.0 mg/dL by week 2 and maintained this concentration through week 52 (p < 0.001) compared with those treated with allopurinol (42%, n = 98). During weeks 9–52, the overall frequency of gout flares was similar across treatment groups (64% [n = 147] with febuxostat 80 mg/day, 70% [n = 150] with febuxostat 120 mg/day, and 64% [n = 150] for allopurinol). The percent reduction of tophi varied among the groups, with an 83% (n = 32) reduction in the febuxostat 80-mg group, a 66% (n = 26) reduction in the febuxostat 120-mg group, and a 50% (n = 30) reduction in the allopurinol group, but these differences were not statistically significant. More patients receiving febuxostat withdrew from the study due to loss to follow-up or adverse effects (e.g., gout flares, abnormal liver function test values) compared with the allopurinol group (p = 0.003 for febuxostat 120 mg [39%] versus allopurinol [26%]). Even though febuxostat was more efficacious in reducing serum uric acid levels, it was not tolerated as well as allopurinol, primarily due to an increased rate of occurrence of gout flares with febuxostat 80 and 120 mg (3.9% [n = 10] and 11% [n = 28] versus 3.5% [n = 9, p < 0.001 for both comparisons] in the allopurinol group).[35,36]

Allopurinol and Placebo-controlled Efficacy Study of Febuxostat The Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat (APEX) sought to confirm and expand on the results of FACT by comparing the safety and efficacy of febuxostat 80 mg (n = 267), 120 mg (n = 269), or 240 mg (n = 134) with those of allopurinol 300 mg or 100 mg (n = 268) (for patients with renal impairment [serum creatinine {SCr} concentration of >1.5 but ≤2.0 mg/dL]) and placebo (n = 134) in 1072 patients with hyperuricemia and gout.[37] Either colchicine 0.6 mg once daily or naproxen 250 mg twice daily was provided during a washout period and continued for the first 8 weeks of the study as prophylaxis for gout regardless of prior gout therapy. Most study participants were white (94%), men (78%), and age 45–65 years (56%). The mean duration of gout was 10.9 years, and 89% of patients had experienced a gout flare within the past year. Tophi had been present for a mean of 5.7 years, and 29% of patients had a palpable tophus. The primary endpoint—a serum uric acid concentration of <6 mg/dL—was assessed over 28 weeks and attained by 48% (n = 126), 65% (n = 175), 69% (n = 92), 22% (n = 60), and 0% of patients receiving febuxostat 80 mg, febuxostat 120 mg, febuxostat 240 mg, allopurinol, and placebo, respectively (p < 0.001 for all groups versus placebo). In patients with impaired renal function, the primary endpoint was reached by 44% (n = 4), 46% (n = 5), and 60% (n = 3) of those receiving febuxostat 80, 120, and 240 mg, respectively, and 0% in the allopurinol and placebo groups. At week 28 and the final visit (after baseline visit), there were significant decreases (p ≤ 0.05) from baseline in serum uric acid levels in all febuxostat groups (48% and 45% for 80 mg, 55% and 52% for 120 mg, and 68% and 66% for 240 mg, respectively) versus allopurinol (34% and 34%, respectively) and placebo (4% and 3%, respectively). The number of patients requiring treatment for gout flares decreased with continued treatment. Overall, there were no statistically significant differences between the groups regarding patients requiring treatment for gout flares in week 8 (after the prophylaxis period) through week 28. During the prophylaxis period, more patients receiving febuxostat 120 mg (36%, n = 97) and 240 mg (26%, n = 69) required treatment for gout flares (p ≤ 0.05) compared with those receiving febuxostat 80 mg (28%, n = 73), allopurinol (23%, n = 61), or placebo (20%, n = 27). A decrease in the number of tophi observed with febuxostat 120 mg (1.2) versus placebo (0.3) was significant (p ≤ 0.05) at week 28, but no significant differences were noticed with the other treatment groups. Adverse effects were similar across all treatment groups, except diarrhea (3% [n = 4] versus <1% [n = 1]) and dizziness (7% [n = 9] versus 2% [n = 6], respectively) with febuxostat 240 mg versus allopurinol (p ≤ 0.05).

Confirmation of Febuxostat in Reducing and Maintaining Serum Urate trial The Confirmation of Febuxostat in Reducing and Maintaining Serum Urate (CONFIRMS) trial compared the safety and efficacy of febuxostat 40 mg (n = 757) and 80 mg (n = 756) with allopurinol (n = 755) dosed based on renal function in 2268 patients with hyperuricemia and gout.[38] Patients with normal renal function or mild impairment (CLcr of 60–89 mL/min) received a 300-mg dose of allopurinol, and patients with moderate renal impairment (CLcr of 30–59 mL/min) received a 200-mg dose. Prophylaxis for gout was given in the form of colchicine 0.6 mg daily or naproxen 250 mg daily with lansoprazole 15 mg daily for a 30-day washout period for subjects receiving prior uric-acid-lowering therapy and throughout the six-month treatment period for all subjects. The primary endpoint was the percentage of patients who achieved a final serum uric acid concentration of <6 mg/dL. The secondary endpoint was the percentage of patients with mild or moderate renal impairment who achieved a final serum uric acid concentration of <6 mg/dL. There were no significant differences in regard to demographics or gout-related or comorbid characteristics across the treatment groups. Most subjects were white (82%, n = 1860), men (94%, n = 2133), and obese (body mass index of ≥30 kg/m2; 64%, n = 1452) and reported drinking alcohol (68%, n = 1543). A three- to five-year open label uric-acid-lowering therapy trial with either febuxostat or allopurinol had been previously completed by 276 of the patients participating in the CONFIRMS trial.[38] When compared with patients who had not previously participated in either long-term study, patients from the prior trial had fewer tophi at baseline (22.3% [n = 444] versus 12.5% [n = 34], respectively; p < 0.001). The primary endpoint was achieved by 45.2% (n = 342), 67.1% (n = 507), and 42.1% (n = 318) of patients in the febuxostat 40-mg, febuxostat 80-mg, and allopurinol groups, respectively. Febuxostat 80 mg was superior to febuxostat 40 mg and allopurinol in lowering serum uric acid levels (p < 0.001). In patients with mild or moderate renal impairment (n = 1483), febuxostat 80 mg lowered serum uric acid levels more than did febuxostat 40 mg (71.6% [n = 360] versus 49.7% [n = 238], p < 0.0001), and febuxostat 80 and 40 mg lowered serum uric acid levels more than did allopurinol (42.3% [n = 212] for allopurinol, p < 0.0001 compared with febuxostat 80 mg and p = 0.021 compared with febuxostat 40 mg). Adverse-event rates were similar across all treatment groups. The CONFIRMS study demonstrated that febuxostat 80 mg was more effective at lowering serum uric acid levels than were febuxostat 40 mg and allopurinol. In patients with renal impairment, febuxostat was more effective than allopurinol, with a comparable adverse-effect profile.

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