Febuxostat for Treatment of Chronic Gout

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


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

In This Article

Long-term Studies

Two long-term, open-label studies, which were extensions of previously published trials, assessed the clinical efficacy, safety, and tolerability of serum uric acid lowering and maintenance with febuxostat in patients with gout.

Febuxostat Open-label Clinical Trial of Urate-lowering Efficacy and Safety

The Febuxostat Open-Label Clinical Trial of Urate-Lowering Efficacy and Safety (FOCUS) is a five-year extension of the previously discussed febuxostat versus placebo 28-day Phase II trial.[10,39] The number of patients achieving and maintaining a serum uric acid concentration of <6.0 mg/dL was the primary endpoint; the percent reduction from the baseline serum uric acid level was a secondary endpoint. A total of 116 patients in the extension study received febuxostat 80 mg daily for 4 weeks followed by febuxostat 40 mg (n = 8), 80 mg (n = 79), or 120 mg (n = 29) daily for weeks 4–24 in order to keep their serum uric acid concentration between 3.0 and <6.0 mg/dL; then, a stable dose was maintained beyond week 24. Most patients (62%, n = 72) remained on the initial febuxostat 80-mg/day dose. Study subjects were primarily Caucasian (85%, n = 99) and men (91%, n = 105) with a mean age of 53.3 years. Tophi were present in about one fourth of the subjects at baseline. Antiinflammatory medications and analgesics were among the most commonly used concomitant medications, as 98% (n = 114) of patients used medications other than febuxostat and prophylactic colchicine.

The serum uric acid concentration was <6.0 mg/dL in 93% (n = 54) of all patients at year 5 who remained in the study and in 83% (n = 95) of all patients at the final visit defined as the last visit on study drug at any point during the study. After 12 months of treatment, patients with baseline tophi reported gout flare rates as high as 31% (n = 8) compared with 10% (n = 9) for patients without baseline tophi, but flares did decrease to less than 10% (n = 2) in the former group by year 4. FOCUS demonstrated the ability of febuxostat to lower and maintain the serum uric acid concentration of <6.0 mg/dL for up to five years.[39] The number of gout flares declined to zero in subjects who remained in the study after five years of therapy with febuxostat. Of the 116 patients who were enrolled in the study, 58 discontinued prematurely, with 38 discontinuing enrollment in year 1. Personal reasons (19%, n = 22) and adverse events (11.2%, n = 13) were the most common reasons for discontinuation. Although most adverse events were mild or moderate in severity, 13 patients cited an adverse event (e.g., abnormal liver function test value, cancer, increased SCr value) as a primary reason for premature discontinuation.

Febuxostat/Allopurinol Comparative Extension Long-term Study

The Febuxostat/Allopurinol Comparative Extension Long-Term (EXCEL) study included 1086 participants of either FACT[35] or APEX,[37] both of which were double-blind Phase III trials.[11] Patients initially received febuxostat 80 mg daily (n = 351), but the protocol was modified to randomly assign patients in a 2:2:1 ratio to febuxostat 80 mg daily (n = 299), febuxostat 120 mg daily (n = 291), or allopurinol (dosed according to renal function) (n = 145). Patients could change febuxostat dosages during the first six months of the trial, but dosages were to be stabilized and maintained by month 6. Subjects received colchicine (0.6 mg daily) or naproxen (250 mg daily) during the first two months of the study to reduce gout flares. The number of patients achieving and maintaining a serum uric acid concentration of <6.0 mg/dL at each visit was the primary endpoint, and the percent reduction from the baseline serum urea acid level was a secondary endpoint.

Most patients were Caucasian (80%, n = 519) with a mean age of 51.34 years. Alcohol use (1–14 drinks imbibed weekly) was reported by 68% of patients (n = 433). At baseline, defined as entry into either previous Phase III trial, normal renal function (SCr of <1.5 mg/dL) was present in 98% of patients (n = 1066). At least one palpable tophus was present in 214 patients (20%). Concomitant medication use (i.e., antiinflammatory drugs and anti-rheumatics, analgesics, antibiotics, and antihyperlipidemics) was reported by 95% (n = 1086) of patients.

Premature study discontinuation occurred in 32% (n = 194), 44.1% (n = 171), and 62% (n = 57) of patients in the febuxostat 80-mg, febuxostat 120-mg, and allopurinol groups, respectively. Reasons for withdrawal included adverse events, personal reasons, lost to follow-up, and therapeutic failure.

Patients receiving febuxostat 80 mg (81%, n = 501) and 120 mg (87%, n = 241) achieved the primary endpoint after one month of therapy, and at least 80% of patients in both groups maintained the primary endpoint for the duration of treatment. Only 46% of patients (n = 64) in the allopurinol group achieved the primary endpoint after one month of therapy, but this increased to 82% (n = 37) of patients by month 12. The mean reductions from baseline serum uric acid levels were 47% (n = 291), 53% (n = 147), and 32% (n = 44) with febuxostat 80 mg, febuxostat 120 mg, and allopurinol, respectively. The number and size of tophi decreased across all treatment groups. Complete resolution of to-phi was achieved by 46% (n = 299) of patients in the febuxostat 80-mg group, 36% (n = 104) of patients in the febuxostat 120-mg group, and 29% (n = 42) of patients in the allopurinol group.

Adverse events were similar across all treatment groups but were summarized according to the treatment the patient was receiving at the time of the event. Adverse events adjusted for duration of exposure were reported as 227, 216, and 245 events per 100 patient-years of exposure, and serious adverse events were 11, 9, and 12 events per 100 patient-years of exposure for the febuxostat 80-mg, febuxostat 120-mg, and allopurinol groups, respectively. Serious adverse events were reported by 161 patients, with cardiac disorders being reported most frequently by 48 patients, all of whom had a history of cardiovascular disease or other underlying risk factors.

Ten patients died during the study while receiving febuxostat (80 mg, n = 7; 120 mg, n = 3). Cardiovascular events were associated with the death of 6 patients, all of whom had an extensive history of cardiovascular disease. Two deaths were due to cancer, one was due to postsurgical sepsis, and one was due to a bleeding event in a patient receiving warfarin and heparin. Four patients who died were 65 years of age or younger, two were age 65–74 years, and four were age 75 years or older. When the deaths were assessed by the investigators, no evident relationship between the drug dose or length of therapy was identified.[11]


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