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

Safety

Febuxostat is approved only for use in adults. The safety and effectiveness of febuxostat in pediatric patients have not been established at this time. Based on data reported from clinical trials, febuxostat appears to be generally well tolerated. No Q-T interval prolongation was seen with febuxostat 80 or 300 mg daily for four days.[27] The most common treatment-related adverse effects documented were headache, arthralgias, abdominal pain, nausea, abnormal liver function test values, flushing, and dizziness. Patients treated with febuxostat should be monitored for signs and symptoms of cardiovascular events (e.g., myocardial infarction [MI], stroke). In clinical trials there were higher rates of cardiovascular thromboembolic events, including cardiovascular death, nonfatal MI, and nonfatal stroke with febuxostat versus allopurinol. In their 28-week, Phase III trial, Schumacher et al.[37] documented adverse cardiovascular events across all treatment groups. A total of 11 cardiovascular events occurred in the febuxostat group, with 5 (2%) occurring in the febuxostat 80-mg group, 5 (2%) in the 120-mg group, and 1 (<1%) in the 240-mg group. Two other cardiovascular events occurred, 1 (<1%) in the placebo group and 1 (<1%) in the allopurinol group. The difference in cardiovascular events among groups was not statistically significant. Cardiovascular events included chest pain, coronary artery disease, MI, and atrial fibrillation in subjects with a history of underlying cardiovascular disease or risk factors. A Phase III trial is currently being conducted to evaluate the cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities.[40]

Data suggest an increased risk of flares after the initiation of uric-acid-lowering therapy.[41] The mechanism for this effect is poorly understood but has been attributed to sudden changes in uric acid concentrations.[22,41] In addition to the initiation of uric-acid-lowering therapy, gouty flares can be caused by other precipitating factors, such as infection, surgery, alcohol consumption, and pharmacologic agents that increase uric acid concentrations.[5] Prophylactic therapy has proved beneficial when administered before uric-acid-lowering pharmacotherapy. Febuxostat-treated patients had higher rates of acute gout flares and early study withdrawal in published comparative trials with allopurinol.[35,37] Bruce[26] detailed that up to 70% of patients had febuxostat-induced gout flares despite adequate prophylaxis. In a 28-day, Phase II study in which participants received febuxostat 40, 80, or 120 mg or placebo, the overall frequency of gout flares was similar in the 40-mg (35%) and placebo groups (37%) but higher in the 80-mg (43%) and 120-mg (55%) groups.[10] Increased flares after initiation of febuxostat may be secondary to rapid reduction in serum uric acid levels and induced mobilization of uric acid stores.[25]

As a xanthine oxidase inhibitor, febuxostat may interact with drugs that are metabolized by xanthine oxidase. Febuxostat is currently contraindicated in patients concurrently using azathioprine, mercaptopurine, or theophylline. Drug interaction studies with theophylline, mercaptopurine, and azathioprine have not yet been completed. One of the methods of metabolism for azathioprine and mercaptopurine is mediated by xanthine oxidase, and theophylline is a xanthine oxidase substrate. Inhibition of xanthine oxidase in the presence of these drugs may cause increased plasma concentrations of these drugs and potentiate toxicity. Febuxostat is highly protein bound, and in vitro studies have demonstrated a minimal impact of other protein-bound medications on the binding of febuxostat.[28]

Additional information is needed regarding the potential extent to which febuxostat displaces other protein-bound drugs in vivo. Most studies conducted with this novel agent evaluate medications commonly administered concurrently in patients with hyperuricemia and gout.[26] Current findings suggest a low drug–drug interaction potential for febuxostat.

The most common adverse effect leading to discontinuation from febuxostat in clinical trials was abnormal liver function test values, occurring in up to 6.6% of patients taking febuxostat.[26] In clinical trials, 2–3% of patients treated with febuxostat developed transaminase elevations of greater than three times the upper limit of normal.[3] These studies did not establish a dose– effect relationship between febuxostat and abnormal liver function test values. Compared with other uric-acid-lowering agents, the serum uric-acid-lowering effects of febuxostat were unaltered in individuals with renal impairment.[31,35] There are in-sufficient data in patients with severe renal impairment, as most studies did not evaluate individuals with a CLcr of <30 mL/min. Febuxostat pharmacodynamics or pharmaco-kinetics have not been investigated with respect to race.

Deaths in patients treated with febuxostat were reported in several clinical trials. Of 116 participants in FOCUS, 6 had occurrences of atrial fibrillation or atrioventricular block, determined to be unrelated to febuxostat.[39] Serious cardiovascular events (chest pain, coronary artery disease, MI, and atrial fibrillation) occurred with similar frequency (3–4%) across all treatment groups in APEX.[37] The EXCEL trial documented serious adverse events across all treatment groups.[11] However, of the 10 documented deaths that occurred in participants receiving febuxostat, 6 were cardiovascular-related deaths.[11] The 4 deaths reported in FACT and the 5 in the CONFIRMS trial were not related to febuxostat.[35,38]

While febuxostat is excreted in the milk of rats, it is unknown if febuxostat is excreted in human breast milk. Febuxostat is a pregnancy category C drug, as no well-controlled studies have included pregnant women. For patients for whom febuxostat is prescribed, it would seem prudent to complete laboratory assessments of liver function. Recommendations from the manufacturer include liver function assessment two and four months after the initiation of therapy and periodically thereafter.[30] Serum uric acid concentration should also be monitored at treatment initiation and regular intervals.

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