Febuxostat is a newly introduced non-purine xanthine oxidase inhibitor used for the treatment of gout. Chronic febuxostat therapy has been associated with minor serum aminotransferase elevations, but has yet to be linked to clinically apparent cases of acute liver injury.
Febuxostat is a non-purine inhibitor of xanthine oxidase that shares no structural homology to allopurinol or to hypoxanthine. Therapy with febuxostat leads to lowering of serum uric acid levels within a few weeks, and chronic therapy has been shown to decrease uric acid levels into target levels of <6 mg/dL and to decrease acute gouty attacks. Febuxostat was approved for use in Europe in 2008 and in the United States in 2009. Current indications include therapy and prevention of gout, uric acid nephropathy, and the hyperuricemia caused by malignancy and anticancer therapy. Febuxostat is not recommended as therapy of asymptomatic hyperuricemia. Febuxostat is available in tablets of 40 and 80 mg under the brand names of Uloric and Adenuric. The recommended initial dose for therapy of gout is 40 mg daily which can be increased to 80 mg daily to achieve uric acid levels below 6 mg/dL. Common side effects include nausea, diarrhea, dizziness and precipitation of acute gout for which reason it is often given in combination with colchicine for the first few months of treatment.
Liver test abnormalities have been reported to occur in 2% to 13% (average ~3.5%) of patients receiving febuxostat, but the levels are generally mild-to-moderate and self-limited. The height, nature and timing of these abnormalities have not been described. However, liver test elevations were the major reason for febuxostat discontinuation for adverse events (~2%) in clinical trials, despite the fact that no cases of jaundice or acute hepatitis were reported. The product labelling for febuxostat, however, lists potential side effects of hepatic steatosis, hepatitis and hepatomegaly. Another unrelated, nonpurine xanthine oxidase inhibitor (benzbromarone) was not approved for use in the United States because of its potential for hepatic toxicity.
Mechanism of Injury
The mechanism of febuxostat hepatotoxicity is believed to be due to its hepatic metabolism, the major pathway being glucuronidation with minor metabolism via the CYP 450 system.
Outcome and Management
The minor liver test abnormalities are reported to be self-limited, resolving with stopping drug and, in many instances, resolving rapidly even with drug continuation. No instances of acute liver failure or chronic liver injury have been reported due to febuxostat, but the clinical experience with this agent is limited.
REPRESENTATIVE TRADE NAMES
FDA product labeling at DailyMed, National Library of Medicine, NIH
Uloric® (febuxostat) Product Labeling, Takeda Pharmaceuticals America, Inc., February 2009.
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References updated: 27 September 2011
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Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Palo WA, Eustace D, Vernillet L, Joseph-Ridge N. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005; 353: 2450-61. PubMed Citation (762 patients at 112 North American centers received either allopurinol [300 mg/day] or febuxostat [80, 120 or 240 mg/day] for 52 weeks; reduction of uric acid to <6 mg/dL achieved in 53-62% of febuxostat- vs 21% of allopurinol-treated patients; rates of acute gout were similar; liver test abnormalities in 4-5% of febuxostat vs 4% of allopurinol recipients; most common cause of discontinuation [2.3%]).
Becker MA, Schumacher HR, Wortmann RL, MacDonald PA, Palo WA, Eustace D, Vernillet L, Joseph-Ridge N. 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. Arthr Rheum 2005; 52: 916-23. PubMed Citation (153 patients were randomized to febuxostat [40, 80 or 120 mg/day] or placebo for 28 days; fall of uric acid to <6 mg/dL in 56-94% of treated but none on placebo; abnormal liver tests in 9.5% of febuxostat but none of placebo-recipients).
Bruce SP. Febuxostat: a selective xanthine oxidase inhibitor for the treatment of hyperuricemia and gout. Ann Pharmacother 2006; 40: 2187-94. PubMed Citation (Review of pharmacology, mechanisms of action, clinical efficacy and side effects of febuxostat: liver test abnormalities occur in 7.5-13.5% on febuxostat compared to 0% on placebo).
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Schumacher HR Jr, Becker MA, Wortmann RL, MacDonald PA, Hunt B, Streit J, Lademacher C, Joseph-Ridge N. 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: 1540-8. PubMed Citation (1072 patients with gout randomized to febuxostat, allopurinol or placebo and treated for 28 weeks; abnormal liver tests [=1.5 times ULN] occurred in 4-6% on febuxostat, 2% placebo, and 6% allopurinol).
Hair PI, McCormack PL, Keating GM. Febuxostat. Drugs 2008; 68: 1865-74. PubMed Citation (Review of mechanism of action, pharmacokinetics, tolerability and efficacy of febuxostat; in pooled analyses liver test elevations occurred in 3.5% of febuxostat treated [80 mg/day] leading to withdrawal in 2% compared to 4.2% rate of liver test elevations and 0.5% withdrawals with allopurinol [300 mg/day]).
Pascual E, Sivera F, Yasothan U, Kirkpatrick P. Febuxostat. Nat Rev Drug Discov 2009; 8: 191-2. PubMed Citation (Brief review of febuxostat therapy in gout).
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; 48:188-94. PubMed Citation (Open label extension of phase 2 study [Becker 2005]; of 116 patients with dose adjustment of 40-120 mg/day; gradual decrease in episodes of acute gout from 25/month to none, but also gradual increasing drop out rate [to 58 patients at 5 years]: liver test abnormalities in 13%, requiring discontinuation in 3%, no hepatitis or jaundice reported).
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; 1273-82. PubMed Citation (1086 subjects enrolled in extension study of febuxostat or allopurinol for 31-40 months; ALT elevations ultimately required withdrawal in 9 of 801 patients [1.1%] on febuxostat [80 mg/day], two episodes of jaundice, but both thought to be due to unrelated biliary disease: stone and bile duct cancer).