Febuxostat is a newly introduced nonpurine 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 cases of clinically apparent acute liver injury.
Febuxostat (fe bux' oh stat) is a nonpurine 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 labeling 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 the 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.
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Case 1. Cholestatic hepatitis due to
[Modified from: DILIN Case 102-0191]
A 34 year old man with obesity and severe gout developed fatigue, nausea and abdominal pain followed by dark urine, jaundice and itching approximately 2 months after adding febuxostat (40 mg daily) to his regular regimen of colchicine (1.2 mg daily) and allopurinol (300 mg daily). He had no history of liver disease, alcohol use or risk factors for viral hepatitis. His other medical problems included severe obesity, hypertension, dyslipidemia, sleep apnea, depression and inactive sarcoidosis. Other medications included lisinopril, hydrochlorothiazide, amitriptyline and acetaminophen with codeine (1-2 tablets daily). he denied use of herbal medications or other over-the-counter products. On examination,
he was obese and jaundiced, but had no fever, rash or signs of chronic liver disease. Laboratory tests showed serum bilirubin 8.3 mg/dL, alkaline phosphatase 201 U/L, ALT 148 U/L and amylase 778 U/L (Table). A complete blood count was normal with 5% eosinophils. The INR was 1.09. He was admitted for evaluation and allopurinol, lisinopril and hydrochlorothiazide were stopped, while febuxostat was continued. Tests for hepatitis A, B, C
and E were negative as were antinuclear and smooth muscle autoantibodies. Ultrasound and CT Imaging of the abdomen showed biliary sludge and possible gallstones but no
evidence of biliary obstruction. ERCP confirmed these findings and a sphincterotomy was performed. Laboratory tests, however, improved minimally. A liver biopsy showed changes of intrahepatic cholestasis with mild inflammation and necrosis without bile duct injury or fibrosis. Forty days after initial presentation, febuxostat was discontinued. Within two weeks of stopping, symptoms resolved, and by four weeks after stopping, liver tests returned to normal. A gastric bypass procedure and concurrent cholecystectomy were done, the gallbladder showing evidence of acute and chronic inflammation but no gallstones. Allopurinol, lisinopril and hydrochlorothiazide were restarted and liver tests remained normal at follow up 6 months later.
||Febuxostat (40 mg daily)
||3+ (jaundice, hospitalization)
||Allopurinol, colchicine, lisinopril, hydrochlorothiazide, amitriptyline, acetaminophen, codeine, hydrocodone
|Time After Starting
||Time After Stopping
||Alk P (U/L)
||Spincterotomy, liver biopsy
Febuxostat has been associated with serum ALT levels in approximately 5% of treated patients, but cases of clinically apparent liver injury have not been reported. The current case was submitted to and rejected by five journals, perhaps explaining why there may be a dearth of reports of drug-induced liver injury even for agents that are strongly implicated in causing rare instances of hepatotoxicity. The present case was complicated by multiple coexisting medical conditions and coadministration of multiple medications, many of which have been implicated in causing liver injury (allopurinol, amitriptyline and in rare instances, lisinopril and even hydrochlorothiazide). In this instance, however, the liver injury persisted when the more conventional agents were stopped, but resolved rapidly once febuxostat was discontinued. The liver injury was cholestatic and without evidence of hypersensitivity (typical of allopurinol injury) or autoimmune features.
REPRESENTATIVE TRADE NAMES
Febuxostat – Uloric®
Antigout Agents/Gout Suppressants
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NO
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References updated: 14 March 2014
Grosser T, Smyth E, FitzGerald GA. Pharmacology of gout. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 994-1004. (Textbook of pharmacology and therapeutics).
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 occurred 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 occurred in 56-94% of treated but none on placebo; abnormal liver tests arose 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% of patients on febuxostat compared to 0% on placebo).
Yu KH. Febuxostat: a novel non-purine selective inhibitor of xanthine oxidase for the treatment of hyperuricemia in gout. Recent Pat Inflamm Allergy Drug Discov 2007; 1: 69-75. PubMed Citation (Critical review of literature on febuxostat).
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).
Becker MA, MacDonald PA, Hunt B, Gunawardhana L. Treating hyperuricemia of
gout: safety and efficacy of febuxostat and allopurinol in older versus younger
subjects. Nucleosides Nucleotides Nucleic Acids 2011; 30: 1011-7. PubMed Citation (Reanalysis of a 6 month trial of febuxostat comparing 374 older [>65 years of age] to 1895 younger patients found ALT elevations were less common among older than younger patients [10% vs 3% were >2 times, 3% vs 1% >3 times ULN], and no patient developed jaundice in association with ALT elevations).
Gray CL, Walters-Smith NE. Febuxostat for treatment of chronic gout. Am J
Health Syst Pharm 2011; 68: 389-98. PubMed Citation (Review of structure, mechanism of action, pharmacology, clinical efficacy and safety of febuxostat; the most commmon adverse event leading to discontinuation was ALT elevations, which occurred in 6.6% of recipients).
Faruque LI, Ehteshami-Afshar A, Wiebe N, Tjosvold L, Homik J, Tonelli M. A
systematic review and meta-analysis on the safety and efficacy of febuxostat
versus allopurinol in chronic gout. Semin Arthritis Rheum 2013; 43: 367-75.
PubMed Citation. (Review of efficacy and safety of febuxostat in comparison to allopurinol concludes that there is no evidence to justify the routine use of febuxostat at present; no discussion of hepatotoxicity or ALT elevations).
Huang X, Du H, Gu J, Zhao D, Jiang L, Li X, Zuo X, et al. An allopurinol-controlled, multicenter,
randomized, double-blind, parallel between-group, comparative study of febuxostat
in Chinese patients with gout and hyperuricemia. Int J Rheum Dis 2014 Jan 28.
[Epub ahead of print] PubMed Citation. (Trial of two doses of febuxostat vs allopurinol in 512 Chinese patients with gout found similar rates of side effects, liver test abnormalities arising in 3.5% of allopurinol and 2.9% and 1.2% of febuxostat treated subjects; no mention of clinically apparent liver injury).