OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

View in own window

DRUG	CAS REGISTRY NO	MOLECULAR FORMULA	STRUCTURE
Febuxostat	144060-53-7	C16-H16-N2-O3-S

ANNOTATED BIBLIOGRAPHY

References updated: 29 January 2018

• 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: 16339094]

  (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: 15751090]

  (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: 17132810]

  (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: 19075968]

  (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: 18975369]

  (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: 18729537]

  (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: 19247302]

  (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: 19141576]

  (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: 19286847]

  (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: 22132950]

  (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: 21330679]

  (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: 24326033]

  (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).
• Febuxostat: hepatic failure. Prescrire Int 2013; 22: 297. [PubMed: 24600733]

  (News report mentions that 13 reports of acute liver failure during febuxostat therapy have been reported to the European pharmacovigilance databse, 6 of which were fatal).
• 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; 17: 679-86. [PubMed: 24467549]

  (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).
• Ito K, Ueda Y, Miyazawa H, Kaku Y, Hirai K, Hoshino T, Nabata A, et al. Acute severe liver dysfunction induced by febuxostat in a patient undergoing hemodialysis. CEN Case Rep 2014; 3: 158-61. [PMC free article: PMC5411563] [PubMed: 28509193]

  (58 year old man with type 2 dfiabetes and chronic renal failure developed marked serum enzyme elevations within 2 days of starting hemodialysis and switching from allopurinol to febuxostat [ALT rising from 13 to 1134 U/L, Alk P and bilirubin normal], abnormalities resolving within 2 weeks of stopping).
• Chou HY, Chen CB, Cheng CY, Chen YA, Ng CY, Kuo KL, Chen WL, Chen CH. Febuxostat-associated drug reaction with eosinophilia and systemic symptoms (DRESS). J Clin Pharm Ther 2015; 40: 689-92. [PubMed: 26365588]

  (81 year old Taiwanese man developed fever, severe rash, lymphadenopathy and facial edema without eosinophilia 2 days after starting febuxostat [ALT 66 rising to 210 U/L, bilirubin normal], resolving within 3 weeks of stopping).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 8 [0.9%] were attributed to agents used to treat gout, including 7 to allopurinol and 1 to febuxostat [Bohm 2016]).
• Bohm M, Vuppalanchi R, Chalasani N; Drug-Induced Liver Injury Network (DILIN). Febuxostat-induced acute liver injury. Hepatology 2016; 63: 1047-9. [PMC free article: PMC4764455] [PubMed: 26679098]

  (34 year old man with gout developed jaundice 2 months after adding febuxostat to a regimen of allopurinol and colchicine [bilirubin 8.3 mg/dL, ALT 148 U/L, Alk P 201 U/L] with persistence of injury for over a month at the time of a normal ERCP, but then resolution within 3 weeks of stopping febuxostat).