Expanding the boundaries of urate-lowering therapy: place of febuxostat in gout treatment

I.Yu. Golovach, Ye.D. Yehudina


Gout is a chronic disease requiring the appointment of a permanent urate-lowering therapy. The gold standard of such therapy is allopurinol. Over the last decade, a new drug, febuxostat, a selective xanthine oxidase inhibitor, namely xanthine reductase, has appeared in the doctors’ arsenal. The article reviewed the literature on the main clinical studies of this drug, which showed its effectiveness, comparable or exceeding the effectiveness of allopurinol, and also demonstrated its possible appointment to patients with reduced kidney function, with an allergic reaction or resistance to allopurinol, that significantly improves the prognosis. Elderly patients, patients with mild or moderate kidney failure (glomerular filtration rate 30–89 ml/min), mild and moderate hepatic insufficiency do not require febuxostat dose adjustment, which greatly expands the possibilities of using this drug to achieve the target levels of uric acid. The article discusses the cardio-safety of the urate-lowering therapy, first of all of febuxostat, as well as assesses the results of the last known researches on cardiovascular safety of allopurinol and febuxostat. The algorithms of choice of preparation for the starting therapy of gout in case of intolerance of allopurinol, cardiovascular diseases, renal dysfunction are presented. Patients with contraindications to allopurinol should start treatment with uricosuric agent or febuxostat, in accordance with their concomitant diseases. If the target uricemia is not achieved after a gradual increase in dose to the maximum permissible one, a doctor should discuss with the patient a combination of febuxostat with uricosuric agent.


gout; hyperuricemia; uric acid; urate-lowering therapy; treatment; safety; allopurinol; febuxostat; review


Murrell GA, Rapeport WG. Clinical pharmacokinetics of allopurinol. Clin Pharmacokinet. 1986; 11:343–353.

Golovach І.Yu. Suchasna terapia podagry kris pryzmu efektivnosta I bezpechnosti. Bol. Sustavy. Pozvonochnik. 2015; 2(18):37-43.

Richette P., Doherty M., Pascual E., et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017 ;76(1):29-42. doi: 10.1136/annrheumdis-2016-209707.

EMA (European Medicines Agency).

Khanna D., Fitzgerald J.D., Khanna P.P., et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) 2012; 64:1431–1446.

Li S., Yang H., Guo Y., et al. Comparative efficacy and safety of urate-lowering therapy for the treatment of hyperuricemia: A systematic review and network meta-analysis. Sci Rep. 2016;6:33082. doi: 10.1038/srep33082.

Sun Y., Li L., Zhou T.Y., Lu W. A model-based meta-analysis to compare urate-lowering response rate of febuxostat and allopurinol in gout patient. Yao Xue Xue Bao. 2014;49:1674–1683.

Zhou Q., Su J., Zhou T., et al. A study comparing the safety and efficacy of febuxostat, allopurinol, and benzbromarone in Chinese gout patients: a retrospective cohort study . Int J Clin Pharmacol Ther. 2017;55(2):163-168. doi: 10.5414/CP202629

Wang S. The efficacy of febuxostat and allopurinol in the treatment of gout with hyperuricemia. Pak J Pharm Sci. 2018;31(4(Special)):1623-1627.

Faruque L.I., Ehteshami-Afshar A., Wiebe N., et al. A systematic review and meta-analysis on the safety and efficacy of febuxostat versus allopurinol in chronic gout. Semin Arthritis Rheum. 2013;43:367–375. doi: 10.1016/j.semarthrit.2013.05.004

Takano Y., Hase-Aoki K., Horiuchi H., et al. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci. 2005;76:1835–1847. doi: 10.1016/j.lfs.2004.10.031

Okamoto K., Eger B.T., Nishino T., et al. An extremely potent inhibitor of xanthinoxidoreductase. J Biol Chem. 2003;278(3): 1848-55.

Chinchilla S.P., Urionaguena I., Perez-Ruiz F. Febuxostat for the chronic management of hyperuricemia in patients with gout. Expert Rev Clin Pharmacol. 2016;9:665–673. doi: 10.1586/17512433.2016.1162094

Frampton J.E. Febuxostat: a review of its use in the treatment of hyperuricaemia in patients with gout. Drugs 2015; 75:427–438. doi: 10.1007/s40265-015-0360-7.

Juge P.A., Truchetet M.E., Pillebout E., et al. Efficacy and safety of febuxostat in 73 gouty patients with stage 4/5 chronic kidney disease: a retrospective study of 10 centers. Joint Bone Spine 2017; 84:595–598. doi: 10.1016/j.jbspin.2016.09.020.

Lim D.H., Oh J.S., Ahn S.M., et al. Febuxostat in hyperuricemic patients with advanced CKD. Am J Kidney Dis. 2016; 68:819–821. doi: 10.1053/j.ajkd.2016.07.001

Seegmiller J.E. Xantine stone formation. Am J Med. 1968;45(5):780-3.

Schumacher H.R. Jr, Becker M.A., Wortmann R.L., et al. 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; 59:1540–1548. doi: 10.1002/art.24209.

Becker M.A., Schumacher H.R. Jr, Wortmann R.L., et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005; 353:2450–2461. DOI: 10.1056/NEJMoa050373

Becker M.A., Schumacher H.R., Espinoza L.R., et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010; 12:R63. doi: 10.1186/ar2978.

Becker M.A., Fitz-Patrick D., Choi H.K., et al. An open-label, 6-month study of allopurinol safety in gout: the LASSO study. Semin Arthritis Rheum 2015; 45:174–18. doi: 10.1016/j.semarthrit.2015.05.005

Stamp L.K., Chapman P.T., Barclay M.L., et al. A randomised controlled trial of the efficacy and safety of allopurinol dose escalation to achieve target serum urate in people with gout. Ann Rheum Dis. 2017; 76:1522–1528. doi: 10.1136/annrheumdis-2016-210872

Stamp L.K., Chapman P.T., Barclay M., et al. Allopurinol dose escalation to achieve serum urate below 6 mg/dL: an open-label extension study. Ann Rheum Dis. 2017; 76:2065–2070. doi: 10.1136/annrheumdis-2017-211873

Registration file, MIOL febuxostat risk management plan v.4.1, Oct 2013.

Bardin T., Chales G., Pascart T., et al. Risk of cutaneous adverse events with febuxostat treatment in patients with skin reaction to allopurinol. A retrospective, hospital-based study of 101 patients with consecutive allopurinol and febuxostat treatment. Joint Bone Spine. 2016; 83:314–317. doi: 10.1016/j.jbspin.2015.07.011.

Ryu H.J., Song R., Kim H.W., et al. Clinical risk factors for adverse events in allopurinol users. J Clin Pharmacol. 2013; 53:211–216. doi: 10.1177/0091270012439715.

Yu K.H., Lai J.H., Hsu P.N., et al. Safety and efficacy of oral febuxostat for treatment of HLA-B_5801-negative gout: a randomized, open-label, multicentre, allopurinol-controlled study. Scand J Rheumatol.2016;45:304–311. doi: 10.3109/03009742.2015.1099729

Kim S.C., Newcomb C., Margolis D., et al. Severe cutaneous reactions requiring hospitalization in allopurinol initiators: a population-based cohort study. Arthritis Care Res (Hoboken) 2013; 65:578–584. doi: 10.1002/acr.21817.

Lu N., Rai S.K., Terkeltaub R., et al. Racial disparities in the risk of Stevens–Johnson Syndrome and toxic epidermal necrolysis as urate-lowering drug adverse events in the United States. Semin Arthritis Rheum. 2016; 46:253–258. doi: 10.1016/j.semarthrit.2016.03.014.

Yang C.Y., Chen C.H., Deng S.T., et al. Allopurinol use and risk of fatal hypersensitivity reactions: a nationwide population-based study in Taiwan. JAMA Intern Med. 2015; 175:1550–1557. doi: 10.1001/jamainternmed.2015.3536.

Hung S.I., Chung W.H., Liou L.B., et al. HLA-B_5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci USA. 2005; 102:4134–4139. DOI:10.1073/pnas.0409500102

Ko T.M., Tsai C.Y., Chen S.Y., et al. Use of HLA-B_58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study. BMJ. 2015; 351:h4848. doi:

Chou H.Y., Chen C.B., Cheng C.Y., et al. Febuxostat-associated drug reaction with eosinophilia and systemic symptoms (DRESS). J Clin Pharm Ther. 2015; 40:689–692. doi: 10.1111/jcpt.12322

Lien Y.H., Logan J.L. Cross-reactions between allopurinol and febuxostat. Am J Med. 2017; 130:e67–e68. doi: 10.1016/j.amjmed.2016.08.042

Chohan S. Safety and efficacy of febuxostat treatment in subjects with gout and severe allopurinol adverse reactions. J Rheumatol. 2011; 38: 1957–1959. doi: 10.3899/jrheum.110092

White W.B., Saag K.G., Becker M.A., et al. Cardiovaрular safety of febuxostat or allopurinol in patients with gout. N Engl J Med. 2018; 378:1200–1210. DOI: 10.1056/NEJMoa1710895

Choi H., Neogi T., Stamp L., Dalbeth N., Terkeltaub R. Implications of the cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular morbidities (CARES) trial and associated FDA public safety alert. Arthritis Rheumatol. 2018; 70:1702–1709. doi: 10.1002/art.40583.

Yokota T., Fukushima A., Kinugawa S., et al. Randomized Trial of Effect of Urate- Lowering Agent Febuxostat in Chronic Heart Failure Patients with Hyperuricemia (LEAF-CHF). Int Heart J. 2018;59(5):976-982. doi: 10.1536/ihj.17-560.

Meng J., Li Y., Yuan X., Lu Y. Effects of febuxostat on insulin resistance and expression of high-sensitivity C-reactive protein in patients with primary gout. Rheumatol Int. 2017;37(2):299-303. doi: 10.1007/s00296- 016-3612-2

Zhang M., Solomon D.H., Desai R.J., et al. Assessment of cardiovascular risk in older patients with gout initiating febuxostat versus allopurinol. Circulation. 2018; 138:1116–1126. doi: 10.1161/CIRCULATIONAHA.118.033992.

MacDonald T.M., Ford I., Nuki G., et al. Members of the FAST Study Group. Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia. BMJ Open. 2014;4:005354.

Kojima S., Matsui K., Ogawa H., et al. Rationale, design, and baseline characteristics of a study to evaluate the effect of febuxostat in preventing cerebral, cardiovascular, and renal events in patients with hyperuricemia. J Cardiol. 2017; 69:169–175. doi: 10.1016/j.jjcc.2016.02.015

Dalbeth N., Kumar S., Stamp L., Gow P. Dose adjustment of allopurinol according to creatinine clearance does not provide adequate control of hyperuricemia in patients with gout. J Rheumatol. 2006; 33:1646–1650.

Stamp L.K., Taylor W.J., Jones P.B., et al. Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol. Arthritis Rheum. 2012; 64:2529–2536. doi: 10.1002/art.34488.

Ivanov D.D. Sinyachenko O.V., Bevzenko T.B., Fedorov D.M. Sravnitelnaya ocenka primeneniya urikodepressantov allopurinola I febuksostata pri podagricheskoj nefropatii. Soobshchenie 1. Klinicheskoe ispytanie. Pochki. 2018; 7(3): 188-195. doi:

Van Echteld I.A., van Durme C., Falzon L., et al. Treatment of Gout Patients with Impairment of Renal Function: A Systematic Literature Review. J Rheumatol. 2014;92 Suppl.:48-54. doi: 10.3899/jrheum.140462. 49.

Tanaka K., Nakayama M., Kanno M., et al. Renoprotective effects of febuxostat in hyper- uricemic patients with chronic kidney dis- ease: a parallel-group, randomized, con- trolled trial. Clin Exp Nephrol. 2015; 19(6):1044-53. doi: 10.1007/s10157-015- 1095-1. Epub 2015 Feb 13.

Sinyachenko O.V., Bevzenko T.B., Fedorov D.M. Sravnitelnaya ocenka primeneniya urikodepressantov allopurinola I febuksostata pri podagricheskoj nefropatii. Soobshchenie 2. Ehksperimentalnoe issledovanie. Pochki. 2018; 7(3): 196-202. doi:

Omori H., Kawada N., Inoue K., et al. Use of xanthine oxidase inhibitor febuxostat inhibits renal interstitial inflammation and fibrosis in unilateral ureteral obstructive nephropathy. Clin Exp Nephrol. 2012;16:549–556. doi: 10.1007/s10157-012-0609-3.

Sezai A., Soma M., Nakata K., et al. Comparison of febuxostat and allopurinol for hyperuricemia in cardiac surgery patients with chronic kidney disease (NU-FLASH trial for CKD) J Cardiol. 2015;66:298–303. doi: 10.1016/j.jjcc.2014.12.017

Shekelle P.G., Newberry S.J., FitzGerald J.D., et al. Management of gout: A systematic review in support of an american college of physicians clinical practice guideline. Ann Intern Med. 2017;166:37-51. doi: 10.7326/L17-0212.

Liu X., Liu K., Sun Q., et al. Efficacy and safety of febuxostat for treating hyperuricemia in patients with chronic kidney disease and in renal transplant recipients: a systematic review and meta-analysis. Exp Ther Med. 2018; 16:1859–1865. doi: 10.3892/etm.2018.6367

Kanellis J, Kang DH. Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease. Semin Nephrol. 2005;25(1):39–42. doi: 10.1016/j.semnephrol.2004.09.007

Squadrito G.L., Cueto R., Splenser A.E., et al. Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid. Arch Biochem Biophys. 2000;376(2):333–337. doi: 10.1006/abbi.2000.1721

Singh J.A., Cleveland J.D. Use of urate-lowering therapies is not associated with an increase in the risk of incident dementia in older adults. Ann Rheum Dis. 2018; 77(8):1243-1245. doi: 10.1136/annrheumdis-2017-212094

Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006;443(7113):787–795. doi: 10.1038/nature05292

Cicero A.F., Desideri G., Grossi G., et al. Serum uric acid and impaired cognitive function in a cohort of healthy young elderly: data from the Brisighella study. Intern Emerg Med. 2015;10(1):25–31. doi: 10.1007/s11739-014-1098-z.

Perna L., Mons U., Schottker B., Brenner H. Association of cognitive function and serum uric acid: are cardiovascular diseases a mediator among women? Exp Gerontol. 2016;81:37–41. doi: 10.1016/j.exger.2016.04.017.

Beydoun M.A., Canas J.A., Dore G.A., et al. Serum uric acid and its association with longitudinal cognitive change among urban adults. J Alzheimers Dis. 2016;52(4):1415–1430. doi: 10.3233/JAD-160028

Hong J.Y., Lan T.Y., Tang G.J., et al. Gout and the risk of dementia: a nationwide population-based cohort study. Arthritis Res Ther. 2015;17:139. doi: 10.1186/s13075-015-0642-1

Iwanaga T., Kobayashi D., Hirayama M., et al. Involvement of uric acid transporter in increased renal clearance of the xanthine oxidase inhibitor oxypurinol induced by a uricosuric agent, benzbromarone. Drug Metab Dispos. 2005; 33:1791–1795.

Day R.O., Graham G.G., Hicks M., et al. Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol. Clin Pharmacokinet 2007; 46:623–644. DOI:10.2165/00003088-200746080-00001

Bardin T., Keenan R.T., Khanna P.P., et al. Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study). Ann Rheum Dis. 2017; 76:811–820. doi: 10.1136/annrheumdis-2016-209213.

Saag K.G., Fitz-Patrick D., Kopicko J., et al. Lesinurad combined with allopurinol: a randomized, double-blind, placebo-controlled study in gout patients with an inadequate response to standard-of-care allopurinol (a US-based study). Arthritis Rheumatol. 2017; 69:203–212. doi: 10.1136/annrheumdis-2016-209213

Dalbeth N., Jones G., Terkeltaub R., et al. Lesinurad, a selective uric acid reabsorption inhibitor, in combination with febuxostat in patients with tophaceous gout: findings of a phase III clinical trial. Arthritis Rheumatol. 2017; 69:1903–1913. doi: 10.1002/art.40159.

Perez-Ruiz F. Failure to Reach Serum Urate Target Is Associated with Elevated Mortality in Gout [abstract]. Arthritis Rheum. 2018;70(Suppl 9):954-955.

Copyright (c) 2019 TRAUMA

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.


© Publishing House Zaslavsky, 1997-2020


   Seo анализ сайта