Gout is a common arthritic disease that is increasing in prevalence, especially in affluent countries such as Australia. A systematic review of published information shows that the prevalence of gout and hyperuricaemia is high in Australia and increasing in relation to comparable countries, such as the United States, the United Kingdom, and New Zealand.
Gout is characterised by the formation of small urate crystals as a result of overproduction or underexcretion of uric acid. Deposition of these crystals in and around the joints leads to inflammation, swelling and pain. Hyperuricaemia has been associated with significant co-morbidity, including diabetes mellitus, metabolic syndrome, obesity and hypertension, and is also an independent risk factor for renal disease, myocardial infarction and stroke. Local and global guidelines recommend that target serum urate levels (sUA) be maintained below 0.36mmol/L for effective long-term management.
To date, the pharmacological agent of choice for urate-lowering treatment has been allopurinol, a xanthine oxidase inhibitor. It is generally safe and effective. However it has been known to cause severe rashes in a small proportion of patients. More severe hypersensitivity reactions, such as the life-threatening multi-system allopurinol hypersensitivity syndrome, are thought to affect around one in 300 patients treated with allopurinol. In addition, the prolonged half-life of the major active metabolite, oxypurinol (14-26 hours) necessitates a dose reduction in patients with renal insufficiency due to the increased risk of adverse effects.
Febuxostat is a new non-purine xanthine oxidase inhibitor that is indicated for the treatment of adults with chronic symptomatic hyperuricaemia in conditions where urate deposition has already occurred (gouty arthritis or tophus formation). It has undergone extensive evaluation in clinical trial programs and has been shown to be more potent than allopurinol in lowering serum urate levels.
When and how to prescribe febuxostat
Febuxostat is currently available as an authority item when the patient meets the following clinical criteria:
- Patient must be diagnosed with chronic gout
- Patient must have a medical contraindication to allopurinol
- Patient must have a documented history of allopurinol hypersensitivity syndrome
- Patient must also have an intolerance to allopurinol requiring permanent treatment discontinuation
It is currently only indicated for hyperuricaemia associated with gout.
Febuxostat is administered once a day and can be taken with or without food. Before prescribing febuxostat, baseline serum uric acid (sUA) levels are measured. Patients are commonly commenced on 40mg daily. If sUA levels remain high after two to four weeks, then the dose can be titrated up to 80mg daily. For patients whose sUA levels remain ≥0.36 mmol/L on 40mg daily, then long-term management with febuxostat 80mg daily is recommended.
Febuxostat should only be commenced after an acute attack of gout has completely subsided, but should not be discontinued if a gout flare occurs during treatment. Similar to allopurinol, an increase in gout flares may occur during initiation of treatment. This tends to occur anytime there is a rapid increase or decrease in sUA levels. It is recommended that prophylaxis against gout flares with either colchicine or non-steroidal anti-inflammatory drugs (NSAIDS) be utilised for up to six months. The frequency and intensity of gout attacks decline with continuous treatment.
How does febuxostat compare with allopurinol?
Approval for the use of febuxostat in Australia is based on the results of two main trials. In both trials, febuxostat achieved a greater rate of efficacy in lowering serum uric acid concentration below the targeted endpoint of 0.36 mmol/L compared to allopurinol. The number and size of tophi were also decreased. The results were more significant in patients receiving doses of febuxostat 80mg daily, where more patients achieved and maintained target sUA levels of < 0.36mmol/L up to one year.
Febuxostat is primarily metabolised by the liver, but its pharmacokinetics are not affected in patients with mild hepatic impairment. Dose adjustments are also not required in patients with mild to moderate renal impartment (creatinine clearance 30-89ml/min). However, the safety and efficacy has not been established in patients with creatinine clearance less than 30ml/min. The pharmacokinetics, pharmacodynamics and safety profile of febuxostat are not significantly affected by age or gender.
Tolerability and adverse effects
Adverse drug reactions to febuxostat that were most commonly reported in clinical trials were abnormalities in liver function, diarrhoea, headache, nausea, dizziness, taste disturbances and gout flares. Gout flares occurred predominately during the initiation of febuxostat.
Trials have also demonstrated an increase in cardiovascular adverse events in the febuxostat group compared to the allopurinol group. However, it was noted that subjects who experienced severe cardiovascular events in the trial had pre-existing cardiovascular disease, including congestive heart failure and coronary artery disease. It is not recommended that febuxostat be used in patients with ischaemic heart disease or congestive heart failure. There was also a reported increase in thyroid stimulating hormone (TSH) in both febuxostat and allopurinol-treated subjects. Therefore, it is recommended that febuxostat is used with caution in patients with thyroid disorders.
Co-administration of febuxostat with azathioprine or 6-mercaptopurine is not recommended as both medications are also metabolised by xanthine oxidase (XO). Plasma levels of azathioprine or 6-mercaptopurine may be significantly elevated, leading to severe toxicity.
Studies indicate febuxostat is a weak inhibitor of cytochrome P2D6, however, may be safely administered with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin, desipramine and other cytochrome P2D6 substrates without any dose adjustment.
The role of febuxostat in chronic gout management is promising. This medication offers an alternative to patients with poor renal function and those who are intolerant, or unable to maintain target serum urate levels, with allopurinol. Long-term reduction in serum urate levels will result in less acute gout attacks, shrinkage and disappearance of tophi, and prevention of tissue damage as a result of the dissolution of existing crystal deposits and prevention of new deposits forming.
- Adenuric®(febuxostat) Australian approved product information. Chatswood: Menarini Australia Pty Ltd. Approved 18 December 2014.
- Arthritis Australia. Arthritis information sheet: gout. Broadway: Arthritis Australia. 2007
- Australian Government Department of Health, Pharmaceutical Benefits Scheme. Febuxostat. http://www.pbs.gov.au/medicine/item/10445R
- Edwards NL. Febuxostat: a new treatment for hyperuricaemia in gout. Rheumatology 2009; 48(2): ii15-9.
- Febuxostat. Australian Prescriber. Volume 38; Number 4; August 2015. 139-140
- Perez-Ruiz F. Treating to target: a strategy to cure gout. Rheumatology 2009; 48(2): ii9-14
- Robinson PC, Taylor W J, Merriman TR. Systematic review of the prevalence of gout and hyperuricaemia in Australia. Intern Med J. 2012; 42(9): 997-1007.
- Rossi S, editor. Australian Medicines Handbook 2015. Adelaide: Australian Medicines Handbook Pty Ltd; 2015.
- Schumacher HR, Becker MA, Wortmann RL, Macdonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005; 353(23): 2450-61.
- Schumacher HR, Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit J, 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(11): 1540–8.