First published 6 May 2015
Approved indication: hyperuricaemia
Adenuric (A Menarini)
80 mg tablets
Australian Medicines Handbook Appendix A
Some patients with gout, such as those with tophi, require treatment to reduce their plasma urate concentration. Allopurinol achieves this by inhibiting xanthine oxidase, an enzyme involved in the production of uric acid.
Febuxostat is also an inhibitor of xanthine oxidase and, like allopurinol, it is taken once a day. It is well absorbed. Most of the dose is metabolised with approximately half the dose being eliminated in the urine. No dose adjustment is recommended if the creatinine clearance is at least 30 mL/min or in patients with mild or moderate liver impairment. Inhibition of xanthine oxidase creates a risk of serious interactions with azathioprine and mercaptopurine.
The Australian approval of febuxostat is based on two main trials (see Table).1,2 In the largest trial, 1072 patients with hyperuricaemia were randomised to take a placebo, allopurinol 300 mg (100 mg in renal impairment) or febuxostat 80 mg, 120 mg or 240 mg daily. Serum urate was measured every four weeks during the 28-week study. The primary end point was the proportion of patients with their last three urate concentrations below 6 mg/dL (0.36 mmol/L). This outcome was achieved by 48% of the patients taking febuxostat 80 mg, 65% of those taking 120 mg and 69% of those taking 240 mg. Only 22% of the allopurinol group and none of the placebo group achieved the same outcome. In the few patients with renal impairment (serum creatinine 1.5–2 mg/dL or 133–177 micromol/L) none of those taking allopurinol (10 patients) or placebo (5 patients) had the required reduction in urate concentrations, compared with four of the nine patients taking febuxostat 80 mg.1
Table Efficacy of febuxostat in chronic gout
|Trial and duration||Number of randomised patients||Treatment||Proportion of patients with serum urate below 0.36 mmol/L at final visit ‡|
febuxostat 80 mg
allopurinol 300 mg§
|febuxostat 80 mg
allopurinol 300 mg
|febuxostat 40 mg
febuxostat 80 mg
allopurinol 300 mg§
‡ Primary outcome in CONFIRMS, secondary outcome in APEX and FACT. § Lower doses of allopurinol were used in patients with renal impairment.
The other pivotal trial also used the same end point of a urate concentration below 6 mg/dL (0.36 mmol/L) for the last three months of therapy. However, this trial studied 52 weeks of treatment. It randomised 762 patients to take daily doses of allopurinol 300 mg, febuxostat 80 mg or febuxostat 120 mg. There was a significantly greater response to febuxostat therapy. The primary end point was reached by 53% of those taking 80 mg and 62% of those taking 120 mg compared with 21% of those taking allopurinol. In the 156 patients with tophi at the start of the study, the median percentage reduction in area was 83% with 80 mg, 66% with 120 mg and 50% with allopurinol. This difference is not statistically significant.2
Another trial (see Table) also compared allopurinol 300 mg to febuxostat 40 mg or 80 mg. Its primary end point was a final urate concentration below 6 mg/dL (0.36 mmol/L) after six months of treatment. Approximately 65% of the 2268 patients in the trial had mild or moderate renal impairment (estimated creatinine clearance 60–89 mL/min or 30–59 mL/min). The target urate concentration was reached by 45% of the patients taking febuxostat 40 mg, 67% of those taking 80 mg and 42% of the allopurinol group. In patients with renal impairment the respective responses were 50%, 72% and 42%.3
In the pivotal trials more patients withdrew from the febuxostat groups than from the allopurinol groups.1,2The most common adverse event leading to withdrawal was abnormal liver function tests. Liver function should therefore be tested before and during treatment with febuxostat.
When treatment to lower urate concentrations begins there can be a flare-up of gout. Flare-ups affected more of the patients taking febuxostat than allopurinol. Prophylaxis with a non-steroidal anti-inflammatory drug or colchicine is recommended for up to six months after starting febuxostat.
The incidence of rash with febuxostat is not significantly different from the incidence with allopurinol. There have been rare reports of serious hypersensitivity reactions including anaphylaxis. In the pivotal trials there were more cardiovascular events with febuxostat than with allopurinol.1,2 An open-label extension of these studies, involving 1086 patients followed for up to 40 months, reported serious adverse cardiac events in 4% of patients taking febuxostat 80 mg and in 3% of the allopurinol group.4 The product information states that febuxostat is not recommended in patients with ischaemic heart disease or congestive heart failure.
More common adverse effects of febuxostat include diarrhoea, nausea and headache. In general, these symptoms had a similar frequency in patients taking allopurinol.
In the extension study more than 80% of the patients taking febuxostat continued to have urate concentrations below 6 mg/dL (0.36 mmol/L). There was also a decrease in the number and size of tophi.4
Although the efficacy of febuxostat 80 mg was significantly greater than the efficacy of allopurinol in the pivotal trials, the allopurinol dose was fixed.1,2 In practice the dose of allopurinol can be adjusted according to the response. The Australian Medicines Handbook also advises on how to prescribe allopurinol in renal impairment. While the trials included higher doses, the recommended starting dose for febuxostat in Australia is 40 mg, only increasing to 80 mg if the serum urate is greater than 0.36 mmol/L after 2–4 weeks.
Febuxostat is indicated for patients who have chronic symptomatic hyperuricaemia with evidence of urate deposition, such as tophi. It is currently not indicated for hyperuricaemia due to causes other than gout. The likely role of febuxostat will be in patients with chronic gout who cannot be managed with allopurinol.
The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
Notes on references
At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).
At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).
At the time the comment was prepared, information about this drug was available on the website of the Therapeutic Goods Administration (www.tga.gov.au/industry/pm-auspar.htm).
- Schumacher HR Jr, 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;59:1540-8.
- Becker MA, Schumacher HR Jr, 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;353:2450-61.
- Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E, 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.
- 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.
Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.