Febuxostat, Adenuric® (Menarini)

Tablets, 80 and 120 mg
Treatment of chronic hyperuricaemia

Three randomised double-blind trials of febuxostat for the treatment of chronic gout found the drug to be more effective than allopurinol in suboptimal dosage, based on a surrogate outcome measure, serum uric acid concentration, although the trials suffered from high drop-out rates due to side-effects. Short-term side-effects, such as gout attacks, have been reported, and are comparable to those from allopurinol. Long-term side-effects have not been studied. It is questionable whether this is enough to earn febuxostat, a me-too drug of allopurinol, a place as a second-line drug for patients who are intolerant of allopurinol or benzbromarone (Desuric®) due to side-effects or for whom no optimal effect is achieved despite raising the dosage. Another issue is whether it might be better to treat the group of patients with mild or moderate kidney disorders (creatinin clearance >30 mL/min.) with febuxostat instead of allopurinol or benzbromarone, in view of febuxostat’s low renal clearance. There is as yet insufficient evidence for this, the only relevant evidence being from the subgroup analysis in the third trial.5 All three trials used a suboptimal allopurinol dosage of 300 mg, whereas national and international guidelines recommend increasing the dosage to 600 mg if no effect is achieved. As a result, the trials probably overestimated the efficacy of febuxostat by showing that a high dosage of febuxostat works better than a low dosage of allopurinol.
The 2009 guideline on arthritis published by the Dutch College of General Practitioners (NHG) states that the aim of uric acid lowering therapy is to reduce the number of gout episodes to a level that is acceptable to the patient, or to resolve the tophi.7 The efficacy of febuxostat on these hard outcome measures has not been proven. Only one trial used predefined clinical outcome measures, and this study did not find febuxostat to be more effective than allopurinol.3 It has to be said, however, that little hard evidence from placebo-controlled trials is available for the efficacy of allopurinol in terms of reducing the number of episodes.8
The choice of non-inferiority margin and the interpretation of the findings are often not in accordance with the requirements and points of concern for non-inferiority studies (Gebu 2015; 49: 27-34). Hence, the results should be interpreted with caution.
In 2012 a meta-analysis was published on febuxostat, which included not only the above double-blind trials (all sponsored by the manufacturer) but also studies with a low level of evidence, i.e. non-blinded studies.8 It concluded that more long-term research is required into the efficacy and safety of febuxostat, in view of the low evidence level of previous studies.
The results of the research cited above confirm what was previously reported in Gebu 2010; 44; 109-115, viz. that there is some evidence for the efficacy of febuxostat in lowering serum uric acid concentrations, but insufficient evidence for its efficacy on clinical outcome measures and for its safety, and that the available evidence is not enough to recommend the routine use of the drug for maintenance therapy in chronic gout. Although evidence of the efficacy of allopurinol on hard endpoints is also lacking, the many years of experience gained with this drug, and the 8-fold higher costs of febuxostat mean that allopurinol remains the drug of first choice. Benzbromarone is available as an alternative if a patient does not tolerate allopurinol or it does not produce sufficient effect, as is also recommend in the NHG guideline on arthritis,7 even though the efficacy of benzbromarone has not been proved on hard endpoints either (Gebu 2010; 44: 114).





1. Productinformatie febuxostat (Adenuric®), via: www.ema.europa.eu, EPARs.
2. GVS-rapport febuxostat (Adenuric®), via: www.zinl.nl, Geneesmiddelbeoordelingen.
3. Becker MA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005; 353: 2450-2461.
4. Schumacher HR Jr, 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.
5. Becker MA, 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.
6. Informatorium Medicamentorum. Den Haag: KNMP, 2015.
7. Janssens HJEM, et al. NHG-standaard ’Artritis’. Huisarts Wet 2009; 52: 439-453.
8. Tayar JH, et al. Febuxostat for treating chronic gout. Cochrane Database Syst Rev 2012: CD008653.

*The literature refers to the Dutch tekst

Authors

  • A. Ramdhan