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Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout

Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout. Angelo L Gaffo Kenneth G Saag Core Evidence 2009:4 25–36. Objective.

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Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout

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  1. Febuxostat: the evidence for its usein the treatment of hyperuricemia and gout Angelo L Gaffo Kenneth G Saag Core Evidence 2009:4 25–36

  2. Objective • Review the clinical evidence of effectiveness of febuxostat (TEI-3420, or TMX-67) on outcomes and its potential for clinical management of hyperuricemia and gout.

  3. Phases II and III evidence Literature searches PubMed Cochrane database American College of Rheumatology European League Against Rheumatism (?) Inclusion exclusion criteria not mentioned Methods

  4. Febuxostat • Orally administered, nonpurine selective inhibitor of xanthine oxidase. • Binds to a channel in the molybdenum center of the enzyme, leading to a very stable and long-lived enzyme-inhibitor interactions with both oxidized and reduced forms of the enzyme

  5. Phase II data • 28-day, multicenter, double-blind, placebo-controlled, dose response clinical trial • Determine safety and efficacy of once daily febuxostat • 40, 80, 120 mg • Inclusion: patients with American College of Rheumatology criteria-defined gout aged 23-80y/o • Exclusion: absence of kidney dysfunction or taking drugs known to affect serum urate (aspirin or diuretics)

  6. Phase II data • Cases of reduction seen in as early as 7 days after start of treatment • Dose-dependent effect • Incidence of gout flares, due to sudden removal and mobilization of uric acid crystals from the tissues • Despite pretreatment with colchicine • Diarrhea, abdominal pain • Abnormal liver function tests • 40mg (14%), 80mg (8%), 120mg (8%)

  7. Other Phase II data • Reductions on tophi volume (by MRI) • Good tolerance in allopurinol-intolerant patient • 3 month colchicine prophylaxis in patients starting with febuxostat • Diarrhea, GI motility disorders, headache, abnormal liver function tests, hyperlipidemia • Japan (128 patients) • reduced SUA regardless of underexcretors or overproducers • Safe and well tolerated • Abnormal liver function tests and gout flares

  8. Phase III data • FACT • APEX • EXCEL • CONFIRMS

  9. Phase III data - FACT • Febuxostat versus Allopurinol Controlled Trial (FACT) • Randomized, double-blind, 52-week, multicenter • Febuxostat 80 and 120 mg/day dose • Allopurinol 300 mg/day fixed dose • Inclusion: adult patients with American College of Rheumatology-defined gout and SUA at least 8.0 mg/dL • Exclusion: kidney dysfunction, concomitant drugs known to affect serum urate, BMI >50, active liver disease, pregnancy, use of prednisone >10 mg/d, or alcohol abuse

  10. Phase III data - FACT • Primary endpoint – SUA of 6.0 mg/dL • Clinical endpoint – reduction in tophus area, change in number of tophi, and proportion of patients requiring treatment for acute gout flares • Prophylaxis with colchicine or naproxen during a 2-week washout period

  11. Phase III data - FACT Losses to follow-up, adverse events, and gout flares

  12. Phase III data - FACT

  13. Phase III data - FACT • Rates of total advers events and serious adverse events were similar • Liver function test abnormalitis (4-5%), diarrhea (3%), headaches (1-3%) • 4 patients in febuxostat group died • Cardiovascular events • Considered unrelated to administration of study medications

  14. Phase III data - APEX • Allopurinol and Placebo-Controlled, Efficacy Study of Febuxostat (APEX) • Additional patients with mild to moderate renal dysfunction (creatinine 2.0 mg/dL) • Febuxostat at 80, 120, 240 mg/d • Allopurinol 300 mg/d (crea 1.5mg/dL), 100 mg/d (crea 1.5-2.0 mg/dL) • Inclusion: 18-85 y/o, American College of Rheumatology-defined gout, SUA ≥8.0 mg/dL, creatinine up to 2.0 mg/dL • Exclusion: intolerances to allopurinol, colchicine, naproxen, history of renal calculi, heavy alcohol intake, baseline transaminases ≥1.5 upper limit of normal

  15. Phase III data - APEX • More gout flares in febuxostat 120 and 240 mg/d arm in first 8 weeks • Similar rates in 8-28 weeks • Diarrhea, liver function test abnormalities

  16. Phase III - EXCEL • Open-label phase III extension of FACT • Continue evaluation response to treatment • Allopurinol compared to febuxostat failed to achieve continuous reduction of SUA 6.0 mg/dL

  17. Phase III - CONFIRMS • Randomized, controlled, multicenter, double-blind

  18. Summary of evidence

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