Angelo L Gaffo Kenneth G Saag Core Evidence 2009:4 25–36 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 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.

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

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

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)

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%)

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

Phase III data FACT APEX EXCEL CONFIRMS

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

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

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

Phase III data - FACT

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

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

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

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

Phase III - CONFIRMS Randomized, controlled, multicenter, double-blind

Summary of evidence