Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout
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Transcript of Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout
Febuxostat: the evidence for its usein the treatment of
hyperuricemia and gout
Angelo L GaffoKenneth 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
762 patients
254Febuxostat 80 mg/d
254Febuxostat 120 mg/d
254Allopurinol 80 mg/d
Discontinued 88 (34%)
Discontinued 98 (39%)
Discontinued 66 (26%)
Losses to follow-up, adverse events, and gout flares
Phase III data - FACT
Primary endpoint
Febuxostat 80 mg/d Febuxostat 120 mg/d Allopurinol 300 mg/d
53% 62% 21%
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
1072 patients
Febuxostat 80 mg/d
Febuxostat 120 mg/d
Febuxostat 240 mg/d Placebo
Allopurinol 300 mg/d or
100 mg/d
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
735 patients
294Febuxostat
80 mg/d
294Febuxostat 120 mg/d
147Allopurinol
80 mg/d
Phase III - CONFIRMS
• Randomized, controlled, multicenter, double-blind
2269 patients
Febuxostat 40 mg/d
Febuxostat 80 mg/d
Allopurinol 200 or 300 mg/d
SUA <6mg/dL45%
SUA <6mg/dL 67%
SUA <6mg/dL 42%
Summary of evidence