1. 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

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

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 mg/dL)
Inclusion: 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