1. Febuxostat for treatment of
chronic gout
2013. 05. 09
臨床藥學與藥物科技所 陳秋縈

2. Outline
 Overview of febuxostat
 Clinical trials
 Practical considerations
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3. Targets for intervention in the treatment and
prophylaxis of gout
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4. Mechanism of Action
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5. Pharmacology
 Chemical name
C16H16N2O3S
2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-
methylthiazole-5-carboxylic acid
 Molecular weight: 316.38
 Mechanism
 Selective xanthine oxidase inhibitor
 Non-purine structure
 Has no effect on other enzymes in the
purine and pyrimidine pathways
 Some of the adverse reactions associated
with allopurinol may be due to its non
selectivity and structural similarity
to naturally occurring purines or
pyrimidines
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6. Pharmacokinetic
Absorption Distribution
 Absorption: 49%
 Tmax: 1-1.5 h
 Effect of food: High-fat meals delay
absorption and reduce AUC by 18%;
pharmacodynamics unaffected
→ may be taken without regard to food
 Vd: 0.7L/kg
 Protein binding: 99.2%
(primarily to albumin)
Metabolism Elimination
 Hepatic
 22–44% conjugation via UGT enzyme
 2–8% oxidation via CYP450 enzyme
into active hydroxyl metabolites
(67M-1, 67M-2, and 67M-4)
 Metabolites undergo enterohepatic
recirculation
 49% urine, 45% feces
 <5% excreted unchanged in urine
 Most elimination through metabolites
 Elimination half life: 5-8 h
6UGT: uridine diphosphate glucuronosyltransferase

7. Pharmacodynamics
 Dose-dependent reduction in serum uric acid concentrations in
the range of 10 to 120 mg/day
 Reduced mean serum uric acid levels from baseline by 25% to 70%
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Once-daily doses of 10, 20, 30, 40, 50, 70, 90,
120, 160, 180, and 240 mg were administered
for 2 weeks in healthy volunteers
Plateau at dosages >120 mg/day

8. Clinical trials- febuxostat vs allopurinol
 Three RCT in patients with gout and serum uric acid level ≥8 mg/dL
 All received naproxen 250 mg twice daily or colchicine 0.6 mg once daily for gout flare
prophylaxis
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N Engl J Med 2005; 353: 2450–61.
Arthritis Rheum. 2008 Nov 15;59(11):1540-8.
Arthritis Res Ther. 2010;12(2):R63
FACT APEX CONFIRMS
Patients (n) 762 1072 2269
Duration 1 year 6 months 6 months
Key exclusion
criteria
Scr >1.5 mg/dL or
Clcr < 50 ml/min
Hepatic dysfunction
Scr > 2 mg/dL
AST/ALT > 1.5 x ULN
Clcr < 30 mL/min
AST/ALT > 1.5 x ULN
Treatment
Febuxostat 80 mg (256)
Febuxostat 120 mg (251)
Allopurinol 300 mg (253)
Febuxostat 80 mg (267)
Febuxostat 120 mg (269)
Febuxostat 240 mg (134)
Allopurinol 100/300 mg (268)
Placebo (134)
Febuxostat 40 mg (757)
Febuxostat 80 mg (756)
Allopurinol 200/300 mg (755)
Renal dose
adjustment
Scr 1.5-2 mg/dL
Allopurinol 100 mg (10)
Clcr 30-59 mL/min
Allopurinol 200 mg (145)
Gout flare
prophylaxis
8 weeks 8 weeks
• Scr > 1.5 mg/dL use colchicine
6 months
• CLcr <50 ml/min use colchicine
• Lansoprazole 15 mg qd with naproxen

9. Results-1
Study
Febuxostat
Allopurinol Placebo
40 mg 80 mg 120 mg 240 mg
FACT 74% 80% 36%
APEX 72% 79% 92% 39% 1%
CONFIRMS 45% 67% 42%
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 Proportion of patients achieve serum uric acid levels < 6 mg/dl
at final visit
Subgroup: mild or moderate renal impairment
APEX 44% 45% 60% 0%
CONFIRMS 50% 72% 42%
P <0.05 vs allopurinol
P <0.05 vs allopurinol, febuxostat 40 mg
• Febuxostat 80/120/240 mg: better than allopurinol
• Febuxostat 40 mg: non-inferior to allopurinol

10. Results-2
 Rates of gout flares requiring treatment
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Study
Febuxostat
Allopurinol Placebo
40 mg 80 mg 120 mg 240 mg
FACT ( flare prophylaxis: 8 wks)
wk 1- 8 22% 36% 21%
wk 9-52 64% 70% 64%
APEX ( flare prophylaxis: 8 wks)
wk 1- 8 28% 36% 46% 23% 20%
P <0.05 vs allopurinol, febuxostat 80 mg
• Febuxostat 120/240 mg significant associated with increased likelihood of
gout flares compared with febuxostat 80 mg or allopurinol

11. FACT trial
Rates of gout flares requiring treatment
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Flare prophylaxis: 8 wks
Naproxen 250 mg bid or
Colchicine 0.6 mg qd
Sharp increases in flare rates after cessation of flare
prophylaxis at wk 9-12
N Engl J Med 2005; 353: 2450–61.

12. CONFIRMS trial
Rates of gout flares requiring treatment
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Flare prophylaxis: 6 months
Naproxen 250 mg bid or
Colchicine 0.6 mg qd
• Rates of gout flares diminished slowly and did not
affect more than 15% of subjects after week 8 of
the study
• We thus recommend gout flare prophylaxis co-
therapy for at least the first six months of ULT
 Febuxostat 80 mg
 Febusostat 40 mg
 Allopurinol 200/300 mg
Arthritis Res Ther. 2010;12(2):R63

13. Approval
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Indications
 Chronic management of hyperuricemia in patients with gout
 Not recommended for the treatment of asymptomatic hyperuricemia
Dosage form
• FDA ULORIC® 40, 80 mg
• EMA ADENURIC® 80, 120 mg
• Japan FEBURIC® 10, 20, 40 mg
• 衛生署 FEBURIC® 80 mg
Dosing
• 40 mg QD; may increase to 80 mg QD in patients who do not achieve a serum
uric acid level <6 mg/dL after 2 weeks
• Can be taken without regard to food or antacid use

14. 健保規範-Febuxostat（Feburic）: 101/4/1
限慢性痛風患者之高尿酸血症使用，且符合以下條件
之一：
1. 曾使用過降尿酸藥物allopurinol及benzbromarone，
經治療反應不佳，尿酸值仍高於6.0 mg/dL。
2. 曾使用過 benzbromarone治療反應不佳，但對
allopurinol有不耐受性，過敏反應，或使用禁忌者使
用。
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15. Special Populations
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Renal impairment
Mild to moderate (Clcr 30-89 ml/min) No dosage adjustment necessary
Severe (Clcr < 30 ml/min) Insufficient data; use caution
• Lower renal clearance and higher AUC and t½ without affecting the overall decrease in serum uric acid
→ decrease in the renal clearance of conjugated febuxostat and a subsequent increase in biliary
excretion and enterohepatic recirculation
Hepatic impairment
Mild to moderate (Child-pugh Class A or B) No dosage adjustment necessary
Severe (Child-pugh Class C) Not studied
Febuxostat 80 mg/day orally for 7 days in 31 patients
Parameters
Normal (N=11)
Clcr > 80 mL/min
Mild (N=6)
Clcr 50-80 mL/min
Moderate (N=7)
Clcr 30-49 mL/min
Severe (N=7)
Clcr 10-29 mL/min
Cmax (mg/mL) 2.87 ± 1.25 4.03 ± 1.69 2.92 ± 1.06 2.98 ± 2.19
AUC24 (mgh/mL) 7.50 ± 2.68 11.1 ± 1.36 11.1 ± 2.92 13.2 ± 11.6
t1/2 (h) 4.71 (2.92–6.79) 7.60 (5.11–14.0) 9.07 (4.66–14.7) 6.97 (3.09–9.49)
Decrease in UA on day 7(%) 58.2 ± 11.2 63.6 ± 6.93 56.7 ± 6.96 55.1 ± 7.94

16. Adverse Effects
 The most common adverse reaction leading to discontinuation from therapy
was liver function abnormalities
 Febuxostat 40 mg: 1.8%, Febuxostat 80 mg: 1.2%, Allopurinol: 0.9%
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Adverse reactions occurring in ≥ 1% of febuxostat treated patients
and at least 0.5% greater than placebo in RCT
Adverse reactions
Placebo Febuxostat Allopurinol
(N=134) 40mg QD (N=757) 80mg QD (N=1279) (N=1277)
Liver function abnormalities 0.7% 6.6% 4.6% 4.2%
Nausea 0.7% 1.1% 1.3% 0.8%
Arthralgia 0% 1.1% 0.7% 0.7%
Rash 0.7% 0.5% 1.6% 1.6%

17. Warnings/Precautions-1
 Hepatic Effects
 Transaminase elevation > 3 x ULN were observed in clinical trial
 Postmarketing reports of fatal and non-fatal hepatic failure
 Monitor liver function test: prior to the initiation of therapy and periodically
thereafter(everey 8 weeks)
 Acute gout flare
 Febuxostat initiation may increase frequency of acute gout attacks
 Due to changing serum uric acid levels resulting in mobilization of urate from
tissue deposits
 If a gout flare occurs, febuxostat does not need to be discontinued
 Prophylactic therapy: NSAID or colchicine with initiation of therapy and
may continue for up to 6 months
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18. Warnings/Precautions-2
 Cardiovascular Events
 Higher rate of cardiovascular thromboembolic events (cardiovascular deaths,
nonfatal MI, nonfatal stroke) was observed in patients treated with febuxostat than
allopurinol in clinical trials
− Febuxostat 40 mg 0 (95% CI 0.00-1.08)
Febuxostat 80 mg 1.09 (95% CI 0.44-2.24)
Allopurinol 0.60 (95% CI 0.16-1.53)
 Risk factors (p=0.001)
− History of atherosclerotic disease
− Myocardial infarction
− Congestive heart failure
− Age older than 60 years
 Causal relationship not established. Monitor for signs and symptoms of MI and stroke
 Treatment with febuxostat in patients with ischaemic heart disease or congestive
heart failure is not recommended (EMA)
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19. Warnings/Precautions-3
 Thyroid disorders
 Increased TSH values (>5.5 µiu/ml) were observed(5.5%) in the long term
open label extension studies
 Caution is required when febuxostat is used in patients with alteration of
thyroid function
 Monitor TSH: every 6 months
 Contain lactose
 Patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this
medicine
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20. Drug Interactions
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Drug Interaction Comments
Azathioprine
Mercaptopurine
• Inhibition of xanthine oxidase-mediated
metabolism
• Increased azathioprine/mercaptopurine
plasma concentrations leading to toxicity
• Contraindicated
Theophylline
• Increase serum concentrations of the active
metabolite of theophylline derivatives
• Approximately 400-fold increase in the
amount of 1-methylxanthine (one of the
major theophylline metabolites) excreted in
urine
• Safety of long-term exposure to 1-
methylxanthine has not been evaluated
• Contraindicated
(canada)
• Used with caution
(FDA)
Monitor theophylline
level

21. 21
Febuxostat Allopurinol
Non-purine xanthine oxidase inhibitor Purine-like xanthine oxidase inhibitor
Frequency Once daily >300 mg/day given in divided doses
Indication • Long-term management of
hyperuricemia in patients with gout
• Long-term management of
hyperuricemia in patients with gout
• Hyperuricemia associated with
chemotherapy
• Recurrent calcium oxalate stones
Pediatric X (< 18 y/o) V
T1/2 5-8 h Allopurinol 1–3 h
Oxypurinol 15 h
Dose adjustment No dosage adjustment Dosage adjustment to renal function
Protein binding 99.2% <1%
Dialyzable X V
Contraindication Concomitant use of azathioprine or
mercaptopurine
Concomitant use of didanosine
Hypersensitivity to allopurinol
Pregnancy C C
Breast Feeding Infant risk cannot be ruled out WHO: compatible with breastfeeding
Common
adverse effects
Liver enzyme elevations, nausea, arthralgia,
rash, gout flares
Skin rash
健保價 25.9/tab 1.5/tab

22. Thank you for your attention
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