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
5
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%
7
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
8
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%
9
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
10
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
11
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
12
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
13
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
15. Special Populations
15
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%
16
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
17
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
20
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