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Febuxostat for treatment of chronic gout
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  • 1. Febuxostat for treatment ofchronic gout2013. 05. 09臨床藥學與藥物科技所 陳秋縈
  • 2. Outline Overview of febuxostat Clinical trials Practical considerations2
  • 3. Targets for intervention in the treatment andprophylaxis of gout3
  • 4. Mechanism of Action4
  • 5. Pharmacology Chemical nameC16H16N2O3S2-[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 thepurine and pyrimidine pathways Some of the adverse reactions associatedwith allopurinol may be due to its nonselectivity and structural similarityto naturally occurring purines orpyrimidines5
  • 6. PharmacokineticAbsorption Distribution Absorption: 49% Tmax: 1-1.5 h Effect of food: High-fat meals delayabsorption 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 enzymeinto active hydroxyl metabolites(67M-1, 67M-2, and 67M-4) Metabolites undergo enterohepaticrecirculation 49% urine, 45% feces <5% excreted unchanged in urine Most elimination through metabolites Elimination half life: 5-8 h6UGT: uridine diphosphate glucuronosyltransferase
  • 7. Pharmacodynamics Dose-dependent reduction in serum uric acid concentrations inthe range of 10 to 120 mg/day Reduced mean serum uric acid levels from baseline by 25% to 70%7Once-daily doses of 10, 20, 30, 40, 50, 70, 90,120, 160, 180, and 240 mg were administeredfor 2 weeks in healthy volunteersPlateau 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 flareprophylaxis8N Engl J Med 2005; 353: 2450–61.Arthritis Rheum. 2008 Nov 15;59(11):1540-8.Arthritis Res Ther. 2010;12(2):R63FACT APEX CONFIRMSPatients (n) 762 1072 2269Duration 1 year 6 months 6 monthsKey exclusioncriteriaScr >1.5 mg/dL orClcr < 50 ml/minHepatic dysfunctionScr > 2 mg/dLAST/ALT > 1.5 x ULNClcr < 30 mL/minAST/ALT > 1.5 x ULNTreatmentFebuxostat 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 doseadjustmentScr 1.5-2 mg/dLAllopurinol 100 mg (10)Clcr 30-59 mL/minAllopurinol 200 mg (145)Gout flareprophylaxis8 weeks 8 weeks• Scr > 1.5 mg/dL use colchicine6 months• CLcr <50 ml/min use colchicine• Lansoprazole 15 mg qd with naproxen
  • 9. Results-1StudyFebuxostatAllopurinol Placebo40 mg 80 mg 120 mg 240 mgFACT 74% 80% 36%APEX 72% 79% 92% 39% 1%CONFIRMS 45% 67% 42%9 Proportion of patients achieve serum uric acid levels < 6 mg/dlat final visitSubgroup: mild or moderate renal impairmentAPEX 44% 45% 60% 0%CONFIRMS 50% 72% 42%P <0.05 vs allopurinolP <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 treatment10StudyFebuxostatAllopurinol Placebo40 mg 80 mg 120 mg 240 mgFACT ( 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 ofgout flares compared with febuxostat 80 mg or allopurinol
  • 11. FACT trialRates of gout flares requiring treatment11Flare prophylaxis: 8 wksNaproxen 250 mg bid orColchicine 0.6 mg qdSharp increases in flare rates after cessation of flareprophylaxis at wk 9-12N Engl J Med 2005; 353: 2450–61.
  • 12. CONFIRMS trialRates of gout flares requiring treatment12Flare prophylaxis: 6 monthsNaproxen 250 mg bid orColchicine 0.6 mg qd• Rates of gout flares diminished slowly and did notaffect more than 15% of subjects after week 8 ofthe 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 mgArthritis Res Ther. 2010;12(2):R63
  • 13. Approval13Indications Chronic management of hyperuricemia in patients with gout Not recommended for the treatment of asymptomatic hyperuricemiaDosage form• FDA ULORIC® 40, 80 mg• EMA ADENURIC® 80, 120 mg• Japan FEBURIC® 10, 20, 40 mg• 衛生署 FEBURIC® 80 mgDosing• 40 mg QD; may increase to 80 mg QD in patients who do not achieve a serumuric 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。14
  • 15. Special Populations15Renal impairmentMild to moderate (Clcr 30-89 ml/min) No dosage adjustment necessarySevere (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 biliaryexcretion and enterohepatic recirculationHepatic impairmentMild to moderate (Child-pugh Class A or B) No dosage adjustment necessarySevere (Child-pugh Class C) Not studiedFebuxostat 80 mg/day orally for 7 days in 31 patientsParametersNormal (N=11)Clcr > 80 mL/minMild (N=6)Clcr 50-80 mL/minModerate (N=7)Clcr 30-49 mL/minSevere (N=7)Clcr 10-29 mL/minCmax (mg/mL) 2.87 ± 1.25 4.03 ± 1.69 2.92 ± 1.06 2.98 ± 2.19AUC24 (mgh/mL) 7.50 ± 2.68 11.1 ± 1.36 11.1 ± 2.92 13.2 ± 11.6t1/2 (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 therapywas liver function abnormalities Febuxostat 40 mg: 1.8%, Febuxostat 80 mg: 1.2%, Allopurinol: 0.9%16Adverse reactions occurring in ≥ 1% of febuxostat treated patientsand at least 0.5% greater than placebo in RCTAdverse reactionsPlacebo 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 periodicallythereafter(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 fromtissue deposits If a gout flare occurs, febuxostat does not need to be discontinued Prophylactic therapy: NSAID or colchicine with initiation of therapy andmay continue for up to 6 months17
  • 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 thanallopurinol 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 congestiveheart failure is not recommended (EMA)18
  • 19. Warnings/Precautions-3 Thyroid disorders Increased TSH values (>5.5 µiu/ml) were observed(5.5%) in the long termopen label extension studies Caution is required when febuxostat is used in patients with alteration ofthyroid function Monitor TSH: every 6 months Contain lactose Patients with rare hereditary problems of galactose intolerance, the Lapplactase deficiency or glucose-galactose malabsorption should not take thismedicine19
  • 20. Drug Interactions20Drug Interaction CommentsAzathioprineMercaptopurine• Inhibition of xanthine oxidase-mediatedmetabolism• Increased azathioprine/mercaptopurineplasma concentrations leading to toxicity• ContraindicatedTheophylline• Increase serum concentrations of the activemetabolite of theophylline derivatives• Approximately 400-fold increase in theamount of 1-methylxanthine (one of themajor theophylline metabolites) excreted inurine• Safety of long-term exposure to 1-methylxanthine has not been evaluated• Contraindicated(canada)• Used with caution(FDA)Monitor theophyllinelevel
  • 21. 21Febuxostat AllopurinolNon-purine xanthine oxidase inhibitor Purine-like xanthine oxidase inhibitorFrequency Once daily >300 mg/day given in divided dosesIndication • Long-term management ofhyperuricemia in patients with gout• Long-term management ofhyperuricemia in patients with gout• Hyperuricemia associated withchemotherapy• Recurrent calcium oxalate stonesPediatric X (< 18 y/o) VT1/2 5-8 h Allopurinol 1–3 hOxypurinol 15 hDose adjustment No dosage adjustment Dosage adjustment to renal functionProtein binding 99.2% <1%Dialyzable X VContraindication Concomitant use of azathioprine ormercaptopurineConcomitant use of didanosineHypersensitivity to allopurinolPregnancy C CBreast Feeding Infant risk cannot be ruled out WHO: compatible with breastfeedingCommonadverse effectsLiver enzyme elevations, nausea, arthralgia,rash, gout flaresSkin rash健保價 25.9/tab 1.5/tab
  • 22. Thank you for your attention22
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