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febuxostat (Uloric)

Indications: - treatment of gout not responding to allopurinol* - useful in patients with mild renal insufficiency * has not been demonstrated to improve clinical outcomes [5] Contrandications: (caution) - creatinine clearance < 30 mL/min - hepatic disease, Child-Pugh class C - use in combination with theophylline, mercaptopurine, or azathioprine Pregnancy category: C Dosage: - start 40 mg PO day - increase to 80 mg/day after 2 weeks if serum uric acid > 6 mg/dL - maximum 80 mg/day Tabs: 40 mg, 80 mg Pharmacokinetics: - metabolized in the liver by both oxidation via cytochrome P450s CYP1A2, CYP2C8, & CYP2C9 & non-P450 enzymes & by conjugation via various uridine diphosphate glucuronosyltransferase - eliminated by both liver & kidneys Dosage adjustment in renal failure: - none for mild to moderate renal insufficiency (CrCl >= 30 mL/min) - febuxostat without effect on renal function in hyperuricemic patients with stage 3 chronic kidney disease* [10] * CKD stage 3 = 30-60 mL/min/1.73 m2 Monitor: - baseline serum uric acid level, LFTs, & CBC - recheck after 2 & 4 months, then periodically [4] Adverse effects: - abnormal liver function tests (4-7%) - nausea (1%) - arthralgia (1%) - rash (1-2%) - frequent gout flares may occur when starting febuxostat - chronic renal failure - allopurinol is associated with less chronic renal failure than febuxostat [8] - increased risk of cardiovascular events? [9] or not [12] * Boxed warning: increased risk of death [11] Drug interactions: - avoid use in combination with theophylline, mercaptopurine, or azathioprine; these drugs are metabolized by xanthine oxidase, thus may accumulate to toxic levels [6,7] Mechanism of action: - xanthine oxidase inhibitor Notes: Cost: ~$160/month (2009)

General

enzyme inhibitor anti-inflammatory agent metabolic agent (metabolic modifier)

References

  1. Prescriber's Letter 16(4): 2009 New Drug: Uloric (Febuxostat) Detail-Document#: 250143 (subscription needed) http://www.prescribersletter.com
  2. Bruce SP. Febuxostat: a selective xanthine oxidase inhibitor for the treatment of hyperuricemia and gout. Ann Pharmacother 2006;40:2187-94 PMID: 17132810
  3. Mayer MD et al Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with renal impairment. Am J Ther 2005;12:22-34. PMID: 15662289
  4. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  5. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013 - Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016
  6. Medical Knowledge Self Assessment Program (MKSAP) 17, 18. American College of Physicians, Philadelphia 2015, 2018.
  7. Khanna D et al 2012 American College of Rheumatology guidelines for management of gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia Arthritis Care & Research, 64(10):1431-1446, October 2012 PMID: 23024028 http://onlinelibrary.wiley.com/doi/10.1002/acr.21772/abstract
  8. Singh JA, Cleveland JD. Comparative effectiveness of allopurinol versus febuxostat for preventing incident renal disease in older adults: An analysis of Medicare claims data. Ann Rheum Dis 2017 Jun 5 PMID: 28584186
  9. FDA Safety Alert. Nov 15, 2017 Febuxostat (Brand Name Uloric): Drug Safety Communication - FDA to Evaluate Increased Risk of Heart-related Death. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm585281.htm
  10. Kimura K, Hosoya T, Uchida S et al. Febuxostat therapy for patients with stage 3 CKD and asymptomatic hyperuricemia: A randomized trial. Am J Kidney Dis 2018 Dec; 72:798-810. PMID: 30177485 Free Article https://www.ajkd.org/article/S0272-6386(18)30834-5/fulltext
  11. FDA Safety Alert. Feb 21, 2019 Uloric (febuxostat): Boxed Warning Added - Due to Increased Risk of Death with Gout Medicine. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM631824 - DA Safety Announcement. Feb 21, 2019 FDA adds Boxed Warning for increased risk of death with gout medicine Uloric (febuxostat). https://www.fda.gov/Drugs/DrugSafety/ucm631182.htm
  12. Mackenzie IS et al. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): A multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet 2020 Nov 9; [e-pub]. PMID: 33181081 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32234-0/fulltext
  13. HIGHLIGHTS OF PRESCRIBING INFORMATION ULORIC. ULORIC (febuxostat) tablets, for oral use https://general.takedapharm.com/ULORICPI