Febuxostat

Febuxostat, sold under the brand names Uloric among others, is a medication used long-term to treat gout due to high uric acid levels.[2] It is generally only recommended in those who cannot take allopurinol.[3][4] When initially started, medications such as NSAIDs are often recommended to prevent gout flares.[2][4] It is taken by mouth.[2]

Febuxostat
Clinical data
Trade namesUloric, Febuday, Adenuric, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa609020
License data
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration    		By mouth
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability~49% absorbed
    Protein binding~99% to albumin
    Metabolismvia CYP1A2, 2C8, 2C9, UGT1A1, 1A3, 1A9, 2B7
    Elimination half-life~5-8 hours
    ExcretionUrine (~49% mostly as metabolites, 3% as unchanged drug); feces (~45% mostly as metabolites, 12% as unchanged drug)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.207.329
    Chemical and physical data
    FormulaC16H16N2O3S
    Molar mass316.374 g/mol g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    Common side effects include liver problems, nausea, joint pain, and a rash.[2] Serious side effects include an increased risk of death as compared with allopurinol, Stevens-Johnson syndrome, and anaphylaxis.[4][3] Use is not recommended during pregnancy or breastfeeding.[4] It inhibits xanthine oxidase, thus reducing production of uric acid in the body.[2]

    Febuxostat was approved for medical use in the European Union in 2008 and in the United States in 2009.[5][2] No generic version is available as of 2019, though one has been approved.[4][6] In the United Kingdom a month of treatment costs the NHS about 24 pounds.[4] In the United States the wholesale cost of a month's worth of medication is about US$320.[7]

    Medical uses

    Febuxostat is used to treat chronic gout and hyperuricemia.[8] Febuxostat is typically only recommended in those who cannot tolerate allopurinol.[9] National Institute for Health and Clinical Excellence concluded that febuxostat is more effective than standard doses of allopurinol, but not more effective than higher doses of allopurinol.[8]

    Uloric 40 mg tablet

    Febuxostat is in the US pregnancy category C; there are no adequate and well-controlled studies in pregnant women.[10]

    Side effects

    The adverse effects associated with febuxostat therapy include nausea, diarrhea, arthralgia, headache, increased hepatic serum enzyme levels and rash.[10][11]

    On 15 November 2017, the FDA issued a safety alert indicating that the preliminary results from a safety clinical trial showed an increased risk of heart-related death with febuxostat compared to allopurinol. The FDA required Takeda to conduct this safety study when the medicine was approved in 2009. The febuxostat drug labels already carry a warning and precaution about cardiovascular events because the clinical trials conducted before approval showed a higher rate of heart-related problems in patients treated with febuxostat compared to allopurinol. These problems included heart attacks, strokes, and heart-related deaths. As a result, the FDA required an additional safety clinical trial after the drug was approved and on the market to better understand these differences, and that trial was finished recently. The safety trial was conducted in over 6,000 patients with gout treated with either febuxostat or allopurinol. The primary outcome was a combination of heart-related death, non-deadly heart attack, non-deadly stroke, and a condition of inadequate blood supply to the heart requiring urgent surgery. The preliminary results show that overall, febuxostat did not increase the risk of these combined events compared to allopurinol. However, when the outcomes were evaluated separately, febuxostat showed an increased risk of heart-related deaths and death from all causes.[12]

    Drug interactions

    Febuxostat is contraindicated with concomitant use of theophylline and chemotherapeutic agents, namely azathioprine and 6-mercaptopurine, because it could increase blood plasma concentrations of these drugs, and therefore their toxicity.[10][13]

    Mechanism of action

    Febuxostat is a non-purine-selective inhibitor of xanthine oxidase.[10] It works by non-competitively blocking the molybdenum pterin center which is the active site on xanthine oxidase. Xanthine oxidase is needed to successively oxidize both hypoxanthine and xanthine to uric acid. Hence, febuxostat inhibits xanthine oxidase, therefore reducing production of uric acid. Febuxostat inhibits both oxidized as well as reduced form of xanthine oxidase because of which febuxostat cannot be easily displaced from the molybdenum pterin site.[11]

    History

    Febuxostat was discovered by scientists at the Japanese pharmaceutical company Teijin in 1998.[14] Teijin partnered the drug with TAP Pharmaceuticals in the US and Ipsen in Europe.[15][16][17]

    Ipsen obtained marketing approval for febuxostat from the European Medicines Agency in April 2008,[18] Takeda obtained FDA approval in February 2009,[19][20] and Teijin obtained approval from the Japanese authorities in 2011.[21] Ipsen exclusively licensed its European rights to Menarini in 2009.[22] Teijin partnered with Astellas for distribution in China and southeast Asia.[23][24]

    Society and culture

    Cost

    In the UK, NICE has found that febuxostat has a higher cost/benefit ratio than allopurinol and on that basis recommended febuxostat as a second-line drug for people who cannot use allopurinol.[8]

    Trade names

    Febuxostat is marketed as Adenuric in Europe, Australia, New Zealand and Pakistan. In Pakistan it is launched by SOLACE Pharmaceuticals a sister subsidiary of SJG, Uloric in the US, Goturic and Goutex in Latin America, Feburic in Japan, Donifoxate in Egypt and is generic in several countries and is available by many names in those countries.[1]

    References
    1. Drugs.com Drugs.com international names for febuxostat Page accessed June 25, 2015
    2. "Febuxostat Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 26 February 2019.
    3. "Drug Safety and Availability - FDA adds Boxed Warning for increased risk of death with gout medicine Uloric (febuxostat)". FDA. 21 February 2019. Retrieved 26 February 2019.
    4. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 1087. ISBN 9780857113382.
    5. "Adenuric". European Medicines Agency - Commission. 17 September 2018. Retrieved 26 February 2019.
    6. "Generic Uloric Availability". Drugs.com. Retrieved 1 August 2019.
    7. "NADAC as of 2019-02-20". Centers for Medicare and Medicaid Services. Retrieved 26 February 2019.
    8. Febuxostat for the management of hyperuricaemia in people with gout (TA164) Chapter 4. Consideration of the evidence Archived October 6, 2010, at the Wayback Machine
    9. "Febuxostat for the management of hyperuricaemia in people with gout Guidance and guidelines". www.nice.org.uk. 17 December 2008. Archived from the original on 28 March 2017. Retrieved 28 March 2017.
    10. Uloric label Updated February, 2009.
    11. Love BL, Barrons R, Veverka A, Snider KM (2010). "Urate-lowering therapy for gout: focus on febuxostat". Pharmacotherapy. 30 (6): 594–608. doi:10.1592/phco.30.6.594. PMID 20500048.
    12. Commissioner, Office of the. "Safety Alerts for Human Medical Products - Febuxostat (Brand Name Uloric): Drug Safety Communication - FDA to Evaluate Increased Risk of Heart-related Death". www.FDA.gov. Retrieved 17 November 2017.
    13. Ashraf Mozayani; Lionel Raymon (2011). Handbook of Drug Interactions: A Clinical and Forensic Guide. Springer Science+Business Media.
    14. Teijin Febuxostat Story Page accessed June 25, 2015
    15. Tomlinson B. Febuxostat (Teijin/Ipsen/TAP). Curr Opin Investig Drugs. 2005 Nov;6(11):1168-78. PMID 16312139
    16. Bruce Japsen for the Chicago Tribune. August 17, 2006. FDA puts gout treatment on hold
    17. Note: TAP Pharmaceuticals was a joint venture between Abbott Laboratories and Takeda that was dissolved in 2008 per this press release: Takeda, Abbott Announce Plans to Conclude TAP Joint Venture
    18. "Adenuric (febuxostat) receives marketing authorisation in the European Union" (PDF). Archived from the original (PDF) on 26 March 2009. Retrieved 28 May 2008.
    19. "Uloric Approved for Gout". U.S. News and World Report. Retrieved 2009-02-16.
    20. Teijin and Takeda. February 14, 2009 Press release: ULORIC® (TMX-67, febuxostat) Receives FDA Approval for the Chronic Management of Hyperuricemia in Patients with Gout
    21. Teijin. January 21, 2011 Press release: TMX-67 (febuxostat) Approved in Japan Archived 2015-06-26 at the Wayback Machine
    22. Genetic Engineering News. October 2009. Menarini to Market Takeda/Ipsen Gout Therapy in 41 European Countries
    23. First Word Pharma. April 1st, 2010 Teijin Pharma and Astellas Pharma enter into agreement for marketing rights of TMX-67 in China and Hong Kong
    24. Research Views. Aug 11 2011 Teijin Pharma Enters Into Distribution Agreement With Astellas Pharma For Febuxostat Archived 2015-06-26 at the Wayback Machine
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