Febuxostat

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Febuxostat
Febuxostat.svg
Clinical data
Trade names Uloric, Adenuric, others[1]
AHFS/Drugs.com Monograph
MedlinePlus a609020
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
Metabolism via CYP1A2, 2C8, 2C9, UGT1A1, 1A3, 1A9, 2B7
Elimination half-life ~5-8 hours
Excretion Urine (~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
ChEMBL
ECHA InfoCard 100.207.329 Edit this at Wikidata
Chemical and physical data
Formula C16H16N2O3S
Molar mass 316.374 g/mol
3D model (JSmol)
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Febuxostat, sold under the brand names Uloric among others, is a medication used in the treatment of chronic gout and hyperuricemia. There are concerns about more heart related deaths with febuxostat compared to allopurinol.[2] It inhibits xanthine oxidase, thus reducing production of uric acid in the body.

Febuxostat was discovered by scientists at the Japanese pharmaceutical company Teijin in 1998. Teijin partnered the drug with TAP Pharmaceuticals in the US and Ipsen in Europe. Ipsen obtained marketing approval for febuxostat from the European Medicines Agency in April 2008, Takeda obtained FDA approval in February 2009, and Teijin obtained approval from the Japanese Pharmaceuticals and Medical Devices Agency in 2011.

Medical uses[edit]

Febuxostat is used to treat chronic gout and hyperuricemia.[3] Febuxostat is typically only recommended in those who cannot tolerate allopurinol.[4] 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.[3]

Uloric 40 mg tablet

Febuxostat is in the US pregnancy category C; there are no adequate and well-controlled studies in pregnant women.[5]

Side effects[edit]

The adverse effects associated with febuxostat therapy include nausea, diarrhea, arthralgia, headache, increased hepatic serum enzyme levels and rash.[5][6]

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.[7]

Drug interactions[edit]

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.[5][8]

Mechanism of action[edit]

Febuxostat is a non-purine-selective inhibitor of xanthine oxidase.[5] 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.[6]

History[edit]

Febuxostat was discovered by scientists at the Japanese pharmaceutical company Teijin in 1998.[9] Teijin partnered the drug with TAP Pharmaceuticals in the US and Ipsen in Europe.[10][11][12]

Ipsen obtained marketing approval for febuxostat from the European Medicines Agency in April 2008,[13] Takeda obtained FDA approval in February 2009,[14][15] and Teijin obtained approval from the Japanese authorities in 2011.[16] Ipsen exclusively licensed its European rights to Menarini in 2009.[17] Teijin partnered with Astellas for distribution in China and southeast Asia.[18][19]

Society and culture[edit]

Cost[edit]

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.[3]

Trade names[edit]

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, and is generic in several countries and is available by many names in those countries.[1]

References[edit]

  1. ^ a b Drugs.com Drugs.com international names for febuxostat Page accessed June 25, 2015
  2. ^ "Safety Alerts for Human Medical Products - Uloric (febuxostat): Drug Safety Communication - FDA to Evaluate Increased Risk of Heart-related Death". FDA. Retrieved 21 November 2017. 
  3. ^ a b c 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.
  4. ^ "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. 
  5. ^ a b c d Uloric label Updated February, 2009.
  6. ^ a b 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. 
  7. ^ 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. 
  8. ^ Ashraf Mozayani; Lionel Raymon (2011). Handbook of Drug Interactions: A Clinical and Forensic Guide. Springer Science+Business Media. 
  9. ^ Teijin Febuxostat Story Page accessed June 25, 2015
  10. ^ Tomlinson B. Febuxostat (Teijin/Ipsen/TAP). Curr Opin Investig Drugs. 2005 Nov;6(11):1168-78. PMID 16312139
  11. ^ Bruce Japsen for the Chicago Tribune. August 17, 2006. FDA puts gout treatment on hold
  12. ^ 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
  13. ^ "Adenuric (febuxostat) receives marketing authorisation in the European Union" (PDF). Retrieved 28 May 2008. 
  14. ^ "Uloric Approved for Gout". U.S. News and World Report. Retrieved 2009-02-16. 
  15. ^ 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
  16. ^ Teijin. January 21, 2011 Press release: TMX-67 (febuxostat) Approved in Japan
  17. ^ Genetic Engineering News. October 2009. Menarini to Market Takeda/Ipsen Gout Therapy in 41 European Countries
  18. ^ 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
  19. ^ Research Views. Aug 11 2011 Teijin Pharma Enters Into Distribution Agreement With Astellas Pharma For Febuxostat