Febuxostat

Source: Wikipedia, the free encyclopedia.
Febuxostat
Clinical data
Trade namesUloric, Adenuric, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa609020
License data
Pregnancy
category
By mouth
ATC code
Legal status
Legal status
UGT1A1, 1A8, 1A9[5]
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
  • 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-
    1,3-thiazole-5-carboxylic acid
JSmol)
  • N#Cc1c(OCC(C)C)ccc(c1)c2nc(c(s2)C(=O)O)C
  • InChI=1S/C16H16N2O3S/c1-9(2)8-21-13-5-4-11(6-12(13)7-17)15-18-10(3)14(22-15)16(19)20/h4-6,9H,8H2,1-3H3,(H,19,20) checkY
  • Key:BQSJTQLCZDPROO-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Febuxostat, sold under the brand names Uloric among others, is a

by mouth.[6]

Common side effects include liver problems, nausea, joint pain, and a rash.[6] Serious side effects include an increased risk of death as compared with allopurinol, Stevens–Johnson syndrome, and anaphylaxis.[8][7] Use is not recommended during pregnancy or breastfeeding.[8] It inhibits xanthine oxidase, thus reducing production of uric acid in the body.[6]

Febuxostat was approved for medical use in the European Union in 2008, and in the United States in 2009.

generic version was approved in 2019.[10][11]

Medical uses

Febuxostat is used to treat chronic

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.[12]

Uloric 40 mg tablet

Side effects

The adverse effects associated with febuxostat therapy include nausea, diarrhea, arthralgia, headache, increased hepatic serum enzyme levels and rash.[14][15]

In 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 in people with a history of

cardiovascular diseases.[16] 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.[when?
] 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.[17]

Drug interactions

Febuxostat is contraindicated with concomitant use of

6-mercaptopurine, because it could increase blood plasma concentrations of these drugs and thereby their toxicity.[14][18]

Pharmacology

Mechanism of action

Febuxostat is a non-purine-selective inhibitor of

molybdenum pterin center, which is the active site of xanthine oxidase. Xanthine oxidase is needed to oxidize successively hypoxanthine and xanthine to uric acid. Thus, febuxostat inhibits xanthine oxidase, thereby reducing production of uric acid. Febuxostat inhibits both the oxidized and the reduced forms of xanthine oxidase by virtue of its tight binding to the molybdenum pterin site.[15]

Pharmacokinetics

After oral intake, at least 84% of the febuxostat dose is absorbed in the gut, and highest blood plasma concentrations are reached after 60 to 90 minutes. When taken together with a fatty meal, febuxostat reaches lower concentrations in the body; but this is not considered clinically relevant. When in the bloodstream, 99.2% of the substance is bound to the plasma protein albumin, and 82–91% of the active metabolites are bound to plasma proteins.[5]

The active metabolites in humans: 67M-1, 67M-2 and 67M-4 (top to bottom)

Febuxostat has three active metabolites in humans, which are formed mainly by a number of

Elimination half-life is five to eight hours.[5][19]

History

FEBURIC (Febuxostat) 80 mg tablet

Febuxostat was discovered by scientists at the Japanese pharmaceutical company Teijin in 1998.[20] Teijin partnered the drug with TAP Pharmaceuticals in the US and Ipsen in Europe.[21][22][23]

Ipsen obtained marketing approval for febuxostat from the

Astellas for distribution in China and southeast Asia.[29][30]

Society and culture

Economics

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.[12]

In 2010, before it became generic in the United States, it cost about US$160 per month as opposed to allopurinol which was about $14 per month.[31]

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. ^ a b "International names for febuxostat". Drugs.com. Retrieved 25 June 2015.
  2. ^ "Febuxostat (Uloric) Use During Pregnancy". Drugs.com. 22 February 2019. Retrieved 17 May 2020.
  3. FDA
    . Retrieved 22 Oct 2023.
  4. ^ "Prescription medicines: registration of new chemical entities in Australia, 2014". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  5. ^ a b c "Adenuric: EPAR – Product Information" (PDF). European Medicines Agency. 2019-08-06.
  6. ^ a b c d e f "Febuxostat Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 26 February 2019.
  7. ^ a b "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.
  8. ^
    ISBN 9780857113382
    .
  9. ^ "Adenuric | European Medicines Agency". European Medicines Agency - Commission. 17 September 2018. Retrieved 26 February 2019.
  10. ^ "Generic Uloric Availability". Drugs.com. Retrieved 1 August 2019.
  11. ^ "Febuxostat Generic Uloric". Retrieved 15 April 2020.
  12. ^ a b c "Febuxostat for the management of hyperuricaemia in people with gout (TA164) Chapter 4. Consideration of the evidence". Archived from the original on October 6, 2010.
  13. ^ "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.
  14. ^ a b c "Uloric label" (PDF). U.S. Food and Drug Administration. February 2009.
  15. ^
    S2CID 6617778
    .
  16. ^ "Uloric (febuxostat) - Increased Risk of Cardiovascular Fatal Outcomes". Health Canada. 4 November 2019.
  17. ^ Office of the Commissioner. "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.
  18. ISBN 978-1-61779-221-2
    .
  19. ^ "Adenuric: EPAR – Public Assessment Report" (PDF). European Medicines Agency. 2008-05-28.
  20. ^ "Febuxostat Storym". Teijin. Retrieved 25 June 2015.
  21. PMID 16312139
    .
  22. ^ Japsen B (17 August 2006). "FDA puts gout treatment on hold". The Chicago Tribune.
  23. ^ 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". Takeda.
  24. ^ "Adenuric (febuxostat) receives marketing authorisation in the European Union" (PDF). Archived from the original (PDF) on 26 March 2009. Retrieved 28 May 2008.
  25. ^ "Uloric Approved for Gout". U.S. News & World Report. Retrieved 2009-02-16.
  26. ^ "Press release: ULORIC (TMX-67, febuxostat) Receives FDA Approval for the Chronic Management of Hyperuricemia in Patients with Gout". Teijin and Takeda. 14 February 2009.
  27. ^ "Press release: TMX-67 (febuxostat) Approved in Japan". Teijin. 21 January 2011. Archived from the original on 2015-06-26.
  28. ^ "Menarini to Market Takeda/Ipsen Gout Therapy in 41 European Countries". Genetic Engineering News. October 2009.
  29. ^ "Teijin Pharma and Astellas Pharma enter into agreement for marketing rights of TMX-67 in China and Hong Kong". First Word Pharma. 1 April 2010.
  30. ^ "Teijin Pharma Enters Into Distribution Agreement With Astellas Pharma For Febuxostat". Research Views. 11 August 2011. Archived from the original on 2015-06-26.
  31. ^ Love BL (2010). "Febuxostat (Uloric) for Hyperuricemia and Gout". American Family Physician. 81 (10): 1287. Retrieved 15 April 2020.
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