Febuxostat

Febuxostat is used to treat chronic gout and hyperuricemia. Febuxostat is typically recommended only for people who cannot tolerate allopurinol.{{cite web|title=Febuxostat for the management of hyperuricaemia in people with gout Guidance and guidelines|url=https://www.nice.org.uk/guidance/TA164|website=www.nice.org.uk|access-date=28 March 2017|date=17 December 2008|url-status=live|archive-url=https://web.archive.org/web/20170328195736/https://www.nice.org.uk/guidance/TA164|archive-date=28 March 2017}} 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.{{cite web | url = http://guidance.nice.org.uk/TA164/Guidance/Considerations_1 | title = Febuxostat for the management of hyperuricaemia in people with gout (TA164) Chapter 4. Consideration of the evidence | date = 17 December 2008 | archive-url = https://web.archive.org/web/20101006212851/http://guidance.nice.org.uk/TA164/Guidance/Considerations_1 | archive-date=6 October 2010 }}

File:Uloric 40 mg tablet.jpg

The adverse effects associated with febuxostat therapy include nausea, diarrhea, arthralgia, headache, increased hepatic serum enzyme levels and rash.{{cite web | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021856lbl.pdf | title =Uloric label | date = February 2009 | publisher = U.S. Food and Drug Administration }}{{cite journal | vauthors = Love BL, Barrons R, Veverka A, Snider KM | title = Urate-lowering therapy for gout: focus on febuxostat | journal = Pharmacotherapy | volume = 30 | issue = 6 | pages = 594–608 | date = June 2010 | pmid = 20500048 | doi = 10.1592/phco.30.6.594 | s2cid = 6617778 }}

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.{{cite web|url=https://recalls-rappels.canada.ca/en/alert-recall/uloric-r-febuxostat-increased-risk-cardiovascular-fatal-outcomes|title=Uloric (febuxostat) - Increased Risk of Cardiovascular Fatal Outcomes|publisher=Health Canada|date=4 November 2019}} 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|date=June 2022}}

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.{{cite web|url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm585281.htm|title=Safety Alerts for Human Medical Products - Febuxostat (Brand Name Uloric): Drug Safety Communication - FDA to Evaluate Increased Risk of Heart-related Death| author = Office of the Commissioner |website=www.FDA.gov|access-date=17 November 2017 |archive-url=https://web.archive.org/web/20180125101103/https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm585281.htm |archive-date=2018-01-25 |date=2017-11-15}}

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 thereby their toxicity.{{cite book | vauthors = Mozayani A, Raymon L |title=Handbook of Drug Interactions: A Clinical and Forensic Guide |year=2011|publisher=Springer Science+Business Media | isbn = 978-1-61779-221-2 }}

Febuxostat is a non-purine selective inhibitor of xanthine oxidase. It works by non-competitively blocking the 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.

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.{{cite web|url=https://www.ema.europa.eu/documents/product-information/adenuric-epar-product-information_en.pdf|title=Adenuric: EPAR – Product Information|publisher=European Medicines Agency|date=6 August 2019}}

File:Febuxostat active metabolites.svgs 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 cytochrome P450 liver enzymes (CYP1A1, 1A2, 2C8, 2C9). One of them is a dicarboxylic acid, the other two are hydroxylated derivatives. These, as well as the original drug, are further glucuronidated, mainly by the enzymes UGT1A1, 1A8, and 1A9. Febuxostat and its metabolites are eliminated via the urine (49% of the total substance, comprising 3% unchanged febuxostat, 30% febuxostat glucuronide, 13% active metabolites and their glucuronides, and 3% unknown entities) and via the faeces (45%, of which 12% unchanged febuxostat, 1% glucuronide, 25% active metabolites and their glucuronides, and 7% unknown entities). Elimination half-life is five to eight hours.{{cite web|url=https://www.ema.europa.eu/documents/assessment-report/adenuric-epar-public-assessment-report_en.pdf|title=Adenuric: EPAR – Public Assessment Report|publisher=European Medicines Agency|date=28 May 2008}}

File:FEBURIC 80 mg (Febuxostat).jpg

Febuxostat was discovered by scientists at the Japanese pharmaceutical company Teijin in 1998.{{cite web | work = Teijin | url = http://www.teijin-pharma.com/project/story01.html | title = Febuxostat Storym | access-date = 25 June 2015 }} Teijin partnered the drug with TAP Pharmaceuticals in the US and Ipsen in Europe.{{cite journal | vauthors = Tomlinson B | title = Febuxostat (Teijin/Ipsen/TAP) | journal = Current Opinion in Investigational Drugs | volume = 6 | issue = 11 | pages = 1168–1178 | date = November 2005 | pmid = 16312139 }}{{cite web | vauthors = Japsen B | work = The Chicago Tribune | date = 17 August 2006 | url = https://www.chicagotribune.com/2006/08/17/fda-puts-gout-treatment-on-hold/ | title = FDA puts gout treatment on hold}}Note: TAP Pharmaceuticals was a joint venture between Abbott Laboratories and Takeda that was dissolved in 2008 per this press release: {{cite web | work = Takeda| url = https://www.takeda.com/news/2008/20080320_3602.html | title = Takeda, Abbott Announce Plans to Conclude TAP Joint Venture }}

Ipsen obtained marketing approval for febuxostat from the European Medicines Agency in April 2008,{{cite web |url=http://www.ipsen.com/articles/mediacentre/pressreleases/20080505___autorisation_adenuric_eu_10.pdf |title=Adenuric (febuxostat) receives marketing authorisation in the European Union |access-date=28 May 2008 |archive-url=https://web.archive.org/web/20090326161450/http://www.ipsen.com/articles/mediacentre/pressreleases/20080505___autorisation_adenuric_eu_10.pdf |archive-date=26 March 2009 |url-status=dead }} Takeda obtained FDA approval in February 2009,{{cite web |url=http://health.usnews.com/articles/health/healthday/2009/02/16/uloric-approved-for-gout.html |title=Uloric Approved for Gout |publisher=U.S. News & World Report | access-date=16 February 2009}}{{cite web | work = Teijin and Takeda | date = 14 February 2009 | url = http://www.takeda.com/news/2009/20090214_3677.html | title = Press release: ULORIC (TMX-67, febuxostat) Receives FDA Approval for the Chronic Management of Hyperuricemia in Patients with Gout }} and Teijin obtained approval from the Japanese authorities in 2011.{{cite web | work = Teijin | date = 21 January 2011 | url = http://www.teijin.com/news/2011/ebd110121_02.html | title = Press release: TMX-67 (febuxostat) Approved in Japan | archive-url = https://web.archive.org/web/20150626115142/http://www.teijin.com/news/2011/ebd110121_02.html | archive-date=26 June 2015 }} Ipsen exclusively licensed its European rights to Menarini in 2009.{{cite web | work = Genetic Engineering News | date = October 2009 | url = http://www.genengnews.com/gen-news-highlights/menarini-to-market-takeda-ipsen-gout-therapy-in-41-european-countries/65931408/?kwrd=Menarini | title = Menarini to Market Takeda/Ipsen Gout Therapy in 41 European Countries }} Teijin partnered with Astellas for distribution in China and southeast Asia.{{cite web | work = First Word Pharma | date = 1 April 2010 | url = http://www.firstwordpharma.com/node/577383?tsid=17#axzz3e6Fm87zP | title = Teijin Pharma and Astellas Pharma enter into agreement for marketing rights of TMX-67 in China and Hong Kong }}{{cite web | work = Research Views | date = 11 August 2011 | url = http://www.researchviews.com/healthcare/pharma/DealReport.aspx?sector=Pharma&DealID=173379 | title = Teijin Pharma Enters Into Distribution Agreement With Astellas Pharma For Febuxostat | archive-url = https://web.archive.org/web/20150626121938/http://www.researchviews.com/healthcare/pharma/DealReport.aspx?sector=Pharma&DealID=173379 | archive-date=26 June 2015 }}

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.

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.{{cite journal |title=Febuxostat (Uloric) for Hyperuricemia and Gout |journal=American Family Physician |date=2010 |volume=81 |issue=10 |page=1287 |url=https://www.aafp.org/afp/2010/0515/p1287.html |access-date=15 April 2020| vauthors = Love BL }}

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.{{cite web | work = Drugs.com | url = https://www.drugs.com/international/febuxostat.html | title = International names for febuxostat | access-date = 25 June 2015 }}

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