Febuxostat

Names
Trade names	Uloric, Adenuric, others[1]
IUPAC name 2-(3-cyano-4-isobutoxyphenyl)-4-methyl- 1,3-thiazole-5-carboxylic acid
Clinical data
Pregnancy category	AU: B1[2] US: N (Not classified yet)[2]
Routes of use	By mouth
Defined daily dose	80 mg[3]
External links
AHFS/Drugs.com	Monograph
MedlinePlus	a609020
Legal
License data	EU EMA: by INN US DailyMed: Febuxostat US FDA: Febuxostat
Legal status	US: ℞-only
Pharmacokinetics
Bioavailability	≥84% absorbed
Protein binding	99.2% to albumin
Metabolism	viaCYP1A1,1A2,2C8,2C9,UGT1A1,1A8,1A9[4]
Eliminationhalf-life	~5–8 hours
Excretion	Urine (~49%, mostly as metabolites, 3% as unchanged drug); feces (~45%, mostly as metabolites, 12% as unchanged drug)
Chemical and physical data
Formula	C16H16N2O3S
Molar mass	316.38 g·mol−1
3D model (JSmol)	Interactive image
SMILES N#Cc1c(OCC(C)C)ccc(c1)c2nc(c(s2)C(=O)O)C
InChI 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) Y Key:BQSJTQLCZDPROO-UHFFFAOYSA-N Y

Febuxostat, sold under the brand namesUloric among others, is a medication used long-term to treatgout due tohigh uric acid levels.^[5] It is generally recommended only for people who cannot takeallopurinol.^[6][7] When initially started, medications such asNSAIDs are often recommended to prevent gout flares.^[5][7] It is taken by mouth.^[5]

Common side effects include liver problems, nausea, joint pain, and a rash.^[5] Serious side effects include an increased risk of death as compared with allopurinol,Stevens–Johnson syndrome, andanaphylaxis.^[7][6] Use is not recommended duringpregnancy orbreastfeeding.^[7] It inhibitsxanthine oxidase, thus reducing production ofuric acid in the body.^[5]

Febuxostat was approved for medical use in the European Union in 2008 and in the United States in 2009.^[8][5] Ageneric version was approved in 2019 and is available as of 2020.^[9][10] In the United Kingdom a month of treatment costs theNHS about 24 pounds.^[7] In the United States the wholesale cost of a month's worth of medication is about US$320.^[11]

Medical uses

Febuxostat is used to treat chronicgout andhyperuricemia.^[12] Febuxostat is typically recommended only for people who cannot tolerate allopurinol.^[13]National Institute for Health and Clinical Excellence concluded that febuxostat is more effective than standard doses ofallopurinol, but not more effective than higher doses of allopurinol.^[12]

Febuxostat is in the USpregnancy category C; there are no adequate and well-controlled studies in pregnant women.^[14]

Dosage

Thedefined daily dose is 80 mg by mouth.^[3]

Side effects

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

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.^[16]

Drug interactions

Febuxostat is contraindicated with concomitant use oftheophylline andchemotherapeutic agents, namelyazathioprine and6-mercaptopurine, because it could increase blood plasma concentrations of these drugs and thereby their toxicity.^[14][17]

Pharmacology

Mechanism of action

Febuxostat is a non-purine-selective inhibitor ofxanthine oxidase.^[14]

It works bynon-competitively blocking themolybdenum pterin center, which is the active site of xanthine oxidase. Xanthine oxidase is needed to oxidize successivelyhypoxanthine andxanthine 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 highestblood 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 proteinalbumin, and 82–91% of theactive metabolites are bound to plasma proteins.^[4]

Febuxostat has three active metabolites in humans, which are formed mainly by a number ofcytochrome P450 liver enzymes (CYP1A1,1A2,2C8,2C9). One of them is adicarboxylic acid, the other two arehydroxylated derivatives. These, as well as the original drug, are furtherglucuronidated, mainly by the enzymesUGT1A1,1A8, and1A9. 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.^[4][19]

History

Febuxostat was discovered by scientists at the Japanese pharmaceutical companyTeijin in 1998.^[20]

Teijin partnered the drug withTAP Pharmaceuticals in the US andIpsen in Europe.^[21][22][23]

Ipsen obtained marketing approval for febuxostat from theEuropean Medicines Agency in April 2008,^[24]

Takeda obtained FDA approval in February 2009,^[25][26] and Teijin obtained approval from the Japanese authorities in 2011.^[27]

Ipsen exclusively licensed its European rights toMenarini in 2009.^[28] Teijin partnered withAstellas for distribution in China and southeast Asia.^[29][30]

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.^[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 $US14 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

External links

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