Febuxostat: Difference between revisions
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{{Short description|Chemical compound}} | {{Short description|Chemical compound}} | ||
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| tradename = Uloric, Adenuric, others | | tradename = Uloric, Adenuric, others | ||
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| bioavailability = ≥84% absorbed | | bioavailability = ≥84% absorbed | ||
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| excretion = Urine (~49%, mostly as metabolites, 3% as unchanged drug); feces (~45%, mostly as metabolites, 12% as unchanged drug) | | excretion = Urine (~49%, mostly as metabolites, 3% as unchanged drug); feces (~45%, mostly as metabolites, 12% as unchanged drug) | ||
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<!-- Identifiers --> | <!-- Identifiers --> | ||
| IUPHAR_ligand = 6817 | | IUPHAR_ligand = 6817 | ||
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| ChEMBL = 1164729 | | ChEMBL = 1164729 | ||
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<!-- Chemical data --> | <!-- Chemical data --> | ||
| IUPAC_name = 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-<br />1,3-thiazole-5-carboxylic acid | | IUPAC_name = 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-<br />1,3-thiazole-5-carboxylic acid | ||
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<!-- Definition and medical uses --> | <!-- Definition and medical uses --> | ||
'''Febuxostat''', sold under the brand names ''Uloric'' among others, is a [[medication]] used long-term to treat [[gout]] due to [[hyperuricemia|high uric acid levels]]. It is generally recommended only for people who cannot take [[allopurinol]]. When initially started, medications such as [[NSAIDs]] are often recommended to prevent gout flares. It is taken [[by mouth]]. | '''Febuxostat''', sold under the brand names ''Uloric'' among others, is a [[medication]] used long-term to treat [[gout]] due to [[hyperuricemia|high uric acid levels]]. It is generally recommended only for people who cannot take [[allopurinol]]. When initially started, medications such as [[NSAIDs]] are often recommended to prevent gout flares. It is taken [[by mouth]]. | ||
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<!-- Side effects and mechanism --> | <!-- Side effects and mechanism --> | ||
Common side effects include liver problems, nausea, joint pain, and a rash. Serious side effects include an increased risk of death as compared with allopurinol, [[Stevens–Johnson syndrome]], and [[anaphylaxis]]. Use is not recommended during [[pregnancy]] or [[breastfeeding]]. It inhibits [[xanthine oxidase]], thus reducing production of [[uric acid]] in the body. | Common side effects include liver problems, nausea, joint pain, and a rash. Serious side effects include an increased risk of death as compared with allopurinol, [[Stevens–Johnson syndrome]], and [[anaphylaxis]]. Use is not recommended during [[pregnancy]] or [[breastfeeding]]. It inhibits [[xanthine oxidase]], thus reducing production of [[uric acid]] in the body. | ||
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<!-- History and culture --> | <!-- History and culture --> | ||
Febuxostat was approved for medical use in the European Union in 2008, and in the United States in 2009. | Febuxostat was approved for medical use in the European Union in 2008, and in the United States in 2009. | ||
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==Medical uses == | ==Medical uses == | ||
Febuxostat is used to treat chronic [[gout]] and [[hyperuricemia]]. Febuxostat is typically recommended only for people who cannot tolerate allopurinol. [[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. | Febuxostat is used to treat chronic [[gout]] and [[hyperuricemia]]. Febuxostat is typically recommended only for people who cannot tolerate allopurinol. [[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. | ||
[[File:Uloric 40 mg tablet.jpg|thumb|right|Uloric 40 mg tablet]] | [[File:Uloric 40 mg tablet.jpg|thumb|right|Uloric 40 mg tablet]] | ||
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==Side effects== | ==Side effects== | ||
The adverse effects associated with febuxostat therapy include nausea, diarrhea, arthralgia, headache, increased hepatic serum enzyme levels and rash. | The adverse effects associated with febuxostat therapy include nausea, diarrhea, arthralgia, headache, increased hepatic serum enzyme levels and rash. | ||
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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. 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. | 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. 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. | 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. | ||
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==Drug interactions== | ==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 thereby their toxicity. | 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. | ||
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== Pharmacology == | == Pharmacology == | ||
=== Mechanism of action === | === Mechanism of action === | ||
Febuxostat is a non-purine-selective inhibitor of [[xanthine oxidase]]. It works by [[Non-competitive inhibition|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. | Febuxostat is a non-purine-selective inhibitor of [[xanthine oxidase]]. It works by [[Non-competitive inhibition|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. | ||
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=== Pharmacokinetics === | === 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 metabolite]]s are bound to plasma proteins. | 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 metabolite]]s are bound to plasma proteins. | ||
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[[File:Febuxostat active metabolites.svg|thumb|right|The [[active metabolite]]s in humans: 67M-1, 67M-2 and 67M-4 (top to bottom)]] | [[File:Febuxostat active metabolites.svg|thumb|right|The [[active metabolite]]s 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]], [[CYP1A2|1A2]], [[CYP2C8|2C8]], [[CYP2C9|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]], [[UGT1A8|1A8]], and [[UGT1A9|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. | Febuxostat has three active metabolites in humans, which are formed mainly by a number of [[cytochrome P450]] liver enzymes ([[CYP1A1]], [[CYP1A2|1A2]], [[CYP2C8|2C8]], [[CYP2C9|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]], [[UGT1A8|1A8]], and [[UGT1A9|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. | ||
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==History== | ==History== | ||
[[File:FEBURIC 80 mg (Febuxostat).jpg|thumb|right|250px|FEBURIC (Febuxostat) 80 mg tablet]] | [[File:FEBURIC 80 mg (Febuxostat).jpg|thumb|right|250px|FEBURIC (Febuxostat) 80 mg tablet]] | ||
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. | 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. | ||
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Ipsen obtained marketing approval for febuxostat from the [[European Medicines Agency]] in April 2008, [[Takeda Pharmaceutical Company|Takeda]] obtained FDA approval in February 2009, and Teijin obtained approval from the Japanese authorities in 2011. Ipsen exclusively licensed its European rights to [[Menarini]] in 2009. Teijin partnered with [[Astellas]] for distribution in China and southeast Asia. | Ipsen obtained marketing approval for febuxostat from the [[European Medicines Agency]] in April 2008, [[Takeda Pharmaceutical Company|Takeda]] obtained FDA approval in February 2009, and Teijin obtained approval from the Japanese authorities in 2011. Ipsen exclusively licensed its European rights to [[Menarini]] in 2009. Teijin partnered with [[Astellas]] for distribution in China and southeast Asia. | ||
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== Society and culture == | == Society and culture == | ||
=== Economics === | === 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. | 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. | ||
<!--T:20--> | |||
In 2010, before it became generic in the United States, it cost about {{US$|160}} per month as opposed to allopurinol which was about $14 per month. | In 2010, before it became generic in the United States, it cost about {{US$|160}} per month as opposed to allopurinol which was about $14 per month. | ||
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===Trade names=== | ===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. | 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. | ||
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{{Antigout preparations}} | {{Antigout preparations}} | ||
{{Purinergics}} | {{Purinergics}} | ||
{{Portal bar | Medicine}} | {{Portal bar | Medicine}} | ||
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{{二次利用|date=29 December 2023}} | {{二次利用|date=29 December 2023}} | ||
[[Category:Antigout agents]] | [[Category:Antigout agents]] | ||
Latest revision as of 20:19, 22 April 2024
 | |
| Clinical data | |
|---|---|
| Trade names | Uloric, Adenuric, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a609020 |
| License data |
|
| Pregnancy category |
|
| Routes of administration | By mouth |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | ≥84% absorbed |
| Protein binding | 99.2% to albumin |
| Metabolism | via CYP1A1, 1A2, 2C8, 2C9, UGT1A1, 1A8, 1A9 |
| 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 | |
| ChEBI | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C16H16N2O3S |
| Molar mass | 316.38 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
  (what is this?) (verify) | |
Febuxostat, sold under the brand names Uloric among others, is a medication used long-term to treat gout due to high uric acid levels. It is generally recommended only for people who cannot take allopurinol. When initially started, medications such as NSAIDs are often recommended to prevent gout flares. It is taken by mouth.
Common side effects include liver problems, nausea, joint pain, and a rash. Serious side effects include an increased risk of death as compared with allopurinol, Stevens–Johnson syndrome, and anaphylaxis. Use is not recommended during pregnancy or breastfeeding. It inhibits xanthine oxidase, thus reducing production of uric acid in the body.
Febuxostat was approved for medical use in the European Union in 2008, and in the United States in 2009.
Medical uses
Febuxostat is used to treat chronic gout and hyperuricemia. Febuxostat is typically recommended only for people who cannot tolerate allopurinol. 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.
Side effects
The adverse effects associated with febuxostat therapy include nausea, diarrhea, arthralgia, headache, increased hepatic serum enzyme levels and rash.
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. 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.
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 thereby their toxicity.
Pharmacology
Mechanism of action
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.
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.
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.
History
.jpg)
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 authorities in 2011. Ipsen exclusively licensed its European rights to Menarini in 2009. Teijin partnered with Astellas for distribution in China and southeast Asia.
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.
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.
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.
 | この記事は、クリエイティブ・コモンズ・表示・継承ライセンス3.0のもとで公表されたウィキペディアの項目Febuxostat(29 December 2023編集記事参照)を素材として二次利用しています。 Item:Q22166  |