Febuxostat/ja: Difference between revisions

==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.

[[File:Uloric 40 mg tablet.jpg|thumb|right|Uloric 40 mg tablet]]

==Side effects==

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-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 ===

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.

[[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.

==History==

[[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.

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.

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.