Febuxostat

Last updated

Febuxostat
Febuxostat.svg
Clinical data
Trade names Uloric, Adenuric, others [1]
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 [6]
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
  • 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-
    1,3-thiazole-5-carboxylic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.207.329 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H16N2O3S
Molar mass 316.38 g·mol−1
3D model (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) Yes check.svgY
  • Key:BQSJTQLCZDPROO-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Febuxostat, sold under the brand name Uloric among others, is a medication used long-term to treat gout due to high uric acid levels. [7] It is generally recommended only for people who cannot take allopurinol. [8] [9] It is taken by mouth. [7]

Contents

Common side effects include liver problems, nausea, joint pain, and a rash. [7] Serious side effects include an increased risk of death as compared with allopurinol, Stevens–Johnson syndrome, and anaphylaxis. [9] [8] Use is not recommended during pregnancy or breastfeeding. [9] It inhibits xanthine oxidase, thus reducing production of uric acid in the body. [7]

Febuxostat was approved for medical use in the European Union in 2008, [5] and in the United States in 2009. [7] A generic version was approved in 2019. [10] [11]

Medical uses

Febuxostat is used to treat chronic gout and hyperuricemia. [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 of allopurinol, but not more effective than higher doses of allopurinol. [12]

Uloric 40 mg tablet Uloric 40 mg tablet.jpg
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 theophylline and chemotherapeutic agents, namely azathioprine and 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 xanthine oxidase. [14] 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. [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. [6]

The active metabolites in humans: 67M-1, 67M-2 and 67M-4 (top to bottom) Febuxostat active metabolites.svg
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 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. [6] [19]

History

FEBURIC (Febuxostat) 80 mg tablet FEBURIC 80 mg (Febuxostat).jpg
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 European 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 to Menarini in 2009. [28] Teijin partnered with 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]

Brand 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]

Related Research Articles

Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of purine nucleotides, and it is a normal component of urine. High blood concentrations of uric acid can lead to gout and are associated with other medical conditions, including diabetes and the formation of ammonium acid urate kidney stones.

<span class="mw-page-title-main">Gout</span> Form of arthritis causing swollen joints

Gout is a form of inflammatory arthritis characterized by recurrent attacks of pain in a red, tender, hot, and swollen joint, caused by the deposition of needle-like crystals of uric acid known as monosodium urate crystals. Pain typically comes on rapidly, reaching maximal intensity in less than 12 hours. The joint at the base of the big toe is affected (Podagra) in about half of cases. It may also result in tophi, kidney stones, or kidney damage.

<span class="mw-page-title-main">Xanthine oxidase</span> Class of enzymes

Xanthine oxidase is a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species. These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid. These enzymes play an important role in the catabolism of purines in some species, including humans.

<span class="mw-page-title-main">Allopurinol</span> Medication

Allopurinol is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken orally or intravenously.

<span class="mw-page-title-main">Colchicine</span> Medication mainly used to treat gout

Colchicine is a medication used to prevent and treat gout, to treat familial Mediterranean fever and Behçet's disease, and to reduce the risk of myocardial infarction. The American College of Rheumatology recommends colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids in the treatment of gout. Other uses for colchicine include the management of pericarditis.

<span class="mw-page-title-main">Hyperuricemia</span> Excess uric acid in the blood

Hyperuricaemia or hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. Serum uric acid concentrations greater than 6 mg/dL for females, 7 mg/dL for males, and 5.5 mg/dL for youth are defined as hyperuricemia. The amount of urate in the body depends on the balance between the amount of purines eaten in food, the amount of urate synthesised within the body, and the amount of urate that is excreted in urine or through the gastrointestinal tract. Hyperuricemia may be the result of increased production of uric acid, decreased excretion of uric acid, or both increased production and reduced excretion.

Tumor lysis syndrome (TLS) is a group of metabolic abnormalities that can occur as a complication from the treatment of cancer, where large amounts of tumor cells are killed off (lysed) from the treatment, releasing their contents into the bloodstream. This occurs most commonly after the treatment of lymphomas and leukemias and in particular when treating non-Hodgkin lymphoma, acute myeloid leukemia, and acute lymphoblastic leukemia. This is a potentially fatal complication and patients at increased risk for TLS should be closely monitored while receiving chemotherapy and should receive preventive measures and treatments as necessary. TLS can also occur on its own although this is less common.

<span class="mw-page-title-main">Lesch–Nyhan syndrome</span> Rare genetic disorder

Lesch–Nyhan syndrome (LNS) is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This deficiency occurs due to mutations in the HPRT1 gene located on the X chromosome. LNS affects about 1 in 380,000 live births. The disorder was first recognized and clinically characterized by American medical student Michael Lesch and his mentor, pediatrician William Nyhan, at Johns Hopkins.

<span class="mw-page-title-main">Rasburicase</span> Pharmaceutical drug

Rasburicase, sold under the brand name Elitek in the US and Fasturtec in the EU, is a medication that helps to clear uric acid from the blood. It is a recombinant version of urate oxidase, an enzyme that metabolizes uric acid to allantoin. Urate oxidase is known to be present in many mammals but does not naturally occur in humans. Rasburicase is produced by a genetically modified Saccharomyces cerevisiae strain. The complementary DNA (cDNA) coding for rasburicase was cloned from a strain of Aspergillus flavus.

<span class="mw-page-title-main">Hypouricemia</span> Lack of uric acid in the blood

Hypouricemia or hypouricaemia is a level of uric acid in blood serum that is below normal. In humans, the normal range of this blood component has a lower threshold set variously in the range of 2 mg/dL to 4 mg/dL, while the upper threshold is 530 μmol/L (6 mg/dL) for women and 619 μmol/L (7 mg/dL) for men. Hypouricemia usually is benign and sometimes is a sign of a medical condition.

<span class="mw-page-title-main">Hyperuricosuria</span> Excess uric acid in the urine

Hyperuricosuria is a medical term referring to the presence of excessive amounts of uric acid in the urine. For men this is at a rate greater than 800 mg/day, and for women, 750 mg/day. Notable direct causes of hyperuricosuria are dissolution of uric acid crystals in the kidneys or urinary bladder, and hyperuricemia. Notable indirect causes include uricosuric drugs, rapid breakdown of bodily tissues containing large quantities of DNA and RNA, and a diet high in purine.

<span class="mw-page-title-main">Vernakalant</span> Medication for the treatment of atrial fibrillation

Vernakalant, sold under the brand name Brinavess, is a class III antiarrhythmic drug for the acute conversion of atrial fibrillation, a kind of irregular heartbeat, in form of an intravenous infusion. It has been approved for use in the European Union and the United Kingdom since 2010. The US Food and Drug Administration denied approval in 2008 and 2019.

<span class="mw-page-title-main">Oxipurinol</span> Chemical compound

Oxipurinol is an inhibitor of xanthine oxidase. It is an active metabolite of allopurinol and it is cleared renally. In cases of renal disease, this metabolite will accumulate to toxic levels. By inhibiting xanthine oxidase, it reduces uric acid production. High serum uric acid levels may result in gout, kidney stones, and other medical conditions.

A xanthine oxidase inhibitor is any substance that inhibits the activity of xanthine oxidase, an enzyme involved in purine metabolism. In humans, inhibition of xanthine oxidase reduces the production of uric acid, and several medications that inhibit xanthine oxidase are indicated for treatment of hyperuricemia and related medical conditions including gout. Xanthine oxidase inhibitors are being investigated for management of reperfusion injury.

<span class="mw-page-title-main">Tivozanib</span> Medication

Tivozanib, sold under the brand name Fotivda, is a medication used for the treatment of advanced renal cell carcinoma. It is an oral VEGF receptor tyrosine kinase inhibitor.

<span class="mw-page-title-main">Lesinurad</span> Pharmaceutical drug for the treatment of gout

Lesinurad is a urate transporter inhibitor for treating high blood uric acid levels associated with gout. It is recommended only as an adjuvant with either allopurinol or febuxostat when these medications are not sufficient.

Lesinurad/allopurinol is a fixed-dose combination drug for the treatment of gout. It contains 200 mg of lesinurad and 300 mg of allopurinol. In August 2017, the US Food and Drug Administration approved it for the treatment of hyperuricemia associated with gout in patients for whom target serum uric acid levels have not been achieved with allopurinol alone. It was approved for medical use in the European Union in August 2018. In February 2019, it was discontinued by its manufacturer for business reasons and is no longer available.

Bempedoic acid, sold under the brand name Nexletol among others, is a medication for the treatment of hypercholesterolemia.

<span class="mw-page-title-main">Ruzinurad</span> Chemical compound

Ruzinurad (SHR4640) is a selective urate transporter 1 (URAT1) inhibitor in development for hyperuricaemia and gout. It is developed by Jiangsu Hengrui.

<span class="mw-page-title-main">Gout suppressants</span> Drugs to control and prevent gout attacks

Gout suppressants are agents which control and prevent gout attacks after the first episode. They can be generally classified into two groups by their purpose: drugs used for induction therapy and that for maintenance therapy.

References

  1. 1 2 "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. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2014". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  4. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  5. 1 2 "Adenuric EPAR". European Medicines Agency (EMA). 21 April 2008. Retrieved 14 September 2024.
  6. 1 2 3 "Adenuric: EPAR – Product Information" (PDF). European Medicines Agency. 6 August 2019.
  7. 1 2 3 4 5 "Febuxostat Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 26 February 2019.
  8. 1 2 "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.
  9. 1 2 3 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 1087. ISBN   9780857113382.
  10. ↑ "Generic Uloric Availability". Drugs.com. Retrieved 1 August 2019.
  11. ↑ "Febuxostat Generic Uloric" . Retrieved 15 April 2020.
  12. 1 2 3 "Febuxostat for the management of hyperuricaemia in people with gout (TA164) Chapter 4. Consideration of the evidence". 17 December 2008. Archived from the original on 6 October 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. 1 2 3 "Uloric label" (PDF). U.S. Food and Drug Administration. February 2009.
  15. 1 2 Love BL, Barrons R, Veverka A, Snider KM (June 2010). "Urate-lowering therapy for gout: focus on febuxostat". Pharmacotherapy. 30 (6): 594–608. doi:10.1592/phco.30.6.594. PMID   20500048. 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.[ dead link ]
  18. ↑ Mozayani A, Raymon L (2011). Handbook of Drug Interactions: A Clinical and Forensic Guide. Springer Science+Business Media. ISBN   978-1-61779-221-2.
  19. ↑ "Adenuric: EPAR – Public Assessment Report" (PDF). European Medicines Agency. 28 May 2008.
  20. ↑ "Febuxostat Storym". Teijin. Retrieved 25 June 2015.
  21. ↑ Tomlinson B (November 2005). "Febuxostat (Teijin/Ipsen/TAP)". Current Opinion in Investigational Drugs. 6 (11): 1168–1178. 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 16 February 2009.
  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 26 June 2015.
  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 26 June 2015.
  31. ↑ Love BL (2010). "Febuxostat (Uloric) for Hyperuricemia and Gout". American Family Physician. 81 (10): 1287. Retrieved 15 April 2020.
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