Valdecoxib is a non-steroidal anti-inflammatory drug (NSAID) used in the treatment of osteoarthritis, rheumatoid arthritis, and painfulmenstruation and menstrual symptoms. It is a cyclooxygenase-2 selective inhibitor.
Valdecoxib was manufactured and marketed under the brand name Bextra by G. D. Searle & Company. It was approved by the United States Food and Drug Administration on November 20, 2001,[1] and was available by prescription in tablet form until 2005, when it was removed from the market due to concerns about possible increased risk of heart attack and stroke. The prodrugparecoxib is available in many countries.
Uses until 2005
In the United States, the Food and Drug Administration (FDA) approved valdecoxib for the treatment of osteoarthritis, adultrheumatoid arthritis, and primary dysmenorrhea.[2]
Valdecoxib was also used off-label for controlling acute pain and various types of surgical pain.[2]
Side-effects and withdrawal from market
On April 7, 2005, Pfizer withdrew Bextra from the U.S. market on recommendation by the FDA, citing an increased risk of heart attackand stroke and also the risk of a serious, sometimes fatal, skin reaction. This was a result of recent attention to prescription NSAIDs, such as Merck’s Vioxx. Other reported side-effects were angina and Stevens–Johnson syndrome.
Pfizer first acknowledged cardiovascular risks associated with Bextra in October 2004. The American Heart Association soon after was presented with a report indicating patients using Bextra while recovering from heart surgery were 2.19 times more likely to suffer a stroke or heart attack than those taking placebos.
In a large study published in JAMA 2006, valdecoxib appeared less adverse for renal (kidney) disease and heart arrhythmia compared to Vioxx, however elevated renal risks were slightly suggested.[3]
2009 settlement for off-label uses promotions
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On September 2, 2009, the United States Department of Justice fined Pfizer $2.3 billion after one of its subsidiaries, Pharmacia & UpJohn Company, pled guilty to marketing four drugs including Bextra “with the intent to defraud or mislead.”[4] Pharmacia & UpJohn admitted to criminal conduct in the promotion of Bextra, and agreed to pay the largest criminal fine ever imposed in the United States for any matter, $1.195 billion.[5] A former Pfizer district sales manager was indicted and sentenced to home confinement for destroying documents regarding the illegal promotion of Bextra.[6][7] In addition, a Regional Manager pled guilty to distribution of a mis-branded product, and was fined $75,000 and twenty-four months on probation.[8]
The remaining $1 billion of the fine was paid to resolve allegations under the civil False Claims Act case and is the largest civil fraud settlement against a pharmaceutical company. Six whistle-blowers were awarded more than $102 million for their role in the investigation.[9] Former Pfizer sales representative John Kopchinski acted as a qui tam relator and filed a complaint in 2004 outlining the illegal conduct in the marketing of Bextra.[10] Kopchinski was awarded $51.5 million for his role in the case because the improper marketing of Bextra was the largest piece of the settlement at $1.8 billion.[11]
Assay of Valdecoxib[13]
Several HPLC-UV methods have been reported for valdecoxib estimation in biological samples like human urine,[14] plasma,.[15][16] Valdecoxib has analytical methods for bioequivalence studies,[17][18] metabolite determination,[19][20][21] and estimation of formulation,[22] HPTLC method for simultaneous estimation in tablet dosage form.[23]
Brief background information
| Salt | ATC | Formula | MM | CAS |
|---|---|---|---|---|
| - | M01AH03 | C 16 H 14 N 2 O 3 S | 314.37 g / mol | 181695-72-7 |
| Systematic (IUPAC) name | |
|---|---|
| 4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide | |
| Clinical data | |
| Trade names | Bextra |
| Pregnancy cat. | C (AU) May cause premature closure of the ductus arteriosus |
| Legal status | Prescription Only (S4) (AU)Withdrawn in U.S., EU, Canada& parts of Asia |
| Routes | Oral |
| Pharmacokinetic data | |
| Bioavailability | 83% |
| Protein binding | 98% |
| Metabolism | Hepatic (CYP3A4 and 2C9involved) |
| Half-life | 8 to 11 hours |
| Excretion | Renal |
| Identifiers | |
| CAS number | 181695-72-7  |
| ATC code | M01AH03 |
| PubChem | CID 119607 |
| DrugBank | DB00580 |
| ChemSpider | 106796  |
| UNII | 2919279Q3W |
| KEGG | D02709 |
| ChEBI | CHEBI:63634 |
| ChEMBL | CHEMBL865 |
| Chemical data | |
| Formula | C16H14N2O3S |
| Mol. mass | 314.364 g/mol |
Using
-
anti-inflammatory
-
antirheumatic
-
COX-2 inhibitor
Classes of substances
-
Benzenesulfonamide (s -imidy), as well as their derivatives
-
Isoxazoles
-
Synthesis pathway
| Synthesis a) |
|---|
 |
Synthesis
Source:[12]
Deoxybenzoin (I) is converted to the corresponding oxime (II) by treatment with NH2OH稨Cl under basic conditions either with sodium acetate in aqueous ethanol or in toluene in presence of potassium hydroxide in absolute ethanol. Deprotonation of the oxime under nitrogen with 2eq of butyllithium in THF followed by cyclization in ethyl acetate or acetic anhydride affords isoxazoline (III). Finally, treatment of (III) with cold chlorosulfonic acid followed by reaction of the intermediate sulfonyl chloride with aqueous ammonia affords the desired product.
J Med Chem2000,43,(5):775
Trade Names
| Country | Trade name | Manufacturer |
|---|---|---|
| Germany | Bextra | Pharmacia |
| USA | - “- | - “- |
| Ukraine | No | No |
Formulations
-
Tablets of 10 mg, 20 mg
Valdecoxib is chemically designated as 4-(5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide and is a diaryl substituted isoxazole.
The empirical formula for valdecoxib is C16H14N2O3S, and the molecular weight is 314.36. Valdecoxib is a white crystalline powder that is relatively insoluble in water (10 µg/mL) at 25° C and pH 7.0, soluble in methanol and ethanol, and freely soluble in organic solvents and alkaline (pH=12) aqueous solutions.
BEXTRA (valdecoxib) Tablets for oral administration contain either 10 mg or 20 mg of valdecoxib. Inactive ingredients include lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium,magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, polysorbate 80, and titanium dioxide
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NMR
Links
-
Talley, JJ et al .: J. Med. Chem. (JMCMAR) 43, 775-777 (2000).
-
US 5,859,257 (GD Searle; 12.1.1999; USA-prior. 13.2.1995).
Literature References:
Selective cyclooxygenase-2 (COX-2) inhibitor. Active metabolite of parecoxib, q.v. Prepn: J. J. Talley et al., WO 9625405 (1996 to Searle); eidem, US 5633272 (1997); and activity: eidem, J. Med. Chem. 43, 775 (2000).
Chromatographic determn of purity: D. A. Roston et al., J. Pharm. Biomed. Anal. 26, 339 (2001).
Gastrointestinal tolerability study: G. M. Eisen et al., Aliment. Pharmacol. Ther. 21, 591 (2005).
Clinical trial in hip arthroplasty: F. Camu et al., Am. J. Ther.9, 43 (2002).
Clinical comparison with oxycodone/acetominophen in dental pain: S. E. Daniels et al., J. Am. Dent. Assoc. 133, 611 (2002).
Clinical trial in migraine: D. Kudrow et al., Headache 45, 1151 (2005).
Review of clinical experience: M. Goldman, S. Schutzer, Formulary 37, 68-77 (2002); of clinical efficacy and safety: G. P. Joshi, Expert Rev. Neurother. 5, 11-24 (2005).
References
- Jump up^ Thomson Micromedex. “Valdecoxib. U.S. FDA Drug Approval.” Last accessed June 8, 2007.
- ^ Jump up to:a b “Pfizer to pay $2.3 billion to resolve criminal and civil health care liability relating to fraudulent marketing and the payment of kickbacks”. Stop Medicare Fraud, US Dept of Health & Human Svc, and of Justice. Retrieved 2012-07-04.
- Jump up^ “Adverse Effects of Cyclooxygenase-2 Inhibitors on Renal and Arrhythmia Events: Meta-Analysis of Randomized Trials”, (JAMA 2006, by Zhang JJ, Ding EL, Song Y.).
- Jump up^ http://news.bbc.co.uk/2/hi/business/8234533.stm Pfizer agrees record fraud fine
- Jump up^ http://www.usdoj.gov/usao/ma/Press%20Office%20-%20Press%20Release%20Files/Sept2009/PharmaciaPlea.html
- Jump up^ http://www.usdoj.gov/usao/ma/Press%20Office%20-%20Press%20Release%20Files/Mar2009/FarinaconvictionPR.html
- Jump up^ http://industry.bnet.com/pharma/10002882/pfizers-off-label-bextra-team-were-called-the-highlanders/
- Jump up^ http://www.usdoj.gov/usao/ma/Press%20Office%20-%20Press%20Release%20Files/June2009/HollowayMarySentencingPR.html
- Jump up^ http://www.fbi.gov/pressrel/pressrel09/justice_090209.htm
- Jump up^ http://www.phillipsandcohen.com/CM/NewsSettlements/NewsSettlements536.asp
- Jump up^ http://www.phillipsandcohen.com/CM/NewsSettlements/NewsSettlements531.asp
- Jump up^ Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. (2000). “4-[5-Methyl-3-phenylisoxazol-4-yl]- benzenesulfonamide, Valdecoxib: A Potent and Selective Inhibitor of COX-2″. Journal of Medicinal Chemistry 43 (5): 775–777. doi:10.1021/jm990577v.PMID 10715145.
- Jump up^ Prafulla Kumar Sahu and M. Mathrusri Annapurna, Analytical method development by liquid chromatography, LAP Lambert Academic Publisher, Germany, 2011 ISBN 3-8443-2869-6.
- Jump up^ Zhang J Y, Fast D M and Breau A P, J Chromatogr B Analyt Technol Biomed Life Sci., 2003, 785(1), 123-134
- Jump up^ Ramakrishna N V S, Vishwottam K N; Wishu S and Koteshwara M, J Chromatogr B Analyt Technol Biomed Life Sci., 2004, 802(2), 271.
- Jump up^ Sane R T, Menon S, Deshpande A Y and Jain A, Chromatogr., 2005, 61(3-4), 137-141.
- Jump up^ Prafulla Kumar Sahu*, K. Ravi Sankar and M. Mathrusri Annapurna, Determination of Valdecoxib in human plasma using Reverse Phase HPLC”, E-Journal of Chemistry, 2011, 8(2), 875-881.
- Jump up^ Mandal U, Jayakumar M, Ganesan M, Nandi S, Pal T K, Chakraborty M K, Roy Chowdhary A. and Chattoraj T K, Indian Drugs, 2004, 41, 59.
- Zhang J.Y, Fast D.M and Breau, A.P, J Pharm Biomed Anal., 2003, 33, 61.
- Werner U, Werner D, Hinz B, Lanbrecht C and Brune K, J Biomed Chromatogr., 2004, 19, 113.
- Zhang J V, Fast D M and Breau A P, J Chromatogr B Anal Technol Biomed Life Sci., 2003, 785, 123.
- Sutariya V B, Rajashree M, Sankalia M G. and Priti P, Indian J Pharm Sci., 2004, 93, 112.
- J Gandhimathi M, Ravi T K, Shukla Nilima and Sowmiya G, Indian J Pharm Sci., 2007, 69(1), 145-147.
External links[edit]
- FDA Alert on Bextra withdrawal
- Large systematic review of adverse renal and arrhythmia risk of valdcoxib and other COX-2 inhibitors, JAMA 2006
Filed under: Uncategorized Tagged: Analgesic (Non-Narcotic), Anti-inflammatory (Nonsteroidal), Bextra, Cyclooxygenase-2 Selective Inhibitor, valdecoxib
