Vioxx®

Typically, funding to embark on information and/or knowledge management initiatives within the life sciences only occurs after a serious failure within the business, such as a project failure or a withdrawal of a medicine from the market. Recently, COX-2 programs across the industry are under close scrutiny since the highly publicized withdrawal of Vioxx [10]. Of course, there has been no withdrawal of aspirin, paracetamol, alcohol, or tobacco products, which are well known as toxic. 

Two large trials, the Vioxx Gastrointestinal Outcomes Research (VIGOR) study and the Celecoxib Long-term Arthritis Safety Study (CLASS), compared selective COX-2 inhibitors and traditional, non-selective NSAID therapy in terms of their ability to prevent clinical PUD (i.e., symptomatic ulcers and ulcer complications). VIGOR (9-month median follow-up) demonstrated that rofecoxib (50 mg daily) therapy was significantly more efficacious than naproxen.28 The CLASS study (6-month median follow-up) found that high-dose celecoxib (400 mg twice daily) was superior to non-selective NSAID therapy (either ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily).29... 

VIGOR Vioxx Gastrointestinal Outcomes Research (study)... 

Carbidopa Celebrex, Vioxx Cl-1040, PD0325901 Clavulanate Digoxin... 

While this book was in production, Vioxx was withdrawn from the market due to unanticipated cardiovascular side effects. Whether this side effect is a specific liability of Vioxx, or a more general effect of all COX2 selective inhibitors remains unresolved at present. 

Both Vioxx and Celebrex derive their COX2 selectivity from the same type of isozyme-specific slow enzyme isomerization mechanism that was detailed here for DuP697. 

Anionic/oxidative reaction sequences have been developed in addition to the domino anionic/reductive processes. For example, with regard to the synthesis of novel diaryl heterocycles as COX-2 inhibitors [500], including rofecoxib (Vioxx) 2-972 [501] (which has recently been withdrawn from the market) or the pyrrolin-2-one derivative 2-973 [494], Pal and coworkers reported on a so-far unique domino aldol condensation/oxidation sequence (Scheme 2.218) [503]. 

Another route to the synthesis of the furanone-containing compounds (e.g., 84, Scheme 18) is via magnesium-mediated carbometallation of propar-gyl alcohols, as described by Forgione et al. [67]. Scheme 20 demonstrates this procedure as a feasible means of producing the Merck anti-inflammatory drug Vioxx, 85. 

Roentgen, Wilhelm Conrad, 21 285 Willem, 11 399 Rofecoxib (Vioxx), 2 820 Roflurane, 4 359t... 

The FDA approved this selective cyclooxigenase (COX)-2 inhibitor (Vioxx) for the treatment of pain and inflammation in 1999. This NSAID demonstrated to have a lower risk of side effects such as gastrointestinal ulcers and bleeding than nonse-lective COX inhibitors, for example, ibuprofen. In 2004, a long-term study of Vioxx in patients at increased risk of colon polyps was halted because of an increased cardiovascular risk (heart attack, stroke) in the rofecoxib group. Subsequently, Merck withdrew the drug from the world market at the end of September 2004 [46]. 

FDA (2004) FDA issues public health advisory on Vioxx as its manufacturer... 

Edwards, I.R., What are the real lessons from Vioxx , Drug Safety, 28, 651-658, 2005. 

That was 2003 and 2004, and of course we now know (and will read about later in the chapter) the Vioxx recall in September, 2004. A tremendous amoxmt of renewed pressure and criticism was directed to the FDA, and the FDA has been re-examining the Agency s methods of monitoring drug safety. Janet Woodcock MD, former director of CDER, and now Deputy Commissioner for Operations, recently gave the following remarks to the lOM ... 

Rofecoxib Vioxx Merck Co. Cox-2 Inhibitor 5/21/1999 9/30/2004 5.33 years Heart attack and stroke US 2.5 billion... 

Valdecoxib (Bextra Pfizer), a second COX-2 specific inhibitor NSAID was taken off the market a few months after Vioxx. In addition to a higher risk of serious skin toxicity, pahents given Vioxx after Coronary Bypass Surgery had a higher rate of myocardial infarchons. 

In the aftermath of the Vioxx and Bextra withdrawals, the FDA studied the CV and GI risks in great detail. A very recent request for strengthening the warnings and precautions on all NSAID products was released, and reads as follows ... 

It is postulated that selective inhibition of COX-2 by Vioxx, for example,... 

Refer to Section 6.3 to describe the phases of a clinical trial. Phase IV trials are necessary to maintain a close watch on the efficacy and adverse events of an approved drug when it is administered to the population at large. For example, even a small percentage of adverse events in Phase III trial for several thousand people may translate into a substantial number when a drug is made available to milhons of people. A case in point is Vioxx and Bextra (see Section 2.9). 

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