Rofecoxib withdrawal from market

Recent data suggest that COX-2 inhibitors, including rofe-coxib, valdecoxib, and celecoxib, may increase the risk for MI and stroke.47 There is also some evidence that the non-selective NSAIDs may increase the risk for cardiovascular events.47,48 Rofecoxib was withdrawn from the market in late 2004 because of safety concerns. The FDA requested the withdrawal of valdecoxib from the market in 2005. The FDA also asked the manufacturers of celecoxib and non-selective NSAIDs (prescription and over-the-counter) to include information about the potential adverse cardiovascular effects of these drugs in their product labeling. The cardiovascular risk with COX-2 inhibitors and NSAIDs may be greatest in patients with a history of, or with risk factors for, cardiovascular disease. The American Heart Association recommends that the use of COX-2 inhibitors be limited to low-dose, short-term therapy in patients for whom there is no appropriate alternative.48 Patients with cardiovascular disease should consult a clinician before using over-the-counter NSAIDs. 

Longer-term studies evaluating the cardiovascular risks associated with the use of COX-2 inhibitors have found a higher incidence of cardiovascular mortality with the use of these agents compared to traditional NSAIDs.29,33,34 This prompted the withdrawal of both rofecoxib and valdecoxib from the market and the inclusion of a black box warning in... 

Another potential use for these drugs was to prevent the formation of adenomatous polyps in patients with a history of colorectal adenomas. Rofecoxib and celecoxib were both tested in this disease. It was the results of this test that prompted Merck to withdraw their drug from the market since this study clearly established the increased risk of cardiovascular events when rofecoxib is used. The results were sufficiently strong to have the safety monitoring board reevaluate the data for a similar trial with celecoxib. On the basis of these data the study with celecoxib was also terminated. Interestingly, another study in which celecoxib was used to prevent polyp formation resulted in no increase in cardiovascular events. The only difference between the two studies was that in the latter case celecoxib was given once a day whereas in the prior study celecoxib was administered at the same dose but twice a day. How this difference in treatment schedules affected the toxic outcomes is unknown at the present time. 

Potential cardiotoxicity resulted in a withdrawal of rofecoxib from the market in October 2004. 

In one of the most publicized drug withdrawals, Merck voluntarily withdrew rofecoxib from the U.S. market in September 2004, followed by Pfizer s withdrawal of valdecoxib in April 2005. Thus, the future of selective COX-2 inhibitors in the treatment of inflammatory disorders is very clouded. 

Tilmacoxib is a COX-2 inhibiting, oxazole-containing, nonsteroidal anti-inflammatory agent, and valdecoxib is an isoxazole NSAID. Formation of the sodium salt of an A -acylated derivative of valdecoxib affords parecoxib, a water-soluble valdecoxib prodrug amenable to injectable formulations. Valdecoxib was withdrawn from the US market in 2005 due to concern of increased risk of heart attack or stroke. While parecoxib is approved for use in the EU, the US FDA issued a letter of nonapproval for the drug, also in 2005. While no documentation for the nonapproval was made public, proximity to the 2004 withdrawal of rofecoxib (Vioxx) cannot be overlooked. 

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