Structure of rofecoxibCHEMICAL FORMULA
C17H14O4S
Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. Worldwide, over two million people were prescribed Vioxx at the time. In 2003, Merck earnt USD$2.5 billion from Vioxx sales. Rofecoxib was available by prescription as tablets and as an oral suspension.
COX-2 inhibitor
Rofecoxib belonged to the group of NSAIDs known as coxibs(cyclooxygenase inhibitors). Like other coxibs, including celebrex, and bextra. It was considered a inhibitor - acting specifically one form of the cyclooxygenase enzyme, whereas other previous NSAIDs inhibited both COX-1 and COX-2. This specificity allowed rofecoxib and other COX-2 inhibitors to reduce inflammation(and pain) while minimizing undesired gastrointestinal adverse effects (such as stomach ulcers) that are common with non-selective NSAIDs.
Interestingly, at the time of its withdrawal, rofecoxib was the only coxib with clinical evidence of its superior gastrointestinal adverse effect profile over conventional NSAIDs. This was largely based on the VIGOR (Vioxx GI Outcomes Research) study, which compared the efficacy and adverse effect profiles of rofecoxib and naproxen. (Bombardier et al., 2000)
Voluntary withdrawal
On 30 September 2004, Merck voluntarily withdrew Vioxx from the market worldwide. This withdrawal was based on preliminary data from the APPROVe study which indicated an increased risk of adverse cardiovascular events associated with long-term use of rofecoxib.
The previous VIGOR study, published in 2003, had indicated a non-significant increased risk of acute myocardial infarct (heart attack) in rofecoxib patients over the naproxen patients in the study. (Bombardier et al., 2000). The results of the VIGOR study were submitted to the United States Food and Drugs Administration (FDA) in February 2001, which lead to the introduction, in April 2002, of warnings on Vioxx labelling concerning the increased risk of cardiovascular events (heart attack and stroke).
In 2001, Merck commenced the APPROVe (Adenomatous Polyp Prevention on Vioxx) study, a three-year trial with the primary aim of evaluating the efficacy of rofecoxib for the prophylaxis of colorectal polyps. Celecoxib had already been approved for this indication, and it was hoped to add this to the indications for rofecoxib as well. An additional aim of the study was to further evaluate the cardiovascular safety of rofecoxib.
The APPROVe study was terminated early when the preliminary data from the study showed an increased relative risk of adverse cardiovascular events (including heart attack and stroke), beginning after 18 months of rofecoxib therapy. In patients taking rofecoxib, versus placebo, the relative risk of these events was 1.97 (rofecoxib 3.50% vs placebo 1.92%). The results from the first 18 months of the APPROVe study did not show an increased relative risk of adverse cardiovascular events. Previous Phase III clinical trials had also not shown this trend. (Swan, 2004)
Put simply, although the risk was still very small, the APPROVe study showed that long-term use of rofecoxib resulted in nearly twice the risk of suffering a heart attack or stroke versus patients receiving a placebo.
References
Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, VIGOR Study Group. 2000).
Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. New England Journal of Medicine. 343 (21), 1520-8.
Swan L, Merck Sharp & Dohme (Australia) Pty Ltd. (1 October 2004).
Urgent Medicine Recall VIOXX® (rofecoxib) - Merck Announces Voluntary Worldwide Withdrawal of VIOXX. Press Release.
