Cox 2 Drugs (Vioxx, Bextra)

 

The first breakthrough in treatment of arthritic pain came some forty years ago with a class of drugs known as salycilates, both efficacious and, unfortunately, toxic to the user. Non- steroidal, non -salicylic pain relievers were heralded as the answer, and none more so than the Cox 2 (or cyclo oxygenase selective) inhibitors which combined the anti-inflammatory properties of the traditional non steroidal anti inflammatories (NSAIDS) while decreasing the known gastrointestinal adverse effects associated with these drugs.

Cox 2 inhibitors such as Vioxx and Bextra may increase the risk of heart attack and stroke.Briefly the mechanism of action in Vioxx and other Cox 2 inhibitors is the inhibition of the cyclooxygenase 2, an enzyme believed to trigger pain and inflammation in the body. It is widely believed that the mechanism of action also suppresses prostacyclin a hormone like substance that dilates blood vessels and reduces blood clotting, leading to increased risk of cardio vascular events such as heart attack and stroke.

In 1999 Merck introduced rofecoxib or Vioxx for the relief of osteoarthritis pain and symptoms. By September 3, 2004 Merck and Co. had voluntarily withdrawn the pharmaceutical blockbuster from the market after it was shown that there was an increased risk of cardiovascular events including heart attack and strokes in those ingesting the drug for 18 months more. At the time more than 100 million prescriptions had been filled.

This withdrawal came on the heels of the now well known Vigor (VIOXX GI Outcomes Research) study, published in November, 2000. This double blinded randomized one year study of 8000 participants provided substantial evidence for gastrointestinal safety, but raised alarming concerns about its cardiovascular toxicity. Merck submitted that these findings could be explained by the cardio protective benefits conferred by the comparator drug Naproxen rather than by any inherent risk in Vioxx.

In early 2001 the Arthritis Drug Advisory Committee of the Food and Dug Administration met to discuss the VIGOR study. Merck was directed to apprise physicians of the Vigor cardiovascular results. Merck immediately directed its sales force to tout the gastrointestinal benefits while avoiding substantive discussions with physicians on the cardiovascular issues surrounding the VIGOR. This and other promotional activities by Merck came under sharp criticism by the FDA and later Congress. But sales continued to climb.

In April 2002, the FDA implemented labeling changes to reflect findings for the Vigor study which included labeling changes about the increased risk of cardiovascular events. The new labeling posted contraindications for rofecoxib use in obvious cases of ischemic heart disease.

The final blow to Merck came in the wake of disturbing findings from another Merck trial known as the APPROVe study which reported a doubling of the risk of heart attack and stroke in users. By September 30, 2004 Vioxx had been withdrawn form the market.

In the interim, Merck’s sales had reached nearly 3 billion dollars.

By November 2004, the United States Justice Department and the SEC had launched an investigation into Merck’s handling of Vioxx. Senate hearings were also launched concerning the FDA response to Vioxx safety issues.

Cox 2 inhibitors such as Vioxx and Bextra may increase the risk of heart attack and stroke.By this time, the issue of class effect applicable to all Cox-2 selective inhibitors was underway. Bextra (Pfizer, Inc) soon became the subject of a new FDA warning to individuals undergoing cardiac surgery. Celebrex (Pfizer, Inc.) was also found to present significant cardiovascular problems in December 2004, but Pfizer declined to withdraw the product form the market.

Bextra was voluntarily withdrawn from the market on April 7, 2005 at the request of the FDA in response to reports of increase risks of heart attack and stroke. Pfizer was instructed simultaneously to include a black box warning on the Celebrex labeling.

Four months later, on August 10, 2005 the first Vioxx trial resulted in a plaintiffs’ verdict on behalf of Carol Ernst.

Vioxx was voluntarily recalled on September 30, 2004, by drug giant Merck following information that people taking Vioxx are twice as likely to have heart attacks and strokes as people who take older anti-inflammatory drugs, such as naproxen.

The Vioxx recall culminates mounting concern in the medical community beginning in early 2001, that Vioxx might cause serious cardiovascular events. On April 11, 2002, the FDA required Merck to include new label precautions for cardiovascular risks. Over two years later, Merck is finally removing this unsafe prescription medication from the market.

Vioxx, a member of a new category of drugs called "Cox inhibitors", has provided pain relief and anti-inflammatory effects for millions of arthritis suffers. It was also indicated for use in acute menstrual pain. It can be said that Vioxx is the progeny of aspirin. The advertised advantage of this new class of drugs over the traditional non-steroidal anti-inflammatory drugs, such as aspirin, ibuprofen and naproxen, is there are supposedly fewer gastrointestinal problems occurring during treatment with Cox inhibitors. However, continuing drug studies reveal GI problems (perforations, ulcerations, and bleeds) as well as serious and potentially deadly, cardiovascular side effects.

The company's decision to recall the drug is based on new three-year data from a prospective, randomized, placebo-controlled clinical trial conducted at The Cleveland Clinic. The company stopped the trial which was designed to evaluate the efficacy of Vioxx at a new dosage of 25 mg to specifically prevent recurrence of colorectal polyps in patients with a history of colorectal adenomas. In other words, Vioxx was being tested for a new indication other than arthritis and menstrual pain.

During the study, it was proven that the Cox inhibitor process throws off the body’s normal chemical balance and blood clots may develop. These blood clots form in the coronary arteries or in the brain and heart attacks or strokes result.

Vioxx was much hailed as a wonder drug for those with painful arthritis symptoms when it was launched on the market in the United States following FDA approval on May 21, 1999. It has since been marketed in more than 80 countries; worldwide sales of Vioxx in 2003 alone were $2.5 billion. Vioxx can clearly be classified as a blockbuster drug.

 

 









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