On April 7, 2005 the Food and Drug Administration requested that Pfizer suspend sales of Bextra in the United States. As a result, Bextra will no longer be available to patients in the United States. For more information, click to the Bextra homepage.

For more information on safe use of COX-2 inhibitors and other NSAIDs, please see Understanding COX-2 inhibitor side effects.

Vioxx recall and recommendations

In late September 2004, Vioxx—a brand of COX-2 inhibitor commonly prescribed for arthritis, acute pain and several types of back pain—was withdrawn from the market. The Vioxx recall occurred after Merck, the drug’s manufacturer, reported findings of increased risk of heart attack and stroke among participants in an ongoing clinical trial. The U.S. Food and Drug Administration (FDA) did not require a Vioxx recall; Merck voluntarily pulled Vioxx from the market on September 30, 2004. All patients who were prescribed Vioxx should stop using the drug and consult their physician.

Since the Vioxx recall, the potential risks of other COX-2 inhibitors (e.g. Celebrex, Bextra) and other types of NSAIDs such as naproxen (e.g. Aleve, Naprosyn) have also been called into question. Many patients have been left with concerns about certain NSAIDs and questions about treatment options. This article explains the events that led to the Vioxx recall and outlines the current FDA recommendations for patients using COX-2 inhibitors and other NSAIDs.

Background on Vioxx and COX-2 inhibitors
Vioxx (chemical name rofecoxib) is a type of COX-2 inhibitor, which is part of a larger class of medications called non-steroidal anti-inflammatory drugs (NSAIDs). In general, NSAIDs work by helping treat inflammation, a common component of back pain and other types of pain. Vioxx was officially approved by the FDA for treatment of osteoarthritis, rheumatoid arthritis, acute pain and menstrual pain.

COX-2 inhibitors are the most commonly prescribed class of drugs for patients with rheumatoid arthritis and osteoarthritis, and are also often used for many common types of back pain. The main function of COX-2 inhibitors is to reduce inflammation in the joints, which in turn relieves the pain and stiffness caused by arthritis. For many patients, the main advantage of COX-2 inhibitors is that they do not have the same level of gastrointestinal side effects as other types of NSAIDs (e.g. aspirin, ibuprofen or naproxen). More information on the role of these medications is available at COX-2 inhibitors - Celebrex and NSAIDs.

Other COX-2 inhibitors still on the market include Celebrex (chemical name celecoxib) and Bextra (chemical name valdecoxib). For more specific information about these brands, please see COX-2 inhibitors: Celebrex and Bextra information.

Research leading to the Vioxx recall
The following timeline helps to explain the events and research findings that led to the voluntarily recall of Vioxx by Merck:

May 1999: Vioxx was originally approved. According to the FDA, “the original safety database included approximately 5,000 patients taking Vioxx and did not show an increased risk of heart attack or stroke” (1).
June 2000: Findings from the Vioxx Gastrointestinal Outcomes Research (VIGOR) study were reported to the FDA. VIGOR was designed to examine the effects of Vioxx on stomach ulcers and bleeding. Patients who were taking Vioxx were found to have fewer gastrointestinal problems than those taking naproxen (another NSAID). However, the study also showed an increased risk of heart attacks for patients taking Vioxx compared to those taking naproxen.
February 2001: The Arthritis Advisory Committee discussed the VIGOR study (1).
April 2002: The FDA added new warnings about increased risk of heart attack to the Vioxx label. Merck began longer-term trials to analyze the cardiovascular risks of Vioxx (1).
September 27, 2004: Merck (Vioxx’s manufacturer) informed the FDA that it had halted a long-term study on patients with colon polyps who were taking Vioxx (the APPROVe trial—Adenomatous Polyp Prevention on Vioxx) (2). In this study, patients who took 25 mg of Vioxx each day for 18 months or longer showed an increased risk of cardiovascular events such as heart attack and stroke compared to those patients taking placebo (sugar-pill) (1).
September 28, 2004: In a meeting with the FDA, Merck stated their decision to voluntarily recall Vioxx from the market (2).
September 30, 2004: Merck officially voluntarily withdrew Vioxx from the market. The FDA’s subsequent Public Health Advisory stated that the risk for an individual patient to have a heart attack or stroke related to Vioxx is very small, but the findings from the APPROVe trial still showed an overall increased risk of cardiovascular problems (2).

Research on other COX-2 inhibitors and NSAIDs
Since the Vioxx recall from the market, greater attention has been called to recent studies on COX-2 inhibitors (e.g. Celebrex and Bextra) and other types of NSAIDs such as naproxen (e.g. Aleve and Naprosyn). The studies involved specific groups of patients taking the drugs for novel uses. At the time of this article, the study results were inconclusive, but several showed an increased risk for cardiovascular events.

The FDA stated the need for additional research and asserted that it will closely monitor the side effects of NSAIDs. The existing studies did not involve a widespread population taking the drugs for currently approved uses, and more studies are currently in progress. The mechanism for increased risk of cardiovascular events is still unclear.

Recent FDA recommendations for COX-2 inhibitors and other NSAIDs
It has been established that elderly patients or patients who take NSAIDs (including COX-2 inhibitors) for long periods of time tend to be at a higher risk for serious adverse side effects (such as heart attack or stroke). Based on recent study results, the FDA has made the following important recommendations regarding use of COX-2 inhibitors and other types of NSAIDs:

Vioxx use should be discontinued: Patients who were prescribed Vioxx should stop using the drug and consult their physician to determine new treatment options. Pharmacies are no longer filling prescriptions for Vioxx.
Dosages for COX-2 inhibitors and other NSAIDs: Patients should strictly follow the specific dosage instructions for COX-2 inhibitors and other NSAIDs to avoid overuse. Over-the-counter NSAIDs such as Aleve should not be taken for longer than 10 days without consulting a physician (3).
New safety warnings for Bextra: Patients who have recently undergone coronary artery bypass graft surgery (CABG) should avoid Bextra. Bextra’s label warnings were also strengthened for serious (and potentially fatal) skin reactions. Use of Bextra should be discontinued immediately if the patient develops a skin rash, mouth sores or any other signs of an allergic reaction (4).

Until more information is known, the FDA has issued a Public Health Advisory with guidelines for prescribing NSAIDs, including COX-2 inhibitors (e.g. Celebrex, Bextra) and naproxen (e.g. Aleve, Naprosyn). Each patient’s treatment options should be determined based on the following factors:

Individual risk factors for gastrointestinal and cardiovascular problems
Treatment needs
Previous and present experiences with NSAIDs (3)

Specific information about other known side effects and cautions for COX-2 inhibitors is available at COX-2 inhibitors: Celebrex and Bextra information.

New information and research will be published in the coming months and years regarding COX-2 inhibitors and other type of NSAIDs. In general, COX-2 inhibitors and other NSAIDs are effective medication when used appropriately and for the right reasons. Patients should not become fearful unnecessarily, but instead should stay informed about the safe use of medications and discuss their medication needs with their physician.

By: Gunnar B.J. Andersson, MD, PhD
January 31, 2005

References:

U.S. Food and Drug Administration. “Vioxx (rofecoxib) Questions and Answers.” September 30, 2004. http://www.fda.gov/cder/drug/infopage/vioxx/vioxxQA.htm.
U.S. Food and Drug Administration. FDA News. “FDA Issues Public Health Advisory on Vioxx as its Manufacturer Voluntarily Withdraws the Product.” September 30, 2004. http://www.fda.gov/bbs/topics/news/2004/NEW01122.html.
U.S. Food and Drug Administration. “Public Health Advisory: Non-Steroidal Anti-Inflammatory Drug Products (NSAIDS).” December 23, 2004. http://www.fda.gov/cder/drug/advisory/nsaids.htm .
U.S. Food and Drug Administration. “Questions and Answers: Strengthened Warnings on Bextra.” December 9, 2004. http://www.fda.gov/cder/drug/infopage/bextra/bextraQA.htm.