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.

New research on COX-2 inhibitors and other NSAIDs

What led to the Vioxx recall?
Vioxx is a COX-2 inhibitor that was originally approved by the FDA in 1999 to be used for pain relief and reducing inflammation for patients with osteoarthritis, as well as for menstrual pain. It was later approved to be used for rheumatoid arthritis.

Vioxx was voluntarily pulled from the market by Merck on September 30, 2004. The Vioxx recall occurred based on findings from the APPROVe trial (Adenomatous Polyp Prevention on Vioxx). The trial showed that after 18 months, those who took 25 milligrams of Vioxx had an increased risk of cardiovascular problems, such as heart attacks and strokes, compared to those receiving the placebo. The study did not show an increased risk of cardiovascular problems for patients taking Vioxx during the first 18 months (1).

Please see Vioxx recall and recommendations for more information.

Were there other warnings about Vioxx side effects and risks?
A 2000 study conducted by Merck (called Vioxx Gastrointestinal Outcomes Research – VIGOR) also found an increased risk of serious cardiovascular problems for patients taking Vioxx compared to those taking naproxen. Following the 2000 study, Merck began longer-term trials of Vioxx (1).

Previous to the recall, the FDA called for changes on the labeling of Vioxx side effects to include information about the increased risk of cardiovascular events such as heart attack and stroke (2). During the APPROVe trial, the FDA was also running studies on Vioxx. The FDA did not require the recall of Vioxx; it was done voluntarily by Merck.

What health risks have studies found for other NSAIDs?
Several of the recent studies and findings have prompted questions about the health risks and side effects of COX-2 inhibitors (e.g. Celebrex, Bextra) and other types of NSAIDs like naproxen (e.g. Aleve, Naprosyn). Important new updates include the following:

• Celebrex side effects: A study by the National Cancer Institute testing to see if Celebrex (chemical name: celecoxib) could help prevent colon cancer among patients who had already had colon polyps removed was halted in December 2004. Patients who took 400 milligrams of Celebrex a day were found to have 2.5 times more fatal and non-fatal heart attacks and strokes than those who did not take Celebrex. Patients who took 800 milligrams of Celebrex each day were found to have 3.4 times more fatal and non-fatal heart attacks and strokes (3).
  
  However, a similar ongoing study comparing Celebrex 400 milligrams once-a-day dose versus placebo for a similar period of time has not shown increased risk (3). The results of these Celebrex studies appear to be inconclusive and require further long-term study.

• Bextra side effects: A recent study by Pfizer (Bextra’s manufacturer) of over 1,500 patients who had recently undergone cardiac surgery showed that those who took Bextra (chemical name: valdecoxib) for their pain had an increased risk of heart and blood clotting problems compared to those who did not take any drug. The health problems included heart attack, stroke, blood clots in the leg and the lungs (4). As with Celebrex, the results of the Bextra study are not conclusive, and the FDA has called for additional investigation on Bextra side effects. The FDA also recently strengthened label warnings for increased cardiovascular risks. Although Bextra is still not approved for post-operative pain, the new warnings state patients who have just had coronary artery bypass graft surgery (CABG) should not take Bextra.
  
  Based on separate study results, the FDA strengthened warnings against serious skin reactions that can result in death, including Steven-Johnson Syndrome and toxic epidermal necrolysis. It is especially important for patients who have an allergy to sulfonamide-type drugs and sulfa to avoid Bextra. The FDA also issued warnings that the use of Bextra should be discontinued immediately if the patient develops a skin rash, mouth sores or any other signs of an allergic reaction (5). 

• Naproxen side effects (e.g. Aleve, Naprosyn): The FDA announced that preliminary results from a long-term study suggest that long-term use of naproxen (e.g. Aleve, Naprosyn) may increase cardiovascular risk compared to placebo. The FDA also cautioned patients to take Aleve and other over-the-counter NSAIDs only in the recommended dosage of 220 milligrams twice a day and not for more than 10 days in a row (6).

What are the next steps being taken to investigate side effects of COX-2 inhibitors and naproxen?
All of the study results are preliminary and some are in conflict with previous studies (3). The FDA has stated that there is a need for long-term studies on other NSAIDs before it can be known what risk the drugs pose. More information is also needed on the means by which the drugs impact the risk for heart attack and stroke. In early 2005, the FDA plans to hold a public advisory committee meeting to discuss the appropriate uses for and risks of NSAIDs (5).

What should patients using NSAIDs do now?
Patients who were prescribed Vioxx should be aware that the risk that an individual patient will suffer a heart attack or stroke related to Vioxx is very small (1). However, thosepreviously taking Vioxx or currently taking Celebrex, Bextra or Aleve (or other brands of naproxen) should still meet with their physicians to discuss their treatment options. The next page of the article explains important guidelines about using COX-2 inhibitors and other types of NSAIDs.

References:

1. U.S. Food and Drug Administration. “Vioxx (rofecoxib) Questions and Answers.” September 30, 2004.  http://www.fda.gov/cder/drug/infopage/vioxx/vioxxQA.htm.

2. 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.

3. U.S. Food and Drug Administration. FDA News. “FDA Statement on the Halting of a Clinical Trial of the Cox-2 Inhibitor Celebrex.” December 17, 2004. http://www.fda.gov/bbs/topics/news/2004/NEW01144.html.

4. U.S. Food and Drug Administration. FDA Talk Paper. “Bextra Label Updated with Boxed Warning Concerning Severe Skin Reactions and Warning Regarding Cardiovascular Risk.” December 9, 2004. http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01331.htm

5. 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.

6. 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.