The Food and Drug Administration (FDA) has issued a warning to physicians that the cyclooxygenase-2 (COX-2) inhibitor valdecoxib (Bextra,ÂR Pfizer ), has been linked to elevated cardiovascular (CV) risk in patients who have undergone coronary artery bypass graft (CABG) surgery, strengthening the existing advisory concerning the risk of life-threatening skin reactions associated with the pain reliever.
The FDA announced in a statement that, based on a study conducted by Pfizer of more than 1500 postsurgical CABG patients, the label for valdecoxib will carry an updated, bolded warning specifying the contraindication for treatment of pain immediately following CABG surgery. The pharmaceutical company also will highlight with a black-box warning in valdecoxib's labeling an extant caution regarding risk for rare but potentially fatal skin reactions associated with the COX-2 agent.1,2
The Pfizer study shows an increased CV risk in those who were treated with valdecoxib as compared to those treated with placebo. Observed events included thromboembolic events (ie, myocardial infarction), cerebrovascular accident (ie, stroke), deep vein thrombosis, and pulmonary embolism. The study findings, as reported to the FDA by Pfizer, confirm the risk in this particular patient population of use of intravenous valdecoxib (~2% of patients had an event) and also show that use of oral valdecoxib is associated with risk, albeit lower (~1% had an event).2
The black-box warning on valdecoxib's labeling provides information related to serious, potentially fatal skin reactions reported in patients taking the drug. As of November 2004, 87 US cases of severe skin reactions associated with valdecoxib, including Stevens-Johnson syndrome and toxic epidermal necrolysis, were received by the FDA; 20 of the cases involved patients with a known allergy to sulfa, and 36 cases involved reported hospitalizations, including 4 deaths. The reactions, which can occur at any time during therapy, are most likely to occur in the first 2 weeks of therapy.2
Risks for these rare, serious skin reactions are also associated with traditional nonsteroidal anti-inflammatory drugs (eg, naproxen, ibuprofen) and other COX-2 selective inhibitors; however, the reported rate of the reactions appears to be greater for valdecoxib than for the other COX-2s.
How are clinical rheumatologists making prescribing decisions in this new era of risk concern, particularly in light of the recent withdrawal of rofecoxib (VioxxÂR)? "This emphasizes the potential seriousness of the problem," David Borenstein, MD, private practitioner with Arthritis and Rheumatism Associates of Washington, DC, told CIAOMed. "You might not use the agent because of the problems, but it makes you ask, 'Is this an appropriate choice for the individual patient?'"
"One has to consider the variety of clinical findings that make a patient either a greater or lesser candidate for a particular agent," said Dr. Borenstein, who is a Fellow of the American College of Rheumatology. "That's what clinical judgments are about."
Valdecoxib, which is indicated for relief of the signs and symptoms of osteoarthritis, adult rheumatoid arthritis, and for treatment of primary dysmenorrhea, had not been approved for treatment of any category of postoperative pain and was not indicated for this use in the labeling. The new bolded warning specifically contraindicates valdecoxib for treatment of pain immediately following CABG.
A concern for CV risks that implicates all COX-2s may be taking root at this time. "There are a lot of people who think that it's a 'class effect,'" Dr. Borenstein observed. "Even though there's a difference between the drugs, they're being painted with a broad brush."
The FDA will continue to monitor the side effects related to valdecoxib and take additional actions as appropriate. The agency will hold a previously announced public advisory committee meeting in February 2005 with the goal of obtaining input from the public and outside experts and discussing safety concerns of all marketed COX-2 class and related drugs.3
Additional information related to the current research findings will be welcome. "Physicians are trying to make decisions based on partial information," Dr. Borenstein stated. "The news that is making the biggest splash isn't really defining a mechanism â€" it's only providing numbers. Some people have problems with some agents, but [the reports] don't tell us why."
Clinicians may await outcomes of the upcoming FDA meeting and anticipate the release of further information with some optimism. "We would be hopeful that whatever processes are ongoing will result in greater understanding of how we're going to move forward with this clinical problem," Dr. Borenstein emphasized.
References:
- Dooley K. Pfizer Will Add Heart Warning for Bextra, FDA Says (Update 2). Bloomberg.com. December 9, 2004. Available at: http://www.bloomberg.com/apps/news?pid=71000001&refer=home&sid=av6QKMB.qz4o . Accessed December 13, 2004.
- U.S. Food and Drug Administration. FDA Talk Paper: Bextra Label Updated with Boxed Warning Concerning Severe Skin Reactions and Warning Regarding Cardiovascular Risk. Available at: http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01331.html. Accessed December 13, 2004.
- U.S. Food and Drug Administration. Questions and Answers: Strengthened Warnings on Bextra. December 9, 2004. Available at: http://www.fda.gov/cder/drug/infopage/bextra/bextraQA.htm . Accessed December 13, 2004.