Pfizer, the manufacturer of both drugs, will be required to make major changes to reflect their CV risk, including a possible black box warning, a ban on direct-to-consumer (DTC) advertising, and enhanced patient education to increase awareness about potential side effects.
CV risk with celecoxib is dose-dependent
Some panel members, including Steven B. Abramson, MD, chairman of rheumatology at the Hospital for Joint Disease in New York City, said that while there is a CV signal with celecoxib, it displayed the "weakest signal" of the coxibs that was supported by the least amount of evidence. Steven Nissen, MD, vice-chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic Foundation in Ohio, agreed. He pointed out that the CV signal for celecoxib is clearly dose-dependent, and most of the trials that showed a signal involved doses that were 2 to 4 times the 200 mg/day upper limit. "The 800-mg dose is likely to produce excess CV risk. [The risk] probably [occurs] at 400 mg, and there is no evidence [of risk] at 200 mg," Dr. Nissen told the panel.
Most panel members favor black box warning and no DTC advertising
Dr. Nissen emphasized that "a black box has to say that there is evidence of increased risk of cardiovascular and cerebrovascular disease, and I also think it's important to discuss that we have seen pretty good evidence of a dose-dependent risk."
Some panel members, including John J. Cush, MD, chief of rheumatology and clinical immunology at Presbyterian Hospital in Dallas, Texas, are opposed to black box warnings for celecoxib, favoring instead a less prominent but strong warning combined with a strategy of risk reduction. The panel did recommend, however, that valdecoxib carry a black box warning for coronary-artery bypass graft (CABG) patients.
Dr. Nissen and others submitted that it might be possible to remove warnings if a trial comparing celecoxib 200 mg to naproxen yields definitive evidence. "That is a strong incentive to do that trial," he observed.
"I do not think direct-to-consumer advertising is appropriate at this point, given that it tends to stimulate excessive use of the drug," Dr. Nissen emphasized, adding that a patient guide explaining these risks in lay language could be a beneficial way to educate the public on safety issues.
Meeting Chair, Alistair J.J. Wood, MD, professor of medicine and pharmacology at Vanderbilt University Medical Center in Nashville, Tennessee, concurred, adding that "the patient guide or package insert should try to specify risk in a more helpful way, with some contextual basis such as [that] it's the same increased risk that [patients] get from smoking X amount of cigarettes a day - so patients have some sense of what they are talking about here."
Contraindications for CABG patients with valdecoxib
Studies have shown that valdecoxib increases the risk of heart attack or stroke in patients undergoing CABG procedures. As a result, some panel members called for contraindication in the post-CABG setting.
Curt D. Furberg, MD, PhD, professor of epidemiology and biostatistics at Wake Forest University in Winston-Salem, North Carolina, voted for the removal of valdecoxib. He said that the absence of good evidence with valdecoxib is not a reason for leaving it on the market. "Take it off the market and it can come back when it has good evidence,"
he told the panel.
Reference:
US Food and Drug Administration. Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee; February 16-18, 2005; Gaithersburg, Md.