COX-2s and NSAIDs must add warnings, patient guides to package inserts
Pfizer agrees to withdraw valdecoxib (Bextra)
Manufacturers of prescription cyclooxygenase-2 (COX-2) selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) soon will have stronger warnings on their labels.
The FDA announced in early April that these inserts must include a boxed warning and a Medication Guide, which will be given to patients. The boxed warning will inform patients about the potential for increased risk of cardiovascular (CV) adverse events and the serious and potentially life-threatening gastrointestinal (GI) bleeding associated with the use of these drugs.
"[The advisory committee’s] conclusion is that the cardiovascular risk of these drugs is what we consider a class effect," says Stephen Galson, MD, acting director of the FDA Center for Drug Evaluation and Research, in a press teleconference. "There may be slight differences between the drugs or even larger differences, but our conclusion is that we don’t have enough data to rank-order these drugs by risk."
Before making this announcement, the FDA had considered presentations, discussions, and votes from a joint public meeting of the FDA Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee held in February to discuss the CV safety concerns for these drugs along with their overall risk-benefit profiles.
The FDA took a further step with valdecoxib (Bextra) by asking its manufacturer Pfizer to voluntarily remove the drug from the market. The decision is based on three facts, Galson says. "First, we don’t feel we have adequate data on the long-term cardiovascular safety of Bextra. We just don’t have those studies. Second, there have been reports of serious and potentially life-threatening skin reactions, including deaths, in patients on Bextra. We looked at this data very carefully in many different ways. It seems clear to us that the reports of life-threatening skin reactions are more common with Bextra than with Celebrex. Third, there isn’t a demonstrated advantage for Bextra compared to other NSAIDs."
Pfizer issued a statement, saying it "respectfully" disagreed with the FDA’s position regarding the overall risk-benefit profile of valdecoxib. The company, however, still agreed to suspend sales of the medicine pending further discussions with the agency.
Since Merck also voluntarily removed rofecoxib (Vioxx) from the market last September, celecoxib (Celebrex) becomes the only COX-2 selective NSAID available to patients. Once the warnings are added to celecoxib, the panel feels that the drug has a positive benefit-risk balance. Galson says. "We think it can stay on the market."
Merck has said it may try to reintroduce rofecoxib. The FDA would consider a proposal from the company carefully, and would bring the proposal to an advisory committee before any changes are made to the drug’s marketing status, Galson says.
Although COX-2 inhibitors have received the most negative press on adverse effects, the FDA also wants manufacturers of nonselective NSAIDs to revise their product labeling. The labels should now include:
- A boxed warning regarding the potential serious adverse CV events and the serious, and potentially life-threatening GI adverse events associated with the use of this class of drugs.
- A contraindication for use in patients who have recently undergone coronary artery bypass surgery.
- A Medication Guide for patients regarding the potential for CV and GI adverse events associated with the use of this class of drugs. Patients must receive the Medication Guide at the time each prescription is dispensed.
The FDA is asking manufacturers of over-the-counter (OTC) NSAIDs to revise their labels, as well, although the agency says available data do not suggest an increased risk of serious CV events for the short-term, low-dose use of the OTC drugs. The revisions should include more information about potential CV and GI risks as well as stronger reminders about limiting the dose and duration of treatment according to the package instructions. The FDA also cautions patients taking aspirin to reduce the risk of CV events not to stop taking the drug.
The announcement of the label revisions is unlikely to be the last word spoken about these drugs, Galson says. He predicts any decision made at this point may look different in light of new information that comes to the forefront through new clinical investigations.
Manufacturers of prescription cyclooxygenase-2 (COX-2) selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) soon will have stronger warnings on their labels.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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