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The FDA Requests Changes to NSAID Labeling

The US Food and Drug Administration (FDA) has requested that manufacturers of non-steroidal anti-inflammatory drugs (NSAIDs) change NSAID product labeling. Manufacturers of prescription NSAIDs, such as Celebrex (celecoxib), Bextra (valdecoxib) and Vioxx (rofecoxib), received requests to add boxed warnings about heart and bleeding risks to labeling. In addition, the FDA has requested that Celebrex (celecoxib) display safety data from clinical trials. Non-prescription NSAID manufacturers have been asked to revise labeling to include specific details about potential cardiovascular (CV) and gastrointestinal (GI) risk of specific products, and reminders of treatment-dose and duration limitations.

Research over several years has shown many NSAIDs are occasionally associated with CV and GI side effects. Results of a recent celecoxib (Celebrex) clinical trial provided additional evidence of the increased CV and GI risks associated with COX-2 selective NSAIDs (see NSAID Selectivity and COX, below), and these findings are reported to have contributed to the FDA's decision.

Celebrex - Clinical Trials Results

In December 2004, researchers at Boston's Brigham and Women's Hospital found, in a large colorectal cancer prevention study, that patients who received celecoxib (Celebrex) daily for an average of almost three years had an increased risk of serious cardiovascular events. Among the events reported were death due to cardiovascular causes, heart attacks, strokes and heart failure.

"These data suggest that there may be an increase in cardiovascular risk associated with the use of celecoxib. This information should be viewed in light of other studies of COX-2 inhibitors that have suggested cardiovascular risk," said Scott Solomon, MD, lead author of the data analysis study, director of Noninvasive Cardiology at BWH and Associate Professor of Medicine at Harvard Medical School.

Dr. Solomon also notes "the cardiovascular events were serious, but the total number of events within the trial were small. These risks will need to be weighed against any potential benefit of celecoxib in preventing colorectal cancer or in relieving pain."

In addition to the general labeling changes for all NSAIDs, the FDA has requested that the Celebrex labels contain additional safety data from long-term treatment trials with celecoxib.

NSAID Selectivity and COX

NSAIDs fall into two basic categories: "COX-2 selective" and "non-selective". The term "COX" is an abbreviation for the "cyclooxygenase", an enzyme involved in prostaglandin production.

Most early NSAIDs were non-selective, blocking the action of both COX-1 and COX-2 enzymes. While this class of NSAIDs offers pain relief, the blockage of COX-1, which is involved in maintaining the health of the stomach lining and kidneys, may lead to GI problems in some people. In contrast, the more recently developed COX-2 selective NSAIDs block only the action of COX-2, and have been shown to offer pain relief with a lower incidence of GI side effects.

Drugs Affected by the FDA Request

In addition to Celebrex (celecoxib), other COX-2 selective NSAIDs targeted by the FDA request include Bextra (valdecoxib) and Vioxx (rofecoxib). Non-selective NSAIDs targeted by the FDA include:

Non-selective NSAIDs

Chemical Name Brand Name
Diclofenac Cataflam, Voltaren, Arthrotec (combination with misoprostol)
Diflunisal Dolobid
Etodolac Lodine, Lodine XL
Fenoprofen Nalfon, Nalfon 200
Flurbiprofen Ansaid
Ibuprofen** Motrin, Motrin IB, Motrin Migraine Pain, Advil, Advil Migraine Liqui-gels, Ibu-Tab 200, Medipren, Cap-Profen, Tab-Profen, Profen, Ibuprohm, Children's Elixsure*, Vicoprofen (combination with hydrocodone), Combunox (combination with oxycodone)
Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethegan
Ketoprofen** Oruvail, Orudis, Actron
Ketorolac Toradol
Mefenamic Acid Ponstel
Meloxicam Mobic
Nabumetone Relafen
Naproxen** Aleve, Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole)
Oxaprozin Daypro
Piroxicam Feldene
Salsalate Disalcid
Sulindac Clinoril
Tolmetin Clinoril, Tolectin, Tolectin DS, Tolectin 600


*There are many OTC Combinations with ibuprofen, including Advil Cold And Sinus, Advil Cold, Advil Allergy Sinus, Children's Advil Allergy Sinus, Ibuprohm Cold and Sinus, Sine-Aid IB and Children's Motrin Cold.
**Over-the-counter versions of these prescription medications are also available.

Posted: June 2005