FDA Considers Loosening Naproxen's CV Warning

January 29, 2014

SILVER SPRING, MD – Data published since 2006 suggest that naproxen does not pose the same cardiovascular risks as other nonsteroidal anti-inflammatory drugs (NSAIDs), according to Food and Drug Administration (FDA) reviewers[1].

In an analysis of data published since the boxed warning was added to the NSAID class in 2005, the FDA says the data "suggest that naproxen is not associated with an increased risk of cardiovascular thrombotic events" and recommends changing the label to reflect this lower risk.

Publishing the recommendations ahead of next month's two-day joint meeting of the Arthritis Advisory Committee (AAC) and Drug Safety and Risk Management Advisory Committee (DSARM), the FDA reviewers highlight a 2013 meta-analysis published in the Lancet by Dr Neeraj Bhala (Oxford University, UK) and colleagues.

"This study reinforces the 2005 conclusions by FDA that the risk for cardiovascular events is present for both nonselective and COX-2–selective NSAIDs but also raises the possibility that, in contrast to the 2005 conclusions, there may be a lower risk for one NSAID, naproxen," writes the FDA's Dr Sharon Hertz in the review.

It's been 10 years since rofecoxib (Vioxx, Merck) was pulled from the global market because of a heightened cardiovascular-risk profile. This led to a 2005 meeting of the AAC and DSARM where the FDA concluded that the three approved COX-2 selective NSAIDs, celecoxib (Celebrex, Pfizer), rofecoxib, and valdecoxib, were associated with an increased risk of serious adverse cardiovascular events compared with placebo. Valdecoxib was eventually withdrawn from the US market and a boxed warning added to all NSAIDs warning of the cardiovascular risk and risk of serious gastrointestinal bleeding.

Celecoxib is still approved for the treatment of osteoarthritis and rheumatoid arthritis, but the FDA is currently questioning a long-term clinical trial known as the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen (PRECISION) that was started after 2005 to evaluate the relative safety of celecoxib, ibuprofen, and naproxen. During the advisory committee meeting, which takes place February 10 and 11, the panel will be asked to determine whether this trial should continue, given the relative safety of naproxen.

According to one reviewer, the results from the Lancet meta-analysis and other observational studies show that naproxen has a better safety profile from cardiovascular thrombotic events than the two comparator drugs and continuing the trial raises the "concern that patients are being exposed to an undue risk by remaining in the PRECISION trial."

The results of PRECISION were expected in 2013, but the study has had trouble with slow enrollment. Full results aren't expected until 2016, but the FDA reviewers say there are legitimate reasons for placing this trial on "clinical hold."


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