FDA
12th February 2014

FDA Panel Does NOT Support Naproxen Being a Safer NSAID

In a 16-9 vote, the FDA advisory committees assessing the cardiovascular safety of NSAIDs said the warning label on naproxen should not be changed to suggest it has a better cardiovascular risk profile than other drugs in its class as there is a lack of [definitive] evidence to support such a claim. 

FDA Panel Does NOT Support Naproxen Being a Safer NSAID

In a 16-9 vote, the FDA advisory committees assessing the cardiovascular safety of NSAIDs said the warning label on naproxen should not be changed to suggest it has a better cardiovascular risk profile than other drugs in its class as there is a lack of [definitive] evidence to support such a claim. 

In this joint meeting of the Arthritis Advisory Committee (AAC) and the Drug Safety and Risk Management Advisory Committee (DSaRM), many individuals had similar opinions, but still differed in their vote – many suggested that the FDA questions were confusing. Nonetheless, panelists who voted “No” on the question regarding relabelling naproxen, indicated that the current evidence on naproxen’s safety — much of which was indirect, coming from studies in which it served as a comparator to a coxib drug — did not meet the standards necessary to support a change to the label.

Interestingly, some of the panelists who voted “yes” said they planned to change their own prescribing habits and, in some cases, their personal medications.

Additionally, the literature also questions another of the FDA’s conclusions from 2005, that short-term use of NSAIDs avoids the cardiovascular risks. A 2011 study, for example, showed that patients with a history of myocardial infarction had an increased risk of death or a recurrent event even during the first week of NSAID exposure.

“It could be clarified that the advice to use an NSAID for the shortest duration possible is not based on the absence of a cardiovascular risk during a short latency period, but is simply a prudent way to limit patient exposure,” according to the FDA review documents.

AAC and DSaRM split more closely on the question regarding label information on the duration of NSAID treatment that raises cardiovascular safety risks. Currently, labels for these drugs say that short-term treatment is relatively safe, and that NSAIDs should be taken in the smallest effective dose for the shortest necessary duration; however, some recent studies have demonstrated no latency period of increased risk. A total of 14 panel members said the current statement should be reconsidered, while 11 voted that the statement is most likely clear to consumers. However, most of those in the latter voting group indicated during the discussion that they believed there is no completely safe dosing period, and the public must understand that.

The meeting represents the latest chapter in the story of the cardiovascular risks of NSAIDs that began when data started to emerge in the early 2000s raising questions about the COX-2 inhibitors, including rofecoxib (Vioxx) and celecoxib. In 2001, a study in the Journal of the American Medical Association linked those two drugs to elevated risks of thrombotic events compared with other NSAIDs.

FDA officials said they called the meeting to help them decide whether it should revisit decisions on labeling made nearly 10 years ago, in light of new studies published since 2005.

In 2005, the agency put a boxed warning on all NSAIDs discussing cardiovascular and gastrointestinal risks after concluding that differences between the drugs could not be discerned. But since then, evidence has been accumulating that the risks are not consistent across the class. Individuals argue, however, that this evidence is not definitive. A key analysis published last year in The Lancet, for example, showed that all NSAIDs carry some degree of cardiovascular risk, but that naproxen appears to be the safest.

Multiple studies — including a meta-analysis in BMJ, another meta-analysis in PLOS Medicine, and the more recent meta-analysis in The Lancet — have found that naproxen carries a lower cardiovascular risk compared with other drugs in the class.

Interestingly, one prominent cardiologist, Milton Packer, MD, of the University of Texas Southwestern Medical Center in Dallas, paid his own way to the meeting so that he could tell panel members in the open public hearing session why the these analyses were flawed; thus, suggesting that they should not be considered conclusive. Dr. Packer pointed out that the trials incorporated into these meta-analyses varied substantially in the patient populations and drug doses. He noted that their results were too weak to support a label change, which supported many of the panelists’ own opinions.

FDA’s, Bob Temple, conceded that the agency had never approved a label claim that one drug was superior to another based solely on meta-analysis results.

With regard to PRECISION trial, one FDA reviewer in the briefing documents called for to be halted because of the evidence of naproxen’s superior safety. He noted that, “a clinical hold is not imposed, subjects should be re-consented so that they can be informed of the findings of the [Lancet] meta-analysis regarding the PRECISION study drugs, and can have the option of withdrawing.”

However, most of the advisory committee members said that, because naproxen’s safety advantage has not been definitively proved, equipoise remains in PRECISION — thus, there is no need to stop it or to require that participants be re-consented.

In 2006, Pfizer started the PRECISION trial to evaluate the relative safety of celecoxib versus naproxen or ibuprofen in patients with osteoarthritis or rheumatoid arthritis who had or were at high risk for cardiovascular disease. PRECISION stands for Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen, and it will be the first randomized trial data regarding the cardiovascular adverse effects of NSAIDs. This trial is still ongoing, and results are expected in late 2015. However, in light of the other studies suggesting greater safety with naproxen, the FDA had been considering whether to stop it or at least require that participants undergo a new consent process.

Sanjay Kaul, MD, of the University of California Los Angeles, said the trial represents the best chance to find out whether naproxen does have a safety advantage, and that stopping it prematurely would do “disservice” to participants as well as the wider community.

Lastly, when panelists were asked whether labeling for over-the-counter NSAIDs should be revised, they generally agreed that the current language on cardiovascular risks could be clarified, but with no consensus on specifics.

Every major pharmaceutical manufacturer in the world markets drugs to reduce pain and inflammation. Key products include both prescription (Rx) and over-the-counter (OTC) options, such as Advil/Motrin (ibuprofen), Celebrex (celecoxib), Naprosyn (naproxen), and Voltaren (diclofenac). 

More than 17,000,000 Americans use nonsteroidal anti-inflammatory drugs (NSAIDs) every day, but is the labeling sufficient? Does one NSAID have a more favorable benefit/risk profile?…Looks like we will have to wait a little longer to find out for sure!

Check out ISS’ original announcement for this meeting HERE!

ISS has over a decade of experience in developing regulatory strategies including support for FDA Advisory Committee meetings. We are involved in more FDA AdComms per year than even the largest pharmaceutical companies. For more information on how ISS can help you prepare for your next meeting, contact info@innovativescience.net.

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