The Latest on Drug Safety Labeling: Naproxen & Saxagliptin

In the wake of the recent concerns about acetaminophen overdose and liver damage, patients seeking pain relief cannot quite turn with ease to NSAIDs like ibuprofen and celecoxib without worrying slightly over CV risk. Now, the FDA has insisted naproxen back down from claims made last year that it is safer than the rest—until stronger evidence appears. Advisers to the FDA concluded recently through a meta-analysis that recent data from a retrospective analysis linking the NSAID naproxen to lower risk of cardiovascular events than other NSAIDs are not reliable. Naproxen was held to be the safer of COX-2 inhibitor choices last year due to its association with lower cardiovascular risk, but now FDA advisers are voting against a new label based on those data.

The original meta-analysis was published in the Lancet in 2013 and found that coxibs or diclofenac conferred increased risk for major vascular events, and ibuprofen showed increased risk for coronary events, relative to placebo. Meanwhile, no such risk increases were seen with naproxen. But now FDA advisers recommend that naproxen's prescribing information stay as is until data is made available from a large, ongoing studio known as the Precision trial. That randomized trial is comparing naproxen with celecoxib or ibuprofen in patients with osteoarthritis or rheumatoid arthritis.

The current available evidence does not prove that the painkiller naproxen, sold under the brand names Aleve and Naprosyn, carries a lower cardiac risk than rival products. In 2005 the FDA determined that all NSAIDs should carry a warning about cardiovascular risk but said there was no evidence that the drugs carried different levels of risk. While the panel agreed that more information has come to light since then, they are looking to Precision to answer the question once and for all.

The FDA's final decision could have wide implications for the way in which these drugs are prescribed and used in the future, and it will have implications for whether the Precision trial is able to continue. One of the key questions in front of the panel was whether to modify the Precision trial, which has been going on for seven years at the request of the FDA. The FDA is not bound to follow the advice of its advisory panels, but typically does so.

Precision is an academically directed trial whose scientific governance resides with an unpaid independent executive committee, Nissen said, and represents the best opportunity to date to answer long-standing questions about the safety of NSAIDs that the FDA has been wrestling with since the withdrawal of Merck & Co.'s Vioxx a decade ago after it was linked to an increased risk of heart attack.

The FDA is also investigating a possible increased risk for heart failure associated with the diabetes drug saxagliptin. The investigation stems from findings from the SAVOR-TIMI 53 trial, in which over 16,000 patients with type 2 diabetes were randomized to saxagliptin or placebo. The trial found no significant difference between the groups in the composite endpoint of cardiovascular death, myocardial infarction, or ischemic stroke. However, there was a significant excess in hospitalizations for heart failure with saxagliptin (3.5% vs. 2.8%).

The FDA said that it has requested trial data from the manufacturer and that it considers current information from the trial to be preliminary. The agency advised that patients should not stop taking the drug but should discuss concerns with their healthcare professionals. The investigation of saxagliptin is part of a broader investigation into the cardiovascular risk of all drugs for type 2 diabetes.

NEJM Journal Watch, Feb. 2014,

CardioExchange, NEJM Practice Community, Feb. 2014,

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