Clinical Pharmacology and Cardiovascular Safety of Naproxen

Abstract

The voluntary withdrawal of Vioxx (rofecoxib) from the market in 2004, as well as the 2005 and 2014 US FDA Advisory Committee meetings about non-steroidal anti-inflammatory drugs (NSAIDs) and cardiovascular risk, have raised questions surrounding the use of NSAIDs in at-risk populations. This paper discusses the cardiovascular safety profile of naproxen in the context of the NSAID class. The balance of evidence suggests that cardiovascular risk correlates with cyclooxygenase (COX)-2 selectivity, and the low COX-2 selectivity of naproxen results in a lower cardiovascular risk than that of other NSAIDs. The over-the-counter (OTC) use of naproxen is expected to pose minimal cardiovascular risk; however, the benefit–risk ratio and appropriate use should be considered at an individual patient level, particularly to assess underlying conditions that may increase the risk of events. Likewise, regulatory authorities should revisit label information periodically to ensure labeling reflects the current understanding of benefits and risks.

Accounting for cardiovascular risk when prescribing NSAIDs

“…7,8,21 Naproxen (perhaps consistent with its potential to provide a sustained inhibition of platelet COX-1), along with ibuprofen (not high-dose), are suggested as 'safer', oral non-aspirin NSAIDs of choice in this regard if NSAID use is necessary. However, the cardioprotective, antiplatelet actions of low-dose aspirin, especially in the context of secondary prevention, may be subverted by oral traditional NSAIDs.…”

“…However, not all NSAIDs are the same and a notable exception to this general pattern of weak effects on platelets of non-aspirin NSAIDs is naproxen, 21 which is capable of sustained COX-1 inhibition associated with a long plasma half-life and subsequent extended duration of antiplatelet action. In further contrast, the profound antiplatelet effect of lowdose aspirin, which is associated with selective, irreversible COX-1 blockade from which platelets cannot recover, appears to confirm the paradigm by actively conferring cardioprotective properties in the setting of the prevention of cardiovascular disease.…”

Treatment of a massive naproxen overdose with therapeutic plasma exchange in a dog

“…TPE is uniquely suited as a method of extracorporeal removal of drugs such as naproxen due to them being highly protein bound with a low volume of distribution and prolonged half‐life . Ultimately, a massive ingestion of 45 mg/kg of naproxen would be expected to cause acute kidney injury and potentially neurological signs which appeared to have been prevented by timely use of TPE in this case.…”

“…At higher exposure doses, drug transporters and glucuronic acid conjugation pathway may become saturated, further contributing to the total drug exposure and thus a longer elimination half‐life. People and dogs have vastly different half‐lives of 12‐17 and 74 hours, respectively . In dogs, metabolism of naproxen is thought to undergo extensive enterohepatic recirculation .…”

“…Naproxen was found to be at least 99% protein bound in a canine experimental study performed by Frey et al evaluating the pharmacokinetics of naproxen . The half‐life of naproxen in people ranges from 12 to 17 hours with a peak plasma concentration of 2‐4 hours and is almost entirely renally excreted . For dogs, the half‐life is approximately 34‐74 hours with a peak plasma concentration between 0.5 and 3 hours .…”