OTC Naproxen Labeling: US FDA Advisory Panel Finds Imprecise Direction In PRECISION

Safety study of celecoxib vs. ibuprofen and naproxen spurs advisory committees to recommend adding aspirin-interaction warning on OTC naproxen labels, but many panelist made clear that PRECISION results had not swayed their thinking on celecoxib CV safety or on the OTC ingredients' interaction with aspirin.

A recommendation by a slim majority of US FDA advisory panel members to add label warnings for OTC naproxen's interaction with aspirin might not impress the agency after many said they weren't impressed with a trial that prompted FDA to request their help.

The Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee met in a joint meeting April 24-25 to discuss the results of Pfizer Inc.'s PRECISION trial comparing the cardiovascular risk of Rx anti-inflammatory celecoxib, the ingredient in the firm's Celebrex, with naproxen and another pain-relief ingredient common in OTCs, ibuprofen.

FDA asked the 21-member joint panel for a recommendation on adding an aspirin-interaction warning on OTC naproxen labels based on results from the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen trial. (See chart below.)

Additionally, the agency asked the committees to vote on recommending whether PRECISION demonstrated comparable CV safety for the three ingredients. (See sidebar.)

Before members voted on the OTC label questions, many made clear that PRECISION results had not swayed their thinking on celecoxib CV safety or on the OTC ingredients' interaction with aspirin. Their misgivings showed when their vote on recommending whether to include an aspirin-interaction warning on OTC naproxen labels was decided by five votes, with two abstentions.

A larger majority of the panel recommended against adding an aspirin-contraindication warning to OTC ibuprofen product labels. With OTC ibuprofen labels already including an aspirin-interaction warning, FDA did not ask for a recommendation on adding the information.

Safe History, Uncertain Label Future

FDA was non-committal about whether it will ask OTC naproxen-containing product marketers to add an aspirin-interaction label warning based on the advisory panel's recommendation.

Because OTC ingredients are approved through the new drug application process, the agency would send supplement request letters and work with manufacturers to make label changes it deems necessary for safety and other reasons.

"FDA cannot speculate about any outcomes from the advisory committee meeting, including any changes to the labels," a CDER representative told the Pink Sheet April 26. The agency currently could not offer additional information "regarding this matter which is pending before the agency."

CDER's decision will be steered by weighing the panel members' comments as strongly as their votes, said Sharon Hertz, director of the center's Division of Anesthesia, Analgesia and Addiction Products.

As they discussed their options for answering the OTC labeling questions, Hertz advised the committee members to "pick a decision and then tell us why you want us to do that after the vote and we'll pay attention to that."

"We look at the why much more than the what because we always get members of our committees who will even vote opposite, yes and no, but will have the exact same explanation as to why," she said.

Bayer AG markets the first-available OTC naproxen product, Aleve, launched after FDA approved an Rx-to-OTC switch NDA in 1994. The German firm, as it explained in its briefing material, says post-marketing safety data have shown no safety signal or trend regarding CV thrombotic and that no overall CV events have been observed with OTC naproxen, with or without concomitant aspirin use.

“We will continue to work collaboratively with the FDA to update our packaging/drug facts label as deemed appropriate,” a representative in Bayer's Whippany, N.J., office said.

Perrigo Co. PLC, the leading manufacturer of nonprescription generics with the ingredient, declined to comment on the FDA advisors' recommendation.

The Consumer Healthcare Products Association points out that advisory committee members said they saw no new data that support adding the aspirin-interaction warning even though they approved the change to naproxen labels.

“CHPA agrees with the advisory committees’ votes on OTC labeling, including their vote in favor of a label change to OTC naproxen. While we support the addition of an aspirin/naproxen warning, we agree with committee members that there is no new data to suggest any additional changes are needed to OTC NSAIDs labeling, including a contraindication statement,” said Barbara Kochanowski, the trade group's senior vice president of regulatory and scientific affairs.

Show Us The Data

The advisory meeting was FDA's second for discussing PRECISION results, and members said little has changed since the 2014 meeting. (Also see "NSAID Safety Review: FDA Panel Seeks Continued PRECISION From Pfizer" - Pink Sheet, 11 Feb, 2014.)

"I am really not sure that I know any more based on the data that was released in 2014," said Christianne Roumie, an internal medicine and pediatrics professor at Vanderbilt University Institute for Public Health, on the first day of the meeting.

"Really no new data on ibuprofen was ever presented," said Magnus Ohman, senior investigator for Duke University's Clinical Research institute.

Ohman, also director of Duke's Program for Advanced Coronary Disease and the Department of Medicine's development and innovation vice-chair, suggested that the options FDA gave for answers on the OTC labeling questions were insufficient. "I have to assume that … I have to pick the least favorite of whatever there might be because we have no new data," he said.

US National Heart, Lung and Blood Institute researcher Yves Rosenberg framed his comment on the study's limits to the results' usefulness in OTC ibuprofen and naproxen labeling. "We really don't have any data on the clinical significance of those interactions," said Rosenberg, chief of the atherothrombosis and coronary disease branch at the National Institutes of Health.

Still, OTC naproxen should have the same label warnings about drug interactions as ibuprofen products, he said, explaining his vote to add the aspirin warning. "I don’t see why there should be any difference in the labeling," Rosenberg said.

And bio-statistics expert Christopher Schmid observed that PRECSISION results provided little guidance on the OTC labeling questions. "I don't think there's any difference in the data we've seen between naproxen and ibuprofen," said Schmid, a bio-statistics professor and Center for Evidence Synthesis in Health co-director at Brown University School of Public Health.

"I don’t think there's really enough data yet to indicate clearly whether this risk is clinically significant or not," he added.

Similarly, Johns Hopkins Center for the Prevention of Heart Disease researcher Michael Blaha said the existing asprin-interaction warning on ibuprofen labels steered him to recommend the same for naproxen OTCs given the ingredients' similar profiles, even though PRECISION didn't show whether the risk is clinically significant for naproxen.

"I don’t see a rational to have different warnings at this time between the two drugs on a pharmacodynamic basis, which I guess is the only basis we have," said Blaha, director of clinical research and a cardiology and epidemiology professor at the Johns Hopkins center.

NSAIDs Safety Prompts Study

PRECISION, a prospective, randomized, double-blind study, included 24,081 patients with osteoarthritis or rheumatoid arthritis who had CV disease or risk factors for CV disease and who were randomized to receive celecoxib 100-200 mg twice a day, ibuprofen 600-800 mg three times a day or naproxen 375-500 mg twice a day.

FDA asked Pfizer to conduct the postmarket study in 2005 to address concerns about the safety of NSAIDs. In September 2004, Merck & Co. Inc. withdrew its COX-2 inhibitor, Vioxx (rofecoxib), from the market due to a cardiovascular safety signal. (Also see "Celebrex Study Is Feel Good Story For Pfizer, But Are There Any Real Benefits?" - Pink Sheet, 20 Nov, 2016.)

In April 2005, FDA asked Pfizer to withdraw its COX-2 inhibitor, Bextra (valdecoxib). The agency then also asked all manufacturers of Rx nonsteroidal anti-inflammatory drugs to include a boxed warning in labeling to highlight the potential for increased risk of CV events and gastrointestinal bleeding.

Advisory Committee Voting Questions
OTC Naproxen Labeling
Which of the following regulatory actions should be taken with respect to naproxen nonprescription labeling: A. No change to the current naproxen Drug Facts label B. Include a warning regarding the interaction between aspirin and naproxen C. Include a contraindication of use for naproxen when taken with aspirin	A – 7 B – 12 C – 2
OTC Ibuprofen Labeling
Which of the following regulatory actions should be taken with respect to ibuprofen nonprescription labeling: A. No change to the current ibuprofen Drug Facts label B. Include a contraindication of use for ibuprofen when taken with aspirin	A – 17 B – 4
Celeoxib CV Safety
Has the PRECISION trial demonstrated comparable cardiovascular safety for celecoxib as compared to naproxen and ibuprofen?	Yes – 15, No – 5, Abstain – 1

From the editors of the Tan Sheet.