Certain over-the-counter NSAIDs could be required to carry warnings regarding long-term heart risk resulting from chronic use following an FDA advisory committee vote.

In a joint meeting of the Arthritis Drugs and Drug Safety & Risk Management advisory panels Feb. 18, drug safety committee member Louis Morris, PhD, recommended labeling changes specific to OTCs.

"For over-the-counter drugs, I would suggest that there be a warning about long-term use at higher doses and the potential for cardiovascular risk," he stated, recommending "an insert for over-the-counter drugs in this class."

"I am in favor of a unit-of-use patient package insert," he said. "I think some of the information...should also be broad and class-wide so people can understand that the concerns extend beyond just COX-2s."

Although OTC NSAIDs are indicated for short-term use, consumers often do not abide by the recommendation, FDA Office of Medical Policy Director Bob Temple, MD, pointed out, adding: "that has to be coped with."

Joint Committee Chair Alastair Wood, MD, Vanderbilt University, noted that labeling changes for OTC NSAIDs such as naproxen, ibuprofen and ketoprofen "have different kinds of implications."

The joint panels unanimously agreed that NSAID labeling should include information on the absence of long-term data relating to CV risk.

Wyeth, which manufactures Advil (ibuprofen), stated Feb. 25 it does not believe the committee's CV warning mandate "is pertinent to OTC NSAIDs, since these products are used for short-term duration (up to 10 days) and at low doses."

Although Wyeth believes the current label for OTC ibuprofen is adequate, the firm "will actively work with FDA regarding any labeling changes that the agency may propose."

FDA Office of New Drugs Director John Jenkins, MD, said the panel vote on labeling requirements would be for NSAIDs excluding COX-2 inhibitors, with naproxen meriting "some special consideration."

Panelists appeared to reach a consensus on naproxen as a near-neutral agent with a proven safety profile relative to other drugs in the class; several panelists recommended the drug as a comparator for future NSAID trials (¹ Also see "Naproxen Could Serve As NSAID Safety Trial Standard, Advisory Panel Says" - Pink Sheet, 21 February, 2005., p. 3).

"I think there has to be equality in labeling across this class until proven otherwise," said Cleveland Clinic Medical Director and voting consultant Steve Nissen, MD. Nissen recommended naproxen be excluded from that class "because I think we know more" about the drug.

"Naproxen has beat COX-2 inhibitors pretty handily in some pretty well-designed clinical trials," he pointed out. "I think we've got some evidence, we've got very good [epidemiological] data on naproxen, and so I don't put it in that class."

Several members stipulated that naproxen should be excluded entirely from CV warnings. Arthritis committee member Norman Ilowite, MD, Schneider Children's Hospital, New Hyde Park, N.Y., said he would be "against a black box warning for either naproxen or ibuprofen."

A number of panelists opposed a universal warning for the class; FDA voting consultant Thomas Fleming, PhD, University of Washington, recommended the agency "approach this thoughtfully, looking at the totality of the data...with agents in the naproxen category looked at in a very different magnitude, in a very different context, certainly without a black box."

"I think it would be a mistake to attach the same warning to all the other non-coxib non-steroidals, absent naproxen which I think we've excluded from any warning," said Richard Platt, MD, Harvard Medical School. "It seems to me we ought to use the information we have to produce an appropriately graded warning while the agency is ensuring that better data is collected." Platt serves on the Drug Safety & Risk Management panel.

Patient representative Leona Malone similarly recommended warnings "of an individualized nature."

"I think what we have to be extremely, extremely careful of is setting off some hysteria with the public, because here we're going from concern about three coxib drugs, and now we're warning against almost anything that these people are taking," she said.

Ibuprofen's known safety profile was less enthusiastically endorsed by the panel than naproxen; several committee members were wary of steering COX-2 patients toward other drugs in the class in the absence of reliable data.

"I want to be reassured that ibuprofen and diclofenac are not worse" than COX-2s, Nissen said. "There is a lot of uncertainty about those other two agents. I think that as we think about changing the landscape of the use of NSAIDs, there are some risks we're taking, and some of the risks are that we shift use to agents that may actually turn out in the final analysis to be less safe, and I think we have to understand that."

"We have to keep our warnings to what we know, and what we do know is - and we've agreed that - celecoxib [Pfizer's Celebrex ] compared to placebo has excess risk, but we don't know whether that risk is excess in comparison to ibuprofen or diclofenac," Nissen asserted.

"Any statement that would tend to suggest using those alternative agents first is probably not warranted by the data, because we simply don't have the data to make such a conclusion."

Wyeth said it "is not aware of any data indicating that short-term use of OTC doses of NSAIDs is associated with cardiovascular risks," and the issue is therefore not applicable to over-the-counter ibuprofen.

The firm maintains that when used as directed, OTC ibuprofen "has a very good safety profile relative to COX-2 inhibitors," and that "epidemiology studies indicate that ibuprofen is the safest non-selective NSAID in terms of gastrointestinal risks."

Wyeth says it has reviewed all available post-approval data and "has not found an association between OTC ibuprofen use and cardiovascular events." The firm notes it "has always submitted all adverse event data associated with ibuprofen to the FDA on an ongoing basis," and "will continue to evaluate all new safety data as they become available."

Bayer, which manufactures Aleve (naproxen sodium), issued a statement Feb. 23 that the panel discussion "affirmed the safety of Aleve and distinguished the safety profile of naproxen."

The firm said it was "pleased" with the meeting's outcome and "appreciate[s] the help of the committees in restoring public confidence in Aleve."

OTC NSAID Labeling Could Be In For Changes Following Advisory Panel Vote

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