Ketoprofen label warning on concurrent NSAID use supported by FDAer, cmte. members.

KETOPROFEN LABEL WARNING AGAINST CONCURRENT NSAID USE was supported by FDA Topical Drug Products Deputy Director Linda Katz, MD, and some members of the agency's Nonprescription Drugs and Arthritis Advisory Committees at a July 14 meeting. During discussion of whether OTC ketoprofen labeling should bear a warning on the risk of taking more than one nonsteroidal anti-inflammatory drug at a time, Katz noted that the goal is "to make sure people understand that if they're taking ibuprofen, they don't want to take ketoprofen." FDA does not "want people taking multiple drugs for the same thing thinking that they're taking different classes of drugs," she added.

Katz suggested that "we try to make sure consumers understand what category of drug they shouldn't be taking if they've got a problem" such as aspirin hypersensitivity. Another potential problem with consumers taking multiple NSAIDs is cumulative "cross-reactions" of doses, she said. Other advisory committee members also expressed support for an NSAID warning, but the group did not vote on the issue.

At the July 14 meeting, the advisory committees unanimously agreed to recommend that Bayer and Whitehall's Rx-to-OTC switch NDAs for ketoprofen for general pain be approved by FDA ("The Tan Sheet" July 17, p. 1). The committees voted against requiring special labeling addressing potential G-I problems or dosing for the elderly, but did urge the use of an alcohol interaction warning. The advisory group asked for Phase IV studies on dosing for dysmenorrhea and whether the drug effectively treats headache ("The Tan Sheet" July 17, pp. 1-3).

Katz asked the committees whether FDA should list each type of NSAID that could cause a problem with concurrent ketoprofen use, changing the label each time another product is approved, or whether it would be better "to become more general?"

Nonprescription Drug Advisory Committee Chair Randy Juhl, PhD, University of Pittsburgh, responded that "it would be easier if we put all other OTC analgesics [on the label], but I'm sure that there is one manufacturer of OTC analgesics that won't agree to that."

Arthritis Advisory Committee Chair George Ehrlich, MD, University of Pennsylvania, commented that "you don't want [consumers] taking NSAIDs with other NSAIDs and if you start listing, you have to list all other NSAIDs." He acknowledged that "this is a complicated problem and I don't think we're going to solve it here today. I would leave it to FDA to figure out some kind of a label that would identify the kind of products with which this should not be taken."

NDAC member Lorie Rice, University of California-San Francisco, proposed a "general warning or notice that if [a consumer is] taking any other medication or OTCs to check with a pharmacist or a health care provider." Ehrlich offered the statement: "This belongs to the class of nonsteroidal anti-inflammatory drugs and should not be taken together with any similar compound." New NDAC member Eric Brass, MD/PhD, Harbor-UCLA Medical Center, objected to that proposal, stating that OTC ketoprofen "isn't even labeled a nonsteroidal."

Commenting on the suggestion that consumers be directed to call a health care provider if they are taking more than one medication, arthritis committee member Michelle Petri, MD, Johns Hopkins University, said, "based on my experience with thousands of patients taking NSAIDs, I've never had a patient call me from the supermarket or pharmacy asking whether or not they should take" a drug. She maintained that "patients make mistakes all the time with OTC NSAIDs, so I'm going to vote in favor of being very specific." She suggested a label warning along the lines of: "Do not combine with similar medicine such as ibuprofen, naproxen sodium and others in the same class."

FDA Office of OTC Drug Evaluation Director Michael Weintraub, MD, interjected that FDA is having a similar problem with the complexity of the labeling issue. "I'm glad that the committee has much the same reaction as the FDA staff when struggling with this particular issue," he said.

Weintraub reminded the panel that "we don't like to mention these drugs having an anti-inflammatory effect because in the doses that they are prescribed commonly for OTC use, they are not antiinflammatory -- but that's a separate issue." He admitted that "it's a complicated discussion," and that he and Katz "wanted to find out if you had some magic that we overlooked somehow in our discussions." The "obvious answer," Juhl replied, "is no."

Katz asked the committees "whether people [would] be able to understand what it is we're talking about" if "we took out the examples [of specific NSAIDs] but listed the category as pain reliever/fever reducer." Several committee members replied that consumers would "probably" understand the warning and Juhl suggested that "we could test it." Weintraub agreed with Juhl, stating that "we'll try it and see."

Weintraub also pointed out that "we have to keep in mind the information supplied about reading comprehension of the label." NDAC member Beth Slingluff, Carondelet St. Mary's Hospital, summarized the results of a readability analysis of the proposed ketoprofen label and package inserts.

Bayer's proposed labeling requires grade levels of 11.4 and 13.3 to read the label and insert, respectively, while Whitehall's product label requires grade levels of 8.5 for the label and 11.2 for the insert, she said. "I would certainly encourage FDA and the sponsors to work collaboratively to come up with labels and packaging inserts that are readable by a large portion of the population," Slingluff stated.