SYNTEX/P&G NAPROXEN SODIUM OTC MAXIMUM DAILY DOSE OF 660 MG

SYNTEX/P&G NAPROXEN SODIUM OTC MAXIMUM DAILY DOSE OF 660 MG, or three 220 mg tablets daily, will appear in labeling if the nonsteroidal anti-inflammatory drug is approved for over-the- counter use, FDA Office of OTC Drug Evaluation Director Michael Weintraub, MD, told the Nonprescription Drugs and Arthritis Advisory Committees in a presentation to the joint panel on Sept. 8. Syntex had initially proposed a maximum daily dose of four 220 mg naproxen sodium tablets (with each tablet containing 200 mg naproxen and 20 mg sodium). Syntex and FDA agreed to the change in response to objections raised by the advisory committees during their June 2 review of the application, Weintraub noted. "Based on a number of comments indicating that there was an adequate scientific basis for lower doses and a solid medical rationale for decreasing the total daily dose, if naproxen were to be approved for OTC use, the originally proposed maximum daily dose of four tablets or 800 mg of naproxen per day would be reduced to three tablets or 600 mg per day," Weintraub said. Weintraub's remarks indicate that FDA is preparing to diverge from the committees' June recommendation against approval of the nonsteroidal anti-inflammatory drug for OTC marketing ("The Tan Sheet" June 7, p. 1). During the Sept. 8 meeting, Weintraub informed the committees of "how the agency and the sponsor have dealt with some of the issues raised . . . as part of the ongoing evaluation of the [Rx- to-OTC] switch application." The discussions between FDA and the sponsor, Weintraub said, "are part of the continuing orderly progression of the assessment review and decision-making process." In addition to the lower maximum daily dose, Weintraub also noted that Syntex has agreed to change the recommended dosing interval. "Several of you pointed out that pharmacokinetic data support a change in the dose interval and that there exist medically sound reasons to change that dose interval," he said. "If naproxen were to be approved, the dosing interval will be lengthened from the original six to 12 hours and extended out to eight to 12 hours." The dose and dosing interval proposed by Syntex were questioned by the committees in June ("The Tan Sheet" June 7, p. 3). "As was discussed in the [June] meeting and in comments that were subsequently sent in," Weintraub continued, "there are data that [indicate] that for improved safety with maintained effectiveness, it would be valuable to have specific instructions for people over 65." If "naproxen were to be approved," he added, "the labeling would have specific directions for people over 65 years of age and the recommended dose would be one tablet with a dosing interval of 12 hours." Naproxen OTC labeling also "would clearly state that the drug should not be given to children under 12 years of age except under the advice and supervision of a physician," Weintraub told the committees. In response to other side effect concerns, Weintraub reported that Syntex has agreed to include "a specific '1-800' telephone number . . . [on] both the carton and the body label so that consumers could then obtain information and report specific adverse events directly to the sponsor." Arthritis committee member George Ehrlich, MD, University of Pennsylvania, noted that the proposed 600 mg maximum daily dose is still above the initial prescription anti-inflammatory dose of 500 mg/day. "Its still a little trouble-some, but I guess less so than it was previously," Ehrlich commented. Ehrlich also proposed that the warning against use in children should be highlighted in the label, a suggestion Weintraub said is "certainly worthy of discussion" with the sponsor. Asked if Syntex will conduct pediatric studies after approval, Weintraub said that FDA has "not approached the sponsor with specific requests for continuing studies for Phase IV." That indicates that a quick approval of the application following the meeting is unlikely. OTC naproxen labeling also would carry a warning statement against a risk of gastrointestinal bleeding in patients who drink excessively. Earlier during the Sept. 8 session, the committee voted that such a warning should be added to labeling for aspirin, ibuprofen and, if approved, naproxen (see related story, p. 11). Procter & Gamble is Syntex' marketing partner for OTC naproxen. No trade name has been disclosed. Syntex, however, has been actively registering slogans related to the blue color of Anaprox prescription tablets. The company has registered phrases, such as "Think Blue," "Big Blue," and "Give Pain the Blues." The slogans may be the basis for an ad campaign to distinguish the prescription product from generic competitors as Syntex prepares to square off against generic naproxen in anticipation of the expiration of the product's patent in December.