NAPROXEN OTC LOWER MAXIMUM DAILY DOSE IS ONE OF LABELING CHANGES NEGOTIATED BETWEEN SYNTEX/P&G AND FDA; AGENCY DIFFERS WITH ADVISORY CMTE. ON APPLICATION

A maximum recommended daily dose for Syntex/Procter & Gamble's naproxen OTC of 600 mg (three tablets per day) will appear in labeling if the NSAID is approved for over-the-counter use, FDA Office of OTC Drug Evaluation Director Michael Weintraub, MD, told the Nonprescription Drugs and Arthritis Advisory Committee Sept. 8. Syntex initially had proposed a maximum daily dose of four 220 mg naproxen sodium tablets (with each tablet containing 200 mg of active ingredient). Syntex and FDA agreed to the change in response to objections raised by the advisory committee during their June 2 joint review of the switch 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 recommendations against approval of the nonsteroidal anti-inflammatory drug for OTC marketing ("The Pink Sheet" June 7, p. 6). 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, Syntex has agreed to change the recommended dosing interval, Weintraub reported. "Several of you pointed out [at the earlier meeting] 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. "As was discussed in the meeting and in comments that were subsequently sent in," Weintraub continued, "there are data that, for improved safety with maintained effectiveness, it would be valuable to have specific instructions for people over 65 years of age." If "naproxen were to be approved, 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," Weintraub said. "If it were to be approved for OTC use, the labeling 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 "a specific '1-800' telephone number would be printed both on the carton and the bottle 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. "It's a little troublesome, but I guess less so than it was previously," Ehrlich said. Ehrlich also proposed that the warning against use in children should be highlighted in the label. Weintraub said the suggestion is "certainly worthy of discussion" with the sponsor. Asked if Syntex will conduct pediatric studies after approval, Weintraub reported that FDA has "not approached the sponsor with specific requests for continuing studies for Phase IV." That indicates that a quick approval following the Sept. 8 meeting is not likely. OTC naproxen labeling also would carry a warning statement against a risk of gastrointestinal bleeding in patients who drink alcohol excessively. Earlier in the day of Sept. 8, the committee voted that such a warning should be added to labeling for aspirin, ibuprofen and, if approved, naproxen. The public update on the status of naproxen OTC appears to allow FDA to dispense with a second formal advisory committee vote on the application while protecting itself from the charge of ignoring expert opinion. Weintraub asked for feedback on his presentation but did not solicit votes on any issue of the application. In reviewing the June meeting, Weintraub interpreted the committees' rejection of the application as resulting from three areas of concern: procedures, policies and scientific issues. That breakdown of the reasons behind the advisory committees' rejection vote is important to the naproxen sodium review: FDA can try to focus specifically on the scientific issues related to naproxen while handling policy and procedural matters on a different level. The agency's handling of the naproxen OTC switch could mark a significant precedent. The drug is the first high- profile application to be handled by the recently-formed OTC drugs office under Weintraub's management. The committees' procedural difficulties stemmed from the "NDA Day" format of the June 2 meeting, Weintraub suggested. He pointed out that Pilot Drug Evaluation Staff Medical Officer John Harter, MD, in his introductory memo to the committee, had described the format as "an experiment for these two committees." "Perhaps we were too ambitious or perhaps we weren't clear enough," Weintraub said, "but many of the members of the committees expressed greater comfort with alternative formats. I want to assure you that both the Pilot Drug Evaluation Staff and the Office of OTC Drug Evaluation will take your views into account as we plan future meetings." Policy issues raised by the committee focused primarily on the appropriateness of the various OTC analgesic indications. Weintraub reported that FDA will re-examine its policies in this area, but added that the agency did not believe it would be fair to "change the rules of the game" for Syntex. Weintraub addressed the "scientific issues" raised by the committees by pointing out the various labeling changes to which Syntex had agreed. "Because FDA requires the sponsor to submit all the data even from exploratory studies which were never intended to provide definitive effectiveness data, the NDA contains flawed, contradictory data and deficient studies," Weintraub acknowledged. "NDAs are not clean, tidy documents. The job we have...is to look over that material very carefully and separate out what is critical for making a regulatory decision. I wanted to make sure you all realize that that is what has happened and will continue to happen." Weintraub stressed the desire "to share information with the committee in an open forum." But "providing the feedback to you and listening to your reactions today, we hope we will also be supporting and maintaining the advisory committee process as open, interactive and responsive." "We do value and carefully consider all of your input," Weintraub reiterated. However, he reminded the advisory committee members, "the final authority for making a regulatory decision rests with FDA." FDA has been preserving its prerogative to make the final NDA decision since the June meeting. Following the vote at the previous meeting, Pilot Drug's Harter reminded the committee that their "no" vote does "not necessarily mean that we won't approve" the application ("The Pink Sheet" June 7, p. 8). Procter & Gamble is the marketing partner for Syntex on naproxen OTC. 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." Those may be the basis of ad campaigns to distinguish the prescription product from generic competitors. The colloquial nature of the phrases, however, may indicate a consumer focus for the Blue campaign.