NAPROXEN SODIUM 220 MG DOSAGE WAS SUGGESTED BY FDA

NAPROXEN SODIUM 220 MG DOSAGE WAS SUGGESTED BY FDA as an appropriate OTC dosage based on an analysis of pharmacokinetic/pharmacodynamic data submitted by Syntex, FDAer Dennis Bashaw indicated in a June 1 presentation to a joint meeting of the Arthritis and OTC Drugs Advisory Committees. "Looking at the data, we felt the best dosage form pursued for development would be the 220 mg sodium tablet in that it had release characteristics and that its rate of absorption seemed to be fast enough," Bashaw told the committee." He reported that "from this information, we asked the sponsor to go back and do a new pharmacokinetic trial with a larger number of studies and a larger number of subjects." Arthritis Advisory Committee member George Ehrlich, MD, University of Pennsylvania, asked Syntex about the dosage choice. "You seem pretty confident from the data that the minimum effective dose is [220 mg] . . . but you've also shown us a considerable body of data that suggests that the 100 mg dose as a second dose is effective." Syntex responded: "The [200 mg] dose is the best single dose [because it is] the lowest consistently effective dose. . . I don't think anybody is suggesting that they want a 100 mg tablet of ibuprofen out there because it isn't going to work consistently enough." Pilot Drug Review Staff Director John Harter indicated that the proposed dose was a pragmatic marketing decision by Syntex. "(BRACKET)The] 200 [mg] is going to be very competitive with ibuprofen, and with acetaminophen. If they were to go into the marketplace with 100 mg, yes, some people would get relief but [Syntex would] get killed . . . with a drug that was not as effective as their main competitors," Harter observed. However, he noted: "I would have liked to have seen 165 mg with the sodium . . . but they elected to go with the dose they did and I think you have to come on the other side of that equation and say, 'how dangerous is that drug for OTC use?'" Initially, Syntex had planned to pursue naproxen as their switch candidate. The company felt that the drug was better known and that consumers might be concerned with the levels of sodium in Anaprox. However, FDA's pilot drug review staff, which analyzed the Syntex submission, urged the company to pursue Anaprox: naproxen plus sodium. FDA's pilot drug review staff examined the Syntex submission and the 187.5 mg naproxen dosage formula that the company had originally intended to pursue as their switch candidate. This was the dosage that the company used in most of its clinical trials. Analyzing the data, FDA determined that the 187.5 mg naproxen tablet "was the bottom line. It had a very slow and prolonged rate of onset in terms of plasma concentration compared to the . . . equivalent sodium dosage form," Bashaw said. To determine a recommended dosage, FDA selected 40 minutes as a target for onset of action, the FDAer explained. "That seemed to be a reasonable time for most people to expect analgesia . . . 40 minutes after taking the dosage form." With that target in mind, FDA went back to an 80-patient dental extraction study to correlate plasma concentrations to pain relief. FDA concluded that the 220 mg dosage form would satisfy the requirements for OTC use.