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PREMARIN ACTIVE INGREDIENT PROFILE TO BE DISCUSSED AT FDA

Executive Summary

PREMARIN ACTIVE INGREDIENT PROFILE TO BE DISCUSSED AT FDA on May 3-4 by a subcommittee of the Fertility and Maternal Health Drugs Advisory Committee. According to a preliminary agenda for the meeting, the ad-hoc subcommittee will consider whether "sodium estrone sulfate and sodium equilin sulfate are the only two components of [Wyeth-Ayerst's] Premarin that have been adequately shown to elicit significant therapeutic effects in humans." According to the preliminary agenda for the subcommittee meeting, FDA will ask whether other components of Premarin should be regarded as active ingredients. FDA is also interested in finding out which moieties and/or metabolites "should be compared to determine bioequivalence of proposed generic versions of Premarin." In addition, FDA will ask the panel to define the therapeutic range for conjugated estrogens. The current range for estrone and equilin contents in 0.625 mg Premarin are based on USP specifications of 73% to 95% of labeled tablet strength and an equilin/estrone ratio of 0.35 to 0.65. "Does the subcommittee believe that these ranges are consistent with the expectation of a constant therapeutic effect from batch to batch of conjugated estrogens tablets?" If not, FDA will ask, "how narrow a range for the individual components does the subcommittee believe is necessary?" In a Feb. 13 Federal Register notice, FDA proposed withdrawal of all ANDAs for conjugated estrogens, citing potential differences in the rate and extent of absorption between Premarin and generic versions ("The Pink Sheet" Feb. 19, T&G-13). At the request of Zenith Labs, FDA has granted companies a 60-day extension to file information, data and analyses relevant to the issues presented in the Federal Register notice. The revised deadline for comments is June 15. In the withdrawal notice, FDA said that it had concluded that higher peak plasma concentrations associated with some generic conjugated estrogens may increase the risk of endometrial cancer and that varying absorption rates could also make a conjugated estrogens product ineffective in the treatment of osteoporosis. At the May 3-4 meeting, the subcommittee also will be asked to consider the agency's assumption that the rate of absorption is a key issue with conjugated estrogens. The subcommittee will be asked whether there is "any evidence that rate of absorption of conjugated estrogens does not affect their safety and efficacy." FDA observes that "bioequivalence can be demonstrated" for certain drugs "even when the generic drug's rate of absorption differs significantly from that of the reference drug." Where rate of absorption differs, FDA says, four criteria must be met to establish bioequivalence: "the difference in rate of absorption is intentional"; "the difference in rate of absorption is reflected in the proposed labeling"; "the difference in rate of absorption is not essential to the attainment of effective body drug concentrations on chronic use"; and "the difference in rate of absorption is considered medically insignificant for the drug."
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