FDA Statement on Generic Premarin
FOR IMMEDIATE RELEASE
May 5, 1997
Food and Drug Administration
Marian Segal: 301-443-3285
Consumer Hotline: 800-532-4440
FDA STATEMENT ON GENERIC PREMARIN
FDA's Center for Drug Evaluation and Research (CDER) announced today that at this time it will not approve synthetic generic forms of the estrogen-replacement drug Premarin. This is because these generic products have not been shown to contain the same active ingredients, and therefore to work the same, as the original drug in treating women with menopausal symptoms and preventing osteoporosis.
In her announcement, CDER's director, Janet Woodcock, M.D., said, "Based on currently available data, there is at this time no way to assure that synthetic generic forms of Premarin have the same active ingredients as the brand-name drug. This is essential for determining they are equivalent to the brand drug, and is also a legal requirement for their approval."
Because generic drug manufacturers do not have to repeat the clinical studies used to develop the original, brand-name drug, they must assure their products are as safe and effective by showing that the active ingredients are the same and that they are bioequivalent--that is, absorbed and used by the body in the same way as the original products.
Premarin, the brand name for conjugated estrogens, is derived from the urine of pregnant mares and contains a number of different estrogens. Precisely how each of these various estrogens contribute to the drug's overall effectiveness has not been definitively determined. Premarin's approval in 1942 predated the current requirements for such comprehensive analysis of products under review for marketing approval.
Previously it was thought that two estrogens--sodium estrone sulfate and sodium equilin sulfate, were the sole active ingredients in Premarin. Newer laboratory and clinical studies show this may not be the case. Rather, other components in Premarin may contribute to the drug's effectiveness for menopausal symptoms and osteoporosis prevention.
In addition, recent studies submitted by Wyeth-Ayerst, the manufacturer of Premarin, show that after repeated doses of Premarin in women, the blood concentration of the active metabolites of the estrogen delta (8,9) dehydroestrone sulfate (DHES) is about the same order of magnitude as the concentration of the active metabolites of estrone and equilin. "
Although this finding does not prove that the DHES in Premarin has an important therapeutic effect," Woodcock says, "it underscores the lack of precise knowledge of the makeup of Premarin and the relative importance of its components, and therefore the lack of a standard on which to evaluate a generic copy."
Over the years, there has been controversy about the required composition and testing of generic conjugated estrogens. In 1991, FDA issued new bioequivalence testing guidelines for the drug, based on recommendations of its Generic Drugs Advisory Committee.
In 1970, conjugated estrogens were officially defined in a U.S. Pharmacopeia monograph as a mixture of sodium estrone sulfate and sodium equilin sulfate. In 1992, in addition to those components, other constituents were described as "concomitant components" and as impurities.
In November 1994, Wyeth-Ayerst filed a citizen petition requesting that DHES be reclassified as a concomitant component. The firm maintained that the compound contributes to the drug's potency, and therefore, effectiveness, and further requested that FDA require the compound to be included in any generic copies of the drug.
The following July, FDA's Fertility and Maternal Health Drugs Advisory Committee reviewed Wyeth-Ayerst's request. At the end of the deliberations, the committee unanimously concluded that not enough data were available to determine whether or not components besides estrone sulfate and equilin sulfate must be present in order for Premarin to achieve its established levels of efficacy and safety.
An ad hoc agency working group on conjugated estrogens was formed in the summer of 1995 to review the scientific data on the composition of conjugated estrogens. Recently, the working group presented a final report compiling scientific information related to the composition of Premarin.
The Center has now concluded that Premarin must be better characterized before its active ingredients can be definitively identified, and that the bioequivalence guidance for conjugated estrogens should be reexamined. The guidance describes how to measure whether the rate and extent of absorption in the blood of the generic version are equivalent to those of Premarin.
The agency encourages the initiation of studies that will permit the scientific determination of the active ingredients in Premarin and provide a potential for approval of generic versions of the drug. Several brand name and generic tablets and patches containing estrogens are available besides Premarin to treat menopausal symptoms, a number of which are also approved for long-term use to prevent osteoporosis.
Date created: May 5, 1997; last update: July 7, 2005