In March of this year, the FDA approved the New Drug Application of Duramed for Cenestin (synthetic conjugated estrogens A). The approval process for Cenestin reads like the script of a B grade Hollywood movie. The battle thus far has pitted women’s groups against consumer advocates and involved intense Congressional lobbying and animal rights activists. Unfortunately, the heroes and villains are nearly indistinguishable from one another.

In 1997, the FDA refused to approve the abbreviated new drug applications from Duramed and Barr Laboratories for a generic version of Premarin (conjugated estrogens). The FDA’s rationale was quite straightforward. A synthetic generic version of Premarin could not be approved because the exact chemical composition of Premarin could not be fully identified.   FDA link

  Available since 1942, Premarin is a complex mixture of at least ten biologically active conjugated estrogens. The source of raw material is pregnant mare urine (hence the name). The care of the source animals and the eventual whereabouts of the foals have been the source of some controversy involving animal rights activists (http://www.premarin.org/). Equally controversial has been the inability of American Home Products (Wyeth Ayerst) to fully characterize the spectrum of active constituents. In 1995, Wyeth Ayerst successfully petitioned the FDA to require the presence of delta 8,9-dehydroestrone in any generic version of Premarin . This component was identified in 1975 and represents a small fraction of the estrogenic compounds contained in Premarin tablets and yet constitutes a significant portion of the eventual active estrogenic metabolite seen in pharmacokinetic studies. Wyeth Ayerst holds a patent on synthetic delta 8,9-dehydroestrone. The requirement for the presence of delta 8,9-dehydroestrone in any generic equivalent along with the patent exclusivity effectively blocks any competitor from producing a synthetic version of Premarin . While competitors are free to use the Wyeth Ayerst process of extraction from horse urine, source animal availability and the inherent political ramifications make the likelihood of generic competition very low.

Because the road to generic competition was blocked, Duramed chose the New Drug Application route. Cenestin is a mixture of nine synthetically derived estrogenic compounds (synthetic delta 8,9-dehydroestrone is noticeably absent) produced from soy and yam sources. Duramed will likely focus heavily on the plant origin of Cenestin in its direct-to-consumer advertising. In fact, a visit to the corporate website demonstrates the likely advertising campaign (http://www.cenestin.com/index1.cfm).

Cenestin is not a conjugated estrogen by compendial standard. It is specifically called synthetic conjugated estrogens-A. The distinction is an important one. While the composition of Cenestin is similar to that of Premarin , it is NOT a substitute. This designation was created by the FDA to distinguish Premarin from other branded conjugated estrogen products. The FDA recognized that others would follow Duramed’s lead and simply create a series of synthetic estrogen compounds with similar but not exact composition. In the near future we are likely to see branded versions of synthetic conjugated estrogens-B, -C and so on. It is important to note that the FDA approval of Duramed’s New Drug Application was obtained on the basis of a single 3-month double-blind placebo-controlled safety and efficacy study involving 117 healthy menopausal women (70 of whom received active drug). The study evaluated the efficacy of Cenestin in the short-term management of moderate to severe vasomotor symptoms associated with the menopause. There are no data for Cenestin for thinning and atrophy of the vaginal epithelium or prevention of osteoporosis, nor are there any long-term safety studies. The effects of Cenestin on serum cholesterol and in the development of coronary artery disease are also unknown at present.

In allowing the marketing of Cenestin , the FDA limited the indications to those for which data existed. As additional studies are conducted by Duramed, it is likely that additional indications will be approved. At the moment, however, Cenestin should only be used for SHORT-TERM management of vasomotor symptoms of menopause. Cenestin should NOT be considered an alternative to LONG-TERM use of Premarin until additional data are made available.