Synthetic Conjugated Estrogens, A Tablets (Cenestin — Duramed)
July 1, 1999 4 minutes read
Synthetic Conjugated Estrogens, A Tablets (Cenestin—Duramed)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
In the business world, as in life, be careful what you wish for. Wyeth-Ayerst, the manufacturer of Premarin, learned this last month when the FDA approved a New Drug Application (NDA) for Duramed’s conjugated estrogen, A (Cenestin). Wyeth had successfully blocked Duramed’s application of an Abbreviated New Drug Application (ANDA)—a request for generic equivalency to Premarin in 1997, when it proved that Duramed’s product did not contain all the estrogenic components present in Premarin. Duramed retooled and applied to the FDA as a unique drug, calling its product "conjugated estrogens, A" to distinguish it from conjugated estrogens. Approval was granted in March for short-term use in the treatment of vasomotor symptoms. Duramed’s conjugated estrogens A is a mixture of nine synthetic estrogenic substances derived from plant sources, as opposed to Premarin, which is derived from the urine of pregnant mares and contains 10 identified and quantified estrogenic compounds.
Indications
Cenestin is indicated in the treatment of moderate to severe vasomotor symptoms associated with menopause.
Dosage
Cenestin is supplied as 0.625 mg and 0.9 mg tablets. The recommended initial dose is 0.625 mg per day and may be titrated up to 1.25 mg. The lowest dose should be used that would adequately control vasomotor symptoms associated with menopause.
Potential Advantages
Synthetic conjugated estrogens are derived from plant sources—not from pregnant mare’s urine. Animal rights groups such as PETA have objected to the treatment of these pregnant mares. There may also be a patient preference for product derived from plants than from animals.
Potential Disadvantages
Cenestin is not identical to Premarin. While Cenestin contains nine of the 10 known estrogenic substances contained in Premarin, it does not contain delta 8,9-dehydroestrone sulfate and possibly other unidentified estrogenic and progestational agents.2 It is not certain if Cenestin is pharmacologically "identical" to Premarin. Cenestin is currently approved for short-term treatment of vasomotor symptoms associated with menopause but not for the treatment of osteoporosis. Cenestin is currently only available in two doses, 0.625 mg and 0.9 mg, while Premarin is also available in 0.3 mg- and 1.25 mg-strengths.
Comments
Cenestin is the first synthetic conjugated estrogen approved by the FDA. It has been designated as conjugated estrogens A, and subsequent products will be designated as B, C, D, etc.3 Its approval was based on a randomized, placebo-controlled multicenter trial in patients with vasomotor symptoms.1 One hundred twenty women were randomized to receive placebo or Cenestin 0.625 mg daily. The dose was titrated upward (2 × 0.625 mg) or reduced (0.3 mg) as necessary. Efficacy was assessed at four, eight, and 12 weeks. Results have not been published; however, the product labeling stated that a reduction in moderate-severe vasomotor symptoms occurred at all time points.1 There are no comparative trials with Premarin; therefore, dose equivalence is not known. In the placebo-controlled trial, 77% of patients required two 0.625 mg-tablets to control symptoms. This compares to the recommended dose of Premarin to treat these symptoms.
The wholesale cost for Cenestin 0.625 mg is $0.42 per tab, which is comparable to Premarin $0.42. However, if patients need a 1.25 mg-dose (77% needed that dose), then Premarin is less expensive ($0.59) since there is no 1.25 mg-strength for Cenestin.
Clinical Implications
Cenestin provides an alternative to Premarin as well as other estrogens such as estradiol. Premarin has the lion’s share of the market, estimated to be about $2 billion yearly. Wyeth Ayerst has aggressively opposed the approval of Cenestin as a generic equivalent to Premarin, contending that delta 8,9-dehydroestrone sulfate and unidentified components of Premarin contribute to its pharmacologic activity.1 After much debate, the FDA did conclude that delta 8,9-dehydroestrone sulfate is active and may contribute to the overall effect of Premarin. The magnitude of the effect has not been determined. The contribution of other unidentified components has also not been determined. There are currently no comparative trials between Premarin and Cenestin and none is required by the FDA. Until the components of Premarin have been adequately characterized, the FDA would only consider approving a generic version if it came from the same natural source (i.e., pregnant mare’s urine). However, synthetic versions may be approved as new drugs. Cenestin is effective for the short-term treatment of vasomotor symptom, but its long-term effectiveness for indications such as osteoporosis is still uncertain.
References
1. Cenestin Product Information. Duramed Pharmaceutical, Inc. March 1999.
2. Woodcock J. CDER. FDA Memorandum. May 5, 1997.
3. FDA Report. The Pink Sheet, March 29, 1999.
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