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NORPLANT FIVE-YEAR IMPLANTABLE CONTRACEPTIVE UNANIMOUSLY RECOMMENDED FOR APPROVAL BY FDA COMMITTEE; WYETH-AYERST EXPECTED TO MARKET IMPLANT IN U.S.

Executive Summary

Norplant (levonorgestrel) should be approved as an alternative to oral contraceptives and IUDs, FDA's Fertility and Maternal Health Drugs Advisory Committee unanimously recommended at an April 27 meeting. "We feel that it is a safe and effective means of contraception from the information derived from Third World countries and it . . . would [also] be a safe and effective means of contraception in the United States," panel member Paul Manganiello, MD, Dartmouth University Medical School, said. He suggested that this "user friendly" implantable contraceptive "may be attractive to some individuals" because it "works on a similar basis as birth control pills." He declared: "This is a modality of contraception that should be marketed." The committee voted 11-0 to recommend approval of the Silastic subdermal progestin implant, which consists of six capsules that are inserted into the fleshy part of a woman's upper arm through a small incision. Developed by the Population Council, Norplant is designed to provide contraception for five years. Each capsule contains 36 mg of levonorgestrel and is 2.4 mm in diameter by 34 mm in length. The capsules release 80 mcg per day in the first few weeks, which is gradually decreased over a period of six months to 25 mcg per day for the remainder of the five years. In opening remarks, committee Executive Secretary Phillip Corfman noted that the Population Council, which sponsored the NDA, is seeking approval so that the U.S. Agency for International Development can provide the contraceptive to developing countries. Wyeth-Ayerst is expected to market Norplant in the U.S. Commenting on Norplant marketing plans in the U.S., the Population Council's Wayne Bardin, MD, reported that "Wyeth-Ayerst expects to market and introduce this method." He noted that the Population Council "will work with Wyeth-Ayerst to transfer this kind of technology to them . . . to assure that people are properly trained in removal and insertion" of the capsules. Bardin also suggested that a clear set of guidelines be provided to both patients and health care providers "to achieve a better introduction in the U.S. than we have in the past, or at least we'll try to match it." The advisory committee made five recommendations on what should be included in labeling and/or patient package insert, including: (1) "removal or replacement of the implants after five years of use" should be emphasized "in both the product labeling and the patient package insert"; (2) labeling should inclu The Norplant NDA includes data from seven studies conducted on 2,470 patients in eight countries: the U.S., Chile, Dominican Republic, Brazil, Jamaica, Sweden, Finland and Denmark. The U.S. studies are being conducted at the University of Southern California's Los Angeles County Hospital; University of California -- San Francisco's Women's General Hospital; and Rutgers University's Robert Wood Johnson Hospital in New Brunswick, N.J. The U.S. trials, in 396 patients, are expected to be completed in early 1990. Additionally, the Population Council has data from studies on 55,000 women in 44 countries, including about 10,000 women from China, approximately 1,000 women from India, 1,000 women from Egypt, and 800 from Sri Lanka. Bardin also reported that a post-marketing surveillance study is being organized by the World Health Organication (WHO) in collaboration with the Population Council and Family Health International. The study "will examine 8,000 women, and they will be followed over five years whether they continue or not . . . There will be a similarly sized group of 8,000 IUD users or sterilized women" as a control, Bardin noted. He explained that the clinical trial is being conducted "to look for [adverse event] rates that we were not able to detect in Phase III clinical trials." In discussions on the safety and efficacy of the contraceptive implant, the committee voiced several concerns in addition to those addressed in the labeling and patient package insert recommendations. The clinical data, for example, indicated that the drug is less effective in women over 70 kg, or 154 lbs. The committee also questioned whether the capsules would migrate over time; if irregular bleeding could mask underlying endometrial cancer; whether HDL levels, which tend to go in the "wrong direction" while using the drug, might have an adverse effect on cardiovascular functioning; and whether or not female children could experience masculinisation abnormalities if the implant remains in the mother during pregnancy. FDA reviewer Ridgely Bennett, MD, also noted several disadvantages of the product, including the need to insert and remove the product by a health professional; that implants may be visible; that approximately 25% of the women who discontinued use of the implant over five years did so because of disturbances in bleeding patterns; and that pain and unnecessary surgery may result from enlarged ovarian follicles, among others. However, despite safety concerns raised at the meeting, the committee agreed unanimously that "Norplant is at least as safe a contraceptive as the other hormonal contraceptives currently on the market."
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