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UPJOHN’s DEPO-PROVERA INJECTABLE CONTRACEPTIVE WILL BE AVAILABLE IN JANUARY

Executive Summary

UPJOHN's DEPO-PROVERA INJECTABLE CONTRACEPTIVE WILL BE AVAILABLE IN JANUARY in the U.S. following FDA approval for the new contraceptive indication on Oct. 29. Upjohn said its general sales representatives and its hospital specialty force will begin detailing Depo-Provera Contraceptive Injection (sterile medroxyprogesterone acetate solution, or DMPA, 150 mg) to physicians and clinics early in 1993. DMPA has been approved in the U.S. previously for the treatment of endometrial and renal cancers. Depo-Provera injections for contraception must be administered intramuscularly on a quarterly basis. A synthetic progesterone, DMPA prevents ovulation by inhibiting the production of human gonadotropin. The drug's effect is reversible after a women stops receiving the injections. The most common side effects of Depo-Provera include menstrual irregularities, such as spotting and irregular or unpredictable bleeding. Upjohn noted that these effects tend to diminish with time and that, after one year of use, up to 50% of women stop having their menses altogether. Other side effects include weight gain, headache, nervousness, abdominal pain, dizziness and fatigue. The product is contraindicated in pregnant women, those with undiagnosed vaginal bleeding, breast cancer, acute liver disease, blood clotting disorders of the legs, lungs or eyes or cerebral vascular disease. The same contraindications apply to other hormonal contraceptives. Women who are nursing should not receive an injection until six weeks post-partum. Approval of Depo-Provera (NDA 20-246) in the U.S. as a contraceptive follows by some 20 years Upjohn's first NDA submission for that indication. The product was reviewed by three different FDA advisory committees, in 1973, 1975 and last June, which recommended, with FDA concurrence, that the drug be approved. Safety concerns -- particularly animal carcinogenicity - - delayed the NDA in the 1970's. Upjohn developed Depo-Provera during the 1960s and first submitted the contraceptive for FDA approval in the 1970s. Upjohn submitted the latest NDA for Depo-Provera on April 29, 1992. Safety issues surrounding the drug date back to 1972 when studies in beagles showed a potential for breast cancer. The World Health Organization began clinical trials in 1979 to determine the potential risks of breast, liver, ovarian, endometrial and cervical cancers from Depo-Provera. Those trials, which accumulated data on 11,890 women, determined no overall increased risks of those cancers in women using DMPA. The results of the WHO trial were presented at the June FDA advisory committee ("The Pink Sheet" June 29, p. 8). However, the committee's review of Depo-Provera focused not on the cancer potential but on issues of low birth-weight babies born to women who had used Depo-Provera and the issue of osteoporosis related to long-term use of DMPA as a contraceptive. The committee concluded that the benefits of using Depo-Provera outweighed the risks of osteoporosis and low birth-weight and recommended approval for a broad patient population. Due to the concerns about low birth- weight babies, approved labeling for Depo-Provera advises physicians to test patients for pregnancy before prescribing the contraceptive. With regard to osteoporosis, Upjohn has agreed to conduct Phase IV postmarketing studies on bone mineral density during the first five years of Depo-Provera treatment. FDA's approval letter notes that Upjohn has committed to submitting its protocol for the osteoporosis study within 90 days of approval. Data presented at the June advisory committee from a New Zealand study showed reductions in bone density in both pre- and postmenopausal women who had used Depo-Provera for at least five years. The losses in bone density were reversible after women stopped using the drug. Upjohn also has committed to biopharmaceutics studies in two phases to provide pharmacokinetic and pharmacodynamic data for both single and multiple doses of Depo-Provera, the FDA approval letter notes. The agency is requesting that the first study (single dose) be completed within one year after the protocol is reviewed. Depo-Provera is available in more than 90 countries and has been used by an estimated 30 mil.-plus women. Depo-Provera is on the World Health Organization's list of "essential drugs." Pricing in the U.S. "has not been determined," Upjohn said, but is expected to be "competitive" with other currently available contraceptives, like oral contraceptives. At the June advisory committee meeting, a representative of the think-tank the Allan Guttmacher Institute said quarterly injections of Depo-Provera cost about $120 a year and cautioned that, while cost-efficient in the long-term, the upfront costs of Depo-Provera and other long-acting contraceptive methods could be a barrier to use by some women. Other long-acting options include intrauterine devices and Wyeth-Ayerst's implantable contraceptive Norplant, which was approved in 1991.
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