UPJOHN DEPO-PROVERA BENEFITS OUTWEIGH RISKS OF OSTEOPOROSIS AND LOW BIRTHWEIGHT, FDA CMTE. CONCLUDES; WOMEN’s HEALTH NETWORK OPPOSES APPROVAL

With a favorable recommendation from FDA's Fertility and Maternal Health Drugs Advisory Committee behind it, Upjohn's long- acting injectable contraceptive Depo-Provera (DMPA) may still face the political obstacle of consumer concerns prior to U.S. commercialization. Several women's health groups voiced opposition to the drug during the June 19 advisory committee meeting ("The Pink Sheet" June 22, p. 3). For example, Cindy Pearson of the National Women's Health Network told the panel that "Depo-Provera is a questionable drug contained within a problematic delivery system. American women may need more contraceptive choices but they need safe choices." Pearson said that NWHN is particularly concerned about the risk of "long-term irreversible effects, specifically cancer and osteoporosis," posed by Depo-Provera. Also speaking against approval at the meeting were: Tracy Agee, National Women's Survival Summit; Luz Alvarez Martinez, National Latina Health Organization; and Julia Scott, National Black Women's Health Project. The advisory committee took up both cancer and osteoporosis concerns in its discussion of the drug. The group concluded that any long-term adverse effects of the progestin are outweighed by its benefits as another contraceptive option. Upjohn submitted studies conducted by the World Health Organization of 11,890 women that indicated Depo-Provera presents no increased risk of five cancers: breast, liver, ovary, endometrium and cervix. The coordinator of the WHO Collaborative studies, David Thomas, MD, Fred Hutchinson Cancer Research Center, Seattle, said that "the risks of cancer associated with using DMPA are low and are no greater than the cancer risk associated with use of oral contraceptives." Breast cancer risk was increased "a little" in the most recent users, who were mainly women under age 35, Thomas said. "Risk did not increase with duration of use." Upjohn filed the original NDA for Depo in 1967. The cancer issue dates back to 1972, when carcinogenicity studies of Depo- Provera in beagles resulted in adenocarcinoma in mammary nodules. WHO began its clinicals in 1979. While cancer risk has been a major issue in previous reviews of the drug, this time FDA also asked the panel to focus on recent reports involving osteoporosis and low birth-weight in relation to the use of DMPA for contraception. * Tim Cundy, MD, Auckland Hospital, New Zealand, presented results from a study of Depo-Provera's effects on bone density in women who used the drug for at least five years. The bone density in the lumbar spine of Depo users was "an average of 7.5% lower than the premenstrual controls" and in the femoral neck was 6.5% lower than premenstrual controls, Cundy said. Postmenopausal controls showed a much greater reduction in bone density. According to prospective studies presented by Cundy, reductions in bone density were reversible after women stopped taking Depo. Women who stopped using the contraceptive gained about 3% in bone density in one year and gained 6% at the end of two years, Cundy said. FDA Epidemiology Branch Chief Bruce Stadel, MD, suggested that more studies of Depo-Provera's effect on bone density should be conducted. "I would like to [see] further studies in postmenopausal women compared to former users," Stadel said. He noted that he does not view "the osteoporosis issue as a major difference in the [risk/benefit] balance," pointing out that, compared to oral contraceptives, Depo does not present "the same issues of cardiovascular risk that were long problems...in relation to estrogen content." The committee also considered a study in Thailand on the outcomes of infants following maternal exposure to Depo after conception. Study investigator Ronald Gray, MD, John Hopkins School of Public Health, said the study determined that "among those pregnancies estimated to have occurred within the first four weeks after a Depo injection, there was a two-fold increased risk of low birth-weight and that risk diminished as we moved further away from time of injection." He pointed out that "if the first injection of DMPA is given within five days of the onset of the last regular menstrual period, then you can avoid giving the drug to already pregnant women." Gray added that even "if the associations that we observed were true, the pregnancy rate with Depo-Provera is low, certainly less than one percent and less than a quarter of the conceptions ...occurred within one month of injection. Therefore, the attributable risks, if any, are very low indeed." FDA's Stadel said that studies on low birth-weight infants should not be a major consideration in evaluating the drug's benefits and risks. "It's an extremely effective contraceptive and I think we've seen that [low birth-weight] appears to be a modest effect," he said. Overall, the committee concluded that possible risks of low birth-weight and osteoporosis could be adequately addressed in labeling and through more studies. Discussing short-term side effects, Upjohn Labs VP Joann Data, MD/PhD, said that "the medical event profile for this drug is similar to other progestational agents that are given by injection" in terms of changes in menstrual bleeding. With continued use, the incidence of amenorrhea increases, Data noted. Irregular menstrual bleeding also occurs. Depo-Provera use also can result in weight gain. Data noted that 60% of women gained weight during the first six months of use; weight gain stabilizes after about three years of use. By the third year, the mean weight gain is 15-16 lbs. Some committee members noted that the size of the weight gain might deter some women from using the contraceptive. According to Data and other meeting participants, psychological effects of Depo-Provera include loss of libido, depression, nervousness and fatigue. Providing clinical perspective for Upjohn's presentation, Andrew Kaunitz, MD, Family Health Services, Jacksonville, Fla., said that in comparing women using Depo-Provera with women using other hormonal methods, "I certainly don't see any differences in terms of [central nervous system] symptoms including fatigue, depression or loss of libido." The advisory committee gave Depo high marks for safety by unanimously recommending approval for a broad patient population. Previous advisory committee recommendations had proposed restricting patient use. In 1973 and 1975, FDA's Obstetrics and Gynecology Advisory Committee recommended approval of Depo-Provera for a limited patient population. Both times FDA concurred with the committee's determinations, but continuing safety issues prevented the agency from approving the drug. The approval in 1991 of a long-acting progestin implant, Wyeth-Ayerst's Norplant (levonorgestrel), probably added to the committee's comfort level with Depo-Provera. * Eleven of the 15 presentations at the committee meeting supported approval of the drug. Groups speaking in favor of Depo included Planned Parenthood and numerous professional organizations. Commenting separately on the contraceptive, the National Institute of Child Health and Human Development stated: "We are all for Depo-Provera." The institute said it believes the drug is safe based on worldwide studies. One factor that may affect Depo's success if it reaches the market is cost. Lisa Kaeser, Allan Guttmacher Institute, said that "long-acting reversible methods like Norplant and [GynoPharma's] ParaGard IUD can be very cost efficient over the long run, but the upfront costs...can place insurmountable barriers for potential users." The quarterly injections of Depo cost about $120 per year, according to Kaunitz. The cost for Norplant, which lasts five years, is about $580, according to Louise Tryrer, MD, Association of Reproductive Health Professionals. Kaeser warned that "the long-acting methods carry some potential for abuse" of women. Upjohn said its patent for Depo-Provera's use in contraception expired in 1984. The company has not filed any patent extension applications.