As a new form of contraceptive is poised to become available in the United States-and internationally- within a few months, researchers are convinced that the convenience, efficacy, and safety it provides will appeal to a broad range of women as an alternative to oral contraceptives (OCs).

To be marketed as Lunelle® in the United States and Lunella® overseas, the contraceptive combines 25 mg of medroxyprogesterone acetate and five milligrams of estradiol cypionate in a single, intramuscular injection administered once a month by a health professional.

Presented as the first monthly combination injection therapy expected to reach market, the new contraceptive was recently described to doctors attending an industry sponsored symposium held during the XVI FIGO World Congress of Gynecology and Obstetrics.

According to symposium chairman Dr. David Grimes, Vice President of Biomedical Affairs, Family Health International; Clinical Professor in Obstetrics and Gynecology, University of North Carolina- Chapel Hill School of Medicine, the new contraceptive comes to market following extensive study by the World Health Organization (WHO) in clinical trials involving 7,000 women worldwide and, more recently, 782 women in the United States.

Dr. Grimes added that the new agent was developed in response to global research concerning the benefits women want a contraceptive to provide. A 1999 Roper Starch Worldwide poll, for instance, found that 63 percent of Italian women, 33 percent of Japanese women, 59 percent of French women, 46 percent of German women, and 53 percent of American women would consider a new contraceptive, provided it was easy to use (91 percent), had few or no side effects (87 percent), could be taken once-monthly (58 percent), and would allow a rapid return to fertility after discontinuation (54 percent).

Drawing on international experience with medroxyprogesterone acetate/estradiol cypionate from WHO trials conducted between 1984 and 1990, Dr. Carolyn Westhoff reviewed how well the monthly injectable contraceptive addresses women's concerns compared to currently available methods.

Dr. Westhoff, Professor, Department of Obstetrics and Gynecology, Joseph L. Mailman School of Public Health, Columbia University College of Physicians and Surgeons, New York, discussed the major advantages associated with monthly injectables, such as the effectiveness in maintaining regular monthly cycles, the rapid reversibility after discontinuation, and the relative lack of metabolic effects-all of which are of high importance to both women and their physicians.

"This particular combination can be given regularly at anywhere from 23- to 33-day intervals, and the more regular the injection, the more regular the withdrawal bleeding will be," she explained. "Clinical trial data from the WHO studies show that within two days, medroxyprogesterone acetate levels peak and then maintain levels sufficient for ovulation suppression for about six weeks, so even if a woman is a few days late for a subsequent injection, she will still be protected. However, the medroxyprogesterone acetate will not stay above the suppression level from month to month; in fact, ovulation returns rapidly once it falls below the protective threshold-in short, return to fertility quickly follows discontinuation."

Similarly, the data show estradiol cypionate levels peak around day two following injection, she added, and then decline steadily over the next 28 days, allowing regular menstrual bleeding to occur. Further, steady state levels are achieved after the first injection, she said, with no evidence to suggest either medroxyprogesterone acetate or estradiol cypionate will accumulate with subsequent injections. In various countries around the world, she confirmed,the WHO studies reported a zero percent failure rate (unwanted pregnancy) per 100 woman-years based on 10,969 woman-months of use.

Conversely, rates of return to fertility after discontinuation were comparable to rates seen with oral contraceptives (OCs) and other long-term methods. The 12-month pregnancy rate was slightly above 80 percent.

No serious adverse events were attributed to medroxyprogesterone acetate/estradiol cypionate use, and nuisance side effects-notably, irregular bleeding-were reported by only a minority of patients. Further, there were few discontinuations. In fact, only seven percent of subjects discontinued use in the WHO study and in the more recent United States trials, she confirmed, with weight change being of more concern to women in the United States.

Contraindications of medroxyprogesterone acetate/estradiol cypionate follow the same guidelines as those pertaining to other contraceptive methods, she said. Pregnancy, breast or endometrial cancer, a current or past history of thromboembolism or other cerebral, vascular, or coronary artery disease, cholestatic jaundice of pregnancy or jaundice with prior contraceptive use, undiagnosed abnormal genital bleeding, and smoking after age 35 all preclude its use.

Building on the global WHO data, Dr. Andrew Kaunitz, Professor and Assistant Chair, Department of Obstetrics and Gynecology, University of Florida Health Science Center; Director of Menopause and Gynecology Services, Medicus Women's Diagnostic Center, Jacksonville, reviewed findings of US Phase III studies in which medroxyprogesterone acetate/estradiol cypionate was compared to the low-dose OC Ortho-Novum 7/7/7 (0.035 ethinyl estradiol, 0.5/0.75/1.0 mg norethindrone) at 42 investigational sites.

In the 60-week, open label, controlled, non-randomized study, participants were between the ages of 18 and 49, were sexually active, and could choose the contraception method they preferred to use. In all, 782 chose medroxyprogesterone acetate/estradiol cypionate, while 321 chose ethinyl estradiol/norethindrone.

As in the WHO trials, results showed the one-year failure rate for medroxyprogesterone acetate/estradiol cypionate was zero percent, compared to 0.34 percent for ethinyl estradiol/norethindrone.

Further, medroxyprogesterone acetate/estradiol cypionate users had more regular bleeding patterns. Regular menses occurred after the first cycle of use at an average interval of 28 days, with a five- to six- day bleeding episode followed by a 21- to 22-day bleeding-free interval. Surprisingly, Dr. Kaunitz added, breakthrough bleeding rates were lower among medroxyprogesterone acetate/estradiol cypionate users.

Other findings showed adverse events were similar in the two groups, although the medroxyprogesterone acetate/estradiol cypionate users experienced a median weight increase of four pounds during seven cycles of use and five pounds over 15 cycles, with heavier women gaining more weight than those weighing 150 lb or less. The reasons for this remain unclear, he said, and warrant further investigation.

Generally, no weight changes were seen in women taking ethinyl estradiol/norethindrone. Increases in trigylceride levels were observed in this group, however, which did not occur among those taking medroxyprogesterone acetate/estradiol cypionate.

Commenting on the results, Dr. Kaunitz said, "We were skeptical US women would elect the injectable, which requires monthly visits to a clinic, but we found it was actually easier and quicker to recruit [medroxyprogesterone acetate/estradiol cypionate] users than it was for OCs. Further, the company has funded continuation trials at some of the 42 sites, including ours, so those women who continued through the 60 weeks of the study have been given the option to continue on the new contraceptive until it becomes commercially available. We still have users who want to continue [with medroxyprogesterone acetate/estradiol cypionate], which underscores the fact we believe a substantial number of US women are willing to put up with the potential inconvenience of monthly injections to obtain the contraceptive security these [injections] provide."

In addition to contraceptive efficacy, he added, US women tend to be concerned about bleeding patterns. Overall, the WHO data show women using medroxyprogesterone acetate/estradiol cypionate have less menstrual flow each month than untreated women taking no hormones, but women taking medroxyprogesterone acetate/estradiol cypionate experience one more day of flow than those on OCs. Unpredictable or breakthrough bleeding is a major cause of discontinuation among OC users, however, which can lead to unintended pregnancy.

"We assumed Lunelle® [medroxyprogesterone acetate/estradiol cypionate] would be associated with more breakthrough bleeding [than ethinyl estradiol/norethindrone], but analysis of our trial results show the incidence was somewhat less than with the OC.

As for the impact on metabolic parameters, Dr. Kaunitz suggested the rise in triglycerides seen with low dose OC use, but not with the medroxyprogesterone acetate/estradiol cypionate group, may reflect a difference between oral administration and intramuscular injection.

"The other laboratory findings we observed-glucose, renal, liver, and immunologic functions-were all reassuring and paralleled the findings of the WHO studies," he added, "with no serious outcomes reported among [medroxyprogesterone acetate/estradiol cypionate] users that resulted in discontinuation."

"In summary, the US trial data show Lunelle® [medroxyprogesterone acetate/estradiol cypionate] is an extremely effective birth control method. Women using the therapy will experience regular monthly cycles, and the rates of breakthrough bleeding are low. Metabolically, it appears to be a neutral, safe contraceptive, and based on our US experience and the WHO studies, we anticipate it [medroxyprogesterone acetate/estradiol cypionate] will be a well-received birth control method when it becomes available in the next few months."