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Author: Andrew M. Kaunitz, MD, Professor and Assistant Chair, Department of Obstetrics and Gynecology, University of Florida Health Science Center, Jacksonville.
Peer Reviewer: Daniel R. Mishell Jr., MD, Professor, Department of Obstetrics and Gynecology, University of Southern California School of Medicine, Los Angeles.
In October 2000, the Food and Drug Administration approved the monthly combination hormone injection Lunelle for contraception. This method, the first new contraceptive to be approved in the United States since 1993, is safe, quickly reversible, and extremely effective in preventing pregnancy.
Some clinicians were skeptical that American women would want to receive a monthly birth control injection. However, researchers were pleasantly surprised to learn that many subjects were enthusiastic about the use of Lunelle - in fact, they preferred to try that method over the Pill when given a choice at the start of the trial - and did not find the prospect of an injection or a monthly visit a deterrent to use.
Lunelle contains 25 mg of medroxyprogesterone acetate (MPA) and 5 mg of estradiol cypionate (E2C), and has been studied clinically for the past 35 years and tested in more than 12,000 women worldwide.1 MPA is the same progestin used in the three-month depot medroxyprogesterone acetate (DMPA or Depo-Provera) contraceptive injection. The estradiol released from Lunelle’s injection site is not the synthetic ethinyl estradiol used in birth control pills, but rather the natural hormone 17-beta estradiol produced by the ovaries. The primary mechanism of action for prevention of pregnancy is inhibition of ovulation.2
The World Health Organization (WHO) performed a pilot study of Lunelle in 1981 and several multinational pharmacological and dose-ranging studies between 1984 and 1990.1 These studies led to the selection of 25 mg of MPA and 5 mg of E2C as the optimal doses for suppressing ovulation and producing the lowest rate of menstrual pattern disturbances.
In Phase III clinical trials conducted by the WHO in various parts of the world, the injectable combination alternately was compared with Mesigyna, another injectable product containing 50 mg of norethisterone enanthate and 5 mg of estradiol valerate, DMPA, and oral contraceptives (OCs).1
Pregnancy Rate. In comparison with Mesigyna, Lunelle had an annual pregnancy rate of 0.2% vs. 0.4%, respectively.1 Overall, five pregnancies in 44,160 woman-months of exposure were reported for Lunelle vs. 12 pregnancies in 41,329 woman-months of exposure for Mesigyna.1
Adverse Events and Coagulation Impact. In studies conducted by the WHO, no clotting, cardiovascular, or other serious events have been attributed to use of Lunelle. In a prospective clinical trial, an OC containing 35 mcg of ethinyl estradiol and 1 mg norethindrone was compared with Lunelle.3 Lunelle had a minimal effect on clotting parameters: Its use produced slight decreases in factors VII and X, an increase in tissue plasminogen factor, and minor decreases in antithrombin III activity and protein C levels. In contrast, the oral contraceptive increased factors VII and X and plasminogen, shortening the activated partial thromboplastin time. In addition, protein C increased by nearly 10%. These changes indicated a mild procoagulant effect associated with OC use.3
Bleeding patterns. Overall, 70% of the subjects in the WHO trials had predictable, regular menstrual cycles after one year on the combination injectable, compared with only 8% of DMPA injectable users. Predictability of cycles increased with time among the combination injectable users.1
Amenorrhea was substantially less common among Lunelle users than among DMPA users and untreated controls.1
Discontinuation Rates. Discontinuations for bleeding-related problems occurred in approximately 8% of subjects overall (although rates varied widely from country to country). There were no discontinuations for serious adverse events.1
Return to Fertility. After a Lunelle injection, follicular activity resumed 41-49 days later, and luteal activity initially occurred 59-87 days post-injection.1 When 70 South American women who used Lunelle for 1-19 cycles were followed after they discontinued the injections because they wished to conceive, Bahamondes et al found that the return to fertility rate at the end of the first month was 1.4 per 100 women and 82.9 per 100 women at one year.4 Fifty-one pregnancies recorded in this study ended in a live birth, two ended in a spontaneous abortion, and one was a hydatidiform mole pregnancy. No congenital anomalies in pregnancies were associated with use of Lunelle.4
Study Protocol. A Phase III study comparing Lunelle to the OC Ortho-Novum 7/7/7 (0.035 mcg ethinyl estradiol, 0.5/0.75/1 mg norethindrone) was conducted in the United States at 42 investigational sites.5 The trial was open-label, controlled, and nonrandomized. All subjects were sexually active and desired contraception, aged 18 to 49 years, and nonlactating. Recent use of hormonal contraception, including OCs, was permitted with the exception of DMPA injections.
Participants were allowed to choose the contraceptive method they would use during the study. Lunelle was chosen by 782 women, and 321 patients chose the OC. The baseline demographics between the two groups were similar, except for a slightly higher proportion of Hispanic women and a lower proportion of white women in the Lunelle vs. OC group. As has been found in other U.S. trials of long-acting contraceptive methods, women who chose the injectable tended to be more likely to have used a nonhormonal method of contraception in the past and have given birth compared with women who chose OCs.
The first injection of Lunelle was given within five days of the onset of menses. Subsequent injections were repeated every 28 days + 5 days.
Pregnancy Rate. There were no pregnancies in the Lunelle group and two in the OC group over the two years of the trial, for a life table pregnancy rate for the injectable of 0% vs. 0.3% for the OC.5
Bleeding Patterns. Irregular bleeding occurred in both groups during the first few months of treatment. However, most women receiving Lunelle had regular menses by the end of the third month of use; indeed, by that time, 80% of Lunelle users vs. 87% of OC users were having a single withdrawal bleed per cycle without any breakthrough bleeding or spotting.5,6
The average cycle interval was 28 days among Lunelle users vs. 27 days among OC users, with a five- to six-day bleeding episode for both types of contraceptives. Mean onset of bleeding occurred on day 22 of the cycle for Lunelle subjects vs. day 24 for OC users (with day 1 being the day of the injection or start of a pill pack). Women who received all injections at regularly spaced intervals had more predictable bleeding patterns.5,6
Breakthrough bleeding and spotting rates decreased after several months of use in both groups, from 8% to 4% in the Lunelle group and from 11% to 6% in the OC group.6
Amenorrhea was experienced by 1% to 4% of the injectable users during the course of the study, compared with 1% of OC users. During cycles 2-12, 15% of Lunelle users and 3% of OC users experienced a missed period.6
Lunelle users (5-6 days) had one more bleeding day per cycle than did OC users (4-5 days); however, when compared with untreated women (6 days) enrolled in the WHO trials, injectable users had somewhat fewer bleeding days.5
Women with a body mass index (BMI) lower than 27.3 were more likely to have a single withdrawal bleed in cycle 13 than were women with a BMI higher than 27.3 (80% vs. 64%, respectively) and less likely to be amenorrheic (11% vs 24%, respectively) during a single month.6
Adverse Events. Eighty-nine percent of injection users and 84% of OC users reported an adverse event. Serious adverse events occurred in only 1.9% of injectable users and 1.3% of OC users.5
Weight Gain. Although mean body weight was unchanged for OC users during the course of the study, injection users experienced a median increase of four pounds during seven months of use, and five pounds over 15 months of use. Women weighing more than 150 pounds tended to gain more weight than women weighing fewer than 150 pounds. This finding differed from the results of the WHO trials.1,6
Laboratory Tests and Metabolic Impact. Laboratory parameters of glucose, hepatic, and renal function and hematologic indices were unaffected by either treatment.5 Laboratory parameters included blood sugar, hematocrit, hemoglobin, creatinine, alanine aminotransferase or asparate aminotransferase and bilirubin were unaffected by either treatment. Coagulation parameters were not assessed in this study.
Discontinuations. The most common reasons for discontinuations in the Lunelle and OC groups were weight gain (5.7% and 0.9%, respectively), metrorrhagia (2.5% and 0.9%), emotional liability (2.5% and 1.6%), and acne (1.9% and 0.9%).5
Patient Compliance. Ninety-seven percent of Lunelle users received at least one subsequent injection between 23 and 33 days after prior injections; 70% had all of their injections within this time frame. Fourteen percent missed two or more pills per cycle.5
Patient Satisfaction. Satisfaction with the monthly injectable method was high and similar between groups, as assessed by questionnaires administered to participants during the trial. Ninety percent of the injectable users reported they would recommend the method to a friend, and 90% said they experienced no difficulties returning to their clinician’s office for the monthly injections.7
Eighty-one percent of Lunelle users said they were very comfortable or comfortable with the route of administration for the contraceptive, compared with 88% and 87% of new and prior OC users, respectively. Ninety-one percent of Lunelle users said they were not bothered by the injections. In contrast, 97% of new OC users and 99% of prior OC users said they were not bothered by having to take a daily pill. Also, 79% of Lunelle users and 90% of all OC users said the methods they were using did not interfere with daily activities, and 86% of Lunelle users and 95% of all OC users said their methods did not interfere with social activities.
Irregular menstrual patterns and amenorrhea are common with Depo-Provera use (with the latter occurring in more than one-half of users by the end of one year), and return of fertility may be delayed for 10-18 months after a final injection. In contrast, Lunelle injections confer regular menstrual cycles, little amenorrhea, and a rapid return to fertility after discontinuation of the method.5,8,9
Both methods require a visit to a provider to initiate and continue use, with Depo-Provera requiring visits every three months and Lunelle monthly. Neither method necessitates a visit or consultation with a provider for discontinuation. Because it contains estrogen, the monthly injection is not appropriate for lactating women or others in whom estrogen use is contraindicated. These women are, however, candidates for Depo-Provera.5, 8,9
Both methods are extremely efficacious, with Lunelle demonstrating a zero failure rate in the U.S. trial.5 With typical use, the failure rate for Depo-Provera is 0.3%.8
Side effects associated with Depo-Provera may include irregular bleeding/spotting, amenorrhea, weight gain, and transient decreases in bone density.8 Side effects of the combination monthly injectable may include menstrual bleeding changes, breast tenderness, and weight gain.5
In comparison to OCs, Lunelle confers comparable efficacy and safety, a more convenient dosing schedule (eliminating the need to take a daily pill), and a similar menstrual pattern and side effect profile.5 In the U.S. trial, the failure rate was zero for Lunelle vs. 0.3% for the OC.10
Further study is needed to adequately characterize the potential noncontraceptive benefits of Lunelle. Like the Pill, it is likely that Lunelle will have bone-protective effects and might prevent ovarian cancer. Like both OCs and the progestin-only injection, it also might reduce the risk of endometrial cancer, iron-deficiency anemia, pelvic inflammatory disease, and ectopic pregnancy.9
Neither Lunelle, Depo-Provera, nor the Pill provide protection against sexually transmitted infections.
Based on currently available data, women of all reproductive ages and socioeconomic strata who are candidates for the Pill are also candidates for Lunelle. Because Lunelle contains estrogen and requires monthly administration, many Depo-Provera candidates may not find Lunelle to be a suitable choice.
Contraindications to Lunelle use are the same as those observed for combination OCs. For instance, the method is not recommended for women with known or suspected pregnancy, a past or present history of thrombophlebitis or thromboembolic disorders, cerebral vascular or coronary artery disease, undiagnosed abnormal genital bleeding, liver dysfunction or disease, or carcinoma of the endometrium or breast.8
Injection Technique. Lunelle is provided in the unit dose formulation and may be administered intramuscularly into the deltoid, quadriceps, or gluteus maximus muscle using a 1- to 1.5-inch needle no thinner than a 23-gauge. The solution must be gently shaken prior to aspiration into the syringe to ensure uniform suspension of the hormone crystals.8,9
Injection Schedule. The initial injection should be given within five days of the onset of a normal menstrual period. It also may be administered within seven days following a first-trimester abortion or between three and six weeks postpartum.8
Subsequent injections should be given within 28-30 days of the preceding injection, although they may be administered as early as 23 days and as late as 33 days.8
Counseling. Patients should be counseled to expect irregular bleeding, particularly during the first three months of use, and instructed to return for repeat injections on as regular a schedule as possible.8 They should be advised to expect cyclic withdrawal bleeding to occur approximately 2-3 weeks after each injection.5
The monthly combination injection Lunelle offers comparable efficacy to that of OCs and DMPA, is quickly reversible with a rapid return of fertility, and has a minimal impact on laboratory and clotting parameters. After three injections, it usually confers a regular menstrual pattern, particularly when the contraceptive is received on a regular schedule, and is well-accepted by patients. The advent of a self-administered subcutaneous formulation, currently in development by Pharmacia Corp. of Peapack, NJ, may make Lunelle even more accessible and convenient for women looking for extremely effective contraception that is not linked to coitus or daily administration.
1. Hall PE. New once-a-month injectable contraceptives, with particular reference to Cyclofem/Cyclo-Provera. Int J Gynaecol Obstet 1998; 62(suppl 1):S43-S56.
2. Rahimy MH, Ryan KK. Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): Assessment of return of ovulation after three monthly injections in surgically sterile women. Contraception 1999; 60: 189-200.
3. Newton JR, d’Arcangues C, Hall PE. Once-a-month combined injectable contraceptives. J Obstet Gynaecol 1994; 14(suppl): S1-S34.
4. Bahamondes L, Lavin P, Ojeda G, et al. Return of fertility after discontinuation of the once-a-month injectable contraceptive Cyclofem. Contraception 1997; 55:307-310.
5. Kaunitz AM, Garceau RJ, Cromie MA. Comparative safety, efficacy, and cycle control of Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension) and Ortho-Novum 7/7/7 oral contraceptive (norethindrone/ethinyl estradiol triphasic). Contraception 1999; 60: 179-187.
6. Garceau RJ, Wajszczuk, Kaunitz AM, and the Lunelle Study Group. Bleeding patterns of women using Lunelle monthly contraceptive injections (medroxyprogesterone acetate and estradiol cypionate injectable suspension) compared with those of women using Ortho-Novum 7/7/7 (norethindrone/ethinyl estradiol triphasic) or other oral contraceptives. Contraception 2000; in press.
7. Shulman LP, Oleen-Burkey M, Willke RJ. Patient acceptability and satisfaction with Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension). Contraception 1999; 60:215-222.
8. Kaunitz AM. Injectable contraception: New and existing options. Obstet Gyn Clin No Am 2000; 27:741-780.
9. Shulman LP. Monthly contraceptive injection. The Female Patient 2000; 25:14-20.
10. Coutinho EM, De Souza JC. Conception control by monthly injections of medroxyprogesterone suspension and a long-acting estrogen. J Reprod Fert 1968; 15:209-214.
To earn CME credit for this issue of Contraceptive Technology Reports, please refer to the enclosed Scantron form for directions on taking the test and submitting your answers.
A. the synthetic ethinyl estradiol used in birth control pills B. 17-beta estradiol, identical to the hormone produced by the ovaries
C. neither of the above
B. oral contraceptives
C. neither of the above