Abstract
Background: Oral contraceptives (OCs) are the most widely used method of reversible contraception. Recent alterations of the standard 28-day regimen have included shortening the traditional hormone-free interval (HFI), supplementing the HFI with low-dose estrogen, or increasing the number of active pills administered, thus extending the time between withdrawal bleeding episodes by a variable number of months. In light of these changes in regimens, clinicians may be seeking evidence that the new regimens are safe and will not result in unexpected adverse events.
Methods: We initiated a long-term extension trial to evaluate the safety of a 91-day extended-regimen OC containing 150 mcg levonorgestrel/30 mcg ethinyl estradiol (EE) for 84 days, followed by 7 days of 10 mcg EE. After participation in a 1-year, open-label, phase 3 contraceptive program, 320 women qualified for enrollment in a multicenter, nonrandomized study of 91-day extended-regimen OCs for up to 3 additional consecutive years; 116 completed the study. We evaluated incidence of reported adverse events (AEs), rates of study discontinuation, and reported bleeding patterns.
Results: Total exposure was equivalent to 8292 28-day cycles. Participants reported no thromboembolic events. Thirty-one (9.7%) women discontinued treatment due to AEs. Unscheduled bleeding and spotting diminished during the course of the trial. Overall rates of study discontinuation and incidence of AEs were consistent with those observed in the phase 3 clinical program.
Conclusion: This study demonstrated that the AE profile of the 91-day extended-regimen OC over 4 years was similar to that seen in the 1-year clinical trials, with no unexpected adverse events.
Two Phase 3 studies assessed a 91-day oral contraceptive (OC) regimen for 1 year—a multicenter, open-label trial that studied safety and efficacy,1 and a multicenter trial that evaluated endometrial safety.2 Results of both studies showed the regimen to be safe, effective, and well tolerated. The regimen: 84 days of combination tablets containing 150 mcg levonorgestrel (LNG) and 30 mcg ethinyl estradiol (EE), followed by 7 days of 10 mcg EE alone instead of placebo to maintain ovarian suppression,3,4 potentially reducing the incidence of intermenstrual bleeding or spotting. To gain longer experience with this regimen, we enrolled selected subjects from both studies in a 3-year extension trial.
Methods
Study design and population
In this nonrandomized, multicenter, open-label extension study, we invited women who had successfully completed 1 year of treatment in either of the Phase 3 trials to participate as part of a convenience sample for an additional 3 years of follow-up. We conducted this study in accordance with ethical guidelines for human subjects and applicable guidelines for good clinical practice.5
Inclusion and exclusion criteria were similar to those used in the Phase 3 studies.1,2 Participants agreed to use the study medication as their primary method of birth control throughout the study. We excluded women who were using a medication that might interfere with the efficacy of OCs, or who had any medical or lifestyle contraindications to OC use (eg, clinically significant abnormal Pap smear; cigarette use if older than 35 years).
We enrolled 320 subjects whose demographic characteristics were similar to those in the earlier Phase 3 trials (TABLE 1).2
TABLE 1
Demographic characteristics of all treated participants (N=320)
| Age at screening, y | |
| Mean (SD) | 28.1 (6.0) |
| Median | 27.5 |
| Min, Max | 18.2, 40.2 |
| Weight, lb | |
| Mean (SD) | 152.3 (37.6) |
| Median | 143.5 |
| Min, Max | 94.0, 360.0 |
| Body mass index, kg/m2 | |
| Mean (SD) | 25.5 (5.8) |
| Median | 24.1 |
| Min, Max | 16.8, 56.5 |
| OC use history, n (%) | |
| Recent user | 225 (70.3%) |
| Prior user | 67 (20.9%) |
| New start | 28 (8.8%) |
| Race, n (%) | |
| African American | 40 (12.5%) |
| Asian | 7 (2.2%) |
| Caucasian | 262 (81.9%) |
| Hispanic | 4 (1.3%) |
| Other | 7 (2.2%) |
| Cigarette use status, n (%) | |
| Nonsmoker | 269 (84.1%) |
| Smoker | 51 (15.9%) |
| OC, oral contraceptive; SD, standard deviation. | |
Regular evaluation of adherence and AEs
Every 3 months at the study site, we assessed adherence with the drug regimen by reviewing participants’ daily diaries and by counting pills in returned used pill packs. We also evaluated subject-reported adverse events (AEs)—side effects, as well as serious adverse events (SAEs) requiring treatment or drug discontinuation—and use of concomitant medications or cigarettes.
Factors in our safety assessment
Our safety analysis included any subject who took at least 1 dose of the study drug. We calculated the incidence rates of subject-reported AEs, overall rates of discontinuation, and cycles of exposure. These included incidence rates of AEs the investigators deemed to be at least “remotely” related to treatment. Safety analyses also included annual changes in laboratory values (complete blood count, serum chemistry, lipid profile, and urinalysis), vital signs, occurrence of pregnancy, and rates of reported bleeding or spotting.
The evaluation included bleeding/spotting that was scheduled—occurring on cycle days 85 through 91 (EE-only tablets)—and unscheduled—intermenstrual or “breakthrough” blood loss occurring on cycle days 1 through 84. We defined bleeding as any vaginal blood loss requiring the use of sanitary protection (pads or tampons); spotting was defined as vaginal blood loss not necessitating sanitary protection.