Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone® and estradiol: pharmacokinetics from a dose-finding study.

BACKGROUND: As part of a program to develop a novel estradiol-releasing contraceptive vaginal ring (CVR), we evaluated the pharmacokinetic (PK) profile of CVRs releasing segesterone acetate (Nestorone® (NES)) combined with one of three different estradiol (E2) doses. STUDY DESIGN: A prospective, double-blind, randomized, multi-centered study to evaluate a 90-day CVR releasing NES [200mcg/day] plus E2, either 10mcg/day, 20mcg/day, or 40mcg/day in healthy reproductive-age women with regular cycles. Participants provided blood samples twice weekly for NES and E2 levels during the first 60 days (ring 1) and the last 30 days (ring 2) of use. A subset underwent formal PK assessments at ring initiation, ring exchange (limited PK), and study completion. RESULTS: The main study enrolled 197 women; 22 participated in the PK substudy. Baseline characteristics between the main and PK participants were comparable, with an average BMI of 25.8 kg/m2 (SD 4.3). In the PK substudy, all three rings showed similar NES PK: mean area under the curve (AUC(0-72)) 34,181 pg*day/mL; concentration maximum (Cmax) 918 pg/mL; time to maximum concentration (Tmax) 3.5 h. For E2, the Cmax occurred at 2 h, and was significantly higher with the 20 mcg/day ring (mean 390 pg/mL); 10 mcg/day, 189 pg/mL, p=.003; 40 mcg/day, 189 pg/mL, p<.001), and declined rapidly to≤50 pg/mL for all doses by 24 h. For all subjects, the median E2 levels remained under 35 pg/mL during treatment. CONCLUSION: PK parameters of NES were not affected when paired with different doses of E2, but E2 levels from all three doses were lower than anticipated and no dose response was observed. IMPLICATIONS: While these novel estradiol-releasing combination contraceptive vaginal rings provided sustained release of contraceptive levels of Nestorone over 90 days, the E2 levels achieved were not consistent with bone protection, and a dose-response was not observed.

Continuous or extended cycle vs. cyclic use of combined oral contraceptives for contraception.

BACKGROUND: The avoidance of menstruation through extended or continuous administration (greater than 28 days of active pills) of combination oral contraceptives (COCs) has gained legitimacy through its use in treating endometriosis, dysmenorrhea, and menstruation-associated symptoms. Avoidance of menstruation through continuous use of COCs for reasons of personal preference may have additional advantages to women, including improved compliance, greater satisfaction, fewer menstrual symptoms, and less menstruation-related absenteeism from work or school. OBJECTIVES: To determine the differences between COCs dosed continuously (greater than 28 days of active pills) compared with traditional cyclic dosing (21 days of active pills and 7 days of placebo). Our hypothesis was that continuously administered COCs have equivalent efficacy and safety but improved bleeding profiles, amenorrhea rates, adherence, continuation, participant satisfaction, and menstrual symptoms compared with cyclic COCs. SEARCH STRATEGY: We searched computerized databases (Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, POPLINE, LILACS) for trials using continuous or extended COCs during the years 1966 to 2005. We also searched the references in review articles and publications identified for inclusion in the protocol. Investigators were contacted regarding additional references. SELECTION CRITERIA: All randomized controlled trials in any language comparing continuous (greater than 28 days of active pills) versus traditional cyclic administration (21 days of active pills and 7 days of placebo) of COCs for contraception. DATA COLLECTION AND ANALYSIS: Titles and abstracts identified from the literature searches were assessed for potential inclusion. Data were extracted onto data collection forms and then entered into RevMan 4.2. Peto odds ratios with 95% confidence intervals were calculated for all outcomes for dichotomous outcomes. Weighted mean difference was calculated for continuous outcomes. The trials were critically appraised by examining the following factors: study design, blinding, randomization method, group allocation concealment, exclusions after randomization, loss to follow-up, and early discontinuation. Because the included trials did not have a standard treatment (type of pill and time length for continuous dosing), we could not aggregate data into meta-analysis. MAIN RESULTS: Six randomized controlled trials met our inclusion criteria. Study findings were similar between 28-day and extended cycles in regard to contraceptive efficacy (i.e., pregnancy rates) and safety profiles. When compliance was reported, no difference between 28-day and extended cycles was found. Participants reported high satisfaction with both dosing regimens, but this was not an outcome universally studied. Overall discontinuation and discontinuation for bleeding problems were not uniformly higher in either group in most studies. The few studies that reported menstrual symptoms found that the extended cycle group fared better in terms of headaches, genital irritation, tiredness, bloating, and menstrual pain. Five out of the six studies found that bleeding patterns were either equivalent between groups or improved with continuous-dosing regimens. Endometrial lining assessments by ultrasound were done in a small number of participants but all endometrial stripe measurements were less than 5 mm. AUTHORS' CONCLUSIONS: Evidence from existing randomized control trials comparing COCs given continuously (greater than 28 days of active pills) to traditional monthly cyclic dosing (21 days of active pills and 7 days of placebo) is of good quality. However, the variations in type of pill and time length for continuous dosing make direct comparisons between regimens impossible. Future studies should choose a previously described type of pill and dosing regimen. More attention needs to be directed towards participant satisfaction and menstruation-associated symptoms.