Metabolic profile of a continuous versus a cyclic low-dose combined oral contraceptive after one year of use.

OBJECTIVES: To compare the effects of a combined oral contraceptive (COC) taken continuously with those of one of similar composition taken cyclically on 30 variables related to haemostasis, lipids, carbohydrates, bone metabolism, and sex hormone-binding globulin (SHBG). METHODS: Randomised, open-label, multicentre, comparative substudy of a larger phase 3 trial involving 147 healthy women (age 18-49 years). Participants received the COC either continuously (levonorgestrel [LNG] 90 µg/ethinylestradiol [EE] 20 µg) or cyclically (21/7 days pattern; LNG 100 µg/EE 20 µg). RESULTS: After 13 pill packs, changes in total cholesterol (+0.23 vs. -0.06 mmol/l), low-density lipoprotein cholesterol (+0.25 vs. -0.12 mmol/l), and high-density lipoprotein cholesterol(3) (-0.06 vs. -0.15 mmol/l) differed significantly (p<0.05) between the continuous and cyclic regimens, respectively. Increases were significantly greater (p <0.05) for protein C antigen (+11.8% vs. +6.1%) and SHBG (+791 vs. +565 nmol/l), and significantly smaller (p <0.05, ranks) for D-dimer (+19 vs. +37 µg FE/l). CONCLUSIONS: Overall, the continuous and cyclic regimens affected metabolic variables similarly. The larger increase in SHBG with the continuous COC is consistent with a higher net oestrogenic effect due to a lower daily dose of LNG. Prospective studies are required to determine the long-term effects of this continuous COC regimen.

Endometrial histology following 1 year of a continuous daily regimen of levonorgestrel 90 micro g/ethinyl estradiol 20 micro g.

OBJECTIVE: The objective of this study was to evaluate the effect of a continuous daily regimen of levonorgestrel (LNG) 90 micro g/ethinyl estradiol (EE) 20 micro g on endometrial histology. METHODS: This was a substudy of a large phase 3 trial conducted in six sites in North America. Healthy and sexually active women aged between 18 and 49 years took LNG 90 micro g/EE 20 micro g daily for 1 year. Results from endometrial biopsies performed at pretreatment baseline and those after at least 6 months of treatment were compared. RESULTS: Of the 146 participants, 93 had a baseline biopsy and completed at least six pill packs. Before treatment, 56 subjects (60%) had an endometrial biopsy with findings classified as "weakly proliferative or proliferative." During the last on-therapy visit, 48 subjects (52%) had an endometrium categorized as "other," which included primarily an inactive or benign endometrium (n=42). No hyperplasia or malignancy was observed during the study. CONCLUSION: The results of a 1-year continuous regimen of LNG 90 micro g/EE 20 micro g were shown to have a good endometrial safety profile.

Evaluation of a continuous regimen of levonorgestrel/ethinyl estradiol: phase 3 study results.

OBJECTIVE: This study was conducted to evaluate the safety and efficacy of a continuous daily regimen of levonorgestrel (LNG) 90 microg/ethinyl estradiol (EE) 20 microg (continuous LNG/EE). METHODS: Healthy women aged 18-49 years with regular menstrual cycles for 3 months enrolled in this single-treatment open-label study and took one pill of LNG 90 microg/EE 20 microg daily for 12 months. RESULTS: For the 2134 subjects enrolled, the Pearl Index method failure was 1.26, and user failure was 0.34. While on Pill Pack 13, 58.7% of subjects reported amenorrhea and 79.0% reported absence of bleeding. Overall, the number of bleeding and spotting days per pill pack declined progressively. Adverse events and discontinuations were comparable to those reported for cyclic oral contraceptive (OC) regimens, except for higher rates in those related to uterine bleeding. CONCLUSIONS: Continuous LNG/EE demonstrated a good safety profile and efficacy similar to cyclic OCs. The regimen continuously inhibited menses, increased the incidence of amenorrhea over time and, except for a subset of women, decreased the number of bleeding and spotting days.

An overview of four studies of a continuous oral contraceptive (levonorgestrel 90 mcg/ethinyl estradiol 20 mcg) on premenstrual dysphoric disorder and premenstrual syndrome.

BACKGROUND: This article presents an overview of four studies that evaluated a continuous oral contraceptive (OC) containing levonorgestrel (90 mcg) and ethinyl estradiol (20 mcg; LNG/EE) for managing premenstrual dysphoric disorder (PMDD) and premenstrual syndrome (PMS). STUDY DESIGN: Three randomized, double-blind, placebo-controlled trials and one open-label, single-treatment substudy examined mean changes from baseline in the Daily Record of Severity of Problems (DRSP) or Penn Daily Symptom Rating (DSR). RESULTS: Improvements from baseline in mean DRSP and DSR scores were observed, but results were not consistent among the studies. Mean percent improvement of premenstrual symptoms ranged from 30% to 59% in controlled trials and 56% to 81% in an open-label substudy. A large placebo effect was also observed in the placebo-controlled studies. Continuous LNG/EE yielded a favorable safety profile. CONCLUSIONS: These data, although not consistent, indicate that continuous LNG/EE may reduce the symptoms of PMDD and PMS, providing an option for women who are appropriate candidates for a continuous OC as a contraceptive, the approved indication for this medication.

Continuous oral levonorgestrel/ethinyl estradiol for treating premenstrual dysphoric disorder.

BACKGROUND: The study was conducted to investigate continuous daily levonorgestrel 90 mcg/ethinyl estradiol 20 mcg (LNG/EE) on premenstrual dysphoric disorder (PMDD). STUDY DESIGN: In this multicenter, randomized, double-blind, placebo-controlled study, women with PMDD received LNG/EE (n=186) or placebo (n=181) daily for 112 days and completed the Daily Record of Severity of Problems (DRSP). RESULTS: Mean DRSP change from baseline to late luteal phase was significantly greater with LNG/EE than placebo at the late luteal phase of the first estimated cycle (-30.52±1.73 [SE] vs. -22.47±1.77; p<.001) and the worst 5 days during the last on-therapy estimated cycle (-26.77±1.83 vs. -20.89±1.82; p=.016). Other primary end points were not statistically significant. Significantly more subject taking LNG/EE (52%) than placebo (40%) responded (≥50% improvement in the DRSP 7-day late luteal phase score and Clinical Global Impression of Severity score of ≥1 improvement) at last on-therapy cycle (p=.025). CONCLUSIONS: Continuous daily LNG 90 mcg/EE 20 mcg was well tolerated and may be useful for managing the physical, psychological and behavioral symptoms and loss of work productivity related to PMDD.

Safety and bleeding profile of continuous levonorgestrel 90 mcg/ethinyl estradiol 20 mcg based on 2 years of clinical trial data in Canada.

BACKGROUND: The study was conducted to evaluate bleeding profile and safety of continuous oral contraceptive (OC) containing levonorgestrel (LNG) 90 mcg/ethinyl estradiol (EE) 20 mcg. STUDY DESIGN: Healthy women who participated at seven Canadian sites in 1-year open-label study of LNG 90 mcg/EE 20 mcg daily were eligible for this second-year extension study. Primary end points included bleeding profile and adverse events. RESULTS: Seventy-nine women enrolled without interrupting pill taking; 62 (78.5%) completed. Adverse events were comparable to cyclic OC regimens, except unscheduled vaginal bleeding. Amenorrhea and absence of bleeding increased to about 80% and 90%, respectively, by Pill Pack 18. Mean (median) number of bleeding days for the last two 90-day intervals was 1.1 (0) and 0.7 (0) days, respectively. CONCLUSIONS: Continuous LNG 90 mcg/EE 20 mcg had a safety profile similar to low-dose cyclic OCs. Short-term safety profile remained excellent, with increasing rates of amenorrhea and decreasing incidence of unscheduled bleeding and/or spotting.

Ovarian activity and safety of a novel levonorgestrel/ethinyl estradiol continuous oral contraceptive regimen.

BACKGROUND: A continuous regimen of oral levonorgestrel (LNG) 90 mcg/ethinyl estradiol (EE) 20 mcg was evaluated for inhibition of ovulation, time to return to ovulation after stopping treatment and safety. STUDY DESIGN: This open-label study was conducted in healthy women aged 18-35 years. Ovulation was documented before treatment, and then participants received oral tablets containing LNG 90 mcg/EE 20 mcg to be taken continuously for three 28-day intervals. Ovarian activity was assessed three times per week during the treatment period with transvaginal ultrasound scans and measurements of serum 17beta-estradiol, progesterone, follicle-stimulating hormone and luteinizing hormone concentrations. Safety assessments included physical examinations, laboratory evaluations and adverse event records. RESULTS: Thirty-seven of the 58 subjects who received treatment met predefined criteria for efficacy analysis. No on-treatment ovulations occurred in the efficacy or intent-to-treat population. There was evidence of ovulation within 37 days of stopping treatment for 46 (98%) of 47 subjects evaluated posttreatment. The final subject with a history of polycystic ovarian syndrome ovulated by Day 66. The safety profile observed during this 84-day continuous regimen was similar to that seen with other low-dose oral contraceptives administered in a cyclic regimen. CONCLUSIONS: The continuous LNG/EE regimen completely inhibited ovulation, with little evidence of follicular development and with rapid return of ovulatory capacity after stopping treatment.

Continuous, daily levonorgestrel/ethinyl estradiol vs. 21-day, cyclic levonorgestrel/ethinyl estradiol: efficacy, safety and bleeding in a randomized, open-label trial.

BACKGROUND: This Phase 3, randomized, open-label, multicenter study conducted at 44 sites in Europe evaluated the safety and efficacy of a continuous, daily regimen of levonorgestrel (LNG) 90 mcg/ethinyl estradiol (EE) 20 mcg compared with a 21-day, cyclic LNG 100 mcg/EE 20 mcg regimen. STUDY DESIGN: Three hundred twenty-three healthy women were randomized to continuous LNG 90 mcg/EE 20 mcg and 318 subjects to cyclic LNG 100 mcg/EE 20 mcg for 1 year (13 pill packs). Pearl index, adverse event (AE) incidence and bleeding profiles were assessed. RESULTS: No pregnancies occurred with the continuous oral contraceptive (OC) (Pearl index=0.00). As the study progressed, the percentage of women who achieved amenorrhea during each 28-day pill pack increased: 40% at pill pack 7, 53% at pill pack 13. The percentage of women with no bleeding [with or without spotting (defined as not requiring sanitary protection)] was 50%, 69% and 79% at pill packs 3, 7 and 13, respectively. The incidence of AEs was similar to that of the cyclic OC (except for metrorrhagia and vaginal bleeding in the first 6 months). CONCLUSIONS: Continuous LNG 90 mcg/EE 20 mcg was shown to be a safe and effective OC in this direct comparison to a cyclic OC. Suppression of menses and the potential for no bleeding requiring sanitary protection may be provided by this continuous, low-dose OC.

Occurrence of menses or pregnancy after cessation of a continuous oral contraceptive.

OBJECTIVE: To evaluate the time to return to spontaneous menses in women after 1 year of daily continuous levonorgestrel (LNG) 90 microg/ethinyl E(2) (EE) 20 microg. DESIGN: Observational study. SETTING: Gynecologic and primary care practices. PATIENT(S): Women aged 18-49 years with a history of regular menstrual cycles. After participation in an open-label, continuous oral contraceptive (OC) trial for at least 6 months, participants agreed to enroll in a separate study of the return to menses or pregnancy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Time to return to spontaneous menses or pregnancy. RESULT(S): The 198 subjects had a mean age of 30.4 +/- 6.6 years with 72% white, 13% Hispanic, and 7% African American. The mean duration of continuous LNG/EE treatment before enrollment was 349 +/- 41 days. Of the 187 (94%) subjects who completed this study, 181 returned to spontaneous menses and 4 became pregnant within 90 days after the last dose of LNG 90 microg/EE 20 microg. The median time to return to menses in the completer population was 32 days, and the incidence of spontaneous menses or pregnancy at day < or = 90 was 98.9%. The duration of amenorrhea during continuous LNG/EE use before stopping treatment was unrelated to the time to the return to menses. CONCLUSIONS: Spontaneous menses or pregnancy occurred in 98.9% of women after cessation of continuous LNG/EE.