A Continuous-Use Regimen of Levonorgestrel/Ethinyl Estradiol Significantly Alleviates Cycle-Related Symptoms: Results of a Phase 3 Study

Abstract

To evaluate the effect of a novel continuous-use regimen of levonorgestrel 90μg/ethinyl estradiol 20μg (LNG/EE Continuous) on cycle-related symptoms (CRS) and work productivity. CRS were assessed in a baseline cycle and during 3 pill packs of study drug use in a phase 3 open-label 1-year trial of contraception. Healthy women aged 18 to 49 years took 1 pill of LNG 90 μg/EE 20 μg daily starting on the first day of the first menstrual cycle and continuing through the study with no pill-free intervals. Besides inclusion criteria for the phase 3 study, CRS subjects had to have a history of CRS or dysmenorrhea. They were categorized per predefined criteria as having premenstrual syndrome (PMS) or milder cyclic symptoms, and/or dysmenorrhea based on symptoms/severity experienced in the screening cycle. Antidepressant or anxiolytic use was prohibited during the CRS portion (first 84 days). Subjects maintained the Penn Daily Symptom Rating (DSR) diary, a validated tool for assessing CRS, for 1 baseline cycle and 3 pill packs; scores ranged from 0 (not present) to 4 (severe). The 17-item Penn DSR had 4 subscales: mood, behavior, pain, and physical. CRS scores were reported as mean total and mean item scores for the last 6 days (premenstrual) and days 6 to 11 (postmenstrual) of each cycle/pill pack. Dysmenorrhea scores were reported for the first 5 days of each cycle/pill pack. Work productivity was also evaluated, using the Endicott Work Productivity Scale (EWPS) that was completed weekly at baseline and in the 3 pill packs for subjects who worked or volunteered. In the PMS group (n = 78), premenstrual total scores, all 17 item scores, as well as the difference between pre- and postmenstrual total scores decreased from baseline at all 3 pill packs (p < 0.001). Postmenstrual total scores were consistent across pill packs but higher than baseline (p < 0.002). Analysis of DSR subscales showed that all premenstrual subscale scores decreased from baseline (p < 0.001) at each pill pack, as did the difference between pre-and postmenstrual subscale scores (p < 0.001); postmenstrual subscale scores increased (p < 0.001). Results were similar in the cyclic symptoms group (n = 36): premenstrual total, all subscale scores, and the difference between pre-and postmenstrual total and subscale scores decreased at all 3 pill packs (p < 0.001). Postmenstrual total scores increased (p < 0.05), as did postmenstrual mood, behavioral, and pain subscale scores (p < 0.001). In women who reported dysmenorrhea (n = 259), LNG/EE Continuous was very effective in reducing cramps; scores decreased from baseline by 71% and 85% in pill packs 2 and 3, respectively (p < 0.001). Work productivity analyses results were consistent with those of CRS analyses, and showed rapid improvement through pill pack 3. EWPS total score decreased from baseline at pill pack 1 (p < 0.001) in PMS and dysmenorrhea groups, and was 37% and 53%, respectively, of baseline score by pill pack 3. LNG/EE Continuous is the first low-dose continuous-use oral contraceptive that significantly alleviates cycle-related symptoms. Relief of these symptoms is more marked and comprehensive than that reported with selective serotonin reuptake inhibitors in the treatment of PMS. In addition, work productivity was improved. LNG/EE Continuous is an option for women seeking relief from cycle-related symptoms and their effects, and who also desire contraception.