Levonorgestrel 52-mg Intrauterine Device Efficacy and Safety After More Than 8 Years of Use.

FUNDING SOURCE: Medicines360. The Sponsor, Medicines360, designed the study and oversaw its conduct, including funding the trial and providing all study product free of charge to participants. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00995150.

Levonorgestrel 52 mg intrauterine system efficacy and safety through 8 years of use.

BACKGROUND: Extending hormonal intrauterine system duration will allow users to have less need for procedures to provide long-term contraception. OBJECTIVE: This study aimed to evaluate the efficacy and safety of the levonorgestrel 52 mg intrauterine system during years 7 and 8 of use. STUDY DESIGN: A total of 1751 nulliparous and multiparous participants aged 16 to 45 years enrolled in a phase 3, multicenter trial to evaluate the efficacy and safety of the use of the Liletta levonorgestrel 52 mg intrauterine system for up to 10 years. Participants aged 36 to 45 years at enrollment underwent safety evaluation only. After the first year, we evaluated participants every 6 months for intrauterine system location confirmation and urine pregnancy testing at each visit. We assessed the Pearl Indices in years 7 and 8 and the life-table analysis for cumulative pregnancy rates through 8 years of use. For the primary efficacy analyses, all participants aged 16 to 35 years at enrollment were included through year 6; years 7 and 8 included only users aged ≤39 years at the start of each use year. Safety outcomes were assessed in all participants regardless of duration of use. We assessed amenorrhea rates, defined as no bleeding or spotting in the 90 days before the end of the year. RESULTS: After intrauterine system placement, we followed 1568 participants aged 16 to 35 years and 146 participants aged 36 to 45 years. The 16- to 35-year-old participants included 986 (57.5%) nulliparous and 433 (25.3%) obese users. Overall, 569 participants started year 7, 478 completed year 7 (380 aged ≤39 years at beginning of year) and 343 completed year 8 (257 aged ≤39 years at beginning of year); 77 completed 10 years of use. Eleven pregnancies occurred over 8 years, 7 (64%) of which were ectopic. Two pregnancies occurred in year 7 (Pearl Index, 0.49; 95% confidence interval, 0.06-1.78), 1 in a participant with implantation 4 days after a desired removal; no pregnancies occurred in year 8. The cumulative life-table pregnancy rate in the primary efficacy population through year 8 was 1.32 (95% confidence interval, 0.69-2.51); without the postremoval pregnancy, the rate was 1.09 (95% confidence interval, 0.56-2.13). Two perforations (0.1%) occurred, none noted after year 1. Expulsion occurred in 71 (4.1%) participants overall, with 3 in year 7 and 2 in year 8. Pelvic infection was diagnosed in 16 (0.9%) participants during intrauterine system use, 1 each in years 7 and 8. Only 44 (2.6%) participants overall discontinued because of bleeding complaints (4 total in years 7 and 8) with rates per year of 0.1% to 0.5% for years 3 to 8. Amenorrhea rates were 39% at both years 7 and 8. CONCLUSION: The levonorgestrel 52 mg intrauterine system is highly effective over 8 years of use and has an excellent extended safety profile. This report details the longest period of efficacy and safety data for continuous use of a levonorgestrel 52 mg intrauterine system for contraception.

Bleeding changes after levonorgestrel 52-mg intrauterine system insertion for contraception in women with self-reported heavy menstrual bleeding.

BACKGROUND: The levonorgestrel 52-mg intrauterine system has proven efficacy for heavy menstrual bleeding treatment in clinical trials, but few data exist to demonstrate how rapidly the effects occur and the effects in women with self-reported heavy bleeding, as seen commonly in clinical practice. OBJECTIVE: Evaluate changes in bleeding patterns in women with self-reported heavy menstrual bleeding before levonorgestrel 52-mg intrauterine system insertion. STUDY DESIGN: A total of 1714 women aged 16-45 years old received a levonorgestrel 52-mg intrauterine system in a multicenter trial evaluating contraceptive efficacy and safety for up to 10 years. At screening, participants described their baseline menstrual bleeding patterns for the previous 3 months. Participants completed daily diaries with subjective evaluation of bleeding information for the first 2 years. For this analysis, we included women with at least 1 complete 28-day cycle of intrauterine system use and excluded women using a hormonal or copper intrauterine contraception in the month prior to study enrollment. We evaluated changes in menstrual bleeding and discontinuation for bleeding complaints per 28-day cycle over 26 cycles (2 years) in women who self-reported their baseline pattern as heavy. We also compared rates of amenorrhea, defined as no bleeding or spotting, within the entire study population in women with subjective heavy menstrual bleeding at baseline compared with those who did not complain of heavy menstrual bleeding. RESULTS: Of the 1513 women in this analysis, 150 (9.9%) reported baseline heavy menstrual bleeding. The majority of women reported no longer experiencing heavy menstrual bleeding by the end of cycle 1 (112/150, 74.7%) with even greater rates by cycle 2 (124/148, 83.8%). At the end of cycles 6, 13, and 26, 129 of 140 (92.1%; 95% confidence interval, 87.7%-96.6%), 114 of 123 (92.7%; 95% confidence interval, 88.1%-97.3%), and 100 of 103 (97.1%; 95% confidence interval, 93.8%-100%) women reported no heavy menstrual bleeding, respectively. After cycles 13 and 26, 63 of 123 (51.2%; 95% confidence interval, 42.4%-60.1%) and 66 of 103 (64.1%; 95% confidence interval, 54.8%-73.3%), respectively, reported their bleeding as amenorrhea or spotting only. A lower proportion of women with baseline self-reported heavy menstrual bleeding reported amenorrhea as compared with women in the overall study cohort without heavy menstrual bleeding at the end of 6 cycles (319 [25.5%] vs 21 [15.0%], P=.005) and 13 cycles (382 [34.4%] vs 26 [21.1%], P=.003); differences were not significant after 19 cycles (367 [37.2%] vs 36 [31.0%], P=.022) and 26 cycles (383 [43.5%] vs 38 [36.9%], P=.21). Only 4 (2.7%) women with baseline heavy menstrual bleeding discontinued for bleeding complaints (2 for heavy menstrual bleeding and 2 for irregular bleeding), all within the first year. CONCLUSION: Most women who self-report heavy menstrual bleeding experience significant improvement quickly after levonorgestrel 52-mg intrauterine system insertion. Discontinuation for bleeding complaints among women with baseline heavy menstrual bleeding is very low.

Six-year contraceptive efficacy and continued safety of a levonorgestrel 52 mg intrauterine system.

OBJECTIVE: To assess 6-year contraceptive efficacy and safety of a levonorgestrel 52 mg intrauterine system (IUS). STUDY DESIGN: We assessed pregnancy rates through 72 months in women aged 16-35 years at enrollment and safety in all participants (aged 16-45 years, n = 1751) in an ongoing 10-year phase-3 trial. RESULTS: Over six years, nine pregnancies occurred (none in year 6) for a life-table pregnancy rate of 0.87 (95% CI 0.44-1.70). Adverse event rates remain low through 6 or more years of use. Two expulsions occurred in year 6. CONCLUSION: This levonorgestrel 52 mg IUS is a highly effective and safe contraceptive over 6 years of use. IMPLICATIONS: The levonorgestrel 52 mg IUS shows high 6-year contraceptive efficacy and a low rate of adverse events through 6 or more years of use.

Five-Year Contraceptive Efficacy and Safety of a Levonorgestrel 52-mg Intrauterine System.

OBJECTIVE: To assess the 5-year contraceptive efficacy and safety of a levonorgestrel (LNG) 52-mg intrauterine system (IUS) from an ongoing 10-year phase 3 contraceptive trial. METHODS: Study investigators enrolled 1,751 nulliparous and parous females aged 16-45 years and desiring contraception to receive a novel LNG 52-mg IUS at 29 centers in the United States, including reproductive health clinics, private offices, and university centers. Participants had scheduled follow-up visits four times during the first year. After year 1, study visits occurred every 6 months, with phone contact at the 3-month point between visits. We assessed the primary outcome of pregnancy rate (Pearl Index) in females aged 16-35 years at enrollment through 60 months. The safety evaluation included all females for their entire duration of participation. RESULTS: The 1,751 enrollees included 1,600 females aged 16-35 years and 151 aged 36-45 years. Successful IUS placement occurred in 1,714 (97.9%) participants. At the time of the data evaluation, 495 participants finished 5 years and 176 had entered the seventh year of IUS use. Nine pregnancies occurred, six of which were ectopic. The Pearl Indices for years 1 and 5 were 0.15 (95% CI 0.02-0.55) and 0.20 (95% CI 0.01-1.13) pregnancies per 100 women-years, respectively. The cumulative life-table pregnancy rate was 0.92% (0.46-1.82%) through 5 years. Participants aged 16-35 years at enrollment were significantly more likely to report new or worsening acne, dyspareunia, pelvic pain, and dysmenorrhea; participants aged 36-45 years at enrollment were more likely to report new or worsening weight increase. Discontinuation for adverse events occurred in 322 (18.8%) participants, most commonly related to expulsion (n=65 [3.8%]). Only 39 (2.2%) IUS users discontinued as a result of bleeding symptoms. Pelvic infection was diagnosed in 14 (0.8%) participants. CONCLUSION: This LNG 52-mg IUS is highly effective and safe over 5 years of use in U.S. females. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT00995150. FUNDING SOURCE: Medicines360.

Bleeding patterns for the Liletta® levonorgestrel 52 mg intrauterine system.

PURPOSE: Evaluate bleeding patterns for the Liletta® levonorgestrel 52 mg intrauterine system (IUS) using the World Health Organization Belsey definitions. MATERIAL AND METHODS: This prospective multicenter trial evaluates the efficacy and safety of Liletta® (Clinicaltrials.gov NCT00995150). We evaluated bleeding patterns for 1700 nulliparous and multiparous women using a daily diary completed by participants for the first 2 years and by questionnaire every 3 months thereafter. We assessed amenorrhea rates over 3 years and the proportion of subjects with infrequent, frequent, prolonged and irregular bleeding per 90-day reference period over 2 years for the entire study population as well as comparing nulliparous and parous women and obese and non-obese women. RESULTS: Amenorrhea rates at 1 and 3 years in levonorgestrel 52 mg IUS users were 19 and 37%, respectively. The infrequent bleeding rate increased from 14% in the first 90 days to 30% at the end of Year 1, and was maintained at the same rate through Year 2. Frequent, prolonged and irregular bleeding declined to low levels by the end of the first year. Discontinuation for bleeding-related complaints occurred in 35 (2.1%, 95% CI 1.3-2.7%) women during the first 36 months; only one subject discontinued for amenorrhea (in Year 2). Outcomes did not vary for nulliparous versus parous or obese versus non-obese women. CONCLUSIONS: Among Liletta users, amenorrhea and infrequent bleeding become more prevalent over time and amenorrhea rates continue to increase after the first year of use. Bleeding patterns do not differ significantly by parity or by obesity-status. Discontinuation for bleeding concerns is uncommon with this product.