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Clinical Trial Results Synopsis Study Design Description Study Sponsor: Bayer Yakuhin Co.LTD. Study Number: 15036 NCT01414140 Study Phase: IV (Prospective Non-Interventional) Official Study Title: Overview of Post-marketing surveillance- Mirena, Japan DUI Therapeutic Area: Women s Healthcare Test Product Name of Test Product: Name of Active Ingredient: Dose and Mode of Administration: Levonorgestrel IUD (Mirena, BAY86-5028) levonorgestrel Mirena was administered through an intrauterine system with a release rate of 20 mcg/24 h. Reference Therapy/Placebo Reference Therapy: Dose and Mode of Administration: Duration of Treatment: Up to 5 years after Mirera insertion Studied period: Date of first subjects first visit: 10-May-2007 Date of last subjects last visit: 25-Jan-2013 Premature Study Suspension / Termination: Substantial Study Protocol Amendments: No substantial amendments Study Centre(s): 55 sites in Japan Methodology: This study is a regulatory post-marketing surveillance in Japan, and it is a local prospective and observational study of women who are inserted Mirena for intrauterine contraception. The objective of this study is to assess safety and effectiveness of Mirena under real-life practice conditions. A total 550 patients were planned to be recruited and followed for 5 years. Indication/ Main Inclusion Criteria: Study Objectives: Women who are inserted Mirena for intrauterine contraception Overall: The objective of this study is to assess safety and effectiveness of Mirena under real-life practice conditions. Evaluation Criteria: Efficacy (Primary): Pregnancy rate Page 1 of 3
Efficacy (Secondary): None Safety: Incidence of adverse drug reactions and serious adverse events in women who are inserted Mirena [ Time Frame: After Mirera insertion, up to 5 years ] Incidence of adverse drug reactions, especially Pelvic inflammatory disease in women who are inserted Mirena [ Time Frame: After Mirera insertion, up to 5 years ] Incidence of adverse drug reactions in subpopulation in a variety of baseline data (such as demographic data, concomitant disease) and duration of Mirena [ Time Frame: After Mirera insertion, up to 5 years ] Statistical Methods: Pharmacokinetics: Released amount of Levonorgestrel Efficacy (Primary): Variables measured were summarized by use of descriptive statistics. Efficacy (Secondary): Safety: Chi-square test and Fisher's exact test were used for the analyses of safety data Number of Subjects: Pharmacokinetics - if applicable: Released amount of Levonorgestrel No. of subjects received treatment:567 No. of Safety analysis set:563 No. of Efficasy analisis set:486 Results Summary Subject Disposition and Baseline Study Results The number of cases collected was 563 (54 investigational sites), all of which were included in the safety analysis, and 486 were included in the efficacy analysis, excluding 77 due to the reasons of "not evaluable for efficacy" and others. The mean age was 39.4 years. Two out of 563 cases were elderly (65 and 78 years old). There was one case with impaired renal function and one case with impaired hepatic function. The duration of the drug placement was at least 5 years in 13 cases, at least 4 years in 127 cases, at least 3 years in 262 cases, at least 2 years in 351 cases and at least one year in 418 cases. Results Summary Efficacy No pregnancy was reported during the investigation among the cases who placed the drug, indicating favorable efficacy in the long-term use. Results Summary Safety Page 2 of 3
A total of 574 adverse drug reactions, etc. were reported in 315 cases (55.95%) out of 563 included in the safety analysis. Adverse drug reactions that were not predicted from the "Precaution for use" in the package insert include anemia in 11 cases, ovarian neoplasm in 10 cases, cystitis in 5 cases, abnormal sensation, breast cancer, dizziness, premenstrual syndrome and hypertension in 2 cases each; other adverse drug reactions were observed in one case each. Out of 10 events of ovarian neoplasm classified as the same preferred term (PT), there was only one unknown adverse drug reaction, which was ovarian neoplasm as the lower level term (LLT); the other 9 were known adverse drug reactions classified as ovarian cystoma as the LLT. Therefore, one out of 10 cases was an unknown ovarian neoplasm. "Blood pressure increased" was listed in the other adverse drug reactions of the "Precaution for use" in July 2012; however, severe hypertension was reported as an unknown adverse drug reaction. The incidence of adverse drug reactions was lower than that reported in the clinical trials up to the time of approval filing, which was 88.80% (428/482). With respect to diabetes mellitus, which is listed in the "Careful administration" of the package insert of the drug, there were no notable findings in the Investigation except diabetes mellitus experienced by 3 cases and type 2 diabetes mellitus experienced by one case. As for the precaution statement in the "Warnings and precautions" that women who have no pregnancy history must not use the drug as the first choice for contraception, there were 95 (16.87%) women with no pregnancy history and 52 (9.24%) with pregnancy history but with no delivery history; however, there were no notable safety issues with or without pregnancy history. The "Warnings and precautions" in the package insert state that the drug should not be inserted until 6 weeks postpartum or until involution of the uterus is complete in order to reduce the incidence of perforation and expulsion. No adverse drug reactions were reported in a case who placed the drug within 6 weeks after the last vaginal delivery. In the safety analysis population, pelvic inflammatory disease (PID) was experienced by 4 cases, and adverse drug reactions extensively interpreted as PID were salpingo-oophoritis in 3 cases and cervicitis in one case. These events occurred within 2 years after placement (6 of them occurred within one year). Two of them were assessed as serious and the other 6 were non-serious. One case had the drug removed, and the other 7 continued the placement. Investigation of the demographic or other baseline factors showing statistically significant differences in cases included in the safety analysis for the Drug Use Investigation revealed no issues of concern requiring new measures to ensure the safety. More than half of the major frequently reported adverse drug reactions of the drug occurred within one year after drug use, and also there were no notable issues of concern in the longterm drug use. Results Summary Pharmacokinetics There were no major differences in the drug exposure estimated on the residual amount in the formulation retrieved after removal compared to the data at the time of approval, i.e., initial release rate: 20µg/day, release rate after 5 years: 10µg/day, mean release rate in 5 years: 14µg/day. Conclusion(s) The results of the Investigation led us to conclude that no factors or concerns affecting the safety or efficacy were observed, thus it is not necessary, at the present moment, to take any special measures such as revising the "Precaution for Use". Publication(s): Date Created or Date Last Updated: 29 OCT 2013 Date of Clinical Study Report: 09 APR 2013 Page 3 of 3
Appendix to Clinical Study Synopsis Product Identification Information Product Type US Brand/Trade Name(s) Brand/Trade Name(s) ex-us Generic Name Main Product Company Code Drug Mirena Mirena LNG IUS Mirena IUS Levonorgestrel BAY86-5028 Other Company Code(s) Chemical Description Other Product Aliases Levonorgestrel: (-)-13-Ethyl-17-hydroxy-18,19-dinor-17alpha-pregn-4-en- 20-yn-3-one Date of last Update/Change: 6 May 2011