Regulatory Decision Summary for Mirena

This Supplement to a New Drug Submission (SNDS) was submitted by Bayer Inc. to obtain market authorization to extend the conception control indication for Mirena (levonorgestrel-releasing intrauterine system, 52 mg) from 5 years to 8 years. Upon review, the proposed extension for contraception was approved. The treatment of idiopathic menorrhagia remains for up to 5 years only.

The contraceptive efficacy of Mirena for an additional 3-years of use beyond 5 years was studied in the Mirena Extension Trial (MET; protocol 18649), a multi-center, open-label, uncontrolled study conducted in the United States. The trial enrolled women 18 to 35 years of age who had been using Mirena for not less than 4.5 years and not more than 5 years at enrollment. The population consisted of 362 women.

The pregnancy rate calculated as the Pearl Index (PI) was the primary efficacy endpoint used to assess contraceptive efficacy. The PI was based on 28-day equivalent exposure cycles; evaluable cycles excluded those in which back-up contraception was used unless a pregnancy occurred in that cycle. The PI for the 6th year of use based on the 1 pregnancy that occurred during Year 6 and within 7 days after Mirena removal or expulsion and 3,870 evaluable cycles was 0.34 with a 95% upper confidence limit of 1.88, and the PI for the 7th year of use based on the 1 pregnancy that occurred during Year 7 and within 7 days after Mirena removal or expulsion and 3,232 evaluable cycles was 0.40 with a 95% upper confidence limit of 2.25. The PI for the 8th year of use based on no pregnancies occurring during Year 8 and within 7 days after Mirena removal or expulsion and 2,534 evaluable cycles was 0.00 with a 95% upper confidence limit of 1.90. The cumulative 3-year pregnancy rate for Years 6, 7 and 8 was estimated by the Kaplan-Meier method. Based on 2 pregnancies (1 in Year 6 and 1 in Year 7) and 10,216 exposure cycles, the cumulative pregnancy rate at the end of the 3-year period of extended use (Years 6, 7 and 8) was 0.68% with a 95% upper confidence limit of 2.71%.

Thus, in this submission, the sponsor has demonstrated that the use of Mirena intrauterine system (IUS) maintained substantial evidence of contraceptive effectiveness (i.e., PI<1) for an additional 3 years of use.

With respect to safety, 362 subjects started the 3-year extension treatment were included in the safety analyses. In the MET study, no deaths occurred during Years 6, 7, and 8 of Mirena use. The most frequent treatment-emergent adverse events (TEAEs) were weight increased (9.1%), bacterial vaginosis (7.5%), urinary tract infection (7.5%), and nasopharyngitis (5.8%). Treatment-emergent adverse events in the additional 3 years of use were generally similar to those encountered in previous 5-year studies, with increased reporting of weight gain and anxiety. The most frequent study drug related TEAEs were heavy menstrual bleeding, vaginal hemorrhage, and pelvic pain (n = 8, 2.2% each).

Adverse events of special interest associated with levonorgestrel IUSs that are considered clinically significant include uterine perforation, device expulsion, pelvic infection (including pelvic inflammatory disease, endometritis, and sepsis), ovarian cysts, ectopic pregnancy, device breakage, and bleeding pattern alteration.

In the MET study, 4 women were diagnosed with uterine perforation during the study (1 reported as preferred term [PT] embedded device [0.3%], and 3 as PT uterine perforation [0.8%]). For 3 of the 4 women with uterine perforation in this study, Mirena was inserted 1 to 2 months after the woman had given birth, and 2 of them were breastfeeding at the time. Two cases were diagnosed during Year 7. Two cases were diagnosed at the end of the 3-year treatment period (year 8) when the women were presenting for removal of the IUS. The overall uterine perforation rate in this MET study was 1.1%. It is labeled in the PM that the risk of uterine perforation was highest when insertion occurred within ≤ 6 weeks postpartum and also higher with breastfeeding at the time of insertion. The observed perforation rate in this MET study is reflective of the higher background/baseline risk in this study population (who had their Mirena placed outside of a controlled study setting). There was a total of 5 (1.4%) device expulsions during the study: 2 partial expulsions during Year 6 of Mirena use, and 2 partial and 1 total expulsions during Year 7 of Mirena use. No expulsion occurred in Year 8 of Mirena use. There were no cases of confirmed pelvic inflammatory disease (PID) during Years 6-8 of Mirena use. There was one suspected case of PID. Eight women (2.2%) were reported to experience ovarian cysts. None of these cysts required treatment or led to subject discontinuation. One case of ectopic pregnancy was reported in Year 7 and one case of spontaneous abortion was reported in Year 6. Device breakage was reported in 3 cases, each associated with a difficult removal during the scheduled Year 8 removal of Mirena. 2 cases of breakage occurred in the 2 cases of perforation that required removal via surgery (hysteroscopy in one, laparoscopy in the other). A third breakage was reported in association with a difficult removal (not associated with a uterine perforation). Uterine bleeding patterns and amenorrhea were consistent with previous Mirena 5 years of use.

In summary, the safety from the MET trial showed a consistent adverse reaction profile in Years 6 through 8 as was shown in the previous 5-year study. The overall treatment-emergent AEs and SAEs during the MET study were consistent with what were observed in other clinical trials of Mirena use up to 5 years. There were no unexpected findings with regards to treatment-emergent adverse events (AEs) and serious adverse events (SAEs).

To support the safety of Mirena use beyond five years, the sponsor compiled and submitted evaluations of AEs in post marketing reports with documentation of over five years of continuous Mirena use (three reports cover between 2013 and 2021). The Sponsor’s three Post marketing Reports indicated that no other unexpected safety signals were identified that might indicate an altered safety profile of Mirena when used for more than 5 years.

In conclusion, the overall efficacy and safety findings from the MET study for Years 6, 7 and 8 of Mirena use and collectively from post-marketing experience support the approval of Mirena for prevention of pregnancy for up to 8 years of use. The potential and identified adverse events are addressed in the Product Monograph (PM). A Risk Management Plan has also been established to monitor known and potential safety issues and minimize associated risks. There were no issues precluding the recommendation for approval reported by the disciplines reviewing this SNDS (Bureau of Pharmaceutical Sciences, Division of Biopharmaceutics Evaluation, Medical Devices Directorate, Clinical Pharmacology and Clinical Efficacy/Safety, Labelling and Marketed Health Products Directorate). The review team concluded that the benefit-risk balance remains positive for Mirena when prescribed within the recommended conditions of use outlined in the PM.

For further details about Mirena, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.