1 INDICATIONS AND USAGE Mirena is a progestin-containing intrauterine system (IUS) indicated for: • Prevention of pregnancy for up to 8 years ( 1.1 ) • Treatment of heavy menstrual bleeding for women who choose to use intrauterine contraception as their method of contraception for up to 5 years.

( 1.2 ) 1.1 Contraception Mirena is indicated for prevention of pregnancy for up to 8 years; replace after the end of the eighth year.

1.2 Heavy Menstrual Bleeding Mirena is indicated for the treatment of heavy menstrual bleeding for up to 5 years in women who choose to use intrauterine contraception as their method of contraception; replace after the end of the fifth year if continued treatment of heavy menstrual bleeding is needed.

6 ADVERSE REACTIONS The following serious or otherwise important adverse reactions are discussed in elsewhere in the labeling: • Ectopic Pregnancy [see Warnings and Precautions ( 5.1 )] • Intrauterine Pregnancy [see Warnings and Precautions ( 5.2 )] • Group A Streptococcal Sepsis (GAS) [see Warnings and Precautions ( 5.3 )] • Pelvic Inflammatory Disease [see Warnings and Precautions ( 5.4 )] • Perforation [see Warnings and Precautions ( 5.5 )] • Expulsion [see Warnings and Precautions ( 5.6 )] • Ovarian Cysts [see Warnings and Precautions ( 5.7 )] • Bleeding Pattern Alterations [see Warnings and Precautions ( 5.8 )] The most common adverse reactions (≥10% users) are alterations of menstrual bleeding patterns, abdominal/pelvic pain, amenorrhea, headache/migraine, genital discharge, and vulvovaginitis.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc.

at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data provided in Table 2 reflect the experience with the use of Mirena in the adequate and well-controlled studies as well as in the supportive and uncontrolled studies for contraception and heavy menstrual bleeding (n=5,091).

The data cover more than 12,101 women-years of exposure up to 5 years of use, mainly in the contraception studies (11,761 women-years).

The frequencies of reported adverse drug reactions represent crude incidences.

The most common adverse reactions (≥10% users) are alterations of menstrual bleeding patterns [including unscheduled uterine bleeding (31.9%), decreased uterine bleeding (23.4%), increased scheduled uterine bleeding (11.9%), and female genital tract bleeding (3.5%)], abdominal/pelvic pain (22.6%), amenorrhea (18.4%), headache/migraine (16.3%), genital discharge (14.9%), and vulvovaginitis (10.5%).

Adverse reactions reported in ≥ 5% of users are shown in Table 2.

Table 2: Adverse Reactions ≥ 5% Reported in Clinical Trials with Mirena System Organ Class Adverse Reactions % (N= 5,091) Reproductive system and breast disorders alteration of menstrual bleeding pattern, including: unscheduled uterine bleeding decreased uterine bleeding increased scheduled uterine bleeding female genital tract bleeding 31.9 23.4 11.9 3.5 amenorrhea 18.4 genital discharge 14.9 vulvovaginitis 10.5 breast pain 8.5 benign ovarian cyst and associated complications 7.5 dysmenorrhea 6.4 Gastrointestinal disorders abdominal/pelvic pain 22.6 Nervous system disorders headache/migraine 16.3 Musculoskeletal and connective tissue disorders back pain 7.9 Skin and subcutaneous tissue disorders acne 6.8 Psychiatric disorders depression/depressive mood 6.4 Other adverse reactions occurring in <5% of subjects include alopecia, (partial and complete) device expulsion, hirsutism, nausea, and PID/endometritis.

A separate study with 362 women who have used Mirena for more than 5 years showed a consistent adverse reaction profile in Years 6 through 8 as shown in Table 2.

By the end of Year 8 of use, amenorrhea and infrequent bleeding are experienced by 34% and 26% of users, respectively; irregular bleeding occurs in 10%, frequent bleeding in 3%, and prolonged bleeding in 3% of users.

In this study, 9% of women reported the adverse event of weight gain; it is unknown if the weight gain was caused by Mirena.

6.2 Postmarketing Experience Adverse Reactions from Postmarketing Spontaneous Reports The following adverse reactions have been identified during post approval use of Mirena.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Arterial thrombotic and venous thromboembolic events, including cases of pulmonary embolism, deep vein thrombosis and stroke • Device breakage • Hypersensitivity (including rash, urticaria and angioedema) • Increased blood pressure Reported Adverse Reactions from Postmarketing Studies Assessment of Perforation and Expulsion of Intrauterine Devices (APEX IUD) Study APEX IUD was a large US retrospective cohort study to assess the impact of breastfeeding and timing of postpartum IUD insertion on uterine perforation and IUD expulsion.

The analyses included a total of 326,658 insertions, 30% (97,824 insertions) of which were performed in women with a delivery in the previous 12 months.

For insertions performed in women who had delivered ≤ 52 weeks before IUD insertion, the majority of postpartum insertions, 57.3% (56,047 insertions) occurred between 6 and 14 weeks postpartum.

Breastfeeding data were available in 94,817 insertions performed in women 52 weeks or less after delivery.

The study results indicated that the risk of uterine perforation was highest in women with IUD insertion ≤ 6 weeks postpartum.

Immediate postpartum insertion (0–3 days) findings are limited due to the relatively small number of insertions occurring within this time interval.

Women who were breastfeeding at the time of insertion were at 33% higher risk of perforation (adjusted hazard ratio [HR]=1.33, 95% confidence interval [CI]: 1.07–1.64) compared to women who were not breastfeeding at the time of insertion.

Progressively lower risk of uterine perforation was observed in postpartum time windows beyond 6 weeks, in both breastfeeding and not breastfeeding women.

Table 3 presents the uterine perforation rates for LNG IUS stratified by breastfeeding status and postpartum interval.

Table 3: Uterine Perforation1 rates for LNG IUS, by Breastfeeding Status and Postpartum Interval Breastfeeding at time of insertion Not breastfeeding at time of insertion Postpartum interval at time of insertion Number of events/ insertions Uterine perforation rate per 1,000 insertions Number of events/ insertions Uterine perforation rate per 1,000 insertions 0 to 3 days 8/1,896 4.22 0/277 0.00 4 days to ≤ 6 weeks 120/10,735 11.18 28/2,377 11.78 > 6 to ≤ 14 weeks 268/29,677 9.03 80/12,011 6.66 > 14 to ≤ 52 weeks 43/6,139 7.00 22/9,089 2.42 > 52 weeks or no delivery no data available 243/184,733 1.32 Risk of expulsion was variable over the postpartum intervals through 52 weeks.

Women who were breastfeeding were at 28% lower risk of IUD expulsion (adjusted HR=0.72, 95% CI: 0.64-0.80) compared to women who were not breastfeeding at time of insertion.

Table 4 presents the IUD expulsion rates for LNG IUS stratified by breastfeeding status and postpartum interval.

Table 4: Expulsion1 Rates for LNG IUS, by Breastfeeding Status and Postpartum Interval Breastfeeding at time of insertion Not breastfeeding at time of insertion Postpartum interval at time of insertion Number of events/ insertions Expulsion rate per 1,000 insertions Number of events/ insertions Expulsion rate per 1,000 insertions 0 to 3 days 187/1,896 98.63 12/277 43.32 4 days to ≤ 6 weeks 185/10,735 17.23 52/2,377 21.88 > 6 to ≤ 14 weeks 421/29,677 14.19 306/12,011 25.48 > 14 to ≤ 52 weeks 120/6,139 19.55 273/9,089 30.04 > 52 weeks or no delivery no data available 5,481/184,733 29.67 1 Expulsion includes both complete and partial expulsion