Kyleena

1 INDICATIONS AND USAGE Kyleena is indicated to prevent pregnancy for up to 5 years. Replace the system after 5 years if continued use is desired. Kyleena is a progestin-containing intrauterine system (IUS) indicated for prevention of pregnancy for up to 5 years. ( 1 )

2 DOSAGE AND ADMINISTRATION • Release rate of levonorgestrel (LNG) is 17.5 mcg/day after 24 days and declines to 7.4 mcg/day after 5 years; Kyleena must be removed or replaced after 5 years. ( 2.1 ) • To be inserted by a trained healthcare provider using strict aseptic technique. Follow insertion instructions exactly as described. ( 2.2 ) • Patient should be re-examined and evaluated 4 to 6 weeks after insertion; then yearly or more often if clinically indicated. ( 2.3 ) 2.1 Dosing Over Time Kyleena contains 19.5 mg of levonorgestrel (LNG) released in vivo at a rate of approximately 17.5 mcg/day after 24 days. This rate decreases progressively to 9.8 mcg/day after 1 year and to 7.4 mcg/day after 5 years. The average in vivo release rate of LNG is approximately 12.6 mcg/day over the first year and 9.0 mcg/day over a period of 5 years . [See Clinical Pharmacology ( 12.3 ).] Kyleena must be removed by the end of the fifth year and can be replaced at the time of removal with a new Kyleena if continued contraceptive protection is desired. Kyleena can be physically distinguished from other intrauterine systems (IUSs) by the combination of the visibility of the silver ring on ultrasound and the blue color of the removal threads. Kyleena is supplied in a sterile package within an inserter that enables single-handed loading (see Figure 1). Do not open the package until required for insertion [see Description ( 11.2 )] . Do not use if the seal of the sterile package is broken or appears compromised. Use strict aseptic techniques throughout the insertion procedure [see Warnings and Precautions ( 5.3 )] . Kyleena and Inserter 2.2. Insertion Instructions • Obtain a complete medical and social history to determine conditions that might influence the selection of a levonorgestrel-releasing intrauterine system (LNG IUS) for contraception . If indicated, perform a physical examination and appropriate tests for any forms of genital or other sexually transmitted infections. [See Contraindications ( 4 ) and Warnings and Precautions ( 5.10 ).] Because irregular bleeding/spotting is common during the first months of Kyleena use, exclude endometrial pathology (polyps or cancer) prior to the insertion of Kyleena in women with persistent or uncharacteristic bleeding [see Warnings and Precautions ( 5.8 )] . • Follow the insertion instructions exactly as described to ensure proper placement and avoid premature release of Kyleena from the inserter. Once released, Kyleena cannot be re-loaded . • Check expiration date of Kyleena prior to initiating insertion. • Kyleena should be inserted by a trained healthcare provider. Healthcare providers should become thoroughly familiar with the insertion instructions before attempting insertion of Kyleena. • Insertion may be associated with some pain and/or bleeding or vasovagal reactions (for example, syncope, bradycardia), or with seizure, especially in patients with a predisposition to these conditions. Consider administering analgesics prior to insertion. Timing of Insertion Table 1: When to Insert Kyleena Starting Kyleena in women not currently using hormonal or intrauterine contraception • Insert Kyleena any time there is reasonable certainty that the woman is not pregnant. Consider the possibility of ovulation and conception prior to initiation of this product [see Contraindications ( 4 )]. • If Kyleena is inserted during the first seven days of the menstrual cycle or immediately after a first trimester abortion, back-up contraception is not needed. • If Kyleena is not inserted during the first seven days of the menstrual cycle, a barrier method of contraception should be used, or the patient should abstain from vaginal intercourse for seven days to prevent pregnancy. Switching to Kyleena from an oral, transdermal or vaginal hormonal contraceptive • Insert Kyleena at any time, including during the hormone-free interval of the previous method. • If inserted during active use of the previous method, continue tha…

5 WARNINGS AND PRECAUTIONS • Remove Kyleena if pregnancy occurs with Kyleena in place. If pregnancy occurs, there is increased risk of ectopic pregnancy including loss of fertility, pregnancy loss, septic abortion (including septicemia, shock and death), and premature labor and delivery. ( 5.1 , 5.2 ) • Group A streptococcal infection has been reported following insertion of LNG IUS; strict aseptic technique is essential during insertion. ( 5.3 ) • Before using Kyleena, consider the risks of PID. ( 5.4 ) • Uterine perforation may occur and may reduce contraceptive effectiveness or require surgery. Risk is increased if inserted in lactating women and may be increased if inserted in women with fixed retroverted uteri and postpartum. ( 5.5 ) • Partial or complete expulsion may occur, which can be unnoticed, leading to loss of contraceptive efficacy. ( 5.6 ) • Evaluate persistent enlarged ovarian follicles or ovarian cysts. ( 5.7 ) • Bleeding patterns become altered, may remain irregular and amenorrhea may ensue. ( 5.8 ) • Kyleena can be safely scanned with MRI only under certain conditions. ( 5.11 ) 5.1 Risk of Ectopic Pregnancy Evaluate women for ectopic pregnancy if they become pregnant with Kyleena in place because the likelihood of a pregnancy being ectopic is increased with Kyleena. Approximately one-half of pregnancies that occur with Kyleena in place are likely to be ectopic. Also consider the possibility of ectopic pregnancy in the case of lower abdominal pain, especially in association with missed menses or if an amenorrheic woman starts bleeding. The incidence of ectopic pregnancy in clinical trials with Kyleena, which excluded women with a history of ectopic pregnancy, was approximately 0.2% per year. The risk of ectopic pregnancy in women who have a history of ectopic pregnancy and use Kyleena is unknown. Women with a previous history of ectopic pregnancy, tubal surgery or pelvic infection carry a higher risk of ectopic pregnancy. Ectopic pregnancy may result in loss of fertility. 5.2 Risks with Intrauterine Pregnancy If pregnancy occurs while using Kyleena, remove Kyleena because leaving it in place may increase the risk of spontaneous abortion and preterm labor. Removal of Kyleena or probing of the uterus may also result in spontaneous abortion. In the event of an intrauterine pregnancy with Kyleena, consider the following: Septic abortion In patients becoming pregnant with an IUS in place, septic abortion—with septicemia, septic shock, and death—may occur. Continuation of pregnancy If a woman becomes pregnant with Kyleena in place and if Kyleena cannot be removed or the woman chooses not to have it removed, warn her that failure to remove Kyleena increases the risk of miscarriage, sepsis, premature labor and premature delivery. Advise her of isolated reports of virilization of the female fetus following local exposure to LNG during pregnancy with an LNG IUS in place [see Use in Specific Populations ( 8.1 )] . Follow her pregnancy closely and advise her to report immediately any symptom that suggests complications of the pregnancy. 5.3 Sepsis Severe infection or sepsis, including Group A streptococcal sepsis (GAS), have been reported following insertion of a LNG-releasing IUS. In some cases, severe pain occurred within hours of insertion followed by sepsis within days. Because death from GAS is more likely if treatment is delayed, it is important to be aware of these rare but serious infections. Aseptic technique during insertion of Kyleena is essential in order to minimize serious infections such as GAS. 5.4 Pelvic Infection Promptly examine users with complaints of lower abdominal or pelvic pain, odorous discharge, unexplained bleeding, fever, genital lesions or sores. Remove Kyleena in cases of recurrent endometritis or pelvic inflammatory disease, or if an acute pelvic infection is severe or does not respond to treatment. Pelvic Inflammatory Disease (PID) Kyleena is contraindicated in the presence of known or su…

4 CONTRAINDICATIONS The use of Kyleena is contraindicated when one or more of the following conditions exist: • Pregnancy or suspicion of pregnancy [see Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.1 )] • For use as post-coital contraception (emergency contraception) • Congenital or acquired uterine anomaly, including fibroids, that distorts the uterine cavity • Acute pelvic inflammatory disease (PID) or a history of PID unless there has been a subsequent intrauterine pregnancy [see Warnings and Precautions ( 5.4 )] • Postpartum endometritis or infected abortion in the past 3 months • Known or suspected uterine or cervical malignancy • Known or suspected breast cancer or other progestin-sensitive cancer, now or in the past • Uterine bleeding of unknown etiology • Untreated acute cervicitis or vaginitis, including bacterial vaginosis or other lower genital tract infections until infection is controlled • Acute liver disease or liver tumor (benign or malignant) • Conditions associated with increased susceptibility to pelvic infections [see Warnings and Precautions ( 5.4 )] • A previously inserted intrauterine device (IUD) that has not been removed • Hypersensitivity to any component of this product [see Adverse Reactions ( 6.2 ) and Description ( 11.1 )] • Pregnancy or suspicion of pregnancy. Cannot be used for post-coital contraception (emergency contraception) ( 4 ) • Congenital or acquired uterine anomaly if it distorts the uterine cavity ( 4 ) • Acute pelvic inflammatory disease (PID) or a history of PID unless there has been a subsequent intrauterine pregnancy ( 4 ) • Postpartum endometritis or infected abortion in the past 3 months ( 4 ) • Known or suspected uterine or cervical malignancy ( 4 ) • Known or suspected breast cancer or other progestin-sensitive cancer ( 4 ) • Uterine bleeding of unknown etiology ( 4 ) • Untreated acute cervicitis or vaginitis or other lower genital tract infections ( 4 ) • Acute liver disease or liver tumor (benign or malignant) ( 4 ) • Increased susceptibility to pelvic infection ( 4 ) • A previous intrauterine device (IUD) that has not been removed ( 4 ) • Hypersensitivity to any component of Kyleena ( 4 )

7 DRUG INTERACTIONS No drug-drug interaction studies have been conducted with Kyleena. Drugs or herbal products that induce or inhibit LNG metabolizing enzymes, including CYP3A4, may decrease or increase, respectively, the serum concentrations of LNG during the use of Kyleena. However, the contraceptive effect of Kyleena is mediated via the direct release of LNG into the uterine cavity and is unlikely to be affected by drug interactions via enzyme induction or inhibition.

8.1 Pregnancy Risk Summary The use of Kyleena is contraindicated in pregnancy or with a suspected pregnancy and Kyleena may cause adverse pregnancy outcomes [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 , 5.2 )]. If a woman becomes pregnant with Kyleena in place, the likelihood of ectopic pregnancy is increased and there is an increased risk of miscarriage, sepsis, premature labor, and premature delivery . Remove Kyleena, if possible, if pregnancy occurs in a woman using Kyleena. If Kyleena cannot be removed, follow the pregnancy closely [see Warnings and Precautions ( 5.1 , 5.2 )] . There have been isolated cases of virilization of the external genitalia of the female fetus following local exposure to LNG during pregnancy with an LNG IUS in place. Animal reproduction studies have not been conducted with Kyleena.

6 ADVERSE REACTIONS The following serious or otherwise important adverse reactions are discussed 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 reported (≥ 5% users) were vulvovaginitis, ovarian cysts, abdominal pain/pelvic pain, headache/migraine, acne/seborrhea, dysmenorrhea/uterine spasm, breast pain/breast discomfort, and increased bleeding. ( 6 ) 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 described below reflect exposure of 1,697 healthy 18 to 41-year-old women (mean age 27.8 ± 5.2 years) to Kyleena. These data come from two multi-center contraceptive trials: A phase 2 study with a 3-year duration was conducted in Europe enrolling generally healthy, 21 to 41-year old women; 217 subjects were exposed to Kyleena for one year and 174 completed three years. The data in this trial cover approximately 8,000 cycles of exposure. A phase 3 study with a 3-year duration and an optional extension of Kyleena use up to 5 years was conducted in the United States (US), Canada, Europe, and Latin America. The population was generally healthy, 18 to 35-year old women. A total of 1,208 subjects were exposed to Kyleena for at least one year; 707 women entered the optional extension phase after 3 years and 550 completed five years. The data in this trial cover approximately 60,000 cycles. In total for both studies, 1,425 subjects were exposed for at least 1 year, and 550 subjects completed 5 years of use. Of the total of 1,697 subjects exposed to Kyleena, 563 were from the US and 1,134 were from Europe, Canada and Latin America; 623 (37%) were nulliparous (mean age 24.6 ± 4.5 years) and 1,074 (63%) were parous (mean age 29.7 ± 4.7 years). Most women who received Kyleena were Caucasian (83%) or Black/African American (4.4%); 9.4% of women were of Hispanic ethnicity. The clinical trials had no upper or lower weight or body mass index (BMI) limit. Mean BMI of Kyleena subjects was 25.2 kg/m2 (range 15.2 – 57.6 kg/m2); 16% had a BMI ≥ 30 kg/m2, and 2.0% had a BMI ≥ 40 kg/m2. The frequencies of reported adverse drug reactions represent crude incidences. The most common adverse reactions (occurring in ≥ 5% users) were vulvovaginitis (24%), ovarian cyst (22%), abdominal pain/pelvic pain (21%), headache/migraine (15%), acne/seborrhea (15%), dysmenorrhea/uterine spasm (10%), breast pain/breast discomfort (10%), and increased bleeding (8%). In the combined studies, 22% discontinued prematurely due to an adverse reaction. The most common adverse reactions (>1%) leading to discontinuation were increased bleeding (4.5%), abdominal pain/pelvic pain (4.2%), device expulsion (3.1%), acne/seborrhea (2.3%), and dysmenorrhea/uterine spasm (1.3%). Common adverse reactions (occurring in ≥1% users) are summarized in Table 4 (presented as crude incidences). Table 4: Adverse reactions that occurred in at least 1% of Kyleena users in clinical trials by System Organ Class (SOC) System Organ Class Adverse Reaction Incidence (%) (N=1,697) Reproductive System and Breast Disorders Vulvovaginitis 24.3 Ovarian cyst a 22.2 Dysmenorrhea/uterine spasm 8.0/2.4 Incr…