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 Increased bleeding b 7.9 Breast pain/discomfort 7.1/3.5 Genital discharge 4.5 Device expulsion (complete and partial) 3.5 Upper genital tract infection 1.5 Gastrointestinal Disorders Abdominal pain/pelvic pain 13.3/8.2 Nausea 4.7 Skin and Subcutaneous Tissue Disorders Acne/Seborrhea 14.1/1.8 Alopecia 1.0 Nervous System Disorders Headache/Migraine 12.9/3.3 Psychiatric Disorders Depression/ Depressed mood 4.4/0.2 a Ovarian cysts were reported as adverse events if they were abnormal, non-functional cysts and/or had a diameter >3 cm on ultrasound examination b Not all bleeding alterations were captured as adverse reactions [see Warnings and Precautions ( 5.8 )] . In the clinical trials, serious adverse reactions occurring in more than a single subject included: ectopic pregnancy/ruptured ectopic pregnancy (10 subjects); pelvic inflammatory disease (6 subjects); missed abortion/incomplete spontaneous abortion/spontaneous abortion (4 subjects); ovarian cyst (3 subjects); abdominal pain (4 subjects); depression/affective disorder (4 subjects); and uterine perforation/embedded device (myometrial perforation) (3 subjects). 6.2 Postmarketing Experience Adverse Reactions from Postmarketing Spontaneous Reports The following adverse reactions have been identified during post-approval use of LNG-releasing IUSs. 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 5 presents the uterine perforation rates for LNG IUS stratified by breastfeeding status and postpartum interval. Table 5: Uterine Perforation 1 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 30/12,011 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 1 Uterine perforation includes both complete and partial perforation 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 6 presents the IUD expulsion rates for LNG IUS stratified by breastfeeding status and postpartum interval. Table 6: Expulsion 1 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

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 )

11 DESCRIPTION Kyleena (levonorgestrel-releasing intrauterine system) contains 19.5 mg of LNG, a progestin, and is intended to provide an initial release rate of approximately17.5 mcg/day of LNG after 24 days. Levonorgestrel USP, (-)-13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one, the active ingredient in Kyleena, has a molecular weight of 312.4, a molecular formula of C 21 H 28 O 2 , and the following structural formula: 11.1 Kyleena Kyleena consists of a T-shaped polyethylene frame (T-body) with a steroid reservoir (hormone elastomer core) around the vertical stem. The white T-body has a loop at one end of the vertical stem and two horizontal arms at the other end. The reservoir consists of a whitish or pale yellow cylinder, made of a mixture of LNG and silicone (polydimethylsiloxane), containing a total of 19.5 mg LNG. The reservoir is covered by a semi-opaque silicone membrane, composed of polydimethylsiloxane and colloidal silica. A ring composed of 99.95% pure silver is located at the top of the vertical stem close to the horizontal arms and is visible by ultrasound. The polyethylene of the T-body is compounded with barium sulfate, which makes it radiopaque. A monofilament blue polypropylene removal thread is attached to a loop at the end of the vertical stem of the T-body. The polypropylene of the removal thread contains <0.5% phthalocyaninato(2-) copper as a colorant (see Figure 10). The components of Kyleena, including its packaging, are not manufactured using natural rubber latex. Figure 10. Kyleena Kyleena 11.2 Inserter Kyleena is packaged sterile within an inserter. The inserter (Figure 11), which is used for insertion of Kyleena into the uterine cavity, consists of a symmetric two-sided body and slider that are integrated with flange, lock, pre-bent insertion tube and plunger. The outer diameter of the insertion tube is 3.8 mm. The vertical stem of Kyleena is loaded in the insertion tube at the tip of the inserter. The arms are pre-aligned in the horizontal position. The removal threads are contained within the insertion tube and handle. Once Kyleena has been placed, the inserter is discarded. Figure 11. Diagram of Inserter Inserter Chem Diagram

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 that method for 7 days after Kyleena insertion or until the end of the current treatment cycle. • If the woman was using continuous hormonal contraception, discontinue that method seven days after Kyleena insertion. Switching to Kyleena from an injectable progestin contraceptive • Insert Kyleena at any time; a non-hormonal back-up birth control (such as condoms or spermicide) should also be used for 7 days if Kyleena is inserted more than 3 months (13 weeks) after the last injection. Switching to Kyleena from a contraceptive implant or another IUS • Insert Kyleena on the same day the implant or IUS is removed. • Insert Kyleena at any time during the menstrual cycle. Inserting Kyleena after first trimester abortion or miscarriage • Insert Kyleena immediately after a first-trimester abortion or miscarriage, unless it is a septic abortion [see Contraindications ( 4 )]. Inserting Kyleena after childbirth or second-trimester abortion or miscarriage • Immediate insertion after childbirth or second-trimester abortion or miscarriage • Insert Kyleena after removal of the placenta. Back-up contraception is not needed. [See Contraindications (4), Warnings and Precautions (5.5, 5.6), Adverse Reactions (6.2)]. • Interval insertion following complete involution of the uterus • Wait a minimum of 6 weeks or until the uterus is fully involuted before inserting Kyleena [see Warnings and Precautions ( 5.5 , 5.6 ), Adverse Reactions ( 6.2 )]. • Insert Kyleena any time there is reasonable certainty the woman is not pregnant. • If Kyleena is not inserted during the first 7 days of the menstrual cycle, a back-up method of contraception should be used, or the woman should abstain from vaginal intercourse for 7 days to prevent pregnancy [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )]. Tools for Insertion Note: The inserter provided with Kyleena (see Figure 1) and the Insertion Procedure described in this section are not applicable for immediate insertion after childbirth or second-trimester abortion or miscarriage. For immediate insertion, remove Kyleena from the inserter by first loading (see Figure 2) and then releasing (see Figure 7) Kyleena from the inserter, and insert according to accepted practice. Preparation • Gloves • Speculum • Sterile uterine sound • Sterile tenaculum • Antiseptic solution, applicator Procedure • Sterile gloves • Kyleena with inserter in sealed package • Instruments and anesthesia for paracervical block, if anticipated • Consider having an unopened back-up Kyleena available • Sterile, sharp curved scissors Preparation for insertion • Exclude pregnancy and confirm that there are no other contraindications to the use of Kyleena. • With the patient comfortably in lithotomy position, do a bimanual exam to establish the size, shape and position of the uterus. • Gently insert a speculum to visualize the cervix. • Thoroughly cleanse the cervix and vagina with a suitable antiseptic solution. • Prepare to sound the uterine cavity. Grasp the upper lip of the cervix with a tenaculum forceps and gently apply traction to stabilize and align the cervical canal with the uterine cavity. Perform a paracervical block if needed. If the uterus is retroverted, it may be more appropriate to grasp the lower lip of the cervix. The tenaculum should remain in position and gentle traction on the cervix should be maintained throughout the insertion procedure. • Gently insert a uterine sound to check the patency of the cervix, measure the depth of the uterine cavity in centimeters, confirm cavity direction, and detect the presence of any uterine anomaly. If you encounter difficulty or cervical stenosis, use dilatation, and not force, to overcome resistance. If cervical dilatation is required, consider using a paracervical block. Insertion Procedure Proceed with insertion only after completing the above steps and ascertaining that the patient is appropriate for Kyleena. Ensure use of aseptic technique throughout the entire procedure . Step 1–Opening of the package • Open the package (Figure 1). The contents of the package are sterile. Figure 1. Opening the Kyleena Package • Using sterile gloves, lift the handle of the sterile inserter and remove from the sterile package. Package Step 2–Load Kyleena into the insertion tube • Push the slider forward as far as possible in the direction of the arrow, thereby moving the insertion tube over the Kyleena T-body to load Kyleena into the insertion tube (Figure 2). The tips of the arms will meet to form a rounded end that extends slightly beyond the insertion tube. Figure 2. Move slider all the way to the forward position to load Kyleena • Maintain forward pressure with your thumb or forefinger on the slider . DO NOT move the slider downward at this time as this may prematurely release the threads of Kyleena. Once the slider is moved below the mark, Kyleena cannot be re-loaded . Load Kyleena Step 3–Setting the Flange • Holding the slider in this forward position, set the upper edge of the flange to correspond to the uterine depth (in centimeters) measured during sounding (Figure 3). Figure 3. Setting the flange Setting Flange Step 4–Kyleena is now ready to be inserted • Continue holding the slider in this forward position. Advance the inserter through the cervix until the flange is approximately 1.5–2 cm from the cervix and then pause (Figure 4). Figure 4. Advancing insertion tube until flange is 1.5 to 2 cm from the cervix Do not force the inserter. If necessary, dilate the cervical canal. Advancing Flange Step 5–Open the arms • While holding the inserter steady, move the slider down to the mark to release the arms of Kyleena (Figure 5). Wait 10 seconds for the horizontal arms to open completely. Figure 5. Move the slider back to the mark to release and open the arms Back to Mark Step 6–Advance to fundal position Advance the inserter gently towards the fundus of the uterus until the flange touches the cervix . If you encounter fundal resistance do not continue to advance. Kyleena is now in the fundal position (Figure 6). Fundal positioning of Kyleena is important to prevent expulsion . Figure 6. Move Kyleena into the fundal position Funda Position Step 7–Release Kyleena and withdraw the inserter • Holding the entire inserter firmly in place, release Kyleena by moving the slider all the way down (Figure 7). Figure 7. Move the slider all the way down to release Kyleena from the insertion tube • Continue to hold the slider all the way down while you slowly and gently withdraw the inserter from the uterus. • Using a sharp, curved scissor, cut the threads perpendicular, leaving about 3 cm visible outside of the cervix [cutting threads at an angle may leave sharp ends (Figure 8)]. Do not apply tension or pull on the threads when cutting to prevent displacing Kyleena. Figure 8. Cutting the threads Kyleena insertion is now complete. Prescribe analgesics, if indicated. Record the Kyleena lot number in the patient records. Moving Slider Cutting Threads Important information to consider during or after insertion • If you suspect that Kyleena is not in the correct position, check placement (for example, using transvaginal ultrasound). Remove Kyleena if it is not positioned completely within the uterus. Do not reinsert a removed Kyleena. • If there is clinical concern, exceptional pain or bleeding during or after insertion, take appropriate steps (such as physical examination and ultrasound) immediately to exclude perforation. 2.3 Patient Follow-up • Reexamine and evaluate patients 4 to 6 weeks after insertion and once a year thereafter, or more frequently if clinically indicated. 2.4 Removal of Kyleena Timing of Removal • Kyleena should not remain in the uterus after 5 years. • If pregnancy is not desired, remove Kyleena during the first 7 days of the menstrual cycle, provided the woman is still experiencing regular menses. If removal will occur at other times during the cycle or the woman does not experience regular menses, she is at risk of pregnancy; start a new contraceptive method a week prior to removal for these women. [See Dosage and Administration ( 2.5 ).] Tools for Removal Preparation • Gloves • Speculum Procedure • Sterile forceps Removal Procedure • Remove Kyleena by applying gentle traction on the threads with forceps (Figure 9). Figure 9. Removal of Kyleena • If the threads are not visible, determine location of Kyleena by ultrasound [see Warnings and Precautions ( 5.10 )] . • If Kyleena is found to be in the uterine cavity on ultrasound exam, it may be removed using a narrow forceps, such as an alligator forceps. This may require dilation of the cervical canal. After removal of Kyleena, examine the system to ensure that it is intact. • Removal may be associated with some pain and/or bleeding or vasovagal reactions (for example, syncope, bradycardia) or seizure, especially in patients with a predisposition to these conditions. Removal 2.5 Continuation of Contraception after Removal • If pregnancy is not desired and if a woman wishes to continue using Kyleena, a new system can be inserted immediately after removal any time during the cycle. • If a patient with regular cycles wants to start a different contraceptive method, time removal and initiation of the new method to ensure continuous contraception. Either remove Kyleena during the first 7 days of the menstrual cycle and start the new method immediately thereafter or start the new method at least 7 days prior to removing Kyleena if removal is to occur at other times during the cycle. • If a patient with irregular cycles or amenorrhea wants to start a different contraceptive method, start the new method at least 7 days before removal.

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 )

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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The local mechanism by which continuously released LNG contributes to the contraceptive effectiveness of Kyleena has not been conclusively demonstrated. Studies of Kyleena and similar LNG IUS prototypes have suggested several mechanisms that prevent pregnancy: thickening of cervical mucus preventing passage of sperm into the uterus, inhibition of sperm capacitation or survival, and alteration of the endometrium . 12.2 Pharmacodynamics Kyleena has mainly local progestogenic effects in the uterine cavity. The local concentrations of LNG lead to morphological changes including stromal pseudodecidualization, glandular atrophy, a leukocytic infiltration and a decrease in glandular and stromal mitoses. In clinical trials with Kyleena, ovulation was assessed based on serum progesterone values >2.5 ng/mL in one study and serum progesterone values >2.5 ng/mL together with serum estradiol levels <27.24 pg/mL in another study. Evidence of ovulation by these criteria was seen in 23 out of 26 women in the first year, in 19 out of 20 women in the second year, and in all 16 women in the third year . In the fourth year, evidence of ovulation was observed in the one woman remaining in the subset and in the fifth year, no women remained in this subset. 12.3 Pharmacokinetics Absorption Low doses of LNG are administered into the uterine cavity with the Kyleena intrauterine delivery system. The in vivo release rate is approximately 17.5 mcg/day after 24 days and is reduced to approximately 15.3 mcg/day after 60 days and to 9.8 mcg/day after 1 year. It then declines progressively to approximately 7.9 mcg/day after 3 years and 7.4 mcg/day after 5 years. The average LNG in vivo release rate is approximately 12.6 mcg/day over the first year and 9.0 mcg/day over the period of 5 years. In a subset of 6 subjects, the maximum observed serum LNG concentration (mean ±SD) was 302 ± 170 pg/mL, reached after 7.5 days (median) of Kyleena insertion. Thereafter, the LNG serum concentrations (mean ±SD) at Year 1, 2, 3, 4 and 5 were 199 ± 171 pg/mL (N=6), 120 ± 57 pg/mL (N=6), 122 ± 65 pg/mL (N=6), 79 ± 12 pg/mL (N=3) and 65 ± 15 pg/mL (N=3), respectively. A population pharmacokinetic evaluation based on a broader database (>1000 patients) showed a similar declining concentration profile, with 175 ± 74 pg/mL at 7 days after placement, 125 ± 50 pg/mL at 1 year, 99 ± 41 pg/mL after 3 years, and 90 ± 35 pg/mL after 5 years. Distribution The apparent volume of distribution of LNG is reported to be approximately 1.8 L/kg. LNG is bound non-specifically to serum albumin and specifically to sex hormone binding globulin (SHBG). Accordingly, changes in the concentration of SHBG in serum result in an increase (at higher SHBG concentration) or a decrease (at lower SHBG concentration) of the total LNG concentration in serum. In a subset of 6 subjects, the concentration of SHBG declined on average by about 30% during the first 3 months after insertion of Kyleena and remained relatively stable over the 5 year period of use. Less than 2% of the circulating LNG is present as free steroid. Elimination Following intravenous administration of 0.09 mg LNG to healthy volunteers, the total clearance of LNG is approximately 1 mL/min/kg and the elimination half-life is approximately 20 hours. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for wide individual variations in LNG concentrations seen in individuals using LNG–containing contraceptive products. Metabolism Following absorption, LNG is extensively metabolized. The most important metabolic pathways are the reduction of the Δ4-3-oxo group and hydroxylations at positions 2α, 1β and 16β, followed by conjugation. Significant amounts of conjugated and unconjugated 3α, 5β- are also present in serum, along with much smaller amounts of 3α, 5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. CYP3A4 is the main enzyme involved in the oxidative metabolism of LNG. Excretion LNG and its phase I metabolites are excreted primarily as glucuronide conjugates. About 45% of LNG and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. Specific Populations Pediatric: Safety and efficacy of Kyleena have been established in women of reproductive age. Use of this product before menarche is not indicated. Geriatric: Kyleena has not been studied in women over age 65 and is not approved for use in this population . Race: No studies have evaluated the effect of race on the pharmacokinetics of Kyleena. Hepatic Impairment: No studies were conducted to evaluate the effect of hepatic disease on the disposition of Kyleena . Renal Impairment: No formal studies were conducted to evaluate the effect of renal disease on the disposition of Kyleena. Drug-Drug Interactions No drug-drug interaction studies were conducted with Kyleena [see Drug Interactions ( 7 )] .

12.1 Mechanism of Action The local mechanism by which continuously released LNG contributes to the contraceptive effectiveness of Kyleena has not been conclusively demonstrated. Studies of Kyleena and similar LNG IUS prototypes have suggested several mechanisms that prevent pregnancy: thickening of cervical mucus preventing passage of sperm into the uterus, inhibition of sperm capacitation or survival, and alteration of the endometrium .

12.2 Pharmacodynamics Kyleena has mainly local progestogenic effects in the uterine cavity. The local concentrations of LNG lead to morphological changes including stromal pseudodecidualization, glandular atrophy, a leukocytic infiltration and a decrease in glandular and stromal mitoses. In clinical trials with Kyleena, ovulation was assessed based on serum progesterone values >2.5 ng/mL in one study and serum progesterone values >2.5 ng/mL together with serum estradiol levels <27.24 pg/mL in another study. Evidence of ovulation by these criteria was seen in 23 out of 26 women in the first year, in 19 out of 20 women in the second year, and in all 16 women in the third year . In the fourth year, evidence of ovulation was observed in the one woman remaining in the subset and in the fifth year, no women remained in this subset.

12.3 Pharmacokinetics Absorption Low doses of LNG are administered into the uterine cavity with the Kyleena intrauterine delivery system. The in vivo release rate is approximately 17.5 mcg/day after 24 days and is reduced to approximately 15.3 mcg/day after 60 days and to 9.8 mcg/day after 1 year. It then declines progressively to approximately 7.9 mcg/day after 3 years and 7.4 mcg/day after 5 years. The average LNG in vivo release rate is approximately 12.6 mcg/day over the first year and 9.0 mcg/day over the period of 5 years. In a subset of 6 subjects, the maximum observed serum LNG concentration (mean ±SD) was 302 ± 170 pg/mL, reached after 7.5 days (median) of Kyleena insertion. Thereafter, the LNG serum concentrations (mean ±SD) at Year 1, 2, 3, 4 and 5 were 199 ± 171 pg/mL (N=6), 120 ± 57 pg/mL (N=6), 122 ± 65 pg/mL (N=6), 79 ± 12 pg/mL (N=3) and 65 ± 15 pg/mL (N=3), respectively. A population pharmacokinetic evaluation based on a broader database (>1000 patients) showed a similar declining concentration profile, with 175 ± 74 pg/mL at 7 days after placement, 125 ± 50 pg/mL at 1 year, 99 ± 41 pg/mL after 3 years, and 90 ± 35 pg/mL after 5 years. Distribution The apparent volume of distribution of LNG is reported to be approximately 1.8 L/kg. LNG is bound non-specifically to serum albumin and specifically to sex hormone binding globulin (SHBG). Accordingly, changes in the concentration of SHBG in serum result in an increase (at higher SHBG concentration) or a decrease (at lower SHBG concentration) of the total LNG concentration in serum. In a subset of 6 subjects, the concentration of SHBG declined on average by about 30% during the first 3 months after insertion of Kyleena and remained relatively stable over the 5 year period of use. Less than 2% of the circulating LNG is present as free steroid. Elimination Following intravenous administration of 0.09 mg LNG to healthy volunteers, the total clearance of LNG is approximately 1 mL/min/kg and the elimination half-life is approximately 20 hours. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for wide individual variations in LNG concentrations seen in individuals using LNG–containing contraceptive products. Metabolism Following absorption, LNG is extensively metabolized. The most important metabolic pathways are the reduction of the Δ4-3-oxo group and hydroxylations at positions 2α, 1β and 16β, followed by conjugation. Significant amounts of conjugated and unconjugated 3α, 5β- are also present in serum, along with much smaller amounts of 3α, 5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. CYP3A4 is the main enzyme involved in the oxidative metabolism of LNG. Excretion LNG and its phase I metabolites are excreted primarily as glucuronide conjugates. About 45% of LNG and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. Specific Populations Pediatric: Safety and efficacy of Kyleena have been established in women of reproductive age. Use of this product before menarche is not indicated. Geriatric: Kyleena has not been studied in women over age 65 and is not approved for use in this population . Race: No studies have evaluated the effect of race on the pharmacokinetics of Kyleena. Hepatic Impairment: No studies were conducted to evaluate the effect of hepatic disease on the disposition of Kyleena . Renal Impairment: No formal studies were conducted to evaluate the effect of renal disease on the disposition of Kyleena. Drug-Drug Interactions No drug-drug interaction studies were conducted with Kyleena [see Drug Interactions ( 7 )] .

20230131

10

3 DOSAGE FORMS AND STRENGTHS Kyleena is a LNG-releasing IUS (a type of intrauterine device, or IUD) consisting of a T-shaped polyethylene frame with a steroid reservoir containing a total of 19.5 mg LNG. • One sterile intrauterine system consisting of a T-shaped polyethylene frame with a steroid reservoir containing 19.5 mg levonorgestrel, packaged within a sterile inserter ( 3 )

Kyleena Levonorgestrel LEVONORGESTREL LEVONORGESTREL DIMETHICONE BARIUM SULFATE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility [See Warnings and Precautions ( 5.9 ).]

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility [See Warnings and Precautions ( 5.9 ).]

NDA208224

Kyleena

Levonorgestrel

50419-424

HUMAN PRESCRIPTION DRUG

INTRAUTERINE

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 50419-424-011 Sterile Unit Rx only www.kyleena.com IMPORTANT: To be inserted in the uterus by or under the supervision of a licensed clinician. See physician insert for detailed instructions for use. Kyleena (levonorgestrel-releasing intrauterine system) — 19.5 mg levonorgestrel — 1 sterile unit — intrauterine use Kyleena Carton

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). • Sexually Transmitted Infections: Advise the patient that this product does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs). • Risk of Ectopic Pregnancy: Advise the patient about the risks of ectopic pregnancy, including the loss of fertility. Teach her to recognize and report to her healthcare provider promptly any symptoms of ectopic pregnancy. [See Warnings and Precautions ( 5.1 ).] • Risks of Intrauterine Pregnancy: Advise the patient to contact her healthcare provider if she thinks she might be pregnant. Inform the patient about the risks of intrauterine pregnancy while using Kyleena, including the risks of leaving Kyleena in place and the risks of removing Kyleena or probing of the uterus. If Kyleena cannot be removed in a pregnant patient, advise her to report immediately any symptom that suggests complications of the pregnancy. 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 Warnings and Precautions ( 5.2 ) and Use in Special Populations ( 8.1 ).] • Sepsis: Advise the patient that severe infection or sepsis, including Group A streptococcal sepsis (GAS), can occur within the first few days after Kyleena is inserted. Instruct her to contact a healthcare provider immediately if she develops severe pain or fever shortly after Kyleena is inserted. [See Warnings and Precautions ( 5.3 ).] • Pelvic Infection: Advise the patient about the possibility of pelvic infections, including PID, and that these infections can cause tubal damage leading to ectopic pregnancy or infertility, or infrequently can necessitate hysterectomy, or cause death. Teach patients to recognize and report to their healthcare provider promptly any symptoms of pelvic infection. These symptoms include development of menstrual disorders (prolonged or heavy bleeding), unusual vaginal discharge, abdominal or pelvic pain or tenderness, dyspareunia, chills, and fever. [See Warnings and Precautions ( 5.4 ).] • Perforation and Expulsion: Advise the patient that the IUS may be expelled from or perforate the uterus and instruct her on how she can check that the threads still protrude from the cervix. Inform her that excessive pain or vaginal bleeding during Kyleena placement, worsening pain or bleeding after placement, or the inability to feel Kyleena strings may occur with Kyleena perforation and expulsion. Caution her not to pull on the threads and displace Kyleena. Inform her that there is no contraceptive protection if Kyleena is displaced or expelled. Instruct the patient to contact her healthcare provider if she cannot feel the threads and to avoid intercourse or use a non-hormonal back-up birth control (such as condoms or spermicide) until the location of Kyleena has been confirmed. Advise her that if perforation occurs, Kyleena will have to be located and removed; surgery may be required. [See Warnings and Precautions ( 5.5 , 5.6 , 5.10 ).] • Ovarian Cysts: Advise the patient regarding the risk of ovarian cysts and that cysts can cause clinical symptoms including pelvic pain, abdominal pain or dyspareunia. Advise the patient to contact her healthcare provider if she experiences these symptoms. [See Warnings and Precautions ( 5.7 ).] • Bleeding Pattern Alterations: Advise the patient that irregular or prolonged bleeding and spotting, and/or cramps may occur during the first few weeks after insertion. Inform the patient that, during the first 6 months of Kyleena use, the number of bleeding and spotting days may be higher and bleeding patterns may be irregular. If her symptoms continue or are severe she should report them to her healthcare provider. [See Warnings and Precautions ( 5.8 ).] • Clinical Considerations for Use and Removal: Advise the patient to contact her healthcare provider if she experiences any of the following: • A stroke or heart attack • Very severe or migraine headaches • Unexplained fever • Yellowing of the skin or whites of the eyes, as these may be signs of serious liver problems • Pregnancy or suspected pregnancy • Pelvic pain, abdominal pain, or pain during sex • HIV positive seroconversion in herself or her partner • Possible exposure to STIs • Unusual vaginal discharge or genital sores • Severe vaginal bleeding or bleeding that lasts a long time, or if she misses a menstrual period • Inability to feel Kyleena's threads • Magnetic Resonance Imaging (MRI) Safety Information: Inform the patient that Kyleena can be safely scanned with MRI only under specific conditions [see Warnings and Precautions ( 5.11 )] . Instruct patients who will have an MRI to tell their doctor that they have Kyleena. Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981 © 2016, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.

14 CLINICAL STUDIES The contraceptive efficacy of Kyleena was evaluated in a clinical trial that enrolled generally healthy women aged 18–35, of whom 1,452 received Kyleena. Of these, 40% (574) were nulliparous women, 870 (60%) women completed 3 years of the study, 707 (49%) elected to enroll in an extension phase up to a total of 5 years, and 550 (38%) completed 5 years of use. The trial was a multicenter, multi-national, randomized, open-label study conducted in 11 countries in Europe, Latin America, the US and Canada. Women less than six weeks postpartum, with a history of ectopic pregnancy, with clinically significant ovarian cysts or with HIV or otherwise at high risk for sexually transmitted infections were excluded. A total of 563 (39%) were treated at US sites and 889 (61%) were at non-US sites. The racial demographics of enrolled women who received Kyleena was: Caucasian (80%), Black/African American (5.1%), Other (2.6%) and Asian (1.2%); 11% indicated Hispanic ethnicity. The clinical trial had no upper or lower weight or BMI limit. The weight range was 38 to 173 kg (mean weight: 68.7 kg) and mean BMI was 25.3 kg/m 2 (range 15.2–57.6 kg/m 2 ). Of Kyleena-treated women, 22% discontinued the study treatment due to an adverse reaction, 5.0% were lost to follow-up, 2.3% withdrew for unspecified reasons, 1.2% discontinued due to a protocol deviation, 0.9% discontinued due to pregnancy, and 20% discontinued due to other reasons. The pregnancy rate calculated as the Pearl Index (PI) in women aged 18–35 years was the primary efficacy endpoint used to assess contraceptive reliability. The PI was calculated 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 Year 1 PI was based on 2 pregnancies and the cumulative 5-year pregnancy rate was based on 13 pregnancies that occurred after the onset of treatment and within 7 days after Kyleena removal or expulsion. Table 5 shows the calculated annual and cumulative pregnancy rates. Table 7: Pearl Indices by Year and 5-Year Cumulative Pregnancy Rate Kyleena Clinical Trial Pearl Index Cumulative 5-Year Kaplan Meier Rate Year 1 Year 2 Year 3 Year 4 Year 5 Number of Evaluable 28-day Cycles of Exposure 16,207 13,853 11,610 8,556 7,087 57,313 Pregnancy Rate (95% Confidence Interval) 0.16 (0.02, 0.58) 0.38 (0.10, 0.96) 0.45 (0.12, 1.15) 0.15 (0.00, 0.85) 0.37 (0.04, 1.33) 1.45 (0.82, 2.53)

15 REFERENCES 1 http://www.cdc.gov/std/tg2015/pid.htm . Accessed August 22, 2016.

8.5 Geriatric Use Kyleena has not been studied in women over age 65 and is not approved for use in this population.

8.4 Pediatric Use Safety and efficacy of Kyleena have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal females under the age of 18 as for users 18 years and older. Use of this product before menarche is not indicated.

8.1 Pregnancy Risk Summary The use of Kyleena is contraindicated in pregnancy or with a suspected 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The use of Kyleena is contraindicated in pregnancy or with a suspected 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. 8.2 Lactation Risk Summary Published studies report the presence of LNG in human milk. Small amounts of progestins (approximately 0.1% of the total maternal doses) were detected in the breast milk of nursing mothers who used other LNG-releasing IUSs, resulting in exposure of LNG to the breastfed infants. There are no reports of adverse effects in breastfed infants with maternal use of progestin-only contraceptives. Isolated cases of decreased milk production have been reported with a LNG-releasing IUS. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Kyleena and any potential adverse effects on the breastfed child from Kyleena or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Return to Fertility After Discontinuing Kyleena About 71% of 163 women who desired pregnancy after study discontinuation and provided follow-up information, conceived within 12 months after removal of Kyleena. 8.4 Pediatric Use Safety and efficacy of Kyleena have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal females under the age of 18 as for users 18 years and older. Use of this product before menarche is not indicated. 8.5 Geriatric Use Kyleena has not been studied in women over age 65 and is not approved for use in this population.

16 HOW SUPPLIED/STORAGE AND HANDLING Kyleena (levonorgestrel-releasing intrauterine system), containing a total of 19.5 mg LNG, is available in a carton of one sterile unit. NDC# 50419-424-01 Kyleena is supplied sterile. Kyleena is sterilized with ethylene oxide. Do not resterilize. For single use only. Do not use if the inner package is damaged or open. Insert before the end of the month shown on the label. Store at 25°C (77°F); with excursions permitted between 15–30°C (59–86°F) [see USP Controlled Room Temperature].