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1 INDICATIONS AND USAGE Skyla ® is indicated to prevent pregnancy for up to 3 years. Replace the system after 3 years if continued use is desired. Skyla is a progestin-containing intrauterine system (IUS) indicated for prevention of pregnancy for up to 3 years. ( 1 )

2 DOSAGE AND ADMINISTRATION • Release rate of levonorgestrel (LNG) is 14 mcg/day after 24 days and declines to 5 mcg/day after 3 years; Skyla must be removed or replaced after 3 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 Skyla contains 13.5 mg of levonorgestrel (LNG) released in vivo at a rate of approximately 14 mcg/day after 24 days. This rate decreases progressively to approximately 6 mcg/day after 1 year and to 5 mcg/day after 3 years. The average in vivo release rate of LNG is approximately 8 mcg/day over the first year of use and 6 mcg/day over a period of 3 years. [See Clinical Pharmacology ( 12.3 ).] Skyla must be removed by the end of the third year and can be replaced at the time of removal with a new Skyla if continued contraceptive protection is desired. Skyla can be physically distinguished from other intrauterine systems (IUSs) by the combination of the visibility of the silver ring on ultrasound and the brown color of the removal threads. Skyla 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 )] . 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 Skyla use, exclude endometrial pathology (polyps or cancer) prior to the insertion of Skyla 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 Skyla from the inserter. Once released, Skyla cannot be re-loaded . • Skyla should be inserted by a trained healthcare provider. Healthcare providers should become thoroughly familiar with the insertion instructions before attempting insertion of Skyla. • 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 Skyla Starting Skyla in women not currently using hormonal or intrauterine contraception • Insert Skyla 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 Skyla is inserted during the first seven days of the menstrual cycle or immediately after a first trimester abortion, back-up contraception is not needed.

ertainty that the woman is not pregnant. Consider the possibility of ovulation and conception prior to initiation of this product [see Contraindications ( 4 )]. • If Skyla 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 Skyla 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 Skyla from an oral, transdermal or vaginal hormonal contraceptive • Insert Skyla 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 Skyla insertion or until the end of the current treatment cycle. • If the woman was using continuous hormonal contraception, discontinue that method seven days after Skyla insertion. Switching to Skyla from an injectable progestin contraceptive • Insert Skyla at any time; a non-hormonal back-up birth control (such as condoms or spermicide) should also be used for 7 days if Skyla is inserted more than 3 months (13 weeks) after the last injection. Switching to Skyla from a contraceptive implant or another IUS • Insert Skyla on the same day the implant or IUS is removed. • Insert Skyla at any time during the menstrual cycle. Inserting Skyla after first trimester abortion or miscarriage • Insert Skyla immediately after a first-trimester abortion or miscarriage, unless it is a septic abortion [see Contraindications ( 4 )]. Inserting Skyla after childbirth or second-trimester abortion or miscarriage Immediate insertion after childbirth or second-trimester abortion or miscarriage • Insert Skyla 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 Skyla [see Warnings and Precautions ( 5.5 , 5.6 ), Adverse Reactions ( 6.2 )]. • Insert Skyla any time there is reasonable certainty the woman is not pregnant. • If Skyla 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 Skyla (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 Skyla from the inserter by first loading (see Figure 2) and then releasing (see Figure 7) Skyla from the inserter, and insert according to accepted practice. Preparation • Gloves • Speculum • Sterile uterine sound • Sterile tenaculum • Antiseptic solution, applicator Procedure • Sterile gloves • Skyla with inserter in sealed package • Instruments and anesthesia for paracervical block, if anticipated • Consider having an unopened back-up Skyla available • Sterile, sharp curved scissors Preparation for insertion • Exclude pregnancy and confirm that there are no other contraindications to the use of Skyla. • Check expiration date of Skyla prior to initiating insertion. • 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.

itiating insertion. • 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 Skyla. 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 Skyla Package • Using sterile gloves, lift the handle of the sterile inserter and remove from the sterile package. Opening the Package Step 2–Load Skyla 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 Skyla T-body to load Skyla 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 Skyla • 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 Skyla. Once the slider is moved below the mark, Skyla cannot be re-loaded . Loading Skyla 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–Skyla 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 Tube Step 5–Open the arms • While holding the inserter steady, move the slider down to the mark to release the arms of Skyla (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 Releasing Arms 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. Skyla is now in the fundal position (Figure 6). Fundal positioning of Skyla is important to prevent expulsion . Figure 6. Move Skyla into the fundal position Fundal Position Step 7–Release Skyla and withdraw the inserter • Holding the entire inserter firmly in place, release Skyla by moving the slider all the way down (Figure 7). Figure 7.

undal position (Figure 6). Fundal positioning of Skyla is important to prevent expulsion . Figure 6. Move Skyla into the fundal position Fundal Position Step 7–Release Skyla and withdraw the inserter • Holding the entire inserter firmly in place, release Skyla by moving the slider all the way down (Figure 7). Figure 7. Move the slider all the way down to release Skyla 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 Skyla. . Figure 8. Cutting the threads Skyla insertion is now complete. Prescribe analgesics, if indicated. Record the Skyla lot number in the patient records. Moving Slider to Release Cutting Threads Important information to consider during or after insertion • If you suspect that Skyla is not in the correct position, check placement (for example, using transvaginal ultrasound). Remove Skyla if it is not positioned completely within the uterus. Do not reinsert a removed Skyla. • 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 Skyla Timing of Removal • Skyla should not remain in the uterus after 3 years. • If pregnancy is not desired, remove Skyla 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 Skyla by applying gentle traction on the threads with forceps (Figure 9). Figure 9. Removal of Skyla • If the threads are not visible, determine location of Skyla by ultrasound [see Warnings and Precautions ( 5.10 )] . • If Skyla 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 Skyla, examine the system to ensure that it is intact. If unable to remove with gentle traction, determine Skyla location and exclude perforation by ultrasound or other imaging [see Warnings and Precautions ( 5.10 ) ]. • Removal may be associated with some: o pain and/or bleeding or vasovagal reactions (for example, syncope, bradycardia) or seizure, especially in patients with a predisposition to these conditions. o breakage or embedment of Skyla in the myometrium that can make removal difficult [see Warnings and Precautions ( 5.5 )]. Analgesia, paracervical anesthesia, cervical dilation, alligator forceps or other grasping instrument, or hysteroscopy may be used to assist in removal. Remove Skyla 2.5 Continuation of Contraception after Removal • If pregnancy is not desired and if a woman wishes to continue using Skyla, 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.

pregnancy is not desired and if a woman wishes to continue using Skyla, 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 Skyla 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 Skyla 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.

3 DOSAGE FORMS AND STRENGTHS Skyla 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 13.5 mg LNG. • One sterile intrauterine system consisting of a T-shaped polyethylene frame with a steroid reservoir containing 13.5 mg levonorgestrel packaged within a sterile inserter ( 3 )

4 CONTRAINDICATIONS The use of Skyla 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 Skyla ( 4 )

5 WARNINGS AND PRECAUTIONS • Remove Skyla if pregnancy occurs with Skyla in place. If a 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 Skyla, 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 ) • Skyla 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 Skyla in place because the likelihood of a pregnancy being ectopic is increased with Skyla. Approximately one-half of pregnancies that occur with Skyla 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 Skyla, which excluded women with a history of ectopic pregnancy, was approximately 0.1% per year. The risk of ectopic pregnancy in women who have a history of ectopic pregnancy and use Skyla 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 Skyla, remove Skyla because leaving it in place may increase the risk of spontaneous abortion and preterm labor. Removal of Skyla or probing of the uterus may also result in spontaneous abortion. In the event of an intrauterine pregnancy with Skyla, 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 Skyla in place and if Skyla cannot be removed or the woman chooses not to have it removed, warn her that failure to remove Skyla 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.

roup 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 Skyla is essential in order to minimize serious infections such as GAS. 5.4 Pelvic Infection Pelvic Inflammatory Disease (PID) Skyla is contraindicated in the presence of known or suspected PID or in women with a history of PID unless there has been a subsequent intrauterine pregnancy [see Contraindications ( 4 )] . IUDs have been associated with an increased risk of PID, most likely due to organisms being introduced into the uterus during insertion. In clinical trials, PID was observed in 0.4% of women overall and occurred more frequently within the first year and most often within the first month after insertion of Skyla. Promptly examine users with complaints of lower abdominal or pelvic pain, odorous discharge, unexplained bleeding , fever, genital lesions or sores. Remove Skyla in cases of recurrent endometritis or pelvic inflammatory disease, or if an acute pelvic infection is severe or does not respond to treatment. Women at increased risk for PID PID is often associated with a sexually transmitted infection (STI), and Skyla does not protect against STI. The risk of PID is greater for women who have multiple sexual partners, and also for women whose sexual partner(s) have multiple sexual partners. Women who have had PID are at increased risk for a recurrence or re-infection. In particular, ascertain whether the woman is at increased risk of infection (for example, leukemia, acquired immune deficiency syndrome [AIDS], intravenous drug abuse). Subclinical PID PID may be asymptomatic but still result in tubal damage and its sequelae. Treatment of PID Following a diagnosis of PID, or suspected PID, bacteriologic specimens should be obtained, and antibiotic therapy should be initiated promptly. Removal of Skyla after initiation of antibiotic therapy is usually appropriate. Actinomycosis Actinomycosis has been associated with IUDs. Remove Skyla from symptomatic women and treat with antibiotics. The significance of actinomyces-like organisms on Pap smear in an asymptomatic IUD user is unknown, and so this finding alone does not always require Skyla removal and treatment. When possible, confirm a Pap smear diagnosis with cultures. 5.5 Perforation Perforation (total or partial, including penetration/embedment of Skyla in the uterine wall or cervix) may occur most often during insertion, although the perforation may not be detected until sometime later. The incidence of perforation during clinical trials was < 0.1%. The risk of uterine perforation is increased in women who have recently given birth, and in women who are breastfeeding at the time of insertion. In a large postmarketing safety study conducted in the US, the risk of uterine perforation was highest when insertion occurred within ≤ 6 weeks postpartum, and also higher with breastfeeding at the time of insertion [see Adverse Reactions ( 6.2 )]. The risk of perforation may be increased if Skyla is inserted when the uterus is fixed, retroverted or not completely involuted. If perforation occurs, locate and remove Skyla. Surgery may be required. Delayed detection or removal of Skyla in case of perforation may result in migration outside the uterine cavity, adhesions, peritonitis, intestinal perforations, intestinal obstruction, abscesses and erosion of adjacent viscera. In addition, perforation may reduce contraceptive efficacy and result in pregnancy.

quired. Delayed detection or removal of Skyla in case of perforation may result in migration outside the uterine cavity, adhesions, peritonitis, intestinal perforations, intestinal obstruction, abscesses and erosion of adjacent viscera. In addition, perforation may reduce contraceptive efficacy and result in pregnancy. 5.6 Expulsion Partial or complete expulsion of Skyla may occur resulting in the loss of efficacy. Expulsion may be associated with symptoms of bleeding or pain, or it may be asymptomatic and go unnoticed. Skyla typically decreases menstrual bleeding over time; therefore, an increase of menstrual bleeding may be indicative of an expulsion. Consider further diagnostic imaging, such as x-ray, if expulsion is suspected based on ultrasound [see Warnings and Precautions ( 5.10 )]. In clinical trials, a 3-year expulsion rate of 3.2% (54 out of 1,665 subjects) was reported. The risk of expulsion is increased with insertions immediately after delivery and appears to be increased with insertion after second-trimester abortion based on limited data. In a large postmarketing safety study conducted in the US, the risk of expulsion was lower with breastfeeding status [see Adverse Reactions ( 6.2 )]. Remove a partially expelled Skyla. If expulsion has occurred, a new Skyla can be inserted any time the provider can be reasonably certain the woman is not pregnant. 5.7 Ovarian Cysts Because the contraceptive effect of Skyla is mainly due to its local effects within the uterus, ovulatory cycles with follicular rupture usually occur in women of fertile age using Skyla. Ovarian cysts (reported as adverse reactions if they were abnormal, non-functional cysts and/or had a diameter >3 cm on ultrasound examination) were reported at least once over the course of clinical trials in 13.2% of women using Skyla, and 0.3% of subjects discontinued because of an ovarian cyst. Most ovarian cysts are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia. In most cases the ovarian cysts disappear spontaneously during two to three months observation. Evaluate persistent ovarian cysts. Surgical intervention is not usually required. 5.8 Bleeding Pattern Alterations Skyla can alter the bleeding pattern and result in spotting, irregular bleeding, heavy bleeding, oligomenorrhea and amenorrhea. During the first 3–6 months of Skyla use, the number of bleeding and spotting days may be higher and bleeding patterns may be irregular. Thereafter, the number of bleeding and spotting days usually decreases but bleeding may remain irregular. In Skyla clinical trials, amenorrhea developed by the end of the first year of use in approximately 6% of Skyla users. A total of 77 subjects out of 1,672 (4.6%) discontinued due to uterine bleeding complaints. Table 2 shows the bleeding patterns as documented in the Skyla clinical trials based on 90-day reference periods. Table 3 shows the number of bleeding and spotting days based on 28-day cycle equivalents. Table 2: Bleeding Patterns Reported with Skyla in Contraception Studies (by 90-day reference periods) Skyla First 90 days N=1,531 Second 90 days N=1,475 End of year 1 N=1,329 End of year 3 N=903 Amenorrhea 1 <1% 3% 6% 12% Infrequent bleeding 2 8% 19% 20% 22% Frequent bleeding 3 31% 12% 8% 4% Prolonged bleeding 4 55% 14% 6% 2% Irregular bleeding 5 39% 25% 18% 15% 1 Defined as subjects with no bleeding/spotting throughout the 90-day reference period 2 Defined as subjects with 1 or 2 bleeding/spotting episodes in the 90-day reference period 3 Defined as subjects with more than 5 bleeding/spotting episodes in the 90-day reference period 4 Defined as subjects with bleeding/spotting episodes lasting more than 14 days in the 90-day reference period.

ay reference period 2 Defined as subjects with 1 or 2 bleeding/spotting episodes in the 90-day reference period 3 Defined as subjects with more than 5 bleeding/spotting episodes in the 90-day reference period 4 Defined as subjects with bleeding/spotting episodes lasting more than 14 days in the 90-day reference period. Subjects with prolonged bleeding may also be included in one of the other categories (excluding amenorrhea) 5 Defined as subjects with 3 to 5 bleeding/spotting episodes and less than 3 bleeding/spotting-free intervals of 14 or more days. Table 3: Mean number of Bleeding and Spotting Days per 28-day Cycle Equivalent 28-day Cycle Equivalent Cycle 1 N=1,588 Cycle 4 N=1,535 Cycle 7 N=1,468 Cycle 13 N=1,345 Cycle 39 N=781 Days on treatment 1–28 85–112 169–196 337–364 1065–1092 Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Number of bleeding days 7.3 (5.6) 3.5 (3.4) 2.8 (3.1) 2.1 (2.7) 1.4 (2.1) Number of spotting days 9.2 (6.1) 4.8 (4.4) 3.8 (3.6) 3.3 (3.1) 2.7 (2.7) If a significant change in bleeding develops during prolonged use, take appropriate diagnostic measures to rule out endometrial pathology . Consider the possibility of pregnancy if menstruation does not occur within six weeks of the onset of a previous menstruation. Once pregnancy has been excluded, repeated pregnancy tests are generally not necessary in amenorrheic women unless indicated, for example, by other signs of pregnancy or by pelvic pain. 5.9 Breast Cancer Women who currently have or have had breast cancer, or have a suspicion of breast cancer, should not use hormonal contraception, including Skyla because some breast cancers are hormone-sensitive [see Contraindications ( 4 )] . Spontaneous reports of breast cancer have been received during postmarketing experience with a LNG-releasing IUS. Observational studies of the risk of breast cancer with use of a LNG-releasing IUS do not provide conclusive evidence of increased risk. 5.10 Clinical Considerations for Use and Removal Use Skyla with caution after careful assessment if any of the following conditions exist, and consider removal of the system if any of them arise during use: • Coagulopathy or use of anticoagulants • Migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia • Exceptionally severe headache • Marked increase of blood pressure • Severe arterial disease such as stroke or myocardial infarction In addition, consider removing Skyla if any of the following conditions arise during use : • Uterine or cervical malignancy • Jaundice • If the threads are not visible or are significantly shortened they may have broken or retracted into the cervical canal or uterus. Consider the possibility that the system may have been displaced, (for example, expelled or perforated the uterus) [see Warnings and Precautions ( 5.5 , 5.6 )]. Exclude pregnancy and verify the location of Skyla, for example, by sonography, X-ray, or by gentle exploration of the cervical canal with a suitable instrument. If Skyla is displaced, remove it. A new Skyla may be inserted at that time or during the next menses if it is certain that conception has not occurred. If Skyla is in place with no evidence of perforation, no intervention is indicated. 5.11 Magnetic Resonance Imaging (MRI) Safety Information Non-clinical testing has demonstrated that Skyla is MR Conditional.

Skyla may be inserted at that time or during the next menses if it is certain that conception has not occurred. If Skyla is in place with no evidence of perforation, no intervention is indicated. 5.11 Magnetic Resonance Imaging (MRI) Safety Information Non-clinical testing has demonstrated that Skyla is MR Conditional. A patient with Skyla can be safely scanned in an MR system meeting the following conditions: • Static magnetic field of 3.0 T or less • Maximum spatial field gradient of 36,000 gauss/cm (360 T/m) • Maximum MR system reported, whole body averaged specific absorption rate (SAR) of 4W/kg (First Level Controlled Operating Mode) Under the scan conditions defined above, the Skyla IUS is expected to produce a maximum temperature rise of less than 2°C after 15 minutes of continuous scanning. In non-clinical testing, the image artifact caused by the IUS extended up to 5 mm from the IUS when imaged with a gradient echo pulse sequence and a 3.0 T MRI system.

<table width="100%"><caption>Table 2: Bleeding Patterns Reported with Skyla in Contraception Studies (by 90-day reference periods)</caption><col width="21%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Skyla</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">First 90 days</content> <content styleCode="bold">N=1,531</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Second 90 days</content> <content styleCode="bold">N=1,475</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">End of year 1</content> <content styleCode="bold">N=1,329</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">End of year 3</content> <content styleCode="bold">N=903</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Amenorrhea¹</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Infrequent bleeding²</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Frequent bleeding³</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>31%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Prolonged bleeding⁴</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>55%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">Irregular bleeding⁵</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><pa

/td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">Irregular bleeding⁵</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><pa ragraph>39%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>15%</paragraph></td></tr></tbody></table>

graph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>15%</paragraph></td></tr></tbody></table> <table cellpadding="0pt" width="100%"><caption>Table 3: Mean number of Bleeding and Spotting Days per 28-day Cycle Equivalent</caption><col width="16%"/><col width="17%"/><col width="17%"/><col width="17%"/><col width="17%"/><col width="17%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">28-day Cycle Equivalent</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Cycle 1</content></paragraph><paragraph><content styleCode="bold">N=1,588</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Cycle 4</content></paragraph><paragraph><content styleCode="bold">N=1,535</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Cycle 7</content></paragraph><paragraph><content styleCode="bold">N=1,468</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Cycle 13</content></paragraph><paragraph><content styleCode="bold">N=1,345</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Cycle 39</content></paragraph><paragraph><content styleCode="bold">N=781</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Days on treatment</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1&#x2013;28</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>85&#x2013;112</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>169&#x2013;196</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>337&#x2013;364</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1065&#x2013;1092</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"/><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Mean</paragraph><paragraph>(SD)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Mean</paragraph><paragraph>(SD)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Mean</paragraph><paragraph>(SD)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Mean</paragraph><paragraph>(SD)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Mean</paragraph><paragraph>(SD)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Number of bleeding days</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>7.3</paragraph><paragraph>(5.6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>3.5</paragraph><paragraph>(3.4)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>2.8</paragraph><paragraph>(3.1)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>2.1</paragraph><paragra

Lrule Botrule " valign="middle"><paragraph>3.5</paragraph><paragraph>(3.4)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>2.8</paragraph><paragraph>(3.1)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>2.1</paragraph><paragra ph>(2.7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1.4</paragraph><paragraph>(2.1)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph><content styleCode="bold">Number of spotting days</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>9.2</paragraph><paragraph>(6.1)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>4.8</paragraph><paragraph>(4.4)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>3.8</paragraph><paragraph>(3.6)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>3.3</paragraph><paragraph>(3.1)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>2.7</paragraph><paragraph>(2.7)</paragraph></td></tr></tbody></table>

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 (>10% users) are bleeding pattern alterations, vulvovaginitis, abdominal/pelvic pain, acne/seborrhea, headache/migraine, ovarian cyst and dysmenorrhea/uterine spasm. ( 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 to Skyla in 1,672 patients in two contraception studies, including 1,383 exposed for one year and 993 who completed the three year studies. The population was generally healthy, 18 to 40-year old females requesting contraception and predominately Caucasian (82.6%). The data cover more than 40,000 cycles of exposure. The frequencies of reported adverse drug reactions represent crude incidences. Most common adverse reactions (occurring in ≥ 5% users) were increased bleeding (7.8%), vulvovaginitis (20.2%), abdominal/pelvic pain (18.9%), acne/seborrhea (15.0%), ovarian cyst (13.2%), headache (12.4%), dysmenorrhea (8.6%), breast pain/discomfort (8.6%) and nausea (5.5%). In the contraception studies, 18% discontinued prematurely due to an adverse reaction. The most common adverse reactions leading to discontinuation (in >1% of users) were uterine bleeding complaints (4.6%), device expulsion (3.2%), acne/seborrhea (2.9%), abdominal pain (2.5%) dysmenorrhea/uterine spasms (2.0%) and pelvic pain (1.8%). Other common adverse reactions (occurring in ≥ 1% users) by System Organ Class (SOC): The frequencies of adverse reactions observed in clinical trials are summarized in Table 4 by SOC (presented as crude incidences). Table 4: Adverse reactions that occurred in at least 1% of Skyla users in clinical trials by SOC System Organ Class Adverse Reaction Incidence (%) (N=1,672) Reproductive System and Breast Disorders Vulvovaginitis 20.2 Ovarian cyst Ovarian cysts were reported as adverse events if they were abnormal, non-functional cysts and/or had a diameter >3 cm on ultrasound examination 13.2 Dysmenorrhea 8.6 Increased bleeding Not all bleeding alterations were captured as adverse reactions [see Warnings and Precautions (5.8)].

Vulvovaginitis 20.2 Ovarian cyst Ovarian cysts were reported as adverse events if they were abnormal, non-functional cysts and/or had a diameter >3 cm on ultrasound examination 13.2 Dysmenorrhea 8.6 Increased bleeding Not all bleeding alterations were captured as adverse reactions [see Warnings and Precautions (5.8)]. 7.8 Breast pain/discomfort 5.3/3.3 Genital discharge 4.2 Device expulsion (complete and partial) 3.2 Upper genital tract infection 1.4 Gastrointestinal Disorders Abdominal pain/pelvic pain 12.7/6.2 Nausea 5.5 Skin and Subcutaneous Tissue Disorders Acne/Seborrhea 13.6/1.4 Alopecia 1.2 Nervous System Disorders Headache 12.4 Migraine 2.3 Psychiatric Disorders Depression/Depressed mood 3.8/0.5 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 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 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.

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: 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

<table width="100%"><caption>Table 4: Adverse reactions that occurred in at least 1% of Skyla users in clinical trials by SOC </caption><col width="33%"/><col width="37%"/><col width="29%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">System Organ Class</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Incidence (%)</content> <content styleCode="bold">(N=1,672)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Reproductive System and Breast Disorders</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Vulvovaginitis</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>20.2</item></list></td></tr><tr><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Ovarian cyst<footnote ID="_Ref395171791">^{Ovarian cysts were reported as adverse events if they were abnormal, non-functional cysts and/or had a diameter &gt;3 cm on ultrasound examination}</footnote></item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>13.2</item></list></td></tr><tr><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Dysmenorrhea</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>8.6</item></list></td></tr><tr><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Increased bleeding<footnote ID="_Ref395171919">^{Not all bleeding alterations were captured as adverse reactions [see Warnings and Precautions (5.8)].}</footnote></item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>7.8</item></list></td></tr><tr><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Breast pain/discomfort</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>5.3/3.3</item></list></td></tr><tr><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Genital discharge</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>4.2</item></list></td></tr><tr><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Device expulsion (complete and partial)</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>3.2</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Upper genital

</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>3.2</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Upper genital tract infection</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>1.4</item></list></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Gastrointestinal Disorders</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Abdominal pain/pelvic pain</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>12.7/6.2</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Nausea</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>5.5</item></list></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Skin and Subcutaneous Tissue Disorders</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Acne/Seborrhea</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>13.6/1.4</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Alopecia</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>1.2</item></list></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Nervous System Disorders</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Headache</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>12.4</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Migraine</item></list></td><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>2.3</item></list></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Psychiatric Disorders</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Depression/Depressed mood</item></list></td><td styleCode="Rrule Botrule Lrule " valign="top"><list listType="unordered"><item><caption> </caption>3.8/0.5</item></list></td></tr></tbody></table>

orders</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Depression/Depressed mood</item></list></td><td styleCode="Rrule Botrule Lrule " valign="top"><list listType="unordered"><item><caption> </caption>3.8/0.5</item></list></td></tr></tbody></table> <table cellpadding="0pt" width="100%"><caption>Table 5: Uterine Perforation1 rates for LNG IUS, by Breastfeeding Status and Postpartum Interval</caption><col width="20%"/><col width="18%"/><col width="22%"/><col width="17%"/><col width="23%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"/><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Breastfeeding at time of insertion</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Not breastfeeding at time of insertion</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Postpartum interval at time of insertion</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Number of events/ insertions</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Uterine perforation rate per 1,000 insertions</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Number of events/ insertions</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Uterine perforation rate per 1,000 insertions</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">0 to 3 days</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>8/1,896</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>4.22</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>0/277</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>0.00</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">4 days to &#x2264; 6 weeks</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>120/10,735</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>11.18</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>28/2,377</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>11.78</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">&gt; 6 to &#x2264; 14 weeks</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>268/29,677</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>9.03</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>80/12,011</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>6.66</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">&gt; 14 to &#x2264; 52 weeks</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>43/6,139</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " vali

r><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">&gt; 14 to &#x2264; 52 weeks</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>43/6,139</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " vali gn="middle"><paragraph>7.00</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>22/9,089</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>2.42</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">&gt; 52 weeks or no delivery </content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>no data available</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>243/184,733</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>1.32</paragraph></td></tr></tbody></table>

rule Toprule " valign="middle"><paragraph>no data available</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>243/184,733</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>1.32</paragraph></td></tr></tbody></table> <table cellpadding="0pt" width="100%"><caption>Table 6: Expulsion1 Rates for LNG IUS, by Breastfeeding Status and Postpartum Interval </caption><col width="20%"/><col width="18%"/><col width="22%"/><col width="17%"/><col width="23%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"/><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Breastfeeding at time of insertion</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Not breastfeeding at time of insertion</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Postpartum interval at time of insertion</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Number of events/ insertions</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Expulsion rate per 1,000 insertions</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Number of events/ insertions</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Expulsion rate per 1,000 insertions</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">0 to 3 days</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>187/1,896</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>98.63</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>12/277</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>43.32</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">4 days to &#x2264; 6 weeks</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>185/10,735</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>17.23</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>52/2,377</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>21.88</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">&gt; 6 to &#x2264; 14 weeks</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>421/29,677</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14.19</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>306/12,011</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>25.48</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">&gt; 14 to &#x2264; 52 weeks</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>120/6,139</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>19.55</paragraph><

valign="top"><paragraph><content styleCode="bold">&gt; 14 to &#x2264; 52 weeks</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>120/6,139</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>19.55</paragraph>< /td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>273/9,089</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>30.04</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">&gt; 52 weeks or no delivery </content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>no data available</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>5,481/184,733</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>29.67</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS No drug-drug interaction studies have been conducted with Skyla. 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 Skyla. However, the contraceptive effect of Skyla 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The use of Skyla is contraindicated in pregnancy or with a suspected pregnancy and Skyla may cause adverse pregnancy outcomes [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 , 5.2 )]. If a woman becomes pregnant with Skyla in place, the likelihood of ectopic pregnancy is increased and there is an increased risk of miscarriage, sepsis, premature labor, and premature delivery . Remove Skyla, if possible, if pregnancy occurs in a woman using Skyla. If Skyla 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 Skyla. 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 Skyla and any potential adverse effects on the breastfed child from Skyla or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Return to Fertility After Discontinuing Skyla About 77% of women who desired pregnancy after study discontinuation and provided follow-up information, conceived within 12 months after removal of Skyla. 8.4 Pediatric Use Safety and efficacy of Skyla 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 Skyla has not been studied in women over age 65 and is not approved for use in this population.

8.1 Pregnancy Risk Summary The use of Skyla is contraindicated in pregnancy or with a suspected pregnancy and Skyla may cause adverse pregnancy outcomes [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 , 5.2 )]. If a woman becomes pregnant with Skyla in place, the likelihood of ectopic pregnancy is increased and there is an increased risk of miscarriage, sepsis, premature labor, and premature delivery . Remove Skyla, if possible, if pregnancy occurs in a woman using Skyla. If Skyla 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 Skyla.

Risk Summary The use of Skyla is contraindicated in pregnancy or with a suspected pregnancy and Skyla may cause adverse pregnancy outcomes [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 , 5.2 )]. If a woman becomes pregnant with Skyla in place, the likelihood of ectopic pregnancy is increased and there is an increased risk of miscarriage, sepsis, premature labor, and premature delivery . Remove Skyla, if possible, if pregnancy occurs in a woman using Skyla. If Skyla 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 Skyla. 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 Skyla and any potential adverse effects on the breastfed child from Skyla or from the underlying maternal condition.

8.4 Pediatric Use Safety and efficacy of Skyla 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.

11 DESCRIPTION Skyla (levonorgestrel-releasing intrauterine system) contains 13.5 mg of LNG, a progestin, and is intended to provide an initial release rate of approximately14 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 Skyla, has a molecular weight of 312.4, a molecular formula of C 21 H 28 O 2 , and the following structural formula: 11.1 Skyla Skyla 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 13.5 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 brown polyethylene removal thread is attached to a loop at the end of the vertical stem of the T-body. The polyethylene of the removal thread contains iron oxide as a colorant (see Figure 10). The components of Skyla, including its packaging, are not manufactured using natural rubber latex. Figure 10. Skyla Skyle Fig 10 11.2 Inserter Skyla is packaged sterile within an inserter. The inserter (Figure 11), which is used for insertion of Skyla 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 Skyla 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 Skyla has been placed, the inserter is discarded. Figure 11. Diagram of Inserter Inserter Diagram Chemical Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The local mechanism by which continuously released LNG contributes to the contraceptive effectiveness of Skyla has not been conclusively demonstrated. Studies of Skyla 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 Skyla 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 Skyla, 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 34 out of 35 women in the first year, in 26 out of 27 women in the second year, and in all 26 women in the third year. 12.3 Pharmacokinetics Absorption Low doses of LNG are administered into the uterine cavity with the Skyla intrauterine delivery system. The in vivo release rate is approximately 14 mcg/day after 24 days and is reduced to approximately 10 mcg/day after 60 days and then declines progressively to approximately 6 mcg/day after 1 year and 5 mcg/day after 3 years. The average LNG in vivo release rate is approximately 8 mcg/day over the first year of use and 6 mcg/day over the period of 3 years. In a subset of 7 subjects, the maximum observed serum LNG concentration (mean ±SD) was 192 ± 105 pg/mL, reached after 2 days (median) of Skyla insertion. Thereafter, the LNG serum concentrations (mean ±SD) at year 1, 2, and 3 were 77 ± 21 pg/mL, 62 ± 38 pg/mL, and 72 ± 29 pg/mL, respectively. A population pharmacokinetic evaluation based on a broader database (>1000 patients) showed similar concentration data of 168 ± 46 pg/mL at 7 days after placement. Thereafter, LNG serum concentrations decline slowly to a value 61 ± 19 pg/mL after 3 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 7 subjects, the concentration of SHBG declined by a mean value of 18% within 2 weeks after insertion of Skyla and remained relatively stable over the 3 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.

vidual 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 Skyla have been established in women of reproductive age. Use of this product before menarche is not indicated . In a one-year phase 3 study in post-menarcheal female adolescents (mean age 16.2, range 12 to 18 years) using Skyla, the population pharmacokinetic analysis of 278 adolescents showed mean estimated LNG serum concentrations slightly higher (approximately 10%) in adolescents compared to prior data in adults. This correlates to the generally lower body weight in adolescents. The ranges estimated for adolescents lie within the ranges estimated for adults. Geriatric: Skyla has not been studied in women over age 65 and is not approved for use in this population . Race: A three-year phase 3 study in the Asian-Pacific region (93% Asian women, the majority of whom were Chinese, 7% other ethnicities) using Skyla was performed. The population pharmacokinetic analysis of the Asian (Chinese) population in this study showed that estimated LNG serum concentrations in Asian women were slightly higher (approximately 4 to 16%) than those in another phase 3 study which was performed in mainly Caucasian women (79.7%). This slightly higher exposure might be explained by the lower body weight of Asian women. Hepatic Impairment: No studies were conducted to evaluate the effect of hepatic disease on the disposition of Skyla . Renal Impairment: No formal studies were conducted to evaluate the effect of renal disease on the disposition of Skyla. Drug-Drug Interactions No drug-drug interaction studies were conducted with Skyla [see Drug Interactions ( 7 )] .

12.1 Mechanism of Action The local mechanism by which continuously released LNG contributes to the contraceptive effectiveness of Skyla has not been conclusively demonstrated. Studies of Skyla 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 Skyla 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 Skyla, 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 34 out of 35 women in the first year, in 26 out of 27 women in the second year, and in all 26 women in the third year.

12.3 Pharmacokinetics Absorption Low doses of LNG are administered into the uterine cavity with the Skyla intrauterine delivery system. The in vivo release rate is approximately 14 mcg/day after 24 days and is reduced to approximately 10 mcg/day after 60 days and then declines progressively to approximately 6 mcg/day after 1 year and 5 mcg/day after 3 years. The average LNG in vivo release rate is approximately 8 mcg/day over the first year of use and 6 mcg/day over the period of 3 years. In a subset of 7 subjects, the maximum observed serum LNG concentration (mean ±SD) was 192 ± 105 pg/mL, reached after 2 days (median) of Skyla insertion. Thereafter, the LNG serum concentrations (mean ±SD) at year 1, 2, and 3 were 77 ± 21 pg/mL, 62 ± 38 pg/mL, and 72 ± 29 pg/mL, respectively. A population pharmacokinetic evaluation based on a broader database (>1000 patients) showed similar concentration data of 168 ± 46 pg/mL at 7 days after placement. Thereafter, LNG serum concentrations decline slowly to a value 61 ± 19 pg/mL after 3 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 7 subjects, the concentration of SHBG declined by a mean value of 18% within 2 weeks after insertion of Skyla and remained relatively stable over the 3 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 Skyla have been established in women of reproductive age. Use of this product before menarche is not indicated . In a one-year phase 3 study in post-menarcheal female adolescents (mean age 16.2, range 12 to 18 years) using Skyla, the population pharmacokinetic analysis of 278 adolescents showed mean estimated LNG serum concentrations slightly higher (approximately 10%) in adolescents compared to prior data in adults. This correlates to the generally lower body weight in adolescents. The ranges estimated for adolescents lie within the ranges estimated for adults.

rmacokinetic analysis of 278 adolescents showed mean estimated LNG serum concentrations slightly higher (approximately 10%) in adolescents compared to prior data in adults. This correlates to the generally lower body weight in adolescents. The ranges estimated for adolescents lie within the ranges estimated for adults. Geriatric: Skyla has not been studied in women over age 65 and is not approved for use in this population . Race: A three-year phase 3 study in the Asian-Pacific region (93% Asian women, the majority of whom were Chinese, 7% other ethnicities) using Skyla was performed. The population pharmacokinetic analysis of the Asian (Chinese) population in this study showed that estimated LNG serum concentrations in Asian women were slightly higher (approximately 4 to 16%) than those in another phase 3 study which was performed in mainly Caucasian women (79.7%). This slightly higher exposure might be explained by the lower body weight of Asian women. Hepatic Impairment: No studies were conducted to evaluate the effect of hepatic disease on the disposition of Skyla . Renal Impairment: No formal studies were conducted to evaluate the effect of renal disease on the disposition of Skyla. Drug-Drug Interactions No drug-drug interaction studies were conducted with Skyla [see Drug Interactions ( 7 )] .

14 CLINICAL STUDIES The contraceptive efficacy of Skyla was evaluated in a clinical trial that enrolled generally healthy women aged 18–35, 1,432 of whom received Skyla. Of these, 38.8 % (556) were nulliparous women, and 819 women completed 3 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 540 (37.7%) were treated at US sites and 892 (62.3%) were at non-US sites. The racial demographics of enrolled women who received Skyla was: Caucasian (79.7%), Hispanic (11.5%), Black/African Americans (5.2%), Other (2.7%) and Asian (0.8%). The weight range was 38 to 155 kg (mean weight: 68.7 kg) and mean BMI was 25.3 kg/m 2 (range 16–55 kg/m 2 ). The clinical trial had no upper or lower weight or BMI limit. Of Skyla-treated women, 21.9% discontinued the study treatment due to an adverse event, 4.4% were lost to follow up, 1.8% withdrew for unspecified reasons, 1.1% discontinued due to protocol deviation, 0.6% discontinued due to pregnancy, and 13.0% 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. Skyla-treated women provided 15,763 evaluable 28-day cycle equivalents in the first year and 39,368 evaluable cycles over the three year treatment period. The PI estimate for the first year of use based on the 5 pregnancies that occurred after the onset of treatment and within 7 days after Skyla removal or expulsion was 0.41 with a 95% upper confidence limit of 0.96. The cumulative 3-year pregnancy rate, based on 10 pregnancies, estimated by the Kaplan-Meier method was 0.9 per 100 women or 0.9%, with a 95% upper confidence limit of 1.7%.

16 HOW SUPPLIED/STORAGE AND HANDLING Skyla (levonorgestrel-releasing intrauterine system), containing a total of 13.5 mg LNG, is available in a carton of one sterile unit. NDC# 50419-422-01 Skyla is supplied sterile. Skyla 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].

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 Skyla, including the risks of leaving Skyla in place and the risks of removing Skyla or probing of the uterus. If Skyla 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 Skyla is inserted. Instruct her to contact a healthcare provider immediately if she develops severe pain or fever shortly after Skyla 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 Skyla placement, worsening pain or bleeding after placement, or the inability to feel Skyla strings may occur with Skyla perforation and expulsion. Caution her not to pull on the threads and displace Skyla. Inform her that there is no contraceptive protection if Skyla 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 Skyla has been confirmed. Advise her that if perforation occurs, Skyla 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.

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 3–6 months of Skyla 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 Skyla's threads • Magnetic Resonance Imaging (MRI) Safety Information: Inform the patient that Skyla 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 Skyla. Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981 © 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.

Patient Information Skyla (sky-lah) (levonorgestrel-releasing intrauterine system) Read this Patient Information carefully before you decide if Skyla is right for you. This information does not take the place of talking with your gynecologist or other healthcare provider who specializes in women’s health. If you have any questions about Skyla, ask your healthcare provider. You should also learn about other birth control methods to choose the one that is best for you. Skyla does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs). What is Skyla? • Skyla is a hormone-releasing system placed in your uterus by your healthcare provider to prevent pregnancy for up to 3 years. • Skyla can be removed by your healthcare provider at any time. • Skyla can be used whether or not you have given birth to a child. Skyla is a small, flexible plastic T-shaped system that slowly releases a progestin hormone called levonorgestrel (LNG) that is often used in birth control pills. Because Skyla releases LNG into your uterus, only small amounts of the hormone enter your blood. Skyla does not contain estrogen. Two thin threads are attached to the stem (lower end) of Skyla. The threads are the only part of Skyla you can feel when Skyla is in your uterus; however, unlike a tampon string, the threads do not extend outside your body. Skyla is small and flexible What if I need birth control for more than 3 years? Skyla must be removed after 3 years. Your healthcare provider can place a new Skyla during the same office visit if you choose to continue using Skyla. What if I want to stop using Skyla? Skyla is intended for use up to 3 years but you can stop using Skyla at any time by asking your healthcare provider to remove it. You could become pregnant as soon as Skyla is removed, so you should use another method of birth control if you do not want to become pregnant. Talk to your healthcare provider about the best birth control methods for you, because your new method may need to be started 7 days before Skyla is removed to prevent pregnancy. What if I change my mind about birth control and want to become pregnant in less than 3 years? Your healthcare provider can remove Skyla at any time. You may become pregnant as soon as Skyla is removed. About 3 out of 4 women who want to become pregnant will become pregnant sometime in the first year after Skyla is removed. How does Skyla work? Skyla may work in several ways including thickening cervical mucus, inhibiting sperm movement, reducing sperm survival, and thinning the lining of your uterus. It is not known exactly how these actions work together to prevent pregnancy. How well does Skyla work for contraception? The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant. Skyla, an intrauterine device (IUD) also known as an intrauterine system (IUS),, is in the box at the top of the chart. Who might use Skyla?

methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant. Skyla, an intrauterine device (IUD) also known as an intrauterine system (IUS),, is in the box at the top of the chart. Who might use Skyla? You might choose Skyla if you: • want long-term birth control that provides a low chance of getting pregnant (less than 1 in 100) • want birth control that works continuously for up to 3 years • want birth control that is reversible • want a birth control method that you do not need to take daily • are willing to use a birth control method that is placed in the uterus • want birth control that does not contain estrogen Do not use Skyla if you: • are or might be pregnant; Skyla cannot be used as an emergency contraceptive • have a serious pelvic infection called pelvic inflammatory disease (PID) or have had PID in the past unless you have had a normal pregnancy after the infection went away • have an untreated genital infection now • have had a serious pelvic infection in the past 3 months after a pregnancy • can get infections easily. For example, if you: • have multiple sexual partners or your partner has multiple sexual partners • have problems with your immune system • use or abuse intravenous drugs • have or suspect you might have cancer of the uterus or cervix • have bleeding from the vagina that has not been explained • have liver disease or a liver tumor • have breast cancer or any other cancer that is sensitive to progestin (a female hormone), now or in the past • have an intrauterine device in your uterus already • have a condition of the uterus that changes the shape of the uterine cavity, such as large fibroid tumors • are allergic to levonorgestrel, silicone, polyethylene, silver, silica, barium sulfate or iron oxide Before having Skyla placed, tell your healthcare provider about all of your medical conditions including if you: • have any of the conditions listed above • have had a heart attack • have had a stroke • were born with heart disease or have problems with your heart valves • have problems with blood clotting or take medicine to reduce clotting • have high blood pressure • recently had a baby or are breastfeeding • have severe headaches or migraine headaches • have AIDS, HIV, or any other sexually transmitted infection Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How is Skyla placed? Skyla is placed by your healthcare provider during an in-office visit or immediately after giving birth. First, your healthcare provider will examine your pelvis to find the exact position of your uterus. Your healthcare provider will then clean your vagina and cervix with an antiseptic solution and slide a slim plastic tube containing Skyla through the cervix into your uterus. Your healthcare provider will then remove the plastic tube, and leave Skyla in your uterus. Your healthcare provider will cut the threads to the right length. You may experience pain, bleeding or dizziness during and after placement. If your symptoms do not pass within 30 minutes after placement, Skyla may not have been placed correctly. Your healthcare provider will examine you to see if Skyla needs to be removed or replaced. Should I check that Skyla is in place? Yes, you should check that Skyla is in proper position by feeling the removal threads. It is a good habit to do this 1 time a month. Your healthcare provider should teach you how to check that Skyla is in place. First, wash your hands with soap and water. You can check by reaching up to the top of your vagina with clean fingers to feel the removal threads. Do not pull on the threads.

the removal threads. It is a good habit to do this 1 time a month. Your healthcare provider should teach you how to check that Skyla is in place. First, wash your hands with soap and water. You can check by reaching up to the top of your vagina with clean fingers to feel the removal threads. Do not pull on the threads. If you feel more than just the threads or if you cannot feel the threads, Skyla may not be in the right position and may not prevent pregnancy. Avoid intercourse or use non-hormonal back-up birth control (such as condoms or spermicide) and ask your healthcare provider to check that Skyla is still in the right place. How soon after placement of Skyla should I return to my healthcare provider? Call your healthcare provider if you have any questions or concerns (see “When should I call my healthcare provider?”). Otherwise, you should return to your healthcare provider for a follow-up visit 4 to 6 weeks after Skyla is placed to make sure that Skyla is in the right position. Can I use tampons or menstrual cups with Skyla? Yes, tampons or menstrual cups may be used with Skyla. Change tampons or menstrual cups with care to avoid pulling the threads of Skyla. If you think you may have pulled Skyla out of place, avoid intercourse or use a non-hormonal back-up birth control (such as condoms or spermicide), and contact your healthcare provider. What if I become pregnant while using Skyla? Call your healthcare provider right away if you think you may be pregnant. If possible, also do a urine pregnancy test. If you get pregnant while using Skyla, you may have an ectopic pregnancy. This means that the pregnancy is not in the uterus. Unusual vaginal bleeding or abdominal pain may be a sign of ectopic pregnancy. Ectopic pregnancy is a medical emergency that often requires surgery. Ectopic pregnancy can cause internal bleeding, infertility, and even death. There are also risks if you get pregnant while using Skyla and the pregnancy is in the uterus. Severe infection, miscarriage, premature delivery, and even death can occur with pregnancies that continue with an intrauterine device (IUD). Because of this, your healthcare provider may try to remove Skyla, even though removing it may cause a miscarriage. If Skyla cannot be removed, talk with your healthcare provider about the benefits and risks of continuing the pregnancy and possible effects of the hormone on your unborn baby. If you continue your pregnancy, see your healthcare provider regularly. Call your healthcare provider right away if you get flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge, or fluid leaking from your vagina. These may be signs of infection. How will Skyla change my periods? For the first 3 to 6 months, your period may become irregular and the number of bleeding days may increase. You may also have frequent spotting or light bleeding. Some women have heavy bleeding during this time. You may also have cramping during the first few weeks. After you have used Skyla for a while, the number of bleeding and spotting days is likely to lessen. For some women, periods will stop altogether. When Skyla is removed, your menstrual periods should return. Is it safe to breastfeed while using Skyla? You may use Skyla when you are breastfeeding. Skyla is not likely to affect the quality or amount of your breast milk or the health of your nursing baby. However, isolated cases of decreased milk production have been reported. The risk of Skyla going into the wall of the uterus (becoming embedded) or going through the wall of the uterus is increased if Skyla is inserted while you are breastfeeding. Will Skyla interfere with sexual intercourse? You and your partner should not feel Skyla during intercourse. Skyla is placed in the uterus, not in the vagina.

kyla going into the wall of the uterus (becoming embedded) or going through the wall of the uterus is increased if Skyla is inserted while you are breastfeeding. Will Skyla interfere with sexual intercourse? You and your partner should not feel Skyla during intercourse. Skyla is placed in the uterus, not in the vagina. Sometimes your partner may feel the threads. If this occurs, or if you or your partner experience pain during sex, talk with your healthcare provider. Can I have an MRI with Skyla in place? Skyla can be safely scanned with MRI only under specific conditions. Before you have an MRI, tell your healthcare provider that you have Skyla, an intrauterine device (IUD), in place. What are the possible side effects of Skyla? Skyla can cause serious side effects, including: • Ectopic pregnancy and intrauterine pregnancy risks. There are risks if you become pregnant while using Skyla (see “What if I become pregnant while using Skyla?”). • Life-threatening infection. Life-threatening infection can occur within the first few days after Skyla is placed. Call your healthcare provider immediately if you develop severe pain or fever shortly after Skyla is placed. • Pelvic inflammatory disease (PID). Some IUD users get a serious pelvic infection called pelvic inflammatory disease. PID is usually sexually transmitted. You have a higher chance of getting PID if you or your partner has sex with other partners. PID can cause serious problems such as infertility, ectopic pregnancy or pelvic pain that does not go away. PID is usually treated with antibiotics. More serious cases of PID may require surgery including removal of the uterus (hysterectomy). In rare cases, infections that start as PID can even cause death. Tell your healthcare provider right away if you have any of these signs of PID: long-lasting or heavy bleeding, unusual vaginal discharge, low abdominal (stomach area) pain, painful sex, chills, fever, genital lesions or sores. • Perforation. Skyla may go into the wall of the uterus (become embedded) or go through the wall of the uterus. This is called perforation. If this occurs, Skyla may no longer prevent pregnancy. If perforation occurs, Skyla may move outside the uterus and can cause internal scarring, infection, or damage to other organs, and you may need surgery to have Skyla removed. Excessive pain or vaginal bleeding during placement of Skyla, pain or bleeding that gets worse after placement, or not being able to feel the threads may happen with perforation. The risk of perforation is increased if Skyla is inserted while you are breastfeeding, or if you have recently given birth. • Expulsion. Skyla may come out by itself. This is called expulsion. Expulsion occurs in about 3 out of 100 women. Excessive pain or vaginal bleeding during placement of Skyla, pain or bleeding that gets worse after placement, or not being able to feel the threads may happen with expulsion. You may become pregnant if Skyla comes out. If you think that Skyla has come out, avoid intercourse or use a non-hormonal backup birth control (such as condoms or spermicide) and call your healthcare provider. The risk of expulsion is increased with insertion right after delivery or second-trimester abortion. Common side effects of Skyla include: • Pain, bleeding or dizziness during and after placement. If these symptoms do not stop 30 minutes after placement, Skyla may not have been placed correctly. Your healthcare provider will examine you to see if Skyla needs to be removed or replaced. • Changes in bleeding. You may have bleeding and spotting between menstrual periods, especially during the first 3–6 months. Sometimes the bleeding is heavier than usual at first. However, the bleeding usually becomes lighter than usual and may be irregular.

examine you to see if Skyla needs to be removed or replaced. • Changes in bleeding. You may have bleeding and spotting between menstrual periods, especially during the first 3–6 months. Sometimes the bleeding is heavier than usual at first. However, the bleeding usually becomes lighter than usual and may be irregular. Call your healthcare provider if the bleeding remains heavier than usual or increases after it has been light for a while. • Missed menstrual periods. About 1 out of 16 women stop having periods after 1 year of Skyla use. If you have any concerns that you may be pregnant while using Skyla, do a urine pregnancy test and call your healthcare provider. If you do not have a period for 6 weeks during Skyla use, call your healthcare provider. When Skyla is removed, your menstrual periods should return. • Cysts on the ovary. About 14 out of 100 women using Skyla develop a cyst on the ovary. These cysts usually disappear on their own in two to three months. However, cysts can cause pain and sometimes cysts will need surgery. Other common side effects include: • abdominal or pelvic pain • acne or greasy skin • headache or migraine • inflammation or infection of the outer part of your vagina (vulvovaginitis) • painful periods These are not all of the possible side effects with Skyla. For more information, ask your healthcare provider. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Bayer Healthcare Pharmaceuticals at 1-888-842-2937. After Skyla has been placed, when should I call my healthcare provider? If Skyla is accidentally removed and you had vaginal intercourse within the preceding week, you may be at risk of pregnancy, and you should talk to a healthcare provider. Call your healthcare provider if you have any concerns about Skyla. Be sure to call if you: • think you are pregnant • have pelvic pain, abdominal pain, or pain during sex • have unusual vaginal discharge or genital sores • have unexplained fever, flu-like symptoms or chills • might be exposed to sexually transmitted infections (STIs) • are concerned that Skyla may have been expelled (came out) • cannot feel Skyla's threads • develop very severe or migraine headaches • have yellowing of the skin or whites of the eyes. These may be signs of liver problems. • have had a stroke or heart attack • become HIV positive or your partner becomes HIV positive • have severe vaginal bleeding or bleeding that lasts a long time or concerns you General advice about the safe and effective use of Skyla Medicines are sometimes prescribed for conditions other than those listed in patient information leaflets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about Skyla that is written for healthcare professionals. What are the ingredients in Skyla? Active ingredient: levonorgestrel Inactive ingredients: silicone, polyethylene, silver, silica, barium sulfate, iron oxide Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981 © 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. For more information, go to www.skyla-us.com or call 1-888-842-2937. This Patient Information has been approved by the U.S. Food and Drug Administration. 7/2021 Skyla is small Skyla is Flexible Uterus Pregnancy Chart

<table width="100%"><col width="51%"/><col width="49%"/><tbody><tr><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Patient Information</content></paragraph><paragraph><content styleCode="bold">Skyla (sky-lah)</content></paragraph><paragraph>(levonorgestrel-releasing intrauterine system)</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Read this Patient Information carefully before you decide if Skyla is right for you. This information does not take the place of talking with your gynecologist or other healthcare provider who specializes in women&#x2019;s health. If you have any questions about Skyla, ask your healthcare provider. You should also learn about other birth control methods to choose the one that is best for you.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skyla does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs).</content></paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What is Skyla?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Skyla is a hormone-releasing system placed in your uterus by your healthcare provider to prevent pregnancy for up to 3 years.</item><item><caption>&#x2022;</caption>Skyla can be removed by your healthcare provider at any time.</item><item><caption>&#x2022;</caption>Skyla can be used whether or not you have given birth to a child.</item></list><paragraph>Skyla is a small, flexible plastic T-shaped system that slowly releases a progestin hormone called levonorgestrel (LNG) that is often used in birth control pills. Because Skyla releases LNG into your uterus, only small amounts of the hormone enter your blood. Skyla does not contain estrogen.</paragraph><paragraph>Two thin threads are attached to the stem (lower end) of Skyla. The threads are the only part of Skyla you can feel when Skyla is in your uterus; however, unlike a tampon string, the threads do not extend outside your body.</paragraph></td></tr><tr><td align="center" styleCode="Lrule Botrule " valign="top"><renderMultiMedia ID="id-1428654908" referencedObject="E6BCC43D-5CDE-455E-A826-554072558642"/><paragraph>Skyla is small</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><renderMultiMedia ID="id1852380331" referencedObject="C0E4DF8D-0FC8-456D-8517-571432A0A476"/><paragraph>and flexible</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What if I need birth control for more than 3 years?</content></paragraph><paragraph>Skyla must be removed after 3 years. Your healthcare provider can place a new Skyla during the same office visit if you choose to continue using Skyla.</paragraph><paragraph><content styleCode="bold">What if I want to stop using Skyla?</content></paragraph><paragraph>Skyla is intended for use up to 3 years but you can stop using Skyla at any time by asking your healthcare provider to remove it. You could become pregnant as soon as Skyla is removed, so you should use another method of birth control if you do not want to become pregnant.

p using Skyla?</content></paragraph><paragraph>Skyla is intended for use up to 3 years but you can stop using Skyla at any time by asking your healthcare provider to remove it. You could become pregnant as soon as Skyla is removed, so you should use another method of birth control if you do not want to become pregnant. Talk to your healthcare provider about the best birth control methods for you, because your new method may need to be started 7 days before Skyla is removed to prevent pregnancy.</paragraph><paragraph><content styleCode="bold">What if I change my mind about birth control and want to become pregnant in less than 3 years?</content></paragraph><paragraph>Your healthcare provider can remove Skyla at any time. You may become pregnant as soon as Skyla is removed. About 3 out of 4 women who want to become pregnant will become pregnant sometime in the first year after Skyla is removed.</paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How does Skyla work?</content></paragraph><paragraph>Skyla may work in several ways including thickening cervical mucus, inhibiting sperm movement, reducing sperm survival, and thinning the lining of your uterus. It is not known exactly how these actions work together to prevent pregnancy.</paragraph><renderMultiMedia ID="id-1360653765" referencedObject="ID_15277c84-30db-4d49-abf3-130c40151807"/></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How well does Skyla work for contraception?</content></paragraph><paragraph>The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.</paragraph><paragraph>Skyla, an intrauterine device (IUD) also known as an intrauterine system (IUS),, is in the box at the top of the chart.</paragraph><renderMultiMedia ID="id-1627768992" referencedObject="ID_9be895cd-46f9-4fc6-93e1-3bf3261962e9"/><paragraph><content styleCode="bold">Who might use Skyla?

et pregnant.</paragraph><paragraph>Skyla, an intrauterine device (IUD) also known as an intrauterine system (IUS),, is in the box at the top of the chart.</paragraph><renderMultiMedia ID="id-1627768992" referencedObject="ID_9be895cd-46f9-4fc6-93e1-3bf3261962e9"/><paragraph><content styleCode="bold">Who might use Skyla? </content></paragraph><paragraph>You might choose Skyla if you:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>want long-term birth control that provides a low chance of getting pregnant (less than 1 in 100)</item><item><caption>&#x2022;</caption>want birth control that works continuously for up to 3 years </item><item><caption>&#x2022;</caption>want birth control that is reversible</item><item><caption>&#x2022;</caption>want a birth control method that you do not need to take daily</item><item><caption>&#x2022;</caption>are willing to use a birth control method that is placed in the uterus </item><item><caption>&#x2022;</caption>want birth control that does not contain estrogen</item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Do not use Skyla if you:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>are or might be pregnant; Skyla cannot be used as an emergency contraceptive </item><item><caption>&#x2022;</caption>have a serious pelvic infection called pelvic inflammatory disease (PID) or have had PID in the past unless you have had a normal pregnancy after the infection went away</item><item><caption>&#x2022;</caption>have an untreated genital infection now</item><item><caption>&#x2022;</caption>have had a serious pelvic infection in the past 3 months after a pregnancy</item><item><caption>&#x2022;</caption>can get infections easily.

you have had a normal pregnancy after the infection went away</item><item><caption>&#x2022;</caption>have an untreated genital infection now</item><item><caption>&#x2022;</caption>have had a serious pelvic infection in the past 3 months after a pregnancy</item><item><caption>&#x2022;</caption>can get infections easily. For example, if you:</item><item><caption>&#x2022;</caption>have multiple sexual partners or your partner has multiple sexual partners</item><item><caption>&#x2022;</caption>have problems with your immune system</item><item><caption>&#x2022;</caption>use or abuse intravenous drugs</item><item><caption>&#x2022;</caption>have or suspect you might have cancer of the uterus or cervix</item><item><caption>&#x2022;</caption>have bleeding from the vagina that has not been explained</item><item><caption>&#x2022;</caption>have liver disease or a liver tumor</item><item><caption>&#x2022;</caption>have breast cancer or any other cancer that is sensitive to progestin (a female hormone), now or in the past</item><item><caption>&#x2022;</caption>have an intrauterine device in your uterus already</item><item><caption>&#x2022;</caption>have a condition of the uterus that changes the shape of the uterine cavity, such as large fibroid tumors</item><item><caption>&#x2022;</caption>are allergic to levonorgestrel, silicone, polyethylene, silver, silica, barium sulfate or iron oxide</item></list><paragraph><content styleCode="bold">Before having Skyla placed, tell your healthcare provider about all of your medical conditions including if you:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>have any of the conditions listed above</item><item><caption>&#x2022;</caption>have had a heart attack</item><item><caption>&#x2022;</caption>have had a stroke</item><item><caption>&#x2022;</caption>were born with heart disease or have problems with your heart valves</item><item><caption>&#x2022;</caption>have problems with blood clotting or take medicine to reduce clotting</item><item><caption>&#x2022;</caption>have high blood pressure</item><item><caption>&#x2022;</caption>recently had a baby or are breastfeeding</item><item><caption>&#x2022;</caption>have severe headaches or migraine headaches</item><item><caption>&#x2022;</caption>have AIDS, HIV, or any other sexually transmitted infection</item></list><paragraph>Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How is Skyla placed?</content></paragraph><paragraph>Skyla is placed by your healthcare provider during an in-office visit or immediately after giving birth.</paragraph><paragraph>First, your healthcare provider will examine your pelvis to find the exact position of your uterus. Your healthcare provider will then clean your vagina and cervix with an antiseptic solution and slide a slim plastic tube containing Skyla through the cervix into your uterus. Your healthcare provider will then remove the plastic tube, and leave Skyla in your uterus. Your healthcare provider will cut the threads to the right length.</paragraph><paragraph>You may experience pain, bleeding or dizziness during and after placement. If your symptoms do not pass within 30 minutes after placement, Skyla may not have been placed correctly. Your healthcare provider will examine you to see if Skyla needs to be removed or replaced.</paragraph><paragraph><content styleCode="bold">Should I check that Skyla is in place?</content></paragraph><paragraph>Yes, you should check that Skyla is in proper position by feeling the removal threads. It is a good habit to do this 1 time a month.

er will examine you to see if Skyla needs to be removed or replaced.</paragraph><paragraph><content styleCode="bold">Should I check that Skyla is in place?</content></paragraph><paragraph>Yes, you should check that Skyla is in proper position by feeling the removal threads. It is a good habit to do this 1 time a month. Your healthcare provider should teach you how to check that Skyla is in place. First, wash your hands with soap and water. You can check by reaching up to the top of your vagina with clean fingers to feel the removal threads. Do not pull on the threads. If you feel more than just the threads or if you cannot feel the threads, Skyla may not be in the right position and may not prevent pregnancy. Avoid intercourse or use non-hormonal back-up birth control (such as condoms or spermicide) and ask your healthcare provider to check that Skyla is still in the right place.</paragraph><paragraph><content styleCode="bold">How soon after placement of Skyla should I return to my healthcare provider?</content></paragraph><paragraph>Call your healthcare provider if you have any questions or concerns (see &#x201C;When should I call my healthcare provider?&#x201D;). Otherwise, you should return to your healthcare provider for a follow-up visit 4 to 6 weeks after Skyla is placed to make sure that Skyla is in the right position.</paragraph><paragraph><content styleCode="bold">Can I use tampons or menstrual cups with Skyla?</content></paragraph><paragraph>Yes, tampons or menstrual cups may be used with Skyla. Change tampons or menstrual cups with care to avoid pulling the threads of Skyla. If you think you may have pulled Skyla out of place, avoid intercourse or use a non-hormonal back-up birth control (such as condoms or spermicide), and contact your healthcare provider.</paragraph><paragraph><content styleCode="bold">What if I become pregnant while using Skyla?</content></paragraph><paragraph>Call your healthcare provider right away if you think you may be pregnant. If possible, also do a urine pregnancy test. If you get pregnant while using Skyla, you may have an ectopic pregnancy. This means that the pregnancy is not in the uterus. Unusual vaginal bleeding or abdominal pain may be a sign of ectopic pregnancy.</paragraph><paragraph>Ectopic pregnancy is a medical emergency that often requires surgery. Ectopic pregnancy can cause internal bleeding, infertility, and even death.</paragraph><paragraph>There are also risks if you get pregnant while using Skyla and the pregnancy is in the uterus. Severe infection, miscarriage, premature delivery, and even death can occur with pregnancies that continue with an intrauterine device (IUD). Because of this, your healthcare provider may try to remove Skyla, even though removing it may cause a miscarriage. If Skyla cannot be removed, talk with your healthcare provider about the benefits and risks of continuing the pregnancy and possible effects of the hormone on your unborn baby. </paragraph><paragraph>If you continue your pregnancy, see your healthcare provider regularly. Call your healthcare provider right away if you get flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge, or fluid leaking from your vagina. These may be signs of infection.</paragraph><paragraph><content styleCode="bold">How will Skyla change my periods? </content></paragraph><paragraph>For the first 3 to 6 months, your period may become irregular and the number of bleeding days may increase. You may also have frequent spotting or light bleeding. Some women have heavy bleeding during this time. You may also have cramping during the first few weeks. After you have used Skyla for a while, the number of bleeding and spotting days is likely to lessen. For some women, periods will stop altogether.

may increase. You may also have frequent spotting or light bleeding. Some women have heavy bleeding during this time. You may also have cramping during the first few weeks. After you have used Skyla for a while, the number of bleeding and spotting days is likely to lessen. For some women, periods will stop altogether. When Skyla is removed, your menstrual periods should return.</paragraph><paragraph><content styleCode="bold">Is it safe to breastfeed while using Skyla?</content></paragraph><paragraph>You may use Skyla when you are breastfeeding. Skyla is not likely to affect the quality or amount of your breast milk or the health of your nursing baby. However, isolated cases of decreased milk production have been reported. The risk of Skyla going into the wall of the uterus (becoming embedded) or going through the wall of the uterus is increased if Skyla is inserted while you are breastfeeding. </paragraph><paragraph><content styleCode="bold">Will Skyla interfere with sexual intercourse?</content></paragraph><paragraph>You and your partner should not feel Skyla during intercourse. Skyla is placed in the uterus, not in the vagina. Sometimes your partner may feel the threads. If this occurs, or if you or your partner experience pain during sex, talk with your healthcare provider.</paragraph><paragraph><content styleCode="bold">Can I have an MRI with Skyla in place?</content></paragraph><paragraph>Skyla can be safely scanned with MRI only under specific conditions. Before you have an MRI, tell your healthcare provider that you have Skyla, an intrauterine device (IUD), in place.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are the possible side effects of Skyla?</content></paragraph><paragraph><content styleCode="bold">Skyla can cause serious side effects, including:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Ectopic pregnancy and intrauterine pregnancy risks.</content> There are risks if you become pregnant while using Skyla (see &#x201C;What if I become pregnant while using Skyla?&#x201D;). </item><item><caption>&#x2022;</caption><content styleCode="bold">Life-threatening infection.</content> Life-threatening infection can occur within the first few days after Skyla is placed. Call your healthcare provider immediately if you develop severe pain or fever shortly after Skyla is placed.</item><item><caption>&#x2022;</caption><content styleCode="bold">Pelvic inflammatory disease (PID).</content> Some IUD users get a serious pelvic infection called pelvic inflammatory disease. PID is usually sexually transmitted. You have a higher chance of getting PID if you or your partner has sex with other partners. PID can cause serious problems such as infertility, ectopic pregnancy or pelvic pain that does not go away. PID is usually treated with antibiotics. More serious cases of PID may require surgery including removal of the uterus (hysterectomy). In rare cases, infections that start as PID can even cause death.</item><item><caption> </caption>Tell your healthcare provider right away if you have any of these signs of PID: long-lasting or heavy bleeding, unusual vaginal discharge, low abdominal (stomach area) pain, painful sex, chills, fever, genital lesions or sores.</item><item><caption>&#x2022;</caption><content styleCode="bold">Perforation.</content> Skyla may go into the wall of the uterus (become embedded) or go through the wall of the uterus. This is called perforation. If this occurs, Skyla may no longer prevent pregnancy. If perforation occurs, Skyla may move outside the uterus and can cause internal scarring, infection, or damage to other organs, and you may need surgery to have Skyla removed.

terus (become embedded) or go through the wall of the uterus. This is called perforation. If this occurs, Skyla may no longer prevent pregnancy. If perforation occurs, Skyla may move outside the uterus and can cause internal scarring, infection, or damage to other organs, and you may need surgery to have Skyla removed. Excessive pain or vaginal bleeding during placement of Skyla, pain or bleeding that gets worse after placement, or not being able to feel the threads may happen with perforation. The risk of perforation is increased if Skyla is inserted while you are breastfeeding, or if you have recently given birth.</item><item><caption>&#x2022;</caption><content styleCode="bold">Expulsion.</content> Skyla may come out by itself. This is called expulsion. Expulsion occurs in about 3 out of 100 women. Excessive pain or vaginal bleeding during placement of Skyla, pain or bleeding that gets worse after placement, or not being able to feel the threads may happen with expulsion. You may become pregnant if Skyla comes out. If you think that Skyla has come out, avoid intercourse or use a non-hormonal backup birth control (such as condoms or spermicide) and call your healthcare provider. The risk of expulsion is increased with insertion right after delivery or second-trimester abortion. </item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Common side effects of Skyla include: </content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Pain, bleeding or dizziness during and after placement.</content> If these symptoms do not stop 30 minutes after placement, Skyla may not have been placed correctly. Your healthcare provider will examine you to see if Skyla needs to be removed or replaced.</item><item><caption>&#x2022;</caption><content styleCode="bold">Changes in bleeding.</content> You may have bleeding and spotting between menstrual periods, especially during the first 3&#x2013;6 months. Sometimes the bleeding is heavier than usual at first. However, the bleeding usually becomes lighter than usual and may be irregular. Call your healthcare provider if the bleeding remains heavier than usual or increases after it has been light for a while.</item><item><caption>&#x2022;</caption><content styleCode="bold">Missed menstrual periods.</content> About 1 out of 16 women stop having periods after 1 year of Skyla use. If you have any concerns that you may be pregnant while using Skyla, do a urine pregnancy test and call your healthcare provider. If you do not have a period for 6 weeks during Skyla use, call your healthcare provider. When Skyla is removed, your menstrual periods should return.</item><item><caption>&#x2022;</caption><content styleCode="bold">Cysts on the ovary.</content> About 14 out of 100 women using Skyla develop a cyst on the ovary. These cysts usually disappear on their own in two to three months. However, cysts can cause pain and sometimes cysts will need surgery.</item></list><paragraph>Other common side effects include:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>abdominal or pelvic pain</item><item><caption>&#x2022;</caption>acne or greasy skin</item><item><caption>&#x2022;</caption>headache or migraine</item><item><caption>&#x2022;</caption>inflammation or infection of the outer part of your vagina (vulvovaginitis)</item><item><caption>&#x2022;</caption>painful periods</item></list><paragraph>These are not all of the possible side effects with Skyla. For more information, ask your healthcare provider.</paragraph><paragraph><content styleCode="bold">Call your doctor for medical advice about side effects.</content> You may report side effects to FDA at 1-800-FDA-1088.

n>painful periods</item></list><paragraph>These are not all of the possible side effects with Skyla. For more information, ask your healthcare provider.</paragraph><paragraph><content styleCode="bold">Call your doctor for medical advice about side effects.</content> You may report side effects to FDA at 1-800-FDA-1088. </paragraph><paragraph>You may also report side effects to Bayer Healthcare Pharmaceuticals at 1-888-842-2937.</paragraph><paragraph><content styleCode="bold">After Skyla has been placed, when should I call my healthcare provider?</content></paragraph><paragraph>If Skyla is accidentally removed and you had vaginal intercourse within the preceding week, you may be at risk of pregnancy, and you should talk to a healthcare provider.</paragraph><paragraph>Call your healthcare provider if you have any concerns about Skyla. Be sure to call if you:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>think you are pregnant</item><item><caption>&#x2022;</caption>have pelvic pain, abdominal pain, or pain during sex</item><item><caption>&#x2022;</caption>have unusual vaginal discharge or genital sores</item><item><caption>&#x2022;</caption>have unexplained fever, flu-like symptoms or chills</item><item><caption>&#x2022;</caption>might be exposed to sexually transmitted infections (STIs)</item><item><caption>&#x2022;</caption>are concerned that Skyla may have been expelled (came out)</item><item><caption>&#x2022;</caption>cannot feel Skyla&apos;s threads</item><item><caption>&#x2022;</caption>develop very severe or migraine headaches</item><item><caption>&#x2022;</caption>have yellowing of the skin or whites of the eyes. These may be signs of liver problems.</item><item><caption>&#x2022;</caption>have had a stroke or heart attack</item><item><caption>&#x2022;</caption>become HIV positive or your partner becomes HIV positive</item><item><caption>&#x2022;</caption>have severe vaginal bleeding or bleeding that lasts a long time or concerns you</item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General advice about the safe and effective use of Skyla</content></paragraph><paragraph>Medicines are sometimes prescribed for conditions other than those listed in patient information leaflets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about Skyla that is written for healthcare professionals.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in Skyla?</content></paragraph><paragraph>Active ingredient: levonorgestrel</paragraph><paragraph>Inactive ingredients: silicone, polyethylene, silver, silica, barium sulfate, iron oxide</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Manufactured for: Bayer HealthCare Pharmaceuticals Inc.</paragraph><paragraph>Whippany, NJ 07981</paragraph><paragraph>&#xA9; 2013, Bayer HealthCare Pharmaceuticals Inc.</paragraph><paragraph>All rights reserved.</paragraph><paragraph>For more information, go to www.skyla-us.com or call 1-888-842-2937.</paragraph></td></tr></tbody></table>

Indications and Usage, Heavy Menstrual Bleeding ( 1.2 ) 06/2023 Dosage and Administration, Dosing Over Time ( 2.1 ) 06/2023 Dosage and Administration, Insertion Instructions ( 2.3 ) 11/2022 Dosage and Administration, Removal of LILETTA ( 2.6 ) 06/2023 Contraindications ( 4 ) 06/2023 Warnings and Precautions, Expulsion ( 5.6 ) 06/2023

<table><col width="343"/><col width="343"/><tbody><tr><td>Indications and Usage, Heavy Menstrual Bleeding (<linkHtml href="#_1_2_Heavy_Menstrual">1.2</linkHtml>)</td><td>06/2023</td></tr><tr><td>Dosage and Administration, Dosing Over Time (<linkHtml href="#_2_1_Dosing_Over_1">2.1</linkHtml>)</td><td>06/2023</td></tr><tr><td>Dosage and Administration, Insertion Instructions (<linkHtml href="#_2_3_Insertion_Instructions_1">2.3</linkHtml>)</td><td>11/2022</td></tr><tr><td>Dosage and Administration, Removal of LILETTA (<linkHtml href="#_2_6_Removal_of">2.6</linkHtml>)</td><td>06/2023</td></tr><tr><td>Contraindications (<linkHtml href="#_4_CONTRAINDICATIONS">4</linkHtml>)</td><td>06/2023</td></tr><tr><td>Warnings and Precautions, Expulsion (<linkHtml href="#_5_6_Expulsion">5.6</linkHtml>)</td><td>06/2023</td></tr></tbody></table>

1 INDICATIONS AND USAGE LILETTA is a progestin-containing intrauterine system indicated for: Prevention of pregnancy for up to 8 years ( 1.1 ) Treatment of heavy menstrual bleeding for up to 5 years in patients who choose intrauterine contraception as their method of contraception ( 1.2 ) 1.1 Contraception LILETTA is indicated for prevention of pregnancy for up to 8 years. 1.2 Heavy Menstrual Bleeding LILETTA is indicated for the treatment of heavy menstrual bleeding for up to 5 years in patients 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.

2 DOSAGE AND ADMINISTRATION The initial release rate of levonorgestrel (LNG) is approximately 20 mcg/day and declines progressively to approximately 6.5 mcg/day after 8 years; LILETTA can be removed at any time but must be removed by the end of the eighth year. ( 2.1 ) To be inserted into the uterine cavity with the provided inserter by a trained healthcare professional using strict aseptic technique. Follow insertion instructions exactly as described. ( 2.3 ) Re-examination and evaluation should be considered 4 to 6 weeks after insertion and during routine care, or more often if clinically indicated. ( 2.5 ) Figure 1a Figure 1b Figure 2 Figure 3 Figure 4 Figure 5 Figure 6: Close-up of Hemispherical Dome at Tip of Tube Figure 7 Figure 8 Figure 9: Releasing and Opening the Arms of the IUS Figure 10: Move LILETTA into the Fundal Position Figure 11: Releasing LILETTA from the Inserter Tube Figure 12 Figure 13 Figure 14: Removal of LILETTA 2. 1 Dosing Over Time LILETTA contains 52 mg of levonorgestrel (LNG). Initially, LNG is released in vivo at a rate of approximately 20 mcg/day. This rate decreases progressively to approximately 6.5 mcg/day after 8 years. The average in vivo release rate of LNG is approximately 13.5 mcg/day over a period of 8 years. For contraception, remove LILETTA by the end of the eighth year. LILETTA can be replaced at the time of removal with a new LILETTA if continued contraceptive protection is desired. For treatment of heavy menstrual bleeding, replace LILETTA by the end of the fifth year if continued use is needed. 2.2 Timing of Insertion Refer to Table 1 for instructions on when to start use of LILETTA. Table 1: When to Insert LILETTA Starting LILETTA in patients not currently using hormonal or intrauterine contraception LILETTA can be inserted any time there is reasonable certainty the patient is not pregnant. Consider the possibility of ovulation and conception prior to initiation of LILETTA [see Contraindications ( 4 )] . If LILETTA is inserted after the first 7 days of the menstrual cycle, the patient should use a barrier method of contraception (such as condoms) or abstain from vaginal intercourse for 7 days after insertion to prevent pregnancy. Switching to LILETTA from an oral, transdermal , or vaginal hormonal contraceptive LILETTA may be inserted at any time during the hormone-free interval of the previous method. If LILETTA is inserted during active use of the previous method, continue that method for 7 days after LILETTA insertion or until the end of the current treatment cycle. If using continuous hormonal contraception, discontinue that method 7 days after LILETTA insertion. Switching to LILETTA from an injectable progestin contraceptive LILETTA may be inserted at any time. If LILETTA is inserted more than 3 months (13 weeks) after the last injection, the patient should use a barrier method of contraception (such as condoms) or abstain from vaginal intercourse for 7 days after insertion to prevent pregnancy. Switching to LILETTA from a contraceptive implant or another IUS Insert LILETTA on the same day the implant or IUS is removed. This switch to LILETTA may be at any time during the menstrual cycle. Back-up contraception is not needed. Inserting LILETTA after pregnancy After f irst-trimester abortion or miscarriage LILETTA may be inserted immediately after a first-trimester surgical or completed medical abortion or miscarriage, unless it is a septic abortion [ see Contraindications ( 4 )] .

ng the menstrual cycle. Back-up contraception is not needed. Inserting LILETTA after pregnancy After f irst-trimester abortion or miscarriage LILETTA may be inserted immediately after a first-trimester surgical or completed medical abortion or miscarriage, unless it is a septic abortion [ see Contraindications ( 4 )] . Back-up contraception is not needed. After childbirth or second-trimester abortion or miscarriage If immediate, insert LILETTA after expulsion/removal of the placenta, unless infection is present. [See Contraindication ( 4 ), Warnings and Precautions ( 5.5 , 5.6 ), Adverse Reactions ( 6.1 )] Back-up contraception is not needed. If not immediate: Delay inserting LILETTA a minimum of 4 weeks or until the uterus is fully involuted [see Warnings and Precautions ( 5.5 , 5.6 ) , Adverse Reactions ( 6.1 ) ] . If the patient has not yet had a period, consider the possibility of ovulation and conception occurring prior to insertion of LILETTA [ s ee Contraindications ( 4 ) , Warnings and Precautions ( 5.2 ) , and FDA-Approved Patient Labeling ] . LILETTA can be inserted any time there is reasonable certainty the patient is not pregnant. If LILETTA is not inserted during the first 7 days of the menstrual cycle, the patient should use a barrier method of contraception (such as condoms) or abstain from vaginal intercourse for 7 days after insertion to prevent pregnancy [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 ) ]. The risk of perforation may be increased if an IUS is inserted in a lactating woman [see Warnings and Precautions ( 5.5 ) ] . 2.3 Insertion Instructions LILETTA (Figure 1a) is provided in a tray, sealed with a peel-off lid and is inserted into the uterine cavity with the provided inserter (Figure 1b) [ see Description ( 11 ) ] by carefully following the insertion instructions. 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 ) ] . LILETTA is for single use only. Note: The inserter provided with LILETTA (see Figure 1b) and the Insertion Instructions in this section are not applicable for immediate insertion after childbirth or second-trimester abortion or miscarriage. For immediate insertion, remove LILETTA from the inserter by pulling LILETTA out of the top of the inserter and insert according to accepted practice. Figure 1 a: LILETTA Intrauterine Contraceptive System (IUS) Figure 1b : LILETTA IU S with Inserter The LILETTA IUS is packaged partially preloaded within the inserter. The threads are passed through the insertion tube and exit through an opening in the handle at the cleft. The handle of the inserter contains a BLUE slider labeled with the number 1 and a GREEN slider labeled with the number 2. The handle is labeled with the number 3. The sliders are labeled with the numbers 1 and 2, and the handle is labeled with the number 3 to assist with the insertion process (Figure 2). Moving the sliders achieves the positions required to complete the insertion process. F igure 2 : Inserter Slider s Planning for I nsertion LILETTA should only be inserted by a trained healthcare professional. Healthcare professionals should become thoroughly familiar with the product, product educational materials, product insertion instructions, prescribing information, and patient labeling before attempting insertion of LILETTA. Obtain a complete medical and social history to determine conditions that might influence the selection of LILETTA for contraception. If indicated, perform a physical examination and appropriate tests for genital or sexually transmitted infections. 1 [See Contraindications ( 4 ) and Warnings and Precautions ( 5.4 , 5.10 )]. Check the expiration date on the box before opening it.

ditions that might influence the selection of LILETTA for contraception. If indicated, perform a physical examination and appropriate tests for genital or sexually transmitted infections. 1 [See Contraindications ( 4 ) and Warnings and Precautions ( 5.4 , 5.10 )]. Check the expiration date on the box before opening it. Do not insert LILETTA after the expiration date. Visually inspect the packaging containing LILETTA to verify that the packaging has not been damaged (e.g., torn, punctured, etc.). If the packaging has any visual damage that could compromise sterility, do not use the unit for insertion [see Warnings and Precautions ( 5.3 )]. Complete the pelvic examination, speculum placement, tenaculum placement, and sounding of the uterus before opening the LILETTA packaging. Do not open the packaging to insert LILETTA if the following clinical findings occur: the cervix is unable to be properly visualized the uterus cannot be adequately instrumented (during sounding) the uterus sounds to less than 5.5 cm Preparation for Insertion Ensure all needed items for LILETTA insertion are readily available: Gloves Sterile speculum Sterile uterine sound Sterile tenaculum Antiseptic solution LILETTA with inserter tray, sealed with a peel-off lid Sterile, blunt-tipped scissors Additional items may be useful: Local anesthesia, needle, and syringe Sterile os finder and/or cervical dilators Ultrasound with abdominal probe Exclude pregnancy and confirm that there are no other contraindications to the insertion and use of LILETTA. Follow the insertion instructions exactly as described to ensure proper insertion. If you encounter cervical stenosis at any time during uterine sounding or LILETTA insertion, use cervical dilators, not force, to overcome resistance. If necessary, dilation, sounding, and insertion may be performed with ultrasound guidance. Insertion may be associated with some pain and/or bleeding or vasovagal reactions (e.g., diaphoresis, syncope, bradycardia, or seizure), especially in patients with a predisposition to these conditions. Consider administering analgesics prior to insertion. Use aseptic technique during the entire insertion procedure. Insertion P rocedure The overall insertion process is conducted in 5 steps. Step 1 – Preparation of Patient for Insertion With the patient comfortably in lithotomy position, do a bimanual exam to establish the size, shape, and position of the uterus and to evaluate any signs of uterine infection. Gently insert a speculum to visualize the cervix. Thoroughly cleanse the cervix and vagina with antiseptic solution. Administer cervical anesthetic, if needed. Apply a tenaculum to the cervix and use gentle traction to align the cervical canal with the uterine cavity. If the uterus is retroverted, it may be more appropriate to grasp the lower lip of the cervix. Keep the tenaculum in position and maintain gentle traction on the cervix throughout the insertion procedure. Carefully sound the uterus to measure its depth. The uterus should sound to a depth of at least 5.5 cm. Insertion of LILETTA into a uterine cavity that sounds to less than 5.5 cm may increase the incidence of expulsion, bleeding, pain, perforation, and possibly pregnancy. LILETTA should not be inserted if the uterus sounds to less than 5.5 cm. After ascertaining that the patient is appropriate for LILETTA, replace contaminated glove(s) and open the packaging containing LILETTA, noting the lot number. Step 2 – Opening the Sterile LILETTA Packaging Remove the sealed tray containing LILETTA from the box. Inspect the sealed tray and do not use the product if the packaging, inserter, or IUS is damaged. Lay the tray on a flat surface with the peel-off lid side up. Remove peel-off lid.

ning LILETTA, noting the lot number. Step 2 – Opening the Sterile LILETTA Packaging Remove the sealed tray containing LILETTA from the box. Inspect the sealed tray and do not use the product if the packaging, inserter, or IUS is damaged. Lay the tray on a flat surface with the peel-off lid side up. Remove peel-off lid. Step 3 – Loading LILETTA into the Inserter To remove the inserter from the tray, grasp the handle below the sliders and twist gently (Figure 3). NOTE: Do not attempt to remove the inserter by pulling on the tube. Figure 3: Removing Inserter from Tray Ensure both sliders (labeled 1 and 2) are fully forward (Figure 4): The BLUE slider (labeled with the number 1) has a single line marking that will align with the handle’s single line marking. The GREEN slider (labeled with the number 2) has a double line marking that will align with the handle’s double line marking. Grip the handle keeping your thumb or finger in the groove of the BLUE slider (over the numeral 1) and apply forward pressure while ensuring both sliders are fully forward . Figure 4 : Sliders Completely Forward for Loading LILETTA Load LILETTA into the inserter: Ensure the arms of the IUS are horizontal (aligned to the horizontal plane of the handle and flange); adjust the rotation of the IUS as needed using the flat sterile surface of the tray. While maintaining forward pressure on the BLUE slider, gently pull the threads straight back to load LILETTA into the insertion tube. Ensure even tension is applied to both threads when pulling. Pull the threads upward or downward to lock the threads into the cleft at the bottom end of the handle (Figure 5); you must lock the threads in the cleft to prevent the IUS from moving out of the top of the insertion tube. Once the threads are locked in the cleft, stop holding the threads . After the IUS is loaded, continue to sustain forward pressure on the BLUE slider to maintain a hemispherical dome with the tips of the IUS. When correctly loaded, the IUS is completely within the insertion tube with the tips of the arms forming a hemispherical dome at the top of the tube (Figure 6). If the IUS is not correctly loaded, do not attempt insertion . To re-load LILETTA: ▪ Pull the BLUE slider back with your thumb until the groove becomes aligned with the GREEN slider to release the IUS. ▪ Manually pull the threads out of the cleft. ▪ Return the BLUE slider to the forward position and repeat the loading steps. Figure 5 : Locking the Threads in Cleft Figure 6 : Close-up of Hemispherical Dome at Tip of Tube Adjust the flange to the measured uterine depth based on sounding. To adjust, place the flat side of the flange in the tray notch (Figure 7) or against a sterile edge inside of the tray. Slide the insertion tube as necessary to move the flange to the correct measurement. Ensure the flat sides of the flange are in the same horizontal plane as the handle. If, at any step, there is a need to touch the flange or another sterile surface, sterile gloves should be used. Figure 7 : Adjusting the Flange If an adjustment to the curvature of the insertion tube is required to accommodate the anatomical orientation of the uterus, you may bend or straighten the insertion tube, but do not touch above the flange unless using sterile gloves. When bending the tube, avoid sharp bends to prevent kinking. Once the flange has been properly positioned, avoid contact of flange against objects that can change its position (e.g., tray, speculum, tenaculum, etc.). Step 4 – Inserting LILETTA into the Uterus Apply gentle traction on the tenaculum and continue to apply forward pressur e on the BLUE slider while inserting the loaded insertion tube through the cervical os. Advance the tube until the upper edge of the flange is 1.5-2 cm from the external cervical os (Figure 8).

etc.). Step 4 – Inserting LILETTA into the Uterus Apply gentle traction on the tenaculum and continue to apply forward pressur e on the BLUE slider while inserting the loaded insertion tube through the cervical os. Advance the tube until the upper edge of the flange is 1.5-2 cm from the external cervical os (Figure 8). Maintain forward pressure on the BLUE slider throughout the insertion process. ○ DO NOT advance flange to the cervix at this time. ○ DO NOT force the inserter. If necessary, dilate the cervical canal. Figure 8 : Advancing Insertion Tube until Flange is 1.5 to 2 cm from the External Cervix ● Using your thumb or finger, gently slide only the BLUE slider back. You will feel slight resistance initially to move the BLUE slider out of its starting position. Continue to move the BLUE slider back until you feel slight resistance again as the BLUE and GREEN sliders will merge together to form a joint slider recess. Do not move the BLUE slider any more than is necessary to create the recess. Maintain the GREEN slider so that the double line markings on the slider and the insertion handle remain aligned (Figure 9). This will allow the IUS arms to open in the lower uterine segment. Do not pull the sliders back any further as this could result in premature release of the IUS at the incorrect location. Figure 9 : Releasing and Opening the Arms of the IUS Wait 10-15 seconds to allow for the arms of the IUS to fully open. Without moving the sliders, advance the inserter until the flange touches the cervix. If fundal resistance is encountered, do not continue to advance. LILETTA is now in the fundal position (Figure 10). Note: Fundal position is important to prevent expulsions. Figure 10 : Move LILETTA into the Fundal Position Step 5 – Releasing LILETTA and Procedure Completion While holding the inserter steady and maintaining its position relative to the cervix, move both sliders (BLUE and GREEN) together while maintaining the joint slider recess down toward the number 3 on the handle (Figure 11) until a click is heard and the GREEN indicator at the bottom of the handle is visible, signifying deployment (Figure 12). Figure 11 : Releas ing LILETTA from the Inserter Tube Look at the cleft to ensure the threads were properly released (Figure 12); if not released or if a click is not heard, grasp the threads and gently pull the threads out of the cleft. Figure 12 : Green Indicator Visible and Threads Released from Cleft Withdraw the inserter from the uterus. Use blunt-tipped sharp scissors to cut the IUS threads perpendicular to the thread length, leaving about 3 cm outside of the cervix (Figure 13). Note: Do not c ut threads at an angle as this may leave sharp ends. Do not apply tension or pull on the threads when cutting to prevent displacing the IUS. Figure 13 : Cut the Threads about 3 cm from the Cervix Insertion of LILETTA is now complete. Important information to consider during or after insertion: If you suspect the IUS is not in the correct position, conduct the following procedures: Check insertion with an ultrasound or other appropriate radiologic test. If incorrect insertion is confirmed, remove LILETTA. Do not reinsert the same LILETTA IUS after removal. Difficult I nsertion If insertion is difficult because the uterus cannot be appropriately instrumented, consider the following measures: Use of cervical anesthesia to make sounding and manipulation more tolerable. Use of dilators to dilate the cervix if needed to allow passage of the sound or inserter. Abdominal ultrasound guidance during dilation and/or insertion.

because the uterus cannot be appropriately instrumented, consider the following measures: Use of cervical anesthesia to make sounding and manipulation more tolerable. Use of dilators to dilate the cervix if needed to allow passage of the sound or inserter. Abdominal ultrasound guidance during dilation and/or insertion. 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 uterine perforation [see Warnings and Precautions ( 5.5 )]. 2.4 Patient Counseling and Record - Keeping Counsel the patient on what to expect following LILETTA insertion. Discuss expected bleeding patterns with LILETTA use. Review the signs and symptoms associated with infection, perforation, and expulsion that may occur with use of LILETTA [see Patient Counseling Information ( 17 ) ]. Prescribe analgesics, if indicated. 2.5 Patient Follow- Up The healthcare professional should consider re-examining and evaluating patients 4 to 6 weeks after insertion and during routine care, or more frequently if clinically indicated. The IUS threads should be checked during each evaluation. 2.6 Removal of LILETTA Planning and T iming of Removal If pregnancy is desired, LILETTA can be removed at any time. If pregnancy is not desired, LILETTA can be removed at any time; however, a contraception method should be started prior to removal of LILETTA [see Dosage and Administration ( 2.5 )]. Counsel patients that they are at risk of pregnancy if they had intercourse in the week prior to removal without use of a backup contraceptive method. For contraception, LILETTA should be removed after 8 years. LILETTA can be replaced at the time of removal with a new LILETTA if continued contraceptive protection is desired. For treatment of heavy menstrual bleeding, LILETTA should be replaced at the end of the fifth year if continued treatment is needed. Preparation for Removal Ensure all needed items for LILETTA removal are readily available: Gloves Sterile speculum Sterile forceps Additional items may be required: Local anesthetic, needle, and syringe Sterile os finder and/or cervical dilators Ultrasound with abdominal transducer Sterile tenaculum Antiseptic solution Sterile long, narrow forceps or intrauterine thread retriever Removal may be associated with some pain and/or bleeding or vasovagal reactions (e.g., syncope, bradycardia, or seizure), especially in patients with a predisposition to these conditions. After removal of LILETTA, examine the system to ensure that it is intact. The hormone cylinder may slide over and cover the horizontal arms, giving the appearance of missing arms. This does not require further intervention if the system is verified to be intact. Breakage, embedment in the myometrium, or perforation of LILETTA can make removal difficult [see Warnings and Precautions ( 5.5 )]. IUS breakage may be associated with removal. Analgesia, paracervical anesthesia, cervical dilation, alligator forceps or other grasping instrument, or hysteroscopy may assist in removal. Removal Procedure With the patient comfortably in lithotomy position, place a speculum and visualize the cervix. When the threads of LILETTA are visible: Remove the IUS by applying gentle traction on the threads with forceps (Figure 14). The arms of the device will fold upward as it is withdrawn from the uterus. If the IUS cannot be removed with gentle traction on the threads, perform an ultrasound examination to confirm location of the IUS, including assessment for embedment in the myometrium or partial- or total-perforation. If the IUS is in the uterus, use long, narrow forceps to grasp LILETTA. Consider use of a tenaculum, cervical anesthesia, cervical dilators, and/or ultrasound guidance as needed.

ultrasound examination to confirm location of the IUS, including assessment for embedment in the myometrium or partial- or total-perforation. If the IUS is in the uterus, use long, narrow forceps to grasp LILETTA. Consider use of a tenaculum, cervical anesthesia, cervical dilators, and/or ultrasound guidance as needed. After removal, examine the system to ensure it is intact. If the threads of LILETTA are not visible: Determine location of the IUS and exclude embedment or perforation by ultrasound examination [see Warnings and Precautions ( 5.10 )]. If the IUS is in the uterine cavity, thoroughly cleanse the cervix and vagina with antiseptic solution. Use a thread retriever to capture the threads or a long, narrow forceps (e.g., Alligator forceps) to grasp LILETTA. Consider use of a tenaculum, cervical anesthesia, cervical dilators, and/or ultrasound guidance as needed. If LILETTA cannot be removed using the above techniques, consider hysteroscopic evaluation for removal. If the IUS is not in the uterine cavity, consider an abdominal x-ray or CT scan to evaluate if the IUS is in the abdominal cavity. Consider laparoscopic evaluation for removal, as clinically indicated. After removal, examine the system to ensure it is intact. Figure 14 : Removal of LILETTA 2.7 Continuation of Contraception after Removal If a patient wishes to continue using LILETTA or another intrauterine contraceptive, insertion can occur immediately after removal. If a patient with regular cycles wants to start a different birth control method, time the removal and initiation of a new method to ensure continuous contraception. Either remove LILETTA during the first 7 days of the menstrual cycle and start the new method or start the new method at least 7 days prior to removing LILETTA if removal is to occur at other times during the cycle. If a patient with irregular cycles or amenorrhea wants to start a different birth control method, start the new method at least 7 days before LILETTA removal. If LILETTA is removed but no other contraceptive method has already been started, the new contraceptive method can be started on the day LILETTA is removed. The patient should use a backup barrier method of contraception (e.g., condoms) or abstain from vaginal intercourse for 7 days to prevent pregnancy.

3 DOSAGE FORMS AND STRENGTHS LILETTA is a levonorgestrel-releasing intrauterine system consisting of a T-shaped polyethylene frame with a drug reservoir containing 52 mg levonorgestrel, packaged within a sterile inserter. One intrauterine system consisting of a T-shaped polyethylene frame with a drug reservoir containing 52 mg LNG, packaged within a sterile inserter. ( 3 )

4 CONTRAINDICATIONS LILETTA is contraindicated when one or more of the following conditions exist: Pregnancy [see Use in Specific Populations ( 8.1 ) ] For use as post-coital contraception (emergency contraception) Congenital or acquired uterine anomaly, including leiomyomas, that distorts the uterine cavity and would be incompatible with correct IUS placement [see Warnings and Precautions ( 5.10 )] Acute pelvic inflammatory disease (PID) [see Warnings and Precautions ( 5.4 )] Postpartum endometritis or infected abortion in the past 3 months [see Warnings and Precautions ( 5.2 , 5.4 )] Known or suspected uterine or cervical malignancy Known or suspected breast cancer or other hormone-sensitive cancer, now or in the past [see Warnings and Precautions ( 5.9 )] Uterine bleeding of unknown etiology [see Warnings and Precautions ( 5.10 )] Untreated acute cervicitis or vaginitis, including bacterial vaginosis, known chlamydial or gonococcal cervical infection, or other lower genital tract infections until infection is controlled [see Warnings and Precautions ( 5.4 )] 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 IUS that has not been removed A history of hypersensitivity reaction to any component of LILETTA. Reactions may include rash, urticaria, and angioedema [see Adverse Reactions ( 6.2 )] . Pregnancy ( 4 ) Use for post-coital contraception (emergency contraception) ( 4 ) Congenital or acquired uterine anomaly that distorts the uterine cavity and would be incompatible with correct IUS placement ( 4 ) Acute pelvic inflammatory disease (PID) ( 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 hormone-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 infections ( 4 ) A previously inserted IUS that has not been removed ( 4 ) Hypersensitivity to any component of LILETTA ( 4 )

5 WARNINGS AND PRECAUTIONS Remove LILETTA if pregnancy occurs with LILETTA in place and LILETTA is in the uterus. 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 ) Severe infection or sepsis, including Group A streptococcal sepsis (GAS), have been reported following insertion of LNG-releasing IUSs; strict aseptic technique is essential during insertion. ( 5.3 ) Before using LILETTA, consider the risks of pelvic infection. ( 5.4 ) Perforation may occur and reduce contraceptive effectiveness or require surgery. Risk is increased if inserted in patients who have fixed retroverted uteri, are postpartum, or are lactating. ( 5.5 ) Partial or complete expulsion may occur. ( 5.6 ) Evaluate persistent enlarged ovarian follicles or ovarian cysts. ( 5.7 ) Bleeding patterns can become altered, may remain irregular, and amenorrhea may ensue. ( 5.8 ) 5.1 Ectopic Pregnancy Evaluate patients for ectopic pregnancy if they become pregnant with LILETTA in place because the likelihood of a pregnancy being ectopic is increased with use of an IUS. Approximately half of pregnancies that occur with an IUS 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 new onset bleeding in an amenorrheic patient. If an ectopic pregnancy is confirmed, LILETTA should be removed. The incidence of ectopic pregnancy in the clinical study on contraception with LILETTA, which excluded participants with a history of ectopic pregnancy who did not have a subsequent intrauterine pregnancy, was approximately 0.12 per 100 women-years. There were no ectopic pregnancies in the clinical study on heavy menstrual bleeding with LILETTA. The risk of ectopic pregnancy in patients who have a history of ectopic pregnancy and use LILETTA is unknown. Patients with a previous history of ectopic pregnancy, tubal surgery, or pelvic infection have a higher risk of ectopic pregnancy. Ectopic pregnancy may require surgery and may result in loss of fertility. Patients who use LILETTA should be informed about recognizing the signs and symptoms of ectopic pregnancy and promptly reporting them to their healthcare professional, and about the associated risks of ectopic pregnancy (e.g., loss of fertility). 5.2 Intrauterine Pregnancy If pregnancy occurs while using LILETTA, determine if LILETTA is in the uterus. If LILETTA is in the uterus, attempt to remove LILETTA because leaving it in place may increase the risk of spontaneous abortion and preterm labor. Removal of LILETTA or probing of the uterus may also result in spontaneous abortion. In the event of an intrauterine pregnancy with LILETTA, consider the following: Septic A bortion If a patient becomes pregnant with an IUS in place, septic abortion—potentially including septicemia, septic shock, and death—may occur. Septic abortion typically requires hospitalization and treatment with intravenous antibiotics. Septic abortion may result in spontaneous abortion or a medical indication for pregnancy termination. Should severe infection of the uterus occur, hysterectomy may be required, which will result in permanent infertility. LILETTA is contraindicated in patients who have had an infected abortion in the prior 3 months.

cs. Septic abortion may result in spontaneous abortion or a medical indication for pregnancy termination. Should severe infection of the uterus occur, hysterectomy may be required, which will result in permanent infertility. LILETTA is contraindicated in patients who have had an infected abortion in the prior 3 months. Continuation of P regnancy If a patient becomes pregnant with LILETTA in place and if LILETTA cannot be removed or the patient chooses not to have it removed, warn the patient that failure to remove LILETTA increases the risk of miscarriage, sepsis, premature labor, and premature delivery. Prenatal care should include counseling about these risks and instructions to immediately report any flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge or leakage of fluid, or any other 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 LNG-releasing IUSs. 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 LILETTA is essential to minimize serious infections such as GAS. 5.4 Pelvic Inflammatory Disease or Endometritis Insertion of LILETTA is contraindicated in the presence of known or suspected PID or endometritis. As well, it is contraindicated in patients with untreated acute cervicitis or vaginitis (including bacterial vaginosis), known chlamydial or gonococcal cervical infection, or other known lower genital tract infections, until the infection is controlled . IUSs have been associated with an increased risk of PID, most likely due to organisms being introduced into the uterus during insertion. Assess risk factors for infection accordingly. Patients who use LILETTA should be counseled to promptly notify a healthcare professional if they develop lower abdominal or pelvic pain, fever, chills, unusual or malodorous discharge, unexplained bleeding, genital lesions or sores, or dyspareunia. In such circumstances, perform a pelvic examination promptly to evaluate for possible pelvic infection. Remove LILETTA in cases of recurrent PID or endometritis, or if an acute pelvic infection is severe or does not respond to treatment. In the clinical study on contraception with LILETTA, pelvic infection was diagnosed in 0.8% of participants. Pelvic infection was diagnosed as PID in 0.5% of participants and as endometritis in 0.3% of participants. Infections occurred following variable duration-of-use. One participant diagnosed with PID and two participants diagnosed with endometritis developed the infection within a week of LILETTA insertion. One case of endometritis was diagnosed at 39 days after LILETTA insertion. The remaining 11 cases of PID and endometritis were diagnosed more than six months after insertion, including one at 30 days after IUS removal. In the clinical study on heavy menstrual bleeding with LILETTA, there was one participant diagnosed with PID approximately 5 months after LILETTA insertion. Patients at Increased Risk for PID or Endometritis PID and endometritis are often associated with a sexually transmitted infection (STI), and LILETTA does not protect against STIs. The risk of PID or endometritis is greater for patients who have multiple sexual partners, and for patients whose sexual partner(s) have multiple sexual partners. Patients who have had PID or endometritis are at increased risk for recurrence or re-infection. Other risk factors for these infections include unprotected sex and acquired immune deficiency syndrome (AIDS).

ients who have multiple sexual partners, and for patients whose sexual partner(s) have multiple sexual partners. Patients who have had PID or endometritis are at increased risk for recurrence or re-infection. Other risk factors for these infections include unprotected sex and acquired immune deficiency syndrome (AIDS). Asymptomatic PID or Endometritis PID or endometritis may be asymptomatic but still result in tubal damage and its sequelae. Treatment of PID or Endometritis In IUS users with suspected or diagnosed PID or endometritis, obtain microbial specimens, including those for sexually transmitted infections, and initiate antibiotic treatment promptly. After initiation of antibiotic treatment, the IUS may be removed or kept in place. The patient should continue to receive antibiotic treatment according to current recommendations and should have close clinical follow-up. Guidelines for PID or endometritis treatment are available from the Centers for Disease Control (CDC), Atlanta, Georgia. 1 If the patient opts for discontinuing IUS use, remove LILETTA after initiation of antibiotic treatment to avoid the potential risk for bacterial spread resulting from the removal procedure. If the patient opts for ongoing IUS contraception, the patient may forego immediate removal of LILETTA after initiation of antibiotic treatment. However, the patient should have close clinical follow-up. If no clinical improvement occurs within 48–72 hours of initiating treatment, IUS removal is appropriate with continued antibiotic therapy, as indicated. In the LILETTA clinical study on contraception, 12 of the 14 participants who developed PID or endometritis were successfully treated without removal of LILETTA (one of the 14 participants developed PID 30 days after removal). Actinomycosis Actinomycosis has been associated with IUS use. Symptomatic patients with known actinomycosis infection should have LILETTA removed and receive antibiotics. Actinomycetes can be found in the genital tract cultures in healthy patients without IUSs. The significance of actinomyces-like organisms on Pap test in an asymptomatic IUS user is unknown, and so this finding alone does not always require LILETTA removal and treatment. When possible, confirm a Pap test diagnosis with cultures. 5.5 Perforation Perforation (total or partial, including penetration/embedment of LILETTA in the uterine wall or cervix) may occur, most often during insertion, although the perforation may not be detected until sometime later. Perforation may also occur at any time during IUS use. Perforation may reduce contraceptive efficacy and result in pregnancy. This may be associated with severe pain and continued bleeding. The risk of perforation may be increased if an IUS is inserted when the uterus is fixed retroverted or not completely involuted during the post-partum period. Delay LILETTA insertion a minimum of four weeks or until involution is complete following a delivery or a second trimester abortion. If perforation is suspected the IUS should be removed as soon as possible, surgery may be required. Delayed detection or removal of LILETTA in case of perforation may result in migration outside the uterine cavity, adhesions, peritonitis, intestinal perforations, intestinal obstruction, abscesses, and erosion of adjacent viscera. In a large prospective comparative non-interventional cohort study with another IUS the incidence of uterine perforation was reported as 6.3 per 1,000 insertions for lactating participants, compared to 1.0 per 1,000 insertions for non-lactating participants. The incidence of perforation during or following LILETTA insertion in the clinical studies, which excluded breastfeeding participants, was 0.1%.

the incidence of uterine perforation was reported as 6.3 per 1,000 insertions for lactating participants, compared to 1.0 per 1,000 insertions for non-lactating participants. The incidence of perforation during or following LILETTA insertion in the clinical studies, which excluded breastfeeding participants, was 0.1%. 5.6 Expulsion Partial or complete expulsion of LILETTA may occur, resulting in the loss of contraceptive protection. In the clinical study on contraception with LILETTA, an overall expulsion rate of 4.1% over 8 years was reported, with a rate of 2.4% in nulliparous participants and 6.4% in parous participants. The majority (70.4%) occur in the first 12 months, with 23.9% occurring in the first three months and 42.3% in the first six months, cumulatively. Risk of expulsion is increased for patients with a history of heavy menstrual bleeding or greater than normal BMI at the time of insertion. In the clinical study on heavy menstrual bleeding with LILETTA, 8.6% of participants experienced expulsions, with two-thirds occurring within the first 90 days. About 90% of the expulsions occurred in overweight or obese participants. Expulsion may be associated with symptoms of bleeding or pain, or it may be asymptomatic and go unnoticed. LILETTA typically decreases menstrual bleeding over time; therefore, an increase in menstrual bleeding may be indicative of an expulsion. Consider further diagnostic imaging, such as sonography or X-ray, to confirm expulsion if LILETTA is not found in the uterus. The risk of expulsion is increased with insertions performed immediately after delivery; it appears to be increased with insertions performed after second-trimester abortion, based on limited data. Remove a partially expelled LILETTA. If expulsion has occurred, a new LILETTA may be inserted when there is reasonable certainty the patient is not pregnant. 5.7 Ovarian Cysts The contraceptive effect of LILETTA is mainly due to its local effects within the uterus; therefore, ovulatory cycles with follicular rupture usually occur in patients of fertile age using LILETTA. Most ovarian cysts that occur during use of LNG-releasing IUSs are asymptomatic and disappear spontaneously during two to three months of observation. Cysts that cause clinical symptoms can result in pelvic or abdominal pain or dyspareunia. In the clinical study on contraception, symptomatic ovarian cysts occurred in 4.7% of participants using LILETTA over the course of 8 years, and 0.3% of participants discontinued use of LILETTA because of an ovarian cyst. In the clinical study on heavy menstrual bleeding, symptomatic ovarian cysts occurred in 1.0% of participants using LILETTA over the course of 6 months. Evaluate persistent ovarian cysts. Surgical intervention is not usually required, but may be necessary in some cases, and occurred in 1 (0.06%) of participants in the LILETTA study. Discuss this risk with patients, as indicated. 5.8 Bleeding Pattern Alterations LILETTA can alter the bleeding pattern and result in spotting, irregular bleeding, heavy bleeding, oligomenorrhea, and amenorrhea. During the first three to six months of LILETTA use, the number of bleeding and spotting days may increase and irregular bleeding patterns may develop. Thereafter, the number of bleeding and spotting days usually decreases but bleeding may remain irregular. Contraception Study The amenorrhea rates observed in the LILETTA clinical study on contraception are shown in Table 2. The bleeding and spotting days, based on 28-day cycle equivalents, are shown in Table 3. In this study, 2.5% of participants discontinued LILETTA due to bleeding complaints.

eding may remain irregular. Contraception Study The amenorrhea rates observed in the LILETTA clinical study on contraception are shown in Table 2. The bleeding and spotting days, based on 28-day cycle equivalents, are shown in Table 3. In this study, 2.5% of participants discontinued LILETTA due to bleeding complaints. Table 2: Amenorrhea Rates Last 90-Day Interval of Year Year 1 2 3 4 5 6 7 8 Amenorrhea Rate* 19% 27% 37% 37% 40% 40% 39% 39% *Amenorrhea is defined as no bleeding and/or spotting. Table 3: Bleeding and Spotting Days per 28-Day Cycle Equivalent 28- D ay Cycle Equivalent N* Cycle 1 N=1,691 Cycle 4 N=1,5 93 Cycle 7 N=1, 519 Cycle 13 N= 1,395 Cycle 26 N= 1,109 Days on treatment 1-28 85-112 169-196 337-364 674-728 Mean SD Mean SD Mean SD Mean SD Mean SD Number of bleeding days 5.8 5.2 2.3 3.3 1.6 2.7 1.2 2.4 0.8 1.8 Number of spotting days 9.0 5.9 4.3 4.2 3.2 3.6 2.7 3.4 1.9 2.8 *N includes all LILETTA participants in the clinical study on contraception. Heavy Menstrual Bleeding Study The amenorrhea rates observed in the LILETTA clinical study on heavy menstrual bleeding (HMB) are shown in Table 4. Amenorrhea developed in 19% of LILETTA study participants by Cycle 6. Table 4: Amenorrhea Rates for 28-Day Treatment Cycles 28-Day Cycle N Baseline N=87 Cycle 1 N=87 Cycle 2 N=88 Cycle 3 N=88 Cycle 4 N=82 Cycle 5 N=82 Cycle 6 N=79 Amenorrhea Rate* 0% 3% 8% 11% 13% 17% 19% *Amenorrhea is defined as no bleeding and/or spotting. Percentages within each cycle are based on the number of participants who completed the cycle. The bleeding and spotting days, based on 28-day cycle equivalents, are shown in Table 5. In this study, 3.8% of LILETTA participants discontinued due to bleeding complaints. Table 5: Bleeding and Spotting Days from Baseline to Treatment Cycle 3 and Cycle 6 28-Day Cycle N* Baseline N=87 Cycle 3 N=88 Cycle 6 N=79 Mean SD Mean SD Mean SD Number of Bleeding Days 4.9 1.5 3.7 3.8 2.2 3.5 Number of Spotting Days 1.8 1.1 7.3 7.0 5.1 5.8 *N includes participants with at least one complete 28-day cycle of product-use. Calculations are based on complete 28-day cycles (at least 23 days in length). Resumption of Menses After Discontinuation In the LILETTA clinical study on contraception, 651 of 652 (99.8%) participants 16-35 years of age at enrollment that were evaluated resumed menses after LILETTA removal. This excludes twelve participants (9 became pregnant, 2 had a hysterectomy, and 1 had ovulatory dysfunction). Other Bleeding Pattern Changes If a significant change in bleeding develops during prolonged use, conduct diagnostic tests to assess possible endometrial pathology. Consider the possibility of pregnancy, including ectopic pregnancy, if menstruation does not occur within six weeks of the onset of a previous menstruation. After excluding pregnancy, repeat pregnancy tests are generally not necessary in amenorrheic patients unless indicated by other signs of pregnancy or pelvic pain. 5.9 Breast Cancer Patients who currently have or have had breast cancer, or have a suspicion of breast cancer, should not use hormonal contraception, including LILETTA, because some breast cancers are hormone-sensitive [ see Contraindications ( 4 ) ] . Spontaneous reports of breast cancer have been received during postmarketing experience with LNG-releasing IUSs. Observational studies have not provided consistent evidence of an increased risk of breast cancer with use of an LNG-releasing IUS. 5.10 Clinical Considerations for Use and Removal Obtain a complete medical and social history, including partner status, to determine conditions that might influence the selection of an IUS for contraception.

s have not provided consistent evidence of an increased risk of breast cancer with use of an LNG-releasing IUS. 5.10 Clinical Considerations for Use and Removal Obtain a complete medical and social history, including partner status, to determine conditions that might influence the selection of an IUS for contraception. Exclude underlying endometrial pathology (e.g., polyps or cancer) prior to the insertion of LILETTA in patients with persistent or uncharacteristic bleeding because irregular bleeding/spotting is common during the first months of LILETTA use and may preclude adequate assessment after insertion. LILETTA is contraindicated in patients with uterine bleeding of unknown etiology. Exclude underlying congenital or acquired uterine anomalies, including leiomyomas, that distort the uterine cavity and would be incompatible with correct IUS placement [see Contraindications ( 4 )] . Ensure a previously inserted IUS has been removed prior to insertion of LILETTA [see Contraindications ( 4 )]. Assess whether the patient is at increased risk of pelvic infection (e.g., unprotected sex, history of PID, or acquired immune deficiency syndrome [AIDS]). LILETTA does not protect against HIV/STI transmission [ s ee Warnings and Precautions ( 5.4 )] . Use LILETTA with caution after careful assessment if any of the following conditions exist, and consider removal of the IUS if any of them arise during use: Coagulopathy or use of anticoagulants Migraine, focal migraine with asymmetrical visual loss, or other symptoms indicating transient cerebral ischemia Exceptionally severe or frequent headache Marked increase of blood pressure Severe arterial disease such as stroke or myocardial infarction Consider removing LILETTA if any of the following conditions arise during use [ see Contraindications ( 4 ) ] : Uterine or cervical malignancy Jaundice If the threads are not visible or are significantly shortened, they may have broken or retracted into the cervical canal or uterus. Consider the possibility that the IUS may have been displaced, (e.g., expulsed or perforated the uterus) [ see Warnings and Precautions ( 5.5 , 5.6 ) ] . Exclude pregnancy and verify the location of LILETTA by an appropriate diagnostic method (e.g., ultrasonography, X-ray, or gentle exploration of the cervical canal with a suitable instrument) [ see Dosage and Administration ( 2.6 )] . If LILETTA is displaced, remove it. A new LILETTA may be inserted at that time or during the next menses if it is certain that conception has not occurred. If LILETTA is in place with no evidence of perforation, no intervention is indicated. 5.11 Magnetic Resonance Imaging (MRI) Information LILETTA is MR-Safe. LILETTA is compatible with MRI and should not interfere with imaging.

<table><caption>Table 2: Amenorrhea Rates Last 90-Day Interval of Year</caption><col width="124"/><col width="42"/><col width="39"/><col width="39"/><col width="39"/><col width="39"/><col width="39"/><col width="39"/><col width="39"/><tbody><tr><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Year</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">1</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">2</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">3</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">4</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">5</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">6</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">7</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">8</content></td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Amenorrhea Rate*</content></td><td styleCode="Toprule Lrule Rrule " align="center"> 19%</td><td styleCode="Toprule Lrule Rrule " align="center">27%</td><td styleCode="Toprule Lrule Rrule " align="center">37%</td><td styleCode="Toprule Lrule Rrule " align="center">37%</td><td styleCode="Toprule Lrule Rrule " align="center">40%</td><td styleCode="Toprule Lrule Rrule " align="center">40%</td><td styleCode="Toprule Lrule Rrule " align="center">39%</td><td styleCode="Toprule Lrule Rrule " align="center">39%</td></tr></tbody></table>

td styleCode="Toprule Lrule Rrule " align="center">37%</td><td styleCode="Toprule Lrule Rrule " align="center">40%</td><td styleCode="Toprule Lrule Rrule " align="center">40%</td><td styleCode="Toprule Lrule Rrule " align="center">39%</td><td styleCode="Toprule Lrule Rrule " align="center">39%</td></tr></tbody></table> <table><caption>Table 3: Bleeding and Spotting Days per 28-Day Cycle Equivalent</caption><col width="121"/><col width="57"/><col width="57"/><col width="57"/><col width="57"/><col width="57"/><col width="57"/><col width="57"/><col width="57"/><col width="57"/><col width="57"/><tbody><tr><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">28-</content><content styleCode="bold">D</content><content styleCode="bold">ay Cycle Equivalent</content> <content styleCode="bold">N*</content></td><td styleCode="Toprule Lrule Rrule " colspan="2" valign="bottom" align="center"><content styleCode="bold">Cycle 1</content> <content styleCode="bold">N=1,691</content></td><td styleCode="Toprule Lrule Rrule " colspan="2" valign="bottom" align="center"><content styleCode="bold">Cycle 4</content> <content styleCode="bold">N=1,5</content><content styleCode="bold">93</content></td><td styleCode="Toprule Lrule Rrule " colspan="2" valign="bottom" align="center"><content styleCode="bold">Cycle 7</content> <content styleCode="bold">N=1,</content><content styleCode="bold">519</content></td><td styleCode="Toprule Lrule Rrule " colspan="2" valign="bottom" align="center"><content styleCode="bold">Cycle 13</content> <content styleCode="bold">N=</content><content styleCode="bold">1,395</content></td><td styleCode="Toprule Lrule Rrule " colspan="2" valign="bottom" align="center"><content styleCode="bold">Cycle 26</content> <content styleCode="bold">N=</content><content styleCode="bold">1,109</content></td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Days on treatment</content></td><td styleCode="Toprule Lrule Rrule " colspan="2" align="center">1-28</td><td styleCode="Toprule Lrule Rrule " colspan="2" align="center">85-112</td><td styleCode="Toprule Lrule Rrule " colspan="2" align="center">169-196</td><td styleCode="Toprule Lrule Rrule " colspan="2" align="center">337-364</td><td styleCode="Toprule Lrule Rrule " colspan="2" align="center">674-728</td></tr><tr><td styleCode="Toprule Lrule Rrule "/><td styleCode="Toprule Lrule Rrule " align="center">Mean</td><td styleCode="Toprule Lrule Rrule " align="center">SD</td><td styleCode="Toprule Lrule Rrule " align="center">Mean</td><td styleCode="Toprule Lrule Rrule " align="center">SD</td><td styleCode="Toprule Lrule Rrule " align="center">Mean</td><td styleCode="Toprule Lrule Rrule " align="center">SD</td><td styleCode="Toprule Lrule Rrule " align="center">Mean</td><td styleCode="Toprule Lrule Rrule " align="center">SD</td><td styleCode="Toprule Lrule Rrule " align="center">Mean</td><td styleCode="Toprule Lrule Rrule " align="center">SD</td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Number of bleeding days</content></td><td styleCode="Toprule Lrule Rrule " align="center">5.8</td><td styleCode="Toprule Lrule Rrule " align="center">5.2</td><td styleCode="Toprule Lrule Rrule " align="center">2.3</td><td styleCode="Toprule Lrule Rrule " align="center">3.3</td><td styleCode="Toprule Lrule Rrule " align="center">1.6</td><td styleCode="Toprule Lrule Rrule " align="center">2.7</td><td styleCode="Toprule Lrule Rrule " align="center">1.2</td><td styleCode="Toprule Lrule Rrule " align="center">2.4</td><td styleCode="Toprule Lrule Rrule " align="center">0.8</td><td styleCode="Toprule Lrule Rrule " align="center">1.8</td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Number of spotting days</content></td><td styleCode="Toprule Lrule Rru

d styleCode="Toprule Lrule Rrule " align="center">2.4</td><td styleCode="Toprule Lrule Rrule " align="center">0.8</td><td styleCode="Toprule Lrule Rrule " align="center">1.8</td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Number of spotting days</content></td><td styleCode="Toprule Lrule Rru le " align="center">9.0</td><td styleCode="Toprule Lrule Rrule " align="center">5.9</td><td styleCode="Toprule Lrule Rrule " align="center">4.3</td><td styleCode="Toprule Lrule Rrule " align="center">4.2</td><td styleCode="Toprule Lrule Rrule " align="center">3.2</td><td styleCode="Toprule Lrule Rrule " align="center">3.6</td><td styleCode="Toprule Lrule Rrule " align="center">2.7</td><td styleCode="Toprule Lrule Rrule " align="center">3.4</td><td styleCode="Toprule Lrule Rrule " align="center">1.9</td><td styleCode="Toprule Lrule Rrule " align="center">2.8</td></tr></tbody></table>

td styleCode="Toprule Lrule Rrule " align="center">3.6</td><td styleCode="Toprule Lrule Rrule " align="center">2.7</td><td styleCode="Toprule Lrule Rrule " align="center">3.4</td><td styleCode="Toprule Lrule Rrule " align="center">1.9</td><td styleCode="Toprule Lrule Rrule " align="center">2.8</td></tr></tbody></table> <table><caption>Table 4: Amenorrhea Rates for 28-Day Treatment Cycles</caption><col width="134"/><col width="63"/><col width="63"/><col width="63"/><col width="63"/><col width="63"/><col width="63"/><col width="63"/><tbody><tr><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">28-Day Cycle</content> <content styleCode="bold">N</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Baseline</content> N=87</td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Cycle 1</content> N=87</td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Cycle 2</content> N=88</td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Cycle 3</content> N=88</td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Cycle 4</content> N=82</td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Cycle 5</content> N=82</td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Cycle 6</content> N=79</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Amenorrhea Rate*</content></td><td styleCode="Toprule Lrule Rrule " align="center">0%</td><td styleCode="Toprule Lrule Rrule " align="center">3%</td><td styleCode="Toprule Lrule Rrule " align="center">8%</td><td styleCode="Toprule Lrule Rrule " align="center">11%</td><td styleCode="Toprule Lrule Rrule " align="center">13%</td><td styleCode="Toprule Lrule Rrule " align="center">17%</td><td styleCode="Toprule Lrule Rrule " align="center">19%</td></tr></tbody></table>

<td styleCode="Toprule Lrule Rrule " align="center">8%</td><td styleCode="Toprule Lrule Rrule " align="center">11%</td><td styleCode="Toprule Lrule Rrule " align="center">13%</td><td styleCode="Toprule Lrule Rrule " align="center">17%</td><td styleCode="Toprule Lrule Rrule " align="center">19%</td></tr></tbody></table> <table><caption>Table 5: Bleeding and Spotting Days from Baseline to Treatment Cycle 3 and Cycle 6</caption><col width="108"/><col width="82"/><col width="95"/><col width="95"/><col width="95"/><col width="95"/><col width="95"/><tbody><tr><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">28-Day Cycle</content> <content styleCode="bold">N*</content></td><td styleCode="Toprule Lrule Rrule " colspan="2" align="center"><content styleCode="bold">Baseline</content> N=87</td><td styleCode="Toprule Lrule Rrule " colspan="2" align="center"><content styleCode="bold">Cycle 3</content> N=88</td><td styleCode="Toprule Lrule Rrule " colspan="2" align="center"><content styleCode="bold">Cycle 6</content> N=79</td></tr><tr><td styleCode="Toprule Lrule Rrule "/><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Mean</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">SD</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Mean</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">SD</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Mean</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">SD</content></td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Number of Bleeding Days</content></td><td styleCode="Toprule Lrule Rrule " align="center">4.9</td><td styleCode="Toprule Lrule Rrule " align="center">1.5</td><td styleCode="Toprule Lrule Rrule " align="center">3.7</td><td styleCode="Toprule Lrule Rrule " align="center">3.8</td><td styleCode="Toprule Lrule Rrule " align="center">2.2</td><td styleCode="Toprule Lrule Rrule " align="center">3.5</td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Number of Spotting Days</content></td><td styleCode="Toprule Lrule Rrule " align="center">1.8</td><td styleCode="Toprule Lrule Rrule " align="center">1.1</td><td styleCode="Toprule Lrule Rrule " align="center">7.3</td><td styleCode="Toprule Lrule Rrule " align="center">7.0</td><td styleCode="Toprule Lrule Rrule " align="center">5.1</td><td styleCode="Toprule Lrule Rrule " align="center">5.8</td></tr></tbody></table>

6 ADVERSE REACTIONS The following serious or 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 or Endometritis [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 in clinical studies (> 10% participants) are vulvovaginal mycotic infections, vaginal bacterial infections, acne, and nausea or vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Study Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The data described below reflect exposure of 1,751 generally healthy participants, 16 to 45 years of age, to LILETTA in a large, multi-center contraceptive study conducted in the US. Participants included 1,401 exposed for 1 year and 380 who completed 8 years of use; 58% were nulliparous (mean age 25.1 ± 4.3 years) and 42% were parous (mean age 30.3 ± 6.1 years). Most participants who received LILETTA were Caucasian (78.4%) or Black/African American (13.3%); 14.7% of participants were of Hispanic ethnicity. Mean BMI of LILETTA participants was 26.9 kg/m 2 (range 15.8 – 61.6 kg/m 2 ); 25.1% had a BMI ≥ 30 kg/m 2 of which 5.3% had a BMI ≥ 40 kg/m 2 . The data cover more than 80,221 28-day cycles of LILETTA exposure. The frequencies of reported adverse drug reactions represent crude incidences. The most common adverse reactions during the LILETTA clinical study on contraception (occurring in ≥ 5% of participants) are shown in Table 6. The most common adverse reactions during the first year of use were acne (11.4%), bacterial vaginitis (9.0%), and vulvovaginal mycotic infection (7.9%). Table 6: Adverse Reactions in ≥ 5% of LILETTA Participants in the Phase 3 Clinical Study on Contraception Adverse Reaction % LILETTA Participants (N = 1 , 751) Vulvovaginal mycotic infections 20.2% Vaginal bacterial infections 19.2% Acne 15.5% Nausea or vomiting 10.5% Headache 10.1% Breast tenderness or pain 10.1% Abdominal discomfort or pain 10.0% Dyspareunia 9.6% Anxiety 9.6% Depression 9.1% Pelvic discomfort or pain 8.7% Dysmenorrhea 7.3% Mood changes 6.5% Back pain 6.5% Weight increased 6.1% Vaginal discharge 5.8% In the clinical study, 20.1% of LILETTA participants discontinued prematurely due to an adverse reaction. The most common adverse reactions reported by participants as reason for discontinuation were expulsion (4.1%), bleeding complaints (2.5%), acne (1.4%), dysmenorrhea (1.0%), weight increased (1.0%), mood swings (0.8%), uterine spasm (0.7%), dyspareunia (0.6%) and pelvic pain (0.6%). Two participants discontinued the clinical study due to PID and one due to endometritis. The most common adverse reactions reported by participants as reason for discontinuation during the first year of use were expulsion (2.9%) and acne (0.7%).

s (0.8%), uterine spasm (0.7%), dyspareunia (0.6%) and pelvic pain (0.6%). Two participants discontinued the clinical study due to PID and one due to endometritis. The most common adverse reactions reported by participants as reason for discontinuation during the first year of use were expulsion (2.9%) and acne (0.7%). In the clinical study, serious adverse reactions related to LILETTA were ectopic pregnancies, ovarian cysts, and IUS perforation requiring laparoscopic surgery. In the LILETTA clinical study on heavy menstrual bleeding, which included 105 participants who were 18- to 50-years old, the adverse reaction profile was consistent with the adverse reaction profile for LILETTA participants in the contraception study as shown in Table 6. Approximately 11% of LILETTA study participants discontinued prematurely due to an adverse reaction. The most common adverse reactions leading to discontinuation were expulsions (4.8%) and bleeding pattern alterations (3.8%). 6.2 Postmarketing Experience 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 emboli, deep vein thrombosis, and stroke Hypersensitivity (including rash, urticaria, and angioedema) Increased blood pressure Dizziness Device breakage

<table><caption>Table 6: Adverse Reactions in &#x2265; 5% of LILETTA Participants in the Phase 3 Clinical Study on Contraception</caption><col width="340"/><col width="340"/><tbody><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Adverse Reaction</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">% </content><content styleCode="bold">LILETTA</content><content styleCode="bold"> </content><content styleCode="bold">Participants</content><content styleCode="bold"> (N = 1</content><content styleCode="bold">,</content><content styleCode="bold">751)</content></td></tr><tr><td styleCode="Toprule Lrule Rrule ">Vulvovaginal mycotic infections</td><td styleCode="Toprule Lrule Rrule " align="center">20.2%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Vaginal bacterial infections</td><td styleCode="Toprule Lrule Rrule " align="center">19.2%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Acne</td><td styleCode="Toprule Lrule Rrule " align="center">15.5%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Nausea or vomiting</td><td styleCode="Toprule Lrule Rrule " align="center">10.5%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Headache </td><td styleCode="Toprule Lrule Rrule " align="center">10.1%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Breast tenderness or pain </td><td styleCode="Toprule Lrule Rrule " align="center">10.1%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Abdominal discomfort or pain</td><td styleCode="Toprule Lrule Rrule " align="center">10.0%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Dyspareunia</td><td styleCode="Toprule Lrule Rrule " align="center">9.6%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Anxiety</td><td styleCode="Toprule Lrule Rrule " align="center">9.6%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Depression </td><td styleCode="Toprule Lrule Rrule " align="center">9.1%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Pelvic discomfort or pain</td><td styleCode="Toprule Lrule Rrule " align="center">8.7%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Dysmenorrhea</td><td styleCode="Toprule Lrule Rrule " align="center">7.3%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Mood changes</td><td styleCode="Toprule Lrule Rrule " align="center">6.5%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Back pain</td><td styleCode="Toprule Lrule Rrule " align="center">6.5%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Weight increased</td><td styleCode="Toprule Lrule Rrule " align="center">6.1%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Vaginal discharge</td><td styleCode="Toprule Lrule Rrule " align="center">5.8%</td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary LILETTA is contraindicated for use in pregnant patients and LILETTA may cause adverse pregnancy outcomes. If a patient becomes pregnant with LILETTA in place, there is an increased risk of miscarriage, sepsis, premature labor, and premature delivery. Published studies report no harmful effects on fetal development associated with long-term use of contraceptive doses of oral progestins in a pregnant patient. 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 LILETTA. The background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. 8.2 Lactation Ris k 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. Isolated cases of decreased milk production have been reported with another LNG-releasing IUS. There are no reports of adverse effects in breastfed infants with maternal use of progestin-only contraceptives. The infant’s developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LILETTA, underlying maternal conditions, and any potential adverse effects from LILETTA on the infant. The incidence of uterine perforation appears higher in lactating patients [ s ee Warnings and Precautions ( 5.5 )] . 8.3 Females and Males of Reproductive Potential Pregnancy Testing Assess pregnancy status prior to inserting LILETTA, as recommended [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.1 )]. 8.4 Pediatric Use Safety and effectiveness of LILETTA have been established in females of reproductive potential. The safety and effectiveness are expected to be the same for postpubertal females under the age of 16 as for users 16 years and older. The LILETTA clinical study on contraception included 11 participants who were 16 to 17 years of age; no differences in safety or effectiveness were identified in these participants through 8 years of use of LILETTA. Use of this product is not indicated before menarche. 8.5 Geriatric Use LILETTA is not indicated in patients after menopause and has not been studied in this population. 8.6 Hepatic Impairment No studies were conducted to evaluate the effect of hepatic disease on the disposition of LNG released from LILETTA [ see Contraindications ( 4 ) ].

8.1 Pregnancy Risk Summary LILETTA is contraindicated for use in pregnant patients and LILETTA may cause adverse pregnancy outcomes. If a patient becomes pregnant with LILETTA in place, there is an increased risk of miscarriage, sepsis, premature labor, and premature delivery. Published studies report no harmful effects on fetal development associated with long-term use of contraceptive doses of oral progestins in a pregnant patient. 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 LILETTA. The background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

8.4 Pediatric Use Safety and effectiveness of LILETTA have been established in females of reproductive potential. The safety and effectiveness are expected to be the same for postpubertal females under the age of 16 as for users 16 years and older. The LILETTA clinical study on contraception included 11 participants who were 16 to 17 years of age; no differences in safety or effectiveness were identified in these participants through 8 years of use of LILETTA. Use of this product is not indicated before menarche.

11 DESCRIPTION the following structural formula: Levonorgestrel USP, (-)-13-ethyl-17-hydroxy-18,19-dinor-17-pregn-4-en-20-yn-3-one, the active ingredient in LILETTA, is the levorotatory form of norgestrel, which consists of a racemic mixture of D-(–)-norgestrel (levonorgestrel) and L-(+)-norgestrel (dextronorgestrel). It has a molecular weight of 312.45, a molecular formula of C21H28O2. Figure 15 Figure 16 11.1 LILETTA LILETTA (levonorgestrel-releasing intrauterine system) contains 52 mg of levonorgestrel, a progestin, and is intended to provide an initial release rate of 20.4 mcg/day of levonorgestrel. Levonorgestrel USP, (-)-13-ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one, the active ingredient in LILETTA, is the levorotatory form of norgestrel, which consists of a racemic mixture of D-(–)-norgestrel (levonorgestrel) and L-(+)-norgestrel (dextronorgestrel). It has a molecular weight of 312.45, a molecular formula of C 21 H 28 O 2 , and the following structural formula: LILETTA consists of a T-shaped polyethylene frame (T-frame) with a drug reservoir around the vertical stem (Figure 15). The T-frame has a loop at one end of the vertical stem and two horizontal arms at the other end. The drug reservoir consists of a cylinder, made of a mixture of 52 mg levonorgestrel and polydimethylsiloxane (PDMS) formed from silicone base, tetra-n-propyl silicate, and stannous octoate. The drug reservoir is covered by a translucent PDMS membrane. The low-density polyethylene of the T-frame is compounded with barium sulfate, which makes it radio-opaque. A blue polypropylene monofilament removal thread is attached to an eyelet at the end of the vertical stem of the T-frame. The polypropylene of the removal thread contains a copper-containing pigment as a colorant. The components of LILETTA, including its packaging, are not manufactured using natural rubber latex. Figure 15 : Diagram of LILETTA 11.2 Inserter The inserter device provided with LILETTA is a single-use, disposable, sterile insertion system (tube, flange, handle; Figure 16), partially preloaded with the IUS product for intrauterine administration. Once LILETTA has been inserted, the inserter is discarded. Figure 16 : Diagram of Inserter

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The local mechanism by which continuously released LNG provides contraception has not been conclusively demonstrated. Studies of LNG-releasing IUSs suggest several mechanisms for pregnancy prevention: prevention of fertilization due to the thickening of the cervical mucus, which inhibits sperm passage through the cervix, and inhibition of sperm mobility and function (capacitation), and alteration of the endometrium. 12.2 Pharmacodynamics LILETTA has mainly local progestogenic effects in the uterine cavity which change the endometrium and may lead to alterations in the menstrual bleeding pattern [ see Warnings and Precautions ( 5.8 ) ] . High local concentrations of LNG lead to morphological changes including stromal pseudo-decidualization, glandular atrophy, a leukocytic infiltration, and a decrease in glandular and stromal mitoses. In clinical studies with other LNG-releasing IUSs with an LNG release rate similar to LILETTA, approximately 45-75% of menstrual cycles were ovulatory. 12.3 Pharmacokinetics Absorption Low doses of LNG are administered into the uterine cavity with the LILETTA intrauterine delivery system. The initial in vivo release rate is 20.4 mcg/day and decreases to 17.7 mcg/day at 1 year, 15.3 mcg/day at 2 years, 13.3 mcg/day at 3 years, 11.5 mcg/day at 4 years, 10.0 mcg/day at 5 years, 8.7 mcg/day at 6 years, 7.5 mcg/day at 7 years, and 6.5 mcg/day at 8 years. In the clinical study on contraception, systemic plasma LNG concentrations were assessed in a subset of participants through Month 30 and in all participants in the study at Month 36 and after. Plasma LNG concentrations following insertion of LILETTA are shown in Table 7. Table 7: Plasma LNG Concentrations (mean ± SD, pg/mL) Following LILETTA Insertion 7 Days (n=40) 6 Months (n=36) 12 Months (n=33) 24 Months (n=30) 36 Months (n=914) 48 Months (n=793) 60 Months (n=608) 72 Months (n=243) 84 Months (n=211) 96 Months (n=142) 252±123 195±68 168±51 150±47 132±54 114±52 101±42 92±43 90±38 88±37 Distribution The apparent volume of distribution of LNG at steady-state following oral administration is reported to be approximately 1.8 L/kg. It is about 98.9% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. Elimination The elimination half-life of LNG after a single oral administration is approximately 13.9 ± 3.2 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 conjugated at the 17β-OH position to form sulfate conjugates and, to a lesser extent, glucuronide conjugates in serum. Significant amounts of conjugated and unconjugated 3α, 5β-tetrahydrolevonorgestrel are also present in serum, along with much smaller amounts of 3α, 5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. In vitro studies have demonstrated that oxidative metabolism of LNG is catalyzed by CYP enzymes, especially CYP3A4. Excretion About 45% of LNG and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates.

, 5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. In vitro studies have demonstrated that oxidative metabolism of LNG is catalyzed by CYP enzymes, especially CYP3A4. Excretion 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 Rac ial or Ethnic Groups : The effect of race on plasma LNG concentrations after LILETTA insertion was assessed in 731 (80%) White participants, 106 (12%) Black participants, 40 (4%) Asian participants, 8 (1%) American Indian/Alaska Native participants, and 21 (2%) multiple-race participants. Race does not appear to affect LNG concentrations following LILETTA insertion [see Clinical Studies ( 14 )] . BMI/Body Weight : The effect of BMI on LNG exposure was assessed in 687 non-obese (BMI < 30 kg/m 2 ) and 225 obese participants (BMI ≥ 30 kg/m 2 ). Plasma LNG concentrations were approximately 21-34% lower in obese participants than in non-obese participants based on data collected from Months 36 to 96. However, since LILETTA has a mainly local progestogenic effect in the uterine cavity, the clinical relevance of the reduced systemic exposure is unclear [see Clinical Studies ( 14 )] . Drug Interaction Studies Contraceptive effect of LILETTA 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.

12.1 Mechanism of Action The local mechanism by which continuously released LNG provides contraception has not been conclusively demonstrated. Studies of LNG-releasing IUSs suggest several mechanisms for pregnancy prevention: prevention of fertilization due to the thickening of the cervical mucus, which inhibits sperm passage through the cervix, and inhibition of sperm mobility and function (capacitation), and alteration of the endometrium.

12.2 Pharmacodynamics LILETTA has mainly local progestogenic effects in the uterine cavity which change the endometrium and may lead to alterations in the menstrual bleeding pattern [ see Warnings and Precautions ( 5.8 ) ] . High local concentrations of LNG lead to morphological changes including stromal pseudo-decidualization, glandular atrophy, a leukocytic infiltration, and a decrease in glandular and stromal mitoses. In clinical studies with other LNG-releasing IUSs with an LNG release rate similar to LILETTA, approximately 45-75% of menstrual cycles were ovulatory.

12.3 Pharmacokinetics Absorption Low doses of LNG are administered into the uterine cavity with the LILETTA intrauterine delivery system. The initial in vivo release rate is 20.4 mcg/day and decreases to 17.7 mcg/day at 1 year, 15.3 mcg/day at 2 years, 13.3 mcg/day at 3 years, 11.5 mcg/day at 4 years, 10.0 mcg/day at 5 years, 8.7 mcg/day at 6 years, 7.5 mcg/day at 7 years, and 6.5 mcg/day at 8 years. In the clinical study on contraception, systemic plasma LNG concentrations were assessed in a subset of participants through Month 30 and in all participants in the study at Month 36 and after. Plasma LNG concentrations following insertion of LILETTA are shown in Table 7. Table 7: Plasma LNG Concentrations (mean ± SD, pg/mL) Following LILETTA Insertion 7 Days (n=40) 6 Months (n=36) 12 Months (n=33) 24 Months (n=30) 36 Months (n=914) 48 Months (n=793) 60 Months (n=608) 72 Months (n=243) 84 Months (n=211) 96 Months (n=142) 252±123 195±68 168±51 150±47 132±54 114±52 101±42 92±43 90±38 88±37 Distribution The apparent volume of distribution of LNG at steady-state following oral administration is reported to be approximately 1.8 L/kg. It is about 98.9% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. Elimination The elimination half-life of LNG after a single oral administration is approximately 13.9 ± 3.2 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 conjugated at the 17β-OH position to form sulfate conjugates and, to a lesser extent, glucuronide conjugates in serum. Significant amounts of conjugated and unconjugated 3α, 5β-tetrahydrolevonorgestrel are also present in serum, along with much smaller amounts of 3α, 5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. In vitro studies have demonstrated that oxidative metabolism of LNG is catalyzed by CYP enzymes, especially CYP3A4. Excretion 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 Rac ial or Ethnic Groups : The effect of race on plasma LNG concentrations after LILETTA insertion was assessed in 731 (80%) White participants, 106 (12%) Black participants, 40 (4%) Asian participants, 8 (1%) American Indian/Alaska Native participants, and 21 (2%) multiple-race participants. Race does not appear to affect LNG concentrations following LILETTA insertion [see Clinical Studies ( 14 )] . BMI/Body Weight : The effect of BMI on LNG exposure was assessed in 687 non-obese (BMI < 30 kg/m 2 ) and 225 obese participants (BMI ≥ 30 kg/m 2 ). Plasma LNG concentrations were approximately 21-34% lower in obese participants than in non-obese participants based on data collected from Months 36 to 96. However, since LILETTA has a mainly local progestogenic effect in the uterine cavity, the clinical relevance of the reduced systemic exposure is unclear [see Clinical Studies ( 14 )] . Drug Interaction Studies Contraceptive effect of LILETTA 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.

<table><caption>Table 7: Plasma LNG Concentrations (mean &#xB1; SD, pg/mL) Following LILETTA Insertion</caption><col width="81"/><col width="68"/><col width="68"/><col width="68"/><col width="69"/><col width="69"/><col width="69"/><col width="69"/><col width="68"/><col width="68"/><tbody><tr><td styleCode="Toprule Lrule Rrule " align="center">7 Days (n=40)</td><td styleCode="Toprule Lrule Rrule " align="center">6 Months (n=36)</td><td styleCode="Toprule Lrule Rrule " align="center">12 Months (n=33)</td><td styleCode="Toprule Lrule Rrule " align="center">24 Months (n=30)</td><td styleCode="Toprule Lrule Rrule " align="center">36 Months (n=914)</td><td styleCode="Toprule Lrule Rrule " align="center">48 Months (n=793)</td><td styleCode="Toprule Lrule Rrule " align="center">60 Months (n=608)</td><td styleCode="Toprule Lrule Rrule " align="center">72 Months (n=243)</td><td styleCode="Toprule Lrule Rrule " align="center">84 Months (n=211)</td><td styleCode="Toprule Lrule Rrule " align="center">96 Months (n=142)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">252&#xB1;123</td><td styleCode="Toprule Lrule Rrule " align="center">195&#xB1;68</td><td styleCode="Toprule Lrule Rrule " align="center">168&#xB1;51</td><td styleCode="Toprule Lrule Rrule " align="center">150&#xB1;47</td><td styleCode="Toprule Lrule Rrule " align="center">132&#xB1;54</td><td styleCode="Toprule Lrule Rrule " align="center">114&#xB1;52</td><td styleCode="Toprule Lrule Rrule " align="center">101&#xB1;42</td><td styleCode="Toprule Lrule Rrule " align="center">92&#xB1;43</td><td styleCode="Toprule Lrule Rrule " align="center">90&#xB1;38</td><td styleCode="Toprule Lrule Rrule " align="center">88&#xB1;37</td></tr></tbody></table>

14 CLINICAL STUDIES Figure 17 and 18 14.1 Clinical Study on Contraception The efficacy of LILETTA for contraception was studied in a multicenter, randomized, open-label clinical study conducted in the US that enrolled 1,910 generally healthy participants aged 16 to 45 years, 1,751 of whom received LILETTA. LILETTA was inserted in 1,011 (58%) nulliparous and 740 (42%) parous participants. Participants with a history of ectopic pregnancy, PID, or trophoblastic disease without a subsequent intrauterine pregnancy, who were less than 4 weeks post-pregnancy, had HIV, or were not in a mutually monogamous relationship at study entry were excluded. The demographic profile of enrolled participants who received LILETTA are as follows: White 78.4%, Black or African American 13.3%, Asian 3.9%, American Indian or Alaska Native 1.2%, Native Hawaiian or Other Pacific Islander 0.3%; 2.9% identified multiple races; 14.7% indicated Hispanic ethnicity. The clinical study had no limit on weight (minimum or maximum) or BMI (range was 15.8 – 61.6 kg/m 2 ). The mean BMI of LILETTA participants was 26.9 kg/m 2 ; 24% were overweight, 24% were obese (BMI ≥ 30 kg/m 2 ), and 5% were morbidly obese (BMI ≥ 40 kg/m 2 ). The pregnancy rate calculated as the Pearl Index (PI) in participants 16 to 35 years of age, inclusive, 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 two pregnancies and the cumulative 8-year pregnancy rate was calculated by the life table method, based on a total of eleven pregnancies that occurred after the onset of treatment and within 7 days after LILETTA removal or expulsion. Table 8 shows the annual PI for each of the eight years and the calculated cumulative life table pregnancy rates through years 1, 2, 3, 4, 5, 6, 7, and 8. For Year 7 and Year 8, participants who were more than 39 years of age at the beginning of the respective study year were excluded from the efficacy analysis. Table 8: Contraceptive Efficacy: Pregnancy Rates L ILETTA Clinical Study Number of 28-Day Cycles of Exposure By Year Year-by-Year Pearl Index Pregnancy Rate (95% CI) Cumulative 28-Day Cycles of Exposure Cumulative Year Life Table Pregnancy Rate (95% CI) Year 1 17,175 0.15 (0.02, 0.55) 17,175 0.14 (0.04, 0.57) Year 2 14,205 0.37 (0.10, 0.94) 31,380 0.50 (0.22, 1.10) Year 3 11,760 0.11 (0.00, 0.62) 43,140 0.60 (0.29, 1.27) Year 4 9,891 0.13 (0.00, 0.73) 53,031 0.73 (0.36, 1.48) Year 5 8,337 0.16 (0.00, 0.87) 61,368 0.89 (0.45, 1.74) Year 6 6,916 0.00 (0.00, 0.69) 68,284 0.89 (0.45, 1.74) Year 7* 5,280 0.49 (0.06, 1.78) 73,564 1.37 (0.71, 2.62) Year 8* 3,657 0.00 (0.00, 1.31) 77,221 1.37 (0.71, 2.62) *Excludes participants >39 years of age at the beginning of the respective year. Conception rates after the removal of LILETTA were assessed and appeared consistent with conception rates in the general population having regular unprotected sexual intercourse for 12 months. Of 244 participants who desired pregnancy after study discontinuation, 63.1% conceived within 6 months after removal of LILETTA and 83.2% conceived within 12 months after removal of LILETTA .

appeared consistent with conception rates in the general population having regular unprotected sexual intercourse for 12 months. Of 244 participants who desired pregnancy after study discontinuation, 63.1% conceived within 6 months after removal of LILETTA and 83.2% conceived within 12 months after removal of LILETTA . 14.2 Clinical Study on Treatment of Heavy Menstrual Bleeding The efficacy of LILETTA in the treatment of heavy menstrual bleeding was studied in a non-comparative, open-label clinical study conducted in the US. The study enrolled 105 generally healthy participants 18 to 50 years of age, with no contraindications to LILETTA, and with confirmed heavy menstrual bleeding (≥ 80 mL menstrual blood loss [MBL] per menses) determined using the alkaline hematin method. Participants with any structural (e.g., leiomyomas > 2 cm in greatest diameter or more than 3 leiomyomas > 1.5 cm in greatest diameter) or diagnosed pathophysiologic conditions that may cause heavy uterine bleeding were excluded. The study population was 64.8% White, 23.8% African American, and 11.4% Other; 9.5% of enrolled participants were of Hispanic ethnicity. The median BMI was 29.7 kg/m 2 (with 23.8% overweight and 48.6% obese). The median baseline MBL was 143.2 mL. The primary efficacy endpoint was the proportion of women with successful treatment, defined as (1) an end-of-study MBL volume < 80 mL and (2) ≥ 50% reduction in MBL from baseline to end-of-study. Treatment outcomes with LILETTA are summarized in Figures 17 and 18. The proportion of participants meeting both criteria defining successful treatment was 80% at the end of the study, with a 95% confidence interval of 71-88% (Figure 17). The quantitative reduction in median MBL volume from baseline to mid-study and to end-of-study is shown in Figure 18. The median MBL percent reduction from baseline to mid-study was 91% and to end-of-study was 96%.

ccessful treatment was 80% at the end of the study, with a 95% confidence interval of 71-88% (Figure 17). The quantitative reduction in median MBL volume from baseline to mid-study and to end-of-study is shown in Figure 18. The median MBL percent reduction from baseline to mid-study was 91% and to end-of-study was 96%. 14.1 Clinical Study on Contraception The efficacy of LILETTA for contraception was studied in a multicenter, randomized, open-label clinical study conducted in the US that enrolled 1,910 generally healthy participants aged 16 to 45 years, 1,751 of whom received LILETTA. LILETTA was inserted in 1,011 (58%) nulliparous and 740 (42%) parous participants. Participants with a history of ectopic pregnancy, PID, or trophoblastic disease without a subsequent intrauterine pregnancy, who were less than 4 weeks post-pregnancy, had HIV, or were not in a mutually monogamous relationship at study entry were excluded. The demographic profile of enrolled participants who received LILETTA are as follows: White 78.4%, Black or African American 13.3%, Asian 3.9%, American Indian or Alaska Native 1.2%, Native Hawaiian or Other Pacific Islander 0.3%; 2.9% identified multiple races; 14.7% indicated Hispanic ethnicity. The clinical study had no limit on weight (minimum or maximum) or BMI (range was 15.8 – 61.6 kg/m 2 ). The mean BMI of LILETTA participants was 26.9 kg/m 2 ; 24% were overweight, 24% were obese (BMI ≥ 30 kg/m 2 ), and 5% were morbidly obese (BMI ≥ 40 kg/m 2 ). The pregnancy rate calculated as the Pearl Index (PI) in participants 16 to 35 years of age, inclusive, 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 two pregnancies and the cumulative 8-year pregnancy rate was calculated by the life table method, based on a total of eleven pregnancies that occurred after the onset of treatment and within 7 days after LILETTA removal or expulsion. Table 8 shows the annual PI for each of the eight years and the calculated cumulative life table pregnancy rates through years 1, 2, 3, 4, 5, 6, 7, and 8. For Year 7 and Year 8, participants who were more than 39 years of age at the beginning of the respective study year were excluded from the efficacy analysis. Table 8: Contraceptive Efficacy: Pregnancy Rates L ILETTA Clinical Study Number of 28-Day Cycles of Exposure By Year Year-by-Year Pearl Index Pregnancy Rate (95% CI) Cumulative 28-Day Cycles of Exposure Cumulative Year Life Table Pregnancy Rate (95% CI) Year 1 17,175 0.15 (0.02, 0.55) 17,175 0.14 (0.04, 0.57) Year 2 14,205 0.37 (0.10, 0.94) 31,380 0.50 (0.22, 1.10) Year 3 11,760 0.11 (0.00, 0.62) 43,140 0.60 (0.29, 1.27) Year 4 9,891 0.13 (0.00, 0.73) 53,031 0.73 (0.36, 1.48) Year 5 8,337 0.16 (0.00, 0.87) 61,368 0.89 (0.45, 1.74) Year 6 6,916 0.00 (0.00, 0.69) 68,284 0.89 (0.45, 1.74) Year 7* 5,280 0.49 (0.06, 1.78) 73,564 1.37 (0.71, 2.62) Year 8* 3,657 0.00 (0.00, 1.31) 77,221 1.37 (0.71, 2.62) *Excludes participants >39 years of age at the beginning of the respective year. Conception rates after the removal of LILETTA were assessed and appeared consistent with conception rates in the general population having regular unprotected sexual intercourse for 12 months. Of 244 participants who desired pregnancy after study discontinuation, 63.1% conceived within 6 months after removal of LILETTA and 83.2% conceived within 12 months after removal of LILETTA .

<table><caption>Table 8: Contraceptive Efficacy: Pregnancy Rates</caption><col width="128"/><col width="128"/><col width="128"/><col width="128"/><col width="128"/><tbody><tr><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">L</content><content styleCode="bold">ILETTA</content><content styleCode="bold"> Clinical </content><content styleCode="bold">Study</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Number of 28-Day Cycles of Exposure</content> <content styleCode="bold">By Year</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold"> Year-by-Year</content> <content styleCode="bold">Pearl Index</content> Pregnancy Rate (95% CI)</td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Cumulative 28-Day Cycles of Exposure</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Cumulative </content><content styleCode="bold">Year</content><content styleCode="bold"> </content> <content styleCode="bold">Life Table</content> Pregnancy Rate (95% CI)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Year 1</td><td styleCode="Toprule Lrule Rrule " align="center">17,175</td><td styleCode="Toprule Lrule Rrule " align="center">0.15 (0.02, 0.55)</td><td styleCode="Toprule Lrule Rrule " align="center">17,175</td><td styleCode="Toprule Lrule Rrule " align="center">0.14 (0.04, 0.57)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Year 2</td><td styleCode="Toprule Lrule Rrule " align="center">14,205</td><td styleCode="Toprule Lrule Rrule " align="center">0.37 (0.10, 0.94)</td><td styleCode="Toprule Lrule Rrule " align="center">31,380</td><td styleCode="Toprule Lrule Rrule " align="center">0.50 (0.22, 1.10)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Year 3</td><td styleCode="Toprule Lrule Rrule " align="center">11,760</td><td styleCode="Toprule Lrule Rrule " align="center">0.11 (0.00, 0.62)</td><td styleCode="Toprule Lrule Rrule " align="center">43,140</td><td styleCode="Toprule Lrule Rrule " align="center">0.60 (0.29, 1.27)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Year 4</td><td styleCode="Toprule Lrule Rrule " align="center">9,891</td><td styleCode="Toprule Lrule Rrule " align="center">0.13 (0.00, 0.73)</td><td styleCode="Toprule Lrule Rrule " align="center">53,031</td><td styleCode="Toprule Lrule Rrule " align="center">0.73 (0.36, 1.48)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Year 5</td><td styleCode="Toprule Lrule Rrule " align="center">8,337</td><td styleCode="Toprule Lrule Rrule " align="center">0.16 (0.00, 0.87)</td><td styleCode="Toprule Lrule Rrule " align="center">61,368</td><td styleCode="Toprule Lrule Rrule " align="center">0.89 (0.45, 1.74)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Year 6</td><td styleCode="Toprule Lrule Rrule " align="center">6,916</td><td styleCode="Toprule Lrule Rrule " align="center">0.00 (0.00, 0.69)</td><td styleCode="Toprule Lrule Rrule " align="center">68,284</td><td styleCode="Toprule Lrule Rrule " align="center">0.89 (0.45, 1.74)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Year 7*</td><td styleCode="Toprule Lrule Rrule " align="center">5,280</td><td styleCode="Toprule Lrule Rrule " align="center">0.49 (0.06, 1.78)</td><td styleCode="Toprule Lrule Rrule " align="center">73,564</td><td styleCode="Toprule Lru

0.89 (0.45, 1.74)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Year 7*</td><td styleCode="Toprule Lrule Rrule " align="center">5,280</td><td styleCode="Toprule Lrule Rrule " align="center">0.49 (0.06, 1.78)</td><td styleCode="Toprule Lrule Rrule " align="center">73,564</td><td styleCode="Toprule Lru le Rrule " align="center">1.37 (0.71, 2.62)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Year 8*</td><td styleCode="Toprule Lrule Rrule " align="center">3,657</td><td styleCode="Toprule Lrule Rrule " align="center">0.00 (0.00, 1.31)</td><td styleCode="Toprule Lrule Rrule " align="center">77,221</td><td styleCode="Toprule Lrule Rrule " align="center">1.37 (0.71, 2.62)</td></tr></tbody></table>

lign="center">Year 8*</td><td styleCode="Toprule Lrule Rrule " align="center">3,657</td><td styleCode="Toprule Lrule Rrule " align="center">0.00 (0.00, 1.31)</td><td styleCode="Toprule Lrule Rrule " align="center">77,221</td><td styleCode="Toprule Lrule Rrule " align="center">1.37 (0.71, 2.62)</td></tr></tbody></table> <table><caption>Table 8: Contraceptive Efficacy: Pregnancy Rates</caption><col width="128"/><col width="128"/><col width="128"/><col width="128"/><col width="128"/><tbody><tr><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">L</content><content styleCode="bold">ILETTA</content><content styleCode="bold"> Clinical </content><content styleCode="bold">Study</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Number of 28-Day Cycles of Exposure</content> <content styleCode="bold">By Year</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold"> Year-by-Year</content> <content styleCode="bold">Pearl Index</content> Pregnancy Rate (95% CI)</td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Cumulative 28-Day Cycles of Exposure</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Cumulative </content><content styleCode="bold">Year</content><content styleCode="bold"> </content> <content styleCode="bold">Life Table</content> Pregnancy Rate (95% CI)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Year 1</td><td styleCode="Toprule Lrule Rrule " align="center">17,175</td><td styleCode="Toprule Lrule Rrule " align="center">0.15 (0.02, 0.55)</td><td styleCode="Toprule Lrule Rrule " align="center">17,175</td><td styleCode="Toprule Lrule Rrule " align="center">0.14 (0.04, 0.57)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Year 2</td><td styleCode="Toprule Lrule Rrule " align="center">14,205</td><td styleCode="Toprule Lrule Rrule " align="center">0.37 (0.10, 0.94)</td><td styleCode="Toprule Lrule Rrule " align="center">31,380</td><td styleCode="Toprule Lrule Rrule " align="center">0.50 (0.22, 1.10)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Year 3</td><td styleCode="Toprule Lrule Rrule " align="center">11,760</td><td styleCode="Toprule Lrule Rrule " align="center">0.11 (0.00, 0.62)</td><td styleCode="Toprule Lrule Rrule " align="center">43,140</td><td styleCode="Toprule Lrule Rrule " align="center">0.60 (0.29, 1.27)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Year 4</td><td styleCode="Toprule Lrule Rrule " align="center">9,891</td><td styleCode="Toprule Lrule Rrule " align="center">0.13 (0.00, 0.73)</td><td styleCode="Toprule Lrule Rrule " align="center">53,031</td><td styleCode="Toprule Lrule Rrule " align="center">0.73 (0.36, 1.48)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Year 5</td><td styleCode="Toprule Lrule Rrule " align="center">8,337</td><td styleCode="Toprule Lrule Rrule " align="center">0.16 (0.00, 0.87)</td><td styleCode="Toprule Lrule Rrule " align="center">61,368</td><td styleCode="Toprule Lrule Rrule " align="center">0.89 (0.45, 1.74)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Year 6</td><td styleCode="Toprule Lrule Rrule " align="center">6,916</td><td styleCode="Toprule Lrule Rrule " align="center">0.00 (0.00, 0.69)</td><td styleCode="Toprule Lrule Rrule " align="center">68,284</td><td styleCode="Toprule Lrule Rrule " align="center">0.89 (0.45, 1.74)</td></tr><tr><td styleCode="Toprule Lrule Rrule " align="center">Year 7*</td><td styleCode="Toprule Lrule Rrule " align="center">5,280</td><td styleCode="Toprule Lrule Rrule " align="center">0.49 (0.06, 1.78)</td><td styleCode="Toprule Lrule Rrule " align="center">73,564</td><td styleCode="Toprule Lru

16 HOW SUPPLIED/STORAGE AND HANDLING LILETTA (levonorgestrel-releasing intrauterine system), containing 52 mg levonorgestrel, is supplied partially preloaded within the inserter and packaged in a clear plastic tray with lid. LILETTA is available in a carton of one sterile unit. NDC # 0023-5858-01. LILETTA is supplied sterile. LILETTA is sterilized with ethylene oxide. Do not re-sterilize. Do not use if the packaging is damaged, or if the packaging is opened. Insert before the end of the month shown on the packaging. Store at 20°C – 25°C (68°F – 77°F), with excursions permitted between 15°C – 30°C (59°F – 86°F) [See USP Controlled Room Temperature]. Store the sealed tray with peel-off lid in outer carton until use to protect from light.

17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling ( Patient Information ). Advise patients that this product does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs). Advise patients about the risks of ectopic pregnancy, including the loss of fertility. Advise them to recognize and report promptly to their healthcare professional any symptoms of ectopic pregnancy, including lower abdominal pain, especially in association with missed periods [see Warnings and Precautions ( 5.1 )]. Advise patients about the following concerns and precautions if pregnancy occurs while using LILETTA: LILETTA will likely need to be removed because leaving it in place may increase the risk of spontaneous abortion and preterm labor; however, removal of LILETTA or probing of the uterus may also result in spontaneous abortion [see Warnings and Precautions ( 5.2 )]. Report promptly to their healthcare professional any symptoms that suggest complications of the pregnancy, including flu-like symptoms, fever, chills, cramping, pain, bleeding, and vaginal discharge or leakage of fluid [see Warnings and Precautions ( 5.2 )]. Septic abortion may occur. Advise them that if LILETTA cannot be removed or they choose not to have it removed, there may be an increased risk of miscarriage, sepsis, premature labor, and premature delivery [see Warnings and Precautions ( 5.2 )]. Advise patients that severe infection or sepsis, including Group A streptococcal sepsis (GAS), can occur within the first few days after LILETTA is inserted. Advise them to contact a healthcare professional immediately if they develop severe pain or fever shortly after LILETTA is inserted [see Warnings and Precautions ( 5.3 )]. Advise patients about the possibility of PID or endometritis and that these infections can cause tubal damage leading to ectopic pregnancy or infertility, or infrequently can necessitate hysterectomy, or cause death. Advise the patient to recognize and report to their healthcare professional any of the following signs and symptoms of possible infection [see Warnings and Precautions ( 5.4 )] : lower abdominal or pelvic pain or tenderness fever chills unusual or malodorous vaginal discharge atypical or unexplained bleeding (prolonged or heavy bleeding) genital lesions or sores. dyspareunia Advise patients that perforation may occur, most often during insertion, although the perforation may not be detected until sometime later. Perforation may also occur at any time during IUS use. Advise them that if perforation occurs, LILETTA will have to be located and removed. Surgery may be required. Advise them that delayed detection or removal of LILETTA in case of perforation may have the following results [see Warnings and Precautions ( 5.5 )]: migration of IUS outside the uterus intestinal perforations adhesions intestinal obstruction peritonitis erosion of adjacent viscera abscesses loss of contraceptive protection Review with patients the signs and symptoms of LILETTA expulsion. Advise patients on how they can check that the threads still protrude from their cervix, and not to pull on them. Advise them that there is no contraceptive protection if LILETTA is displaced or expelled [see Warnings and Precautions ( 5.6 )].

protection Review with patients the signs and symptoms of LILETTA expulsion. Advise patients on how they can check that the threads still protrude from their cervix, and not to pull on them. Advise them that there is no contraceptive protection if LILETTA is displaced or expelled [see Warnings and Precautions ( 5.6 )]. Advise patients that excessive pain or vaginal bleeding during insertion, worsening pain or bleeding after insertion, or the inability to feel the threads may occur with perforation and expulsion [see Warnings and Precautions ( 5.5 , 5.6 )]. Advise patients regarding the risk of ovarian cysts and that cysts can cause clinical symptoms including pelvic pain, abdominal pain or dyspareunia and infrequently will need surgery [see Warnings and Precautions ( 5.7 )]. Advise patients that irregular or prolonged bleeding and spotting, and/or cramps may occur during the first three to six months after insertion. If their symptoms continue or are severe, they should report them to their healthcare professional [see Warnings and Precautions ( 5.8 )]. Advise patients to contact their healthcare professional if they experience any of the following symptoms or conditions: 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 Severe vaginal bleeding or bleeding that lasts a long time, or if they miss a menstrual period Pelvic pain or pain during sex Patient or partner becomes HIV positive Possible exposure to sexually transmitted infections (STIs) Unusual or malodorous vaginal discharge Genital sores Inability to feel LILETTA's threads Inform patients that LILETTA is compatible with MRI and should not interfere with imaging [see Warnings and Precautions ( 5.11 )]. LILETTA and its design are trademarks of Odyssea Pharma SPRL, an AbbVie company . Medicines360 and its design are trademarks of Medicines360 . Manufactured by: Odyssea Pharma, SPRL, Belgium An affiliated company of AbbVie Distributed by: AbbVie Inc. North Chicago, Illinois 60064 Marketed by: AbbVie Inc. Medicines360 North Chicago, IL 60064 San Francisco, CA 94105 © 20 2 3 AbbVie and Medicines360. All rights reserved. V4.1USPI5858

<table><col width="343"/><col width="343"/><tbody><tr><td><list listType="unordered" styleCode="Disc"><item>migration of IUS outside the uterus</item></list></td><td><list listType="unordered" styleCode="Disc"><item>intestinal perforations</item></list></td></tr><tr><td><list listType="unordered" styleCode="Disc"><item>adhesions </item></list></td><td><list listType="unordered" styleCode="Disc"><item>intestinal obstruction</item></list></td></tr><tr><td><list listType="unordered" styleCode="Disc"><item>peritonitis </item></list></td><td><list listType="unordered" styleCode="Disc"><item>erosion of adjacent viscera</item></list></td></tr><tr><td><list listType="unordered" styleCode="Disc"><item>abscesses</item></list></td><td><list listType="unordered" styleCode="Disc"><item>loss of contraceptive protection</item></list></td></tr></tbody></table>

PATIENT INFORMATION LILETTA (lye-LET-uh) (levonorgestrel-releasing intrauterine system) Read this Patient Information carefully before you decide if LILETTA is right for you. This information does not take the place of talking with your gynecologist or other healthcare professional. If you have any questions about LILETTA, ask your healthcare professional. You should also learn about other birth control methods to choose the one that is best for you. LILETTA does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs). What is LILETTA? LILETTA is a hormone-releasing system placed in your uterus by your healthcare professional to prevent pregnancy for up to 8 years. LILETTA can also help with heavy periods, also known as heavy menstrual bleeding (HMB), for up to 5 years. LILETTA can be removed by your healthcare professional at any time. LILETTA can be used whether or not you have given birth to a child. LILETTA is a small, flexible plastic T-shaped system that slowly releases a progestin hormone called levonorgestrel (LNG) that is often used in birth control pills. Because LILETTA releases LNG into your uterus, only small amounts of the hormone enter your blood. LILETTA does not contain estrogen. Two thin threads are attached to the stem (lower end) of LILETTA. The threads are the only part of LILETTA you can feel when LILETTA is in your uterus; however, unlike a tampon string, the threads do not extend outside your body. LILETTA is small and flexible What if I need birth control for more than 8 years? LILETTA must be removed after 8 years. Your healthcare professional can place a new LILETTA during the same office visit if you choose to continue using LILETTA. What if I need treatment for heavy menstrual flow for more than 5 years? For continued treatment of heavy menstrual flow after 5 years, your healthcare professional can remove LILETTA and place a new LILETTA during the same office visit. What if I want to stop using LILETTA? LILETTA is intended for use as birth control for up to 8 years, but you can stop using LILETTA at any time by asking your healthcare professional to remove it. You could become pregnant as soon as LILETTA is removed, so you should use another method of birth control if you do not want to become pregnant. Talk to your healthcare professional about the best birth control methods for you, because your new method may need to be started 7 days before LILETTA is removed to prevent pregnancy. What if I change my mind about birth control and want to become pregnant in less than 8 years? Your healthcare professional can remove LILETTA at any time. You could become pregnant as soon as LILETTA is removed. About 5 out of 6 patients who want to become pregnant will become pregnant sometime in the first year after LILETTA is removed. How does LILETTA work for birth control ? LILETTA may work in several ways including thickening cervical mucus, inhibiting sperm movement, reducing sperm survival, and thinning the lining of your uterus. It is not known exactly how these actions work together to prevent pregnancy. How does LILETTA work for heavy menstrual bleeding? The hormone in LILETTA, levonorgestrel, acts by controlling the monthly development of the womb (uterus) lining, making it thinner, so that there is less bleeding every month. How well does LILETTA work for birth control ?

e actions work together to prevent pregnancy. How does LILETTA work for heavy menstrual bleeding? The hormone in LILETTA, levonorgestrel, acts by controlling the monthly development of the womb (uterus) lining, making it thinner, so that there is less bleeding every month. How well does LILETTA work for birth control ? The following chart shows the chance of getting pregnant for patients who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for patients who do not use birth control and are trying to get pregnant. LILETTA, an intrauterine system (IUS), is also known as an intrauterine device (IUD), which is shown in the box at the top of the chart. How well does LILETTA work for treating heavy menstrual bleeding? In the clinical trial performed in patients with heavy menstrual bleeding and treated with LILETTA, the majority of (or 8 out of 10) patients were treated successfully. That is, their menstrual cycle blood loss was reduced to less than 80 mL and reduced by more than half by the end of treatment at six months. Who might use LILETTA? You might choose LILETTA if you are willing to use a birth control method that is placed in the uterus, and want birth control with the following features: long-term birth control that provides a low chance of getting pregnant (less than 1 in 100) works continuously for up to 8 years is reversible does not need to be taken daily does not contain estrogen treats heavy menstrual bleeding Do not use LILETTA if you have any of the following conditions : you are or might be pregnant; LILETTA cannot be used as an emergency contraceptive a serious pelvic infection called pelvic inflammatory disease (PID) an untreated lower genital infection now a serious pelvic infection after an abortion or pregnancy within the last 3 months a condition or behavior that can allow you to get infections more easily, such as those listed below: ○ problems with your immune system ○ having multiple sexual partners or your partner has multiple sexual partners ○ history of PID cancer of the uterus or cervix, known or suspected bleeding from the vagina that has not been explained short-term (acute) liver disease or a liver tumor breast cancer or any other cancer that is sensitive to progestin (a female hormone), now or in the past an intrauterine contraceptive system in your uterus already a condition of the uterus that changes the shape of the uterine cavity, such as large fibroid tumors an allergy to levonorgestrel, silicone, polyethylene, or barium sulfate Before having LILETTA placed, tell your healthcare professional if you have o r had any medical conditions, including those listed below: any of the conditions listed above you recently had a baby, or you are breastfeeding heart attack stroke heart disease you were born with, or problems with your heart valves blood clotting problems, or condition for which you take medicine to reduce clotting high blood pressure severe migraine headaches severe or frequent headaches AIDS, HIV, or any other sexually transmitted infection Tell your healthcare professional about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How is LILETTA placed? LILETTA is placed by your healthcare professional during an in-office visit. First, your healthcare professional will examine your pelvis to find the exact position of your uterus. Your healthcare professional will then clean your vagina and cervix with an antiseptic solution and slide a plastic tube containing LILETTA through the cervix into your uterus.

professional during an in-office visit. First, your healthcare professional will examine your pelvis to find the exact position of your uterus. Your healthcare professional will then clean your vagina and cervix with an antiseptic solution and slide a plastic tube containing LILETTA through the cervix into your uterus. Your healthcare professional will then remove the plastic tube and leave LILETTA in your uterus. Your healthcare professional will trim the threads to the right length. You may experience pain, bleeding, or dizziness during and after placement. If your symptoms do not pass within 30 minutes after placement, LILETTA may not have been placed correctly. Your healthcare professional will examine you to see if LILETTA needs to be removed or replaced. Should I check that LILETTA is in place? Yes, you should check that LILETTA is in proper position by feeling the threads. It is a good habit to do this 1 time a month. Your healthcare professional should teach you how to check that LILETTA is in place. First, wash your hands with soap and water. You can check by reaching up to the top of your vagina with clean fingers to feel the threads. Do not pull on the threads. If you feel more than just the threads or if you cannot feel the threads, LILETTA may not be in the right position and may not prevent pregnancy. Use non-hormonal back-up birth control (such as condoms) and ask your healthcare professional to check that LILETTA is still in the right place. How soon after placement of LILETTA should I return to my healthcare professional? Call your healthcare professional if you have any questions or concerns (see “When should I call my healthcare professional?”). Generally, patients have a follow-up visit 4 to 6 weeks after LILETTA is placed to make sure that LILETTA is in the right position, and routine visits thereafter. Follow-up plans may vary according to patient needs. Can I use tampons or menstrual cups with LILETTA? Yes, tampons or menstrual cups may be used with LILETTA. Change tampons or menstrual cups with care to avoid pulling the threads of LILETTA. If you think you may have pulled LILETTA out of place, avoid intercourse or use a non-hormonal back-up birth control (such as condoms), and contact your healthcare professional. What if I become pregnant while using LILETTA? Call your healthcare professional right away if you think you are pregnant. If possible, also do a urine pregnancy test. If you get pregnant while using LILETTA, you may have an ectopic pregnancy. This means that the pregnancy is not in the uterus. Unusual vaginal bleeding or abdominal pain, especially with missed periods, may be a sign of ectopic pregnancy. Ectopic pregnancy is a medical emergency that often requires surgery. Ectopic pregnancy can cause internal bleeding, infertility, and even death. There are also risks if you get pregnant while using LILETTA and the pregnancy is in the uterus. Severe infection, miscarriage, premature labor, premature delivery, and even death can occur with pregnancies that continue with an intrauterine system (IUS). Because of this, your healthcare professional may try to remove LILETTA, even though removing it may cause a miscarriage. If LILETTA cannot be removed, talk with your healthcare professional about the benefits and risks of continuing the pregnancy. If you continue your pregnancy, see your healthcare professional regularly. Call your healthcare professional right away if you get flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge, or fluid leaking from your vagina. These may be signs of infection. It is not known if LILETTA can cause long-term effects on the fetus if it stays in place during a pregnancy. How will LILETTA change my periods?

sional right away if you get flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge, or fluid leaking from your vagina. These may be signs of infection. It is not known if LILETTA can cause long-term effects on the fetus if it stays in place during a pregnancy. How will LILETTA change my periods? For the first 3 to 6 months, your period may become irregular and the number of bleeding days may increase. You may also have frequent spotting or light bleeding and cramping. Some patients have heavy bleeding during this time. After you have used LILETTA for a while, the number of bleeding and spotting days is likely to lessen. For some patients, menstrual periods will stop altogether. When LILETTA is removed, your menstrual periods will likely return to their former pattern. Is it safe to breastfeed while using LILETTA? You may use LILETTA when you are breastfeeding. LILETTA is not likely to affect the quality or amount of your breast milk or the health of your nursing baby. However, isolated cases of decreased milk production have been reported among patients using progestin-only birth control pills. The risk of LILETTA becoming attached to (embedded) or going through the wall of the uterus is increased when LILETTA is inserted while you are breastfeeding. Will LILETTA interfere with sexual intercourse? You and your partner should not feel LILETTA during intercourse. LILETTA is placed in the uterus, not in the vagina. In some cases, your partner may feel the threads. If this occurs, or if you or your partner experience pain during sex, talk with your healthcare professional. Can I have a magnetic resonance imaging (MRI) procedure with LILETTA in place? Yes, LILETTA should not interfere with imaging. Tell your healthcare professional you have an intrauterine contraceptive in place. What are the possible side effects of LILETTA? LILETTA can cause serious side effects, including those listed below : ectopic pregnancy . If you get pregnant while using LILETTA, you might have an ectopic pregnancy. This means that the pregnancy is not in the uterus. Unusual vaginal bleeding or abdominal pain, especially with missed periods, may be a sign of ectopic pregnancy. Ectopic pregnancy is a medical emergency that often requires surgery. Ectopic pregnancy can cause internal bleeding, infertility, and even death. intrauterine pregnancy risks . There are also risks if you get pregnant while using LILETTA and the pregnancy is in the uterus. Severe infection, miscarriage, premature labor, premature delivery, and even death can occur with pregnancies that continue with an intrauterine system (IUS). Because of this, your healthcare professional may try to remove LILETTA, even though removing it may cause a miscarriage. If LILETTA cannot be removed, talk with your healthcare professional about the benefits and risks of continuing the pregnancy. If, after seeing your healthcare professional, you choose to continue your pregnancy, see your healthcare professional regularly. Call your healthcare professional right away if you get flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge, or fluid leaking from your vagina. These may be signs of infection. It is not known if LILETTA can cause long-term effects on the fetus if it stays in place during a pregnancy. life-threatening infection . Life-threatening infection can occur within the first few days after LILETTA is placed. Call your healthcare professional immediately if you develop severe pain or fever shortly after LILETTA is placed. pelvic inflammatory disease (PID ) or endometritis . Some IUS users get a serious pelvic infection called pelvic inflammatory disease (PID) or endometritis. PID and endometritis may be sexually transmitted.

all your healthcare professional immediately if you develop severe pain or fever shortly after LILETTA is placed. pelvic inflammatory disease (PID ) or endometritis . Some IUS users get a serious pelvic infection called pelvic inflammatory disease (PID) or endometritis. PID and endometritis may be sexually transmitted. You have a higher chance of getting PID or endometritis if you or your partner have sex with other partners. PID or endometritis can cause serious problems such as infertility, ectopic pregnancy, or pelvic pain that does not go away. PID is usually treated with antibiotics. More serious cases of PID or endometritis may require surgery. Removal of the uterus (hysterectomy) is sometimes needed. In rare cases, infections that start as PID or endometritis can even cause death. Tell your healthcare professional right away if you have any of these signs of PID or endometritis: long-lasting or heavy bleeding, unusual or foul-smelling vaginal discharge, low abdominal or pelvic pain, painful sex, genital lesions or sores, chills, or fever. perforation . LILETTA may partially go into the wall of the uterus (become embedded) or go completely through the wall of the uterus (perforate). If this occurs, LILETTA may no longer prevent pregnancy. If perforation occurs, LILETTA may move outside the uterus and can cause internal scarring, infection, or damage to other organs. You may need surgery to have LILETTA removed if it is embedded or perforation occurs. The risk of perforation is increased in breastfeeding patients. expulsion . LILETTA may come out of your uterus (expulsion). Expulsion occurs in about 4 out of 100 patients, most often in the first year of use. You may become pregnant if LILETTA comes out. If you think that LILETTA has come out, use another birth control method (such as condoms) or do not have sex (vaginal intercourse) until you are seen by a healthcare professional. cysts on the ovary . Some patients using LILETTA develop a cyst on the ovary. These cysts usually disappear on their own in 2 to 3 months. However, a cyst can cause pain and sometimes will need surgery. changes in bleeding . You may have bleeding and spotting between menstrual periods, especially during the first 3 to 6 months. Sometimes the bleeding is heavier than usual at first. Over time the bleeding often becomes lighter than usual and may be irregular. Call your healthcare professional if the bleeding remains heavier than usual or increases after it has been light for a while. LILETTA’s most common side effects are listed below: • acne • vaginal discharge • headache • vaginal bacterial infection • breast pain • yeast infection of your vulva and vagina (vulvovaginal) • abdominal pain • nausea or vomiting • pelvic pain • weight increase • menstrual-like cramping • mood changes • pain during sex • anxiety • back pain • depression Pain, bleeding, or dizziness during and after placement. If these symptoms do not stop within 30 minutes after placement, LILETTA may not have been placed correctly, or they may be symptoms of perforation or expulsion. Your healthcare professional will examine you to see if LILETTA needs to be removed or replaced. Missed menstrual periods. About 2 out of 10 patients stop having periods after 1 year of LILETTA use. If you have any concerns that you may be pregnant while using LILETTA, do a urine pregnancy test and call your healthcare professional. When LILETTA is removed, your menstrual periods will usually return to your previous pattern. These are not all the possible side effects of LILETTA. For more information, ask your healthcare professional or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to AbbVie at 1-800-678-1605.

your previous pattern. These are not all the possible side effects of LILETTA. For more information, ask your healthcare professional or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to AbbVie at 1-800-678-1605. After LILETTA has been placed , when should I call my healthcare professional? Call your healthcare professional if you have any concerns about LILETTA. Be sure to call if you have any of the conditions listed below: are pregnant or think you are pregnant pelvic pain or pain during sex unusual or foul-smelling vaginal discharge or genital sores unexplained fever, chills, or flu-like symptoms might be exposed to sexually transmitted infections (STIs) concern that LILETTA may have come out or expelled cannot feel LILETTA's threads very severe or migraine headaches yellowing of the skin or whites of the eyes (these may be signs of liver problems) stroke or heart attack you or your partner become HIV positive severe vaginal bleeding, bleeding that lasts a long time, or you miss your period General information about the safe and effective use of LILETTA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare professional for information about LILETTA that is written for health professionals. For more information, go to www.LILETTA.com or call 1-855-LILETTA (1-855-545-3882). LILETTA and its design are trademarks of Odyssea Pharma SPRL, an AbbVie company . Medicines360 and its design are trademarks of Medicines360 . Manufactured by: Odyssea Pharma, SPRL, Belgium An affiliated company of AbbVie Distributed by: AbbVie Inc. North Chicago, Illinois 60064 Marketed by: AbbVie Inc. Medicines360 North Chicago, IL 60064 San Francisco, CA 94105 © 20 2 3 AbbVie and Medicines360. All rights reserved. This Patient Information has been approved by the U.S. Food and Drug Administration 06 / 2023 V 4 .0 P PI5858 LILETTA is small and flexible IUD in Uterus Box

<table ID="PATIENTINFORMATION"><col width="296"/><col width="35"/><col width="355"/><tbody><tr><td styleCode="Toprule Lrule Rrule " colspan="3" align="center"><content styleCode="bold">PATIENT INFORMATION</content> LILETTA (lye-LET-uh) (levonorgestrel-releasing intrauterine system) </td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3" align="center">Read this Patient Information carefully before you decide if LILETTA is right for you. This information does not take the place of talking with your gynecologist or other healthcare professional. If you have any questions about LILETTA, ask your healthcare professional. You should also learn about other birth control methods to choose the one that is best for you.<content styleCode="bold"> </content></td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">LILETTA does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs).</content></td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">What is LILETTA?</content> <list listType="unordered" styleCode="Disc"><item>LILETTA is a hormone-releasing system placed in your uterus by your healthcare professional to prevent pregnancy for up to 8 years. </item><item>LILETTA can also help with heavy periods, also known as heavy menstrual bleeding (HMB), for up to 5 years. </item><item>LILETTA can be removed by your healthcare professional at any time. </item><item>LILETTA can be used whether or not you have given birth to a child.</item></list>LILETTA is a small, flexible plastic T-shaped system that slowly releases a progestin hormone called levonorgestrel (LNG) that is often used in birth control pills. Because LILETTA releases LNG into your uterus, only small amounts of the hormone enter your blood. LILETTA does not contain estrogen. Two thin threads are attached to the stem (lower end) of LILETTA. The threads are the only part of LILETTA you can feel when LILETTA is in your uterus; however, unlike a tampon string, the threads do not extend outside your body.</td></tr><tr><td styleCode="Lrule "><renderMultiMedia referencedObject="MM03000015"/></td><td styleCode="Rrule " colspan="2"><renderMultiMedia referencedObject="MM03000016"/></td></tr><tr><td styleCode="Lrule "><content styleCode="bold">LILETTA is small</content></td><td styleCode="Rrule " colspan="2"><content styleCode="bold">and flexible</content></td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">What if I need birth control for more than </content><content styleCode="bold">8</content><content styleCode="bold"> years?</content> LILETTA must be removed after 8 years. Your healthcare professional can place a new LILETTA during the same office visit if you choose to continue using LILETTA.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">What if I need treatment for heavy menstrual flow for more than 5 years?</content> For continued treatment of heavy menstrual flow after 5 years, your healthcare professional can remove LILETTA and place a new LILETTA during the same office visit.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">What if I want to stop using LILETTA?</content> LILETTA is intended for use as birth control for up to 8 years, but you can stop using LILETTA at any time by asking your healthcare professional to remove it.

g the same office visit.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">What if I want to stop using LILETTA?</content> LILETTA is intended for use as birth control for up to 8 years, but you can stop using LILETTA at any time by asking your healthcare professional to remove it. You could become pregnant as soon as LILETTA is removed, so you should use another method of birth control if you do not want to become pregnant. Talk to your healthcare professional about the best birth control methods for you, because your new method may need to be started 7 days before LILETTA is removed to prevent pregnancy.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">What if I change my mind about birth control and want to become pregnant in less than </content><content styleCode="bold">8</content><content styleCode="bold"> years?</content> Your healthcare professional can remove LILETTA at any time. You could become pregnant as soon as LILETTA is removed. About 5 out of 6 patients who want to become pregnant will become pregnant sometime in the first year after LILETTA is removed.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">How does LILETTA work</content><content styleCode="bold"> for birth control</content><content styleCode="bold">?</content> LILETTA may work in several ways including thickening cervical mucus, inhibiting sperm movement, reducing sperm survival, and thinning the lining of your uterus. It is not known exactly how these actions work together to prevent pregnancy. <renderMultiMedia referencedObject="MM03000017"/></td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">How does LILETTA work for heavy menstrual bleeding?</content> The hormone in LILETTA, levonorgestrel, acts by controlling the monthly development of the womb (uterus) lining, making it thinner, so that there is less bleeding every month.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">How well does LILETTA work for </content><content styleCode="bold">birth control</content><content styleCode="bold">?</content> The following chart shows the chance of getting pregnant for patients who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for patients who do not use birth control and are trying to get pregnant. LILETTA, an intrauterine system (IUS), is also known as an intrauterine device (IUD), which is shown in the box at the top of the chart. <renderMultiMedia referencedObject="MM02000018"/></td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">How well does LILETTA work for treating heavy menstrual bleeding?</content> In the clinical trial performed in patients with heavy menstrual bleeding and treated with LILETTA, the majority of (or 8 out of 10) patients were treated successfully. That is, their menstrual cycle blood loss was reduced to less than 80 mL and reduced by more than half by the end of treatment at six months.

/content> In the clinical trial performed in patients with heavy menstrual bleeding and treated with LILETTA, the majority of (or 8 out of 10) patients were treated successfully. That is, their menstrual cycle blood loss was reduced to less than 80 mL and reduced by more than half by the end of treatment at six months. </td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">Who might use LILETTA?</content> You might choose LILETTA if you are willing to use a birth control method that is placed in the uterus, and want birth control with the following features:<list listType="unordered" styleCode="Disc"><item>long-term birth control that provides a low chance of getting pregnant (less than 1 in 100) </item><item>works continuously for up to 8 years </item><item>is reversible </item><item>does not need to be taken daily </item><item>does not contain estrogen </item><item>treats heavy menstrual bleeding</item></list></td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">Do not use LILETTA if you</content><content styleCode="bold"> have any of the following conditions</content><content styleCode="bold">:</content><list listType="unordered" styleCode="Disc"><item>you are or might be pregnant; LILETTA cannot be used as an emergency contraceptive </item><item>a serious pelvic infection called pelvic inflammatory disease (PID) </item><item>an untreated lower genital infection now </item><item>a serious pelvic infection after an abortion or pregnancy within the last 3 months </item><item>a condition or behavior that can allow you to get infections more easily, such as those listed below: &#x25CB; problems with your immune system &#x25CB; having multiple sexual partners or your partner has multiple sexual partners &#x25CB; history of PID </item><item>cancer of the uterus or cervix, known or suspected </item><item>bleeding from the vagina that has not been explained </item><item>short-term (acute) liver disease or a liver tumor </item><item>breast cancer or any other cancer that is sensitive to progestin (a female hormone), now or in the past </item><item>an intrauterine contraceptive system in your uterus already </item><item>a condition of the uterus that changes the shape of the uterine cavity, such as large fibroid tumors </item><item>an allergy to levonorgestrel, silicone, polyethylene, or barium sulfate</item></list></td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">Before having LILETTA placed, tell your healthcare professional if you have o</content><content styleCode="bold">r</content><content styleCode="bold"> had any medical conditions, including those listed below:</content> <list listType="unordered" styleCode="Disc"><item>any of the conditions listed above </item><item>you recently had a baby, or you are breastfeeding </item><item>heart attack </item><item>stroke </item><item>heart disease you were born with, or problems with your heart valves </item><item>blood clotting problems, or condition for which you take medicine to reduce clotting </item><item>high blood pressure </item><item>severe migraine headaches </item><item>severe or frequent headaches </item><item>AIDS, HIV, or any other sexually transmitted infection</item></list>Tell your healthcare professional about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">How is LILETTA placed?</content> LILETTA is placed by your healthcare professional during an in-office visit. First, your healthcare professional will examine your pelvis to find the exact position of your uterus.

erbal supplements.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">How is LILETTA placed?</content> LILETTA is placed by your healthcare professional during an in-office visit. First, your healthcare professional will examine your pelvis to find the exact position of your uterus. Your healthcare professional will then clean your vagina and cervix with an antiseptic solution and slide a plastic tube containing LILETTA through the cervix into your uterus. Your healthcare professional will then remove the plastic tube and leave LILETTA in your uterus. Your healthcare professional will trim the threads to the right length. You may experience pain, bleeding, or dizziness during and after placement. If your symptoms do not pass within 30 minutes after placement, LILETTA may not have been placed correctly. Your healthcare professional will examine you to see if LILETTA needs to be removed or replaced.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">Should I check that LILETTA is in place?</content> Yes, you should check that LILETTA is in proper position by feeling the threads. It is a good habit to do this 1 time a month. Your healthcare professional should teach you how to check that LILETTA is in place. First, wash your hands with soap and water. You can check by reaching up to the top of your vagina with clean fingers to feel the threads. Do not pull on the threads. If you feel more than just the threads or if you cannot feel the threads, LILETTA may not be in the right position and may not prevent pregnancy. Use non-hormonal back-up birth control (such as condoms) and ask your healthcare professional to check that LILETTA is still in the right place.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">How soon after placement of LILETTA should I return to my healthcare professional?</content> Call your healthcare professional if you have any questions or concerns (see &#x201C;When should I call my healthcare professional?&#x201D;). Generally, patients have a follow-up visit 4 to 6 weeks after LILETTA is placed to make sure that LILETTA is in the right position, and routine visits thereafter. Follow-up plans may vary according to patient needs.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">Can I use tampons</content><content styleCode="bold"> or menstrual cups</content><content styleCode="bold"> with LILETTA?</content> Yes, tampons or menstrual cups may be used with LILETTA. Change tampons or menstrual cups with care to avoid pulling the threads of LILETTA. If you think you may have pulled LILETTA out of place, avoid intercourse or use a non-hormonal back-up birth control (such as condoms), and contact your healthcare professional.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">What if I become pregnant while using LILETTA?</content> Call your healthcare professional right away if you think you are pregnant. If possible, also do a urine pregnancy test. If you get pregnant while using LILETTA, you may have an ectopic pregnancy. This means that the pregnancy is not in the uterus. Unusual vaginal bleeding or abdominal pain, especially with missed periods, may be a sign of ectopic pregnancy. Ectopic pregnancy is a medical emergency that often requires surgery. Ectopic pregnancy can cause internal bleeding, infertility, and even death. There are also risks if you get pregnant while using LILETTA and the pregnancy is in the uterus. Severe infection, miscarriage, premature labor, premature delivery, and even death can occur with pregnancies that continue with an intrauterine system (IUS).

gnancy can cause internal bleeding, infertility, and even death. There are also risks if you get pregnant while using LILETTA and the pregnancy is in the uterus. Severe infection, miscarriage, premature labor, premature delivery, and even death can occur with pregnancies that continue with an intrauterine system (IUS). Because of this, your healthcare professional may try to remove LILETTA, even though removing it may cause a miscarriage. If LILETTA cannot be removed, talk with your healthcare professional about the benefits and risks of continuing the pregnancy. If you continue your pregnancy, see your healthcare professional regularly. Call your healthcare professional right away if you get flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge, or fluid leaking from your vagina. These may be signs of infection. It is not known if LILETTA can cause long-term effects on the fetus if it stays in place during a pregnancy.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">How will LILETTA change my periods?</content> For the first 3 to 6 months, your period may become irregular and the number of bleeding days may increase. You may also have frequent spotting or light bleeding and cramping. Some patients have heavy bleeding during this time. After you have used LILETTA for a while, the number of bleeding and spotting days is likely to lessen. For some patients, menstrual periods will stop altogether. When LILETTA is removed, your menstrual periods will likely return to their former pattern. </td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">Is it safe to breastfeed while using LILETTA?</content> You may use LILETTA when you are breastfeeding. LILETTA is not likely to affect the quality or amount of your breast milk or the health of your nursing baby. However, isolated cases of decreased milk production have been reported among patients using progestin-only birth control pills. The risk of LILETTA becoming attached to (embedded) or going through the wall of the uterus is increased when LILETTA is inserted while you are breastfeeding.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">Will LILETTA interfere with sexual intercourse?</content> You and your partner should not feel LILETTA during intercourse. LILETTA is placed in the uterus, not in the vagina. In some cases, your partner may feel the threads. If this occurs, or if you or your partner experience pain during sex, talk with your healthcare professional.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">Can I have a magnetic resonance imaging (MRI) procedure with LILETTA in place?</content> Yes, LILETTA should not interfere with imaging. Tell your healthcare professional you have an intrauterine contraceptive in place.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">What are the possible side effects of LILETTA?</content> <content styleCode="bold">LILETTA can cause serious side effects, including</content><content styleCode="bold"> those listed below</content><content styleCode="bold">:</content> <list listType="unordered" styleCode="Disc"><item><content styleCode="bold">ectopic pregnancy</content>. If you get pregnant while using LILETTA, you might have an ectopic pregnancy. This means that the pregnancy is not in the uterus. Unusual vaginal bleeding or abdominal pain, especially with missed periods, may be a sign of ectopic pregnancy. Ectopic pregnancy is a medical emergency that often requires surgery. Ectopic pregnancy can cause internal bleeding, infertility, and even death. </item><item><content styleCode="bold">intrauterine pregnancy risks</content>.

bleeding or abdominal pain, especially with missed periods, may be a sign of ectopic pregnancy. Ectopic pregnancy is a medical emergency that often requires surgery. Ectopic pregnancy can cause internal bleeding, infertility, and even death. </item><item><content styleCode="bold">intrauterine pregnancy risks</content>. There are also risks if you get pregnant while using LILETTA and the pregnancy is in the uterus. Severe infection, miscarriage, premature labor, premature delivery, and even death can occur with pregnancies that continue with an intrauterine system (IUS). Because of this, your healthcare professional may try to remove LILETTA, even though removing it may cause a miscarriage. If LILETTA cannot be removed, talk with your healthcare professional about the benefits and risks of continuing the pregnancy. If, after seeing your healthcare professional, you choose to continue your pregnancy, see your healthcare professional regularly. Call your healthcare professional right away if you get flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge, or fluid leaking from your vagina. These may be signs of infection. It is not known if LILETTA can cause long-term effects on the fetus if it stays in place during a pregnancy. </item><item><content styleCode="bold">life-threatening infection</content>. Life-threatening infection can occur within the first few days after LILETTA is placed. Call your healthcare professional immediately if you develop severe pain or fever shortly after LILETTA is placed. </item><item><content styleCode="bold">pelvic inflammatory disease (PID</content>)<content styleCode="bold"> </content><content styleCode="bold">or endometritis</content>. Some IUS users get a serious pelvic infection called pelvic inflammatory disease (PID) or endometritis. PID and endometritis may be sexually transmitted. You have a higher chance of getting PID or endometritis if you or your partner have sex with other partners. PID or endometritis can cause serious problems such as infertility, ectopic pregnancy, or pelvic pain that does not go away. PID is usually treated with antibiotics. More serious cases of PID or endometritis may require surgery. Removal of the uterus (hysterectomy) is sometimes needed. In rare cases, infections that start as PID or endometritis can even cause death. Tell your healthcare professional right away if you have any of these signs of PID or endometritis: long-lasting or heavy bleeding, unusual or foul-smelling vaginal discharge, low abdominal or pelvic pain, painful sex, genital lesions or sores, chills, or fever. </item><item><content styleCode="bold">perforation</content>. LILETTA may partially go into the wall of the uterus (become embedded) or go completely through the wall of the uterus (perforate). If this occurs, LILETTA may no longer prevent pregnancy. If perforation occurs, LILETTA may move outside the uterus and can cause internal scarring, infection, or damage to other organs. You may need surgery to have LILETTA removed if it is embedded or perforation occurs. The risk of perforation is increased in breastfeeding patients. </item><item><content styleCode="bold">expulsion</content>. LILETTA may come out of your uterus (expulsion). Expulsion occurs in about 4 out of 100 patients, most often in the first year of use. You may become pregnant if LILETTA comes out. If you think that LILETTA has come out, use another birth control method (such as condoms) or do not have sex (vaginal intercourse) until you are seen by a healthcare professional. </item><item><content styleCode="bold">cysts on the ovary</content>. Some patients using LILETTA develop a cyst on the ovary. These cysts usually disappear on their own in 2 to 3 months. However, a cyst can cause pain and sometimes will need surgery.

vaginal intercourse) until you are seen by a healthcare professional. </item><item><content styleCode="bold">cysts on the ovary</content>. Some patients using LILETTA develop a cyst on the ovary. These cysts usually disappear on their own in 2 to 3 months. However, a cyst can cause pain and sometimes will need surgery. </item><item><content styleCode="bold">changes in bleeding</content>. You may have bleeding and spotting between menstrual periods, especially during the first 3 to 6 months. Sometimes the bleeding is heavier than usual at first. Over time the bleeding often becomes lighter than usual and may be irregular. Call your healthcare professional if the bleeding remains heavier than usual or increases after it has been light for a while.</item></list><content styleCode="bold">LILETTA&#x2019;s</content><content styleCode="bold"> most common side effects </content><content styleCode="bold">are listed below:</content></td></tr><tr><td styleCode="Lrule " colspan="2">&#x2022; acne</td><td styleCode="Rrule ">&#x2022; vaginal discharge</td></tr><tr><td styleCode="Lrule " colspan="2">&#x2022; headache</td><td styleCode="Rrule ">&#x2022; vaginal bacterial infection</td></tr><tr><td styleCode="Lrule " colspan="2">&#x2022; breast pain</td><td styleCode="Rrule ">&#x2022; yeast infection of your vulva and vagina (vulvovaginal)</td></tr><tr><td styleCode="Lrule " colspan="2">&#x2022; abdominal pain</td><td styleCode="Rrule ">&#x2022; nausea or vomiting</td></tr><tr><td styleCode="Lrule " colspan="2">&#x2022; pelvic pain</td><td styleCode="Rrule ">&#x2022; weight increase</td></tr><tr><td styleCode="Lrule " colspan="2">&#x2022; menstrual-like cramping</td><td styleCode="Rrule ">&#x2022; mood changes</td></tr><tr><td styleCode="Lrule " colspan="2">&#x2022; pain during sex</td><td styleCode="Rrule ">&#x2022; anxiety</td></tr><tr><td styleCode="Lrule " colspan="2">&#x2022; back pain</td><td styleCode="Rrule ">&#x2022; depression</td></tr><tr><td styleCode="Lrule Rrule " colspan="3"><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Pain, bleeding, or dizziness during and after placement.</content> If these symptoms do not stop within 30 minutes after placement, LILETTA may not have been placed correctly, or they may be symptoms of perforation or expulsion. Your healthcare professional will examine you to see if LILETTA needs to be removed or replaced. </item><item><content styleCode="bold">Missed menstrual periods.</content> About 2 out of 10 patients stop having periods after 1 year of LILETTA use. If you have any concerns that you may be pregnant while using LILETTA, do a urine pregnancy test and call your healthcare professional. When LILETTA is removed, your menstrual periods will usually return to your previous pattern.</item></list>These are not all the possible side effects of LILETTA. For more information, ask your healthcare professional or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to AbbVie at 1-800-678-1605.</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">After LILETTA has been </content><content styleCode="bold">placed</content><content styleCode="bold">, when should I call my healthcare professional?</content> Call your healthcare professional if you have any concerns about LILETTA.

td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">After LILETTA has been </content><content styleCode="bold">placed</content><content styleCode="bold">, when should I call my healthcare professional?</content> Call your healthcare professional if you have any concerns about LILETTA. Be sure to call if you have any of the conditions listed below: <list listType="unordered" styleCode="Disc"><item>are pregnant or think you are pregnant </item><item>pelvic pain or pain during sex </item><item>unusual or foul-smelling vaginal discharge or genital sores </item><item>unexplained fever, chills, or flu-like symptoms </item><item>might be exposed to sexually transmitted infections (STIs) </item><item>concern that LILETTA may have come out or expelled </item><item>cannot feel LILETTA&apos;s threads </item><item>very severe or migraine headaches </item><item>yellowing of the skin or whites of the eyes (these may be signs of liver problems) </item><item>stroke or heart attack </item><item>you or your partner become HIV positive </item><item>severe vaginal bleeding, bleeding that lasts a long time, or you miss your period</item></list></td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">General information about the safe and effective use of LILETTA.</content> Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare professional for information about LILETTA that is written for health professionals. For more information, go to www.LILETTA.com or call 1-855-LILETTA (1-855-545-3882).</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="3"><content styleCode="bold">LILETTA</content><content styleCode="bold"> </content><content styleCode="bold">and its design are trademarks of Odyssea Pharma SPRL, an </content><content styleCode="bold">AbbVie company</content>. <content styleCode="bold">Medicines360 and its design are trademarks of Medicines360</content><content styleCode="bold">.</content> Manufactured by: Odyssea Pharma, SPRL, Belgium An affiliated company of AbbVie Distributed by: AbbVie Inc. North Chicago, Illinois 60064 Marketed by: AbbVie Inc. Medicines360 North Chicago, IL 60064 San Francisco, CA 94105 <content styleCode="bold">&#xA9; 20</content><content styleCode="bold">2</content><content styleCode="bold">3</content><content styleCode="bold"> </content><content styleCode="bold">AbbVie</content><content styleCode="bold"> </content><content styleCode="bold">and Medicines360. All rights reserved.</content> </td></tr></tbody></table>

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 )].

e 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.

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.

tep 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. • If unable to remove with gentle traction, determine Kyleena location and exclude perforation by ultrasound or other imaging [see Warnings and Precautions ( 5.10 )]. • Removal may be associated with some: o pain and/or bleeding or vasovagal reactions (for example, syncope, bradycardia) or seizure, especially in patients with a predisposition to these conditions. o breakage or embedment of Kyleena in the myometrium that can make removal difficult [see Warnings and Precautions ( 5.5 )]. Analgesia, paracervical anesthesia, cervical dilation, alligator forceps or other grasping instrument, or hysteroscopy may be used to assist in removal. 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.

tion, alligator forceps or other grasping instrument, or hysteroscopy may be used to assist in removal. 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.

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 )

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 )

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.

roup 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 suspected PID or in women with a history of PID unless there has been a subsequent intrauterine pregnancy [see Contraindications ( 4 )] . IUDs have been associated with an increased risk of PID, most likely due to organisms being introduced into the uterus during insertion. In clinical trials, PID was observed in 0.5% of women overall and occurred more frequently within the first year and most often within the first month after insertion of Kyleena. Women at increased risk for PID PID is often associated with a sexually transmitted infection (STI), and Kyleena does not protect against STI. The risk of PID is greater for women who have multiple sexual partners, and also for women whose sexual partner(s) have multiple sexual partners. Women who have had PID are at increased risk for a recurrence or re-infection. In particular, ascertain whether the woman is at increased risk of infection (for example, leukemia, acquired immune deficiency syndrome [AIDS], intravenous drug abuse). Subclinical PID PID may be asymptomatic but still result in tubal damage and its sequelae. Treatment of PID Following a diagnosis of PID, or suspected PID, bacteriologic specimens should be obtained, and antibiotic therapy should be initiated promptly. Removal of Kyleena after initiation of antibiotic therapy is usually appropriate. 1 Actinomycosis Actinomycosis has been associated with IUDs. Remove Kyleena from symptomatic women and treat with antibiotics. The significance of actinomyces-like organisms on Pap smear in an asymptomatic IUD user is unknown, and so this finding alone does not always require Kyleena removal and treatment. When possible, confirm a Pap smear diagnosis with cultures. 5.5 Perforation Perforation (total or partial, including penetration/embedment of Kyleena in the uterine wall or cervix) may occur most often during insertion, although the perforation may not be detected until sometime later. The incidence of perforation during clinical trials was < 0.1%. The risk of uterine perforation is increased in women who have recently given birth, and in women who are breastfeeding at the time of insertion. In a large postmarketing safety study conducted in the US, the risk of uterine perforation was highest when insertion occurred within ≤ 6 weeks postpartum, and also higher with breastfeeding at the time of insertion [see Adverse Reactions ( 6.2 )]. The risk of perforation may be increased if Kyleena is inserted when the uterus is fixed, retroverted or not completely involuted. If perforation occurs, locate and remove Kyleena. Surgery may be required. Delayed detection or removal of Kyleena in case of perforation may result in migration outside the uterine cavity, adhesions, peritonitis, intestinal perforations, intestinal obstruction, abscesses and erosion of adjacent viscera. In addition, perforation may reduce contraceptive efficacy and result in pregnancy.

ired. Delayed detection or removal of Kyleena in case of perforation may result in migration outside the uterine cavity, adhesions, peritonitis, intestinal perforations, intestinal obstruction, abscesses and erosion of adjacent viscera. In addition, perforation may reduce contraceptive efficacy and result in pregnancy. 5.6 Expulsion Partial or complete expulsion of Kyleena may occur resulting in the loss of efficacy. Expulsion may be associated with symptoms of bleeding or pain, or it may be asymptomatic and go unnoticed. Kyleena typically decreases menstrual bleeding over time; therefore, an increase of menstrual bleeding may be indicative of an expulsion. Consider further diagnostic imaging, such as x-ray, if expulsion is suspected based on ultrasound [see Warnings and Precautions ( 5.10 )]. In clinical trials, a 5-year expulsion rate of 3.5% (59 out of 1,690 subjects) was reported. The risk of expulsion is increased with insertions immediately after delivery and appears to be increased with insertion after second-trimester abortion based on limited data. In a large postmarketing safety study conducted in the US, the risk of expulsion was lower with breastfeeding status [see Adverse Reactions ( 6.2 )]. Remove a partially expelled Kyleena. If expulsion has occurred, a new Kyleena can be inserted any time the provider can be reasonably certain the woman is not pregnant. 5.7 Ovarian Cysts Because the contraceptive effect of Kyleena is mainly due to its local effects within the uterus, ovulatory cycles with follicular rupture usually occur in women of fertile age using Kyleena. Ovarian cysts (reported as adverse reactions if they were abnormal, non-functional cysts and/or had a diameter >3 cm on ultrasound examination) were reported at least once over the course of clinical trials in 22% of women using Kyleena, and 0.6% of subjects discontinued because of an ovarian cyst. Most ovarian cysts are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia. In most cases the ovarian cysts disappear spontaneously during two to three months observation. Evaluate persistent ovarian cysts. Surgical intervention is not usually required. 5.8 Bleeding Pattern Alterations Kyleena can alter the bleeding pattern and result in spotting, irregular bleeding, heavy bleeding, oligomenorrhea and amenorrhea. During the first 3–6 months of Kyleena use, the number of bleeding and spotting days may be higher and bleeding patterns may be irregular. Thereafter, the number of bleeding and spotting days usually decreases but bleeding may remain irregular. In Kyleena clinical trials, amenorrhea developed by the end of the first year of use in approximately 12% of Kyleena users. A total of 81 subjects out of 1,697 (4.8%) discontinued due to uterine bleeding complaints. Table 2 shows the bleeding patterns as documented in the Kyleena clinical trials based on 90-day reference periods. Table 3 shows the number of bleeding and spotting days based on 28-day cycle equivalents. Table 2: Bleeding Patterns Reported with Kyleena in Contraception Studies (by 90-day reference periods) Kyleena First 90 days N=1,566 Second 90 days N=1,511 End of year 1 N=1,371 End of year 3 N=975 End of year 5 N=530 Amenorrhea 1 <1% 5% 12% 20% 23% Infrequent bleeding 2 10% 20% 26% 26% 26% Frequent bleeding 3 25% 10% 4% 2% 2% Prolonged bleeding 4 57% 14% 6% 2% 1% Irregular bleeding 5 43% 25% 17% 10% 9% 1 Defined as subjects with no bleeding/spotting throughout the 90-day reference period 2 Defined as subjects with 1 or 2 bleeding/spotting episodes in the 90-day reference period 3 Defined as subjects with more than 5 bleeding/spotting episodes in the 90-day reference period 4 Defined as subjects with bleeding/spotting episodes lasting more than 14 days in the 90-day reference period.

ay reference period 2 Defined as subjects with 1 or 2 bleeding/spotting episodes in the 90-day reference period 3 Defined as subjects with more than 5 bleeding/spotting episodes in the 90-day reference period 4 Defined as subjects with bleeding/spotting episodes lasting more than 14 days in the 90-day reference period. Subjects with prolonged bleeding may also be included in one of the other categories (excluding amenorrhea) 5 Defined as subjects with 3 to 5 bleeding/spotting episodes and less than 3 bleeding/spotting-free intervals of 14 or more days Table 3: Mean number of Bleeding and Spotting Days per 28-day Cycle Equivalent 28-day Cycle Equivalent Cycle 1 N=1,619 Cycle 4 N=1,575 Cycle 7 N=1,518 Cycle 13 N=1,394 Cycle 39 N=913 Cycle 65 N=322 Days on treatment 1–28 85–112 169–196 337–364 1065–1092 1793-1820 Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Number of bleeding days 7.2 (5.9) 3.2 (3.6) 2.2 (3.0) 1.5 (2.4) 1.0 (2.0) 0.9 (1.8) Number of spotting days 8.6 (6.0) 4.6 (4.4) 3.5 (3.4) 2.9 (3.0) 2.2 (2.6) 2.1 (2.4) If a significant change in bleeding develops during prolonged use, take appropriate diagnostic measures to rule out endometrial pathology . Consider the possibility of pregnancy if menstruation does not occur within six weeks of the onset of a previous menstruation. Once pregnancy has been excluded, repeated pregnancy tests are generally not necessary in amenorrheic women unless indicated, for example, by other signs of pregnancy or by pelvic pain. 5.9 Breast Cancer Women who currently have or have had breast cancer, or have a suspicion of breast cancer, should not use hormonal contraception, including Kyleena, because some breast cancers are hormone-sensitive [see Contraindications ( 4 )] . Spontaneous reports of breast cancer have been received during postmarketing experience with a LNG-releasing IUS. Observational studies of the risk of breast cancer with use of a LNG-releasing IUS do not provide conclusive evidence of increased risk. 5.10 Clinical Considerations for Use and Removal Use Kyleena with caution after careful assessment if any of the following conditions exist, and consider removal of the system if any of them arise during use: • Coagulopathy or use of anticoagulants • Migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia • Exceptionally severe headache • Marked increase of blood pressure • Severe arterial disease such as stroke or myocardial infarction In addition, consider removing Kyleena if any of the following conditions arise during use: • Uterine or cervical malignancy • Jaundice If the threads are not visible or are significantly shortened, they may have broken or retracted into the cervical canal or uterus. Consider the possibility that the system may have been displaced (for example, expelled or perforated the uterus) [see Warnings and Precautions ( 5.5 , 5.6 )]. Exclude pregnancy and verify the location of Kyleena, for example, by sonography, X-ray, or by gentle exploration of the cervical canal with a suitable instrument. If Kyleena is displaced, remove it. A new Kyleena may be inserted at that time or during the next menses if it is certain that conception has not occurred. If Kyleena is in place with no evidence of perforation, no intervention is indicated. 5.11 Magnetic Resonance Imaging (MRI) Safety Information Non-clinical testing has demonstrated that Kyleena is MR Conditional.

a may be inserted at that time or during the next menses if it is certain that conception has not occurred. If Kyleena is in place with no evidence of perforation, no intervention is indicated. 5.11 Magnetic Resonance Imaging (MRI) Safety Information Non-clinical testing has demonstrated that Kyleena is MR Conditional. A patient with Kyleena can be safely scanned in an MR system meeting the following conditions: • Static magnetic field of 3.0 T or less • Maximum spatial field gradient of 36,000 gauss/cm (360 T/m) • Maximum MR system reported, whole body averaged specific absorption rate (SAR) of 4W/kg (First Level Controlled Operating Mode) Under the scan conditions defined above, the Kyleena IUS is expected to produce a maximum temperature rise of less than 2°C after 15 minutes of continuous scanning. In non-clinical testing, the image artifact caused by the IUS extended up to 5 mm from the IUS when imaged with a gradient echo pulse sequence and a 3.0 T MRI system. MRI

<table width="100%"><caption>Table 2: Bleeding Patterns Reported with Kyleena in Contraception Studies (by 90-day reference periods)</caption><col width="20%"/><col width="14%"/><col width="18%"/><col width="17%"/><col width="15%"/><col width="15%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Kyleena</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">First 90 days</content> <content styleCode="bold">N=1,566</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Second 90 days</content> <content styleCode="bold">N=1,511</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">End of year 1</content> <content styleCode="bold">N=1,371</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">End of year 3</content> <content styleCode="bold">N=975</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">End of year 5</content></paragraph><paragraph><content styleCode="bold">N=530</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Amenorrhea¹</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Infrequent bleeding²</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Frequent bleeding³</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Prolonged bleeding⁴</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>57

ign="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Prolonged bleeding⁴</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>57 %</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">Irregular bleeding⁵</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>43%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>9%</paragraph></td></tr></tbody></table>

agraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>9%</paragraph></td></tr></tbody></table> <table cellpadding="0pt" width="100%"><caption>Table 3: Mean number of Bleeding and Spotting Days per 28-day Cycle Equivalent</caption><col width="16%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">28-day Cycle Equivalent</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Cycle 1</content></paragraph><paragraph><content styleCode="bold">N=1,619</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Cycle 4</content></paragraph><paragraph><content styleCode="bold">N=1,575</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Cycle 7</content></paragraph><paragraph><content styleCode="bold">N=1,518</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Cycle 13</content></paragraph><paragraph><content styleCode="bold">N=1,394</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Cycle 39</content></paragraph><paragraph><content styleCode="bold">N=913</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cycle 65</content></paragraph><paragraph><content styleCode="bold">N=322</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Days on treatment</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1&#x2013;28</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>85&#x2013;112</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>169&#x2013;196</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>337&#x2013;364</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1065&#x2013;1092</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1793-1820</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"/><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Mean (SD)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Mean (SD)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Mean (SD)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Mean (SD)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Mean (SD)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Mean (SD)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Number of bleeding days</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>7.2 (5.9)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "

paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Number of bleeding days</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>7.2 (5.9)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>3.2 (3.6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>2.2 (3.0)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1.5 (2.4)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1.0 (2.0)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.9 (1.8)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph><content styleCode="bold">Number of spotting days</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>8.6 (6.0)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>4.6 (4.4)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>3.5 (3.4)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>2.9 (3.0)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>2.2 (2.6)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>2.1 (2.4)</paragraph></td></tr></tbody></table>

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.

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.

ed 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 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 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

<table cellpadding="3.5pt" width="100%"><caption>Table 4: Adverse reactions that occurred in at least 1% of Kyleena users in clinical trials by System Organ Class (SOC)</caption><col width="25%"/><col width="38%"/><col width="37%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">System Organ Class</content></th><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Adverse Reaction</content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Incidence (%)</content> <content styleCode="bold">(N=1,697)</content></th></tr></thead><tbody><tr><td rowspan="8" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Reproductive System and Breast Disorders</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Vulvovaginitis</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>24.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Ovarian cyst^a</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>22.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Dysmenorrhea/uterine spasm</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>8.0/2.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Increased bleeding^b</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>7.9</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Breast pain/discomfort</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>7.1/3.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Genital discharge</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>4.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Device expulsion (complete and partial)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>3.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Upper genital tract infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1.5</paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gastrointestinal Disorders</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Abdominal pain/pelvic pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>13.3/8.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>4.7</paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Skin and Subcutaneous Tissue Disorders</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Acne/Seborrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>14.1/1.8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="m

<paragraph>Skin and Subcutaneous Tissue Disorders</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Acne/Seborrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>14.1/1.8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="m iddle"><paragraph>Alopecia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Nervous System Disorders</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Headache/Migraine</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>12.9/3.3</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Psychiatric Disorders</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Depression/ Depressed mood</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>4.4/0.2</paragraph></td></tr></tbody></table>

="Rrule Botrule Lrule " valign="middle"><paragraph>Psychiatric Disorders</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Depression/ Depressed mood</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>4.4/0.2</paragraph></td></tr></tbody></table> <table cellpadding="0pt" width="100%"><caption>Table 5: Uterine Perforation¹ rates for LNG IUS, by Breastfeeding Status and Postpartum Interval </caption><col width="20%"/><col width="18%"/><col width="22%"/><col width="17%"/><col width="23%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"/><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Breastfeeding at time of insertion</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Not breastfeeding at time of insertion</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Postpartum interval at time of insertion</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Number of events/ insertions</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Uterine perforation rate per 1,000 insertions</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Number of events/ insertions</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Uterine perforation rate per 1,000 insertions</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">0 to 3 days</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>8/1,896</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>4.22</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>0/277</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>0.00</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">4 days to &#x2264; 6 weeks</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>120/10,735</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>11.18</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>28/2,377</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>11.78</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">&gt; 6 to &#x2264; 14 weeks</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>268/29,677</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>9.03</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>80/12,011</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>6.66</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">&gt; 14 to &#x2264; 52 weeks</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>43/6,139</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Bo

</td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">&gt; 14 to &#x2264; 52 weeks</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>43/6,139</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Bo trule " valign="middle"><paragraph>7.00</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>22/9,089</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>2.42</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">&gt; 52 weeks or no delivery </content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>no data available</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>243/184,733</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>1.32</paragraph></td></tr></tbody></table>

rule Toprule " valign="middle"><paragraph>no data available</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>243/184,733</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>1.32</paragraph></td></tr></tbody></table> <table cellpadding="0pt" width="100%"><caption>Table 6: Expulsion¹ Rates for LNG IUS, by Breastfeeding Status and Postpartum Interval</caption><col width="20%"/><col width="18%"/><col width="22%"/><col width="17%"/><col width="23%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"/><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Breastfeeding at time of insertion</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Not breastfeeding at time of insertion</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Postpartum interval at time of insertion</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Number of events/ insertions</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Expulsion rate per 1,000 insertions</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Number of events/ insertions</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Expulsion rate per 1,000 insertions</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">0 to 3 days</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>187/1,896</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>98.63</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>12/277</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>43.32</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">4 days to &#x2264; 6 weeks</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>185/10,735</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>17.23</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>52/2,377</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>21.88</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">&gt; 6 to &#x2264; 14 weeks</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>421/29,677</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14.19</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>306/12,011</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>25.48</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">&gt; 14 to &#x2264; 52 weeks</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>120/6,139</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>19.55</p

Botrule " valign="top"><paragraph><content styleCode="bold">&gt; 14 to &#x2264; 52 weeks</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>120/6,139</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>19.55</p aragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>273/9,089</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>30.04</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">&gt; 52 weeks or no delivery </content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>no data available</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>5,481/184,733</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>29.67</paragraph></td></tr></tbody></table>

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 USE IN SPECIFIC POPULATIONS 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. 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.

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.

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. 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.

8.4 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.

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

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.

emained 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 .

ed. 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 )] .

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)

<table width="100%"><caption>Table 7: Pearl Indices by Year and 5-Year Cumulative Pregnancy Rate</caption><col width="21%"/><col width="21%"/><col width="10%"/><col width="10%"/><col width="10%"/><col width="10%"/><col width="17%"/><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Kyleena Clinical Trial</content></paragraph></td><td align="center" colspan="5" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Pearl Index</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cumulative 5-Year Kaplan Meier Rate</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Year 1</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Year 2</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Year 3</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Year 4</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Year 5</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Number of Evaluable 28-day Cycles of Exposure</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>16,207</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>13,853</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>11,610</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>8,556</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>7,087</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>57,313</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Pregnancy Rate (95% Confidence Interval)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0.16</paragraph><paragraph>(0.02, 0.58)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0.38</paragraph><paragraph>(0.10, 0.96)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0.45</paragraph><paragraph>(0.12, 1.15)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0.15</paragraph><paragraph>(0.00, 0.85)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0.37</paragraph><paragraph>(0.04, 1.33)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1.45</paragraph><paragraph>(0.82, 2.53)</paragraph></td></tr></tbody></table>

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].

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.

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.

Patient Package Insert Patient Information Kyleena (Ki-lee-nah) (levonorgestrel-releasing intrauterine system) Read this Patient Information carefully before you decide if Kyleena is right for you. This information does not take the place of talking with your gynecologist or other healthcare provider who specializes in women's health. If you have any questions about Kyleena, ask your healthcare provider. You should also learn about other birth control methods to choose the one that is best for you. Kyleena does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs). What is Kyleena? • Kyleena is a hormone-releasing system placed in your uterus by your healthcare provider to prevent pregnancy for up to 5 years. • Kyleena can be removed by your healthcare provider at any time. • Kyleena can be used whether or not you have given birth to a child. Kyleena is a small, flexible plastic T-shaped system that slowly releases a progestin hormone called levonorgestrel (LNG) that is often used in birth control pills. Because Kyleena releases LNG into your uterus, only small amounts of the hormone enter your blood. Kyleena does not contain estrogen. Two thin threads are attached to the stem (lower end) of Kyleena. The threads are the only part of Kyleena you can feel when Kyleena is in your uterus; however, unlike a tampon string, the threads do not extend outside your body. Kyleena is small and Flexible What if I need birth control for more than 5 years? Kyleena must be removed after 5 years. Your healthcare provider can place a new Kyleena during the same office visit if you choose to continue using Kyleena. What if I want to stop using Kyleena? Kyleena is intended for use up to 5 years, but you can stop using Kyleena at any time by asking your healthcare provider to remove it. You could become pregnant as soon as Kyleena is removed, so you should use another method of birth control if you do not want to become pregnant. Talk to your healthcare provider about the best birth control methods for you, because your new method may need to be started 7 days before Kyleena is removed to prevent pregnancy. What if I change my mind about birth control and want to become pregnant in less than 5 years? Your healthcare provider can remove Kyleena at any time. You may become pregnant as soon as Kyleena is removed. About 7 out of 10 women who want to become pregnant will become pregnant sometime in the first year after Kyleena is removed. How does Kyleena work? Kyleena may work in several ways including thickening cervical mucus, inhibiting sperm movement, reducing sperm survival, and thinning the lining of your uterus. It is not known exactly how these actions work together to prevent pregnancy. How well does Kyleena work for contraception? The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant. Kyleena, an intrauterine device (IUD), also known as an intrauterine system (IUS), is in the box at the top of the chart. Who might use Kyleena?

ods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant. Kyleena, an intrauterine device (IUD), also known as an intrauterine system (IUS), is in the box at the top of the chart. Who might use Kyleena? You might choose Kyleena if you: • want long-term birth control that provides a low chance of getting pregnant (less than 1 in 100) • want birth control that works continuously for up to 5 years • want birth control that is reversible • want a birth control method that you do not need to take daily • are willing to use a birth control method that is placed in the uterus • want birth control that does not contain estrogen Do not use Kyleena if you: • are or might be pregnant; Kyleena cannot be used as an emergency contraceptive • have a serious pelvic infection called pelvic inflammatory disease (PID) or have had PID in the past unless you have had a normal pregnancy after the infection went away • have an untreated genital infection now • have had a serious pelvic infection in the past 3 months after a pregnancy • can get infections easily. For example, if you: o have multiple sexual partners or your partner has multiple sexual partners o have problems with your immune system o use or abuse intravenous drugs • have or suspect you might have cancer of the uterus or cervix • have bleeding from the vagina that has not been explained • have liver disease or a liver tumor • have breast cancer or any other cancer that is sensitive to progestin (a female hormone), now or in the past • have an intrauterine device in your uterus already • have a condition of the uterus that changes the shape of the uterine cavity, such as large fibroid tumors • are allergic to levonorgestrel, silicone, polyethylene, silver, silica, barium sulfate, polypropylene, or copper phthalocyanine Before having Kyleena placed, tell your healthcare provider about all of your medical conditions including if you: • have any of the conditions listed above • have had a heart attack • have had a stroke • were born with heart disease or have problems with your heart valves • have problems with blood clotting or take medicine to reduce clotting • have high blood pressure • recently had a baby or are breastfeeding • have severe headaches or migraine headaches • have AIDS, HIV, or any other sexually transmitted infection Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How is Kyleena placed? Kyleena is placed by your healthcare provider during an in-office visit or immediately after giving birth. First, your healthcare provider will examine your pelvis to find the exact position of your uterus. Your healthcare provider will then clean your vagina and cervix with an antiseptic solution and slide a slim plastic tube containing Kyleena through the cervix into your uterus. Your healthcare provider will then remove the plastic tube, and leave Kyleena in your uterus. Your healthcare provider will cut the threads to the right length. You may experience pain, bleeding or dizziness during and after placement. If your symptoms do not pass within 30 minutes after placement, Kyleena may not have been placed correctly. Your healthcare provider will examine you to see if Kyleena needs to be removed or replaced. Should I check that Kyleena is in place? Yes, you should check that Kyleena is in proper position by feeling the removal threads. It is a good habit to do this 1 time a month. Your healthcare provider should teach you how to check that Kyleena is in place. First, wash your hands with soap and water.

emoved or replaced. Should I check that Kyleena is in place? Yes, you should check that Kyleena is in proper position by feeling the removal threads. It is a good habit to do this 1 time a month. Your healthcare provider should teach you how to check that Kyleena is in place. First, wash your hands with soap and water. You can check by reaching up to the top of your vagina with clean fingers to feel the removal threads. Do not pull on the threads. If you feel more than just the threads or if you cannot feel the threads, Kyleena may not be in the right position and may not prevent pregnancy. Avoid intercourse or use non-hormonal back-up birth control (such as condoms or spermicide) and ask your healthcare provider to check that Kyleena is still in the right place. How soon after placement of Kyleena should I return to my healthcare provider? Call your healthcare provider if you have any questions or concerns (see "When should I call my healthcare provider?"). Otherwise, you should return to your healthcare provider for a follow-up visit 4 to 6 weeks after Kyleena is placed to make sure that Kyleena is in the right position. Can I use tampons or menstrual cups with Kyleena? Yes, tampons or menstrual cups may be used with Kyleena. Change tampons or menstrual cups with care to avoid pulling the threads of Kyleena. If you think you may have pulled Kyleena out of place, avoid intercourse or use a non-hormonal back-up birth control (such as condoms or spermicide), and contact your healthcare provider. What if I become pregnant while using Kyleena? Call your healthcare provider right away if you think you may be pregnant. If possible, also do a urine pregnancy test. If you get pregnant while using Kyleena, you may have an ectopic pregnancy. This means that the pregnancy is not in the uterus. Unusual vaginal bleeding or abdominal pain may be a sign of ectopic pregnancy. Ectopic pregnancy is a medical emergency that often requires surgery. Ectopic pregnancy can cause internal bleeding, infertility, and even death. There are also risks if you get pregnant while using Kyleena and the pregnancy is in the uterus. Severe infection, miscarriage, premature delivery, and even death can occur with pregnancies that continue with an intrauterine device (IUD). Because of this, your healthcare provider may try to remove Kyleena, even though removing it may cause a miscarriage. If Kyleena cannot be removed, talk with your healthcare provider about the benefits and risks of continuing the pregnancy and possible effects of the hormone on your unborn baby. If you continue your pregnancy, see your healthcare provider regularly. Call your healthcare provider right away if you get flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge, or fluid leaking from your vagina. These may be signs of infection. How will Kyleena change my periods? For the first 3 to 6 months, your period may become irregular and the number of bleeding days may increase. You may also have frequent spotting or light bleeding. Some women have heavy bleeding during this time. You may also have cramping during the first few weeks. After you have used Kyleena for a while, the number of bleeding and spotting days is likely to lessen. For some women, periods will stop altogether. When Kyleena is removed, your menstrual periods should return. Is it safe to breastfeed while using Kyleena? You may use Kyleena when you are breastfeeding. Kyleena is not likely to affect the quality or amount of your breast milk or the health of your nursing baby. However, isolated cases of decreased milk production have been reported. The risk of Kyleena going into the wall of the uterus (becoming embedded) or going through the wall of the uterus is increased if Kyleena is inserted while you are breastfeeding.

ty or amount of your breast milk or the health of your nursing baby. However, isolated cases of decreased milk production have been reported. The risk of Kyleena going into the wall of the uterus (becoming embedded) or going through the wall of the uterus is increased if Kyleena is inserted while you are breastfeeding. Will Kyleena interfere with sexual intercourse? You and your partner should not feel Kyleena during intercourse. Kyleena is placed in the uterus, not in the vagina. Sometimes your partner may feel the threads. If this occurs, or if you or your partner experience pain during sex, talk with your healthcare provider. Can I have an MRI with Kyleena in place? Kyleena can be safely scanned with MRI only under specific conditions. Before you have an MRI, tell your healthcare provider that you have Kyleena, an intrauterine device (IUD), in place. What are the possible side effects of Kyleena? Kyleena can cause serious side effects including: • Ectopic pregnancy and intrauterine pregnancy risks . There are risks if you become pregnant while using Kyleena (see "What if I become pregnant while using Kyleena?"). • Life-threatening infection . Life-threatening infection can occur within the first few days after Kyleena is placed. Call your healthcare provider immediately if you develop severe pain or fever shortly after Kyleena is placed. • Pelvic inflammatory disease (PID). Some IUD users get a serious pelvic infection called pelvic inflammatory disease. PID is usually sexually transmitted. You have a higher chance of getting PID if you or your partner has sex with other partners. PID can cause serious problems such as infertility, ectopic pregnancy or pelvic pain that does not go away. PID is usually treated with antibiotics. More serious cases of PID may require surgery including removal of the uterus (hysterectomy). In rare cases, infections that start as PID can even cause death. Tell your healthcare provider right away if you have any of these signs of PID: long-lasting or heavy bleeding, unusual vaginal discharge, low abdominal (stomach area) pain, painful sex, chills, fever, genital lesions or sores. • Perforation. Kyleena may go into the wall of the uterus (become embedded) or go through the wall of the uterus. This is called perforation. If this occurs, Kyleena may no longer prevent pregnancy. If perforation occurs, Kyleena may move outside the uterus and can cause internal scarring, infection, or damage to other organs, and you may need surgery to have Kyleena removed. Excessive pain or vaginal bleeding during placement of Kyleena, pain or bleeding that gets worse after placement, or not being able to feel the threads may happen with perforation. The risk of perforation is increased if Kyleena is inserted while you are breastfeeding, or if you have recently given birth. • Expulsion. Kyleena may come out by itself. This is called expulsion. Expulsion occurs in about 4 out of 100 women. Excessive pain or vaginal bleeding during placement of Kyleena, pain or bleeding that gets worse after placement, or not being able to feel the threads may happen with expulsion. You may become pregnant if Kyleena comes out. If you think that Kyleena has come out, avoid intercourse or use a non-hormonal back-up birth control (such as condoms or spermicide) and call your healthcare provider. The risk of expulsion is increased with insertion right after delivery or second-trimester abortion. Common side effects of Kyleena include: • Pain, bleeding or dizziness during and after placement. If these symptoms do not stop 30 minutes after placement, Kyleena may not have been placed correctly. Your healthcare provider will examine you to see if Kyleena needs to be removed or replaced. • Changes in bleeding.

ion. Common side effects of Kyleena include: • Pain, bleeding or dizziness during and after placement. If these symptoms do not stop 30 minutes after placement, Kyleena may not have been placed correctly. Your healthcare provider will examine you to see if Kyleena needs to be removed or replaced. • Changes in bleeding. You may have bleeding and spotting between menstrual periods, especially during the first 3–6 months. Sometimes the bleeding is heavier than usual at first. However, the bleeding usually becomes lighter than usual and may be irregular. Call your healthcare provider if the bleeding remains heavier than usual or increases after it has been light for a while. • Missed menstrual periods. About 12 out of 100 women stop having periods after 1 year of Kyleena use. If you have any concerns that you may be pregnant while using Kyleena, do a urine pregnancy test and call your healthcare provider. If you do not have a period for 6 weeks during Kyleena use, call your healthcare provider. When Kyleena is removed, your menstrual periods should return. • Cysts on the ovary. About 22 out of 100 women using Kyleena develop a cyst on the ovary. These cysts usually disappear on their own in 2 to 3 months. However, cysts can cause pain and sometimes cysts will need surgery. Other common side effects include: • inflammation or infection of the outer part of your vagina (vulvovaginitis) • abdominal or pelvic pain • headache or migraine • acne or greasy skin • painful periods • sore or painful breasts These are not all of the possible side effects with Kyleena. For more information, ask your healthcare provider. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Bayer Healthcare Pharmaceuticals at 1-888-842-2937. After Kyleena has been placed, when should I call my healthcare provider? If Kyleena is accidentally removed and you had vaginal intercourse within the preceding week, you may be at risk of pregnancy, and you should talk to a healthcare provider. Call your healthcare provider if you have any concerns about Kyleena. Be sure to call if you: • think you are pregnant • have pelvic pain, abdominal pain, or pain during sex • have unusual vaginal discharge or genital sores • have unexplained fever, flu-like symptoms or chills • might be exposed to sexually transmitted infections (STIs) • are concerned that Kyleena may have been expelled (came out) • cannot feel Kyleena's threads • develop very severe or migraine headaches • have yellowing of the skin or whites of the eyes. These may be signs of liver problems. • have had a stroke or heart attack • become HIV positive or your partner becomes HIV positive • have severe vaginal bleeding or bleeding that lasts a long time or concerns you General advice about the safe and effective use of Kyleena. Medicines are sometimes prescribed for conditions other than those listed in patient information leaflets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about Kyleena that is written for health professionals. What are the ingredients in KYLEENA? Active ingredient: levonorgestrel Inactive ingredients: silicone, polyethylene, silver, silica, barium sulfate, polypropylene, copper phthalocyanine Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981 © 2016, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. For more information, go to www.Kyleena.com or call 1-888-842-2937 This Patient Information has been approved by the U.S. Food and Drug Administration.7/2021 Kyleena is Small flexible.jpg uterus Chart

<table width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Patient Information</content></paragraph><paragraph><content styleCode="bold">Kyleena (Ki-lee-nah)</content></paragraph><paragraph>(levonorgestrel-releasing intrauterine system)</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Read this Patient Information carefully before you decide if Kyleena is right for you. This information does not take the place of talking with your gynecologist or other healthcare provider who specializes in women&apos;s health. If you have any questions about Kyleena, ask your healthcare provider. You should also learn about other birth control methods to choose the one that is best for you.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Kyleena does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs).</content></paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">What is Kyleena?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Kyleena is a hormone-releasing system placed in your uterus by your healthcare provider to prevent pregnancy for up to 5 years.</item><item><caption>&#x2022;</caption>Kyleena can be removed by your healthcare provider at any time.</item><item><caption>&#x2022;</caption>Kyleena can be used whether or not you have given birth to a child.</item></list><paragraph>Kyleena is a small, flexible plastic T-shaped system that slowly releases a progestin hormone called levonorgestrel (LNG) that is often used in birth control pills. Because Kyleena releases LNG into your uterus, only small amounts of the hormone enter your blood. Kyleena does not contain estrogen.</paragraph><paragraph>Two thin threads are attached to the stem (lower end) of Kyleena. The threads are the only part of Kyleena you can feel when Kyleena is in your uterus; however, unlike a tampon string, the threads do not extend outside your body. </paragraph></td></tr><tr><td valign="top"><renderMultiMedia ID="id-832379536" referencedObject="CE91E03F-BCD4-4E23-BC50-3E81810B8352"/></td><td valign="top"><renderMultiMedia ID="id1651944329" referencedObject="ID_8672f2c2-0b4c-4c35-8990-feffbe4686a9"/></td></tr><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Kyleena is small</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">and Flexible</content></paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What if I need birth control for more than 5 years?</content></paragraph><paragraph>Kyleena must be removed after 5 years. Your healthcare provider can place a new Kyleena during the same office visit if you choose to continue using Kyleena.</paragraph><paragraph><content styleCode="bold">What if I want to stop using Kyleena?</content></paragraph><paragraph>Kyleena is intended for use up to 5 years, but you can stop using Kyleena at any time by asking your healthcare provider to remove it. You could become pregnant as soon as Kyleena is removed, so you should use another method of birth control if you do not want to become pregnant.

yleena?</content></paragraph><paragraph>Kyleena is intended for use up to 5 years, but you can stop using Kyleena at any time by asking your healthcare provider to remove it. You could become pregnant as soon as Kyleena is removed, so you should use another method of birth control if you do not want to become pregnant. Talk to your healthcare provider about the best birth control methods for you, because your new method may need to be started 7 days before Kyleena is removed to prevent pregnancy.</paragraph><paragraph><content styleCode="bold">What if I change my mind about birth control and want to become pregnant in less than 5 years?</content></paragraph><paragraph>Your healthcare provider can remove Kyleena at any time. You may become pregnant as soon as Kyleena is removed. About 7 out of 10 women who want to become pregnant will become pregnant sometime in the first year after Kyleena is removed.</paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How does Kyleena work?</content></paragraph><paragraph>Kyleena may work in several ways including thickening cervical mucus, inhibiting sperm movement, reducing sperm survival, and thinning the lining of your uterus. It is not known exactly how these actions work together to prevent pregnancy.</paragraph><renderMultiMedia ID="id-1296750603" referencedObject="FECBA003-8CD5-48BA-A0E0-BE6DFB2D82E0"/></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How well does Kyleena work for contraception?</content></paragraph><paragraph>The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.</paragraph><paragraph>Kyleena, an intrauterine device (IUD), also known as an intrauterine system (IUS), is in the box at the top of the chart.</paragraph><renderMultiMedia ID="id636533866" referencedObject="CC928624-BBAE-4A40-8492-DC155A163ADC"/><paragraph><content styleCode="bold">Who might use Kyleena?

get pregnant.</paragraph><paragraph>Kyleena, an intrauterine device (IUD), also known as an intrauterine system (IUS), is in the box at the top of the chart.</paragraph><renderMultiMedia ID="id636533866" referencedObject="CC928624-BBAE-4A40-8492-DC155A163ADC"/><paragraph><content styleCode="bold">Who might use Kyleena? </content></paragraph><paragraph>You might choose Kyleena if you:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>want long-term birth control that provides a low chance of getting pregnant (less than 1 in 100)</item><item><caption>&#x2022;</caption>want birth control that works continuously for up to 5 years </item><item><caption>&#x2022;</caption>want birth control that is reversible</item><item><caption>&#x2022;</caption>want a birth control method that you do not need to take daily</item><item><caption>&#x2022;</caption>are willing to use a birth control method that is placed in the uterus </item><item><caption>&#x2022;</caption>want birth control that does not contain estrogen</item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Do not use Kyleena if you:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>are or might be pregnant; Kyleena cannot be used as an emergency contraceptive</item><item><caption>&#x2022;</caption>have a serious pelvic infection called pelvic inflammatory disease (PID) or have had PID in the past unless you have had a normal pregnancy after the infection went away</item><item><caption>&#x2022;</caption>have an untreated genital infection now</item><item><caption>&#x2022;</caption>have had a serious pelvic infection in the past 3 months after a pregnancy</item><item><caption>&#x2022;</caption>can get infections easily.

you have had a normal pregnancy after the infection went away</item><item><caption>&#x2022;</caption>have an untreated genital infection now</item><item><caption>&#x2022;</caption>have had a serious pelvic infection in the past 3 months after a pregnancy</item><item><caption>&#x2022;</caption>can get infections easily. For example, if you:</item><item><caption>o</caption>have multiple sexual partners or your partner has multiple sexual partners</item><item><caption>o</caption>have problems with your immune system</item><item><caption>o</caption>use or abuse intravenous drugs</item><item><caption>&#x2022;</caption>have or suspect you might have cancer of the uterus or cervix</item><item><caption>&#x2022;</caption>have bleeding from the vagina that has not been explained</item><item><caption>&#x2022;</caption>have liver disease or a liver tumor</item><item><caption>&#x2022;</caption>have breast cancer or any other cancer that is sensitive to progestin (a female hormone), now or in the past</item><item><caption>&#x2022;</caption>have an intrauterine device in your uterus already</item><item><caption>&#x2022;</caption>have a condition of the uterus that changes the shape of the uterine cavity, such as large fibroid tumors</item><item><caption>&#x2022;</caption>are allergic to levonorgestrel, silicone, polyethylene, silver, silica, barium sulfate, polypropylene, or copper phthalocyanine</item></list><paragraph><content styleCode="bold">Before having Kyleena placed, tell your healthcare provider about all of your medical conditions including if you:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>have any of the conditions listed above</item><item><caption>&#x2022;</caption>have had a heart attack</item><item><caption>&#x2022;</caption>have had a stroke</item><item><caption>&#x2022;</caption>were born with heart disease or have problems with your heart valves</item><item><caption>&#x2022;</caption>have problems with blood clotting or take medicine to reduce clotting</item><item><caption>&#x2022;</caption>have high blood pressure</item><item><caption>&#x2022;</caption>recently had a baby or are breastfeeding</item><item><caption>&#x2022;</caption>have severe headaches or migraine headaches</item><item><caption>&#x2022;</caption>have AIDS, HIV, or any other sexually transmitted infection</item></list><paragraph>Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How is Kyleena placed?</content></paragraph><paragraph>Kyleena is placed by your healthcare provider during an in-office visit or immediately after giving birth.</paragraph><paragraph>First, your healthcare provider will examine your pelvis to find the exact position of your uterus. Your healthcare provider will then clean your vagina and cervix with an antiseptic solution and slide a slim plastic tube containing Kyleena through the cervix into your uterus. Your healthcare provider will then remove the plastic tube, and leave Kyleena in your uterus. Your healthcare provider will cut the threads to the right length.</paragraph><paragraph>You may experience pain, bleeding or dizziness during and after placement. If your symptoms do not pass within 30 minutes after placement, Kyleena may not have been placed correctly. Your healthcare provider will examine you to see if Kyleena needs to be removed or replaced.</paragraph><paragraph><content styleCode="bold">Should I check that Kyleena is in place?</content></paragraph><paragraph>Yes, you should check that Kyleena is in proper position by feeling the removal threads.

placed correctly. Your healthcare provider will examine you to see if Kyleena needs to be removed or replaced.</paragraph><paragraph><content styleCode="bold">Should I check that Kyleena is in place?</content></paragraph><paragraph>Yes, you should check that Kyleena is in proper position by feeling the removal threads. It is a good habit to do this 1 time a month. Your healthcare provider should teach you how to check that Kyleena is in place. First, wash your hands with soap and water. You can check by reaching up to the top of your vagina with clean fingers to feel the removal threads. Do not pull on the threads. If you feel more than just the threads or if you cannot feel the threads, Kyleena may not be in the right position and may not prevent pregnancy. Avoid intercourse or use non-hormonal back-up birth control (such as condoms or spermicide) and ask your healthcare provider to check that Kyleena is still in the right place.</paragraph><paragraph><content styleCode="bold">How soon after placement of Kyleena should I return to my healthcare provider?</content></paragraph><paragraph>Call your healthcare provider if you have any questions or concerns (see &quot;When should I call my healthcare provider?&quot;). Otherwise, you should return to your healthcare provider for a follow-up visit 4 to 6 weeks after Kyleena is placed to make sure that Kyleena is in the right position.</paragraph><paragraph><content styleCode="bold">Can I use tampons or menstrual cups with Kyleena?</content></paragraph><paragraph>Yes, tampons or menstrual cups may be used with Kyleena. Change tampons or menstrual cups with care to avoid pulling the threads of Kyleena. If you think you may have pulled Kyleena out of place, avoid intercourse or use a non-hormonal back-up birth control (such as condoms or spermicide), and contact your healthcare provider.</paragraph><paragraph><content styleCode="bold">What if I become pregnant while using Kyleena?</content></paragraph><paragraph>Call your healthcare provider right away if you think you may be pregnant. If possible, also do a urine pregnancy test. If you get pregnant while using Kyleena, you may have an ectopic pregnancy. This means that the pregnancy is not in the uterus. Unusual vaginal bleeding or abdominal pain may be a sign of ectopic pregnancy.</paragraph><paragraph>Ectopic pregnancy is a medical emergency that often requires surgery. Ectopic pregnancy can cause internal bleeding, infertility, and even death.</paragraph><paragraph>There are also risks if you get pregnant while using Kyleena and the pregnancy is in the uterus. Severe infection, miscarriage, premature delivery, and even death can occur with pregnancies that continue with an intrauterine device (IUD). Because of this, your healthcare provider may try to remove Kyleena, even though removing it may cause a miscarriage. If Kyleena cannot be removed, talk with your healthcare provider about the benefits and risks of continuing the pregnancy and possible effects of the hormone on your unborn baby.</paragraph><paragraph>If you continue your pregnancy, see your healthcare provider regularly. Call your healthcare provider right away if you get flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge, or fluid leaking from your vagina. These may be signs of infection.</paragraph><paragraph><content styleCode="bold">How will Kyleena change my periods? </content></paragraph><paragraph>For the first 3 to 6 months, your period may become irregular and the number of bleeding days may increase. You may also have frequent spotting or light bleeding. Some women have heavy bleeding during this time. You may also have cramping during the first few weeks. After you have used Kyleena for a while, the number of bleeding and spotting days is likely to lessen.

me irregular and the number of bleeding days may increase. You may also have frequent spotting or light bleeding. Some women have heavy bleeding during this time. You may also have cramping during the first few weeks. After you have used Kyleena for a while, the number of bleeding and spotting days is likely to lessen. For some women, periods will stop altogether. When Kyleena is removed, your menstrual periods should return.</paragraph><paragraph><content styleCode="bold">Is it safe to breastfeed while using Kyleena?</content></paragraph><paragraph>You may use Kyleena when you are breastfeeding. Kyleena is not likely to affect the quality or amount of your breast milk or the health of your nursing baby. However, isolated cases of decreased milk production have been reported. The risk of Kyleena going into the wall of the uterus (becoming embedded) or going through the wall of the uterus is increased if Kyleena is inserted while you are breastfeeding.</paragraph><paragraph><content styleCode="bold">Will Kyleena interfere with sexual intercourse?</content></paragraph><paragraph>You and your partner should not feel Kyleena during intercourse. Kyleena is placed in the uterus, not in the vagina. Sometimes your partner may feel the threads. If this occurs, or if you or your partner experience pain during sex, talk with your healthcare provider.</paragraph><paragraph><content styleCode="bold">Can I have an MRI with Kyleena in place?</content></paragraph><paragraph>Kyleena can be safely scanned with MRI only under specific conditions. Before you have an MRI, tell your healthcare provider that you have Kyleena, an intrauterine device (IUD), in place.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are the possible side effects of Kyleena?</content></paragraph><paragraph><content styleCode="bold">Kyleena can cause serious side effects including:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Ectopic pregnancy and intrauterine pregnancy risks</content>. There are risks if you become pregnant while using Kyleena (see &quot;What if I become pregnant while using Kyleena?&quot;). </item><item><caption>&#x2022;</caption><content styleCode="bold">Life-threatening infection<content styleCode="italics">.</content></content> Life-threatening infection can occur within the first few days after Kyleena is placed. Call your healthcare provider immediately if you develop severe pain or fever shortly after Kyleena is placed.</item><item><caption>&#x2022;</caption><content styleCode="bold">Pelvic inflammatory disease (PID).</content> Some IUD users get a serious pelvic infection called pelvic inflammatory disease. PID is usually sexually transmitted. You have a higher chance of getting PID if you or your partner has sex with other partners. PID can cause serious problems such as infertility, ectopic pregnancy or pelvic pain that does not go away. PID is usually treated with antibiotics. More serious cases of PID may require surgery including removal of the uterus (hysterectomy). In rare cases, infections that start as PID can even cause death.</item><item><caption> </caption>Tell your healthcare provider right away if you have any of these signs of PID: long-lasting or heavy bleeding, unusual vaginal discharge, low abdominal (stomach area) pain, painful sex, chills, fever, genital lesions or sores.</item><item><caption>&#x2022;</caption><content styleCode="bold">Perforation.</content> Kyleena may go into the wall of the uterus (become embedded) or go through the wall of the uterus. This is called perforation. If this occurs, Kyleena may no longer prevent pregnancy.

ul sex, chills, fever, genital lesions or sores.</item><item><caption>&#x2022;</caption><content styleCode="bold">Perforation.</content> Kyleena may go into the wall of the uterus (become embedded) or go through the wall of the uterus. This is called perforation. If this occurs, Kyleena may no longer prevent pregnancy. If perforation occurs, Kyleena may move outside the uterus and can cause internal scarring, infection, or damage to other organs, and you may need surgery to have Kyleena removed. Excessive pain or vaginal bleeding during placement of Kyleena, pain or bleeding that gets worse after placement, or not being able to feel the threads may happen with perforation. The risk of perforation is increased if Kyleena is inserted while you are breastfeeding, or if you have recently given birth.</item><item><caption>&#x2022;</caption><content styleCode="bold">Expulsion.</content> Kyleena may come out by itself. This is called expulsion. Expulsion occurs in about 4 out of 100 women. Excessive pain or vaginal bleeding during placement of Kyleena, pain or bleeding that gets worse after placement, or not being able to feel the threads may happen with expulsion. You may become pregnant if Kyleena comes out. If you think that Kyleena has come out, avoid intercourse or use a non-hormonal back-up birth control (such as condoms or spermicide) and call your healthcare provider. The risk of expulsion is increased with insertion right after delivery or second-trimester abortion.</item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Common side effects of Kyleena include: </content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Pain, bleeding or dizziness during and after placement.</content> If these symptoms do not stop 30 minutes after placement, Kyleena may not have been placed correctly. Your healthcare provider will examine you to see if Kyleena needs to be removed or replaced.</item><item><caption>&#x2022;</caption><content styleCode="bold">Changes in bleeding.</content> You may have bleeding and spotting between menstrual periods, especially during the first 3&#x2013;6 months. Sometimes the bleeding is heavier than usual at first. However, the bleeding usually becomes lighter than usual and may be irregular. Call your healthcare provider if the bleeding remains heavier than usual or increases after it has been light for a while.</item><item><caption>&#x2022;</caption><content styleCode="bold">Missed menstrual periods.</content> About 12 out of 100 women stop having periods after 1 year of Kyleena use. If you have any concerns that you may be pregnant while using Kyleena, do a urine pregnancy test and call your healthcare provider. If you do not have a period for 6 weeks during Kyleena use, call your healthcare provider. When Kyleena is removed, your menstrual periods should return.</item><item><caption>&#x2022;</caption><content styleCode="bold">Cysts on the ovary.</content> About 22 out of 100 women using Kyleena develop a cyst on the ovary. These cysts usually disappear on their own in 2 to 3 months.

, call your healthcare provider. When Kyleena is removed, your menstrual periods should return.</item><item><caption>&#x2022;</caption><content styleCode="bold">Cysts on the ovary.</content> About 22 out of 100 women using Kyleena develop a cyst on the ovary. These cysts usually disappear on their own in 2 to 3 months. However, cysts can cause pain and sometimes cysts will need surgery.</item></list><paragraph>Other common side effects include:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>inflammation or infection of the outer part of your vagina (vulvovaginitis)</item><item><caption>&#x2022;</caption>abdominal or pelvic pain</item><item><caption>&#x2022;</caption>headache or migraine</item><item><caption>&#x2022;</caption>acne or greasy skin</item><item><caption>&#x2022;</caption>painful periods</item><item><caption>&#x2022;</caption>sore or painful breasts</item></list><paragraph>These are not all of the possible side effects with Kyleena. For more information, ask your healthcare provider. </paragraph><paragraph><content styleCode="bold">Call your doctor for medical advice about side effects.</content> You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Bayer Healthcare Pharmaceuticals at 1-888-842-2937.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">After Kyleena has been placed, when should I call my healthcare provider?</content></paragraph><paragraph>If Kyleena is accidentally removed and you had vaginal intercourse within the preceding week, you may be at risk of pregnancy, and you should talk to a healthcare provider.</paragraph><paragraph>Call your healthcare provider if you have any concerns about Kyleena. Be sure to call if you:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>think you are pregnant</item><item><caption>&#x2022;</caption>have pelvic pain, abdominal pain, or pain during sex</item><item><caption>&#x2022;</caption>have unusual vaginal discharge or genital sores</item><item><caption>&#x2022;</caption>have unexplained fever, flu-like symptoms or chills</item><item><caption>&#x2022;</caption>might be exposed to sexually transmitted infections (STIs)</item><item><caption>&#x2022;</caption>are concerned that Kyleena may have been expelled (came out)</item><item><caption>&#x2022;</caption>cannot feel Kyleena&apos;s threads</item><item><caption>&#x2022;</caption>develop very severe or migraine headaches</item><item><caption>&#x2022;</caption>have yellowing of the skin or whites of the eyes. These may be signs of liver problems.</item><item><caption>&#x2022;</caption>have had a stroke or heart attack</item><item><caption>&#x2022;</caption>become HIV positive or your partner becomes HIV positive</item><item><caption>&#x2022;</caption>have severe vaginal bleeding or bleeding that lasts a long time or concerns you</item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General advice about the safe and effective use of Kyleena.</content></paragraph><paragraph>Medicines are sometimes prescribed for conditions other than those listed in patient information leaflets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about Kyleena that is written for health professionals.

</content></paragraph><paragraph>Medicines are sometimes prescribed for conditions other than those listed in patient information leaflets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about Kyleena that is written for health professionals. </paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in KYLEENA?</content></paragraph><paragraph><content styleCode="bold">Active ingredient: </content>levonorgestrel</paragraph><paragraph><content styleCode="bold">Inactive ingredients: </content>silicone, polyethylene, silver, silica, barium sulfate, polypropylene, copper phthalocyanine</paragraph><paragraph>Manufactured for: </paragraph><paragraph>Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981</paragraph><paragraph>&#xA9; 2016, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.</paragraph><paragraph>For more information, go to www.Kyleena.com or call 1-888-842-2937</paragraph></td></tr></tbody></table>