LILETTA

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%). 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

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 )

11 DESCRIPTION The following structural formula for 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

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 )] . 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. 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. 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). 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. 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. 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.

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.

7 DRUG INTERACTIONS No drug-drug interaction studies have been conducted with LILETTA.

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. 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.

20230629

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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 )

LILETTA Levonorgestrel LEVONORGESTREL LEVONORGESTREL DIMETHICONE BARIUM SULFATE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility [ s ee Warnings and Precautions ( 5.9 ) ]

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

NDA206229

LILETTA

Levonorgestrel

0023-5858

HUMAN PRESCRIPTION DRUG

INTRAUTERINE

PRINCIPAL DISPLAY PANEL NDC 0023-5858-01 Rx Only LILETTA (levonorgestrel-releasing intrauterine system) 52 mg Single-Handed Insertion Device 1 Sterile Unite Intrauterine use Allergan/Medicine 360 NDC 0023-5858-01 Rx Only LILETTA (levonorgestrel-releasing intrauterine system) 52 mg Single-Handed Insertion Device 1 Sterile Unite Intrauterine use Allergan/Medicine 360

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

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 )]. 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

14 CLINICAL STUDIES Figure 17 and Figure 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 . 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%. Figure 17: Proportion of Participants with Successful Treatment of HMB Over Time Figure 18: Median Menstrual Blood Loss (MBL) Over Time

15 REFERENCES (1) Centers for Disease Control and Prevention (CDC). CDC STI Treatment Guidelines [online] Available at: https://www.cdc.gov/std/treatment-guidelines/pid.htm

8.5 Geriatric Use LILETTA is not indicated in patients after menopause and has not been studied in this population.

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.

8.1 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 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 ) ].

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.