LILETTA

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 )] . 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 ) ] …

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. 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 pregna…

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 )

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

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.

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 advers…