Skyla

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. • 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 usi…

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. 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 occ…

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 )

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.

8.1 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.

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)]. 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 br…