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CLINICAL PHARMACOLOGY Mechanism Of Action The local mechanism by which continuously released LNG enhances 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. Pharmacodynamics Skyla has mainly local progestogenic effects in the uterine cavity. The high local levels of LNG2 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 observed in the majority of a subset of subjects studied. Evidence of ovulation 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 27 women in the third year. 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 decreases progressively to approximately 5 mcg/day after three years. The average LNG in vivo release rate is approximately 6 mcg/day over the period of three years. In a subset of 7 subjects, maximum observed serum LNG concentration was 192 ± 105 pg/mL, reached after 2 days (median) of Skyla insertion. Thereafter, LNG serum concentration decreased after long-term use of 12, 24, and 36 months to concentrations of 77 ± 21 pg/mL, 62 ± 38 pg/mL, and 72 ± 29 pg/mL, respectively. A population pharmacokinetic evaluation based on a broader data base (>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. Levonorgestrel 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 remains relatively stable over the 3 year period of use. Thereafter, plateau-like SHBG concentrations were observed. Less than 2 % of the circulating LNG is present as free steroid. 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 16βhydroxylevonorgestrel. LNG and its phase I metabolites are excreted primarily as glucuronide conjugates. 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. 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. The elimination half-life of LNG after parenteral administration is approximately 20 hours. 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. Geriatric Skyla has not been studied in women over age 65 and is not currently approved for use in this population. Race No studies have evaluated the effect of race on pharmacokinetics of Skyla. 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]. Clinical Studies Clinical Trials On Contraception The contraceptive efficacy of Skyla was demonstrated in a clinical trial that enrolled generally healthy women aged 18– 35, 1,432 of whom received Skyla. The Skyla arm included 38.8 % (556) nulliparous women. 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. For Skyla-treated women, 540 (37.7%) were treated at US sites and 892 (62.3%) were at non-US sites. The racial demographic of enrolled women who received Skyla was: Caucasian (79.7%), Hispanic (11.5%), Black (5.2%), Asian (0.8%), and Other (2.7%). The weight range for treated women was 38 to 155 kg (mean weight: 68.7 kg) and mean BMI was 25.3 kg/m2 (range 16–55 kg/m2). 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 their consent, 13.0% discontinued due to other reason, 1.1% discontinued due to protocol deviation, and 0.6% discontinued due to pregnancy. 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%. About 77% of women wishing to become pregnant conceived within 12 months after removal of Skyla.

CLINICAL PHARMACOLOGY Mechanism Of Action The local mechanism by which continuously released LNG enhances contraceptive effectiveness of Mirena has not been conclusively demonstrated. Studies of Mirena 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. Pharmacodynamics Mirena has mainly local progestogenic effects in the uterine cavity. The high local levels of LNG2 lead to morphological changes including stromal pseudodecidualization, glandular atrophy, a leukocytic infiltration and a decrease in glandular and stromal mitoses. Ovulation is inhibited in some women using Mirena. In a 1-year study, approximately 45% of menstrual cycles were ovulatory, and in another study after 4 years, 75% of cycles were ovulatory. Pharmacokinetics Absorption Low doses of LNG are administered into the uterine cavity with the Mirena intrauterine delivery system. The initial release rate is approximately 20 mcg/day over the first 3 months tested (day 0 to day 90). It is reduced to approximately 18 mcg/day after 1 year and then decreases progressively to approximately 10 mcg/day after 5 years. A stable serum concentration, without peaks and troughs, of LNG of 150-200 pg/mL occurs after the first few weeks following insertion of Mirena. LNG concentrations after long-term use of 12, 24, and 60 months were 180±66 pg/mL, 192±140 pg/mL, and 159±59 pg/mL, respectively. Distribution The apparent volume of distribution of LNG is reported to be approximately 1.8 L/kg. It is about 97.5 to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. 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 16βhydroxylevonorgestrel. LNG and its phase I metabolites are excreted primarily as glucuronide conjugates. 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. 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. The elimination half-life of LNG after daily oral doses is approximately 17 hours. Specific Populations Pediatric: Safety and efficacy of Mirena have been established in women of reproductive age. Use of this product before menarche is not indicated. Geriatric: Mirena has not been studied in women over age 65 and is not currently approved for use in this population. Race: No studies have evaluated the effect of race on pharmacokinetics of Mirena. Hepatic Impairment: No studies were conducted to evaluate the effect of hepatic disease on the disposition of Mirena. Renal Impairment: No formal studies were conducted to evaluate the effect of renal disease on the disposition of Mirena. Drug-Drug Interactions No drug-drug interaction studies were conducted with Mirena [see DRUG INTERACTIONS]. Clinical Studies Clinical Trials On Contraception Mirena has been studied for safety and efficacy in two large clinical trials in Finland and Sweden. In study sites having verifiable data and informed consent, 1,169 women 18 to 35 years of age at enrollment used Mirena for up to 5 years, for a total of 45,000 women-months of exposure. Subjects had previously been pregnant, had no history of ectopic pregnancy, had no history of pelvic inflammatory disease over the preceding 12 months, were predominantly Caucasian, and over 70% of the participants had previously used IUDs (intrauterine devices). The reported 12-month pregnancy rates were less than or equal to 0.2 per 100 women (0.2%) and the cumulative 5-year pregnancy rate was approximately 0.7 per 100 women (0.7%). About 80% of women wishing to become pregnant conceived within 12 months after removal of Mirena. Clinical Trial On Heavy Menstrual Bleeding The efficacy of Mirena in the treatment of heavy menstrual bleeding was studied in a randomized, open-label, active-control, parallel-group trial comparing Mirena (n=79) to an approved therapy, medroxyprogesterone acetate (MPA) (n=81), over 6 cycles. The subjects included reproductive-aged women in good health, with no contraindications to the drug products and with confirmed heavy menstrual bleeding ( ≥ 80 mL menstrual blood loss [MBL]) determined using the alkaline hematin method. Excluded were women with organic or systemic conditions that may cause heavy uterine bleeding (except small fibroids, with total volume not > 5 mL). Treatment with Mirena showed a statistically significantly greater reduction in MBL (see Figure 12) and a statistically significantly greater number of subjects with successful treatment (see Figure 13). Successful treatment was defined as proportion of subjects with (1) end-of-study MBL < 80 mL and (2) a ≥ 50% decrease in MBL from baseline to end-of-study. Figure 12: Median Menstrual Blood Loss (MBL) by Time and Treatment Figure 13. Proportion of Subjects with Successful Treatment REFERENCES 2Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T. Tissue concentrations of LNG in women using a LNG-releasing IUD. Clinical Endocrinol 1982;17:529-536.

CLINICAL PHARMACOLOGY 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. Pharmacodynamics LILETTA has mainly local progestogenic effects in the uterine cavity and cervix. High local concentrations of LNG lead to morphological changes including stromal pseudodecidualization, glandular atrophy, a leukocytic infiltration, and a decrease in glandular and stromal mitoses. Changes in the uterine endometrium may lead to alterations in the menstrual bleeding pattern [see WARNINGS AND PRECAUTIONS]. In clinical trials with other LNG-releasing IUSs, ovulation was inhibited in some women but most cycles were ovulatory. 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 18.6 μg/day and decreases to 16.3 μg/day at 1 year, 14.3 μg/day at 2 years, and 12.6 μg/day after 3 years. In the phase 3 study, systemic LNG concentrations were assessed in a subset of subjects through Month 30 and in all subjects at Month 36. Plasma LNG concentrations following insertion of LILETTA are shown in Table 4. Table 4: Plasma LNG Concentrations (mean ± SD, pg/mL) Following LILETTA Insertion Initial (7 days) (N = 40) 6 Months (N = 36) 12 Months (N = 33) 24 Months (N = 29) 30 Months (N = 9) 36 Months (N=243) 252± 123 195 ± 69 170 ± 50 147 ± 46 133 ± 28 135 ± 51 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. 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, 5αtetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. LNG and its phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by severalfold, and this may account in part for wide individual variations in LNG concentrations seen in individuals using LNG–containing contraceptive products. 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. The elimination half-life of LNG after a single oral administration is approximately 13.9 ± 3.2 hours. Specific Populations Pediatric: Safety and efficacy of LILETTA have been established in females of reproductive age. The LILETTA clinical trial included 11 subjects aged 16 to 17 years; no pregnancies occurred in these subjects. Race: The LILETTA clinical trial included 199 (13%) Black/African American subjects and 226 (15%) subjects of Hispanic ethnicity. Race does not appear to affect LNG concentrations following LILETTA insertion. Obesity: The LILETTA clinical trial included overweight (24%), obese (24%), and morbidly obese (5%) women. LNG systemic exposure decreased with increasing body weight; however, there was no apparent effect of body mass index (BMI) or body weight on contraceptive efficacy. Clinical Studies Clinical Trial On Contraception LILETTA was studied in a multicenter, randomized, open-label clinical trial conducted in the US that enrolled 1,910 generally healthy women aged 16 to 45 years, 1,751 of whom received LILETTA. LILETTA was inserted in 1,011 (58%) nulliparous and 740 (42%) parous women. Women 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 demographics of enrolled women who received LILETTA were: Caucasian 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 trial had no upper or lower weight or BMI limit and the BMI range was 15.8 – 61.6 kg/m². The mean BMI of LILETTA subjects was 26.9 kg/m²; 24% were overweight, 24% were obese (BMI ≥ 30 kg/m²), and 5% were morbidly obese (BMI ≥ 40). The pregnancy rate calculated as the Pearl Index (PI) in women aged 16 to 35 years, inclusive, was the primary efficacy endpoint used to assess contraceptive reliability. The PI was calculated based on 28day 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 3-year pregnancy rate was calculated by the life table method, based on a total of six pregnancies that occurred after the onset of treatment and within 7 days after LILETTA removal or expulsion. Contraceptive protection did not appear to vary by parity, race or body mass index. Table 5 shows the calculated cumulative pregnancy rates. Table 5: Cumulative Pregnancy Rates LILETTA Clinical Trial Year 1 Pearl Index Cumulative 3-Year Life Table Number of 28-day Cycles of Exposure 17,125 34,711 Pregnancy Rate (95% CI) 0.15 (0.02, 0.55) 0.55 (0.24, 1.23) Of 68 women who desired pregnancy after study discontinuation, 71% conceived within 6 months following LILETTA removal, and 87% conceived within 12 months after removal of LILETTA. REFERENCES (1) Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010 Dec 17;59(RR12):1-110.

Find Lowest Prices on SKYLA (levonorgestrel-releasing) Intrauterine System 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 C21H28O2, and the following structural formula: Skyla Skyla consists of a T-shaped polyethylene frame (T-body) with a steroid reservoir (hormone elastomer core) around the vertical stem. The 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 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

Find Lowest Prices on MIRENA (levonorgestrel-releasing) Intrauterine System DESCRIPTION Mirena (levonorgestrel-releasing intrauterine system) contains 52 mg of LNG, a progestin, and is intended to provide an initial release rate of approximately 20 mcg/day of LNG. Levonorgestrel USP, (-)-13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one, the active ingredient in Mirena, has a molecular weight of 312.4, a molecular formula of C21H28O2, and the following structural formula: Mirena Mirena consists of a T-shaped polyethylene frame (T-body) with a steroid reservoir (hormone elastomer core) around the vertical stem. The reservoir consists of a white or almost white cylinder, made of a mixture of levonorgestrel and silicone (polydimethylsiloxane), containing a total of 52 mg levonorgestrel. The reservoir is covered by a semi-opaque silicone (polydimethylsiloxane) membrane. The T-body is 32 mm in both the horizontal and vertical directions. 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 Mirena, including its packaging, are not manufactured using natural rubber latex. Figure 10: Mirena Inserter Mirena is packaged sterile within an inserter. The inserter (Figure 11), which is used for insertion of Mirena 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 4.4 mm. The vertical stem of Mirena 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 Mirena has been placed, the inserter is discarded. Figure 11: Diagram of Inserter

Find Lowest Prices on LILETTA (levonorgestrel-releasing) Intrauterine System DESCRIPTION LILETTA (levonorgestrel-releasing intrauterine system) contains 52 mg of levonorgestrel, a progestin, and is intended to provide an initial release rate of 18.6 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, has a molecular weight of 312.45, a molecular formula of C21H28O2, and the following structural formula: LILETTA LILETTA consists of a T-shaped polyethylene frame (T-frame) with a drug reservoir around the vertical stem (Figure 14). 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 14: Diagram of LILETTA Inserter The inserter device provided with LILETTA is a single-use, disposable, sterile insertion system (tube, flange, rod; Figure 15), partially preloaded with the IUS product for intrauterine administration. Once LILETTA has been inserted, the inserter is discarded. Figure 15: Diagram of Inserter

INDICATIONS Skyla® is indicated to prevent pregnancy for up to 3 years. The system should be replaced after 3 years if continued use is desired. DOSAGE AND ADMINISTRATION 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 5 mcg/day after 3 years. The average in vivo release rate of LNG is approximately 6 mcg/day over a period of 3 years. 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 is supplied within an inserter in a sterile package (see Figure 1) that must not be opened until required for insertion [see DESCRIPTION]. 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]. Insertion Instructions A complete medical and social history should be obtained 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 and WARNINGS AND PRECAUTIONS.] Follow the insertion instructions exactly as described in order 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 seizure in an epileptic patient, especially in patients with a predisposition to these symptoms. Consider administering analgesics prior to insertion. Timing Of Insertion Insert Skyla into the uterine cavity during the first seven days of the menstrual cycle or immediately after a first trimester abortion. Back up contraception is not needed when Skyla is inserted as directed. Postpone postpartum insertion and insertions following second trimester abortions a minimum of six weeks or until the uterus is fully involuted. If involution is delayed, wait until involution is complete before insertion [see WARNINGS AND PRECAUTIONS]. Tools For Insertion 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 backup Skyla available Sterile, sharp curved scissors Preparation For Insertion Exclude pregnancy and confirm that there are no other contraindications to the use of Skyla. Ensure that the patient understands the contents of the Patient Information Booklet and obtain the signed patient informed consent located on the last page of the Patient Information Booklet. 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. 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. 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. 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 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. 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 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 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. Keep a copy of the Consent Form with lot number for your records. 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. A removed Skyla must not be re-inserted. If there is clinical concern, exceptional pain or bleeding during or after insertion, appropriate steps (such as physical examination and ultrasound) should be taken immediately to exclude perforation. Patient Follow-Up Reexamine and evaluate patients 4 to 6 weeks after insertion and once a year thereafter, or more frequently if clinically indicated. Removal Of Skyla Timing Of Removal Skyla should not remain in the uterus after 3 years. If pregnancy is not desired, the removal should be carried out during menstruation, provided the woman is still experiencing regular menses. If removal will occur at other times during the cycle, consider starting a new contraceptive method a week prior to removal. If removal occurs at other times during the cycle and the woman has had intercourse in the week prior to removal, she is at risk of pregnancy. [See Continuation Of Contraception After Removal.] 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]. 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. Removal may be associated with some pain and/or bleeding or vasovagal reactions (for example, syncope, or a seizure in an epileptic patient). 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 birth control method, time removal and initiation of 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 birth control method, start the new method at least 7 days before removal. HOW SUPPLIED Dosage Forms And Strengths Skyla is a LNG-releasing IUS consisting of a T-shaped polyethylene frame with a steroid reservoir containing a total of 13.5 mg LNG. 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]. REFERENCES 1Farley T M M, Rosenberg M J, Rowe P J, Chen J, Meirik O. Intrauterine devices and pelvic inflammatory disease: an international perspective. Lancet 1992; 339:785-788. 2Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T. Tissue concentrations of LNG in women using a LNG-releasing IUD. Clinical Endocrinol 1982; 17:529-536. Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981. Revised: December 2016

INDICATIONS Mirena is indicated for intrauterine contraception for up to 5 years. Mirena is also indicated for the treatment of heavy menstrual bleeding in women who choose to use intrauterine contraception as their method of contraception. Mirena is recommended for women who have had at least one child. The system should be replaced after 5 years if continued use is desired. DOSAGE AND ADMINISTRATION Mirena contains 52 mg of levonorgestrel (LNG). Initially, LNG is released at a rate of approximately 20 mcg/day. This rate decreases progressively to half that value after 5 years. Mirena must be removed by the end of the fifth year and can be replaced at the time of removal with a new Mirena if continued contraceptive protection is desired. Mirena is supplied within an inserter in a sterile package (see Figure 1) that must not be opened until required for insertion [see DESCRIPTION]. 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]. Insertion Instructions A complete medical and social history should be obtained 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 and WARNINGS AND PRECAUTIONS] Follow the insertion instructions Exactly as described in order to ensure proper placement and avoid premature release of Mirena from the inserter. Once released, Mirena cannot be re-loaded. Mirena should be inserted by a trained healthcare provider. Healthcare providers should become thoroughly familiar with the insertion instructions before attempting insertion of Mirena. Insertion may be associated with some pain and/or bleeding or vasovagal reactions (for example, syncope, bradycardia), or with seizure in an epileptic patient, especially in patients with a predisposition to these symptoms. Consider administering analgesics prior to insertion. Timing Of Insertion Insert Mirena into the uterine cavity during the first seven days of the menstrual cycle or immediately after a first trimester abortion. Back up contraception is not needed when Mirena is inserted as directed. Postpone postpartum insertion and insertions following second trimester abortions a minimum of six weeks or until the uterus is fully involuted. If involution is delayed, wait until involution is complete before insertion [see WARNINGS AND PRECAUTIONS]. Tools For Insertion Preparation Gloves Speculum Sterile uterine sound Sterile tenaculum Antiseptic solution, applicator Procedure Sterile gloves Mirena with inserter in sealed package Instruments and anesthesia for paracervical block, if anticipated Consider having an unopened backup Mirena available Sterile, sharp curved scissors Preparation For Insertion Exclude pregnancy and confirm that there are no other contraindications to the use of Mirena. Ensure that the patient understands the contents of the Patient Information Booklet and obtain the signed patient informed consent located on the last page of the Patient Information Booklet. 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. The uterus should sound to a depth of 6 to 10 cm. Insertion of Mirena into a uterine cavity less than 6 cm by sounding may increase the incidence of expulsion, bleeding, pain, perforation, and possibly pregnancy. Insertion Procedure Proceed with insertion only after completing the above steps and ascertaining that the patient is appropriate for Mirena. 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 Mirena Package Using sterile gloves lift the handle of the sterile inserter and remove from the sterile package. Step 2-Load Mirena 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 Mirena T-body to load Mirena 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 Mirena 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 Mirena. Once the slider is moved below the mark, Mirena cannot be re-loaded. 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 Step 4-Mirena 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. Step 5-Open the Arms While holding the inserter steady, move the slider down to the mark to release the arms of Mirena (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 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. Mirena is now in the fundal position (Figure 6). Fundal positioning of Mirena is important to prevent expulsion. Figure 6: Move Mirena into the fundal position Step 7-Release Mirena and Withdraw the Inserter Holding the entire inserter firmly in place, release Mirena by moving the slider all the way down (Figure 7). Figure 7. Move the slider all the way down to release Mirena 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 Mirena. Figure 8: Cutting the threads Mirena insertion is now complete. Prescribe analgesics, if indicated. Keep a copy of the Consent Form with lot number for your records. Important Information To Consider During Or After Insertion If you suspect that Mirena is not in the correct position, check placement (for example, using transvaginal ultrasound). Remove Mirena if it is not positioned completely within the uterus. A removed Mirena must not be re-inserted. If there is clinical concern, exceptional pain or bleeding during or after insertion, appropriate steps (such as physical examination and ultrasound) should be taken immediately to exclude perforation. Patient Follow-up Reexamine and evaluate patients 4 to 6 weeks after insertion and once a year thereafter, or more frequently if clinically indicated. Removal Of Mirena Timing of Removal Mirena should not remain in the uterus after 5 years. If pregnancy is not desired, the removal should be carried out during menstruation, provided the woman is still experiencing regular menses. If removal will occur at other times during the cycle, consider starting a new contraceptive method a week prior to removal. If removal occurs at other times during the cycle and the woman has had intercourse in the week prior to removal, she is at risk of pregnancy. [See Continuation of Contraception after Removal] Tools for Removal Preparation Gloves Speculum Procedure Sterile forceps Removal Procedure Remove Mirena by applying gentle traction on the threads with forceps. (Figure 9). Figure 9: Removal of Mirena If the threads are not visible, determine location of Mirena by ultrasound [see WARNINGS AND PRECAUTIONS]. If Mirena 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 Mirena, examine the system to ensure that it is intact. Removal may be associated with some pain and/or bleeding or vasovagal reactions (for example, syncope, or a seizure in an epileptic patient). Continuation Of Contraception After Removal If pregnancy is not desired and if a woman wishes to continue using Mirena, 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 birth control method, time removal and initiation of new method to ensure continuous contraception. Either remove Mirena 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 Mirena 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 removal. HOW SUPPLIED Dosage Forms And Strengths Mirena is a LNG-releasing IUS consisting of a T-shaped polyethylene frame with a steroid reservoir containing a total of 52 mg LNG. Storage And Handling Mirena (levonorgestrel-releasing intrauterine system), containing a total of 52 mg LNG, is available in a carton of one sterile unit NDC# 50419-423-01. Mirena is supplied sterile. Mirena 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]. Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981. Manufactured in Finland. Revised: Dec 2016

INDICATIONS LILETTA™ is indicated for prevention of pregnancy for up to 3 years. The system should be replaced after 3 years if continued use is desired. DOSAGE AND ADMINISTRATION LILETTA contains 52 mg of levonorgestrel (LNG). Initially, LNG is released at a rate of 18.6 mcg/day. This rate decreases progressively to approximately 16.3 mcg/day at 1 year, 14.3 mcg/day at 2 years, and 12.6 mcg/day at 3 years after insertion. The average in vivo release rate of LNG is approximately 15.6 mcg/day over a period of 3 years. LILETTA can be removed at any time but must be removed by the end of the third year. LILETTA can be replaced at the time of removal with a new LILETTA if continued contraceptive protection is desired. Insertion Instructions LILETTA (Figure 1) is provided in a sterile pouch [see DESCRIPTION] and is inserted into the uterine cavity with the provided inserter (Figure 2) by carefully following the insertion instructions. Use strict aseptic techniques throughout the insertion procedure [see WARNINGS AND PRECAUTIONS]. Insertion Figure 1 : LILETTA Intrauterine Contraceptive System (IUS) Figure 2: LILETTA IUS with Inserter LILETTA should only be inserted by a trained healthcare provider. Healthcare providers 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 a levonorgestrel-releasing intrauterine system (LILETTA) for contraception. If indicated, perform a physical examination and appropriate tests for genital or sexually transmitted infections. [See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS] Check the expiration date on the box before opening it. Do not insert LILETTA after the expiration date. Visually inspect the packaging (sealed pouch) 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]. Ensure that the patient understands the contents of the Patient Information Booklet and obtain consent. A sample consent form that includes the lot number is on the last page of the Patient Information Booklet. Complete the pelvic examination, speculum placement, tenaculum placement, and sounding of the uterus before opening the LILETTA pouch. Do not open the pouch to insert LILETTA if the cervix is unable to be properly visualized, if the uterus cannot be adequately instrumented (during sounding), or if the uterus sounds to less than 5.5 cm. 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 women not currently using hormonal or intrauterine contraception LILETTA can be inserted any time the provider can be reasonably certain the woman is not pregnant. Consider the possibility of ovulation and conception prior to initiation of this product. If LILETTA is not inserted during the first 7 days of the menstrual cycle, a barrier method of contraception (such as condoms and spermicide) should be used or the patient should abstain from vaginal intercourse for 7 days to prevent pregnancy. Switching to LILETTA from an oral, transdermal or vaginal hormonal contraceptive LILETTA may be inserted at any time. May be inserted during the hormone-free interval of the previous method If inserted during active use of the previous method, continue the previous method after LILETTA insertion for seven days or until the end of the current cycle. If using continuous hormonal contraception, discontinue the method seven days after LILETTA insertion. Switching to LILETTA from an injectable progestin contraceptive LILETTA may be inserted at any time; a barrier method of contraception (such as condoms and spermicide) should also be used for 7 days if LILETTA is inserted as instructed more than 3 months (13 weeks) after the last injection. Switching to LILETTA from a contraceptive implant or another IUS Insert LILETTA on the same day the implant or IUS is removed. LILETTA may be inserted at any time during the menstrual cycle. Inserting LILETTA after abortion or miscarriage First-trimester LILETTA may be inserted immediately after a first-trimester abortion or miscarriage. Second-trimester Do not insert LILETTA until a minimum of 6 weeks after second trimester abortion or miscarriage, or until the uterus is fully involuted. If involution is delayed, wait until involution is complete before insertion [see WARNINGS AND PRECAUTIONS]. If the woman has not yet had a period, consider the possibility of ovulation and conception occurring prior to insertion of LILETTA. [See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and FDA-Approved Patient Labeling.] LILETTA can be inserted any time the provider can be reasonably certain the woman is not pregnant. If LILETTA is not inserted during the first 7 days of the menstrual cycle, a barrier method of contraception should be used or the patient should abstain from vaginal intercourse for 7 days to prevent pregnancy. Inserting LILETTA after Childbirth Do not insert LILETTA until a minimum of 6 weeks after delivery, or until the uterus is fully involuted. If involution is delayed, wait until involution is complete before insertion [see WARNINGS AND PRECAUTIONS]. If the woman has not yet had a period, consider the possibility of ovulation and conception occurring prior to insertion of LILETTA. [See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and FDA-Approved Patient Labeling.] LILETTA can be inserted any time the provider can be reasonably certain the woman is not pregnant. If LILETTA is not inserted during the first 7 days of the menstrual cycle, a barrier method of contraception should be used or the patient should abstain from vaginal intercourse for 7 days to prevent pregnancy. There appears to be an increased risk of perforation in lactating women. [See WARNINGS AND PRECAUTIONS.] Planning for Insertion Ensure all needed items for LILETTA insertion are readily available: Gloves Speculum Sterile uterine sound Sterile tenaculum Antiseptic solution LILETTA with inserter in sealed pouch Sterile, blunt-tipped scissors Additional items that may be useful could include: Local anesthesia, needle, and syringe 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 in order 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. Loading and inserting LILETTA does not require sterile gloves. If not using sterile gloves, complete all steps for loading the IUS (Steps 1-7) inside the pouch. Maintain sterility during LILETTA insertion; do not touch LILETTA or parts of any sterile instrument that will pierce tissue (e.g., a tenaculum on the cervix) or go into the uterine cavity. Preparation 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, open the pouch containing LILETTA. Insertion Procedure Loading the IUS into the Inserter Step 1 Place the LILETTA pouch on a flat surface with the clear side of the pouch facing up (Figure 3). Figure 3: Place the LILETTA pouch on a flat surface. Open the sterile LILETTA pouch from the bottom (end with the rod ring) approximately 1/3 of the way until the lower ends of the IUS threads, the rod, and the insertion tube are exposed (Figure 4). If using sterile gloves, you can open the pouch completely before putting on the sterile gloves. Figure 4: Release the threads from the flange and insert the rod. Step 2 Pull back the blue threads to dislodge them from the flange. Be careful to not pull the IUS down at the same time (Figure 4). Step 3 Hold the exposed end of the insertion tube containing the IUS (Figure 4) while keeping the end of the insertion tube with the IUS inside the packaging. Remove the rod from the pouch. Do not touch the end of the rod that will go into the insertion tube. Place the rod into the insertion tube (alongside the IUS threads) to about the 5 cm marking (Figure 4). Step 4 While holding the insertion tube and the rod firmly between the fingers and thumb of one hand, pull downward on both blue threads with the other hand to draw the IUS into the insertion tube (Figure 5). The arms of the IUS should be kept in a horizontal plane, parallel to the flat side of the flange (refer to Figure 4). Do not pull the IUS all of the way through the insertion tube; only pull the threads until the IUS is loaded at the top of the insertion tube. Note: If you accidentally remove the IUS completely out of the insertion tube, do not use or attempt to re-load. Figure 5: Pull on the threads to pull the IUS into the tube. Figure 6: Adjust the Flange. Step 5 Hold the insertion tube and the rod firmly with one hand. With the other hand, adjust the position of the flange (through the sterile packaging if not using sterile gloves) by moving the tube to correspond to the sound measurement (Figure 6). The top end of the flange should be at the measurement corresponding to the sounded depth of the uterus. Step 6 Final IUS positioning: position the IUS in the tube so that the knobs of the lateral arms are opposed to each other and protrude slightly above the tip of the insertion tube to form a hemispherical dome (Figure 7). Hold the tube at its proximal end between your fingers and thumb of one hand. With the other hand, while pulling on the blue threads, slowly advance the rod forward to adjust the position of the IUS. When the IUS tips are in the correct position (slightly protruding), pinch and hold the proximal end of the tube firmly to maintain rod position. The proximal end of the insertion tube will be approximately at the top of the first indent on the rod (Figure 7). Figure 7: Final IUS Positioning ENSURE A HEMISPHERICAL DOME IS ACHIEVED. When the IUS is in the correct position, the lower end of the tube will be aligned approximately at the upper edge of the upper indent on the rod. Step 7 Check to make sure the IUS is correctly loaded. You should note the following: The IUS is completely within the insertion tube with the knobs of the arms forming a hemispherical dome at the top of the tube. The top of the rod is touching the bottom of the IUS. The blue threads are hanging through the end of the insertion tube. The flange is marking the depth of the uterus based on pre-insertion sounding. Step 8 Remove the loaded IUS insertion tube from the pouch while holding the lower end of the tube firmly between your fingers and thumb. If not using sterile gloves, do not touch the flange and any part of the insertion tube above the flange during this step and through the IUS insertion procedure. IUS Insertion into the Uterus Step 1 Apply gentle traction on the tenaculum to straighten the alignment of the cervical canal and uterine cavity. While still firmly pinching the proximal end of the insertion tube to maintain the IUS in the correct position (Hand A), slide the loaded IUS insertion tube through the cervical canal until the upper edge of the flange is approximately 1.5 – 2.0 cm from the cervix (Figure 8). DO NOT advance flange to the cervix at this step. DO NOT force the inserter. If necessary, dilate the cervical canal. Figure 8: While holding the rod and the tube, advance into the uterine cavity. Advance to 1.5 – 2.0 cm from the cervix. Figure 9: Hold the rod still and pull back the tube until the second indent on the rod. Step 2 Release hold on the tenaculum. Hold the insertion tube with the fingers of one hand (Hand A) and the rod with the fingers of the other hand (Hand B). Hold the rod still (Hand B), relax the firmness of the pinch on the tube, and pull the insertion tube back with Hand A to the edge of the second indent of the rod (Figure 9). This will allow the IUS arms to open in the lower uterine segment. Step 3 Wait 10 – 15 seconds for the arms of the IUS to fully open. Step 4 Apply gentle traction with the tenaculum before advancing the IUS. With Hand A still holding the proximal end of the tube, advance both the insertion tube and rod simultaneously up to the uterine fundus (Figure 10). You will feel slight resistance when the IUS is at the fundus. The flange should be touching the cervix when the IUS reaches the uterine fundus. Note: Fundal positioning is important to prevent expulsion. Figure 10: After 10 – 15 seconds, advance to the fundus while holding both the rod and the tube. Step 5 Hold the rod still (Hand B) while pulling the insertion tube back with Hand A to the ring of the rod (Figure 11). Figure 11: Hold the rod still and pull back the tube to the ring on the rod. Step 6 While holding the inserter tube with Hand A, withdraw the rod from the insertion tube all of the way out to prevent the rod from catching on the knot at the lower end of the IUS. Note: Ensure the tube is held firmly in place until the rod is completely pulled outside of the tube as there will be some slight resistance while removing the rod from the tube. Step 7 Completely remove the insertion tube. Step 8 Use blunt-tipped sharp scissors to cut the IUS threads perpendicular to the thread length, leaving about 3 cm outside of the cervix (Figure 12). Note: Cutting threads at an angle may leave sharp ends. Do not apply tension or pull on the threads when cutting to prevent displacing the IUS. Figure 12: 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: Check insertion with an ultrasound or other appropriate radiologic test. If incorrect insertion is suspected, remove LILETTA. A removed LILETTA must not be reinserted. Difficult insertion If insertion is difficult because the uterus cannot be appropriately instrumented, the following measures can be considered: 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. 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 perforation. Patient Counseling And Record-Keeping Keep a copy of the consent form and LILETTA lot number for your records. Counsel the patient on what to expect following LILETTA insertion. Give her the Patient Information Booklet, which includes the website address (www.LILETTA.com). Discuss expected bleeding patterns with LILETTA use. Review the signs and symptoms of LILETTA expulsion. [See PATIENT INFORMATION] Prescribe analgesics, if indicated. Patient Follow-Up Re-examine and evaluate patients 4 to 6 weeks after insertion and once a year thereafter, or more frequently if clinically indicated. Removal Of LILETTA Timing 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]. Counsel your patient that if she has intercourse in the week prior to removal without use of a backup contraceptive method, she is at risk of pregnancy. LILETTA should be removed after 3 years. LILETTA can be replaced at the time of removal with a new LILETTA if continued contraceptive protection is desired. Planning for Removal Ensure all needed items for LILETTA removal are readily available: Gloves Speculum Sterile forceps Additional items that may be required could include: Local anesthetic, needle, and syringe Os finder and/or cervical dilators Ultrasound with abdominal probe Sterile tenaculum Antiseptic solution Long, narrow forceps 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. Removal Instructions 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 13). The arms of the device will fold upward as it is withdrawn from the uterus. If the IUS cannot be removed with traction on the threads, perform an ultrasound examination to confirm location of the IUS, including assessment for partial or total perforation. If the IUS is in the uterus, use a long, narrow forceps to grasp LILETTA. Consider use of a tenaculum, cervical anesthesia, cervical dilators, and/or ultrasound guidance as needed. If the threads of LILETTA are not visible: Determine location of the IUS by ultrasound examination. If the IUS is in the uterine cavity, use 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. Figure 13: Removal of LILETTA Continuation Of Contraception After Removal If pregnancy is not desired and if a woman wishes to continue using LILETTA, 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 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 and spermicide) or abstain from vaginal intercourse for 7 days to prevent pregnancy. HOW SUPPLIED 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. Storage And Handling LILETTA (levonorgestrel-releasing intrauterine system), containing 52 mg levonorgestrel, is packaged together with an inserter in a peelable pouch, and is available in a carton of one sterile unit. NDC # 52544-035-54. LILETTA is supplied sterile. LILETTA is sterilized with ethylene oxide. Do not resterilize. For single use only. Do not use if the inner pouch is damaged or opened. Insert before the end of the month shown on the pouch. Store at 20 – 25°C (68 – 77°F), with excursions permitted between 15 – 30°C (59 – 86°F) [See USP Controlled Room Temperature]. Store pouch in outer carton until use to protect from light. Manufactured by: Odyssea Pharma, Belgium an affiliated company of Actavis Pharma, inc. Distributed by: Actavis Pharma, inc. Parsippany, NJ 07054. Marketed by: Actavis Pharma, inc. Medicines360 Parsippany, NJ 07054 San Francisco, Ca 94111. Revised: February 2015

PATIENT INFORMATION Skyla (sky-lah) (levonorgestrel-releasing) Intrauterine System Skyla does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs). 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. 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 had a child. Skyla is a small, flexible plastic T-shaped system that slowly releases a progestin hormone called levonorgestrel that is often used in birth control pills. Because Skyla releases levonorgestrel 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 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 Skyla is 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 long-term use 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. 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), 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 Who should not use Skyla? Do not use Skyla if you: Are or might be pregnant; Skyla cannot be used as an emergency contraceptive Have had a serious pelvic infection called pelvic inflammatory disease (PID) unless you have had a normal pregnancy after the infection went away Have an untreated pelvic 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 Problems with your immune system Intravenous drug abuse 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 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 if you: 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 if you are breastfeeding Have severe migraine headaches How is Skyla placed? Skyla is placed by your healthcare provider during an in-office visit. 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 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. Placement takes only a few minutes. 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 once a month. Your healthcare provider should tell 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. Use non-hormonal back-up birth control (such as condoms and 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 with Skyla? Tampons may be used with Skyla. What if I become pregnant while using Skyla? Call your healthcare provider right away if you think you are pregnant. 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. 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. It is not known if Skyla can cause long-term effects on the fetus if it stays in place during a pregnancy. 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. After you have used Skyla for a while, the number of bleeding and spotting days is likely to lessen. There is a small chance that your periods will stop altogether. Is it safe to breastfeed while using Skyla? You may use Skyla when you are breastfeeding if more than six weeks have passed since you had your baby. If 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 among women using progestin-only birth control pills. The risk of Skyla becoming attached to (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 feels the threads. If this occurs, 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. What are the possible side effects of Skyla? Skyla can cause serious side effects, including: 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 have 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. A hysterectomy (removal of the uterus) is sometimes needed. 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, or fever. 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. Perforation. Skyla may become attached to (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. The risk of perforation is increased if Skyla is inserted while you are breastfeeding. 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. Expulsion. Skyla may come out by itself. This is called expulsion. Expulsion occurs in about 3 out of 100 women. You may become pregnant if Skyla comes out. If you think that Skyla has come out, use a backup birth control method like condoms and spermicide and call your healthcare provider. Missed menstrual periods. About 1 out of 16 women stop having periods after 1 year of Skyla use. If you do not have a period for 6 weeks during Skyla use, call your healthcare provider. When Skyla is removed, your menstrual periods will come back. 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. 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 a month or two. However, cysts can cause pain and sometimes cysts will need surgery. This is not a complete list of 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 the manufacturer at 1-888-842-2937, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. After Skyla has been placed, when should I call my 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 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) 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 Or your partner becomes HIV positive Have severe vaginal bleeding or bleeding that lasts a long time General advice about prescription medicines Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. This leaflet summarizes the most important information about Skyla. 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 health providers. 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.

PATIENT INFORMATION Mirena® (mur-a-nah) (levonorgestrel-releasing) Intrauterine System Mirena does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs). Read this Patient Information carefully before you decide if Mirena 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 Mirena, ask your healthcare provider. You should also learn about other birth control methods to choose the one that is best for you. What is Mirena? Mirena is a hormone-releasing system placed in your uterus by your healthcare provider to prevent pregnancy for up to 5 years. Mirena can also lessen menstrual blood loss in women who have heavy menstrual flow and who also want to use a birth control method that is placed in the uterus to prevent pregnancy. Mirena can be removed by your healthcare provider at any time. Mirena is recommended for women who have had at least one child. Mirena is a small flexible plastic T-shaped system that slowly releases a progestin hormone called levonorgestrel that is often used in birth control pills. Because Mirena releases levonorgestrel into your uterus, only small amounts of the hormone enter your blood. Mirena does not contain estrogen. Two thin threads are attached to the stem of Mirena. The threads are the only part of Mirena you can feel when Mirena is in your uterus; however, unlike a tampon string, the threads do not extend outside your body. Mirena is small and flexible What if I need birth control for more than 5 years? Mirena must be removed after 5 years. Your healthcare provider can place a new Mirena during the same office visit if you choose to continue using Mirena. What if I want to stop using Mirena? Mirena is intended for long-term use but you can stop using Mirena at any time by asking your healthcare provider to remove it. You could become pregnant as soon as Mirena is removed, so you should use another method of birth control if you do not want to become pregnant. What if I change my mind about birth control and want to become pregnant in less than 5 years? Your healthcare provider can remove Mirena at any time. You may become pregnant as soon as Mirena is removed. About 8 out of 10 women who want to become pregnant will become pregnant sometime in the first year after Mirena is removed. How does Mirena work? Mirena 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. Mirena can cause your menstrual bleeding to be less by thinning the lining of the uterus. How well does Mirena 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. Mirena, an intrauterine device (IUD), is in the box at the top of the chart. How well does Mirena work for heavy menstrual bleeding? In the clinical trial performed in women with heavy menstrual bleeding and treated with Mirena, almost 9 out of 10 were treated successfully and their blood loss was reduced by more than half. Who might use Mirena? You might choose Mirena 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 Have had at least one child Want treatment for heavy periods and are willing to use a birth control method that is placed in the uterus Want birth control that does not contain estrogen Who should not use Mirena? Do not use Mirena if you: Are or might be pregnant; Mirena cannot be used as an emergency contraceptive Have had a serious pelvic infection called pelvic inflammatory disease (PID) unless you have had a normal pregnancy after the infection went away Have an untreated pelvic 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 Problems with your immune system Intravenous drug abuse. 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 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, silica, barium sulfate or iron oxide Before having Mirena placed, tell your healthcare provider if you: 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 if you are breastfeeding Have severe migraine headaches. How is Mirena placed? Mirena is placed by your healthcare provider during an in-office visit. 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 Mirena into your uterus. Your healthcare provider will then remove the plastic tube, and leave Mirena in your uterus. Your healthcare provider will cut the threads to the right length. Placement takes only a few minutes. You may experience pain, bleeding or dizziness during and after placement. If your symptoms do not pass within 30 minutes after placement, Mirena may not have been placed correctly. Your healthcare provider will examine you to see if Mirena needs to be removed or replaced. Should I check that Mirena is in place? Yes, you should check that Mirena is in proper position by feeling the removal threads. It is a good habit to do this once a month. Your healthcare provider should tell you how to check that Mirena 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, Mirena may not be in the right position and may not prevent pregnancy. Use non-hormonal back-up birth control (such as condoms and spermicide) and ask your healthcare provider to check that Mirena is still in the right place. How soon after placement of Mirena 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 Mirena is placed to make sure that Mirena is in the right position. Can I use tampons with Mirena? Tampons may be used with Mirena. What if I become pregnant while using Mirena? Call your healthcare provider right away if you think you are pregnant. If you get pregnant while using Mirena, 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 Mirena 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 Mirena, even though removing it may cause a miscarriage. If Mirena cannot be removed, talk with your healthcare provider about the benefits and risks of continuing the pregnancy. 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. It is not known if Mirena can cause long-term effects on the fetus if it stays in place during a pregnancy. How will Mirena 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. After you have used Mirena for a while, the number of bleeding and spotting days is likely to lessen. There is a small chance that your periods will stop altogether. In some women with heavy bleeding, the total blood loss per cycle progressively decreases with continued use. The number of spotting and bleeding days may initially increase but then typically decreases in the months that follow. Is it safe to breastfeed while using Mirena? You may use Mirena when you are breastfeeding if more than six weeks have passed since you had your baby. If you are breastfeeding, Mirena 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 women using progestin-only birth control pills. The risk of Mirena becoming attached to (embedded) or going through the wall of the uterus is increased if Mirena is inserted while you are breastfeeding. Will Mirena interfere with sexual intercourse? You and your partner should not feel Mirena during intercourse. Mirena is placed in the uterus, not in the vagina. Sometimes your partner feels the threads. If this occurs, talk with your healthcare provider. What are the possible side effects of using Mirena? Mirena can cause serious side effects including: 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 have 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. A hysterectomy (removal of the uterus) is sometimes needed. 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, or fever. Life-threatening infection. Life-threatening infection can occur within the first few days after Mirena is placed. Call your healthcare provider immediately if you develop severe pain or fever shortly after Mirena is placed. Perforation. Mirena may become attached to (embedded) or go through the wall of the uterus. This is called perforation. If this occurs, Mirena may no longer prevent pregnancy. If perforation occurs, Mirena may move outside the uterus and can cause internal scarring, infection, or damage to other organs, and you may need surgery to have Mirena removed. The risk of perforation is increased if Mirena is inserted while you are breastfeeding. Common side effects of Mirena include: Pain, bleeding or dizziness during and after placement. If these symptoms do not stop 30 minutes after placement, Mirena may not have been placed correctly. Your healthcare provider will examine you to see if Mirena needs to be removed or replaced. Expulsion. Mirena may come out by itself. This is called expulsion. You may become pregnant if Mirena comes out. If you think that Mirena has come out, use a backup birth control method like condoms and spermicide and call your healthcare provider. Missed menstrual periods. About 2 out of 10 women stop having periods after 1 year of Mirena use. If you do not have a period for 6 weeks during Mirena use, call your healthcare provider. When Mirena is removed, your menstrual periods will come back. 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. 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. Cysts on the ovary. About 12 out of 100 women using Mirena develop a cyst on the ovary. These cysts usually disappear on their own in a month or two. However, cysts can cause pain and sometimes cysts will need surgery. This is not a complete list of possible side effects with Mirena. For more information, ask your healthcare provider. Call your doctor for medical advice about side effects. You may report side effects to the manufacturer at 1-888-842-2937, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. After Mirena has been placed, when should I call my healthcare provider? Call your healthcare provider if you have any concerns about Mirena. Be sure to call if you: Think you are pregnant Have pelvic 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) Cannot feel Mirena'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 Or your partner becomes HIV positive Have severe vaginal bleeding or bleeding that lasts a long time General advice about prescription medicines Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. This leaflet summarizes the most important information about Mirena. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about Mirena that is written for health providers. For more information, go to www.mirena-us.com or call 1-888-842-2937

PATIENT INFORMATION LILETTA (lye-LET-uh) (levonorgestrel-releasing) Intrauterine System LILETTA does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIS). 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 provider who specializes in women's health. if you have any questions about LILETTA, ask your healthcare provider. You should also learn about other birth control methods to choose the one that is best for you. What is LILETTA? LILETTA is a hormone-releasing system inserted in your uterus by your healthcare provider to prevent pregnancy for up to 3 years. LILETTA can be removed by your healthcare provider 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 should feel when LILETTA is in your uterus; however, unlike a tampon string, the threads do not extend outside your body. What if I need birth control for more than 3 years? LILETTA must be removed after 3 years. Your healthcare provider can insert a new LILETTA during the same office visit if you choose to continue using LILETTA. What if I want to stop using LILETTA? LILETTA is intended for use up to 3 years, but you can stop using LILETTA at any time by asking your healthcare provider 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. Discuss your options with your healthcare provider, because certain methods should be started 7 days before LILETTA is removed to ensure continued birth control. What if I change my mind about birth control and want to become pregnant in less than 3 years? Your healthcare provider can remove LILETTA at any time. You could become pregnant as soon as LILETTA is removed. About 5 out of 6 women who want to become pregnant will become pregnant sometime in the first year after LILETTA is removed. How does LILETTA work? LILETTA may work in several ways including by 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 LILETTA 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. LILETTA, an intrauterine system (IUS), is in the box at the top of the chart. Who might use LILETTA? You might choose LILETTA if you: want birth control that provides a low chance of getting pregnant (less than 1 in 100) want birth control that works continuously for up to a maximum of 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 inserted in the uterus want birth control that does not contain estrogen Who should not use LILETTA? Do not use LILETTA if you: are or might be pregnant; LILETTA cannot be used as an emergency contraceptive have had a serious pelvic infection called pelvic inflammatory disease (PID) unless you have had a normal pregnancy after the infection went away have an untreated pelvic 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 problems with your immune system have multiple sexual partners or your partner has multiple sexual partners 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 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 system 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, or barium sulfate Before having LILETTA inserted, tell your healthcare provider if you: 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 if you are breastfeeding have severe migraine headaches are or might be pregnant have acute pelvic inflammatory disease or a history of pelvic inflammatory disease have AIDS, HIV, or any other sexually transmitted infection have any other medical conditions Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How is LILETTA inserted? LILETTA is inserted by your healthcare provider during an in-office visit. 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 LILETTA into your uterus. Your healthcare provider will then remove the plastic tube, and leave LILETTA in your uterus. Your healthcare provider will trim the threads to the right length. insertion takes only a few minutes. You may experience pain, bleeding, or dizziness during and after insertion. If your symptoms do not pass within 30 minutes after insertion, LILETTA may not have been inserted correctly. Your healthcare provider 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 provider 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 spermicide) and ask your healthcare provider to check that LILETTA is still in the right place. If LILETTA is accidentally removed and you had vaginal intercourse within the preceding24 hours, you may be at risk of pregnancy, and should talk to a healthcare provider. How soon after insertion of LILETTA 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 LILETTA is inserted to make sure that LILETTA is in the right position. Can I use tampons with LILETTA? Tampons may be used with LILETTA. What if I become pregnant while using LILETTA? Call your healthcare provider right away if you think you are pregnant. 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 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 delivery, and even death can occur with pregnancies that continue with an intrauterine system (IUS). Because of this, your healthcare provider may try to remove LILETTA, even though removing it may cause a miscarriage. If LILETTA cannot be removed, talk with your healthcare provider about the benefits and risks of continuing the pregnancy. 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. 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. Some women 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 women, menstrual periods will stop altogether. When LILETTA is removed, your menstrual periods will likely return to their former pattern. if you have any concerns that you may be pregnant while using LILETTA, do a urine pregnancy test or call your healthcare provider. is it safe to breastfeed while using LILETTA? You may use LILETTA when you are breastfeeding if more than 6 weeks have passed since you had your baby. if 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 women using progestin-only birth control pills. Will LILETTA interfere with sexual intercourse? You and your partner should not feel LILETTA during intercourse. LILETTA is inserted 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 provider. Can I have an MRI with LILETTA in place? LILETTA is MR Safe. it is safe to have an MRI following LILETTA insertion. What are the possible side effects of LILETTA? LILETTA can cause serious side effects, including: 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 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 delivery, and even death can occur with pregnancies that continue with an intrauterine system (IUS). Because of this, your healthcare provider may try to remove LILETTA, even though removing it may cause a miscarriage. If LILETTA cannot be removed, talk with your healthcare provider about the benefits and risks of continuing the pregnancy. If, after seeing your healthcare provider, you choose to 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. 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 inserted. Call your healthcare provider immediately if you develop severe pain or fever shortly after LILETTA is inserted. pelvic inflammatory disease (PID). Some IUS users get a serious pelvic infection called pelvic inflammatory disease (PID). 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. Removal of the uterus (hysterectomy) is sometimes needed. 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 pain, painful sex, chills, or fever. perforation. LILETTA may become attached to (embedded) or go through the wall of the uterus. This is called perforation (or embedment). 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 perforation or embedment occurs. The risk of perforation is increased in breastfeeding women. expulsion. LILETTA may come out of your uterus. This is called expulsion. Expulsion occurs in about 3 out of 100 women. You may become pregnant if LILETTA comes out. if you think that LILETTA has come out, use another birth control method like condoms and spermicide or do not have sex (vaginal intercourse) until you are seen by a healthcare provider. The most common side effects of LILETTA include: vaginal infection infection of the outer part of your vagina (vulvovaginal) acne headache nausea/vomiting pain during sex abdominal pain breast pain pelvic pain depression mood changes Pain, bleeding, or dizziness during and after insertion. If these symptoms do not stop within 30 minutes after insertion, LILETTA may not have been inserted correctly. Your healthcare provider will examine you to see if LILETTA needs to be removed or replaced. Missed menstrual periods. About 1 out of 5 women 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 or call your healthcare provider. When LILETTA is removed, your menstrual periods will usually return to your previous pattern. 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. 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. Cysts on the ovary. Some women using LILETTA develop a painful cyst on the ovary. These cysts usually disappear on their own in 2 to 3 months. However, a cyst can cause pain and sometimes cysts will need surgery. This is not a complete list of possible side effects with LILETTA. For more information, ask your healthcare provider. Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all the possible side effects of LILETTA. For more information, ask your healthcare provider or pharmacist. Call your healthcare provider 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 Actavis at (800) 272-5525. After LILETTA has been inserted, when should I call my healthcare provider? Call your healthcare provider if you have any concerns about LILETTA. Be sure to call if you: think you are pregnant have pelvic 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 the IUS may have been expelled (came out) cannot feel LILETTA'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 you or your partner becomes HIV positive have severe vaginal bleeding or bleeding that concerns you 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. This leaflet summarizes the most important information about LILETTA. if you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider 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). This Patient information has been approved by the U.S. Food and Drug administration.

SIDE EFFECTS The following serious or otherwise important adverse reactions are discussed elsewhere in the labeling: Ectopic Pregnancy [see WARNINGS AND PRECAUTIONS] Intrauterine Pregnancy [see WARNINGS AND PRECAUTIONS] Group A Streptococcal Sepsis (GAS) [see WARNINGS AND PRECAUTIONS] Pelvic Inflammatory Disease [see WARNINGS AND PRECAUTIONS] Bleeding Pattern Alterations [see WARNINGS AND PRECAUTIONS] Perforation [see WARNINGS AND PRECAUTIONS] Expulsion [see WARNINGS AND PRECAUTIONS] Ovarian Cysts [see WARNINGS AND PRECAUTIONS] 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 3 by SOC (presented as crude incidences). Table 3: 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 cysta 13.2 Dysmenorrhoea 8.6 Increased bleeding b 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/Seborrhoea 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 a Ovarian cysts were reported as AEs 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]. Postmarketing Experience The following adverse reactions have been identified during post approval use of a LNG-releasing IUS. 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 Device breakage DRUG INTERACTIONS No drug-drug interaction studies have been conducted with Skyla. Drugs or herbal products that induce enzymes, including CYP3A4, that metabolize progestins may decrease the serum concentrations of progestins. Some drugs or herbal products that may decrease the serum concentration of LNG include: Barbiturates Bosentan Carbamazepine Efavirenz Felbamate Griseofulvin Nevirapine Oxcarbazepine Phenytoin Rifabutin Rifampin St. John’s wort Topiramate Significant changes (increase or decrease) in the serum concentrations of the progestin have been noted in some cases of co-administration with HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels. Consult the labeling of all concurrently used drugs to obtain further information about interactions with Skyla or the potential for enzyme alterations.

SIDE EFFECTS The following serious or otherwise important adverse reactions are discussed in elsewhere in the labeling: Ectopic Pregnancy [see WARNINGS AND PRECAUTIONS] Intrauterine Pregnancy [see WARNINGS AND PRECAUTIONS] Group A Streptococcal Sepsis (GAS) [see WARNINGS AND PRECAUTIONS] Pelvic Inflammatory Disease [see WARNINGS AND PRECAUTIONS] Alterations of Bleeding Patterns [see WARNINGS AND PRECAUTIONS] Perforation [see WARNINGS AND PRECAUTIONS] Expulsion [see WARNINGS AND PRECAUTIONS] Ovarian Cysts [see WARNINGS AND PRECAUTIONS] Clinical Trials Experience Because clinical trials 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 trials of another drug and may not reflect the rates observed in practice. The data provided reflect the experience with the use of Mirena in the adequate and well-controlled studies as well as in the supportive and uncontrolled studies for contraception and heavy menstrual bleeding (n=5,091). The data cover more than 12,101 women-years of exposure, mainly in the contraception studies (11,761 women-years). The frequencies of reported adverse drug reactions represent crude incidences. The most common adverse reactions ( ≥ 10% users) are alterations of menstrual bleeding patterns [including unscheduled uterine bleeding (31.9%), decreased uterine bleeding (23.4%), increased scheduled uterine bleeding (11.9%), and female genital tract bleeding (3.5%)], abdominal/pelvic pain (22.6%), amenorrhea (18.4%), headache/migraine (16.3%), genital discharge (14.9%), and vulvovaginitis (10.5%). Adverse reactions reported in ≥ 5% of users are shown in Table 1. Table 1 : Adverse Reactions ≥ 5% Reported in Clinical Trials with Mirena System Organ Class Adverse Reactions % (N= 5,091) Reproductive system and breast disorders alteration of menstrual bleeding pattern, including: unscheduled uterine bleeding 31.9 decreased uterine bleeding 23.4 increased scheduled uterine bleeding 11.9 female genital tract bleeding 3.5 amenorrhea 18.4 genital discharge 14.9 vulvovaginitis 10.5 breast pain 8.5 benign ovarian cyst and associated complications 7.5 dysmenorrhea 6.4 Gastrointestinal disorders abdominal/pelvic pain 22.6 Nervous system disorders headache/migraine 16.3 Musculoskeletal and connective tissue disorders back pain 7.9 Skin and subcutaneous tissue disorders acne 6.8 Psychiatric disorders depression/depressive mood 6.4 Other adverse reactions occurring in < 5% of subjects include alopecia, (partial and complete) device expulsion, hirsutism, nausea, and PID/endometritis. Postmarketing Experience The following adverse reactions have been identified during post approval use of Mirena. 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 Device breakage Hypersensitivity (including rash, urticaria and angioedema) Increased blood pressure DRUG INTERACTIONS No drug-drug interaction studies have been conducted with Mirena. Drugs or herbal products that induce enzymes, including CYP3A4, that metabolize progestins may decrease the serum concentrations of progestins. Some drugs or herbal products that may decrease the serum concentration of LNG include: Barbiturates Bosentan Carbamazepine Efavirenz Felbamate Griseofulvin Nevirapine Oxcarbazepine Phenytoin Rifabutin Rifampin St. John's wort Topiramate Significant changes (increase or decrease) in the serum concentrations of the progestin have been noted in some cases of co-administration with HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels. Consult the labeling of all concurrently used drugs to obtain further information about interactions with Mirena or the potential for enzyme alterations.

SIDE EFFECTS The following serious or otherwise important adverse reactions are discussed elsewhere in the labeling: Ectopic Pregnancy [see WARNINGS AND PRECAUTIONS] Intrauterine Pregnancy [see WARNINGS AND PRECAUTIONS] Group A Streptococcal Sepsis (GAS) [see WARNINGS AND PRECAUTIONS] Pelvic Inflammatory Disease or Endometritis [see WARNINGS AND PRECAUTIONS] Perforation [see WARNINGS AND PRECAUTIONS] Expulsion [see WARNINGS AND PRECAUTIONS] Ovarian Cysts [see WARNINGS AND PRECAUTIONS] Bleeding Pattern Alterations [see WARNINGS AND PRECAUTIONS] Clinical Trial 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 practice. The data described below reflect exposure of 1,751 generally healthy 16- to 45-year-old women to LILETTA in a large, multi-center contraceptive trial conducted in the US, including 1,412 exposed for 1 year and 383 subjects who completed 3 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 women who received LILETTA were Caucasian (78.4%) or Black/African American (13.3%); 14.7% of women were of Hispanic ethnicity. The clinical trial had no upper or lower weight or BMI limit. Mean BMI of LILETTA subjects was 26.9 kg/m² (range 15.8 – 61.6 kg/m²); 25.1% had a BMI ≥ 30 kg/m², and 5.3% had a BMI ≥ 40 kg/m². The data cover more than 22,000 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 trial (occurring in ≥ 5% users) are shown in Table 3. Table 3: Adverse Reactions in ≥ 5% of LILETTA Users in Phase 3 Clinical Study System Organ Class/ Preferred Term % LILETTA Subjects (N = 1,751) Vaginal infections 13.6% Vulvovaginal infections 13.3% Acne 12.3% Headache or migraine 9.8% Nausea or vomiting 7.9% Dyspareunia 7.0% Abdominal discomfort or pain 6.8% Breast tenderness or pain 6.7% Pelvic discomfort or pain 6.1% Depression or depressed mood 5.4% Mood changes 5.2% In the contraceptive trial, 12.3% of LILETTA users discontinued prematurely due to an adverse reaction. The most common adverse reaction leading to discontinuation was expulsion (3.5%), bleeding complaints (a total of 1.5%). The next most common adverse reactions causing discontinuation were acne (1.3%), mood swings (1.3%), dysmenorrhea (0.6%), and uterine spasm (0.6%). Two women discontinued the clinical study due to PID and one due to endometritis. In the clinical trial, serious adverse reactions included: suicidality and exacerbations of depression and bipolar disorder, ectopic pregnancy, ovarian cysts, and IUS perforation requiring a laparoscopic surgery. Postmarketing Experience The following adverse reactions have been identified during post-approval use of other 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. Hypersensitivity including rash, urticaria, and angioedema Device Breakage DRUG INTERACTIONS No drug-drug interaction studies have been conducted with LILETTA. 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.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS 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 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 periods 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. 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 IUD 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. Follow her pregnancy closely and advise her to report immediately any symptom that suggests complications of the pregnancy. Long-Term Effects And Congenital Anomalies When pregnancy continues with Skyla in place, long-term effects on the offspring are unknown. With a LNG-releasing IUS, congenital anomalies in live births have occurred infrequently. No clear trend towards specific anomalies has been observed. Because of the local exposure of the fetus to LNG, the possibility of teratogenicity following exposure to Skyla cannot be completely excluded. Some observational data support a small increased risk of masculinization of the external genitalia of the female fetus following exposure to progestins at doses greater than those currently used for oral contraception. Whether these data apply to Skyla is unknown. 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. 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]. IUDs have been associated with an increased risk of PID, most likely due to organisms being introduced into the uterus during insertion.1 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, and Skyla does not protect against sexually transmitted infection. 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], IV drug abuse). Asymptomatic 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. Guidelines for PID treatment are available from the Centers for Disease Control (CDC), Atlanta, Georgia. Actinomycosis Actinomycosis has been associated with IUDs. Symptomatic women should have Skyla removed and should receive 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. 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. Amenorrhea develops by the end of the first year of use in approximately 6% of Skyla users. In Skyla clinical trials, a total of 77 subjects out of 1,672 (4.6%) discontinued due to uterine bleeding complaints. Table 1 shows the bleeding patterns as documented in the Skyla clinical trials based on 90-day reference periods. Table 2 shows the number of bleeding and spotting days based on 28-day cycle equivalents. Table 1: 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 Amenorrhea1 <1% 3% 6% 12% Infrequent bleeding2 8% 19% 20% 22% Frequent bleeding3 31% 12% 8% 4% Prolonged bleeding4,6 55% 14% 6% 2% Irregular bleeding5,6 39% 25% 18% 15% 1Defined as subjects with no bleeding/spotting throughout the 90-day reference period 2Defined as subjects with 1 or 2 bleeding/spotting episodes in the 90-day reference period 3Defined as subjects with more than 5 bleeding/spotting episodes in the 90-day reference period 4Defined 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) 5Defined as subjects with 3 to 5 bleeding/spotting episodes and less than 3 bleeding/spotting-free intervals of 14 or more days 6Subjects with irregular and prolonged bleeding may also be included in one of the other categories (excluding amenorrhea) Table 2: 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 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. If a significant change in bleeding develops during prolonged use, take appropriate diagnostic measures to rule out endometrial pathology. The possibility of pregnancy should be considered 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. 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. Perforation may reduce contraceptive efficacy and result in pregnancy. The incidence of perforation during clinical trials was < 0.1%. 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. The risk of perforation may be increased if Skyla is inserted when the uterus is fixed retroverted or not completely involuted. Delay Skyla insertion a minimum of six weeks or until involution is complete following a delivery or a second trimester abortion. Clinical trials with Skyla excluded breast-feeding women. A large postmarketing safety study conducted in Europe over a 1-year observational period reported that lactation at the time of insertion of an IUD/IUS was associated with an increased risk of perforation. For users of another LNG-releasing IUS, the incidence of uterine perforation was reported as 6.3 per 1,000 insertions for lactating women, compared to 1.0 per 1,000 insertions for non-lactating women. Expulsion Partial or complete expulsion of Skyla may occur resulting in the loss of contraceptive protection. 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. The risk of expulsion may be increased when the uterus is not completely involuted. In clinical trials, a 3-year expulsion rate of 3.2% (54 out of 1665 subjects) was reported. Delay Skyla insertion a minimum of six weeks or until uterine involution is complete following a delivery or a second trimester abortion. Remove a partially expelled Skyla. If expulsion has occurred, Skyla may be replaced within 7 days after the onset of a menstrual period, after pregnancy has been ruled out. 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. During clinical trials, 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 in 13.2% of women using Skyla. Most of these 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. Breast Cancer Women who currently have or have had breast cancer, or have a suspicion of breast cancer, should not use hormonal contraception because some breast cancers are hormone-sensitive [see CONTRAINDICATIONS]. 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. 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 [see CONTRAINDICATIONS]: 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 Perforation, Expulsion ]. 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. Magnetic Resonance Imaging (MRI) Information Non-clinical testing has demonstrated that Skyla is MR Conditional. Skyla can be safely scanned only under specific conditions: Static magnetic field of 3 Tesla or less Spatial gradient field of 36,000 Gauss/cm (T/m) or less Maximum whole body averaged specific absorption rate (SAR) of 4W/kg in the First Level Controlled mode for 15 minutes of continuous scanning In non-clinical testing, the Skyla produced a temperature rise of less than 1.8°C at a maximum whole body averaged specific absorption rate (SAR) of 2.9 W/kg, for 15 minutes of MR scanning at 3T using a transit/receive body coil. MR Image quality may be compromised (that is, a small amount of artifact may occur) if the area of interest is in the exact same area or relatively close to the position of Skyla. Image artifact extended up to 5 mm from Skyla in a Gradient Echo pulse sequence. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION) Sexually Transmitted Infections: Counsel the patient that this product does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs). Risk of Ectopic Pregnancy: Inform 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] Pregnancy or Suspected Pregnancy: Counsel the patient to inform her healthcare provider if she determines or suspects she is pregnant with Skyla in place. Pelvic Infection: Inform the patient about the possibility of pelvic inflammatory disease (PID) and that PID can cause tubal damage leading to ectopic pregnancy or infertility, or infrequently can necessitate hysterectomy, or cause death. Teach the patient to recognize and report to her healthcare provider promptly any symptoms of PID. 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] Bleeding Pattern Alterations: Counsel the patient that irregular or prolonged bleeding and spotting, and/or cramps may occur during the first few weeks after insertion. If her symptoms continue or are severe she should report them to her healthcare provider. [See WARNINGS AND PRECAUTIONS] Perforation and Expulsion: Counsel 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. 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. [See WARNINGS AND PRECAUTIONS] Clinical Considerations for Use and Removal: Instruct 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 or pain during sex HIV positive seroconversion in herself or her partner Possible exposure to sexually transmitted infections (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) Information: Inform the patient that Skyla can be safely scanned with MRI only under specific conditions [see WARNINGS AND PRECAUTIONS]. Instruct patients who will have an MRI to tell their doctor that they have Skyla. This information is included on the Follow-Up Reminder Card. Complete the Follow-up Reminder Card and give to the patient. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility [See WARNINGS AND PRECAUTIONS.] Use In Specific Populations Pregnancy The use of Skyla during an existing or suspected pregnancy is contraindicated. Many studies have found no harmful effects on fetal development associated with long-term use of contraceptive doses of oral progestins. The few studies of infant growth and development that have been conducted with progestin-only pills have not demonstrated significant adverse effects. [See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS.] Nursing Mothers In general, no adverse effects of progestin-only contraceptives have been found on breastfeeding performance or on the health, growth, or development of the infant. Isolated postmarketing cases of decreased milk production have been reported. Small amounts of progestins were observed to pass into the breast milk of nursing mothers who used a LNG-releasing IUS, resulting in detectable steroid levels in infant serum. [See WARNINGS AND PRECAUTIONS.] 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. Geriatric Use Skyla has not been studied in women over age 65 and is not approved for use in this population. Hepatic Impairment No studies were conducted to evaluate the effect of hepatic disease on the disposition of LNG released from Skyla [see CONTRAINDICATIONS]. Renal Impairment No studies were conducted to evaluate the effect of renal disease on the disposition of LNG released from Skyla.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Ectopic Pregnancy Evaluate women for ectopic pregnancy if they become pregnant with Mirena in place because the likelihood of a pregnancy being ectopic is increased with Mirena. Up to half of pregnancies that occur with Mirena 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 periods or if an amenorrheic woman starts bleeding. The incidence of ectopic pregnancy in clinical trials with Mirena, 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 Mirena 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. Intrauterine Pregnancy If pregnancy occurs while using Mirena, remove Mirena because leaving it in place may increase the risk of spontaneous abortion and preterm labor. Removal of Mirena or probing of the uterus may also result in spontaneous abortion. In the event of an intrauterine pregnancy with Mirena, consider the following: Septic Abortion In patients becoming pregnant with an IUD in place, septic abortion -with septicemia, septic shock, and death -may occur. Continuation Of Pregnancy If a woman becomes pregnant with Mirena in place and if Mirena cannot be removed or the woman chooses not to have it removed, warn her that failure to remove Mirena increases the risk of miscarriage, sepsis, premature labor and premature delivery. Follow her pregnancy closely and advise her to report immediately any symptom that suggests complications of the pregnancy. Long-term Effects And Congenital Anomalies When pregnancy continues with Mirena in place, long-term effects on the offspring are unknown. Congenital anomalies in live births have occurred infrequently. No clear trend towards specific anomalies has been observed. Because of the local exposure of the fetus to LNG, the possibility of teratogenicity following exposure to Mirena cannot be completely excluded. Some observational data support a small increased risk of masculinization of the external genitalia of the female fetus following exposure to progestins at doses greater than those currently used for oral contraception. Whether these data apply to Mirena is unknown. Sepsis Severe infection or sepsis, including Group A streptococcal sepsis (GAS), have been reported following insertion of Mirena. 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 Mirena is essential in order to minimize serious infections such as GAS. Pelvic Infection Pelvic Inflammatory Disease (PID) Mirena 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]. 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, total combined upper genital infections were reported in 3.5% of Mirena users. More specifically, endometritis was reported in 2.1%, PID in 0.6%, and all other upper genital infections in ≤ 0.5% of women overall. These infections occurred more frequently within the first year. In a clinical trial with other IUDs1 and a clinical trial with an IUD similar to Mirena, the highest rate occurred within the first month after insertion. Promptly examine users with complaints of lower abdominal or pelvic pain, odorous discharge, unexplained bleeding, fever, genital lesions or sores. Remove Mirena in cases of recurrent endometritis or PID, 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, and Mirena does not protect against sexually transmitted infection. 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], IV drug abuse). Asymptomatic 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 Mirena after initiation of antibiotic therapy is usually appropriate. Guidelines for PID treatment are available from the Centers for Disease Control (CDC), Atlanta, Georgia. Actinomycosis Actinomycosis has been associated with IUDs. Symptomatic women should have Mirena removed and should receive 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 Mirena removal and treatment. When possible, confirm a Pap smear diagnosis with cultures. Irregular Bleeding And Amenorrhea Mirena can alter the bleeding pattern and result in spotting, irregular bleeding, heavy bleeding, oligomenorrhea and amenorrhea. During the first three to six months of Mirena use, the number of bleeding and spotting days may be increased and bleeding patterns may be irregular. Thereafter the number of bleeding and spotting days usually decreases but bleeding may remain irregular. If bleeding irregularities develop during prolonged treatment, appropriate diagnostic measures should be taken to rule out endometrial pathology. Amenorrhea develops in approximately 20% of Mirena users by one year. The possibility of pregnancy should be considered if menstruation does not occur within six weeks of the onset of 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 [see Clinical Studies]. In most women with heavy menstrual bleeding, the number of bleeding and spotting days may also increase during the initial months of therapy but usually decrease with continued use; the volume of blood loss per cycle progressively becomes reduced [see Clinical Studies]. Perforation Perforation (total or partial, including penetration/embedment of Mirena in the uterine wall or cervix) may occur most often during insertion, although the perforation may not be detected until sometime later. Perforation may reduce contraceptive efficacy and result in pregnancy. The incidence of perforation during clinical trials, which excluded breast-feeding women, was < 0.1%. If perforation occurs, locate and remove Mirena. Surgery may be required. Delayed detection or removal of Mirena in case of perforation may result in migration outside the uterine cavity, adhesions, peritonitis, intestinal perforations, intestinal obstruction, abscesses and erosion of adjacent viscera. The risk of perforation may be increased if Mirena is inserted when the uterus is fixed retroverted or not completely involuted. Delay Mirena insertion a minimum of six weeks or until involution is complete following a delivery or a second trimester abortion. A large postmarketing safety study conducted in Europe over a 1-year observational period reported that lactation at the time of insertion of an IUD/IUS was associated with an increased risk of perforation. For Mirena users, the incidence of uterine perforation was reported as 6.3 per 1,000 insertions for lactating women, compared to 1.0 per 1,000 insertions for non-lactating women. Expulsion Partial or complete expulsion of Mirena may occur resulting in the loss of contraceptive protection. Expulsion may be associated with symptoms of bleeding or pain, or it may be asymptomatic and go unnoticed. Mirena typically decreases menstrual bleeding over time; therefore, an increase of menstrual bleeding may be indicative of an expulsion. The risk of expulsion may be increased when the uterus is not completely involuted. In clinical trials, a 4.5% expulsion rate was reported over the 5-year study duration. Delay Mirena insertion a minimum of six weeks or until uterine involution is complete following a delivery or a second trimester abortion. Remove a partially expelled Mirena. If expulsion has occurred, Mirena may be replaced within 7 days after the onset of a menstrual period, after pregnancy has been ruled out. Ovarian Cysts Because the contraceptive effect of Mirena is mainly due to its local effects within the uterus, ovulatory cycles with follicular rupture usually occur in women of fertile age using Mirena. Sometime atresia of the follicle is delayed and the follicle may continue to grow. Ovarian cysts have been reported in approximately 8% of women using Mirena. Most of these 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. Breast Cancer Women who currently have or have had breast cancer, or have a suspicion of breast cancer, should not use hormonal contraception because some breast cancers are hormone-sensitive [see CONTRAINDICATIONS]. Spontaneous reports of breast cancer have been received during postmarketing experience with Mirena. Observational studies of the risk of breast cancer with use of a LNG-releasing IUS do not provide conclusive evidence of increased risk. Clinical Considerations For Use And Removal Use Mirena 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 Mirena if any of the following conditions arise during use [see CONTRAINDICATIONS]: 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]. Exclude pregnancy and verify the location of Mirena, for example, by sonography, X-ray, or by gentle exploration of the cervical canal with a suitable instrument. If Mirena is displaced, remove it. A new Mirena may be inserted at that time or during the next menses if it is certain that conception has not occurred. If Mirena is in place with no evidence of perforation, no intervention is indicated. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION) Sexually Transmitted Infections: Counsel the patient that this product does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs). Risk of Ectopic Pregnancy: Inform 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] Pregnancy or Suspected Pregnancy: Counsel the patient to inform her healthcare provider if she determines or suspects she is pregnant with Mirena in place. Pelvic Infection: Inform the patient about the possibility of pelvic inflammatory disease (PID) and that PID can cause tubal damage leading to ectopic pregnancy or infertility, or infrequently can necessitate hysterectomy, or cause death. Teach the patient to recognize and report to her healthcare provider promptly any symptoms of PID. 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] Irregular Bleeding and Amenorrhea: Counsel the patient that irregular or prolonged bleeding and spotting, and/or cramps may occur during the first few weeks after insertion. If her symptoms continue or are severe she should report them to her healthcare provider. [See WARNINGS AND PRECAUTIONS] Perforation and Expulsion: Counsel 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. Caution her not to pull on the threads and displace Mirena. Inform her that there is no contraceptive protection if Mirena is displaced or expelled. [See WARNINGS AND PRECAUTIONS] Clinical Considerations for Use and Removal: Instruct 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 or pain during sex HIV positive seroconversion in herself or her partner Possible exposure to sexually transmitted infections (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 Mirena's threads Complete the Follow-up Reminder Card and give to the patient. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility [See WARNINGS AND PRECAUTIONS] Use In Specific Populations Pregnancy The use of Mirena during an existing or suspected pregnancy is contraindicated. Many studies have found no harmful effects on fetal development associated with long-term use of contraceptive doses of oral progestins. The few studies of infant growth and development that have been conducted with progestin-only pills have not demonstrated significant adverse effects. [See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS] Nursing Mothers In general, no adverse effects of progestin-only contraceptives have been found on breastfeeding performance or on the health, growth, or development of the infant. Isolated postmarketing cases of decreased milk production have been reported. Small amounts of progestins were observed to pass into the breast milk of nursing mothers who used Mirena, resulting in detectable steroid levels in infant serum. [See WARNINGS AND PRECAUTIONS] Pediatric Use Safety and efficacy of Mirena 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. Geriatric Use Mirena has not been studied in women over age 65 and is not approved for use in this population. Hepatic Impairment No studies were conducted to evaluate the effect of hepatic disease on the disposition of LNG released from Mirena [see CONTRAINDICATIONS]. Renal Impairment No studies were conducted to evaluate the effect of renal disease on the disposition of LNG released from Mirena. REFERENCES 1Farley T M M, Rosenberg M J, Rowe P J, Chen J, Meirik O. Intrauterine devices and pelvic inflammatory disease: an international perspective. Lancet 1992; 339:785-788.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Ectopic Pregnancy Evaluate women for ectopic pregnancy if they become pregnant with LILETTA in place because the likelihood of a pregnancy being ectopic is increased with LILETTA. Approximately half of pregnancies that occur with LILETTA 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 periods or if an amenorrheic woman starts bleeding. If an ectopic pregnancy is confirmed, LILETTA should be removed. The incidence of ectopic pregnancy in the clinical trial with LILETTA, which excluded women with a history of ectopic pregnancy who did not have a subsequent intrauterine pregnancy, was approximately 0.12 per 100 women-years. The risk of ectopic pregnancy in women who have a history of ectopic pregnancy and use LILETTA is unknown. Women 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. Tell women who choose LILETTA about the risks of ectopic pregnancy, including the loss of fertility. Teach them to recognize and report to their healthcare provider promptly any signs of ectopic pregnancy. 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 abortion In patients becoming pregnant with an IUS in place, septic abortion – with 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. Continuation of pregnancy If a woman becomes pregnant with LILETTA in place and if LILETTA cannot be removed or the woman chooses not to have it removed, warn her 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 that she should report immediately 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. Sepsis Severe infection or sepsis, including Group A streptococcal sepsis (GAS), have been reported following insertion of other 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 in order to minimize serious infections such as GAS. Pelvic Inflammatory Disease Or Endometritis Insertion of LILETTA is contraindicated in the presence of known or suspected PID or endometritis or a history of PID unless there has been a subsequent intrauterine pregnancy [see CONTRAINDICATIONS]. IUSs have been associated with an increased risk of PID, most likely due to organisms being introduced into the uterus during insertion. In the clinical trial with LILETTA, pelvic infection was diagnosed in 0.6% of women. The infection was diagnosed as PID in 0.4% of women and as endometritis in 0.2% of women. About 1/3 of women diagnosed with PID developed the infection within a week of LILETTA insertion, while the remainder were diagnosed more than six months after insertion. The cases of endometritis had onset less than 40 days after LILETTA insertion. Counsel women who receive LILETTA to notify a healthcare provider if they have complaints of lower abdominal or pelvic pain, odorous discharge, unexplained bleeding, fever, or genital lesions or sores. 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. Women 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 women who have multiple sexual partners, and also for women whose sexual partner(s) have multiple sexual partners. Women who have had PID or endometritis 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], IV drug abuse). Asymptomatic PID or endometritis PID or endometritis may be asymptomatic but still result in tubal damage and its sequelae. Treatment of PID or endometritis Following a diagnosis of PID or endometritis, or suspected PID or endometritis, perform appropriate testing for sexually transmitted infection and initiate antibiotic therapy promptly. LILETTA does not need to be removed immediately if the woman needs ongoing contraception (1). In the LILETTA clinical trial, 7 of the 10 women who developed PID or endometritis were successfully treated without removal of LILETTA. Reassess the woman in 48-72 hours. If no clinical improvement occurs, continue antibiotics and consider removal of LILETTA. If the woman wants to discontinue use, remove LILETTA after antibiotics have been started to avoid the potential risk for bacterial spread resulting from the removal procedure. Guidelines for PID or endometritis treatment are available from the Centers for Disease Control (CDC), Atlanta, Georgia (1). Actinomycosis Actinomycosis has been associated with IUS use. Symptomatic women with known actinomycosis infection should have LILETTA removed and receive antibiotics. Actinomycetes can be found in the genital tract cultures in healthy women 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. 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 reduce contraceptive efficacy and result in pregnancy. The incidence of perforation during or following LILETTA insertion in the clinical trial, which excluded breastfeeding women, was 0.1%. If perforation occurs, locate and remove LILETTA. 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. A large post-marketing safety study with other IUSs demonstrated an increased risk of perforation in lactating women. The risk of perforation may be increased if LILETTA is inserted when the uterus is fixed retroverted or not completely involuted during the postpartum period. Delay LILETTA insertion a minimum of six weeks or until involution is complete following a delivery or a second trimester abortion. Expulsion Partial or complete expulsion of LILETTA may occur, resulting in the loss of contraceptive protection. In the clinical trial with LILETTA, an overall expulsion rate of 3.5% was reported, with a rate of 2.0% in nulliparous women and 5.6% in parous women. 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. The risk of expulsion may be increased when the uterus is not completely involuted at the time of insertion. Delay LILETTA insertion a minimum of 6 weeks or until uterine involution is complete following a delivery or a second trimester abortion. Remove a partially expelled LILETTA. If expulsion has occurred, a new LILETTA may be inserted within 7 days after the onset of a menstrual period after pregnancy has been ruled out. Ovarian Cysts Because the contraceptive effect of LILETTA is mainly due to its local effects within the uterus, ovulatory cycles with follicular rupture usually occur in women of fertile age using LILETTA. Sometimes atresia of the follicle is delayed and the follicle may continue to grow. 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. Symptomatic ovarian cysts occurred in 3.4% of subjects using LILETTA, and 0.3% of subjects discontinued use of LILETTA because of an ovarian cyst. Evaluate persistent ovarian cysts. Surgical intervention is not usually required, but may be necessary in some cases. Discuss this risk with patients who choose to use LILETTA. 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 be increased and bleeding patterns may be irregular. Thereafter, the number of bleeding and spotting days usually decreases but bleeding may remain irregular. In the LILETTA clinical trial, amenorrhea developed in approximately 19% of LILETTA users by the end of the first year of use, in 26% by the end of the second year of use, and in approximately 38% of users by the end of year 3. In the trial, 1.5% of LILETTA subjects discontinued due to bleeding complaints). Table 2 shows the bleeding and spotting days based on 28-day cycle equivalents. Table 2: Mean Number of Bleeding and Spotting Days per 28-day Cycle Equivalent 28-day Cycle Equivalent Cycle 1 N=1,691 Cycle 4 N=1,525 Cycle 7 N=1,223 Cycle 13 N=791 Cycle 26 N=438 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 1.5 2.6 1.2 2.3 0.8 1.7 Number of spotting days 8.9 6.0 4.3 4.2 3.0 3.6 2.7 3.4 2.0 2.7 Note: Includes all LILETTA subjects. In the LILETTA clinical trial, 248 of 255 (97.3%) of women evaluated experienced menses within 3 months after LILETTA removal. 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. Breast Cancer Women 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]. Spontaneous reports of breast cancer have been received during postmarketing experience with another LNG-releasing IUS. Observational studies have not provided consistent evidence of an increased risk of breast cancer with use of a LNG-releasing IUS. 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. Because irregular bleeding/spotting is common during the first months of LILETTA use, exclude endometrial pathology (polyps or cancer) prior to the insertion of LILETTA in women with persistent or uncharacteristic bleeding. Special attention must be given to ascertaining whether the woman is at increased risk of infection (for example, leukemia, acquired immune deficiency syndrome [AIDS], IV drug abuse), or has a history of PID unless there has been a subsequent intrauterine pregnancy. LILETTA does not protect against HIV/STI transmission. [See Pelvic Inflammatory Disease or Endometritis] 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 headache Marked increase of blood pressure Severe arterial disease such as stroke or myocardial infarction In addition, consider removing LILETTA if any of the following conditions arise during use [see CONTRAINDICATIONS]: 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, (for example, expelled or perforated the uterus) [see Perforation and Expulsion above]. Exclude pregnancy and verify the location of LILETTA, for example, by sonography, by X-ray, or by gentle exploration of the cervical canal with a suitable instrument [see DOSAGE AND ADMINISTRATION]. 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. Magnetic Resonance Imaging (MRI) Information LILETTA is MR Safe. Patient Counseling Information Information For Patients Advise the patient to read the FDA-approved patient labeling (Patient Information). Advise the patient that this product does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs). Inform 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] Counsel the patient that 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] Septic abortion may occur. Warn her that if LILETTA cannot be removed or she chooses not to have it removed, there may be an increased risk of miscarriage, sepsis, premature labor, and premature delivery. [See WARNINGS AND PRECAUTIONS] Counsel the patient that severe infection or sepsis, including Group A streptococcal sepsis (GAS), can occur within the first few days after LILETTA is inserted. Instruct her to contact a healthcare provider immediately if she develops severe pain or fever shortly after LILETTA is inserted. [See WARNINGS AND PRECAUTIONS] Inform the patient 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. Teach the patient to recognize and report to her healthcare provider promptly any symptoms of PID, including 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] Inform the patient that perforation may occur, most often during insertion, although the perforation may not be detected until sometime later. Counsel her that if perforation occurs, LILETTA will have to be located and removed. Surgery may be required. Inform her that delayed detection or removal of LILETTA in case of perforation may result in migration of the IUS outside the uterine cavity, adhesions, peritonitis, intestinal perforations, intestinal obstruction, abscesses, and erosion of adjacent viscera. [See WARNINGS AND PRECAUTIONS] Review the signs and symptoms of LILETTA expulsion with the patient. Counsel the patient on how she can check that the threads still protrude from her cervix, and not to pull on them. Inform her that there is no contraceptive protection if LILETTA is displaced or expelled. [See WARNINGS AND PRECAUTIONS] Counsel the patient 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] Counsel the patient that irregular or prolonged bleeding and spotting, and/or cramps may occur during the first three to six months after insertion. If her symptoms continue or are severe, she should report them to her healthcare provider. [See WARNINGS AND PRECAUTIONS] Inform the patient that LILETTA is MR Safe and that it is safe for her to have an MRI with LILETTA in place. [See WARNINGS AND PRECAUTIONS] Instruct 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 or pain during sex She or her partner becomes HIV positive Possible exposure to sexually transmitted infections (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 LILETTA's threads Complete the Follow-up Reminder Card and give it to the patient. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility [See WARNINGS AND PRECAUTIONS] Use In Specific Populations Pregnancy Risk Summary LILETTA is contraindicated for use in pregnant women because there is no need for pregnancy prevention in a woman who is already pregnant and LILETTA may cause adverse pregnancy outcomes. If a woman 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 woman. 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. Advise a woman of the potential risks if pregnancy occurs with LILETTA in place. 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. 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 another LNG-releasing IUS. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LILETTA and any potential adverse effects on the breastfed child from LILETTA or from the underlying maternal condition. Pediatric Use Safety and efficacy of LILETTA have been established in females of reproductive age. Efficacy is expected to be the same for postpubertal females under the age of 16 as for users 16 years and older. Use of this product before menarche is not indicated [see CLINICAL PHARMACOLOGY]. Geriatric Use LILETTA has not been studied in women over age 65 and is not indicated for postmenopausal women. Hepatic Impairment No studies were conducted to evaluate the effect of hepatic disease on the disposition of LNG released from LILETTA [see CONTRAINDICATIONS]. Renal Impairment No studies were conducted to evaluate the effect of renal disease on the disposition of LNG released from LILETTA. Obesity The safety and efficacy of LILETTA have been evaluated in overweight, obese, and morbidly obese patients. There was no apparent effect of BMI or body weight on contraceptive efficacy [see CLINICAL PHARMACOLOGY].