PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and efficacy of Skyla have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal females under the age of 18 as for users 18 years and older. Use of this product before menarche is not indicated.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious or otherwise important adverse reactions are discussed elsewhere in the labeling:oEctopic Pregnancy [see Warnings and Precautions (5.1)]oIntrauterine Pregnancy [see Warnings and Precautions (5.2)]oGroup Streptococcal Sepsis (GAS) [see Warnings and Precautions (5.3)]oPelvic Inflammatory Disease [see Warnings and Precautions (5.4)]oPerforation [see Warnings and Precautions (5.5)]oExpulsion [see Warnings and Precautions (5.6)]oOvarian Cysts [see Warnings and Precautions (5.7)]oBleeding Pattern Alterations [see Warnings and Precautions (5.8)]. oEctopic Pregnancy [see Warnings and Precautions (5.1)]. oIntrauterine Pregnancy [see Warnings and Precautions (5.2)]. oGroup Streptococcal Sepsis (GAS) [see Warnings and Precautions (5.3)]. oPelvic Inflammatory Disease [see Warnings and Precautions (5.4)]. oPerforation [see Warnings and Precautions (5.5)]. oExpulsion [see Warnings and Precautions (5.6)]. oOvarian Cysts [see Warnings and Precautions (5.7)]. oBleeding Pattern Alterations [see Warnings and Precautions (5.8)]. The most common adverse reactions reported (>10% users) are bleeding pattern alterations, vulvovaginitis, abdominal/pelvic pain, acne/seborrhea, headache/migraine, ovarian cyst and dysmenorrhea/uterine spasm. (6)To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 by SOC (presented as crude incidences). Table 4: Adverse reactions that occurred in at least 1% of Skyla users in clinical trials by SOC System Organ ClassAdverse ReactionIncidence (%)(N=1,672)Reproductive System and Breast Disorders Vulvovaginitis 20.2 Ovarian cystOvarian cysts were reported as adverse events if they were abnormal, non-functional cysts and/or had diameter >3 cm on ultrasound examination 13.2 Dysmenorrhea 8.6 Increased bleedingNot all bleeding alterations were captured as adverse reactions [see Warnings and Precautions (5.8)]. 7.8 Breast pain/discomfort 5.3/3.3 Genital discharge 4.2 Device expulsion (complete and partial) 3.2 Upper genital tract infection 1.4Gastrointestinal Disorders Abdominal pain/pelvic pain 12.7/6.2 Nausea 5.5Skin and SubcutaneousTissue Disorders Acne/Seborrhea 13.6/1.4 Alopecia 1.2Nervous System Disorders Headache 12.4 Migraine 2.3Psychiatric Disorders Depression/Depressed mood 3.8/0.5. Vulvovaginitis. 20.2. Ovarian cystOvarian cysts were reported as adverse events if they were abnormal, non-functional cysts and/or had diameter >3 cm on ultrasound examination. 13.2. Dysmenorrhea. 8.6. Increased bleedingNot all bleeding alterations were captured as adverse reactions [see Warnings and Precautions (5.8)].. 7.8. Breast pain/discomfort. 5.3/3.3. Genital discharge. 4.2. Device expulsion (complete and partial). 3.2. Upper genital tract infection. 1.4. Abdominal pain/pelvic pain. 12.7/6.2. Nausea. 5.5. Acne/Seborrhea. 13.6/1.4. Alopecia. 1.2. Headache. 12.4. Migraine. 2.3. Depression/Depressed mood. 3.8/0.5. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of LNG-releasing IUSs. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. oArterial thrombotic and venous thromboembolic events, including cases of pulmonary embolism, deep vein thrombosis and stroke oDevice breakageoHypersensitivity (including rash, urticaria, and angioedema)oIncreased blood pressure. oArterial thrombotic and venous thromboembolic events, including cases of pulmonary embolism, deep vein thrombosis and stroke oDevice breakage. oHypersensitivity (including rash, urticaria, and angioedema). oIncreased blood pressure. Adverse Reactions from Postmarketing Spontaneous Reports The following adverse reactions have been identified during post-approval use of LNG-releasing IUSs. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. oArterial thrombotic and venous thromboembolic events, including cases of pulmonary embolism, deep vein thrombosis and stroke oDevice breakageoHypersensitivity (including rash, urticaria, and angioedema)oIncreased blood pressure. oArterial thrombotic and venous thromboembolic events, including cases of pulmonary embolism, deep vein thrombosis and stroke oDevice breakage. oHypersensitivity (including rash, urticaria, and angioedema). oIncreased blood pressure. Reported Adverse Reactions from Postmarketing Studies Assessment of Perforation and Expulsion of Intrauterine Devices (APEX IUD) Study APEX IUD was large US retrospective cohort study to assess the impact of breastfeeding and timing of postpartum IUD insertion on uterine perforation and IUD expulsion. The analyses included total of 326,658 insertions, 30% (97,824 insertions) of which were performed in women with delivery in the previous 12 months. For insertions performed in women who had delivered <= 52 weeks before IUD insertion, the majority of postpartum insertions, 57.3% (56,047 insertions) occurred between and 14 weeks postpartum. Breastfeeding data were available in 94,817 insertions performed in women 52 weeks or less after delivery. The study results indicated that the risk of uterine perforation was highest in women with IUD insertion <= weeks postpartum. Immediate postpartum insertion (0-3 days) findings are limited due to the relatively small number of insertions occurring within this time interval. Women who were breastfeeding at the time of insertion were at 33% higher risk of perforation (adjusted hazard ratio [HR]=1.33, 95% confidence interval [CI]: 1.07-1.64) compared to women who were not breastfeeding at the time of insertion. Progressively lower risk of uterine perforation was observed in postpartum time windows beyond weeks, in both breastfeeding and not breastfeeding women. Table presents the uterine perforation rates for LNG IUS stratified by breastfeeding status and postpartum interval. Table 5: Uterine Perforation1 rates for LNG IUS, by Breastfeeding Status and Postpartum IntervalBreastfeeding at time of insertionNot breastfeeding at time of insertionPostpartum interval at time of insertionNumber of events/ insertionsUterine perforation rate per 1,000 insertionsNumber of events/ insertionsUterine perforation rate per 1,000 insertions0 to days8/1,8964.220/2770.004 days to <= weeks120/10,73511.1828/2,37711.78> to <= 14 weeks268/29,6779.0330/12,0116.66> 14 to <= 52 weeks43/6,1397.0022/9,0892.42> 52 weeks or no delivery no data available243/184,7331.321Uterine perforation includes both complete and partialperforationRisk of expulsion was variable over the postpartum intervals through 52 weeks. Women who were breastfeeding were at 28% lower risk of IUD expulsion (adjusted HR=0.72, 95% CI: 0.64-0.80) compared to women who were not breastfeeding at time of insertion. Table presents the IUD expulsion rates for LNG IUS stratified by breastfeeding status and postpartum interval.Table 6: Expulsion1 Rates for LNG IUS, by Breastfeeding Status and Postpartum Interval Breastfeeding at time of insertionNot breastfeeding at time of insertionPostpartum interval at time of insertionNumber of events/ insertionsExpulsion rate per 1,000 insertionsNumber of events/ insertionsExpulsion rate per 1,000 insertions0 to days187/1,89698.6312/27743.324 days to <= weeks185/10,73517.2352/2,37721.88> to <= 14 weeks421/29,67714.19306/12,01125.48> 14 to <= 52 weeks120/6,13919.55273/9,08930.04> 52 weeks or no delivery no data available5,481/184,73329.671Expulsion includes both complete and partial expulsion.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. [See Warnings and Precautions (5.9).].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The local mechanism by which continuously released LNG contributes to the contraceptive effectiveness of Skyla has not been conclusively demonstrated. Studies of Skyla and similar LNG IUS prototypes have suggested several mechanisms that prevent pregnancy: thickening of cervical mucus preventing passage of sperm into the uterus, inhibition of sperm capacitation or survival, and alteration of the endometrium. 12.2 Pharmacodynamics. Skyla has mainly local progestogenic effects in the uterine cavity. The local concentrations of LNG lead to morphological changes including stromal pseudodecidualization, glandular atrophy, leukocytic infiltration and decrease in glandular and stromal mitoses. In clinical trials with Skyla, ovulation was assessed based on serum progesterone values >2.5 ng/mL in one study and serum progesterone values >2.5 ng/mL together with serum estradiol levels <27.24 pg/mL in another study. Evidence of ovulation by these criteria was seen in 34 out of 35 women in the first year, in 26 out of 27 women in the second year, and in all 26 women in the third year.. 12.3 Pharmacokinetics. Absorption. Low doses of LNG are administered into the uterine cavity with the Skyla intrauterine delivery system. The in vivo release rate is approximately 14 mcg/day after 24 days and is reduced to approximately 10 mcg/day after 60 days and then declines progressively to approximately mcg/day after year and mcg/day after years. The average LNG in vivo release rate is approximately mcg/day over the first year of use and mcg/day over the period of years. In subset of subjects, the maximum observed serum LNG concentration (mean +-SD) was 192 +- 105 pg/mL, reached after days (median) of Skyla insertion. Thereafter, the LNG serum concentrations (mean +-SD) at year 1, 2, and were 77 +- 21 pg/mL, 62 +- 38 pg/mL, and 72 +- 29 pg/mL, respectively. population pharmacokinetic evaluation based on broader database (>1000 patients) showed similar concentration data of 168 +- 46 pg/mL at days after placement. Thereafter, LNG serum concentrations decline slowly to value 61 +- 19 pg/mL after years.. Distribution. The apparent volume of distribution of LNG is reported to be approximately 1.8 L/kg. LNG is bound non-specifically to serum albumin and specifically to sex hormone binding globulin (SHBG). Accordingly, changes in the concentration of SHBG in serum result in an increase (at higher SHBG concentration) or decrease (at lower SHBG concentration) of the total LNG concentration in serum. In subset of subjects, the concentration of SHBG declined by mean value of 18% within weeks after insertion of Skyla and remained relatively stable over the year period of use. Less than 2% of the circulating LNG is present as free steroid. Elimination Following intravenous administration of 0.09 mg LNG to healthy volunteers, the total clearance of LNG is approximately mL/min/kg and the elimination half-life is approximately 20 hours. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for wide individual variations in LNG concentrations seen in individuals using LNG-containing contraceptive products.. Metabolism Following absorption, LNG is extensively metabolized. The most important metabolic pathways are the reduction of the 4-3-oxo group and hydroxylations at positions 2, and 16, followed by conjugation. Significant amounts of conjugated and unconjugated 3, 5- are also present in serum, along with much smaller amounts of 3, 5-tetrahydrolevonorgestrel and 16-hydroxylevonorgestrel. CYP3A4 is the main enzyme involved in the oxidative metabolism of LNG. Following absorption, LNG is extensively metabolized. The most important metabolic pathways are the reduction of the 4-3-oxo group and hydroxylations at positions 2, and 16, followed by conjugation. Significant amounts of conjugated and unconjugated 3, 5- are also present in serum, along with much smaller amounts of 3, 5-tetrahydrolevonorgestrel and 16-hydroxylevonorgestrel. CYP3A4 is the main enzyme involved in the oxidative metabolism of LNG. Excretion LNG and its phase metabolites are excreted primarily as glucuronide conjugates. About 45% of LNG and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. Specific Populations. Pediatric: Safety and efficacy of Skyla have been established in women of reproductive age. Use of this product before menarche is not indicated. In one-year phase study in post-menarcheal female adolescents (mean age 16.2, range 12 to 18 years) using Skyla, the population pharmacokinetic analysis of 278 adolescents showed mean estimated LNG serum concentrations slightly higher (approximately 10%) in adolescents compared to prior data in adults. This correlates to the generally lower body weight in adolescents. The ranges estimated for adolescents lie within the ranges estimated for adults.Geriatric: Skyla has not been studied in women over age 65 and is not approved for use in this population. Race: three-year phase study in the Asian-Pacific region (93% Asian women, the majority of whom were Chinese, 7% other ethnicities) using Skyla was performed. The population pharmacokinetic analysis of the Asian (Chinese) population in this study showed that estimated LNG serum concentrations in Asian women were slightly higher (approximately to 16%) than those in another phase study which was performed in mainly Caucasian women (79.7%). This slightly higher exposure might be explained by the lower body weight of Asian women. Hepatic Impairment: No studies were conducted to evaluate the effect of hepatic disease on the disposition of Skyla. Renal Impairment: No formal studies were conducted to evaluate the effect of renal disease on the disposition of Skyla. Drug-Drug Interactions. No drug-drug interaction studies were conducted with Skyla [see Drug Interactions (7)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES The contraceptive efficacy of Skyla was evaluated in clinical trial that enrolled generally healthy women aged 18-35, 1,432 of whom received Skyla. Of these, 38.8 (556) were nulliparous women, and 819 women completed years of use. The trial was 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 history of ectopic pregnancy, with clinically significant ovarian cysts or with HIV or otherwise at high risk for sexually transmitted infections were excluded. total of 540 (37.7%) were treated at US sites and 892 (62.3%) were at non-US sites. The racial demographics of enrolled women who received Skyla was: Caucasian (79.7%), Hispanic (11.5%), Black/African Americans (5.2%), Other (2.7%) and Asian (0.8%). The weight range was 38 to 155 kg (mean weight: 68.7 kg) and mean BMI was 25.3 kg/m2 (range 16-55 kg/m2). The clinical trial had no upper or lower weight or BMI limit. Of Skyla-treated women, 21.9% discontinued the study treatment due to an adverse event, 4.4% were lost to follow up, 1.8% withdrew for unspecified reasons, 1.1% discontinued due to protocol deviation, 0.6% discontinued due to pregnancy, and 13.0% discontinued due to other reasons. The pregnancy rate calculated as the Pearl Index (PI) in women aged 18-35 years was the primary efficacy endpoint used to assess contraceptive reliability. The PI was calculated based on 28-day equivalent exposure cycles; evaluable cycles excluded those in which back-up contraception was used unless 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 pregnancies that occurred after the onset of treatment and within days after Skyla removal or expulsion was 0.41 with 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 95% upper confidence limit of 1.7%.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Skyla has mainly local progestogenic effects in the uterine cavity. The local concentrations of LNG lead to morphological changes including stromal pseudodecidualization, glandular atrophy, leukocytic infiltration and decrease in glandular and stromal mitoses. In clinical trials with Skyla, ovulation was assessed based on serum progesterone values >2.5 ng/mL in one study and serum progesterone values >2.5 ng/mL together with serum estradiol levels <27.24 pg/mL in another study. Evidence of ovulation by these criteria was seen in 34 out of 35 women in the first year, in 26 out of 27 women in the second year, and in all 26 women in the third year.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption. Low doses of LNG are administered into the uterine cavity with the Skyla intrauterine delivery system. The in vivo release rate is approximately 14 mcg/day after 24 days and is reduced to approximately 10 mcg/day after 60 days and then declines progressively to approximately mcg/day after year and mcg/day after years. The average LNG in vivo release rate is approximately mcg/day over the first year of use and mcg/day over the period of years. In subset of subjects, the maximum observed serum LNG concentration (mean +-SD) was 192 +- 105 pg/mL, reached after days (median) of Skyla insertion. Thereafter, the LNG serum concentrations (mean +-SD) at year 1, 2, and were 77 +- 21 pg/mL, 62 +- 38 pg/mL, and 72 +- 29 pg/mL, respectively. population pharmacokinetic evaluation based on broader database (>1000 patients) showed similar concentration data of 168 +- 46 pg/mL at days after placement. Thereafter, LNG serum concentrations decline slowly to value 61 +- 19 pg/mL after years.. Distribution. The apparent volume of distribution of LNG is reported to be approximately 1.8 L/kg. LNG is bound non-specifically to serum albumin and specifically to sex hormone binding globulin (SHBG). Accordingly, changes in the concentration of SHBG in serum result in an increase (at higher SHBG concentration) or decrease (at lower SHBG concentration) of the total LNG concentration in serum. In subset of subjects, the concentration of SHBG declined by mean value of 18% within weeks after insertion of Skyla and remained relatively stable over the year period of use. Less than 2% of the circulating LNG is present as free steroid. Elimination Following intravenous administration of 0.09 mg LNG to healthy volunteers, the total clearance of LNG is approximately mL/min/kg and the elimination half-life is approximately 20 hours. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for wide individual variations in LNG concentrations seen in individuals using LNG-containing contraceptive products.. Metabolism Following absorption, LNG is extensively metabolized. The most important metabolic pathways are the reduction of the 4-3-oxo group and hydroxylations at positions 2, and 16, followed by conjugation. Significant amounts of conjugated and unconjugated 3, 5- are also present in serum, along with much smaller amounts of 3, 5-tetrahydrolevonorgestrel and 16-hydroxylevonorgestrel. CYP3A4 is the main enzyme involved in the oxidative metabolism of LNG. Following absorption, LNG is extensively metabolized. The most important metabolic pathways are the reduction of the 4-3-oxo group and hydroxylations at positions 2, and 16, followed by conjugation. Significant amounts of conjugated and unconjugated 3, 5- are also present in serum, along with much smaller amounts of 3, 5-tetrahydrolevonorgestrel and 16-hydroxylevonorgestrel. CYP3A4 is the main enzyme involved in the oxidative metabolism of LNG. Excretion LNG and its phase metabolites are excreted primarily as glucuronide conjugates. About 45% of LNG and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. Specific Populations. Pediatric: Safety and efficacy of Skyla have been established in women of reproductive age. Use of this product before menarche is not indicated. In one-year phase study in post-menarcheal female adolescents (mean age 16.2, range 12 to 18 years) using Skyla, the population pharmacokinetic analysis of 278 adolescents showed mean estimated LNG serum concentrations slightly higher (approximately 10%) in adolescents compared to prior data in adults. This correlates to the generally lower body weight in adolescents. The ranges estimated for adolescents lie within the ranges estimated for adults.Geriatric: Skyla has not been studied in women over age 65 and is not approved for use in this population. Race: three-year phase study in the Asian-Pacific region (93% Asian women, the majority of whom were Chinese, 7% other ethnicities) using Skyla was performed. The population pharmacokinetic analysis of the Asian (Chinese) population in this study showed that estimated LNG serum concentrations in Asian women were slightly higher (approximately to 16%) than those in another phase study which was performed in mainly Caucasian women (79.7%). This slightly higher exposure might be explained by the lower body weight of Asian women. Hepatic Impairment: No studies were conducted to evaluate the effect of hepatic disease on the disposition of Skyla. Renal Impairment: No formal studies were conducted to evaluate the effect of renal disease on the disposition of Skyla. Drug-Drug Interactions. No drug-drug interaction studies were conducted with Skyla [see Drug Interactions (7)].

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS The use of Skyla is contraindicated when one or more of the following conditions exist:oPregnancy or suspicion of pregnancy [see Warnings and Precautions (5.2), Use in Specific Populations (8.1)]oFor use as post-coital contraception (emergency contraception)oCongenital or acquired uterine anomaly including fibroids, that distorts the uterine cavity oAcute pelvic inflammatory disease (PID) or history of PID unless there has been subsequent intrauterine pregnancy [see Warnings and Precautions (5.4)]oPostpartum endometritis or infected abortion in the past months oKnown or suspected uterine or cervical malignancy oKnown or suspected breast cancer or other progestin-sensitive cancer, now or in the pastoUterine bleeding of unknown etiology oUntreated acute cervicitis or vaginitis, including bacterial vaginosis or other lower genital tract infections until infection is controlled oAcute liver disease or liver tumor (benign or malignant) oConditions associated with increased susceptibility to pelvic infections [see Warnings and Precautions (5.4)]oA previously inserted intrauterine device (IUD) that has not been removedoHypersensitivity to any component of this product [see Adverse Reactions (6.2) and Description (11.1)]. oPregnancy or suspicion of pregnancy [see Warnings and Precautions (5.2), Use in Specific Populations (8.1)]. oFor use as post-coital contraception (emergency contraception). oCongenital or acquired uterine anomaly including fibroids, that distorts the uterine cavity oAcute pelvic inflammatory disease (PID) or history of PID unless there has been subsequent intrauterine pregnancy [see Warnings and Precautions (5.4)]. oPostpartum endometritis or infected abortion in the past months oKnown or suspected uterine or cervical malignancy oKnown or suspected breast cancer or other progestin-sensitive cancer, now or in the past. oUterine bleeding of unknown etiology oUntreated acute cervicitis or vaginitis, including bacterial vaginosis or other lower genital tract infections until infection is controlled oAcute liver disease or liver tumor (benign or malignant) oConditions associated with increased susceptibility to pelvic infections [see Warnings and Precautions (5.4)]. oA previously inserted intrauterine device (IUD) that has not been removed. oHypersensitivity to any component of this product [see Adverse Reactions (6.2) and Description (11.1)]. oPregnancy or suspicion of pregnancy. Cannot be used for post-coital contraception (emergency contraception) (4)oCongenital or acquired uterine anomaly if it distorts the uterine cavity (4)oAcute pelvic inflammatory disease (PID) or history of PID unless there has been subsequent intrauterine pregnancy (4)oPostpartum endometritis or infected abortion in the past months (4)oKnown or suspected uterine or cervical malignancy (4)oKnown or suspected breast cancer or other progestin-sensitive cancer (4)oUterine bleeding of unknown etiology (4)oUntreated acute cervicitis or vaginitis or other lower genital tract infections (4)oAcute liver disease or liver tumor (benign or malignant) (4)oIncreased susceptibility to pelvic infection (4)oA previous intrauterine device (IUD) that has not been removed (4)oHypersensitivity to any component of Skyla (4). oPregnancy or suspicion of pregnancy. Cannot be used for post-coital contraception (emergency contraception) (4). oCongenital or acquired uterine anomaly if it distorts the uterine cavity (4). oAcute pelvic inflammatory disease (PID) or history of PID unless there has been subsequent intrauterine pregnancy (4). oPostpartum endometritis or infected abortion in the past months (4). oKnown or suspected uterine or cervical malignancy (4). oKnown or suspected breast cancer or other progestin-sensitive cancer (4). oUterine bleeding of unknown etiology (4). oUntreated acute cervicitis or vaginitis or other lower genital tract infections (4). oAcute liver disease or liver tumor (benign or malignant) (4). oIncreased susceptibility to pelvic infection (4). oA previous intrauterine device (IUD) that has not been removed (4). oHypersensitivity to any component of Skyla (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Skyla (levonorgestrel-releasing intrauterine system) contains 13.5 mg of LNG, 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-17-pregn-4-en-20-yn-3-one, the active ingredient in Skyla, has molecular weight of 312.4, molecular formula of C21H28O2, and the following structural formula: 11.1 Skyla. Skyla consists of T-shaped polyethylene frame (T-body) with steroid reservoir (hormone elastomer core) around the vertical stem. The white T-body has loop at one end of the vertical stem and two horizontal arms at the other end. The reservoir consists of whitish or pale yellow cylinder, made of mixture of LNG and silicone (polydimethylsiloxane), containing total of 13.5 mg LNG. The reservoir is covered by semi-opaque silicone membrane, composed of polydimethylsiloxane and colloidal silica. 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. monofilament brown polyethylene removal thread is attached to loop at the end of the vertical stem of the T-body. The polyethylene of the removal thread contains iron oxide as colorant (see Figure 10). The components of Skyla, including its packaging, are not manufactured using natural rubber latex.Figure 10. Skyla Skyle Fig 10. 11.2 Inserter Skyla is packaged sterile within an inserter. The inserter (Figure 11), which is used for insertion of Skyla into the uterine cavity, consists of symmetric two-sided body and slider that are integrated with flange, lock, pre-bent insertion tube and plunger. The outer diameter of the insertion tube is 3.8 mm. The vertical stem of Skyla is loaded in the insertion tube at the tip of the inserter. The arms are pre-aligned in the horizontal position. The removal threads are contained within the insertion tube and handle. Once Skyla has been placed, the inserter is discarded. Figure 11. Diagram of Inserter. Inserter Diagram. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oRelease rate of levonorgestrel (LNG) is 14 mcg/day after 24 days and declines to mcg/day after years; Skyla must be removed or replaced after years. (2.1)oTo be inserted by trained healthcare provider using strict aseptic technique. Follow insertion instructions exactly as described. (2.2) oPatient should be re-examined and evaluated to weeks after insertion; then, yearly or more often if clinically indicated. (2.3). oRelease rate of levonorgestrel (LNG) is 14 mcg/day after 24 days and declines to mcg/day after years; Skyla must be removed or replaced after years. (2.1). oTo be inserted by trained healthcare provider using strict aseptic technique. Follow insertion instructions exactly as described. (2.2) oPatient should be re-examined and evaluated to weeks after insertion; then, yearly or more often if clinically indicated. (2.3). 2.1 Dosing Over Time Skyla contains 13.5 mg of levonorgestrel (LNG) released in vivo at rate of approximately 14 mcg/day after 24 days. This rate decreases progressively to approximately mcg/day after year and to mcg/day after years. The average in vivo release rate of LNG is approximately mcg/day over the first year of use and mcg/day over period of years. [See Clinical Pharmacology (12.3).] Skyla must be removed by the end of the third year and can be replaced at the time of removal with new Skyla if continued contraceptive protection is desired. Skyla can be physically distinguished from other intrauterine systems (IUSs) by the combination of the visibility of the silver ring on ultrasound and the brown color of the removal threads.Skyla is supplied in sterile package within an inserter that enables single-handed loading (see Figure 1). Do not open the package until required for insertion [see Description 11.2)]. Do not use if the seal of the sterile package is broken or appears compromised. Use strict aseptic techniques throughout the insertion procedure [see Warnings and Precautions (5.3)].. Inserter. 2.2. Insertion Instructions. oObtain complete medical and social history to determine conditions that might influence the selection of levonorgestrel-releasing intrauterine system (LNG IUS) for contraception. If indicated, perform physical examination, and appropriate tests for any forms of genital or other sexually transmitted infections. [See Contraindications (4) and Warnings and Precautions (5.10).] Because irregular bleeding/spotting is common during the first months of Skyla use, exclude endometrial pathology (polyps or cancer) prior to the insertion of Skyla in women with persistent or uncharacteristic bleeding [see Warnings and Precautions (5.8)]. oFollow the insertion instructions exactly as described to ensure proper placement and avoid premature release of Skyla from the inserter. Once released, Skyla cannot be re-loaded.oSkyla should be inserted by trained healthcare provider. Healthcare providers should become thoroughly familiar with the insertion instructions before attempting insertion of Skyla. oInsertion may be associated with some pain and/or bleeding or vasovagal reactions (for example, syncope, bradycardia) or with seizure, especially in patients with predisposition to these conditions. Consider administering analgesics prior to insertion.. oObtain complete medical and social history to determine conditions that might influence the selection of levonorgestrel-releasing intrauterine system (LNG IUS) for contraception. If indicated, perform physical examination, and appropriate tests for any forms of genital or other sexually transmitted infections. [See Contraindications (4) and Warnings and Precautions (5.10).] Because irregular bleeding/spotting is common during the first months of Skyla use, exclude endometrial pathology (polyps or cancer) prior to the insertion of Skyla in women with persistent or uncharacteristic bleeding [see Warnings and Precautions (5.8)]. oFollow the insertion instructions exactly as described to ensure proper placement and avoid premature release of Skyla from the inserter. Once released, Skyla cannot be re-loaded.. oSkyla should be inserted by trained healthcare provider. Healthcare providers should become thoroughly familiar with the insertion instructions before attempting insertion of Skyla. oInsertion may be associated with some pain and/or bleeding or vasovagal reactions (for example, syncope, bradycardia) or with seizure, especially in patients with predisposition to these conditions. Consider administering analgesics prior to insertion.. Timing of Insertion. Table 1: When to Insert SkylaStarting Skyla in women not currently using hormonal or intrauterine contraceptionoInsert Skyla any time there is reasonable certainty that the woman is not pregnant. Consider the possibility of ovulation and conception prior to initiation of this product [see Contraindications (4)]. oIf Skyla is inserted during the first seven days of the menstrual cycle or immediately after first trimester abortion, back-up contraception is not needed.oIf Skyla is not inserted during the first seven days of the menstrual cycle, barrier method of contraception should be used, or the patient should abstain from vaginal intercourse for seven days to prevent pregnancy.Switching to Skyla from an oral, transdermal or vaginal hormonal contraceptiveoInsert Skyla at any time, including during the hormone-free interval of the previous method.oIf inserted during active use of the previous method, continue that method for days after Skyla insertion or until the end of the current treatment cycle.oIf the woman was using continuous hormonal contraception, discontinue that method seven days after Skyla insertion.Switching to Skyla from an injectable progestin contraceptiveoInsert Skyla at any time; non-hormonal back-up birth control (such as condoms or spermicide) should also be used for days if Skyla is inserted more than months (13 weeks) after the last injection.Switching to Skyla from contraceptive implant or another IUS oInsert Skyla on the same day the implant or IUS is removed. oInsert Skyla at any time during the menstrual cycle.Inserting Skyla after first trimester abortion or miscarriage oInsert Skyla immediately after first-trimester abortion or miscarriage, unless it is septic abortion [see Contraindications (4)]. Inserting Skyla after childbirth or second-trimester abortion or miscarriageoImmediate insertion after childbirth or second-trimester abortion or miscarriageoInsert Skyla after removal of the placenta. Back-up contraception is not needed. [See Contraindications (4), Warnings and Precautions (5.5, 5.6), Adverse Reactions (6.2)]. oInterval insertion following complete involution of the uterusoWait minimum of weeks or until the uterus is fully involuted before inserting Skyla [see Warnings and Precautions (5.5, 5.6), Adverse Reactions (6.2)].oInsert Skyla any time there is reasonable certainty the woman is not pregnant.oIf Skyla is not inserted during the first days of the menstrual cycle, back-up method of contraception should be used, or the woman should abstain from vaginal intercourse for days to prevent pregnancy [see Contraindications (4), Warnings and Precautions (5.2)].. oInsert Skyla any time there is reasonable certainty that the woman is not pregnant. Consider the possibility of ovulation and conception prior to initiation of this product [see Contraindications (4)]. oIf Skyla is inserted during the first seven days of the menstrual cycle or immediately after first trimester abortion, back-up contraception is not needed.. oIf Skyla is not inserted during the first seven days of the menstrual cycle, barrier method of contraception should be used, or the patient should abstain from vaginal intercourse for seven days to prevent pregnancy.. oInsert Skyla at any time, including during the hormone-free interval of the previous method.. oIf inserted during active use of the previous method, continue that method for days after Skyla insertion or until the end of the current treatment cycle.. oIf the woman was using continuous hormonal contraception, discontinue that method seven days after Skyla insertion.. oInsert Skyla at any time; non-hormonal back-up birth control (such as condoms or spermicide) should also be used for days if Skyla is inserted more than months (13 weeks) after the last injection.. oInsert Skyla on the same day the implant or IUS is removed. oInsert Skyla at any time during the menstrual cycle.. oInsert Skyla immediately after first-trimester abortion or miscarriage, unless it is septic abortion [see Contraindications (4)]. oImmediate insertion after childbirth or second-trimester abortion or miscarriage. oInsert Skyla after removal of the placenta. Back-up contraception is not needed. [See Contraindications (4), Warnings and Precautions (5.5, 5.6), Adverse Reactions (6.2)]. o. oWait minimum of weeks or until the uterus is fully involuted before inserting Skyla [see Warnings and Precautions (5.5, 5.6), Adverse Reactions (6.2)].. oInsert Skyla any time there is reasonable certainty the woman is not pregnant.. oIf Skyla is not inserted during the first days of the menstrual cycle, back-up method of contraception should be used, or the woman should abstain from vaginal intercourse for days to prevent pregnancy [see Contraindications (4), Warnings and Precautions (5.2)].. Tools for Insertion. Note: The inserter provided with Skyla (see Figure 1) and the Insertion Procedure described in this section are not applicable for immediate insertion after childbirth or second-trimester abortion or miscarriage. For immediate insertion, remove Skyla from the inserter by first loading (see Figure 2) and then releasing (see Figure 7) Skyla from the inserter, and insert according to accepted practice.. Preparation. oGlovesoSpeculumoSterile uterine soundoSterile tenaculumoAntiseptic solution, applicator. oGloves. oSpeculum. oSterile uterine sound. oSterile tenaculum. oAntiseptic solution, applicator. Procedure. oSterile glovesoSkyla with inserter in sealed packageoInstruments and anesthesia for paracervical block, if anticipatedoConsider having an unopened back-up Skyla availableoSterile, sharp curved scissors. oSterile gloves. oSkyla with inserter in sealed package. oInstruments and anesthesia for paracervical block, if anticipated. oConsider having an unopened back-up Skyla available. oSterile, sharp curved scissors. Preparation for insertion oExclude pregnancy and confirm that there are no other contraindications to the use of Skyla.oCheck expiration date of Skyla prior to initiating insertion. oWith the patient comfortably in lithotomy position, do bimanual exam to establish the size, shape and position of the uterus. oGently insert speculum to visualize the cervix. oThoroughly cleanse the cervix and vagina with suitable antiseptic solution.oPrepare to sound the uterine cavity. Grasp the upper lip of the cervix with tenaculum forceps and gently apply traction to stabilize and align the cervical canal with the uterine cavity. Perform 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.oGently insert 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 paracervical block.. oExclude pregnancy and confirm that there are no other contraindications to the use of Skyla.. oCheck expiration date of Skyla prior to initiating insertion. oWith the patient comfortably in lithotomy position, do bimanual exam to establish the size, shape and position of the uterus. oGently insert speculum to visualize the cervix. oThoroughly cleanse the cervix and vagina with suitable antiseptic solution.. oPrepare to sound the uterine cavity. Grasp the upper lip of the cervix with tenaculum forceps and gently apply traction to stabilize and align the cervical canal with the uterine cavity. Perform 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.. oGently insert 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 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. oOpen the package (Figure 1). The contents of the package are sterile. Figure 1. Opening the Skyla Package oUsing sterile gloves, lift the handle of the sterile inserter and remove from the sterile package.. oOpen the package (Figure 1). The contents of the package are sterile. oUsing sterile gloves, lift the handle of the sterile inserter and remove from the sterile package.. Opening the Package. Step 2-Load Skyla into the insertion tube. oPush 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 rounded end that extends slightly beyond the insertion tube.Figure 2. Move slider all the way to the forward position to load Skyla oMaintain 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.. oPush 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 rounded end that extends slightly beyond the insertion tube.. oMaintain forward pressure with your thumb or forefinger on the slider. DO NOT move the slider downward at this time as this may prematurely release the threads of Skyla. Once the slider is moved below the mark, Skyla cannot be re-loaded.. Loading Skyla. Step 3-Setting the Flange oHolding 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 oHolding 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). Setting Flange. Step 4-Skyla is now ready to be inserted. oContinue 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 cm from the cervix Do not force the inserter. If necessary, dilate the cervical canal.. oContinue 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). Advancing Tube. Step 5-Open the arms. oWhile 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 oWhile 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.. Releasing Arms. Step 6-Advance to fundal position. Advance the inserter gently towards the fundus of the uterus until the flange touches the cervix. If you encounter fundal resistance do not continue to advance. Skyla is now in the fundal position (Figure 6). Fundal positioning of Skyla is important to prevent expulsion.Figure 6. Move Skyla into the fundal position Fundal Position. Step 7-Release Skyla and withdraw the inserter. oHolding 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 oContinue to hold the slider all the way down while you slowly and gently withdraw the inserter from the uterus. oUsing sharp, curved scissor, cut the threads perpendicular, leaving about cm visible outside of the cervix [cutting threads at an angle may leave sharp ends (Figure 8)]. Do not apply tension or pull on the threads when cutting to prevent displacing Skyla. .Figure 8. Cutting the threads Skyla insertion is now complete. Prescribe analgesics, if indicated. Record the Skyla lot number in the patient records.. oHolding the entire inserter firmly in place, release Skyla by moving the slider all the way down (Figure 7).. oContinue to hold the slider all the way down while you slowly and gently withdraw the inserter from the uterus. oUsing sharp, curved scissor, cut the threads perpendicular, leaving about 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. Skyla insertion is now complete. Prescribe analgesics, if indicated. Record the Skyla lot number in the patient records.. Moving Slider to Release. Cutting Threads. Important information to consider during or after insertion. oIf you suspect that Skyla is not in the correct position, check placement (for example, using transvaginal ultrasound). Remove Skyla if it is not positioned completely within the uterus. Do not reinsert removed Skyla. If there is clinical concern, exceptional pain or bleeding during or after insertion, take appropriate steps (such as physical examination and ultrasound) immediately to exclude perforation.. oIf you suspect that Skyla is not in the correct position, check placement (for example, using transvaginal ultrasound). Remove Skyla if it is not positioned completely within the uterus. Do not reinsert removed Skyla. 2.3 Patient Follow-up. Reexamine and evaluate patients to weeks after insertion and once year thereafter, or more frequently if clinically indicated.. 2.4 Removal of Skyla. Timing of Removal. oSkyla should not remain in the uterus after years.oIf pregnancy is not desired, remove Skyla during the first days of the menstrual cycle, provided the woman is still experiencing regular menses. If removal will occur at other times during the cycle or the woman does not experience regular menses, she is at risk of pregnancy, start new contraceptive method week prior to removal for these women. [See Dosage and Administration (2.5).] oSkyla should not remain in the uterus after years.. oIf pregnancy is not desired, remove Skyla during the first days of the menstrual cycle, provided the woman is still experiencing regular menses. If removal will occur at other times during the cycle or the woman does not experience regular menses, she is at risk of pregnancy, start new contraceptive method week prior to removal for these women. [See Dosage and Administration (2.5).] Tools for Removal. Preparation. oGlovesoSpeculum. oGloves. oSpeculum. Procedure. oSterile forceps. oSterile forceps. Removal Procedure. oRemove Skyla by applying gentle traction on the threads with forceps (Figure 9). Figure 9. Removal of Skyla oIf the threads are not visible, determine location of Skyla by ultrasound [see Warnings and Precautions (5.10)].oIf Skyla is found to be in the uterine cavity on ultrasound exam, it may be removed using 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, bradycardia) or seizure, especially in patients with predisposition to these conditions.. oRemove Skyla by applying gentle traction on the threads with forceps (Figure 9). oIf the threads are not visible, determine location of Skyla by ultrasound [see Warnings and Precautions (5.10)].. oIf Skyla is found to be in the uterine cavity on ultrasound exam, it may be removed using 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. Remove Skyla. 2.5 Continuation of Contraception after Removal oIf pregnancy is not desired and if woman wishes to continue using Skyla, new system can be inserted immediately after removal any time during the cycle.oIf patient with regular cycles wants to start different contraceptive method, time removal and initiation of the new method to ensure continuous contraception. Either remove Skyla during the first days of the menstrual cycle and start the new method immediately thereafter or start the new method at least days prior to removing Skyla if removal is to occur at other times during the cycle.If patient with irregular cycles or amenorrhea wants to start different contraceptive method, start the new method at least days before removal.. oIf pregnancy is not desired and if woman wishes to continue using Skyla, new system can be inserted immediately after removal any time during the cycle.. oIf patient with regular cycles wants to start different contraceptive method, time removal and initiation of the new method to ensure continuous contraception. Either remove Skyla during the first days of the menstrual cycle and start the new method immediately thereafter or start the new method at least days prior to removing Skyla if removal is to occur at other times during the cycle.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Skyla is LNG-releasing IUS (a type of intrauterine device, or IUD) consisting of T-shaped polyethylene frame with steroid reservoir containing total of 13.5 mg LNG. oOne sterile intrauterine system consisting of T-shaped polyethylene frame with steroid reservoir containing 13.5 mg levonorgestrel packaged within sterile inserter (3). oOne sterile intrauterine system consisting of T-shaped polyethylene frame with steroid reservoir containing 13.5 mg levonorgestrel packaged within sterile inserter (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. No drug-drug interaction studies have been conducted with Skyla.Drugs or herbal products that induce or inhibit LNG metabolizing enzymes, including CYP3A4, may decrease or increase, respectively, the serum concentrations of LNG during the use of Skyla. However, the contraceptive effect of Skyla is mediated via the direct release of LNG into the uterine cavity and is unlikely to be affected by drug interactions via enzyme induction or inhibition.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential Return to Fertility After Discontinuing Skyla About 77% of women who desired pregnancy after study discontinuation and provided follow-up information, conceived within 12 months after removal of Skyla.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Skyla has not been studied in women over age 65 and is not approved for use in this population.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Skyla (levonorgestrel-releasing intrauterine system), containing total of 13.5 mg LNG, is available in 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 25C (77F); with excursions permitted between 15-30C (59-86F) [see USP Controlled Room Temperature]. Skyla (levonorgestrel-releasing intrauterine system), containing total of 13.5 mg LNG, is available in carton of one sterile unit. NDC 50419-422-01.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information)oSexually Transmitted Infections: Advise the patient that this product does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs).oRisk of Ectopic Pregnancy: Advise the patient about the risks of ectopic pregnancy, including the loss of fertility. Teach her to recognize and report to her healthcare provider promptly any symptoms of ectopic pregnancy. [See Warnings and Precautions (5.1).] oRisks of Intrauterine Pregnancy: Advise the patient to contact her healthcare provider if she thinks she might be pregnant. Inform the patient about the risks of intrauterine pregnancy while using Skyla, including the risks of leaving Skyla in place and the risks of removing Skyla or probing of the uterus. If Skyla cannot be removed in pregnant patient, advise her to report immediately any symptom that suggests complications of the pregnancy. Advise her of isolated reports of virilization of the female fetus following local exposure to LNG during pregnancy with an LNG IUS in place. [See Warnings and Precautions (5.2) and Use in Special Populations (8.1).] oSepsis: Advise the patient that severe infection or sepsis, including Group streptococcal sepsis (GAS), can occur within the first few days after Skyla is inserted. Instruct her to contact healthcare provider immediately if she develops severe pain or fever shortly after Skyla is inserted. [See Warnings and Precautions (5.3).] oPelvic Infection: Advise the patient about the possibility of pelvic infections including PID and that these infections can cause tubal damage leading to ectopic pregnancy or infertility, or infrequently can necessitate hysterectomy, or cause death. Teach patients to recognize and report to their healthcare provider promptly any symptoms of pelvic infection. These symptoms include development of menstrual disorders (prolonged or heavy bleeding), unusual vaginal discharge, abdominal or pelvic pain or tenderness, dyspareunia, chills, and fever. [See Warnings and Precautions (5.4).] oPerforation and Expulsion: Advise the patient that the IUS may be expelled from or perforate the uterus and instruct her on how she can check that the threads still protrude from the cervix. Inform her that excessive pain or vaginal bleeding during Skyla placement, worsening pain or bleeding after placement, or the inability to feel Skyla strings may occur with Skyla perforation and expulsion. Caution her not to pull on the threads and displace Skyla. Inform her that there is no contraceptive protection if Skyla is displaced or expelled. Instruct the patient to contact her healthcare provider if she cannot feel the threads and to avoid intercourse or use non-hormonal back-up birth control (such as condoms or spermicide) until the location of Skyla has been confirmed. Advise her that if perforation occurs, Skyla will have to be located and removed; surgery may be required. [See Warnings and Precautions (5.5, 5.6, 5.10).] oOvarian Cysts: Advise the patient regarding the risk of ovarian cysts and that cysts can cause clinical symptoms including pelvic pain, abdominal pain or dyspareunia. Advise the patient to contact her healthcare provider if she experiences these symptoms. [See Warnings and Precautions (5.7).] oBleeding Pattern Alterations: Advise the patient that irregular or prolonged bleeding and spotting, and/or cramps may occur during the first few weeks after insertion. Inform the patient that, during the first 3-6 months of Skyla use, the number of bleeding and spotting days may be higher and bleeding patterns may be irregular. If her symptoms continue or are severe she should report them to her healthcare provider. [See Warnings and Precautions (5.8).] oClinical Considerations for Use and Removal: Advise the patient to contact her healthcare provider if she experiences any of the following: oA stroke or heart attackoVery severe or migraine headachesoUnexplained feveroYellowing of the skin or whites of the eyes, as these may be signs of serious liver problems oPregnancy or suspected pregnancyoPelvic pain, abdominal pain, or pain during sexoHIV positive seroconversion in herself or her partneroPossible exposure to STIsoUnusual vaginal discharge or genital soresoSevere vaginal bleeding or bleeding that lasts long time, or if she misses menstrual periodoInability to feel Skylas threadsoMagnetic Resonance Imaging (MRI) Safety Information: Inform the patient that Skyla can be safely scanned with MRI only under specific conditions [see Warnings and Precautions (5.11)]. Instruct patients who will have an MRI to tell their doctor that they have Skyla. oSexually Transmitted Infections: Advise the patient that this product does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs).. oRisk of Ectopic Pregnancy: Advise the patient about the risks of ectopic pregnancy, including the loss of fertility. Teach her to recognize and report to her healthcare provider promptly any symptoms of ectopic pregnancy. [See Warnings and Precautions (5.1).] oRisks of Intrauterine Pregnancy: Advise the patient to contact her healthcare provider if she thinks she might be pregnant. Inform the patient about the risks of intrauterine pregnancy while using Skyla, including the risks of leaving Skyla in place and the risks of removing Skyla or probing of the uterus. If Skyla cannot be removed in pregnant patient, advise her to report immediately any symptom that suggests complications of the pregnancy. Advise her of isolated reports of virilization of the female fetus following local exposure to LNG during pregnancy with an LNG IUS in place. [See Warnings and Precautions (5.2) and Use in Special Populations (8.1).] oSepsis: Advise the patient that severe infection or sepsis, including Group streptococcal sepsis (GAS), can occur within the first few days after Skyla is inserted. Instruct her to contact healthcare provider immediately if she develops severe pain or fever shortly after Skyla is inserted. [See Warnings and Precautions (5.3).] oPelvic Infection: Advise the patient about the possibility of pelvic infections including PID and that these infections can cause tubal damage leading to ectopic pregnancy or infertility, or infrequently can necessitate hysterectomy, or cause death. Teach patients to recognize and report to their healthcare provider promptly any symptoms of pelvic infection. These symptoms include development of menstrual disorders (prolonged or heavy bleeding), unusual vaginal discharge, abdominal or pelvic pain or tenderness, dyspareunia, chills, and fever. [See Warnings and Precautions (5.4).] oPerforation and Expulsion: Advise the patient that the IUS may be expelled from or perforate the uterus and instruct her on how she can check that the threads still protrude from the cervix. Inform her that excessive pain or vaginal bleeding during Skyla placement, worsening pain or bleeding after placement, or the inability to feel Skyla strings may occur with Skyla perforation and expulsion. Caution her not to pull on the threads and displace Skyla. Inform her that there is no contraceptive protection if Skyla is displaced or expelled. Instruct the patient to contact her healthcare provider if she cannot feel the threads and to avoid intercourse or use non-hormonal back-up birth control (such as condoms or spermicide) until the location of Skyla has been confirmed. Advise her that if perforation occurs, Skyla will have to be located and removed; surgery may be required. [See Warnings and Precautions (5.5, 5.6, 5.10).] oOvarian Cysts: Advise the patient regarding the risk of ovarian cysts and that cysts can cause clinical symptoms including pelvic pain, abdominal pain or dyspareunia. Advise the patient to contact her healthcare provider if she experiences these symptoms. [See Warnings and Precautions (5.7).] oBleeding Pattern Alterations: Advise the patient that irregular or prolonged bleeding and spotting, and/or cramps may occur during the first few weeks after insertion. Inform the patient that, during the first 3-6 months of Skyla use, the number of bleeding and spotting days may be higher and bleeding patterns may be irregular. If her symptoms continue or are severe she should report them to her healthcare provider. [See Warnings and Precautions (5.8).] oClinical Considerations for Use and Removal: Advise the patient to contact her healthcare provider if she experiences any of the following: oA stroke or heart attack. oVery severe or migraine headaches. oUnexplained fever. oYellowing of the skin or whites of the eyes, as these may be signs of serious liver problems oPregnancy or suspected pregnancy. oPelvic pain, abdominal pain, or pain during sex. oHIV positive seroconversion in herself or her partner. oPossible exposure to STIs. oUnusual vaginal discharge or genital sores. oSevere vaginal bleeding or bleeding that lasts long time, or if she misses menstrual period. oInability to feel Skylas threads. oMagnetic Resonance Imaging (MRI) Safety Information: Inform the patient that Skyla can be safely scanned with MRI only under specific conditions [see Warnings and Precautions (5.11)]. Instruct patients who will have an MRI to tell their doctor that they have Skyla.

LACTATION SECTION.

8.2 Lactation Risk Summary Published studies report the presence of LNG in human milk. Small amounts of progestins (approximately 0.1% of the total maternal doses) were detected in the breast milk of nursing mothers who used other LNG-releasing IUSs, resulting in exposure of LNG to the breastfed infants. There are no reports of adverse effects in breastfed infants with maternal use of progestin-only contraceptives. Isolated cases of decreased milk production have been reported with LNG-releasing IUS. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Skyla and any potential adverse effects on the breastfed child from Skyla or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The local mechanism by which continuously released LNG contributes to the contraceptive effectiveness of Skyla has not been conclusively demonstrated. Studies of Skyla and similar LNG IUS prototypes have suggested several mechanisms that prevent pregnancy: thickening of cervical mucus preventing passage of sperm into the uterus, inhibition of sperm capacitation or survival, and alteration of the endometrium.

NONCLINICAL TOXICOLOGY SECTION.

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

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Skyla (levonorgestrel-releasing intrauterine system) Carton NDC 50419-422-01 Sterile Unit IMPORTANT: To be inserted in the uterus by or under the supervision of licensed clinician. See physician insert for detailed instructions for use. Skyla (levonorgestrel-releasing intrauterine system) Rx only -- 13.5 mg levonorgestrel-- sterile unit-- intrauterine use. skyla carton.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary The use of Skyla is contraindicated in pregnancy or with suspected pregnancy and Skyla may cause adverse pregnancy outcomes [see Contraindications (4), Warnings and Precautions (5.1, 5.2)]. If woman becomes pregnant with Skyla in place, the likelihood of ectopic pregnancy is increased and there is an increased risk of miscarriage, sepsis, premature labor, and premature delivery. Remove Skyla, if possible, if pregnancy occurs in woman using Skyla. If Skyla cannot be removed, follow the pregnancy closely [see Warnings and Precautions (5.1, 5.2)]. There have been isolated cases of virilization of the external genitalia of the female fetus following local exposure to LNG during pregnancy with an LNG IUS in place. Animal reproduction studies have not been conducted with Skyla.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.2)6/2021 Warnings and Precautions (5.2)5/2021 Warnings and Precautions (5.5, 5.6)6/2021. Dosage and Administration (2.2)6/2021 Warnings and Precautions (5.2)5/2021. Warnings and Precautions (5.2)5/2021. Warnings and Precautions (5.5, 5.6)6/2021.

REFERENCES SECTION.

15 REFERENCES. 1http://www.cdc.gov/std/tg2015/pid.htm. Accessed August 22, 2016.

RISKS.

Risk Summary The use of Skyla is contraindicated in pregnancy or with suspected pregnancy and Skyla may cause adverse pregnancy outcomes [see Contraindications (4), Warnings and Precautions (5.1, 5.2)]. If woman becomes pregnant with Skyla in place, the likelihood of ectopic pregnancy is increased and there is an increased risk of miscarriage, sepsis, premature labor, and premature delivery. Remove Skyla, if possible, if pregnancy occurs in woman using Skyla. If Skyla cannot be removed, follow the pregnancy closely [see Warnings and Precautions (5.1, 5.2)]. There have been isolated cases of virilization of the external genitalia of the female fetus following local exposure to LNG during pregnancy with an LNG IUS in place. Animal reproduction studies have not been conducted with Skyla.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationSkyla (sky-lah)(levonorgestrel-releasing intrauterine system)Read this Patient Information carefully before you decide if Skyla is right for you. This information does not take the place of talking with your gynecologist or other healthcare provider who specializes in womens health. If you have any questions about Skyla, ask your healthcare provider. You should also learn about other birth control methods to choose the one that is best for you.Skyla does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs).What is SkylaoSkyla is hormone-releasing system placed in your uterus by your healthcare provider to prevent pregnancy for up to years.oSkyla can be removed by your healthcare provider at any time.oSkyla can be used whether or not you have given birth to child.Skyla is small, flexible plastic T-shaped system that slowly releases progestin hormone called levonorgestrel (LNG) that is often used in birth control pills. Because Skyla releases LNG into your uterus, only small amounts of the hormone enter your blood. Skyla does not contain estrogen.Two thin threads are attached to the stem (lower end) of Skyla. The threads are the only part of Skyla you can feel when Skyla is in your uterus; however, unlike tampon string, the threads do not extend outside your body.Skyla is smalland flexibleWhat if need birth control for more than yearsSkyla must be removed after years. Your healthcare provider can place new Skyla during the same office visit if you choose to continue using Skyla.What if want to stop using SkylaSkyla is intended for use up to years but you can stop using Skyla at any time by asking your healthcare provider to remove it. You could become pregnant as soon as Skyla is removed, so you should use another method of birth control if you do not want to become pregnant. Talk to your healthcare provider about the best birth control methods for you, because your new method may need to be started days before Skyla is removed to prevent pregnancy.What if change my mind about birth control and want to become pregnant in less than yearsYour healthcare provider can remove Skyla at any time. You may become pregnant as soon as Skyla is removed. About out of women who want to become pregnant will become pregnant sometime in the first year after Skyla is removed.How does Skyla workSkyla 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 contraceptionThe following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.Skyla, an intrauterine device (IUD) also known as an intrauterine system (IUS),, is in the box at the top of the chart.Who might use Skyla You might choose Skyla if you:owant long-term birth control that provides low chance of getting pregnant (less than in 100)owant birth control that works continuously for up to years owant birth control that is reversibleowant birth control method that you do not need to take dailyoare willing to use birth control method that is placed in the uterus owant birth control that does not contain estrogenDo not use Skyla if you:oare or might be pregnant; Skyla cannot be used as an emergency contraceptive ohave serious pelvic infection called pelvic inflammatory disease (PID) or have had PID in the past unless you have had normal pregnancy after the infection went awayohave an untreated genital infection nowohave had serious pelvic infection in the past months after pregnancyocan get infections easily. For example, if you:ohave multiple sexual partners or your partner has multiple sexual partnersohave problems with your immune systemouse or abuse intravenous drugsohave or suspect you might have cancer of the uterus or cervixohave bleeding from the vagina that has not been explainedohave liver disease or liver tumorohave breast cancer or any other cancer that is sensitive to progestin (a female hormone), now or in the pastohave an intrauterine device in your uterus alreadyohave condition of the uterus that changes the shape of the uterine cavity, such as large fibroid tumorsoare allergic to levonorgestrel, silicone, polyethylene, silver, silica, barium sulfate or iron oxideBefore having Skyla placed, tell your healthcare provider about all of your medical conditions including if you:ohave any of the conditions listed aboveohave had heart attackohave had strokeowere born with heart disease or have problems with your heart valvesohave problems with blood clotting or take medicine to reduce clottingohave high blood pressureorecently had baby or are breastfeedingohave severe migraine headachesohave AIDS, HIV, or any other sexually transmitted infectionTell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How is Skyla placedSkyla is placed by your healthcare provider during an in-office visit or immediately after giving birth.First, your healthcare provider will examine your pelvis to find the exact position of your uterus. Your healthcare provider will then clean your vagina and cervix with an antiseptic solution and slide slim plastic tube containing Skyla through the cervix into your uterus. Your healthcare provider will then remove the plastic tube, and leave Skyla in your uterus. Your healthcare provider will cut the threads to the right length.You may experience pain, bleeding or dizziness during and after placement. If your symptoms do not pass within 30 minutes after placement, Skyla may not have been placed correctly. Your healthcare provider will examine you to see if Skyla needs to be removed or replaced.Should check that Skyla is in placeYes, you should check that Skyla is in proper position by feeling the removal threads. It is good habit to do this time month. Your healthcare provider should teach you how to check that Skyla is in place. First, wash your hands with soap and water. You can check by reaching up to the top of your vagina with clean fingers to feel the removal threads. Do not pull on the threads. If you feel more than just the threads or if you cannot feel the threads, Skyla may not be in the right position and may not prevent pregnancy. Avoid intercourse or use non-hormonal back-up birth control (such as condoms or spermicide) and ask your healthcare provider to check that Skyla is still in the right place.How soon after placement of Skyla should return to my healthcare providerCall your healthcare provider if you have any questions or concerns (see When should call my healthcare provider). Otherwise, you should return to your healthcare provider for follow-up visit to weeks after Skyla is placed to make sure that Skyla is in the right position.Can use tampons or menstrual cups with SkylaYes, tampons or menstrual cups may be used with Skyla. Change tampons or menstrual cups with care to avoid pulling the threads of Skyla. If you think you may have pulled Skyla out of place, avoid intercourse or use non-hormonal back-up birth control (such as condoms or spermicide), and contact your healthcare provider.What if become pregnant while using SkylaCall your healthcare provider right away if you think you may be pregnant. If possible, also do urine pregnancy test. If you get pregnant while using Skyla, you may have an ectopic pregnancy. This means that the pregnancy is not in the uterus. Unusual vaginal bleeding or abdominal pain may be sign of ectopic pregnancy.Ectopic pregnancy is 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 miscarriage. If Skyla cannot be removed, talk with your healthcare provider about the benefits and risks of continuing the pregnancy and possible effects of the hormone on your unborn baby. If you continue your pregnancy, see your healthcare provider regularly. Call your healthcare provider right away if you get flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge, or fluid leaking from your vagina. These may be signs of infection.How will Skyla change my periods For the first to months, your period may become irregular and the number of bleeding days may increase. You may also have frequent spotting or light bleeding. Some women have heavy bleeding during this time. You may also have cramping during the first few weeks.After you have used Skyla for while, the number of bleeding and spotting days is likely to lessen. For some women, periods will stop altogether. When Skyla is removed, your menstrual periods should return.Is it safe to breastfeed while using SkylaYou may use Skyla when you are breastfeeding. Skyla is not likely to affect the quality or amount of your breast milk or the health of your nursing baby. However, isolated cases of decreased milk production have been reported. The risk of Skyla going into the wall of the uterus (becoming embedded) or going through the wall of the uterus is increased if Skyla is inserted while you are breastfeeding. Will Skyla interfere with sexual intercourseYou and your partner should not feel Skyla during intercourse. Skyla is placed in the uterus, not in the vagina. Sometimes your partner may feel the threads. If this occurs, or if you or your partner experience pain during sex, talk with your healthcare provider.Can have an MRI with Skyla in placeSkyla can be safely scanned with MRI only under specific conditions. Before you have an MRI, tell your healthcare provider that you have Skyla, an intrauterine device (IUD), in place.What are the possible side effects of SkylaSkyla can cause serious side effects, including:oEctopic pregnancy and intrauterine pregnancy risks. There are risks if you become pregnant while using Skyla (see What if become pregnant while using Skyla). oLife-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.oPelvic inflammatory disease (PID). Some IUD users get serious pelvic infection called pelvic inflammatory disease. PID is usually sexually transmitted. You have higher chance of getting PID if you or your partner has sex with other partners. PID can cause serious problems such as infertility, ectopic pregnancy or pelvic pain that does not go away. PID is usually treated with antibiotics. More serious cases of PID may require surgery including removal of the uterus (hysterectomy). In rare cases, infections that start as PID can even cause death. Tell your healthcare provider right away if you have any of these signs of PID: long-lasting or heavy bleeding, unusual vaginal discharge, low abdominal (stomach area) pain, painful sex, chills, fever, genital lesions or sores.oPerforation. Skyla may go into the wall of the uterus (become embedded) or go through the wall of the uterus. This is called perforation. If this occurs, Skyla may no longer prevent pregnancy. If perforation occurs, Skyla may move outside the uterus and can cause internal scarring, infection, or damage to other organs, and you may need surgery to have Skyla removed. Excessive pain or vaginal bleeding during placement of Skyla, pain or bleeding that gets worse after placement, or not being able to feel the threads may happen with perforation. The risk of perforation is increased if Skyla is inserted while you are breastfeeding, or if you have recently given birth.oExpulsion. Skyla may come out by itself. This is called expulsion. Expulsion occurs in about out of 100 women. Excessive pain or vaginal bleeding during placement of Skyla, pain or bleeding that gets worse after placement, or not being able to feel the threads may happen with expulsion. You may become pregnant if Skyla comes out. If you think that Skyla has come out, avoid intercourse or use non-hormonal backup birth control (such as condoms or spermicide) and call your healthcare provider. The risk of expulsion is increased with insertion right after delivery or second-trimester abortion. Common side effects of Skyla include: oPain, 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.oChanges 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 while.oMissed menstrual periods. About out of 16 women stop having periods after year of Skyla use. If you have any concerns that you may be pregnant while using Skyla, do urine pregnancy test and call your healthcare provider. If you do not have period for weeks during Skyla use, call your healthcare provider. When Skyla is removed, your menstrual periods should return.oCysts on the ovary. About 14 out of 100 women using Skyla develop cyst on the ovary. These cysts usually disappear on their own in two to three months. However, cysts can cause pain and sometimes cysts will need surgery.Other common side effects include:oabdominal or pelvic painoacne or greasy skinoheadache or migraineoinflammation or infection of the outer part of your vagina (vulvovaginitis)opainful periodsThese are not all of the possible side effects with Skyla. For more information, ask your healthcare provider.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Bayer Healthcare Pharmaceuticals at 1-888-842-2937.After Skyla has been placed, when should call my healthcare providerIf Skyla is accidentally removed and you had vaginal intercourse within the preceding week, you may be at risk of pregnancy, and you should talk to healthcare provider.Call your healthcare provider if you have any concerns about Skyla. Be sure to call if you:othink you are pregnantohave pelvic pain, abdominal pain, or pain during sexohave unusual vaginal discharge or genital soresohave unexplained fever, flu-like symptoms or chillsomight be exposed to sexually transmitted infections (STIs)oare concerned that Skyla may have been expelled (came out)ocannot feel Skylas threadsodevelop very severe or migraine headachesohave yellowing of the skin or whites of the eyes. These may be signs of liver problems.ohave had stroke or heart attackobecome HIV positive or your partner becomes HIV positiveohave severe vaginal bleeding or bleeding that lasts long time or concerns youGeneral advice about the safe and effective use of SkylaMedicines are sometimes prescribed for conditions other than those listed in patient information leaflets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about Skyla that is written for healthcare professionals.What are the ingredients in SkylaActive ingredient: levonorgestrelInactive ingredients: silicone, polyethylene, silver, silica, barium sulfate, iron oxideManufactured for: Bayer HealthCare Pharmaceuticals Inc.Whippany, NJ 07981(C) 2013, Bayer HealthCare Pharmaceuticals Inc.All rights reserved.For more information, go to www.skyla-us.com or call 1-888-842-2937. This Patient Information has been approved by the U.S. Food and Drug Administration.5/2021. oSkyla is hormone-releasing system placed in your uterus by your healthcare provider to prevent pregnancy for up to years.. oSkyla can be removed by your healthcare provider at any time.. oSkyla can be used whether or not you have given birth to child.. owant long-term birth control that provides low chance of getting pregnant (less than in 100). owant birth control that works continuously for up to years owant birth control that is reversible. owant birth control method that you do not need to take daily. oare willing to use birth control method that is placed in the uterus owant birth control that does not contain estrogen. oare or might be pregnant; Skyla cannot be used as an emergency contraceptive ohave serious pelvic infection called pelvic inflammatory disease (PID) or have had PID in the past unless you have had normal pregnancy after the infection went away. ohave an untreated genital infection now. ohave had serious pelvic infection in the past months after pregnancy. ocan get infections easily. For example, if you:. ohave multiple sexual partners or your partner has multiple sexual partners. ohave problems with your immune system. ouse or abuse intravenous drugs. ohave or suspect you might have cancer of the uterus or cervix. ohave bleeding from the vagina that has not been explained. ohave liver disease or liver tumor. ohave breast cancer or any other cancer that is sensitive to progestin (a female hormone), now or in the past. ohave an intrauterine device in your uterus already. ohave condition of the uterus that changes the shape of the uterine cavity, such as large fibroid tumors. oare allergic to levonorgestrel, silicone, polyethylene, silver, silica, barium sulfate or iron oxide. ohave any of the conditions listed above. ohave had heart attack. ohave had stroke. owere born with heart disease or have problems with your heart valves. ohave problems with blood clotting or take medicine to reduce clotting. ohave high blood pressure. orecently had baby or are breastfeeding. ohave severe migraine headaches. ohave AIDS, HIV, or any other sexually transmitted infection. oEctopic pregnancy and intrauterine pregnancy risks. There are risks if you become pregnant while using Skyla (see What if become pregnant while using Skyla). oLife-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.. oPelvic inflammatory disease (PID). Some IUD users get serious pelvic infection called pelvic inflammatory disease. PID is usually sexually transmitted. You have higher chance of getting PID if you or your partner has sex with other partners. PID can cause serious problems such as infertility, ectopic pregnancy or pelvic pain that does not go away. PID is usually treated with antibiotics. More serious cases of PID may require surgery including removal of the uterus (hysterectomy). In rare cases, infections that start as PID can even cause death.. Tell your healthcare provider right away if you have any of these signs of PID: long-lasting or heavy bleeding, unusual vaginal discharge, low abdominal (stomach area) pain, painful sex, chills, fever, genital lesions or sores.. oPerforation. Skyla may go into the wall of the uterus (become embedded) or go through the wall of the uterus. This is called perforation. If this occurs, Skyla may no longer prevent pregnancy. If perforation occurs, Skyla may move outside the uterus and can cause internal scarring, infection, or damage to other organs, and you may need surgery to have Skyla removed. Excessive pain or vaginal bleeding during placement of Skyla, pain or bleeding that gets worse after placement, or not being able to feel the threads may happen with perforation. The risk of perforation is increased if Skyla is inserted while you are breastfeeding, or if you have recently given birth.. oExpulsion. Skyla may come out by itself. This is called expulsion. Expulsion occurs in about out of 100 women. Excessive pain or vaginal bleeding during placement of Skyla, pain or bleeding that gets worse after placement, or not being able to feel the threads may happen with expulsion. You may become pregnant if Skyla comes out. If you think that Skyla has come out, avoid intercourse or use non-hormonal backup birth control (such as condoms or spermicide) and call your healthcare provider. The risk of expulsion is increased with insertion right after delivery or second-trimester abortion. oPain, 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.. oChanges 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 while.. oMissed menstrual periods. About out of 16 women stop having periods after year of Skyla use. If you have any concerns that you may be pregnant while using Skyla, do urine pregnancy test and call your healthcare provider. If you do not have period for weeks during Skyla use, call your healthcare provider. When Skyla is removed, your menstrual periods should return.. oCysts on the ovary. About 14 out of 100 women using Skyla develop cyst on the ovary. These cysts usually disappear on their own in two to three months. However, cysts can cause pain and sometimes cysts will need surgery.. oabdominal or pelvic pain. oacne or greasy skin. oheadache or migraine. oinflammation or infection of the outer part of your vagina (vulvovaginitis). opainful periods. othink you are pregnant. ohave pelvic pain, abdominal pain, or pain during sex. ohave unusual vaginal discharge or genital sores. ohave unexplained fever, flu-like symptoms or chills. omight be exposed to sexually transmitted infections (STIs). oare concerned that Skyla may have been expelled (came out). ocannot feel Skylas threads. odevelop very severe or migraine headaches. ohave yellowing of the skin or whites of the eyes. These may be signs of liver problems.. ohave had stroke or heart attack. obecome HIV positive or your partner becomes HIV positive. ohave severe vaginal bleeding or bleeding that lasts long time or concerns you. This Patient Information has been approved by the U.S. Food and Drug Administration.5/2021. Skyla is small. Skyla is Flexible. Uterus. Pregnancy Chart.

SPL UNCLASSIFIED SECTION.

2.1 Dosing Over Time Skyla contains 13.5 mg of levonorgestrel (LNG) released in vivo at rate of approximately 14 mcg/day after 24 days. This rate decreases progressively to approximately mcg/day after year and to mcg/day after years. The average in vivo release rate of LNG is approximately mcg/day over the first year of use and mcg/day over period of years. [See Clinical Pharmacology (12.3).] Skyla must be removed by the end of the third year and can be replaced at the time of removal with new Skyla if continued contraceptive protection is desired. Skyla can be physically distinguished from other intrauterine systems (IUSs) by the combination of the visibility of the silver ring on ultrasound and the brown color of the removal threads.Skyla is supplied in sterile package within an inserter that enables single-handed loading (see Figure 1). Do not open the package until required for insertion [see Description 11.2)]. Do not use if the seal of the sterile package is broken or appears compromised. Use strict aseptic techniques throughout the insertion procedure [see Warnings and Precautions (5.3)].. Inserter.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy. Risk Summary The use of Skyla is contraindicated in pregnancy or with suspected pregnancy and Skyla may cause adverse pregnancy outcomes [see Contraindications (4), Warnings and Precautions (5.1, 5.2)]. If woman becomes pregnant with Skyla in place, the likelihood of ectopic pregnancy is increased and there is an increased risk of miscarriage, sepsis, premature labor, and premature delivery. Remove Skyla, if possible, if pregnancy occurs in woman using Skyla. If Skyla cannot be removed, follow the pregnancy closely [see Warnings and Precautions (5.1, 5.2)]. There have been isolated cases of virilization of the external genitalia of the female fetus following local exposure to LNG during pregnancy with an LNG IUS in place. Animal reproduction studies have not been conducted with Skyla.. 8.2 Lactation Risk Summary Published studies report the presence of LNG in human milk. Small amounts of progestins (approximately 0.1% of the total maternal doses) were detected in the breast milk of nursing mothers who used other LNG-releasing IUSs, resulting in exposure of LNG to the breastfed infants. There are no reports of adverse effects in breastfed infants with maternal use of progestin-only contraceptives. Isolated cases of decreased milk production have been reported with LNG-releasing IUS. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Skyla and any potential adverse effects on the breastfed child from Skyla or from the underlying maternal condition.. 8.3 Females and Males of Reproductive Potential Return to Fertility After Discontinuing Skyla About 77% of women who desired pregnancy after study discontinuation and provided follow-up information, conceived within 12 months after removal of Skyla. 8.4 Pediatric Use. Safety and efficacy of Skyla have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal females under the age of 18 as for users 18 years and older. Use of this product before menarche is not indicated. 8.5 Geriatric Use. Skyla has not been studied in women over age 65 and is not approved for use in this population.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oRemove Skyla if pregnancy occurs with Skyla in place. If pregnancy occurs, there is increased risk of ectopic pregnancy including loss of fertility, pregnancy loss, septic abortion (including septicemia, shock and death), and premature labor and delivery. (5.1, 5.2)oGroup streptococcal infection has been reported following insertion of LNG IUS; strict aseptic technique is essential during insertion. (5.3)oBefore using Skyla, consider the risks of PID. (5.4)oUterine perforation may occur and may reduce contraceptive effectiveness or require surgery. Risk is increased if inserted in lactating women and may be increased if inserted in women with fixed retroverted uteri and postpartum. (5.5)oPartial or complete expulsion may occur, which can be unnoticed, leading to loss of contraceptive efficacy. (5.6)oEvaluate persistent enlarged ovarian follicles or ovarian cysts. (5.7)oBleeding patterns become altered, may remain irregular and amenorrhea may ensue. (5.8)oSkyla can be safely scanned with MRI only under certain conditions (5.11). oRemove Skyla if pregnancy occurs with Skyla in place. If pregnancy occurs, there is increased risk of ectopic pregnancy including loss of fertility, pregnancy loss, septic abortion (including septicemia, shock and death), and premature labor and delivery. (5.1, 5.2). oGroup streptococcal infection has been reported following insertion of LNG IUS; strict aseptic technique is essential during insertion. (5.3). oBefore using Skyla, consider the risks of PID. (5.4). oUterine perforation may occur and may reduce contraceptive effectiveness or require surgery. Risk is increased if inserted in lactating women and may be increased if inserted in women with fixed retroverted uteri and postpartum. (5.5). oPartial or complete expulsion may occur, which can be unnoticed, leading to loss of contraceptive efficacy. (5.6). oEvaluate persistent enlarged ovarian follicles or ovarian cysts. (5.7). oBleeding patterns become altered, may remain irregular and amenorrhea may ensue. (5.8). oSkyla can be safely scanned with MRI only under certain conditions (5.11). 5.1 Risk of Ectopic Pregnancy. Evaluate women for ectopic pregnancy if they become pregnant with Skyla in place because the likelihood of pregnancy being ectopic is increased with Skyla. Approximately one-half of pregnancies that occur with Skyla in place are likely to be ectopic. Also consider the possibility of ectopic pregnancy in the case of lower abdominal pain, especially in association with missed menses or if an amenorrheic woman starts bleeding. The incidence of ectopic pregnancy in clinical trials with Skyla, which excluded women with history of ectopic pregnancy, was approximately 0.1% per year. The risk of ectopic pregnancy in women who have history of ectopic pregnancy and use Skyla is unknown. Women with previous history of ectopic pregnancy, tubal surgery or pelvic infection carry higher risk of ectopic pregnancy. Ectopic pregnancy may result in loss of fertility. Evaluate women for ectopic pregnancy if they become pregnant with Skyla in place because the likelihood of pregnancy being ectopic is increased with Skyla. Approximately one-half of pregnancies that occur with Skyla in place are likely to be ectopic. Also consider the possibility of ectopic pregnancy in the case of lower abdominal pain, especially in association with missed menses or if an amenorrheic woman starts bleeding. 5.2 Risks with Intrauterine Pregnancy If pregnancy occurs while using Skyla, remove Skyla because leaving it in place may increase the risk of spontaneous abortion and preterm labor. Removal of Skyla or probing of the uterus may also result in spontaneous abortion. In the event of an intrauterine pregnancy with Skyla, consider the following:. Septic abortion In patients becoming pregnant with an IUS in place, septic abortion--with septicemia, septic shock, and death--may occur. Continuation of pregnancy If woman becomes pregnant with Skyla in place and if Skyla cannot be removed or the woman chooses not to have it removed, warn her that failure to remove Skyla increases the risk of miscarriage, sepsis, premature labor and premature delivery. Advise her of isolated reports of virilization of the female fetus following local exposure to LNG during pregnancy with an LNG IUS in place [see Use in Specific Populations (8.1)]. Follow her pregnancy closely and advise her to report immediately any symptom that suggests complications of the pregnancy. 5.3 Sepsis. Severe infection or sepsis, including Group streptococcal sepsis (GAS), have been reported following insertion of LNG-releasing IUS. In some cases, severe pain occurred within hours of insertion followed by sepsis within days. Because death from GAS is more likely if treatment is delayed, it is important to be aware of these rare but serious infections. Aseptic technique during insertion of Skyla is essential in order to minimize serious infections such as GAS. 5.4 Pelvic Infection. Pelvic Inflammatory Disease (PID). Skyla is contraindicated in the presence of known or suspected PID or in women with history of PID unless there has been subsequent intrauterine pregnancy [see Contraindications (4)]. IUDs have been associated with an increased risk of PID, most likely due to organisms being introduced into the uterus during insertion. In clinical trials, PID was observed in 0.4% of women overall and occurred more frequently within the first year and most often within the first month after insertion of Skyla. Promptly examine users with complaints of lower abdominal or pelvic pain, odorous discharge, unexplained bleeding, fever, genital lesions or sores. Remove Skyla in cases of recurrent endometritis or pelvic inflammatory disease, or if an acute pelvic infection is severe or does not respond to treatment. Women at increased risk for PID PID is often associated with sexually transmitted infection (STI), and Skyla does not protect against STI. The risk of PID is greater for women who have multiple sexual partners, and also for women whose sexual partner(s) have multiple sexual partners. Women who have had PID are at increased risk for recurrence or re-infection. In particular, ascertain whether the woman is at increased risk of infection (for example, leukemia, acquired immune deficiency syndrome [AIDS], intravenous drug abuse).. Subclinical PID PID may be asymptomatic but still result in tubal damage and its sequelae.. Treatment of PID Following diagnosis of PID, or suspected PID, bacteriologic specimens should be obtained, and antibiotic therapy should be initiated promptly. Removal of Skyla after initiation of antibiotic therapy is usually appropriate. Actinomycosis. Actinomycosis has been associated with IUDs. Remove Skyla from symptomatic women and treat with antibiotics. The significance of actinomyces-like organisms on Pap smear in an asymptomatic IUD user is unknown, and so this finding alone does not always require Skyla removal and treatment. When possible, confirm Pap smear diagnosis with cultures.. 5.5 Perforation. Perforation (total or partial, including penetration/embedment of Skyla in the uterine wall or cervix) may occur most often during insertion, although the perforation may not be detected until sometime later. The incidence of perforation during clinical trials was 0.1%.The risk of uterine perforation is increased in women who have recently given birth, and in women who are breastfeeding at the time of insertion. In large postmarketing safety study conducted in the US, the risk of uterine perforation was highest when insertion occurred within <= weeks postpartum, and also higher with breastfeeding at the time of insertion [see Adverse Reactions (6.2)]. The risk of perforation may be increased if Skyla is inserted when the uterus is fixed, retroverted or not completely involuted.If perforation occurs, locate and remove Skyla. Surgery may be required. Delayed detection or removal of Skyla in case of perforation may result in migration outside the uterine cavity, adhesions, peritonitis, intestinal perforations, intestinal obstruction, abscesses and erosion of adjacent viscera. In addition, perforation may reduce contraceptive efficacy and result in pregnancy.. 5.6 Expulsion. Partial or complete expulsion of Skyla may occur resulting in the loss of efficacy. Expulsion may be associated with symptoms of bleeding or pain, or it may be asymptomatic and go unnoticed. Skyla typically decreases menstrual bleeding over time; therefore, an increase of menstrual bleeding may be indicative of an expulsion. Consider further diagnostic imaging, such as x-ray, if expulsion is suspected based on ultrasound [see Warnings and Precautions (5.10)]. In clinical trials, 5-year expulsion rate of 3.5% (59 out of 1,690 subjects) was reported. The risk of expulsion is increased with insertions immediately after delivery and appears to be increased with insertion after second-trimester abortion based on limited data. In large postmarketing safety study conducted in the US, the risk of expulsion was lower with breastfeeding status [see Adverse Reactions (6.2)].Remove partially expelled Skyla. If expulsion has occurred, new Skyla can be inserted any time the provider can be reasonably certain the woman is not pregnant. 5.7 Ovarian Cysts Because the contraceptive effect of Skyla is mainly due to its local effects within the uterus, ovulatory cycles with follicular rupture usually occur in women of fertile age using Skyla. Ovarian cysts (reported as adverse reactions if they were abnormal, non-functional cysts and/or had diameter >3 cm on ultrasound examination) were reported at least once over the course of clinical trials in 13.2% of women using Skyla, and 0.3% of subjects discontinued because of an ovarian cyst. Most ovarian cysts are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia. In most cases the ovarian cysts disappear spontaneously during two to three months observation. Evaluate persistent ovarian cysts. Surgical intervention is not usually required.. 5.8 Bleeding Pattern Alterations. Skyla can alter the bleeding pattern and result in spotting, irregular bleeding, heavy bleeding, oligomenorrhea and amenorrhea. During the first 3-6 months of Skyla use, the number of bleeding and spotting days may be higher and bleeding patterns may be irregular. Thereafter, the number of bleeding and spotting days usually decreases but bleeding may remain irregular.In Skyla clinical trials, amenorrhea developed by the end of the first year of use in approximately 6% of Skyla users. total of 77 subjects out of 1,672 (4.6%) discontinued due to uterine bleeding complaints. Table shows the bleeding patterns as documented in the Skyla clinical trials based on 90-day reference periods. Table shows the number of bleeding and spotting days based on 28-day cycle equivalents. Table 2: Bleeding Patterns Reported with Skyla in Contraception Studies (by 90-day reference periods)SkylaFirst 90 daysN=1,531Second 90 daysN=1,475End of year 1N=1,329End of year 3N=903Amenorrhea1 <1%3%6%12%Infrequent bleeding2 8%19%20%22%Frequent bleeding3 31%12%8%4%Prolonged bleeding4 55%14%6%2%Irregular bleeding5 39%25%18%15%1Defined as subjects with no bleeding/spotting throughout the 90-day reference period2Defined as subjects with or bleeding/spotting episodes in the 90-day reference period 3Defined as subjects with more than bleeding/spotting episodes in the 90-day reference period4Defined 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 to bleeding/spotting episodes and less than bleeding/spotting-free intervals of 14 or more days. Table 3: Mean number of Bleeding and Spotting Days per 28-day Cycle Equivalent28-day Cycle EquivalentCycle 1N=1,588Cycle 4N=1,535Cycle 7N=1,468Cycle 13N=1,345Cycle 39N=781Days on treatment1-2885-112169-196337-3641065-1092Mean(SD)Mean(SD)Mean(SD)Mean(SD)Mean(SD)Number of bleeding days7.3(5.6)3.5(3.4)2.8(3.1)2.1(2.7)1.4(2.1)Number of spotting days9.2(6.1)4.8(4.4)3.8(3.6)3.3(3.1)2.7(2.7)If 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 previous menstruation. Once pregnancy has been excluded, repeated pregnancy tests are generally not necessary in amenorrheic women unless indicated, for example, by other signs of pregnancy or by pelvic pain. 5.9 Breast Cancer Women who currently have or have had breast cancer, or have suspicion of breast cancer, should not use hormonal contraception, including Skyla because some breast cancers are hormone-sensitive [see Contraindications (4)]. Spontaneous reports of breast cancer have been received during postmarketing experience with LNG-releasing IUS. Observational studies of the risk of breast cancer with use of LNG-releasing IUS do not provide conclusive evidence of increased risk. 5.10 Clinical Considerations for Use and Removal. Use Skyla with caution after careful assessment if any of the following conditions exist, and consider removal of the system if any of them arise during use:oCoagulopathy or use of anticoagulantsoMigraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemiaoExceptionally severe headacheoMarked increase of blood pressureoSevere arterial disease such as stroke or myocardial infarctionIn addition, consider removing Skyla if any of the following conditions arise during use: oUterine or cervical malignancy oJaundiceoIf the threads are not visible or are significantly shortened they may have broken or retracted into the cervical canal or uterus. Consider the possibility that the system may have been displaced, (for example, expelled or perforated the uterus) [see Warnings and Precautions (5.5, 5.6)]. Exclude pregnancy and verify the location of Skyla, for example, by sonography, X-ray, or by gentle exploration of the cervical canal with suitable instrument. If Skyla is displaced, remove it. 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.. oCoagulopathy or use of anticoagulants. oMigraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia. oExceptionally severe headache. oMarked increase of blood pressure. oSevere arterial disease such as stroke or myocardial infarction. oUterine or cervical malignancy oJaundice. oIf the threads are not visible or are significantly shortened they may have broken or retracted into the cervical canal or uterus. Consider the possibility that the system may have been displaced, (for example, expelled or perforated the uterus) [see Warnings and Precautions (5.5, 5.6)]. Exclude pregnancy and verify the location of Skyla, for example, by sonography, X-ray, or by gentle exploration of the cervical canal with suitable instrument. If Skyla is displaced, remove it. new Skyla may be inserted at that time or during the next menses if it is certain that conception has not occurred. If Skyla is in place with no evidence of perforation, no intervention is indicated.. 5.11 Magnetic Resonance Imaging (MRI) Safety Information. Non-clinical testing has demonstrated that Skyla is MR Conditional. patient with Skyla can be safely scanned in an MR system meeting the following conditions:oStatic magnetic field of 3.0 or lessoMaximum spatial field gradient of 36,000 gauss/cm (360 T/m)oMaximum MR system reported, whole body averaged specific absorption rate (SAR) of 4W/kg (First Level Controlled Operating Mode) Under the scan conditions defined above, the Skyla IUS is expected to produce maximum temperature rise of less than 2C after 15 minutes of continuous scanning.In non-clinical testing, the image artifact caused by the IUS extended up to mm from the IUS when imaged with gradient echo pulse sequence and 3.0 MRI system.. oStatic magnetic field of 3.0 or less. oMaximum spatial field gradient of 36,000 gauss/cm (360 T/m). oMaximum MR system reported, whole body averaged specific absorption rate (SAR) of 4W/kg (First Level Controlled Operating Mode).