CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. See Warnings and Precautions (5.3, 5.12) and Use in Specific Populations (8.1).Norelgestromin was tested in in vitro mutagenicity assays (bacterial plate incorporation mutation assay, CHO/HGPRT mutation assay, chromosomal aberration assay using cultured human peripheral lymphocytes) and in one in vivo test (rat micronucleus assay) and found to have no genotoxic potential.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. NGMN is the active progestin largely responsible for the progestational activity that occurs in women following application of norelgestromin and ethinyl estradiol transdermal system. NGMN is also the primary active metabolite produced following oral administration of NGM, the progestin component of some oral contraceptive products.Combination hormonal contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).. 12.2 Pharmacodynamics. One clinical trial assessed the return of hypothalamic-pituitary-ovarian axis function post-therapy and found that follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol mean values, though suppressed during therapy, returned to near baseline values during the weeks post-therapy.. 12.3 Pharmacokinetics. Absorption. The systemic delivery rate of NGMN and EE from norelgestromin and ethinyl estradiol transdermal system is approximately 150 mcg of NGMN and 35 mcg of EE per day based on comparative analysis with intravenous (IV) data. Following single application of norelgestromin and ethinyl estradiol transdermal system, both NGMN and EE reach plateau by approximately 48 hours. Pooled data from the clinical studies have demonstrated that steady state is reached within weeks of application. In one of the clinical studies, Css concentrations across all subjects ranged from 0.305 to 1.53 ng/mL for NGMN and from 23 to 137 pg/mL for EE.Absorption of NGMN and EE following application of norelgestromin and ethinyl estradiol transdermal system to the buttock, upper outer arm, abdomen and upper torso (excluding breast) was examined. While absorption from the abdomen was slightly lower than from other sites, absorption from these anatomic sites was considered to be therapeutically equivalent.The mean (%CV) PK parameters Css and AUC0-168 for NGMN and EE following single buttock application of norelgestromin and ethinyl estradiol transdermal system are summarized in Table 5.In multiple dose studies, AUC0-168 for NGMN and EE was found to increase over time (Table 5). In three-cycle study, these PK parameters reached steady state conditions during Cycle (Figures and 4). Upon removal of the patch, serum levels of EE and NGMN reach very low or non-measurable levels within days. Table 5: Mean (%CV%CV is of Coefficient of variation 100 (standard deviation/mean)) PK Parameters of NGMN and EE Following Three Consecutive Cycles of Norelgestromin and Ethinyl Estradiol Transdermal System Wear on the Buttocknc not calculatedAnalyte Parameter Cycle Cycle Cycle Cycle Week Week Week Week NGMN Css (ng/mL) 0.70 (39.4) 0.70 (41.8) 0.80 (28.7) 0.70 (45.3) AUC0-168 (ng.h/mL) 107 (44.2)105 (43.2)132 (43.4)120 (43.9)t1/2 (h)nc nc nc 32.1 (40.3) EE Css (pg/mL) 46.4 (38.5) 47.6 (36.4) 59.0 (42.5) 49.6 (54.4) AUC0-168 (pg.h/mL) 6796 (39.3)7160 (40.4)10054 (41.8)8840 (58.6)t1/2 (h) nc nc nc 21.0 (43.2) Figure 3: Mean Serum NGMN Concentrations (ng/mL) in Healthy Female Volunteers Following Application of Norelgestromin and Ethinyl Estradiol Transdermal System on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal)Figure 4: Mean Serum EE Concentrations (pg/mL) in Healthy Female Volunteers Following Application of Norelgestromin and Ethinyl Estradiol Transdermal System on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal.)The absorption of NGMN and EE following application of norelgestromin and ethinyl estradiol transdermal system was studied under conditions encountered in health club (sauna, whirlpool and treadmill) and in cold water bath. The results indicated that for NGMN, there were no significant treatment effects on Css or AUC when compared to normal wear. For EE, increased exposures were observed due to sauna, whirlpool and treadmill. There was no significant effect of cold water on these parameters.Results from study of consecutive norelgestromin and ethinyl estradiol transdermal system wear for days and 10 days indicated that serum concentrations of NGMN and EE dropped slightly during the first hours after the patch replacement, and recovered within 12 hours. By Day 10 of patch administration, both NGMN and EE concentrations had decreased by approximately 25% when compared to Day concentrations.. Figure 3: Mean Serum NGMN Concentrations (ng/mL) in Healthy Female Volunteers Following Application of Xulane on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal). Figure 4: Mean Serum EE Concentrations (pg/mL) in Healthy Female Volunteers Following Application of Xulane on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal.). Metabolism. Since norelgestromin and ethinyl estradiol transdermal system is applied transdermally, first-pass metabolism (via the gastrointestinal tract and/or liver) of NGMN and EE that would be expected with oral administration does not occur. Hepatic metabolism of NGMN occurs and metabolites include norgestrel, which is highly bound to SHBG, and various hydroxylated and conjugated metabolites. EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.. Distribution. NGMN and norgestrel (a serum metabolite of NGMN) are highly bound (> 97%) to serum proteins. NGMN is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG, which limits its biological activity. EE is extensively bound to serum albumin and induces an increase in the serum concentrations of SHBG (see Table 5).. Elimination. Following removal of patches, the elimination kinetics of NGMN and EE were consistent for all studies with half-life values of approximately 28 hours and 17 hours, respectively. The metabolites of NGMN and EE are eliminated by renal and fecal pathways. Transdermal versus Oral Contraceptives. The norelgestromin and ethinyl estradiol transdermal system delivers EE and NGMN over 7-day period while oral contraceptives (containing NGM 250 mcg EE 35 mcg) are administered on daily basis. Figures and present mean PK profiles for EE and NGMN following administration of an oral contraceptive (containing NGM 250 mcg EE 35 mcg) compared to the 7-day norelgestromin and ethinyl estradiol transdermal system (containing NGMN 4.86 mg EE 0.53 mg) during Cycle in 32 healthy female volunteers.Figure 5: Mean Serum Concentration-Time Profiles of NGMN Following Once-Daily Administration of an Oral Contraceptive for Two Cycles or Application of Norelgestromin and Ethinyl Estradiol Transdermal System for Two Cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15 to 21, Norelgestromin and Ethinyl Estradiol Transdermal System: Cycle 2, Week 3] Figure 6: Mean Serum Concentration-Time Profiles of EE Following Once-Daily Administration of an Oral Contraceptive for Two Cycles or Application of Norelgestromin and Ethinyl Estradiol Transdermal System for Two Cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15 to 21, Norelgestromin and Ethinyl Estradiol Transdermal System: Cycle 2, Week 3] Table provides the mean (%CV) for NGMN and EE pharmacokinetic (PK) parameters.Table 6: Mean (%CV) NGMN and EE Steady State Pharmacokinetic Parameters Following Application of Norelgestromin and Ethinyl Estradiol Transdermal System and Once-Daily Administration of an Oral Contraceptive (containing NGM 250 mcg EE 35 mcg) in Healthy Female VolunteersParameterNorelgestromin and Ethinyl Estradiol Transdermal SystemCycle 2, Week 3ORAL CONTRACEPTIVECycle 2, Day 21NGMNNGM is rapidly metabolized to NGMN following oral administration Cmax (ng/mL) 1.12 (33.6)2.16 (25.2)AUC0-168 (ng.h/mL)145 (36.8)123 (30.2)Average weekly exposure, calculated as AUC24 7 Css (ng/mL)0.888 (36.6)0.732 (30.2)Cavg EECmax (pg/mL) 97.4 (31.6)133 (27.7)AUC0-168 (pg.h/mL)12,971 (33.1)8,281(26.9) Css (pg/mL)80.0 (33.5)49.3 (26.9) In general, overall exposure for NGMN and EE (AUC and Css) was higher in subjects treated with norelgestromin and ethinyl estradiol transdermal system for both Cycle and Cycle 2, compared to that for the oral contraceptive, while Cmax values were higher in subjects administered the oral contraceptive. Under steady state conditions, AUC0-168 and Css for EE were approximately 55% and 60% higher, respectively, for the transdermal patch, and the Cmax was about 35% higher for the oral contraceptive, respectively. Inter-subject variability (%CV) for the PK parameters following delivery from norelgestromin and ethinyl estradiol transdermal system was higher relative to the variability determined from the oral contraceptive. The mean PK profiles are different between the two products and caution should be exercised when making direct comparison of these PK parameters.In Table 7, percent change in concentrations (%CV) of markers of systemic estrogenic activity (Sex Hormone Binding Globulin [SHBG] and Corticosteroid Binding Globulin [CBG]) from Cycle Day to Cycle Day 22 is presented. Percent change in SHBG concentrations was higher for norelgestromin and ethinyl estradiol transdermal system users compared to women taking the oral contraceptive; percent change in CBG concentrations was similar for norelgestromin and ethinyl estradiol transdermal system and oral contraceptive users. Within each group, the absolute values for SHBG were similar for Cycle 1, Day 22 and Cycle 2, Day 22.Table 7: Mean Percent Change (%CV) in SHBG and CBG Concentrations Following Once-Daily Administration of an Oral Contraceptive (containing NGM 250 mcg EE 35 mcg) for One Cycle and Application of Norelgestromin and Ethinyl Estradiol Transdermal System for One Cycle in Healthy Female VolunteersParameter Norelgestromin and Ethinyl Estradiol Transdermal SystemORAL CONTRACEPTIVE(% change fromDay to Day 22)(% change fromDay to Day 22)SHBG 334 (39.3)200 (43.2)CBG 153 (40.2)157 (33.4). Figure 5: Mean Serum Concentration-Time Profiles of NGMN Following Once-Daily Administration of an Oral Contraceptive for two cycles or Application of Norelgestromin and Ethinyl Estradiol Transdermal System for two cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15 to 21, Norelgestromin and Ethinyl Estradiol Transdermal System: Cycle 2, Week 3]. Figure 6: Mean Serum Concentration-Time Profiles of EE Following Once-Daily Administration of an Oral Contraceptive for two cycles or Application of Norelgestromin and Ethinyl Estradiol Transdermal System for two cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15 to 21, Norelgestromin and Ethinyl Estradiol Transdermal System: Cycle 2, Week 3]. Drug Interactions. In PK drug interaction study, oral administration of tetracycline HCl, 500 mg four times daily for days prior to and days during wear of norelgestromin and ethinyl estradiol transdermal system did not significantly affect the PK of NGMN or EE.. Use in Specific Populations. Effects of Age, Body Weight, Body Surface Area and RaceThe effects of age, body weight, body surface area and race on the PK of NGMN and EE were evaluated in 230 healthy women from nine pharmacokinetic studies of single 7-day applications of norelgestromin and ethinyl estradiol transdermal system. For both NGMN and EE, increasing age, body weight and body surface area each were associated with slight decreases in Css and AUC values. However, only small fraction (10% to 25%) of the overall variability in the PK of NGMN and EE following application of norelgestromin and ethinyl estradiol transdermal system may be associated with any or all of the above demographic parameters. There was no significant effect of race with respect to Caucasians, Hispanics and Blacks.

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. The following serious adverse reactions with the use of combination hormonal contraceptives, including Xulane, are discussed elsewhere in the labeling:oSerious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions (5.1)]oVascular events, including venous and arterial thromboembolic events [see Warnings and Precautions (5.1)]oLiver disease [see Warnings and Precautions (5.3)]Adverse reactions commonly reported by users of combination hormonal contraceptives are: oIrregular uterine bleedingoNausea oBreast tenderness oHeadache. oSerious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions (5.1)]. oVascular events, including venous and arterial thromboembolic events [see Warnings and Precautions (5.1)]. oLiver disease [see Warnings and Precautions (5.3)]. oIrregular uterine bleeding. oNausea oBreast tenderness oHeadache. The most frequent adverse reactions reported during clinical trials (>= 5%) were breast symptoms, nausea/vomiting, headache, application site disorder, abdominal pain, dysmenorrhea, vaginal bleeding and menstrual disorders, and mood, affect and anxiety disorders. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) 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 norelgestromin and ethinyl estradiol transdermal system in 3330 sexually active women (3322 of whom had safety data) who participated in three Phase clinical trials designed to evaluate contraceptive efficacy and safety. These subjects received six or 13 cycles of contraception (norelgestromin and ethinyl estradiol transdermal system or an oral contraceptive comparator in of the trials). The women ranged in age from 18 to 45 years and were predominantly white (91%). The most common adverse reactions (>= 5%) reported during clinical trials were breast symptoms, nausea/vomiting, headache, application site disorder, abdominal pain, dysmenorrhea, vaginal bleeding and menstrual disorders, and mood, affect and anxiety disorders. The most common events leading to discontinuation were application site reaction, breast symptoms (including breast discomfort, engorgement and pain), nausea and/or vomiting, headache and emotional lability. Adverse drug reactions reported by >= 2.5% of norelgestromin and ethinyl estradiol transdermal system-treated subjects in these trials are shown in Table 3.Table 3: Adverse Drug Reactions Reported by >= 2.5% of Norelgestromin and Ethinyl Estradiol Transdermal System-treated Subjects in Three Phase Clinical TrialsSystem/Organ ClassMedDRA version 10.0Adverse reactionNorelgestromin and Ethinyl Estradiol Transdermal System(n 3322)Reproductive system and breast disorders Breast symptomsRepresents bundle of similar terms 22.4%Dysmenorrhea 7.8%Vaginal bleeding and menstrual disorders 6.4%Gastrointestinal disorders Nausea 16.6%Abdominal pain 8.1%Vomiting 5.1%Diarrhea 4.2%Nervous system disorders Headache 21.0%Dizziness 3.3%Migraine 2.7%General disorders and administration site conditions Application site disorder 17.1%Fatigue 2.6%Psychiatric disorders Mood, affect and anxiety disorders 6.3%Skin and subcutaneous tissue disorders Acne 2.9%Pruritus 2.5%Infections and infestations Vaginal yeast infection 3.9%Investigations Weight increased 2.7%Additional adverse drug reactions that occurred in 2.5% of norelgestromin and ethinyl estradiol transdermal system-treated subjects in the above clinical trials datasets are: oGastrointestinal disorders: Abdominal distensionoGeneral disorders and administration site conditions: Fluid retention1, malaiseoHepatobiliary disorders: Cholecystitis oInvestigations: Blood pressure increased, lipid disorders1 oMusculoskeletal and connective tissue disorders: Muscle spasms oPsychiatric disorders: Insomnia, libido decreased, libido increased oReproductive system and breast disorders: Galactorrhea, genital discharge, premenstrual syndrome, uterine spasm, vaginal discharge, vulvovaginal dryness oRespiratory, thoracic and mediastinal disorders: Pulmonary embolism oSkin and subcutaneous tissue disorders: Chloasma, dermatitis contact, erythema, skin irritation1Represents bundle of similar terms. oGastrointestinal disorders: Abdominal distension. oGeneral disorders and administration site conditions: Fluid retention1, malaise. oHepatobiliary disorders: Cholecystitis oInvestigations: Blood pressure increased, lipid disorders1 oMusculoskeletal and connective tissue disorders: Muscle spasms oPsychiatric disorders: Insomnia, libido decreased, libido increased oReproductive system and breast disorders: Galactorrhea, genital discharge, premenstrual syndrome, uterine spasm, vaginal discharge, vulvovaginal dryness oRespiratory, thoracic and mediastinal disorders: Pulmonary embolism oSkin and subcutaneous tissue disorders: Chloasma, dermatitis contact, erythema, skin irritation. 6.2 Postmarketing Experience. The following adverse reactions (Table 4) have been identified during postapproval use of norelgestromin and ethinyl estradiol transdermal system. 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.Table 4: Alphabetical List of Adverse Drug Reactions Identified During Postmarketing Experience with Norelgestromin and Ethinyl Estradiol Transdermal System by System Organ ClassMedDRA version 10.0 System Organ ClassAdverse Drug ReactionsCardiac disordersMyocardial infarctionRepresents bundle of similar terms Endocrine disordersHyperglycemia, insulin resistanceEye disordersContact lens intolerance or complicationGastrointestinal disordersColitisGeneral disorders and administration site conditionsApplication site reaction, edema Hepatobiliary disordersBlood cholesterol abnormal, cholelithiasis, cholestasis, hepatic lesion, jaundice cholestatic, low density lipoprotein increased Immune system disordersAllergic reaction, urticaria InvestigationsBlood glucose abnormal, blood glucose decreased Metabolism and nutrition disordersIncreased appetiteNeoplasms benign, malignant and unspecified (Incl. cysts and polyps)Breast cancer, cervix carcinoma, hepatic adenoma, hepatic neoplasm Nervous system disordersDysgeusia, migraine with aura Psychiatric disordersAnger, emotional disorder, frustration, irritability Reproductive system and breast disordersBreast mass, cervical dysplasia, fibroadenoma of breast, menstrual disorder, suppressed lactation, uterine leiomyoma Skin and subcutaneous tissues disordersAlopecia, eczema, erythema multiforme, erythema nodosum, photosensitivity reaction, pruritus generalized, rash, seborrheic dermatitis, skin reaction Vascular disordersArterial thrombosis, cerebrovascular accident, deep vein thrombosis, hemorrhage intracranial, hypertension, hypertensive crisis, pulmonary embolism, thrombosis.

BOXED WARNING SECTION.


WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH SMOKING, RISK OF VENOUS THROMBOEMBOLISM, AND PHARMACOKINETIC PROFILE OF ETHINYL ESTRADIOL. Cigarette Smoking and Serious Cardiovascular RisksCigarette smoking increases the risk of serious cardiovascular events from hormonal contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, hormonal contraceptives, including Xulane, should not be used by women who are over 35 years of age and smoke. Risk of Venous Thromboembolism The risk of venous thromboembolism (VTE) among women aged 15 to 44 who used the norelgestromin and ethinyl estradiol transdermal system compared to women who used several different oral contraceptives was assessed in five U.S. epidemiologic studies using electronic healthcare claims data. The relative risk estimates ranged from 1.2 to 2.2; one of the studies found statistically significant increased relative risk of VTE for current users of norelgestromin and ethinyl estradiol transdermal system [see Warnings and Precautions (5.1)]. Pharmacokinetic (PK) Profile of Ethinyl Estradiol (EE) The PK profile for the norelgestromin and ethinyl estradiol transdermal system is different from the PK profile for oral contraceptives in that it has higher steady state concentrations and lower peak concentration. Area under the time-concentration curve (AUC) and average concentration at steady state (Css) for EE are approximately 60% higher in women using norelgestromin and ethinyl estradiol transdermal system compared with women using an oral contraceptive containing 35 mcg of EE. In contrast, the peak concentration (Cmax) for EE is approximately 25% lower in women using norelgestromin and ethinyl estradiol transdermal system. It is not known whether there are changes in the risk of serious adverse events based on the differences in PK profiles of EE in women using norelgestromin and ethinyl estradiol transdermal system compared with women using oral contraceptives containing 30 mcg to 35 mcg of EE. Increased estrogen exposure may increase the risk of adverse events, including VTE [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH SMOKING, RISK OF VENOUS THROMBOEMBOLISM, AND PHARMACOKINETIC PROFILE OF ETHINYL ESTRADIOLSee full prescribing information for complete boxed warning.Women over 35 years old who smoke should not use Xulane. (4) Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptives (CHC) use. (4) There may be an increased risk of venous thromboembolism (VTE) among women who use the Xulane patch compared to women who use certain oral contraceptives. (5.1) The pharmacokinetic (PK) profile of ethinyl estradiol (EE) for the norelgestromin and ethinyl estradiol transdermal system is different from the PK profile for oral contraceptives in that it has higher area under the time-concentration curve, steady state concentrations and lower peak concentrations. (5.2).

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. In large clinical trials lasting 12 months, in North America, Europe and South Africa, 3,330 women (ages 18 to 45) completed 22,155 cycles of norelgestromin and ethinyl estradiol transdermal system use, the pregnancy rate in women aged 18 to 35 years was 1.07 (95% confidence interval 0.60, 1.76) per 100 woman-years of norelgestromin and ethinyl estradiol transdermal system use. The racial distribution was 91% Caucasian, 4.9% Black, 1.6% Asian, and 2.4% Other.With respect to weight, of the 15 pregnancies reported with norelgestromin and ethinyl estradiol transdermal system use were among women with baseline body weight >= 198 lbs. (90 kg), which constituted 3% of the study population. The greater proportion of pregnancies among women at or above 198 lbs. was statistically significant and suggests that norelgestromin and ethinyl estradiol transdermal system may be less effective in these women. Patch AdhesionIn the clinical trials with norelgestromin and ethinyl estradiol transdermal system, approximately 2% of the cumulative number of patches completely detached and 3% partially detached. The proportion of subjects with at least one patch that completely detached ranged from 2% to 6%, with reduction from Cycle (6%) to Cycle 13 (2%). For instructions on how to manage detachment of patches, refer to Dosage and Administration (2).

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. Do not prescribe Xulane to women who are known to have the following conditions: oA high risk of arterial or venous thrombotic diseases. Examples include women who are known to: oSmoke, if over age 35 [see Boxed Warning, and Warnings and Precautions (5.1)]oHave deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1)]oHave inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)] oHave cerebrovascular disease [see Warnings and Precautions (5.1)]oHave coronary artery disease [see Warnings and Precautions (5.1)]oHave thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)]oHave uncontrolled hypertension [see Warnings and Precautions (5.5)]oHave diabetes mellitus with vascular disease [see Warnings and Precautions (5.7)]oHave headaches with focal neurological symptoms or have migraine headaches with aura Women over age 35 with any migraine headaches [see Warnings and Precautions (5.8)]oLiver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.3) Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]oUndiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.9)] oPregnancy, because there is no reason to use hormonal contraceptives during pregnancy [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)]oBreast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions (5.12)]oUse of Hepatitis drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for alanine aminotransferase (ALT) elevations [see Warnings and Precautions (5.4)]. oA high risk of arterial or venous thrombotic diseases. Examples include women who are known to: oSmoke, if over age 35 [see Boxed Warning, and Warnings and Precautions (5.1)]oHave deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1)]oHave inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)] oHave cerebrovascular disease [see Warnings and Precautions (5.1)]oHave coronary artery disease [see Warnings and Precautions (5.1)]oHave thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)]oHave uncontrolled hypertension [see Warnings and Precautions (5.5)]oHave diabetes mellitus with vascular disease [see Warnings and Precautions (5.7)]oHave headaches with focal neurological symptoms or have migraine headaches with aura Women over age 35 with any migraine headaches [see Warnings and Precautions (5.8)]. oSmoke, if over age 35 [see Boxed Warning, and Warnings and Precautions (5.1)]. oHave deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1)]. oHave inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)] oHave cerebrovascular disease [see Warnings and Precautions (5.1)]. oHave coronary artery disease [see Warnings and Precautions (5.1)]. oHave thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)]. oHave uncontrolled hypertension [see Warnings and Precautions (5.5)]. oHave diabetes mellitus with vascular disease [see Warnings and Precautions (5.7)]. oHave headaches with focal neurological symptoms or have migraine headaches with aura Women over age 35 with any migraine headaches [see Warnings and Precautions (5.8)]. Women over age 35 with any migraine headaches [see Warnings and Precautions (5.8)]. oLiver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.3) Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. oUndiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.9)] oPregnancy, because there is no reason to use hormonal contraceptives during pregnancy [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)]. oBreast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions (5.12)]. oUse of Hepatitis drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for alanine aminotransferase (ALT) elevations [see Warnings and Precautions (5.4)]. oA high risk of arterial or venous thrombotic diseases (4)oBreast cancer or other estrogen- or progestin-sensitive cancer (4)oLiver tumors or liver disease (4)oUndiagnosed abnormal uterine bleeding (4)oPregnancy (4)oCo-administration with Hepatitis drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (4). oA high risk of arterial or venous thrombotic diseases (4). oBreast cancer or other estrogen- or progestin-sensitive cancer (4). oLiver tumors or liver disease (4). oUndiagnosed abnormal uterine bleeding (4). oPregnancy (4). oCo-administration with Hepatitis drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (4).

DESCRIPTION SECTION.


11 DESCRIPTION. Xulane is transdermal system with contact surface area of 14 cm2. It contains 4.86 mg norelgestromin, USP (NGMN) and 0.53 mg ethinyl estradiol, USP (EE), and its delivery rate is approximately 150 mcg of NGMN and 35 mcg of EE per day. Systemic exposures (as measured by area under the curve [AUC] and steady state concentration [Css]) of NGMN and EE during use of norelgestromin and ethinyl estradiol transdermal system are higher and the Cmax is lower than those produced by an oral contraceptive containing NGM 250 mcg EE 35 mcg. [See Boxed Warning and Clinical Pharmacology (12.3).] Xulane is thin, matrix-type transdermal system consisting of three layers. The backing layer is composed of peach flexible film consisting of pigmented polyethylene outer layer and polyester inner layer. It provides structural support and protects the middle adhesive layer from the environment. The middle layer contains polyisobutene adhesive, crospovidone, mineral oil, non-woven polyester fabric, oleyl alcohol and dipropylene glycol as inactive components. The active components in this layer are the hormones, NGMN and EE. The third layer is the release liner, which protects the adhesive layer during storage and is removed just prior to application. It is transparent polyester film with fluoropolymer coating on the side that is in contact with the middle adhesive layer.The outside of the backing layer is printed with Xulane(R) (norelgestromin and ethinyl estradiol) 150/35 mcg per day in brown ink.Xulane transdermal systems are packaged with additional pieces of protective film above and below the system within each pouch. These pieces of protective film are removed and discarded at the time of use.The structural formulas of the components are:Molecular weight, NGMN: 327.47 Molecular weight, EE: 296.41 Chemical name for NGMN: 18, 19-dinorpregn-4-en-20-yn-3-one, 13-ethyl-, 17-hydroxy, 3-oxime, (17)- Chemical name for EE: 19-Norpregna-1,3,5(10)-trien-20-yne-3, 17-diol, (17)-. Norelgestromin and Ethinyl Estradiol Structural Formulas.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. To achieve maximum contraceptive effectiveness, Xulane must be used exactly as directed. Complete instructions to facilitate patient counseling on proper system usage may be found in the FDA-Approved Patient Labeling.. oXulane uses 28-day (4-week) cycle. Apply new patch to the upper outer arm, abdomen, buttock or back each week for weeks (21 total days). Week is patch-free. (2.1, 2.3) oApply each new patch on the same day of the week. Wear only one patch at time. (2.1) oDo not cut or alter the patch in any way. (2.1) oXulane uses 28-day (4-week) cycle. Apply new patch to the upper outer arm, abdomen, buttock or back each week for weeks (21 total days). Week is patch-free. (2.1, 2.3) oApply each new patch on the same day of the week. Wear only one patch at time. (2.1) oDo not cut or alter the patch in any way. (2.1) 2.1 How to Use Xulane. The Xulane transdermal system uses 28-day (4-week) cycle. new patch is applied each week for weeks (21 total days). Week is patch-free. Withdrawal bleeding is expected during this time. Every new patch should be applied on the same day of the week. This day is known as the Patch Change Day. For example, if the first patch is applied on Monday, all subsequent patches should be applied on Monday. Only one patch should be worn at time. Do not cut, damage or alter the Xulane patch in any way. If the Xulane patch is cut, damaged or altered in size, contraceptive efficacy may be impaired. On the day after Week ends, new 4-week cycle is started by applying new patch. Under no circumstances should there be more than 7-day patch-free interval between dosing cycles. 2.2 How to Start Using Xulane The woman has two options for starting the patch and she should choose the option that is right for her: oFirst Day Start--The woman should apply her first patch during the first 24 hours of her menstrual period. oSunday Start--The woman should apply her first patch on the first Sunday after her menstrual period begins. With this option, non-hormonal backup method of birth control, such as condom and spermicide or diaphragm and spermicide, is needed for the first days of the first cycle only. If her period starts on Sunday, the first patch should be applied that day, and no backup contraception is needed. oWhen Switching From the Pill or Vaginal Contraceptive Ring to the Patch--If the woman is switching from the pill or vaginal contraceptive ring to Xulane, she should complete her current pill cycle or vaginal ring cycle and apply the first Xulane patch on the day she would normally start her next pill or insert her next vaginal ring. If she does not get her period within week after taking the last active pill or removing the last vaginal ring, she should check with her healthcare professional to be sure that she is not pregnant, but she may go ahead and start Xulane for contraception. If the patch is applied more than week after taking the last active pill or removal of the last vaginal ring, she should use non-hormonal contraceptive concurrently for the first days of patch use. oFirst Day Start--The woman should apply her first patch during the first 24 hours of her menstrual period. oSunday Start--The woman should apply her first patch on the first Sunday after her menstrual period begins. With this option, non-hormonal backup method of birth control, such as condom and spermicide or diaphragm and spermicide, is needed for the first days of the first cycle only. If her period starts on Sunday, the first patch should be applied that day, and no backup contraception is needed. oWhen Switching From the Pill or Vaginal Contraceptive Ring to the Patch--If the woman is switching from the pill or vaginal contraceptive ring to Xulane, she should complete her current pill cycle or vaginal ring cycle and apply the first Xulane patch on the day she would normally start her next pill or insert her next vaginal ring. If she does not get her period within week after taking the last active pill or removing the last vaginal ring, she should check with her healthcare professional to be sure that she is not pregnant, but she may go ahead and start Xulane for contraception. If the patch is applied more than week after taking the last active pill or removal of the last vaginal ring, she should use non-hormonal contraceptive concurrently for the first days of patch use. Use after Childbirth Start contraceptive therapy with Xulane in women who elect not to breastfeed no sooner than weeks after childbirth due to increased risk of thromboembolism. If woman begins using Xulane postpartum, and has not yet had period, consider the possibility of ovulation and conception occurring prior to use of Xulane, and instruct her to use an additional method of contraception, such as condom and spermicide or diaphragm and spermicide, for the first days. [See Warnings and Precautions (5.1) and Pregnancy (8.1).] Use after Abortion or Miscarriage After an abortion or miscarriage that occurs in the first trimester, Xulane may be started immediately. An additional method of contraception is not needed if Xulane is started immediately. If use of Xulane is not started within days following first trimester abortion, the woman should follow the instructions for woman starting Xulane for the first time. In the meantime she should be advised to use non-hormonal contraceptive method. Ovulation may occur within 10 days of an abortion or miscarriage. Start Xulane no earlier than weeks after second trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. [See Contraindications (4) and Warnings and Precautions (5.1).] 2.3 How to Apply Xulane CHOOSING PLACE ON THE BODY TO PUT THE PATCH oThe patch may be placed on the upper outer arm, abdomen, buttock or back in place where it wont be rubbed by tight clothing. For example, it should not be placed under the waistband of clothing. oThe patch should not be placed on the breasts, on cut or irritated skin, or on the same location as the previous patch. Before applying the patch: oThe woman should make sure the skin is clean and dry. oShe should not use lotions, creams, oils, powders, or make-up at the patch site. It may cause the patch to fail to stick properly or to become loose.HOW TO APPLY THE PATCH oThe woman should tear open the pouch at the top edge and one side edge. She should peel open the foil pouch. She should gently remove the contents of the foil pouch and discard the additional pieces of film above and below the patch.oThe woman should peel away half of the clear plastic. She should avoid touching the sticky surface with her fingers.oThe woman should apply the sticky side of the patch on the skin she has cleaned and dried. She should then remove the other half of the clear plastic and attach the entire patch to her skin.oThe woman should press firmly on the patch with the palm of her hand for 10 seconds, making sure that the whole patch adheres to her skin.oShe should run her fingers over the entire surface area to smooth out any wrinkles around the outer edges of the patch. The woman should check her patch every day to make sure all edges are sticking correctly.WHEN TO CHANGE THE XULANE PATCHoThe patch works for days (1 week). The woman should apply new patch on the same day each week (her Patch Change Day) for weeks in row. She must make sure she has removed her old patch prior to applying the new patch.oDuring Week 4, she DOES NOT wear patch. She must make sure she removes her old patch. (Her period should begin during this week.)oFollowing Week 4, she repeats the cycle of three weekly applications followed by patch-free week.WHAT IF THE PATCH BECOMES LOOSE OR FALLS OFFThe patch must stick securely to the skin to work properly. If the Xulane patch becomes partially or completely detached and remains detached, insufficient drug delivery occurs. The woman should not try to reapply patch if it is no longer sticky, if it has become stuck to itself or another surface, or if it has other material stuck to it.If patch edge lifts up:oThe woman should press down firmly on the patch with the palm of her hand for 10 seconds, making sure that the whole patch adheres to her skin. She should run her fingers over the entire surface area to smooth out any wrinkles around the edges of the patch. oIf her patch does not stick completely, she should remove it and apply replacement patch.oShe should not tape or wrap the patch to her skin or reapply patch that is partially adhered to clothing. If the patch has been off or partially off:oFor less than Day, she should try to reapply it. If the patch does not adhere completely, she should apply new patch immediately. (No backup contraception is needed and her Patch Change Day will stay the same). oFor more than Day or if she is not sure for how long, she may not be protected from pregnancy. To reduce this risk, she should apply new patch and start new 4-week cycle. She will now have new Patch Change Day and MUST USE NON-HORMONULLL BACKUP CONTRACEPTION (such as condom and spermicide or diaphragm and spermicide) for the first week of her new cycle. IF THE WOMAN FORGETS TO CHANGE HER PATCH oat the start of any patch cycle (Week 1/Day 1): SHE MAY NOT BE PROTECTED FROM PREGNULLNCY. She should apply the first patch of her new cycle as soon as she remembers. There is now new Patch Change Day and new Day 1. The woman must use back-up contraception, such as condom and spermicide or diaphragm and spermicide, for the first week of the new cycle.oin the middle of the patch cycle (Week 2/Day or Week 3/Day 15),ofor or days (up to 48 hours), she should apply new patch immediately. The next patch should be applied on the usual Patch Change Day. No back-up contraception is needed. ofor more than days (48 hours or more), SHE MAY NOT BE PROTECTED FROM PREGNULLNCY. She should stop the current contraceptive cycle and start new 4-week cycle immediately by putting on new patch. There is now new Patch Change Day and new Day 1. The woman must use back-up contraception for week.oat the end of the patch cycle (Week 4/Day 22),oIf the woman forgets to remove her patch, she should take it off as soon as she remembers. The next cycle should be started on the usual Patch Change Day, which is the day after Day 28. No back-up contraception is needed. Under no circumstances should there be more than 7-day patch-free interval between cycles. If there are more than patch-free days, THE WOMAN MAY NOT BE PROTECTED FROM PREGNULLNCY and back-up contraception, such as condom and spermicide or diaphragm and spermicide, must be used for days. As with combined oral contraceptives, the risk of ovulation increases with each day beyond the recommended drug-free period. If she has had intercourse during such an extended patch-free interval, consider the possibility of pregnancy.. oThe patch may be placed on the upper outer arm, abdomen, buttock or back in place where it wont be rubbed by tight clothing. For example, it should not be placed under the waistband of clothing. oThe patch should not be placed on the breasts, on cut or irritated skin, or on the same location as the previous patch. oThe woman should make sure the skin is clean and dry. oShe should not use lotions, creams, oils, powders, or make-up at the patch site. It may cause the patch to fail to stick properly or to become loose.. oThe woman should tear open the pouch at the top edge and one side edge. She should peel open the foil pouch. She should gently remove the contents of the foil pouch and discard the additional pieces of film above and below the patch.. oThe woman should peel away half of the clear plastic. She should avoid touching the sticky surface with her fingers.. oThe woman should apply the sticky side of the patch on the skin she has cleaned and dried. She should then remove the other half of the clear plastic and attach the entire patch to her skin.. oThe woman should press firmly on the patch with the palm of her hand for 10 seconds, making sure that the whole patch adheres to her skin.. oShe should run her fingers over the entire surface area to smooth out any wrinkles around the outer edges of the patch.. oThe patch works for days (1 week). The woman should apply new patch on the same day each week (her Patch Change Day) for weeks in row. She must make sure she has removed her old patch prior to applying the new patch.. oDuring Week 4, she DOES NOT wear patch. She must make sure she removes her old patch. (Her period should begin during this week.). oFollowing Week 4, she repeats the cycle of three weekly applications followed by patch-free week.. oThe woman should press down firmly on the patch with the palm of her hand for 10 seconds, making sure that the whole patch adheres to her skin. She should run her fingers over the entire surface area to smooth out any wrinkles around the edges of the patch. oIf her patch does not stick completely, she should remove it and apply replacement patch.. oShe should not tape or wrap the patch to her skin or reapply patch that is partially adhered to clothing. oFor less than Day, she should try to reapply it. If the patch does not adhere completely, she should apply new patch immediately. (No backup contraception is needed and her Patch Change Day will stay the same). oFor more than Day or if she is not sure for how long, she may not be protected from pregnancy. To reduce this risk, she should apply new patch and start new 4-week cycle. She will now have new Patch Change Day and MUST USE NON-HORMONULLL BACKUP CONTRACEPTION (such as condom and spermicide or diaphragm and spermicide) for the first week of her new cycle. oat the start of any patch cycle (Week 1/Day 1): SHE MAY NOT BE PROTECTED FROM PREGNULLNCY. She should apply the first patch of her new cycle as soon as she remembers. There is now new Patch Change Day and new Day 1. The woman must use back-up contraception, such as condom and spermicide or diaphragm and spermicide, for the first week of the new cycle.. oin the middle of the patch cycle (Week 2/Day or Week 3/Day 15),ofor or days (up to 48 hours), she should apply new patch immediately. The next patch should be applied on the usual Patch Change Day. No back-up contraception is needed. ofor more than days (48 hours or more), SHE MAY NOT BE PROTECTED FROM PREGNULLNCY. She should stop the current contraceptive cycle and start new 4-week cycle immediately by putting on new patch. There is now new Patch Change Day and new Day 1. The woman must use back-up contraception for week.. ofor or days (up to 48 hours), she should apply new patch immediately. The next patch should be applied on the usual Patch Change Day. No back-up contraception is needed. ofor more than days (48 hours or more), SHE MAY NOT BE PROTECTED FROM PREGNULLNCY. She should stop the current contraceptive cycle and start new 4-week cycle immediately by putting on new patch. There is now new Patch Change Day and new Day 1. The woman must use back-up contraception for week.. oat the end of the patch cycle (Week 4/Day 22),oIf the woman forgets to remove her patch, she should take it off as soon as she remembers. The next cycle should be started on the usual Patch Change Day, which is the day after Day 28. No back-up contraception is needed. oIf the woman forgets to remove her patch, she should take it off as soon as she remembers. The next cycle should be started on the usual Patch Change Day, which is the day after Day 28. No back-up contraception is needed. Change Day Adjustment If the woman wishes to change her Patch Change Day, she should complete her current cycle, removing the third Xulane patch on the correct day. During the patch-free week, she may select an earlier Patch Day Change by applying new Xulane patch on the desired day. In no case should there be more than consecutive patch-free days. Breakthrough Bleeding or Spotting In the event of unscheduled or breakthrough bleeding or spotting (bleeding that occurs on the days that Xulane is worn), treatment should be continued. If unscheduled bleeding persists longer than few cycles, consider causes other than Xulane. If the woman does not have scheduled or withdrawal bleeding (bleeding that should occur during the patch-free week), she should resume treatment on the next scheduled Change Day. If Xulane has been used correctly, the absence of withdrawal bleeding is not necessarily an indication of pregnancy. Nevertheless, consider the possibility of pregnancy, especially if absence of withdrawal bleeding occurs in consecutive cycles. Discontinue Xulane if pregnancy is confirmed. In Case of Skin Irritation If patch use results in uncomfortable irritation, the patch may be removed and new patch may be applied to different location until the next Change Day. Only one patch should be worn at time. Additional Instructions for Dosing Unscheduled bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing hormonal contraceptives. In case of breakthrough bleeding, as in all cases of irregular bleeding from the vagina, consider nonfunctional causes. In case of undiagnosed persistent or recurrent abnormal bleeding from the vagina, take adequate diagnostic measures to rule out pregnancy or malignancy. If pathology has been excluded, time or change to another method of contraception may solve the problem. Use of Hormonal Contraceptives in the Event of Missed Menstrual Period 1.If the woman has not adhered to the prescribed schedule, consider the possibility of pregnancy at the time of the first missed period. Discontinue use of Xulane if pregnancy is confirmed. 2.If the woman has adhered to the prescribed regimen and misses one period, she should continue using her contraceptive patches. However, if she has adhered to the prescribed regimen, misses one period and has symptoms associated with pregnancy, rule out pregnancy. Discontinue Xulane use if pregnancy is confirmed.3.If the woman has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Discontinue Xulane use if pregnancy is confirmed. 1.If the woman has not adhered to the prescribed schedule, consider the possibility of pregnancy at the time of the first missed period. Discontinue use of Xulane if pregnancy is confirmed. 2.If the woman has adhered to the prescribed regimen and misses one period, she should continue using her contraceptive patches. However, if she has adhered to the prescribed regimen, misses one period and has symptoms associated with pregnancy, rule out pregnancy. Discontinue Xulane use if pregnancy is confirmed.. 3.If the woman has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Discontinue Xulane use if pregnancy is confirmed. Choosing place on the body to put the patch. How to apply the patch Figure 1. How to apply the patch Figure 2. How to apply the patch Figure 3. How to apply the patch Figure 4.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. Xulane(R) (norelgestromin and ethinyl estradiol transdermal system) is available in one strength of 150 mcg/day norelgestromin (NGMN) and 35 mcg/day ethinyl estradiol (EE).Xulane(R) is 14 cm2 peach, transdermal system printed with Xulane(R) (norelgestromin and ethinyl estradiol) 150/35 mcg per day in brown ink. Each system contains 4.86 mg norelgestromin, USP and 0.53 mg ethinyl estradiol, USP.. Transdermal system: 150 mcg/day norelgestromin and 35 mcg/day ethinyl estradiol. (3).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.. Drugs or herbal products that induce certain enzymes (for example CYP3A4) may decrease the effectiveness of CHCs or increase breakthrough bleeding. Counsel patients to use back-up or alternative method of contraception when enzyme inducers are used with CHCs. (7.1) 7.1 Effects of Other Drugs on Combined Hormonal Contraceptives. Substances Decreasing the Plasma Concentrations of CHCs and Potentially Diminishing the Efficacy of CHCs. Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of CHCs and potentially diminish the effectiveness of CHCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. Johns wort. Interactions between hormonal contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or back-up method when enzyme inducers are used with CHCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.. Substances Increasing the Plasma Concentrations of CHCs. Co-administration of atorvastatin or rosuvastatin and certain CHCs containing EE increase AUC values for EE by approximately 20% to 25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations.. Human Immunodeficiency Virus (HIV)/Hepatitis Virus (HCV) Protease Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors. Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritnoavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).. 7.2 Effects of Combined Hormonal Contraceptives on Other Drugs. CHCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. CHCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, and temazepam. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of CHCs [see Warnings and Precautions (5.13) ].. 7.3Concomitant Use with HCV Combination Therapy Liver Enzyme Elevation Do not co-administer Xulane with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.4)]. 7.4 Interference with Laboratory Tests. The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

GERIATRIC USE SECTION.


8.5 Geriatric Use. Xulane has not been studied in postmenopausal women and is not indicated in this population.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. Product: 50090-1683NDC: 50090-1683-0 d in POUCH.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. Xulane is indicated for the prevention of pregnancy in women who elect to use transdermal patch as method of contraception. Limitation of Use: oXulane may be less effective in preventing pregnancy in women who weigh 198 lbs (90 kg) or more. oXulane may be less effective in preventing pregnancy in women who weigh 198 lbs (90 kg) or more. Xulane is an estrogen/progestin combination hormonal contraceptive (CHC), indicated for the prevention of pregnancy in women who elect to use transdermal patch. (1) Limitation of Use: Xulane may be less effective in preventing pregnancy in women at or above 198 lbs (90 kg). (1).

SPL UNCLASSIFIED SECTION.


2.1 How to Use Xulane. The Xulane transdermal system uses 28-day (4-week) cycle. new patch is applied each week for weeks (21 total days). Week is patch-free. Withdrawal bleeding is expected during this time. Every new patch should be applied on the same day of the week. This day is known as the Patch Change Day. For example, if the first patch is applied on Monday, all subsequent patches should be applied on Monday. Only one patch should be worn at time. Do not cut, damage or alter the Xulane patch in any way. If the Xulane patch is cut, damaged or altered in size, contraceptive efficacy may be impaired. On the day after Week ends, new 4-week cycle is started by applying new patch. Under no circumstances should there be more than 7-day patch-free interval between dosing cycles.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (Patient Information and Instructions for Use). 17.1 General. Counsel patients about the following information: oCigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptive use, and that women who are over 35 years old and smoke should not use combined hormonal contraceptives.oThe use of CHCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of CHCs. The risk of VTE in women using CHCs is to 12 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of CHCs and when restarting hormonal contraception after break of weeks or longer. The risk of thromboembolic disease due to CHCs gradually disappears after use is discontinued.oXulane does not protect against HIV infection (AIDS) and other sexually transmitted infections. oThe Warnings and Precautions associated with combined hormonal contraceptives.oXulane is not to be used during pregnancy; if pregnancy occurs during use of Xulane, instruct the patient to stop further use.oApply single patch the same day every week (Weeks through 3). Instruct patients what to do in the event patch is missed. See WHAT IF FORGET TO CHANGE MY PATCH section in FDA-Approved Patient Labeling. oUse back-up or alternative method of contraception when enzyme inducers are used with Xulane. oCombined hormonal contraceptives may reduce breast milk production; this is less likely to occur if breastfeeding is well established.oWomen who start combined hormonal contraceptives postpartum, and who have not yet had period, should use an additional method of contraception until they have used patch for consecutive days.oAmenorrhea may occur. Consider pregnancy in the event of amenorrhea. Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles, amenorrhea in one cycle if the woman has not adhered to the dosing schedule, or if associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness.oIf the Xulane patch becomes partially or completely detached and remains detached, insufficient drug delivery occurs.oA patch should not be re-applied if it is no longer sticky, becomes stuck to itself or another surface, has other material stuck to it, or has become loose or fallen off before. If patch cannot be re-applied, new patch should be applied immediately. Supplemental adhesives or wraps should not be used.oA woman may not be protected from pregnancy if patch is partially or completely detached for >= 24 hours (or if the woman is not sure how long the patch has been detached). She should start new cycle immediately by applying new patch. Back-up contraception, such as condom and spermicide or diaphragm and spermicide, must be used for the first week of the new cycle.The brands listed are trademarks of their respective owners.. oCigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptive use, and that women who are over 35 years old and smoke should not use combined hormonal contraceptives.. oThe use of CHCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of CHCs. The risk of VTE in women using CHCs is to 12 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of CHCs and when restarting hormonal contraception after break of weeks or longer. The risk of thromboembolic disease due to CHCs gradually disappears after use is discontinued.. oXulane does not protect against HIV infection (AIDS) and other sexually transmitted infections. oThe Warnings and Precautions associated with combined hormonal contraceptives.. oXulane is not to be used during pregnancy; if pregnancy occurs during use of Xulane, instruct the patient to stop further use.. oApply single patch the same day every week (Weeks through 3). Instruct patients what to do in the event patch is missed. See WHAT IF FORGET TO CHANGE MY PATCH section in FDA-Approved Patient Labeling. oUse back-up or alternative method of contraception when enzyme inducers are used with Xulane. oCombined hormonal contraceptives may reduce breast milk production; this is less likely to occur if breastfeeding is well established.. oWomen who start combined hormonal contraceptives postpartum, and who have not yet had period, should use an additional method of contraception until they have used patch for consecutive days.. oAmenorrhea may occur. Consider pregnancy in the event of amenorrhea. Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles, amenorrhea in one cycle if the woman has not adhered to the dosing schedule, or if associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness.. oIf the Xulane patch becomes partially or completely detached and remains detached, insufficient drug delivery occurs.oA patch should not be re-applied if it is no longer sticky, becomes stuck to itself or another surface, has other material stuck to it, or has become loose or fallen off before. If patch cannot be re-applied, new patch should be applied immediately. Supplemental adhesives or wraps should not be used.oA woman may not be protected from pregnancy if patch is partially or completely detached for >= 24 hours (or if the woman is not sure how long the patch has been detached). She should start new cycle immediately by applying new patch. Back-up contraception, such as condom and spermicide or diaphragm and spermicide, must be used for the first week of the new cycle.. oA patch should not be re-applied if it is no longer sticky, becomes stuck to itself or another surface, has other material stuck to it, or has become loose or fallen off before. If patch cannot be re-applied, new patch should be applied immediately. Supplemental adhesives or wraps should not be used.. oA woman may not be protected from pregnancy if patch is partially or completely detached for >= 24 hours (or if the woman is not sure how long the patch has been detached). She should start new cycle immediately by applying new patch. Back-up contraception, such as condom and spermicide or diaphragm and spermicide, must be used for the first week of the new cycle.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. NGMN is the active progestin largely responsible for the progestational activity that occurs in women following application of norelgestromin and ethinyl estradiol transdermal system. NGMN is also the primary active metabolite produced following oral administration of NGM, the progestin component of some oral contraceptive products.Combination hormonal contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. See Warnings and Precautions (5.3, 5.12) and Use in Specific Populations (8.1).Norelgestromin was tested in in vitro mutagenicity assays (bacterial plate incorporation mutation assay, CHO/HGPRT mutation assay, chromosomal aberration assay using cultured human peripheral lymphocytes) and in one in vivo test (rat micronucleus assay) and found to have no genotoxic potential.

NURSING MOTHERS SECTION.


8.3 Nursing Mothers. The effects of Xulane in nursing mothers have not been evaluated and are unknown. When possible, advise the nursing mother to use other forms of contraception until she has completely weaned her child. Estrogen-containing CHCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of contraceptive steroids and/or metabolites are present in breast milk.

OVERDOSAGE SECTION.


10 OVERDOSAGE. Overdosage may cause nausea and vomiting, and withdrawal bleeding may occur in females. In case of suspected overdose, all Xulane patches should be removed and symptomatic treatment given.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


norelgestromin and ethinyl estradiol. Label Image.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. Safety and efficacy of norelgestromin and ethinyl estradiol transdermal system have been established in women of reproductive age. Efficacy is expected to be the same for post-pubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.

PHARMACODYNULLMICS SECTION.


12.2 Pharmacodynamics. One clinical trial assessed the return of hypothalamic-pituitary-ovarian axis function post-therapy and found that follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol mean values, though suppressed during therapy, returned to near baseline values during the weeks post-therapy.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. Absorption. The systemic delivery rate of NGMN and EE from norelgestromin and ethinyl estradiol transdermal system is approximately 150 mcg of NGMN and 35 mcg of EE per day based on comparative analysis with intravenous (IV) data. Following single application of norelgestromin and ethinyl estradiol transdermal system, both NGMN and EE reach plateau by approximately 48 hours. Pooled data from the clinical studies have demonstrated that steady state is reached within weeks of application. In one of the clinical studies, Css concentrations across all subjects ranged from 0.305 to 1.53 ng/mL for NGMN and from 23 to 137 pg/mL for EE.Absorption of NGMN and EE following application of norelgestromin and ethinyl estradiol transdermal system to the buttock, upper outer arm, abdomen and upper torso (excluding breast) was examined. While absorption from the abdomen was slightly lower than from other sites, absorption from these anatomic sites was considered to be therapeutically equivalent.The mean (%CV) PK parameters Css and AUC0-168 for NGMN and EE following single buttock application of norelgestromin and ethinyl estradiol transdermal system are summarized in Table 5.In multiple dose studies, AUC0-168 for NGMN and EE was found to increase over time (Table 5). In three-cycle study, these PK parameters reached steady state conditions during Cycle (Figures and 4). Upon removal of the patch, serum levels of EE and NGMN reach very low or non-measurable levels within days. Table 5: Mean (%CV%CV is of Coefficient of variation 100 (standard deviation/mean)) PK Parameters of NGMN and EE Following Three Consecutive Cycles of Norelgestromin and Ethinyl Estradiol Transdermal System Wear on the Buttocknc not calculatedAnalyte Parameter Cycle Cycle Cycle Cycle Week Week Week Week NGMN Css (ng/mL) 0.70 (39.4) 0.70 (41.8) 0.80 (28.7) 0.70 (45.3) AUC0-168 (ng.h/mL) 107 (44.2)105 (43.2)132 (43.4)120 (43.9)t1/2 (h)nc nc nc 32.1 (40.3) EE Css (pg/mL) 46.4 (38.5) 47.6 (36.4) 59.0 (42.5) 49.6 (54.4) AUC0-168 (pg.h/mL) 6796 (39.3)7160 (40.4)10054 (41.8)8840 (58.6)t1/2 (h) nc nc nc 21.0 (43.2) Figure 3: Mean Serum NGMN Concentrations (ng/mL) in Healthy Female Volunteers Following Application of Norelgestromin and Ethinyl Estradiol Transdermal System on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal)Figure 4: Mean Serum EE Concentrations (pg/mL) in Healthy Female Volunteers Following Application of Norelgestromin and Ethinyl Estradiol Transdermal System on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal.)The absorption of NGMN and EE following application of norelgestromin and ethinyl estradiol transdermal system was studied under conditions encountered in health club (sauna, whirlpool and treadmill) and in cold water bath. The results indicated that for NGMN, there were no significant treatment effects on Css or AUC when compared to normal wear. For EE, increased exposures were observed due to sauna, whirlpool and treadmill. There was no significant effect of cold water on these parameters.Results from study of consecutive norelgestromin and ethinyl estradiol transdermal system wear for days and 10 days indicated that serum concentrations of NGMN and EE dropped slightly during the first hours after the patch replacement, and recovered within 12 hours. By Day 10 of patch administration, both NGMN and EE concentrations had decreased by approximately 25% when compared to Day concentrations.. Figure 3: Mean Serum NGMN Concentrations (ng/mL) in Healthy Female Volunteers Following Application of Xulane on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal). Figure 4: Mean Serum EE Concentrations (pg/mL) in Healthy Female Volunteers Following Application of Xulane on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal.). Metabolism. Since norelgestromin and ethinyl estradiol transdermal system is applied transdermally, first-pass metabolism (via the gastrointestinal tract and/or liver) of NGMN and EE that would be expected with oral administration does not occur. Hepatic metabolism of NGMN occurs and metabolites include norgestrel, which is highly bound to SHBG, and various hydroxylated and conjugated metabolites. EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.. Distribution. NGMN and norgestrel (a serum metabolite of NGMN) are highly bound (> 97%) to serum proteins. NGMN is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG, which limits its biological activity. EE is extensively bound to serum albumin and induces an increase in the serum concentrations of SHBG (see Table 5).. Elimination. Following removal of patches, the elimination kinetics of NGMN and EE were consistent for all studies with half-life values of approximately 28 hours and 17 hours, respectively. The metabolites of NGMN and EE are eliminated by renal and fecal pathways. Transdermal versus Oral Contraceptives. The norelgestromin and ethinyl estradiol transdermal system delivers EE and NGMN over 7-day period while oral contraceptives (containing NGM 250 mcg EE 35 mcg) are administered on daily basis. Figures and present mean PK profiles for EE and NGMN following administration of an oral contraceptive (containing NGM 250 mcg EE 35 mcg) compared to the 7-day norelgestromin and ethinyl estradiol transdermal system (containing NGMN 4.86 mg EE 0.53 mg) during Cycle in 32 healthy female volunteers.Figure 5: Mean Serum Concentration-Time Profiles of NGMN Following Once-Daily Administration of an Oral Contraceptive for Two Cycles or Application of Norelgestromin and Ethinyl Estradiol Transdermal System for Two Cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15 to 21, Norelgestromin and Ethinyl Estradiol Transdermal System: Cycle 2, Week 3] Figure 6: Mean Serum Concentration-Time Profiles of EE Following Once-Daily Administration of an Oral Contraceptive for Two Cycles or Application of Norelgestromin and Ethinyl Estradiol Transdermal System for Two Cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15 to 21, Norelgestromin and Ethinyl Estradiol Transdermal System: Cycle 2, Week 3] Table provides the mean (%CV) for NGMN and EE pharmacokinetic (PK) parameters.Table 6: Mean (%CV) NGMN and EE Steady State Pharmacokinetic Parameters Following Application of Norelgestromin and Ethinyl Estradiol Transdermal System and Once-Daily Administration of an Oral Contraceptive (containing NGM 250 mcg EE 35 mcg) in Healthy Female VolunteersParameterNorelgestromin and Ethinyl Estradiol Transdermal SystemCycle 2, Week 3ORAL CONTRACEPTIVECycle 2, Day 21NGMNNGM is rapidly metabolized to NGMN following oral administration Cmax (ng/mL) 1.12 (33.6)2.16 (25.2)AUC0-168 (ng.h/mL)145 (36.8)123 (30.2)Average weekly exposure, calculated as AUC24 7 Css (ng/mL)0.888 (36.6)0.732 (30.2)Cavg EECmax (pg/mL) 97.4 (31.6)133 (27.7)AUC0-168 (pg.h/mL)12,971 (33.1)8,281(26.9) Css (pg/mL)80.0 (33.5)49.3 (26.9) In general, overall exposure for NGMN and EE (AUC and Css) was higher in subjects treated with norelgestromin and ethinyl estradiol transdermal system for both Cycle and Cycle 2, compared to that for the oral contraceptive, while Cmax values were higher in subjects administered the oral contraceptive. Under steady state conditions, AUC0-168 and Css for EE were approximately 55% and 60% higher, respectively, for the transdermal patch, and the Cmax was about 35% higher for the oral contraceptive, respectively. Inter-subject variability (%CV) for the PK parameters following delivery from norelgestromin and ethinyl estradiol transdermal system was higher relative to the variability determined from the oral contraceptive. The mean PK profiles are different between the two products and caution should be exercised when making direct comparison of these PK parameters.In Table 7, percent change in concentrations (%CV) of markers of systemic estrogenic activity (Sex Hormone Binding Globulin [SHBG] and Corticosteroid Binding Globulin [CBG]) from Cycle Day to Cycle Day 22 is presented. Percent change in SHBG concentrations was higher for norelgestromin and ethinyl estradiol transdermal system users compared to women taking the oral contraceptive; percent change in CBG concentrations was similar for norelgestromin and ethinyl estradiol transdermal system and oral contraceptive users. Within each group, the absolute values for SHBG were similar for Cycle 1, Day 22 and Cycle 2, Day 22.Table 7: Mean Percent Change (%CV) in SHBG and CBG Concentrations Following Once-Daily Administration of an Oral Contraceptive (containing NGM 250 mcg EE 35 mcg) for One Cycle and Application of Norelgestromin and Ethinyl Estradiol Transdermal System for One Cycle in Healthy Female VolunteersParameter Norelgestromin and Ethinyl Estradiol Transdermal SystemORAL CONTRACEPTIVE(% change fromDay to Day 22)(% change fromDay to Day 22)SHBG 334 (39.3)200 (43.2)CBG 153 (40.2)157 (33.4). Figure 5: Mean Serum Concentration-Time Profiles of NGMN Following Once-Daily Administration of an Oral Contraceptive for two cycles or Application of Norelgestromin and Ethinyl Estradiol Transdermal System for two cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15 to 21, Norelgestromin and Ethinyl Estradiol Transdermal System: Cycle 2, Week 3]. Figure 6: Mean Serum Concentration-Time Profiles of EE Following Once-Daily Administration of an Oral Contraceptive for two cycles or Application of Norelgestromin and Ethinyl Estradiol Transdermal System for two cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15 to 21, Norelgestromin and Ethinyl Estradiol Transdermal System: Cycle 2, Week 3]. Drug Interactions. In PK drug interaction study, oral administration of tetracycline HCl, 500 mg four times daily for days prior to and days during wear of norelgestromin and ethinyl estradiol transdermal system did not significantly affect the PK of NGMN or EE.. Use in Specific Populations. Effects of Age, Body Weight, Body Surface Area and RaceThe effects of age, body weight, body surface area and race on the PK of NGMN and EE were evaluated in 230 healthy women from nine pharmacokinetic studies of single 7-day applications of norelgestromin and ethinyl estradiol transdermal system. For both NGMN and EE, increasing age, body weight and body surface area each were associated with slight decreases in Css and AUC values. However, only small fraction (10% to 25%) of the overall variability in the PK of NGMN and EE following application of norelgestromin and ethinyl estradiol transdermal system may be associated with any or all of the above demographic parameters. There was no significant effect of race with respect to Caucasians, Hispanics and Blacks.

PREGNULLNCY SECTION.


8.1 Pregnancy. There is little or no increased risk of birth defects in women who inadvertently use hormonal contraceptives during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose hormonal contraceptives prior to conception or during early pregnancy.The administration of hormonal contraceptives to induce withdrawal bleeding should not be used as test for pregnancy. Hormonal contraceptives should not be used during pregnancy to treat threatened or habitual abortion.

RECENT MAJOR CHANGES SECTION.


Contraindications (4) 4/2017Warnings (5.4) 4/2017.

REFERENCES SECTION.


15 REFERENCES. 1.Cole JA, Norman H, Doherty M, Walker AM. Venous Thromboembolism, Myocardial Infarction, and Stroke among Transdermal Contraceptive System Users. Obstetrics Gynecology 2007; 109(2):339-346.2.Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous thromboembolism in women using contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 mcg of ethinyl estradiol. Contraception 2006; 73: 223-228.3.Jick S, Kaye JA, Jick H. Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 ug of EE. Contraception 2007; 76: 4-7.4.Jick S, Hagberg K, Hernandez R, Kaye J. Postmarketing study of ORTHO EVRA(R) and levonorgestrel oral contraceptives containing hormonal contraceptives with 30 mcg of ethinyl estradiol in relation to nonfatal venous thromboembolism. Contraception 2010; 81: 16-21.5.Jick S, Hagberg K, Kaye J. ORTHO EVRA(R) and venous thromboembolism: an update. Letter to the Editor. Contraception 2010; 81: 452-453.6.Dore D, Norman H, Loughlin J, Seeger D. Extended case-control study results on thromboembolic outcomes among transdermal contraceptive users. Contraception 2010; 81: 408-413.7.Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users [published erratum appears in Obstet Gynecol 2008; 111:1449].8.Dore D, Norman H, Seeger, J. Eligibility criteria in venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Letter to the Editor. Obstetrics Gynecology 2009; 114(1):175.9.Combined hormonal contraceptives (CHCs) and the risk of cardiovascular endpoints. Sidney,S. (primary author) http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf, accessed Oct 27, 2011.10.Heit JA, Kobbervig CE, James AH, Petterson TM, Kent R. Bailey, KR; Melton LJ. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: 30-year population-based study. Ann Intern Med. 2005; 143: 697-706.. 1.Cole JA, Norman H, Doherty M, Walker AM. Venous Thromboembolism, Myocardial Infarction, and Stroke among Transdermal Contraceptive System Users. Obstetrics Gynecology 2007; 109(2):339-346.. 2.Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous thromboembolism in women using contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 mcg of ethinyl estradiol. Contraception 2006; 73: 223-228.. 3.Jick S, Kaye JA, Jick H. Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 ug of EE. Contraception 2007; 76: 4-7.. 4.Jick S, Hagberg K, Hernandez R, Kaye J. Postmarketing study of ORTHO EVRA(R) and levonorgestrel oral contraceptives containing hormonal contraceptives with 30 mcg of ethinyl estradiol in relation to nonfatal venous thromboembolism. Contraception 2010; 81: 16-21.. 5.Jick S, Hagberg K, Kaye J. ORTHO EVRA(R) and venous thromboembolism: an update. Letter to the Editor. Contraception 2010; 81: 452-453.. 6.Dore D, Norman H, Loughlin J, Seeger D. Extended case-control study results on thromboembolic outcomes among transdermal contraceptive users. Contraception 2010; 81: 408-413.. 7.Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users [published erratum appears in Obstet Gynecol 2008; 111:1449].. 8.Dore D, Norman H, Seeger, J. Eligibility criteria in venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Letter to the Editor. Obstetrics Gynecology 2009; 114(1):175.. 9.Combined hormonal contraceptives (CHCs) and the risk of cardiovascular endpoints. Sidney,S. (primary author) http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf, accessed Oct 27, 2011.. 10.Heit JA, Kobbervig CE, James AH, Petterson TM, Kent R. Bailey, KR; Melton LJ. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: 30-year population-based study. Ann Intern Med. 2005; 143: 697-706.

SPL PATIENT PACKAGE INSERT SECTION.


Instructions for Use. Xulane is for skin use only. Do not cut, damage, or alter the Xulane patch in any way. How to start using your Xulane patch: oIf you are not currently using hormonal birth control, you have ways to begin using your Xulane patch. Choose the way that is best for you: oFirst day start: Apply your first Xulane patch during the first 24 hours of your menstrual period. oSunday start: Apply your first Xulane patch on the first Sunday after your menstrual period begins. Use non-hormonal contraceptive method of birth control, such as condom and spermicide or diaphragm and spermicide, for the first days of your first cycle only. If your period starts on Sunday, apply your first Xulane patch that day, and no back-up birth control is needed. oIf you are changing from the pill or vaginal contraceptive ring to the Xulane patch: oComplete your current pill cycle or vaginal ring cycle. Apply your first Xulane patch on the day you would normally start your next pill or insert your next vaginal ring. oIf you do not get your period within week after taking your last active pill or removing your last vaginal ring, check with your healthcare provider to make sure you are not pregnant. You may still go ahead and start Xulane for contraception. oIf you apply your Xulane patch more than week after taking your last active pill or removing your last vaginal ring, use non-hormonal contraceptive method with the Xulane patch for the first days of patch use. oIf you are starting Xulane after childbirth: oIf you are not breastfeeding, wait weeks before using Xulane and use non-hormonal contraceptive method of birth control, such as condom and spermicide or diaphragm and spermicide, for the first days of your first cycle only. If you have had sex since your baby was born, wait for your first period, or see your healthcare provider to make sure you are not pregnant before starting Xulane. oIf you are starting Xulane after miscarriage or abortion: oYou may start Xulane immediately after miscarriage or abortion that occurs in the first 12 weeks (first trimester) of pregnancy. You do not need to use another contraceptive method. oIf you do not start Xulane within days after first trimester miscarriage or abortion, use non-hormonal contraceptive method of birth control, such as condom and spermicide or diaphragm and spermicide, while you wait for your period to start. You have ways to begin using your Xulane patch. Choose the way that is best for you: First day start: Apply your first Xulane patch during the first 24 hours of your menstrual period. Sunday start: Apply your first Xulane patch on the first Sunday after your menstrual period begins. Use non-hormonal contraceptive method of birth control, such as condom and spermicide or diaphragm and spermicide, for the first days of your first cycle only. If your period starts on Sunday, apply your first Xulane patch that day, and no back-up birth control is needed. oIf you are starting Xulane after miscarriage or abortion that occurs after the first 12 weeks of pregnancy (second trimester), wait weeks before using Xulane and use non-hormonal contraceptive method of birth control, such as condom and spermicide or diaphragm and spermicide, for the first days of your first cycle only. If you have had sex since your miscarriage or abortion, wait for your first period, or see your healthcare provider to make sure you are not pregnant before starting Xulane. Figure is picture of the Xulane patch. Step 1. Choose place on your body for your Xulane patchoThe Xulane patch may be placed on your upper outer arm, abdomen, buttock or back in place where it will not be rubbed by tight clothing. Avoid the waistline because clothing and belts may cause your patch to be rubbed off. oDo not apply the patch to your breasts. oApply the Xulane patch only to skin that is clean, dry, and free of any powder, make-up, cream, oil, or lotion.oDo not apply the Xulane patch to cut or irritated skin, or in the same location as the previous Xulane patch. Step 2: Apply your Xulane patchoTear open the pouch at the top edge and one side edge. Peel open the foil pouch. Gently remove the contents of the foil pouch and discard the additional pieces of film above and below the Xulane patch.oPeel away half of the clear plastic. Avoid touching the sticky surface with your fingers.oApply the sticky side of the Xulane patch to clean, dry skin. Remove the other half of the clear plastic and apply the entire patch to your skin.oPress firmly on the Xulane patch with the palm of your hand for 10 seconds, making sure that the whole patch sticks to your skin.oRun your fingers over the entire surface area to smooth out any wrinkles around the outer edges of the Xulane patch.oCheck your Xulane patch every day to make sure all edges are sticking correctly.Step 3: Throwing away your Xulane patch oTo throw away the Xulane patch, fold the sticky side of the patch together, place it in sturdy child-proof container, and place the container in the trash.oUsed Xulane patches should not be flushed in the toilet. Important notes: oYour Xulane patch must stick securely to your skin to work properly. oDo not try to reapply Xulane patch if it is no longer sticky, if it has become stuck to itself or another surface, or if it has other material stuck to it. Do not tape or wrap the patch to your skin or reapply patch that is partially adhered to clothing. oIf your Xulane patch edge lifts up: oPress down firmly on the patch with the palm of your hand for 10 seconds, making sure that the whole patch sticks to your skin. Run your fingers over the entire surface area to smooth out any wrinkles around the edges of the Xulane patch. oIf your Xulane patch does not stick completely, remove it and apply new Xulane patch. oDo not tape or wrap the Xulane patch to your skin or reapply Xulane patch that is partially stuck to clothing. oIf your Xulane patch has been off or partially off: oFor less than Day, try to reapply it. If the Xulane patch does not stick completely, apply new Xulane patch immediately. No back-up contraception is needed and your Patch Change Day will stay the same. oFor more than Day or if you are not sure for how long, you could become pregnant. To reduce this chance, apply new Xulane patch and start new week cycle. You will now have new Patch Change Day. Use non-hormonal back-up contraception method such as condom and spermicide or diaphragm and spermicide for the first week of your new week Xulane cycle. oIf you want to move your Patch Change Day to different day of the week, finish your current cycle. Remove your third Xulane patch on the correct day. oDuring week 4, the Patch Free Week (Day 22 through Day 28), you may choose an earlier Patch Change Day by applying new patch on the day you prefer. You now have new Day and new Patch Change Day. oIf your Xulane patch becomes uncomfortable or your application site is red, painful or swollen, change your Xulane patch. Remove your Xulane patch and apply new patch to new location until your next Patch Change Day. oIf you forget to change or remove your Xulane patch: oAt the start of any patch cycle (Week 1, Day 1): You could become pregnant. You must use back-up contraception method for days. Apply the first Xulane patch of your new cycle as soon as you remember. You now have new Patch Change Day and new Day 1. oIn the middle of your patch cycle (Week or Week 3): If you forget to change your Xulane patch for or days, apply new Xulane patch as soon as you remember. Apply your next patch on your normal Patch Change Day. No back-up contraception method is needed. If you forget to change your Xulane patch for more than days, you could become pregnant. Start new week cycle as soon as you remember by putting on new Xulane patch. You now have different Patch Change Day and new Day 1. You must use back-up contraception method for the first days of your new cycle. oAt the end of your patch cycle (Week 4): If you forget to remove your Xulane patch, take it off as soon as you remember. Start your next cycle on your normal Patch Change Day, the day after Day 28. No back-up contraception method is needed. oIf you forget to apply your Xulane patch at the start of your next patch cycle, you could become pregnant. Apply the first Xulane patch of your new cycle as soon as you remember. You now have new Patch Change Day and new Day 1. Use non-hormonal back-up contraception method such as condom and spermicide or diaphragm and spermicide for the first days of your new week Xulane cycle. oIf you have trouble remembering to change your Xulane patch, talk to your healthcare provider about how to make patch changing easier or about using another method of contraception. oIf you are not sure how to use your Xulane patch: oUse back-up contraception method such as condom and spermicide or diaphragm and spermicide anytime you have sex. Make sure to have one of these non-hormonal contraception methods ready at all times. oTalk to your healthcare provider for instructions on using your Xulane patch.This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Revised: 4/2017NEETS:R14. oIf you are not currently using hormonal birth control, you have ways to begin using your Xulane patch. Choose the way that is best for you: oFirst day start: Apply your first Xulane patch during the first 24 hours of your menstrual period. oSunday start: Apply your first Xulane patch on the first Sunday after your menstrual period begins. Use non-hormonal contraceptive method of birth control, such as condom and spermicide or diaphragm and spermicide, for the first days of your first cycle only. If your period starts on Sunday, apply your first Xulane patch that day, and no back-up birth control is needed. oFirst day start: Apply your first Xulane patch during the first 24 hours of your menstrual period. oSunday start: Apply your first Xulane patch on the first Sunday after your menstrual period begins. Use non-hormonal contraceptive method of birth control, such as condom and spermicide or diaphragm and spermicide, for the first days of your first cycle only. If your period starts on Sunday, apply your first Xulane patch that day, and no back-up birth control is needed. oIf you are changing from the pill or vaginal contraceptive ring to the Xulane patch: oComplete your current pill cycle or vaginal ring cycle. Apply your first Xulane patch on the day you would normally start your next pill or insert your next vaginal ring. oIf you do not get your period within week after taking your last active pill or removing your last vaginal ring, check with your healthcare provider to make sure you are not pregnant. You may still go ahead and start Xulane for contraception. oIf you apply your Xulane patch more than week after taking your last active pill or removing your last vaginal ring, use non-hormonal contraceptive method with the Xulane patch for the first days of patch use. oComplete your current pill cycle or vaginal ring cycle. Apply your first Xulane patch on the day you would normally start your next pill or insert your next vaginal ring. oIf you do not get your period within week after taking your last active pill or removing your last vaginal ring, check with your healthcare provider to make sure you are not pregnant. You may still go ahead and start Xulane for contraception. oIf you apply your Xulane patch more than week after taking your last active pill or removing your last vaginal ring, use non-hormonal contraceptive method with the Xulane patch for the first days of patch use. oIf you are starting Xulane after childbirth: oIf you are not breastfeeding, wait weeks before using Xulane and use non-hormonal contraceptive method of birth control, such as condom and spermicide or diaphragm and spermicide, for the first days of your first cycle only. If you have had sex since your baby was born, wait for your first period, or see your healthcare provider to make sure you are not pregnant before starting Xulane. oIf you are not breastfeeding, wait weeks before using Xulane and use non-hormonal contraceptive method of birth control, such as condom and spermicide or diaphragm and spermicide, for the first days of your first cycle only. If you have had sex since your baby was born, wait for your first period, or see your healthcare provider to make sure you are not pregnant before starting Xulane. oIf you are starting Xulane after miscarriage or abortion: oYou may start Xulane immediately after miscarriage or abortion that occurs in the first 12 weeks (first trimester) of pregnancy. You do not need to use another contraceptive method. oIf you do not start Xulane within days after first trimester miscarriage or abortion, use non-hormonal contraceptive method of birth control, such as condom and spermicide or diaphragm and spermicide, while you wait for your period to start. You have ways to begin using your Xulane patch. Choose the way that is best for you: First day start: Apply your first Xulane patch during the first 24 hours of your menstrual period. Sunday start: Apply your first Xulane patch on the first Sunday after your menstrual period begins. Use non-hormonal contraceptive method of birth control, such as condom and spermicide or diaphragm and spermicide, for the first days of your first cycle only. If your period starts on Sunday, apply your first Xulane patch that day, and no back-up birth control is needed. oIf you are starting Xulane after miscarriage or abortion that occurs after the first 12 weeks of pregnancy (second trimester), wait weeks before using Xulane and use non-hormonal contraceptive method of birth control, such as condom and spermicide or diaphragm and spermicide, for the first days of your first cycle only. If you have had sex since your miscarriage or abortion, wait for your first period, or see your healthcare provider to make sure you are not pregnant before starting Xulane. oYou may start Xulane immediately after miscarriage or abortion that occurs in the first 12 weeks (first trimester) of pregnancy. You do not need to use another contraceptive method. oIf you do not start Xulane within days after first trimester miscarriage or abortion, use non-hormonal contraceptive method of birth control, such as condom and spermicide or diaphragm and spermicide, while you wait for your period to start. You have ways to begin using your Xulane patch. Choose the way that is best for you: First day start: Apply your first Xulane patch during the first 24 hours of your menstrual period. Sunday start: Apply your first Xulane patch on the first Sunday after your menstrual period begins. Use non-hormonal contraceptive method of birth control, such as condom and spermicide or diaphragm and spermicide, for the first days of your first cycle only. If your period starts on Sunday, apply your first Xulane patch that day, and no back-up birth control is needed. First day start: Apply your first Xulane patch during the first 24 hours of your menstrual period. Sunday start: Apply your first Xulane patch on the first Sunday after your menstrual period begins. Use non-hormonal contraceptive method of birth control, such as condom and spermicide or diaphragm and spermicide, for the first days of your first cycle only. If your period starts on Sunday, apply your first Xulane patch that day, and no back-up birth control is needed. oIf you are starting Xulane after miscarriage or abortion that occurs after the first 12 weeks of pregnancy (second trimester), wait weeks before using Xulane and use non-hormonal contraceptive method of birth control, such as condom and spermicide or diaphragm and spermicide, for the first days of your first cycle only. If you have had sex since your miscarriage or abortion, wait for your first period, or see your healthcare provider to make sure you are not pregnant before starting Xulane. Step 1. Choose place on your body for your Xulane patch. oThe Xulane patch may be placed on your upper outer arm, abdomen, buttock or back in place where it will not be rubbed by tight clothing. Avoid the waistline because clothing and belts may cause your patch to be rubbed off. oDo not apply the patch to your breasts. oApply the Xulane patch only to skin that is clean, dry, and free of any powder, make-up, cream, oil, or lotion.. oDo not apply the Xulane patch to cut or irritated skin, or in the same location as the previous Xulane patch. Step 2: Apply your Xulane patch. oTear open the pouch at the top edge and one side edge. Peel open the foil pouch. Gently remove the contents of the foil pouch and discard the additional pieces of film above and below the Xulane patch.. oPeel away half of the clear plastic. Avoid touching the sticky surface with your fingers.. oApply the sticky side of the Xulane patch to clean, dry skin. Remove the other half of the clear plastic and apply the entire patch to your skin.. oPress firmly on the Xulane patch with the palm of your hand for 10 seconds, making sure that the whole patch sticks to your skin.. oRun your fingers over the entire surface area to smooth out any wrinkles around the outer edges of the Xulane patch.. oCheck your Xulane patch every day to make sure all edges are sticking correctly.. oTo throw away the Xulane patch, fold the sticky side of the patch together, place it in sturdy child-proof container, and place the container in the trash.. oUsed Xulane patches should not be flushed in the toilet. oYour Xulane patch must stick securely to your skin to work properly. oDo not try to reapply Xulane patch if it is no longer sticky, if it has become stuck to itself or another surface, or if it has other material stuck to it. Do not tape or wrap the patch to your skin or reapply patch that is partially adhered to clothing. oIf your Xulane patch edge lifts up: oPress down firmly on the patch with the palm of your hand for 10 seconds, making sure that the whole patch sticks to your skin. Run your fingers over the entire surface area to smooth out any wrinkles around the edges of the Xulane patch. oIf your Xulane patch does not stick completely, remove it and apply new Xulane patch. oDo not tape or wrap the Xulane patch to your skin or reapply Xulane patch that is partially stuck to clothing. oPress down firmly on the patch with the palm of your hand for 10 seconds, making sure that the whole patch sticks to your skin. Run your fingers over the entire surface area to smooth out any wrinkles around the edges of the Xulane patch. oIf your Xulane patch does not stick completely, remove it and apply new Xulane patch. oDo not tape or wrap the Xulane patch to your skin or reapply Xulane patch that is partially stuck to clothing. oIf your Xulane patch has been off or partially off: oFor less than Day, try to reapply it. If the Xulane patch does not stick completely, apply new Xulane patch immediately. No back-up contraception is needed and your Patch Change Day will stay the same. oFor more than Day or if you are not sure for how long, you could become pregnant. To reduce this chance, apply new Xulane patch and start new week cycle. You will now have new Patch Change Day. Use non-hormonal back-up contraception method such as condom and spermicide or diaphragm and spermicide for the first week of your new week Xulane cycle. oFor less than Day, try to reapply it. If the Xulane patch does not stick completely, apply new Xulane patch immediately. No back-up contraception is needed and your Patch Change Day will stay the same. oFor more than Day or if you are not sure for how long, you could become pregnant. To reduce this chance, apply new Xulane patch and start new week cycle. You will now have new Patch Change Day. Use non-hormonal back-up contraception method such as condom and spermicide or diaphragm and spermicide for the first week of your new week Xulane cycle. oIf you want to move your Patch Change Day to different day of the week, finish your current cycle. Remove your third Xulane patch on the correct day. oDuring week 4, the Patch Free Week (Day 22 through Day 28), you may choose an earlier Patch Change Day by applying new patch on the day you prefer. You now have new Day and new Patch Change Day. oDuring week 4, the Patch Free Week (Day 22 through Day 28), you may choose an earlier Patch Change Day by applying new patch on the day you prefer. You now have new Day and new Patch Change Day. oIf your Xulane patch becomes uncomfortable or your application site is red, painful or swollen, change your Xulane patch. Remove your Xulane patch and apply new patch to new location until your next Patch Change Day. oIf you forget to change or remove your Xulane patch: oAt the start of any patch cycle (Week 1, Day 1): You could become pregnant. You must use back-up contraception method for days. Apply the first Xulane patch of your new cycle as soon as you remember. You now have new Patch Change Day and new Day 1. oIn the middle of your patch cycle (Week or Week 3): If you forget to change your Xulane patch for or days, apply new Xulane patch as soon as you remember. Apply your next patch on your normal Patch Change Day. No back-up contraception method is needed. If you forget to change your Xulane patch for more than days, you could become pregnant. Start new week cycle as soon as you remember by putting on new Xulane patch. You now have different Patch Change Day and new Day 1. You must use back-up contraception method for the first days of your new cycle. oAt the end of your patch cycle (Week 4): If you forget to remove your Xulane patch, take it off as soon as you remember. Start your next cycle on your normal Patch Change Day, the day after Day 28. No back-up contraception method is needed. oAt the start of any patch cycle (Week 1, Day 1): You could become pregnant. You must use back-up contraception method for days. Apply the first Xulane patch of your new cycle as soon as you remember. You now have new Patch Change Day and new Day 1. You could become pregnant. You must use back-up contraception method for days. Apply the first Xulane patch of your new cycle as soon as you remember. You now have new Patch Change Day and new Day 1. oIn the middle of your patch cycle (Week or Week 3): If you forget to change your Xulane patch for or days, apply new Xulane patch as soon as you remember. Apply your next patch on your normal Patch Change Day. No back-up contraception method is needed. If you forget to change your Xulane patch for more than days, you could become pregnant. Start new week cycle as soon as you remember by putting on new Xulane patch. You now have different Patch Change Day and new Day 1. You must use back-up contraception method for the first days of your new cycle. If you forget to change your Xulane patch for or days, apply new Xulane patch as soon as you remember. Apply your next patch on your normal Patch Change Day. No back-up contraception method is needed. If you forget to change your Xulane patch for more than days, you could become pregnant. Start new week cycle as soon as you remember by putting on new Xulane patch. You now have different Patch Change Day and new Day 1. You must use back-up contraception method for the first days of your new cycle. oAt the end of your patch cycle (Week 4): If you forget to remove your Xulane patch, take it off as soon as you remember. Start your next cycle on your normal Patch Change Day, the day after Day 28. No back-up contraception method is needed. If you forget to remove your Xulane patch, take it off as soon as you remember. Start your next cycle on your normal Patch Change Day, the day after Day 28. No back-up contraception method is needed. oIf you forget to apply your Xulane patch at the start of your next patch cycle, you could become pregnant. Apply the first Xulane patch of your new cycle as soon as you remember. You now have new Patch Change Day and new Day 1. Use non-hormonal back-up contraception method such as condom and spermicide or diaphragm and spermicide for the first days of your new week Xulane cycle. oIf you have trouble remembering to change your Xulane patch, talk to your healthcare provider about how to make patch changing easier or about using another method of contraception. oIf you are not sure how to use your Xulane patch: oUse back-up contraception method such as condom and spermicide or diaphragm and spermicide anytime you have sex. Make sure to have one of these non-hormonal contraception methods ready at all times. oTalk to your healthcare provider for instructions on using your Xulane patch.. oUse back-up contraception method such as condom and spermicide or diaphragm and spermicide anytime you have sex. Make sure to have one of these non-hormonal contraception methods ready at all times. oTalk to your healthcare provider for instructions on using your Xulane patch.. Instructions for Use Figure A. Instructions for Use Figure B. Instructions for Use Body Placement. Instructions for Use Patch Application Figure 1. Instructions for Use Patch Application Figure 2. Instructions for Use Patch Application Figure 3. Instructions for Use Patch Application Figure 4.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. oNursing mothers: Not recommended; can decrease milk production. (8.3). oNursing mothers: Not recommended; can decrease milk production. (8.3). 8.1 Pregnancy. There is little or no increased risk of birth defects in women who inadvertently use hormonal contraceptives during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose hormonal contraceptives prior to conception or during early pregnancy.The administration of hormonal contraceptives to induce withdrawal bleeding should not be used as test for pregnancy. Hormonal contraceptives should not be used during pregnancy to treat threatened or habitual abortion.. 8.3 Nursing Mothers. The effects of Xulane in nursing mothers have not been evaluated and are unknown. When possible, advise the nursing mother to use other forms of contraception until she has completely weaned her child. Estrogen-containing CHCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of contraceptive steroids and/or metabolites are present in breast milk.. 8.4 Pediatric Use. Safety and efficacy of norelgestromin and ethinyl estradiol transdermal system have been established in women of reproductive age. Efficacy is expected to be the same for post-pubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.. 8.5 Geriatric Use. Xulane has not been studied in postmenopausal women and is not indicated in this population.. 8.6 Hepatic Impairment. No studies with Xulane have been conducted in women with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of combined hormonal contraceptive use until markers of liver function return to normal and combined hormonal contraceptive causation has been excluded. [See Contraindications (4) and Warnings and Precautions (5.3).] 8.7 Renal Impairment. No studies with Xulane have been conducted in women with renal impairment.. 8.8 Women with Weight >= 198 lbs (90 kg). Xulane may be less effective in preventing pregnancy in women who weigh 198 lbs (90 kg) or more.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. oVascular risks: Stop Xulane if thrombotic event occurs. Stop at least weeks before and through weeks after major surgery. Start no earlier than weeks after delivery, in women who are not breastfeeding. (5.1) oLiver disease: Discontinue Xulane if jaundice occurs. (5.3) oHigh blood pressure: Do not prescribe Xulane for women with uncontrolled hypertension or hypertension with vascular disease. (5.5) oCarbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking Xulane. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. (5.7) oHeadache: Evaluate significant change in headaches and discontinue Xulane if indicated. (5.8) oUterine bleeding: Evaluate irregular bleeding or amenorrhea. (5.9) oVascular risks: Stop Xulane if thrombotic event occurs. Stop at least weeks before and through weeks after major surgery. Start no earlier than weeks after delivery, in women who are not breastfeeding. (5.1) oLiver disease: Discontinue Xulane if jaundice occurs. (5.3) oHigh blood pressure: Do not prescribe Xulane for women with uncontrolled hypertension or hypertension with vascular disease. (5.5) oCarbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking Xulane. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. (5.7) oHeadache: Evaluate significant change in headaches and discontinue Xulane if indicated. (5.8) oUterine bleeding: Evaluate irregular bleeding or amenorrhea. (5.9) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop Xulane if an arterial or deep venous thrombotic event (VTE) occurs. Stop Xulane if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. If feasible, stop Xulane at least weeks before and through weeks after major surgery or other surgeries known to have an elevated risk of VTE. Discontinue use of Xulane during prolonged immobilization and resume treatment based on clinical judgment. Start Xulane no earlier than weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. The use of combination hormonal contraceptives (CHCs) increases the risk of VTE. Known risk factors for VTE include smoking, obesity and family history of VTE, in addition to other factors that contraindicate use of CHCs [see Contraindications (4)]. Five epidemiologic studies1- that assessed the risk of VTE associated with use of norelgestromin and ethinyl estradiol transdermal system are described below. These are case control studies, that compared VTE rates among women using norelgestromin and ethinyl estradiol transdermal system to rates among women using an OC comparator, and an FDA-funded cohort study that estimated and compared VTE rates among women using various hormonal contraceptives, including norelgestromin and ethinyl estradiol transdermal system. All five studies were retrospective studies from U.S. electronic healthcare databases and included women aged 15 to 44 (10 to 55 in the FDA-funded study) who used norelgestromin and ethinyl estradiol transdermal system or oral contraceptives containing 20 mcg to 35 mcg of ethinyl estradiol (EE) and levonorgestrel (LNG), norethindrone, or norgestimate (NGM). NGM is the prodrug for NGMN, the progestin in Xulane. Some of the data from the epidemiologic studies suggest an increased risk of VTE with use of norelgestromin and ethinyl estradiol transdermal system compared to use of some combined oral contraceptives (see Table 1). The studies used slightly different designs and reported relative risk estimates ranging from 1.2 to 2.2. None of the studies have adjusted for body mass index, smoking, and family history of VTE, which are potential confounders. The interpretations of these relative risk estimates range from no increase in risk to an approximate doubling of risk. One of the studies found statistically significant increased risk of VTE for current users of norelgestromin and ethinyl estradiol transdermal system.The five studies are: oThe i3 Ingenix study with NGM-containing oral contraceptives as the comparator, including 24-month extension, based on the Ingenix Research Datamart; this study included patient chart review to confirm the VTE occurrence. oThe Boston Collaborative Drug Surveillance Program (BCDSP) with NGM-containing oral contraceptives as the comparator (BCDSP NGM), including two extensions of 17 and 14 months, respectively, based on the Pharmetrics database, using only non-fatal idiopathic cases. VTE cases were not confirmed by chart review. oBCDSP with LNG-containing oral contraceptives as the comparator, based on the Pharmetrics database, using only non-fatal idiopathic cases. VTE cases were not confirmed by chart review. oBCDSP with LNG-containing oral contraceptives as the comparator, based on the Marketscan database, using only non-fatal idiopathic cases. VTE cases were not confirmed by chart review. oFDA-funded study with two groups of comparators [1) LNG-containing oral contraceptives, and 2) oral contraceptives that contain LNG, norethindrone or norgestimate], based on Kaiser Permanente and Medicaid databases. This study used all cases of VTE (idiopathic and non-idiopathic) and included patient chart review to confirm the VTE occurrence. The i3 Ingenix and BCDSP NGM studies have provided data on additional cases identified in study extensions; however, each study extension was not powered to provide independent estimates of risk. The pooled estimates provide the most reliable estimates of VTE risk. Risk ratios from the original and various extensions of the i3 Ingenix and BCDSP NGM studies are provided in Table 1. The results of these studies are presented in Figure 1.Table 1: Estimates (Risk Ratios) of Venous Thromboembolism Risk in Current Users of Norelgestromin and Ethinyl Estradiol Transdermal System Compared to Combined Oral Contraceptive UsersEpidemiologic StudyNew users i.e., women with no prior exposure to the drug studied during pre-specified time period are considered to be the most informative population to study in pharmacoepidemiologic safety studies. All estimates took account of new-user status. The method and time period used to identify new users varied from study to study.Comparator ProductRisk Ratios (95% CI)i3 Ingenix NGM Study in Ingenix Research Datamart1,6,7,8 NGM/35 mcg EENGM norgestimate; EE ethinyl estradiol 2.2Increase in risk of VTE is statistically significant (1.2 4.0)Pooled risk ratio from references and covering the initial 33-month study plus 24-month extension. [Initial 33 months of data: Risk Ratio (95% CI) 2.5C (1.1-5.5); Separate estimate from the 24 months of data on new cases not included in the previous estimate: Risk Ratio (95% CI) 1.4 (0.5-3.7)]. These risk ratios are based on idiopathic cases (those in women without other known risk factors for VTE). If all VTE cases are considered, the pooled risk ratio and 95% CI are 2.0 (1.2-3.3)C. BCDSPBCDSP Boston Collaborative Drug Surveillance Program; the risk ratios are based on idiopathic cases. NGM Study in Pharmetrics database2,3,5 NGM/35 mcg EE1.2 (0.9 1.8)Pooled risk ratio from references 2, and covering the initial 36-month study, plus 17-month and 14-month extensions. [Initial 36 months of data: Risk Ratio (95% CI) 0.9 (0.5-1.6); Separate estimate from 17 months of data on new cases not included in the previous estimate: Risk Ratio (95% CI) 1.1 (0.6-2.1); Separate estimate from 14 months of data on new cases not included in the previous estimates: Risk Ratio (95% CI) 2.4C (1.2-5.0)] BCDSP LNG Study in Pharmetrics database4 LNGLNG levonorgestrel/30 mcg EE2.0 (0.9 4.1)48 months of data. BCDSP LNG Study in Marketscan database4 LNG/30 mcg EE1.3 (0.8 2.1)69 months of data. FDA-funded Study in Kaiser Permanente and Medicaid databases84 months of data in FDA-funded study Results for All users, i.e., initiation and continuing use of study combination hormonal contraception: All progestins/20-35 mcg EE, Risk Ratio (95% CI) 1.6 (1.2-2.1)C and LNG/30 mcg EE, Risk Ratio (95% CI) 1.3 (1.0-1.8). ,9 All progestinsIncludes the following progestins: LNG, norethindrone, norgestimate./20 35 mcg EELNG/30 mcg EE1.4 (0.9 2.0)1.2 (0.8 1.9)Figure 1: VTE Risk of Norelgestromin and Ethinyl Estradiol Transdermal System Relative to Combined Oral ContraceptivesAn increased risk of thromboembolic and thrombotic disease associated with the use of combination hormonal contraceptives (CHCs) is well established. Although the absolute VTE rates are increased for users of CHCs compared to non-users, the rates associated with pregnancy are even greater, especially during the postpartum period (see Figure 2). The frequency of VTE in women using CHCs has been estimated to be to 12 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of CHCs and when restarting hormonal contraception after break of weeks or longer. The risk of thromboembolic disease due to CHCs gradually disappears after CHC use is discontinued.Figure shows the risk of developing VTE for women who are not pregnant and do not use CHCs, for women who use CHCs, for pregnant women, and for women in the postpartum period. To put the risk of developing VTE into perspective: If 10,000 women who are not pregnant and do not use CHCs are followed for one year, between and of these women will develop VTE.Figure 2: Likelihood of Developing VTEUse of CHCs also increases the risk of arterial thromboses such as, cerebrovascular events (thrombotic and hemorrhagic strokes) and myocardial infarctions, especially in women with other risk factors for these events. In general, the risk is greatest among older (> 35 years of age), hypertensive women who also smoke. Use CHCs with caution in women with cardiovascular disease risk factors.. oThe i3 Ingenix study with NGM-containing oral contraceptives as the comparator, including 24-month extension, based on the Ingenix Research Datamart; this study included patient chart review to confirm the VTE occurrence. oThe Boston Collaborative Drug Surveillance Program (BCDSP) with NGM-containing oral contraceptives as the comparator (BCDSP NGM), including two extensions of 17 and 14 months, respectively, based on the Pharmetrics database, using only non-fatal idiopathic cases. VTE cases were not confirmed by chart review. oBCDSP with LNG-containing oral contraceptives as the comparator, based on the Pharmetrics database, using only non-fatal idiopathic cases. VTE cases were not confirmed by chart review. oBCDSP with LNG-containing oral contraceptives as the comparator, based on the Marketscan database, using only non-fatal idiopathic cases. VTE cases were not confirmed by chart review. oFDA-funded study with two groups of comparators [1) LNG-containing oral contraceptives, and 2) oral contraceptives that contain LNG, norethindrone or norgestimate], based on Kaiser Permanente and Medicaid databases. This study used all cases of VTE (idiopathic and non-idiopathic) and included patient chart review to confirm the VTE occurrence. Figure 1: VTE Risk of Norelgestromin and Ethinyl Estradiol Transdermal System Relative to Combined Oral Contraceptives. Figure 2: Likelihood of Developing VTE. 5.2 PK Profile of Ethinyl Estradiol The PK profile for the norelgestromin and ethinyl estradiol transdermal system is different from the PK profile for oral contraceptives in that it has higher Css and lower Cmax. AUC and average Css for EE are approximately 60% higher in women using norelgestromin and ethinyl estradiol transdermal system compared with women using an oral contraceptive containing EE 35 mcg. In contrast, the Cmax for EE is approximately 25% lower in women using norelgestromin and ethinyl estradiol transdermal system. Inter-subject variability results in increased exposure to EE in some women using either norelgestromin and ethinyl estradiol transdermal system or oral contraceptives. However, inter-subject variability in women using norelgestromin and ethinyl estradiol transdermal system is higher. It is not known whether there are changes in the risk of serious adverse events based on the differences in PK profiles of EE in women using norelgestromin and ethinyl estradiol transdermal system compared with women using oral contraceptives containing 30 mcg to 35 mcg of EE. Increased estrogen exposure may increase the risk of adverse events, including venous thromboembolism. [See Boxed Warning and Clinical Pharmacology (12.3).] 5.3 Liver Disease. Impaired Liver Function. Do not use Xulane in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver [see Contraindications (4)]. Discontinue Xulane if jaundice develops. Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal and CHC causation has been excluded. Liver Tumors. Xulane is contraindicated in women with benign and malignant liver tumors [see Contraindications (4)]. Hepatic adenomas are associated with CHC use. An estimate of the attributable risk is 3.3 cases/100,000 CHC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> years) CHC users. However, the risk of liver cancers in CHC users is less than one case per million users.. 5.4Risk of Liver Enzyme Elevations with Concomitant Hepatitis Treatment During clinical trials with the Hepatitis combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as CHCs. Discontinue Xulane prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. Xulane can be restarted approximately weeks following completion of treatment with the Hepatitis combination drug regimen. 5.5 High Blood Pressure. Xulane is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)]. For women with well-controlled hypertension, monitor blood pressure and stop Xulane if blood pressure rises significantly. An increase in blood pressure has been reported in women taking hormonal contraceptives, and this increase is more likely in older women with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin.. 5.6 Gallbladder Disease. Studies suggest small increased relative risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease. past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Women with history of pregnancy-related cholestasis may be at an increased risk for CHC-related cholestasis.. 5.7 Carbohydrate and Lipid Metabolic Effects. Carefully monitor prediabetic and diabetic women who take Xulane. CHCs may decrease glucose tolerance in dose-related fashion. In 6-cycle clinical trial with norelgestromin and ethinyl estradiol transdermal system there were no clinically significant changes in fasting blood glucose from baseline to end of treatment. Consider alternative contraception for women with uncontrolled dyslipidemia. small proportion of women will have adverse lipid changes while on hormonal contraceptives. Women with hypertriglyceridemia, or family history thereof, may be at an increased risk of pancreatitis when using hormonal contraceptives.. 5.8 Headache. If woman taking Xulane develops new headaches that are recurrent, persistent or severe, evaluate the cause and discontinue Xulane if indicated. Consider discontinuation of Xulane in the case of increased frequency or severity of migraine during hormonal contraceptive use (which may be prodromal of cerebrovascular event).. 5.9 Bleeding Irregularities. Unscheduled Bleeding and Spotting. Unscheduled (breakthrough) bleeding and spotting sometimes occur in women using norelgestromin and ethinyl estradiol transdermal system. Consider non-hormonal causes and take adequate diagnostic measures to rule out malignancy, other pathology, or pregnancy in the event of unscheduled bleeding, as in the case of any abnormal vaginal bleeding. If pathology and pregnancy have been excluded, time or change to another contraceptive product may resolve the bleeding. In the clinical trials, most women started their scheduled (withdrawal) bleeding on the fourth day of the drug-free interval, and the median duration of withdrawal bleeding was to days. On average, 26% of women per cycle had or more total days of bleeding and/or spotting (this includes both scheduled and unscheduled bleeding and/or spotting). Three clinical studies of the efficacy of norelgestromin and ethinyl estradiol transdermal system in preventing pregnancy assessed scheduled and unscheduled bleeding [see Clinical Studies (14)] in 3,330 women who completed 22,155 cycles of exposure. total of 36 (1.1%) of the women discontinued norelgestromin and ethinyl estradiol transdermal system at least in part, due to bleeding or spotting.Table summarizes the proportion of subjects who experienced unscheduled (breakthrough) bleeding/spotting by treatment cycle.Table 2: Unscheduled (Breakthrough) Bleeding/Spotting (Subjects Evaluable for Efficacy)Treatment CyclePooled data from studiesN 3319 n%Percentage of subjects with breakthrough bleeding/spotting events. Cycle 1299418.2Cycle 2274311.9Cycle 3269911.6Cycle 4254110.1Cycle 525329.2Cycle 624948.3Cycle 76988.3Cycle 86928.7Cycle 96548.6Cycle 106218.7Cycle 116318.9Cycle 126176.3Cycle 136118.0. Amenorrhea and Oligomenorrhea. In the event of amenorrhea, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one patch or started the patch on day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy.Some women may encounter amenorrhea or oligomenorrhea after discontinuation of hormonal contraceptive use, especially when such condition was pre-existent.. 5.10 Hormonal Contraceptive Use Before or During Early Pregnancy. Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue Xulane use if pregnancy is confirmed. Administration of CHCs should not be used as test for pregnancy [see Use in Specific Populations (8.1)].. 5.11 Depression. Carefully observe women with history of depression and discontinue Xulane if depression recurs to serious degree.. 5.12 Carcinoma of Breasts and Cervix. Xulane is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)]. There is substantial evidence that CHCs do not increase the incidence of breast cancer. Although some past studies have suggested that CHCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. Some studies suggest that combination oral contraceptive use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.. 5.13 Effect on Binding Globulins. The estrogen component of CHCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased.. 5.14 Monitoring. woman who is taking hormonal contraceptive should have yearly visit with her healthcare provider for blood pressure check and for other indicated healthcare.. 5.15 Hereditary Angioedema. In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.. 5.16 Chloasma. Chloasma may occasionally occur, especially in women with history of chloasma gravidarum. Women with tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while using Xulane.