XULANE norelgestromin and ethinyl estradiol 150 ug/d; 35 ug/d Patch

5 WARNINGS AND PRECAUTIONS • Vascular risks: Stop Xulane if a thrombotic event occurs. Stop at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding.

Consider cardiovascular risk factors before initiating in all women, particularly those over 35 years. ( 5.1 ) • Liver disease: Discontinue Xulane if jaundice occurs. ( 5.3 ) • High blood pressure: Do not prescribe Xulane for women with uncontrolled hypertension or hypertension with vascular disease.

( 5.5 ) • Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking Xulane. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.7 ) • Headache: Evaluate significant change in headaches and discontinue Xulane if indicated.

( 5.8 ) • Uterine bleeding: Evaluate irregular bleeding or amenorrhea. ( 5.9 )

5.1Thromboembolic Disorders and Other Vascular Conditions • Stop Xulane if an arterial or venous thromboembolic 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 4 weeks before and through 2 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 4 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. • Before starting Xulane, evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. [see Contraindications (4) ] . Arterial Events The use of CHCs increases the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke.

The risk is greater among older women (> 35 years of age), smokers, and women with hypertension, dyslipidemia, diabetes, or obesity. Xulane is contraindicated in women over 35 years of age who smoke [see Contraindications (4) ] . Cigarette smoking increases the risk of serious cardiovascular events from CHC use.

This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. Venous Events The use of CHCs increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of CHCs.

The risk of VTE may be greater with Xulane in women with a BMI ≥ 30 kg/m 2 compared to women with a lower BMI [see Contraindications (4) ] . While the increased risk of VTE associated with use of CHCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1). The frequency of VTE in women using CHCs has been estimated to be 3 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 a break of 4 weeks or longer. This initial higher risk declines during the first year, but users of CHCs remain at an increased risk of VTE compared to non-users of CHCs. Based on results from a few studies, there is some evidence that this is true for non-oral products as well.

The risk of thromboembolic disease due to CHCs gradually disappears after CHC use is discontinued. Figure 1 shows the risk of developing a VTE for women who are not pregnant and do not use CHCs, for women who use CHCs with a range of doses and routes of administration, for pregnant women, and for women in the postpartum period. To put the risk of developing a VTE into perspec…

6 ADVERSE REACTIONS The following serious adverse reactions with the use of combination hormonal contraceptives, including Xulane, are discussed elsewhere in the labeling: • Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions (5.1) ] • Vascular events, including venous and arterial thromboembolic events [see Warnings and Precautions (5.1) ] • Liver disease [see Warnings and Precautions (5.3) ] Adverse reactions commonly reported by users of combination hormonal contraceptives are: • Irregular uterine bleeding • Nausea • Breast tenderness • Headache 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 at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data described below reflect exposure to norelgestromin and ethinyl estradiol transdermal system in 3330 sexually active women (3322 of whom had safety data) who participated in three Phase 3 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 2 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 3 Clinical Trials System/Organ Class MedDRA version

10.0Adverse reaction Norelgestromin and Ethinyl Estradiol Transdermal System (n = 3322) Reproductive system and breast disorders Breast symptoms Represents a 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: • Gastrointestinal disorders: Abdominal distension • General disorders and administration site conditions: Fluid retention 1 , malaise • Hepatobiliary disorders: Cholecystitis • Investigations: Blood pressure increased, lipid disorders 1 • Musculoskeletal and connective tissue disorders: Muscle spasms • Psychiatric disorders: Insomnia, libido decreased, libido increased • Reproductive system and breast disorders: Galactorrhea, genital discharge, p…

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 a back-up or alternative method of contraception when enzyme inducers are used with CHCs. ( 7.1 )

7.1Effects 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.

John’s 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 a 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 C 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]).

7.2Effects 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) ] .

7.4Interference 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.

Drug Interactions In a PK drug interaction study, oral administration of tetracycline H…