Ethinylside effects

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

Vascular events, including venous and arterial thromboembolic events

Liver disease 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. 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.

6.1 Clinical

Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data described below reflect exposure to 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

10.0 Adverse 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, premenstrual syndrome, uterine spasm, vaginal discharge, vulvovaginal dryness

Respiratory, thoracic and mediastinal disorders: Pulmonary embolism

Skin and subcutaneous tissue disorders: Chloasma, dermatitis contact, erythema, skin irritation 1 Represents a bundle of similar terms

6.2 Postmarketing

Experience Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no associated between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 2). Three studies compared breast cancer risk between current or recent COC users (< 6 months since last use) and never users of COCs (Figure 2). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 - 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8-10 years of COC use.

Figure 2: Risk of Breast Cancer with Combined Oral Contraceptive Use RR = relative risk; OR = odds ration; HR = hazard ration. “ever COC” are females with current or past COC use; “never COC use” are fmales that never used COCs. 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a 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 Class MedDRA version

10.0 System Organ

Class Adverse Drug Reactions Cardiac disorders Myocardial infarction Represents a bundle of similar terms Endocrine disorders Hyperglycemia, insulin resistance Eye disorders Contact lens intolerance or complication Gastrointestinal disorders Colitis General disorders and administration site conditions Application site reaction, edema Hepatobiliary disorders Blood cholesterol abnormal, cholelithiasis, cholestasis, hepatic lesion, jaundice cholestatic, low density lipoprotein increased Immune system disorders Allergic reaction, urticaria Investigations Blood glucose abnormal, blood glucose decreased Metabolism and nutrition disorders Increased appetite Neoplasms benign, malignant and unspecified (Incl. cysts and polyps) Breast cancer, cervix carcinoma, hepatic adenoma, hepatic neoplasm Nervous system disorders Dysgeusia, migraine with aura Psychiatric disorders Anger, emotional disorder, frustration, irritability Reproductive system and breast disorders Breast mass, cervical dysplasia, fibroadenoma of breast, menstrual disorder, suppressed lactation, uterine leiomyoma Skin and subcutaneous tissues disorders Alopecia, eczema, erythema multiforme, erythema nodosum, photosensitivity reaction, pruritus generalized, rash, seborrheic dermatitis, skin reaction Vascular disorders Arterial thrombosis, cerebrovascular accident, deep vein thrombosis, hemorrhage intracranial, hypertension, hypertensive crisis, pulmonary embolism, thrombosis Figure 2: Risk of Breast Cancer with Combined Oral Contraceptive Use