Estradiol Valerate and Estradiol Valerate/Dienogest

1 INDICATIONS AND USAGE • Estradiol Valerate and Estradiol Valerate/Dienogest is an estrogen/progestin COC indicated for use by women to prevent pregnancy. ( 1 ) • Treatment of heavy menstrual bleeding in women without organic pathology who choose to use an oral contraceptive as their method of contraception. ( 1.2 ) • The efficacy of Estradiol Valerate and Estradiol Valerate/Dienogest in women with a body mass index (BMI) of >30 kg/m 2 has not been evaluated. ( 1 , 8.8 ) 1.1 Oral Contraception Estradiol Valerate and Estradiol Valerate/Dienogest is indicated for use by women to prevent pregnancy. The efficacy of Estradiol Valerate and Estradiol Valerate/Dienogest in women with a body mass index (BMI) of > 30 kg/m 2 has not been evaluated. 1.2 Heavy Menstrual Bleeding Estradiol Valerate and Estradiol Valerate/Dienogest is also indicated for the treatment of heavy menstrual bleeding in women without organic pathology who choose to use an oral contraceptive as their method of contraception [see Clinical Studies ( 14.2 )].

2 DOSAGE AND ADMINISTRATION • Take one tablet daily by mouth at the same time every day. ( 2.1 ) • Tablets must be taken in the order directed on the blister pack. ( 2.1 ) • Do not skip or delay intake by more than 12 hours. ( 2.1 ) 2.1 How to Take Estradiol Valerate and Estradiol Valerate/Dienogest To achieve maximum contraceptive effectiveness, Estradiol Valerate and Estradiol Valerate/Dienogest must be taken exactly as directed. Take one tablet by mouth at the same time every day. Tablets must be taken in the order directed on the blister pack. Tablets should not be skipped or intake delayed by more than 12 hours. For patient instructions for missed pills, see FDA-Approved Patient Labeling. 2.2 How to Start Estradiol Valerate and Estradiol Valerate/Dienogest Instruct the patient to begin taking Estradiol Valerate and Estradiol Valerate/Dienogest on Day 1 of her menstrual cycle (that is, the first day of her menstrual bleeding). See FDA-Approved Patient Labeling . Instruct the patient to use a non-hormonal contraceptive as back-up during the first 9 days. For postpartum women who do not breastfeed or after a second trimester abortion, start Estradiol Valerate and Estradiol Valerate/Dienogest no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts on Estradiol Valerate and Estradiol Valerate/Dienogest postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken Estradiol Valerate and Estradiol Valerate/Dienogest for 9 consecutive days. The possibility of ovulation and conception prior to initiation of medication should also be considered. If the patient is switching from a combination hormonal method such as a: • Another pill • Vaginal ring • Patch • Instruct her to take the first dark yellow pill on the first day of her withdrawal bleed. She should not continue taking the pills from her previous birth control pack. If she does not have a withdrawal bleed, rule out pregnancy before starting Estradiol Valerate and Estradiol Valerate/Dienogest. • If she previously used a vaginal ring or transdermal patch, she should start using Estradiol Valerate and Estradiol Valerate/Dienogest on the day the ring or patch is removed. • Instruct the patient to use a non-hormonal back-up method such as a condom or spermicide for the first 9 days. If the patient is switching from a progestin-only method such as a: • Progestin-only pill • Implant • Intrauterine system • Injection • Instruct her to take the first dark yellow pill on the day she would have taken her next progestin-only pill or on the day of removal of her implant or intrauterine system or on the day when she would have had her next injection. • Instruct the patient to use a non-hormonal back-up method such as a condom or spermicide for the first 9 days. 2.3 Advice in Case of Gastrointestinal Disturbances In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3-4 hours after taking a colored tablet, this can be regarded as a missed tablet.

4 CONTRAINDICATIONS Do not prescribe Estradiol Valerate and Estradiol Valerate/Dienogest to women who are known to have the following: • A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: • Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 )] • Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions ( 5.1 )] • Have cerebrovascular disease [see Warnings and Precautions ( 5.1 )] • Have coronary artery disease [see Warnings and Precautions ( 5.1 )] • Have 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 )] • Have inherited or acquired hypercoagulopathies [see Warnings and Precautions ( 5.1 )] • Have uncontrolled hypertension [see Warnings and Precautions ( 5.4 )] • Have diabetes mellitus with vascular disease [see Warnings and Precautions ( 5.6 )] • Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see Warnings and Precautions ( 5.7 )] • Undiagnosed abnormal uterine bleeding [see Warnings and Precautions ( 5.8 )] • Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions ( 5.2 )] • Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )] . • Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions ( 5.9 ) and Use in Specific Populations ( 8.1 )] . • A high risk of arterial or venous thrombotic diseases ( 4 ) • Undiagnosed abnormal uterine bleeding ( 4 ) • Breast cancer or other estrogen- or progestin-sensitive cancer ( 4 ) • Liver tumors or liver disease ( 4 ) • Pregnancy ( 4 )

Not available.

6 ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: • Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions ( 5.1 )] • Vascular events [see Warnings and Precautions ( 5.1 )] • Liver disease [see Warnings and Precautions ( 5.3 )] Adverse reactions commonly reported by COC users are: • Irregular uterine bleeding • Nausea • Breast tenderness • Headache The most common adverse reactions (≥ 2%) in clinical trials for Estradiol Valerate and Estradiol Valerate/Dienogest are headaches, irregular uterine bleeding,headache (including migraines) 13%, breast tenderness,pain 7%, menstrual disorders 7%, nausea/ or vomiting, 6%, acne 4%, mood changes (3%) and increased weight. 3%. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Contraception and Heavy Menstrual Bleeding Studies A total of 2,131 women, 18 to 54 years of age, who took at least one dose of Estradiol Valerate and Estradiol Valerate/Dienogest were enrolled in four clinical phase 3 trials. A total of 1,867 subjects were included in two clinical phase 3 studies with a treatment duration up to 28 cycles with Estradiol Valerate and Estradiol Valerate/Dienogest as an oral contraceptive and 264 subjects in the two phase 3 clinical trials with a treatment duration of 7 cycles evaluating Estradiol Valerate and Estradiol Valerate/Dienogest in the treatment of heavy, prolonged, and/or frequent menstrual bleeding in women without organic pathology. [See Clinical Studies ( 14.1 , 14.2 .)] Adverse Reactions Leading to Study Discontinuation : 11.4% of the women discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were menstrual disorder (metrorrhagia, menorrhagia, menstruation irregular, genital hemorrhage, vaginal hemorrhage, dysfunctional uterine bleeding) (2.3%); mood changes (depression, mood swings, mood altered, depressed mood, dysthymic disorder, crying) (1.2%); acne (1.1%), headache (including migraines) (1.1%), and weight increased (0.7 %). Common Adverse Reactions (≥ 2%): headache (including migraines) (12.7%), breast pain, discomfort or tenderness (7.0%), menstrual disorders (metrorrhagia, menstruation irregular, menorrhagia, vaginal hemorrhage, dysfunctional uterine bleeding, genital hemorrhage, abnormal withdrawal bleeding, uterine hemorrhage) (6.9%), nausea or vomiting (6.0%), acne (3.9%), mood changes (depression, mood swings, depressed mood, mood altered, affect lability, dysthymic disorder, crying) (3.0%) and increased weight (2.9%). Serious Adverse Reactions: myocardial infarction (2 cases), ruptured ovarian cyst (2 cases), deep vein thrombosis, focal nodular hyperplasia of the liver, uterine leiomyoma, acute cholecystitis, and chronic acalculous cholecystitis. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Estradiol Valerate and Estradiol Valerate/Dienogest. 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. Vascular disorders: Venous and arterial thromboembolic events (including pulmonary emboli, deep vein thrombosis, cerebral thrombosis, myocardial infarction and stroke), hypertension Hepatobiliary disorders: Gallbladder disease, hepatitis Immune system disorders: Hypersensitivity Metabolism and nutrition disorders: Fluid retention, hypertriglyceridemia Nervous system disorders: Dizziness Skin and subcutaneous tissue disorders: Chloasma, angioedema, erythema nodosum, erythema multiforme Gastrointestinal disorders: Gastrointestinal symptoms (for example, abdominal pain) Infections and infestations: Vulvovaginal candidiasis