LEVONORGESTREL AND ETHINYL ESTRADIOL AND ETHINYL ESTRADIOL

1 INDICATIONS AND USAGE Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are a combination of levonorgestrel, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. ( 1 ) Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are indicated for use by females of reproductive age to prevent pregnancy.

2 DOSAGE AND ADMINISTRATION • Take one tablet daily by mouth at the same time every day for 91 days in the order directed on the blister pack. ( 2 ) 2.1 How to Start and Take Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets Begin levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the first white to off-white tablet that day. For each 91-day course, take in the following order: 1. Start the first white to off-white tablet on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the tablet on that day. Then take one white to off-white tablet once daily for a total of 42 consecutive days. Use a non-hormonal back-up method of contraception (such as condoms and spermicide) for the first 7 days of treatment. 2. One light peach tablet once daily for 21 consecutive days. 3. One bluish green tablet once daily for 21 days. 4. One yellow tablet once daily for 7 days. Bleeding should occur during yellow tablet use. Begin the next and all subsequent 91-day courses of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets without interruption on the same day of the week (Sunday) on which the first dose of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets was taken. Follow the same schedule as the initial 91-day course: white to off-white tablet once a day for 42 days, light peach tablet once daily for 21 days, bluish green tablet once daily for 21 days, and yellow tablet once daily for 7 days. If the next pill is not started immediately, use a non-hormonal back-up method of contraception until a white to off-white tablet has been taken once daily for 7 consecutive days. Switching to Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets from another oral hormonal contraceptive or from another contraceptive method (transdermal patch, vaginal ring, injection, intrauterine contraceptive, implant) Start on the Sunday after the patient’s next period starts. Use additional non-hormonal contraceptive (such as condoms and spermicide) until the patient has taken 7 white to off-white pills (7 days). Starting Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets after Abortion or Miscarriage First-trimester Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets may be started on the Sunday after an abortion or miscarriage. The patient must use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a white to off-white tablet for 7 days. Second-trimester Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start contraceptive therapy with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets following the instructions for women not currently using hormonal contraception. Use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a white to off-white tablet for 7 days [see Contraindications (4 ) and Warnings and Precautions ( 5.1 )]. Starting Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets after Childbirth Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets following the instructions for women not currently using hormonal contraception. Use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a white to off-white tablet for 7 days [see Contraindications (4 ) and Warnings and Precautions (5.1 )]. Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are not recommended for use in lactating women [see Use in Specific Populations ( 8.2 )] . If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets [see Warnings and Precautions (5.1 ), Use in Specific Populations ( 8.1 )]. 2.2 Dosing Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets Take one tablet by mouth at the same time every day. The dosage of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are one white to off-white tablet once daily for 42 days, one light peach tablet once daily for 21 days, one bluish green tablet once daily for 21 days, and one yellow tablet once daily for 7 days. To achieve maximum contraceptive effectiveness, take levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets exactly as directed, in the order directed, and at intervals not exceeding 24 hours. The failure rate may increase when pills are missed or taken incorrectly. 2.3 Missed Doses Table 1. Instructions for Missed Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets If one white to off-white, light peach, bluish green tablet is missed Take the missed tablet as soon as possible. Take the next tablet at the regular time. Continue taking one tablet a day until the pack is finished. A back-up birth control method is not required if the patient has sex. If two white to off-white, light peach, bluish green tablets in a row are missed Take the two missed tablets as soon as possible, and the next two tablets the next day. Continue taking one tablet a day until the pack is finished. Use additional nonhormonal contraception (such as condoms and spermicide) until tablets have been taken for 7 days after missing tablets. If three or more white to off-white, light peach, bluish green tablets in a row are missed Throw away the missed tablets. Continue taking one tablet every day as indicated on the pack until the pack is finished. Bleeding may occur during the week following the missed tablets. Use additional nonhormonal contraception (such as condoms and spermicide) until tablets have been taken for 7 days after missing tablets. If any of the seven yellow tablets are missed Throw away the missed tablets. Continue taking the remaining tablets until the pack is finished. A backup birth control method is not needed. 2.4 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 to 4 hours after taking a white to off-white, light peach or bluish green tablet, handle this as a missed tablet [see Dosage and Administration ( 2.3 )].

4 CONTRAINDICATIONS • A high risk of arterial or venous thrombotic diseases ( 4 ) • Undiagnosed abnormal uterine bleeding ( 4 ) • Breast cancer ( 4 ) • Liver tumors or liver disease ( 4 ) • Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 ) Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are contraindicated in females who are known to have or develop the following conditions: • A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: o Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 )]. o Have current or history of deep vein thrombosis or pulmonary embolism [see Warnings and Precautions ( 5.1 )]. o Have cerebrovascular disease [see Warnings and Precautions ( 5.1 )]. o Have coronary artery disease [see Warnings and Precautions ( 5.1 )]. o 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 )]. o Have inherited or acquired hypercoagulopathies [see Warnings and Precautions ( 5.1 )]. o Have uncontrolled hypertension or hypertension with vascular disease [see Warnings and Precautions ( 5.5 )]. o Have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or with vascular disease or other end-organ damage, or diabetes mellitus of > 20 years duration [see Warnings and Precautions ( 5.7 )]. o Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [see Warnings and Precautions ( 5.8 )]. • Current diagnosis of, or history of, breast cancer, which may be hormone sensitive [see Warnings and Precautions (5.11 )]. • Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.6 )]. • Undiagnosed abnormal uterine bleeding [see Warnings and Precautions ( 5.9 )]. • Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see Warnings and Precautions ( 5.4 )].

Not available.

6 ADVERSE REACTIONS The most common adverse reactions (≥2%) in clinical trials for levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets were headaches, heavy/irregular vaginal bleeding, nausea/vomiting, acne, dysmenorrhea, weight increased, mood changes, anxiety/panic attack, breast pain and migraines. ( 6 ) 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. The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: • Serious cardiovascular events [see Boxed Warning and Warnings and Precautions ( 5.1 )] • Vascular events [see Warnings and Precautions ( 5.1 )] • Liver disease [see Warnings and Precautions ( 5.2 )] 6.1 Clinical Trial 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 the rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below are from a 12-month, US, open-label study, which enrolled women aged 18-40, of whom 3,597 took at least one dose of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets (2,661 woman-years of exposure) [see Clinical Studies ( 14 )] . Adverse Reactions Leading to Study Discontinuation : 13.3% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (≥1% of women) leading to discontinuation were heavy/irregular bleeding (5.0%), mood swings/alteration/affect lability (1.4%), headaches/migraines (1.3%), weight increased (1.3%) and acne (1.0%). Common Adverse Reactions (≥2% of women) : headaches (12.2%), heavy/irregular vaginal bleeding (9.7%), nausea/vomiting (8.8%), acne (5.4%), dysmenorrhea (5.4%), weight increased (4.6%), mood changes (depression, depressed mood, crying, major depression, affective disorder, depression suicidal, dysthymic disorder) (2.9%), anxiety/panic attack (2.4%), breast tenderness/pain/discomfort (2.2%), migraine (2.0%). Serious Adverse Reactions (≥2 women): Abortion Spontaneous, Suicide Attempt, Cholecystitis/ Cholelithiasis, Deep Vein Thrombosis, Ectopic Pregnancy. 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 association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 3). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 3). 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 3: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs. The following adverse reactions have been identified during post-approval use of extended-cycle COCs containing levonorgestrel and ethinyl estradiol. 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. Gastrointestinal disorders: abdominal distension, vomiting General disorders and administration site conditions: chest pain, fatigue, malaise, edema peripheral, pain Immune system disorders: hypersensitivity reaction Investigations: blood pressure increased Musculoskeletal and connective tissue disorders: muscle spasms, pain in extremity Nervous system disorders: dizziness, loss of consciousness Psychiatric disorders: insomnia Reproductive and breast disorders: dysmenorrhea Respiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary thrombosis Skin and subcutaneous tissue disorders: alopecia Vascular disorders: thrombosis Figure 2: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives