FDA label e0fbb708-74fd-4563-80e6-b2efdb4d9d75

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke. [See Contraindications ( 4 )] WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete boxed warning Women over 35 years old who smoke should not use levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. ( 4 ) Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. ( 4 )

WARNING TO WOMEN WHO SMOKE Do not use levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects from birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.

5 WARNINGS AND PRECAUTIONS Vascular risks: Stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if a thrombotic event occurs. Stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets at least 4 weeks before and through 2 weeks after major surgery. Start levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets no earlier than 4 weeks after delivery, in women who are not breastfeeding. (5.1) Liver disease: Discontinue levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if jaundice occurs. (5.2) High blood pressure: Do not prescribe levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets for women with uncontrolled hypertension or hypertension with vascular disease. (5.3) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. Consider an alternate contraceptive method for women with uncontrolled dyslipidemias. ( 5.6 ) Headache: Evaluate significant change in headaches and discontinue levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if indicated. ( 5.7 ) Uterine bleeding: Evaluate irregular bleeding or amenorrhea. ( 5.8 ) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if an arterial or deep venous thrombotic event (VTE) occurs. Stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. If feasible, stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE. Start levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets 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. The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 per 10,000 woman-years. The risk of VTE is highest during the first year of use of a COC. Data from a large, prospective cohort safety study of various COCs suggest that this increased risk, as compared to that in non-COC users, is greatest during the first 6 months of COC use. Data from this safety study indicate that the greatest risk of VTE is present after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued. Use of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets provides women with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing the same strength synthetic estrogens and progestins (an additional 9 and 13 weeks of exposure to progestin and estrogen, respectively, per year). In the clinical trial, three cases of deep vein thrombosis were reported. Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), and hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors. Use COCs with caution in women with cardiovascular disease risk factors. 5.2 Liver Disease Impaired Liver Function Do not use levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets in women with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications ( 4 )] . Acute disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Discontinue levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if jaundice develops. Liver Tumors Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets is contraindicated in women with benign and malignant liver tumors [see Contraindications ( 4 )] . Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC 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 (> 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users. 5.3 High Blood Pressure Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets 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 levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if blood pressure rises significantly. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin. 5.4 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment During clinical trials with the Hepatitis C combination drug regimen that contains obmitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 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 COCs. Discontinue levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications ( 4 )] . Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen. 5.5 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may also worsen existing gallbladder disease. A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for COC-related cholestasis. 5.6 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. COCs may decrease glucose tolerance in a dose-related fashion. Consider alternative contraception for women with uncontrolled dyslipidemias. A small proportion of women will have adverse lipid changes while on COCs. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs. 5.7 Headache If a woman taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if indicated. Consider discontinuation of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) [see Contraindications ( 4 )] . 5.8 Bleeding Irregularities Bleeding and/or spotting that occurs at any time while taking the first 84 tablets (light pink, pink and purple) of each extended-cycle regimen is considered “unscheduled” bleeding/spotting. Bleeding that occurs during the time a woman takes the seven tablets (yellow) containing 10 mcg of ethinyl estradiol is considered “scheduled” bleeding. Unscheduled and Scheduled Bleeding and Spotting Unscheduled (breakthrough) bleeding and spotting sometimes occur in patients on COCs, especially during the first 3 months of use. If unscheduled bleeding persists or occurs after previously regular cycles on levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC. Before prescribing levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, consider the occurrence of fewer scheduled menses (4 per year instead of 13 per year) against the occurrence of increased unscheduled bleeding and/or spotting. A 12-month open-label study of the efficacy of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets in preventing pregnancy assessed scheduled and unscheduled bleeding [see Clinical Studies ( 14 )] in 3,597 women who completed 34,087 28-day cycles of exposure. A total of 178 (4.9%) of the women discontinued levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, at least in part, due to bleeding or spotting. Scheduled (withdrawal) bleeding and/or spotting remained fairly stable over time, with an average of 3 to 4 days of bleeding and/or spotting per each 91-day cycle. Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 1 below presents the number of days with unscheduled bleeding, spotting, and unscheduled bleeding and/or spotting in Treatment Cycles 1 to 4. Table 1: Number of Unscheduled Bleeding, Spotting and Bleeding and/or Spotting Days per 91-day Cycle Cycle (N) Days of Unscheduled Bleeding per 84-Day Interval Median Days Per Subject-Month Mean Q1 Median Q3 1 (3330) 7.2 0 4 10 1.0 2 (2820) 3.3 0 0 4 0.0 3 (2433) 2.5 0 0 3 0.0 4 (2213) 2.2 0 0 2 0.0 Cycle (N) Days of Unscheduled Spotting per 84-Day Interval Median Days Per Subject-Month Mean Q1 Median Q3 1 (3330) 10.7 2 7 15 1.8 2 (2820) 6.7 0 3 9 0.8 3 (2433) 5.2 0 2 6 0.5 4 (2213) 4.4 0 1 5 0.3 Cycle (N) Days of Unscheduled Bleeding and/or Spotting per 84-Day Interval Median Days Per Subject-Month Mean Q1 Median Q3 1 (3330) 17.9 5 14 27 3.5 2 (2820) 10.0 1 5 14 1.3 3 (2433) 7.7 0 3 10 0.8 4 (2213) 6.6 0 3 8 0.8 Q1=Quartile 1: 25% of women had ≤ this number of days of unscheduled bleeding/spotting Median: 50% of women had ≤ this number of days of unscheduled bleeding/spotting Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled bleeding/spotting Figure 1 shows the percent of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets subjects in the primary clinical trial with ≥7 days or ≥20 days of unscheduled bleeding and/or spotting, or just unscheduled bleeding, during each 91-day treatment cycle. Figure 1: Percent of Women Taking Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets Who Reported Unscheduled Bleeding and/or Spotting Amenorrhea and Oligomenorrhea Women who are not pregnant and use levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets may experience amenorrhea. Based on data from the clinical trial, amenorrhea occurred in approximately 1.9% of women during Cycle 1, 7.7% during Cycle 2, 10.7% during Cycle 3, and 10.1% during Cycle 4 using levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. Rule out pregnancy in the event of amenorrhea. Some women may experience amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent. Figure 1 5.9 COC 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 a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy. Discontinue levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if pregnancy is confirmed. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations ( 8.1 )] . 5.10 Depression Carefully observe women with a history of depression and discontinue levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if depression recurs to a serious degree. Six cases of suicidality (suicide attempts and suicidal behavior) were reported in the clinical trial; several of these cases occurred in women with a psychiatric history. 5.11 Carcinoma of the Breast and Cervix Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets 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 COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings are due to differences in sexual behavior and other factors. 5.12 Effect on Binding Globulins The estrogen component of COCs 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. 5.13 Monitoring A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated health care. 5.14 Hereditary Angioedema In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 5.15 Chloasma Chloasma may occur with COC use, especially in women with a history of chloasma gravidarum. Advise women who tend to develop chloasma to avoid exposure to the sun or ultraviolet radiation while taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.

5.1 Thromboembolic Disorders and Other Vascular Problems Stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if an arterial or deep venous thrombotic event (VTE) occurs. Stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. If feasible, stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE. Start levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets 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. The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 per 10,000 woman-years. The risk of VTE is highest during the first year of use of a COC. Data from a large, prospective cohort safety study of various COCs suggest that this increased risk, as compared to that in non-COC users, is greatest during the first 6 months of COC use. Data from this safety study indicate that the greatest risk of VTE is present after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued. Use of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets provides women with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing the same strength synthetic estrogens and progestins (an additional 9 and 13 weeks of exposure to progestin and estrogen, respectively, per year). In the clinical trial, three cases of deep vein thrombosis were reported. Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), and hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors. Use COCs with caution in women with cardiovascular disease risk factors.

5.2 Liver Disease Impaired Liver Function Do not use levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets in women with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications ( 4 )] . Acute disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Discontinue levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if jaundice develops. Liver Tumors Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets is contraindicated in women with benign and malignant liver tumors [see Contraindications ( 4 )] . Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC 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 (> 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.

5.3 High Blood Pressure Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets 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 levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if blood pressure rises significantly. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin.

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 ( 5.2 )] 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 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 Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 The following adverse reactions have been identified during post-approval use of other 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

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 The following adverse reactions have been identified during post-approval use of other 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