FDA label 57d84675-3d01-cfd2-e063-6294a90aa747

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 who are over 35 years old and smoke should not use AMETHIA tablets. Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use.

5. WARNINGS AND PRECAUTIONS Vascular risks: Stop AMETHIA tablets if a thrombotic event occurs. Stop AMETHIA tablets at least 4 weeks before and through 2 weeks after major surgery. Start AMETHIA tablets no earlier than 4 weeks after delivery, in women who are not breastfeeding. ( 5.1 ) Liver disease: Discontinue AMETHIA tablets if jaundice occurs. ( 5.3 ) High blood pressure: Do not prescribe AMETHIA tablets for women with uncontrolled hypertension or hypertension with vascular disease. ( 5.5 ) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking AMETHIA tablets. Consider an alternate contraceptive method for women with uncontrolled dyslipidemias. ( 5.7 ) Headache: Evaluate significant change in headaches and discontinue AMETHIA tablets if indicated. ( 5.8 ) Uterine bleeding: Evaluate irregular bleeding or amenorrhea ( 5.9 ) 5.1 Thrombotic and Other Vascular Events Stop AMETHIA tablets if an arterial or deep venous thrombotic event occurs. Although the use of COCs increases the risk of venous thromboembolism, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs. The risk of venous thromboembolism in women using COCs is 3 to 9 per 10,000 woman-years. The excess risk is highest during the first year of use of a COC. 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. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued. Use of AMETHIA 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). If feasible, stop AMETHIA tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start AMETHIA tablets no earlier than 4 - 6 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. 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. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. Stop AMETHIA tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. 5.2 Malignant Neoplasms Breast Cancer AMETHIA tablets are contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4) ]. Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [see Postmarketing Experience (6.2) ]. Cervical Cancer 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. 5.3 Liver Disease Discontinue AMETHIA tablets if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic 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. 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. Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use. 5.4 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/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 AMETHIA tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4) ] . AMETHIA tablets can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen. 5.5 High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop AMETHIA tablets if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs. 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. 5.6 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users. 5.7 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking AMETHIA 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. 5.8 Headache If a woman taking AMETHIA tablets develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Levonorgestrel/Ethinyl Estradiol tablets and Ethinyl Estradiol tablets if indicated. An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC. 5.9 Bleeding Irregularities Unscheduled (breakthrough) bleeding and spotting sometimes occur in patients on COCs, especially during the first 3 months of use. If bleeding persists, 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. When prescribing AMETHIA tablets, the convenience of fewer planned menses (4 per year instead of 13 per year) should be weighed against the inconvenience of increased unscheduled bleeding and/or spotting. The primary clinical trial (PSE-301) that evaluated the efficacy of levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets also assessed unscheduled bleeding. The participants in the 12-month clinical trial (N=1,006) completed the equivalent of 8,681 28-day cycles of exposure and were composed primarily of women who had used oral contraceptives previously (89%) as opposed to new users (11%). A total of 82 (8.2%) of the women discontinued levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets, at least in part, due to bleeding or spotting. Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over time, with an average of 3 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 in treatment cycles 1 and 4. Table 2 presents the number of days with unscheduled spotting in treatment cycles 1 and 4. Table 1: Total Number of Days with Unscheduled Bleeding 91-Day Treatment Cycle Days per 84-Day Interval Days per 28-Day Interval Q1 Median Q3 Mean Mean Q1=Quartile 1: 25% of women had this number of days of unscheduled bleeding Median: 50% of women had ≤ this number of days of unscheduled bleeding Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled bleeding 1st 1 4 10 6.9 1.7 4th 0 1 4 3.2 0.8 Table 2: Total Number of Days with Unscheduled Spotting 91-Day Treatment Cycle Days per 84-Day Interval Days per 28-Day Interval Q1 Median Q3 Mean Mean Q1=Quartile 1: 25% of women had ≤ this number of days of unscheduled spotting Median: 50% of women had ≤ this number of days of unscheduled spotting Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled spotting 1st 1 4 11 7.4 1.9 4th 0 2 7 4.4 1.1 Figure 1 shows the percentage of levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets subjects participating in trial PSE-301 with ≥ 7 days or ≥ 20 days of unscheduled bleeding and/or spotting, or only 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 or only Unscheduled Bleeding Amenorrhea sometimes occurs in women who are using COCs. Pregnancy should be ruled out in the event of amenorrhea. Some women may encounter amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent. Figure 1 5.10 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. Oral contraceptive use should be discontinued 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) ] . 5.11 Emotional Disorders Women with a history of depression should be carefully observed and AMETHIA tablets discontinued if depression recurs to a serious degree. 5.12 Interference with Laboratory Tests The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid binding globulin increase with use of COCs. 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 Other Conditions In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs.

<table width="60%" ID="Table1"><caption>Table 1: Total Number of Days with Unscheduled Bleeding</caption><col width="20%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr><th styleCode="Rrule Lrule">91-Day Treatment Cycle</th><th colspan="4" styleCode="Botrule Rrule" valign="middle">Days per 84-Day Interval</th><th styleCode="Rrule Botrule">Days per 28-Day Interval</th></tr><tr><th styleCode="Rrule Lrule"/><th styleCode="Rrule">Q1</th><th styleCode="Rrule">Median</th><th styleCode="Rrule">Q3</th><th styleCode="Rrule">Mean</th><th styleCode="Rrule">Mean</th></tr></thead><tfoot><tr><td colspan="6" align="left" valign="top">Q1=Quartile 1: 25% of women had this number of days of unscheduled bleeding Median: 50% of women had &#x2264; this number of days of unscheduled bleeding Q3=Quartile 3: 75% of women had &#x2264; this number of days of unscheduled bleeding </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Rrule Lrule">1st</td><td styleCode="Rrule">1</td><td styleCode="Rrule">4</td><td styleCode="Rrule">10</td><td styleCode="Rrule">6.9</td><td styleCode="Rrule">1.7</td></tr><tr><td styleCode="Rrule Lrule">4th</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1</td><td styleCode="Rrule">4</td><td styleCode="Rrule">3.2</td><td styleCode="Rrule">0.8</td></tr></tbody></table>

<table width="60%" ID="Table2"><caption>Table 2: Total Number of Days with Unscheduled Spotting</caption><col width="20%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr><th styleCode="Rrule Lrule">91-Day Treatment Cycle</th><th colspan="4" styleCode="Botrule Rrule" valign="middle">Days per 84-Day Interval</th><th styleCode="Rrule Botrule">Days per 28-Day Interval</th></tr><tr><th styleCode="Rrule Lrule"/><th styleCode="Rrule">Q1</th><th styleCode="Rrule">Median</th><th styleCode="Rrule">Q3</th><th styleCode="Rrule">Mean</th><th styleCode="Rrule">Mean</th></tr></thead><tfoot><tr><td colspan="6" align="left" valign="top">Q1=Quartile 1: 25% of women had &#x2264; this number of days of unscheduled spotting Median: 50% of women had &#x2264; this number of days of unscheduled spotting Q3=Quartile 3: 75% of women had &#x2264; this number of days of unscheduled spotting </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Rrule Lrule">1st</td><td styleCode="Rrule">1</td><td styleCode="Rrule">4</td><td styleCode="Rrule">11</td><td styleCode="Rrule">7.4</td><td styleCode="Rrule">1.9</td></tr><tr><td styleCode="Rrule Lrule">4th</td><td styleCode="Rrule">0</td><td styleCode="Rrule">2</td><td styleCode="Rrule">7</td><td styleCode="Rrule">4.4</td><td styleCode="Rrule">1.1</td></tr></tbody></table>

<table width="100%" styleCode="Noautorules"><caption>Figure 1: Percent of Women Taking Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets who Reported Unscheduled Bleeding and/or Spotting or only Unscheduled Bleeding</caption><col width="100%" align="center" valign="top"/><tbody><tr><td><renderMultiMedia referencedObject="MM1"/></td></tr></tbody></table>

6. ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and smoking [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 (≥5%) in clinical trials for levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets are irregular and/or heavy uterine bleeding, weight gain, and acne. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma. at 1-844 -825-8500 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 clinical trial that evaluated the safety and efficacy of levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18-40, of whom 1,006 took at least one dose of levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets. Adverse Reactions Leading to Study Discontinuation : 16.3% 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 irregular and/or heavy uterine bleeding (5.9%), weight gain (2.4%), mood changes (1.5%), and acne (1.0%). Common Treatment-Emergent Adverse Reactions (≥ 5% of women) : irregular and/or heavy uterine bleeding (17%), weight gain (5%), acne (5%). Serious Adverse Reactions: migraine, cholecystitis, cholelithiasis, pancreatitis, abdominal pain, and major depressive disorder. 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 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: 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 levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not 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

<table width="100%" styleCode="Noautorules"><caption>Figure 2: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives</caption><col width="100%" align="center" valign="top"/><tfoot><tr><td align="left">RR = relative risk; OR = odds ratio; HR = hazard ratio. &quot;ever COC&quot; are females with current or past COC use; &quot;never COC use&quot; are females that never used COCs.</td></tr></tfoot><tbody><tr><td><renderMultiMedia referencedObject="MM2"/></td></tr></tbody></table>