Browse the corpus

WARNING: CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, and ENDOMETRIAL CANCER WARNING: CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, and ENDOMETRIAL CANCER See full prescribing information for complete boxed warning. Estrogen Plus Progestin Therapy The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, and myocardial infarction (MI) ( 5.1 ) The WHI estrogen plus progestin substudy reported increased risk of invasive breast cancer ( 5.2 ) The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older ( 5.3 ) Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 ) Estrogen-Alone Therapy There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens ( 5.2 ) The WHI estrogen-alone substudy reported increased risks of stroke and DVT ( 5.1 ) The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older ( 5.3 ) Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 ) Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of pulmonary embolism (PE), deep vein thrombosis (DVT), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions ( 5.1 ) and Clinical Studies ( 14.5 )] . The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.6 )] . Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions ( 5.1 , 5.3 ), and Clinical Studies ( 14.5 , 14.6 )] . Breast Cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions ( 5.2 ) and Clinical Studies ( 14.5 )] . Once daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile.

er estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions ( 5.2 )] . Cardiovascular Disorders and Probable Dementia The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo [see Warnings and Precautions ( 5.1 ) and Clinical Studies ( 14.5 )]. The WHIMS estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.5 ) and Clinical Studies ( 14.6 )]. Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions ( 5.1 , 5.3 ), and Clinical Studies ( 14.5 , 14.6 )]. Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

or other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. What is the most important information I should know about Fyavolv (a combination of estrogen and progestogen)? Do not use estrogens with or without progestogens to prevent heart disease, heart attacks, strokes or dementia (decline of brain function). Using estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. Using estrogens with progestogens may increase your chance of getting dementia, based on a study of women 65 years of age and older. Using estrogen-alone may increase your chance of getting cancer of the uterus (womb). Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia (decline of brain function). Using estrogen-alone may increase your chances of getting strokes or blood clots. Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age and older. Only one estrogen with progestogen product and dose have been shown to increase your chances of getting heart attacks, strokes, breast cancer, blood clots, and dementia. Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. Because other products and doses have not been studied in the same way, it is not known how the use of Fyavolv will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with Fyavolv.

1 INDICATIONS AND USAGE Fyavolv is a combination of an estrogen and progestin indicated in a woman with a uterus for: Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause ( 1.1 ) Prevention of Postmenopausal Osteoporosis ( 1.2 ) 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause 1.2 Prevention of Postmenopausal Osteoporosis Limitation of Use When prescribing solely for the prevention of postmenopausal osteoporosis, first consider the use of non-estrogen medications. Consider estrogen therapy only for women at significant risk of osteoporosis.

2 DOSAGE AND ADMINISTRATION One tablet orally once daily ( 2.1 , 2.2 ) Use estrogen, alone or in combination with a progestogen, at the lowest effective dose and the shortest duration consistent with treatment goals and risks for the individual woman. Re-evaluate postmenopausal women periodically as clinically appropriate to determine whether treatment is still necessary. 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Take a single Fyavolv tablet, orally once daily. 2.2 Prevention of Postmenopausal Osteoporosis Take a single Fyavolv tablet, orally once daily.

3 DOSAGE FORMS AND STRENGTHS Tablet: 0.5 mg norethindrone acetate and 0.0025 mg ethinyl estradiol ( 3 ) Tablet: 1 mg norethindrone acetate and 0.005 mg ethinyl estradiol ( 3 ) The following two strengths of Fyavolv tablets are available: Fyavolv tablets, (0.5 mg/0.0025 mg): Each are white to off-white, round film-coated tablet, debossed with "F51" on one side and "LU" on the other side contains 0.5 mg norethindrone acetate and 0.0025 mg ethinyl estradiol. Fyavolv tablets, (1 mg/0.005 mg): Each are blue, round film-coated tablet, debossed with "F52" on one side and "LU" on the other side contains 1 mg norethindrone acetate and 0.005 mg ethinyl estradiol.

4 CONTRAINDICATIONS Undiagnosed abnormal genital bleeding ( 4 , 5.2 ) Breast cancer or a history of breast cancer ( 4 , 5.2 ) Estrogen-dependent neoplasia ( 4 , 5.2 ) Active DVT, PE, or history of these conditions ( 4 , 5.1 ) Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions ( 4 , 5.1 ) Known anaphylactic reaction, angioedema, or hypersensitivity to Fyavolv ( 4 ) Hepatic impairment or disease ( 4 , 5.10 ) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 ) Fyavolv is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding [see Warnings and Precautions ( 5.2 )] . Breast cancer or a history of breast cancer [see Warnings and Precautions ( 5.2 )] . Estrogen-dependent neoplasia [see Warnings and Precautions ( 5.2 )] . Active DVT, PE or a history of these conditions [see Warnings and Precautions ( 5.1 )] . Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions [see Warnings and Precautions ( 5.1 )] . Known anaphylactic reaction, angioedema, or hypersensitivity to Fyavolv . Hepatic impairment or disease. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders.

5 WARNINGS AND PRECAUTIONS Estrogens increase the risk of gallbladder disease ( 5.4 ) Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs ( 5.5 , 5.6 , 5.9 , 5.10 ) Monitor thyroid function in women on thyroid replacement therapy ( 5.11 , 5.18 ) 5.1 Cardiovascular Disorders Increased risks of PE, DVT, stroke, and MI are reported with estrogen plus progestin therapy. Increased risks of stroke and DVT are reported with estrogen-alone therapy. Immediately discontinue estrogen with or without progestogen therapy if any of these occur or are suspected. Manage appropriately any risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus). Stroke The WHI estrogen plus progestin substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 strokes per 10,000 women-years, respectively) [see Clinical Studies ( 14.5 )] . The increase in risk was demonstrated after the first year and persisted. 1 Immediately discontinue estrogen with or without progestogen therapy if a stroke occurs or is suspected. The WHI estrogen-alone substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving daily conjugated estrogens CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 strokes per 10,000 women-years, respectively). The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies ( 14.5 )] . Immediately discontinue estrogen-alone therapy if a stroke occurs or is suspected. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years). 1 Coronary Heart Disease The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) of coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in those women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years). 1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies ( 14.5 )]. The WHI estrogen-alone substudy reported no overall effect on CHD events in women receiving estrogen-alone compared to placebo 2 [see Clinical Studies ( 14.5 )]. Subgroup analyses of women 50 to 59 years of age, who were less than 10 years since menopause, suggest a reduction (not statistically significant) of CHD events in those women receiving CE (0.625 mg)-alone compared to placebo (8 versus 16 per 10,000 woman-years). 1 In postmenopausal women with documented heart disease (n = 2,763), average 66.7 years of age, in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit.

postmenopausal women with documented heart disease (n = 2,763), average 66.7 years of age, in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established CHD. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand, three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall. Venous Thromboembolism The WHI estrogen plus progestin substudy reported a statistically significant 2-fold greater rate of VTE (DVT and PE) in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted 3 [see Clinical Studies ( 14.5 )] . Immediately discontinue estrogen plus progestogen therapy if a VTE occurs or is suspected. In the WHI estrogen-alone substudy, the risk of VTE was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years 4 [see Clinical Studies ( 14.5 )] . Immediately discontinue estrogen-alone therapy if a VTE occurs or is suspected. If feasible, discontinue estrogens at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism or during periods of prolonged immobilization. 5.2 Malignant Neoplasms Breast Cancer After a mean follow-up of 5.6 years, the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg) reported an increased risk of invasive breast cancer in women who took daily CE plus MPA compared to placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years for CE plus MPA compared with placebo [see Clinical Studies ( 14.5 )] . Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86 and the absolute risk was 46 versus 25 cases per 10,000 women-years for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups 5 [see Clinical Studies ( 14.5 )] .

tage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups 5 [see Clinical Studies ( 14.5 )] . The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. In the WHI estrogen-alone substudy, after an average follow up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80) compared to placebo 6 [see Clinical Studies ( 14.5 )] . Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy. Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. These studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors and prior mammogram results. Endometrial Cancer Endometrial hyperplasia (a possible precursor of endometrial cancer) has been reported to occur at a rate of approximately 1 percent or less with Fyavolv. An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15-to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women using estrogen-alone or estrogen plus progestogen therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestogen to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Ovarian Cancer The CE plus MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer.

ivalent estrogen dose. Adding a progestogen to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Ovarian Cancer The CE plus MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77 to 3.24), but it was not statistically significant. The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years 7 . A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27-1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown. 5.3 Probable Dementia In the WHI Memory Study (WHIMS) estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years 8 [see Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.6 )] . In the WHIMS estrogen-alone ancillary study, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years 8 [see Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.6 )]. When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19 to 2.60). Since both ancillary substudies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.6 )] . 5.4 Gallbladder Disease A 2-to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. 5.5 Hypercalcemia Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including Fyavolv, if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level.

y in postmenopausal women receiving estrogens has been reported. 5.5 Hypercalcemia Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including Fyavolv, if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level. 5.6 Visual Abnormalities Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue Fyavolv pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens, including Fyavolv, if examination reveals papilledema or retinal vascular lesions. 5.7 Addition of a Progestogen When a Woman Has Not Had a Hysterectomy Studies of the addition of a progestogen for 10 or more days of a cycle of estrogen administration or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestogens with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. 5.8 Elevated Blood Pressure In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen. 5.9 Exacerbation of Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Discontinue Fyavolv if pancreatitis occurs. 5.10 Hepatic Impairment and/or a Past History of Cholestatic Jaundice Estrogens may be poorly metabolized in women with hepatic impairment. Exercise caution in any woman with a history of cholestatic jaundice associated with past estrogen use or with pregnancy. In the case of recurrence of cholestatic jaundice, discontinue Fyavolv. 5.11 Exacerbation of Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T 4 and T 3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogen may require increased doses of their thyroid replacement therapy. Monitor thyroid function in these women during treatment with Fyavolv to maintain their free thyroid hormone levels in an acceptable range. 5.12 Fluid Retention Estrogens plus progestogens may cause some degree of fluid retention. Monitor any woman with a condition(s) that might predispose her to fluid retention, such as cardiac or renal impairment. Discontinue estrogen plus progestogen therapy, including Fyavolv, with evidence of medically concerning fluid retention. 5.13 Hypocalcemia Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy, including Fyavolv, outweigh the risks in such women. 5.14 Exacerbation of Endometriosis A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. 5.15 Hereditary Angioedema Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy, including Fyavolv, outweigh the risks in such women.

al implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. 5.15 Hereditary Angioedema Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy, including Fyavolv, outweigh the risks in such women. 5.16 Exacerbation of Other Conditions Estrogen therapy, including Fyavolv, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas. Consider whether the benefits of estrogen therapy outweigh the risks in women with such conditions. 5.17 Laboratory Tests Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of postmenopausal women with moderate to severe vasomotor symptoms. 5.18 Drug-Laboratory Test Interactions Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. Increased TBG levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T 4 levels (by column or by radioimmunoassay) or T 3 levels by radioimmunoassay. T 3 resin uptake is decreased, reflecting the elevated TBG. Free T 4 and free T 3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone. Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Fyavolv 1/5 was associated with an SHBG increase of 22 percent. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). Increased plasma high-density lipoprotein (HDL) and HDL 2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels. Impaired glucose tolerance.

5.17 Laboratory Tests Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of postmenopausal women with moderate to severe vasomotor symptoms.

6 ADVERSE REACTIONS The most common adverse reactions with Fyavolv (incidence greater than or equal to 5 percent) are: headache, abdominal pain, breast pain, and edema (generalized) ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561, or FDA at 1-800-FDA-1088 or www.fda.gov/Medwatch . The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning , Warnings and Precautions ( 5.1 )] . Malignant Neoplasms [see Boxed Warning , Warnings and Precautions ( 5.2 )] . 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. Adverse reactions reported by ≥5 percent of women in controlled clinical studies of norethindrone acetate and ethinyl estradiol are shown in Table 1. Table 1. Associated Adverse Reactions Reported by ≥5 Percent of Women by Body System* * The total number of women for each body system may be less than the number of women with AEs in that body system because a woman may have had more than one AE per body system BODY SYSTEM/ Adverse Reaction Number (Percent) of Subjects Placebo N = 247 Norethindrone Acetate and Ethinyl Estradiol 0.5/2.5 N = 244 Norethindrone Acetate and Ethinyl Estradiol 1/5 N = 258 BODY AS A WHOLE 23 (12.8) 30 (16.9) 30 (15.7) Edema – Generalized 10 (4.0) 12 (4.9) 11 (4.3) Headache 12 (4.9) 14 (5.7) 16 (6.2) DIGESTIVE SYSTEM 8 (4.4) 17 (9.6) 25 (13.1) Abdominal Pain 3 (1.2) 13 (5.3) 14 (6.8) UROGENITAL SYSTEM 20 (11.1) 34 (19.2) 45 (23.6) Breast Pain 9 (3.6) 22 (9.0) 20 (7.8) 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of norethindrone acetate 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. Genitourinary System Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer; uterine cancer; vaginal hemorrhage; ovarian cyst; irregular menstruation; metrorrhagia; menorrhagia; dysmenorrhea; uterine enlargement. Breasts Tenderness, enlargement, breast pain, nipple pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer; breast disorder; breast mass; breast enlargement. Cardiovascular Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; thrombosis; chest pain; myocardial infarction; cerebrovascular accident (stroke); transient ischemic attack; hemiparesis; increase in blood pressure; irregular heart rate; palpitations; dyspnea. Gastrointestinal Nausea, vomiting; cholestatic jaundice; pancreatitis, enlargement of hepatic hemangiomas; bloating, abdominal cramps; abdominal pain; increased incidence of gallbladder disease; cholecystitis; cholelithiasis.

attack; hemiparesis; increase in blood pressure; irregular heart rate; palpitations; dyspnea. Gastrointestinal Nausea, vomiting; cholestatic jaundice; pancreatitis, enlargement of hepatic hemangiomas; bloating, abdominal cramps; abdominal pain; increased incidence of gallbladder disease; cholecystitis; cholelithiasis. Skin Chloasma or melasma that may persist when drug is discontinued; generalized erythema; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; rash, pruritus. Eyes Retinal vascular thrombosis; visual impairment; intolerance to contact lenses. Central Nervous System (CNS) Headache; migraine; dizziness; depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia; paresthesia; insomnia. Miscellaneous Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgias; leg cramps; back pain; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides; blood glucose abnormal; fatigue; myalgia; hypersensitivity.

<table ID="ID461" width="96%" styleCode="Noautorules"><caption> Table 1. Associated Adverse Reactions Reported by &#x2265;5 Percent of Women by Body System* </caption><col width="29%"/><col width="14%"/><col width="28%"/><col width="27%"/><tfoot><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold"> *</content> The total number of women for each body system may be less than the number of women with AEs in that body system because a woman may have had more than one AE per body system</paragraph></td></tr></tfoot><tbody><tr><td valign="top" styleCode=" Toprule" align="left"><content styleCode="bold"> BODY SYSTEM/ Adverse Reaction</content> </td><td valign="top" styleCode=" Toprule Botrule" align="left"> </td><td valign="top" styleCode=" Toprule Botrule" align="left"><content styleCode="bold"> Number (Percent) of Subjects</content> </td><td valign="top" styleCode=" Toprule Botrule" align="left"> </td></tr><tr><td valign="top" styleCode=" Botrule" align="left"> </td><td valign="top" styleCode=" Botrule" align="center"><content styleCode="bold"> Placebo </content> <content styleCode="bold"> N = 247</content> </td><td valign="top" styleCode=" Botrule" align="center"><content styleCode="bold"> Norethindrone Acetate and Ethinyl Estradiol </content><content styleCode="bold"> 0.5/2.5</content> <content styleCode="bold"> N = 244</content> </td><td valign="top" styleCode=" Botrule" align="center"><content styleCode="bold"> Norethindrone Acetate and Ethinyl Estradiol</content><content styleCode="bold"> 1/5 </content> <content styleCode="bold"> N = 258</content> </td></tr><tr><td valign="top" align="left"> BODY AS A WHOLE </td><td valign="top" align="center"> 23 (12.8) </td><td valign="top" align="center"> 30 (16.9) </td><td valign="top" align="center"> 30 (15.7) </td></tr><tr><td valign="top" align="left"> Edema &#x2013; Generalized </td><td valign="top" align="center"> 10 (4.0) </td><td valign="top" align="center"> 12 (4.9) </td><td valign="top" align="center"> 11 (4.3) </td></tr><tr><td valign="top" align="left"> Headache </td><td valign="top" align="center"> 12 (4.9) </td><td valign="top" align="center"> 14 (5.7) </td><td valign="top" align="center"> 16 (6.2) </td></tr><tr><td valign="top" align="left"> DIGESTIVE SYSTEM </td><td valign="top" align="center"> 8 (4.4) </td><td valign="top" align="center"> 17 (9.6) </td><td valign="top" align="center"> 25 (13.1) </td></tr><tr><td valign="top" align="left"> Abdominal Pain </td><td valign="top" align="center"> 3 (1.2) </td><td valign="top" align="center"> 13 (5.3) </td><td valign="top" align="center"> 14 (6.8) </td></tr><tr><td valign="top" align="left"> UROGENITAL SYSTEM </td><td valign="top" align="center"> 20 (11.1) </td><td valign="top" align="center"> 34 (19.2) </td><td valign="top" align="center"> 45 (23.6) </td></tr><tr><td valign="top" styleCode=" Botrule" align="left"> Breast Pain </td><td valign="top" styleCode=" Botrule" align="center"> 9 (3.6) </td><td valign="top" styleCode=" Botrule" align="center"> 22 (9.0) </td><td valign="top" styleCode=" Botrule" align="center"> 20 (7.8) </td></tr></tbody></table>

7 DRUG INTERACTIONS Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. ( 7.1 ) In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen and progestin drug metabolism. Inducers of CYP3A4 such as St. John's wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine and rifampin may decrease the plasma concentration of estrogens and progestins, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase the plasma concentration of the estrogen or the progestin or both and may result in adverse reactions. Co-administration of atorvastatin and certain hormonal products containing ethinyl estradiol increase AUC values for ethinyl estradiol approximately 20 percent. Ascorbic acid and acetaminophen may increase the plasma ethinyl estradiol concentration, possibly by inhibition of conjugation. Combination hormonal products have been shown to significantly decrease the plasma concentration of lamotrigine likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Norethindrone acetate and ethinyl estradiol is not indicated for use in pregnancy. There are no data with the use of norethindrone acetate and ethinyl estradiol in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined (estrogens and progestins) product before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary Estrogens plus progestogens are present in human milk and can reduce milk production in breastfeeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for norethindrone acetate and ethinyl estradiol and any potential adverse effects on the breastfed child from norethindrone acetate and ethinyl estradiol or from the underlying maternal condition. 8.4 Pediatric Use Norethindrone acetate and ethinyl estradiol is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population. 8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing norethindrone acetate and ethinyl estradiol to determine whether those over 65 years of age differ from younger subjects in their response to norethindrone acetate and ethinyl estradiol. The Women's Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies ( 14.5 )] . In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies ( 14.5 )] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.6 )] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.6 )] .

8.1 Pregnancy Risk Summary Norethindrone acetate and ethinyl estradiol is not indicated for use in pregnancy. There are no data with the use of norethindrone acetate and ethinyl estradiol in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined (estrogens and progestins) product before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2 Lactation Risk Summary Estrogens plus progestogens are present in human milk and can reduce milk production in breastfeeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for norethindrone acetate and ethinyl estradiol and any potential adverse effects on the breastfed child from norethindrone acetate and ethinyl estradiol or from the underlying maternal condition.

8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing norethindrone acetate and ethinyl estradiol to determine whether those over 65 years of age differ from younger subjects in their response to norethindrone acetate and ethinyl estradiol. The Women's Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies ( 14.5 )] . In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies ( 14.5 )] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.6 )] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.6 )] .

10 OVERDOSAGE Overdosage of estrogen plus progestogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Fyavolv therapy with institution of appropriate symptomatic care.

11 DESCRIPTION Fyavolv (norethindrone acetate and ethinyl estradiol tablets USP) is a continuous dosage regimen of a progestin-estrogen combination for oral administration. The following strength of Fyavolv tablets is available: Fyavolv (0.5 mg/0.0025 mg): Each white to off-white, round film-coated tablet, debossed with "F51" on one side and "LU" on the other side contains 0.5 mg norethindrone acetate and 0.0025 mg ethinyl estradiol. Fyavolv (1 mg/0.005 mg): Each blue, round film-coated tablet, debossed with "F52" on one side and "LU" on the other side contains 1 mg norethindrone acetate and 0.005 mg ethinyl estradiol. Each tablet contains the following inactive ingredients: calcium stearate, corn starch, hypromellose, lactose monohydrate, microcrystalline cellulose, polyethylene glycol 400, titanium dioxide and vitamin E. Each tablet of 1 mg/0.005 mg also contains FD&C Blue No. 2 Aluminum Lake. The structural formulas are as follows. Ethinyl Estradiol [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-] Molecular Weight: 296.40 Molecular Formula: C 20 H 24 O 2 Norethindrone Acetate [19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17α)-] Molecular Weight: 340.46 Molecular Formula: C 22 H 28 O 3 Figure 1 Figure 2

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. The pharmacologic effects of ethinyl estradiol are similar to those of endogenous estrogens. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, bone, skeletal tissue and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone. 12.2 Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to norethindrone acetate and ethinyl estradiol nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid. 12.3 Pharmacokinetics Absorption Norethindrone acetate (NA) is completely deacetylated to norethindrone after oral administration, and the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol (EE) are absorbed from norethindrone acetate and ethinyl estradiol tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol generally occurring 1 to 2 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64 percent for norethindrone and 55 percent for ethinyl estradiol. Bioavailability of norethindrone acetate and ethinyl estradiol tablet is similar to that from solution for norethindrone and slightly less for ethinyl estradiol. Administration of norethindrone acetate and ethinyl estradiol tablets with a high fat meal decreases rate but not extent of ethinyl estradiol absorption.

iol. Bioavailability of norethindrone acetate and ethinyl estradiol tablet is similar to that from solution for norethindrone and slightly less for ethinyl estradiol. Administration of norethindrone acetate and ethinyl estradiol tablets with a high fat meal decreases rate but not extent of ethinyl estradiol absorption. The extent of norethindrone absorption is increased by 27 percent following administration of norethindrone acetate and ethinyl estradiol tablets with food. The full pharmacokinetic profile of norethindrone acetate and ethinyl estradiol tablet was not characterized due to assay sensitivity limitations. However, the multiple-dose pharmacokinetics were studied at a dose of 1 mg norethindrone acetate and 0.01 mg ethinyl estradiol in 18 postmenopausal women. Mean plasma concentrations are shown below (Figure 1) and pharmacokinetic parameters are found in Table 2. Based on a population pharmacokinetic analysis, mean steady-state concentrations of norethindrone for 1 mg norethindrone acetate and 0.005 mg ethinyl estradiol and 1/10 are slightly more than proportional to dose when compared to 0.5 mg norethindrone acetate and 0.0025 mg ethinyl estradiol tablets. It can be explained by higher SHBG concentrations. Mean steady-state plasma concentrations of ethinyl estradiol for the norethindrone acetate and ethinyl estradiol 0.5/2.5 tablets and norethindrone acetate and ethinyl estradiol 1/5 tablets are proportional to dose, but there is a less than proportional increase in steady-state concentrations for the norethindrone acetate and ethinyl estradiol 1/10 tablet. Figure 1. Mean Steady-State (Day 87) Plasma Norethindrone and Ethinyl Estradiol Concentrations Following Continuous Oral Administration of 1 mg Norethindrone Acetate and 0.01 mg Ethinyl Estradiol Tablets Table 2. Mean (SD) Single-Dose (Day 1) and Steady-State (Day 87) Pharmacokinetic Parameters† Following Administration of 1 mg Norethindrone Acetate and 0.01 mg Ethinyl Estradiol Tablets † C max = Maximum plasma concentration; t max = time of C max ; AUC (0-24) = Area under the plasma concentration-time curve over the dosing interval; and CL/F = Apparent oral clearance; t ½ = Elimination half-life ‡ ND = Not determined C max t max AUC (0-24) CL/F t ½ Norethindrone ng/mL hr ng·hr/mL mL/min hr Day 1 6.0 (3.3) 1.8 (0.8) 29.7 (16.5) 588 (416) 10.3 (3.7) Day 87 10.7 (3.6) 1.8 (0.8) 81.8 (36.7) 226 (139) 13.3 (4.5) Ethinyl pg/mL hr pg·hr/mL mL/min hr Estradiol Day 1 33.5 (13.7) 2.2 (1.0) 339 (113) ND ‡ ND ‡ Day 87 38.3 (11.9) 1.8 (0.7) 471 (132) 383 (119) 23.9 (7.1) Based on a population pharmacokinetic analysis, average steady-state concentrations (Css) of norethindrone and ethinyl estradiol for norethindrone acetate and ethinyl estradiol 1/5 tablets are estimated to be 2.6 ng/mL and 11.4 pg/mL, respectively. Css values of norethindrone and ethinyl estradiol for norethindrone acetate and ethinyl estradiol 0.5/2.5 tablets are estimated to be 1.1 ng/mL and 5.4 ng/mL, respectively. The pharmacokinetics of ethinyl estradiol and norethindrone acetate were not affected by age, (age range 40 to 62 years), in the postmenopausal population studied. Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin. Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (greater than 95 percent); norethindrone binds to both albumin and SHBG, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis.

tion of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (greater than 95 percent); norethindrone binds to both albumin and SHBG, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol, such that exposure to ethinyl estradiol following administration of 1 mg of norethindrone acetate is equivalent to oral administration of 2.8 mcg ethinyl estradiol. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of 1 mg norethindrone acetate and 0.01 mg ethinyl estradiol tablets are approximately 13 hours and 24 hours, respectively. Figure 3 Figure 4

12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. The pharmacologic effects of ethinyl estradiol are similar to those of endogenous estrogens. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, bone, skeletal tissue and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone.

12.2 Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to norethindrone acetate and ethinyl estradiol nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

12.3 Pharmacokinetics Absorption Norethindrone acetate (NA) is completely deacetylated to norethindrone after oral administration, and the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol (EE) are absorbed from norethindrone acetate and ethinyl estradiol tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol generally occurring 1 to 2 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64 percent for norethindrone and 55 percent for ethinyl estradiol. Bioavailability of norethindrone acetate and ethinyl estradiol tablet is similar to that from solution for norethindrone and slightly less for ethinyl estradiol. Administration of norethindrone acetate and ethinyl estradiol tablets with a high fat meal decreases rate but not extent of ethinyl estradiol absorption. The extent of norethindrone absorption is increased by 27 percent following administration of norethindrone acetate and ethinyl estradiol tablets with food. The full pharmacokinetic profile of norethindrone acetate and ethinyl estradiol tablet was not characterized due to assay sensitivity limitations. However, the multiple-dose pharmacokinetics were studied at a dose of 1 mg norethindrone acetate and 0.01 mg ethinyl estradiol in 18 postmenopausal women. Mean plasma concentrations are shown below (Figure 1) and pharmacokinetic parameters are found in Table 2. Based on a population pharmacokinetic analysis, mean steady-state concentrations of norethindrone for 1 mg norethindrone acetate and 0.005 mg ethinyl estradiol and 1/10 are slightly more than proportional to dose when compared to 0.5 mg norethindrone acetate and 0.0025 mg ethinyl estradiol tablets. It can be explained by higher SHBG concentrations. Mean steady-state plasma concentrations of ethinyl estradiol for the norethindrone acetate and ethinyl estradiol 0.5/2.5 tablets and norethindrone acetate and ethinyl estradiol 1/5 tablets are proportional to dose, but there is a less than proportional increase in steady-state concentrations for the norethindrone acetate and ethinyl estradiol 1/10 tablet. Figure 1. Mean Steady-State (Day 87) Plasma Norethindrone and Ethinyl Estradiol Concentrations Following Continuous Oral Administration of 1 mg Norethindrone Acetate and 0.01 mg Ethinyl Estradiol Tablets Table 2. Mean (SD) Single-Dose (Day 1) and Steady-State (Day 87) Pharmacokinetic Parameters† Following Administration of 1 mg Norethindrone Acetate and 0.01 mg Ethinyl Estradiol Tablets † C max = Maximum plasma concentration; t max = time of C max ; AUC (0-24) = Area under the plasma concentration-time curve over the dosing interval; and CL/F = Apparent oral clearance; t ½ = Elimination half-life ‡ ND = Not determined C max t max AUC (0-24) CL/F t ½ Norethindrone ng/mL hr ng·hr/mL mL/min hr Day 1 6.0 (3.3) 1.8 (0.8) 29.7 (16.5) 588 (416) 10.3 (3.7) Day 87 10.7 (3.6) 1.8 (0.8) 81.8 (36.7) 226 (139) 13.3 (4.5) Ethinyl pg/mL hr pg·hr/mL mL/min hr Estradiol Day 1 33.5 (13.7) 2.2 (1.0) 339 (113) ND ‡ ND ‡ Day 87 38.3 (11.9) 1.8 (0.7) 471 (132) 383 (119) 23.9 (7.1) Based on a population pharmacokinetic analysis, average steady-state concentrations (Css) of norethindrone and ethinyl estradiol for norethindrone acetate and ethinyl estradiol 1/5 tablets are estimated to be 2.6 ng/mL and 11.4 pg/mL, respectively.

) ND ‡ ND ‡ Day 87 38.3 (11.9) 1.8 (0.7) 471 (132) 383 (119) 23.9 (7.1) Based on a population pharmacokinetic analysis, average steady-state concentrations (Css) of norethindrone and ethinyl estradiol for norethindrone acetate and ethinyl estradiol 1/5 tablets are estimated to be 2.6 ng/mL and 11.4 pg/mL, respectively. Css values of norethindrone and ethinyl estradiol for norethindrone acetate and ethinyl estradiol 0.5/2.5 tablets are estimated to be 1.1 ng/mL and 5.4 ng/mL, respectively. The pharmacokinetics of ethinyl estradiol and norethindrone acetate were not affected by age, (age range 40 to 62 years), in the postmenopausal population studied. Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin. Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (greater than 95 percent); norethindrone binds to both albumin and SHBG, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol, such that exposure to ethinyl estradiol following administration of 1 mg of norethindrone acetate is equivalent to oral administration of 2.8 mcg ethinyl estradiol. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of 1 mg norethindrone acetate and 0.01 mg ethinyl estradiol tablets are approximately 13 hours and 24 hours, respectively.

<table ID="ID509" width="100%" styleCode="Noautorules"><caption> Table 2. Mean (SD) Single-Dose (Day 1) and Steady-State (Day 87) Pharmacokinetic Parameters&#x2020; Following Administration of 1 mg Norethindrone Acetate and 0.01 mg Ethinyl Estradiol Tablets </caption><col width="25%"/><col width="16%"/><col width="13%"/><col width="17%"/><col width="15%"/><col width="12%"/><tfoot><tr><td align="left" colspan="6"><paragraph styleCode="Footnote"><content styleCode="bold">^&#x2020;</content> C_max = Maximum plasma concentration; t_max = time of C_max; AUC_(0-24) = Area under the plasma concentration-time curve over the dosing interval; and CL/F = Apparent oral clearance; t_&#xBD; = Elimination half-life </paragraph></td></tr><tr><td align="left" colspan="6"><paragraph styleCode="Footnote">^&#x2021;ND = Not determined</paragraph></td></tr></tfoot><tbody><tr><td colspan="2" valign="top" styleCode=" Toprule Botrule" align="left"> C_max </td><td valign="top" styleCode=" Toprule Botrule" align="center"> t_max </td><td valign="top" styleCode=" Toprule Botrule" align="center"> AUC_(0-24) </td><td valign="top" styleCode=" Toprule Botrule" align="center"> CL/F </td><td valign="top" styleCode=" Toprule Botrule" align="center"> t_&#xBD; </td></tr><tr><td valign="top" styleCode=" Botrule" align="left"><content styleCode="bold"> Norethindrone </content> </td><td valign="top" styleCode=" Botrule" align="center"> ng/mL </td><td valign="top" styleCode=" Botrule" align="center"> hr </td><td valign="top" styleCode=" Botrule" align="center"> ng&#xB7;hr/mL </td><td valign="top" styleCode=" Botrule" align="center"> mL/min </td><td valign="top" styleCode=" Botrule" align="right"> hr </td></tr><tr><td valign="top" align="left"> Day 1 </td><td valign="top" align="center"> 6.0 (3.3) </td><td valign="top" align="center"> 1.8 (0.8) </td><td valign="top" align="center"> 29.7 (16.5) </td><td valign="top" align="center"> 588 (416) </td><td valign="top" align="right"> 10.3 (3.7) </td></tr><tr><td valign="top" styleCode=" Botrule" align="left"> Day 87 </td><td valign="top" styleCode=" Botrule" align="center"> 10.7 (3.6) </td><td valign="top" styleCode=" Botrule" align="center"> 1.8 (0.8) </td><td valign="top" styleCode=" Botrule" align="center"> 81.8 (36.7) </td><td valign="top" styleCode=" Botrule" align="center"> 226 (139) </td><td valign="top" styleCode=" Botrule" align="right"> 13.3 (4.5) </td></tr><tr><td valign="top" align="left"><content styleCode="bold"> Ethinyl </content> </td><td valign="top" align="center"> pg/mL </td><td valign="top" align="center"> hr </td><td valign="top" align="center"> pg&#xB7;hr/mL </td><td valign="top" align="center"> mL/min </td><td valign="top" align="right"> hr </td></tr><tr><td valign="top" styleCode=" Botrule" align="left"><content styleCode="bold"> Estradiol </content> </td><td styleCode=" Botrule" colspan="5"/></tr><tr><td valign="top" align="left"> Day 1 </td><td valign="top" align="center"> 33.5 (13.7) </td><td valign="top" align="center"> 2.2 (1.0) </td><td valign="top" align="center"> 339 (113) </td><td valign="top" align="center"> ND^&#x2021; </td><td valign="top" align="right"> ND^&#x2021; </td></tr><tr><td valign="top" styleCode=" Botrule" align="left"> Day 87 </td><td valign="top" styleCode=" Botrule" align="center"> 38.3 (11.9) </td><td valign="top" styleCode=" Botrule" align="center"> 1.8 (0.7) </td><td valign="top" styleCode=" Botrule" align="center"> 471 (132) </

lign="right"> ND^&#x2021; </td></tr><tr><td valign="top" styleCode=" Botrule" align="left"> Day 87 </td><td valign="top" styleCode=" Botrule" align="center"> 38.3 (11.9) </td><td valign="top" styleCode=" Botrule" align="center"> 1.8 (0.7) </td><td valign="top" styleCode=" Botrule" align="center"> 471 (132) </ td><td valign="top" styleCode=" Botrule" align="center"> 383 (119) </td><td valign="top" styleCode=" Botrule" align="right"> 23.9 (7.1) </td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

14 CLINICAL STUDIES 14.1 Effects on Vasomotor Symptoms in Postmenopausal Women A 12-week placebo-controlled, multicenter, randomized clinical trial was conducted in 266 symptomatic women who had at least 56 moderate to severe hot flushes during the week prior to randomization. On average, women had 12 hot flushes per day upon study entry. A total of 66 women were randomized to receive norethindrone acetate and ethinyl estradiol 1/5 and 66 women were randomized to the placebo group. Norethindrone acetate and ethinyl estradiol 1/5 was shown to be statistically better than placebo at weeks 4 and 12 for relief of the frequency of moderate to severe vasomotor symptoms (see Table 3 ). In Table 4, norethindrone acetate and ethinyl estradiol 1/5 was shown to be statistically better than placebo at weeks 4 and 12 for relief of the severity of moderate to severe vasomotor symptoms. Table 3. Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms per Week -ITT Population, LOCF è Denotes statistical significance at the 0.05 level [1] The baseline number of moderate to severe vasomotor symptoms (MSVS) is the weekly average number of MSVS during the two week pre-randomization observation period. [2] ANCOVA -Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95 percent CI -Mann-Whitney confidence interval for the difference between means (not stratified by center). ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval 2 randomized women (1 in Placebo and 1 in norethindrone acetate and ethinyl estradiol) did not return diaries. Visit Placebo (N = 66) Norethindrone Acetate and Ethinyl Estradiol 0.5/2.5 (N = 67) Norethindrone Acetate and Ethinyl Estradiol 1/5 (N = 66) Baseline [1] Mean (SD) 76.5 (21.4) 77.6 (26.5) 70.0 (16.6) Week 4 Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) [2] 39.4 (27.6) -37.0 (26.6) 30.2 (26.1) -47.4 è (26.1) 0.041 (-20.0, -1.0) 20.4 (22.7) -49.6 è (22.1) <0.001 (-22.0,-6.0) Week 12 Mean (SD) Mean Change from Baseline (SD) 31.1 (27.0) -45.3 (30.2) 13.8 (20.4) -63.8 è (27.5) 11.3 (18.9) -58.7 è (23.1) p-Value vs. Placebo (95 percent CI) [2] <0.001 (-27.0, -7.0) <0.001 (-25.0, -5.0) Table 4. Mean Change from Baseline in the Daily Severity Score of Moderate to Severe Vasomotor Symptoms per Week -ITT Population, LOCF ¥ Denotes statistical significance at the 0.05 level [1] The baseline severity of moderate to severe vasomotor symptoms (MSVS) is the daily severity score of MSVS during the two week pre-randomization observation period. [2] ANCOVA -Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95 percent CI -Mann-Whitney confidence interval for the difference between means (not stratified by center). ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval 2 randomized women (1 in Placebo and 1 in norethindrone acetate and ethinyl estradiol) did not return diaries. Visit Placebo (N = 66) Norethindrone Acetate and Ethinyl Estradiol 0.5/2.5 (N = 67) Norethindrone Acetate and Ethinyl Estradiol 1/5 (N = 66) Baseline [1] Mean (SD) 2.49 (0.26) 2.48 (0.22) 2.47 (0.23) Week 4 Mean (SD) Mean Change from Baseline (SD) p-Value vs.

drone acetate and ethinyl estradiol) did not return diaries. Visit Placebo (N = 66) Norethindrone Acetate and Ethinyl Estradiol 0.5/2.5 (N = 67) Norethindrone Acetate and Ethinyl Estradiol 1/5 (N = 66) Baseline [1] Mean (SD) 2.49 (0.26) 2.48 (0.22) 2.47 (0.23) Week 4 Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) [2] 2.13 (0.74) -0.36 (0.68) - 1.88 (0.89) -0.59 (0.83) 0.130 (-0.3, 0.0) 1.45 (1.03) -1.02 ¥ (1.06) <0.001 (-0.9, -0.2) Week 5 Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) [2] 2.06 (0.79) -0.44 (0.74) 1.68 (0.99) -0.80 ¥ (0.94) 0.041 (-0.4, -0.0) 1.23 (1.03) -1.24 ¥ (1.07) <0.001 (-1.2, -0.3) Week 12 Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) [2] 1.82 (1.03) -0.67 (1.02) - 1.22 (1.11) -1.26 ¥ (1.08) 0.002 (-0.9, -0.2) 1.02 (1.16) -1.45 ¥ (1.19) <0.001 (-1.4, -0.3) 14.2 Effects on the Endometrium A 2-year, placebo-controlled, multicenter, randomized clinical trial was conducted to determine the safety and efficacy of norethindrone acetate and ethinyl estradiol on maintaining bone mineral density, protecting the endometrium, and to determine effects on lipids. A total of 1,265 women were enrolled and randomized to either placebo, 0.2 mg norethindrone acetate/1 mcg ethinyl estradiol (NA/EE 0.2/1), 0.5 mg norethindrone acetate/2.5 mcg ethinyl estradiol (NA/EE 0.5/2.5), norethindrone acetate and ethinyl estradiol 1/5 and 1 mg norethindrone acetate/10 mcg ethinyl estradiol (NA/EE 1/10) or matching unopposed EE doses (1, 2.5, 5, or 10 mcg) for a total of 9 treatment groups. All participants received 1000 mg of calcium supplementation daily. Of the 1,265 women randomized to the various treatment arms of this study, 137 were randomized to placebo, 146 to norethindrone acetate and ethinyl estradiol 1/5, 136 to norethindrone acetate/ethinyl estradiol 0.5/2.5 and 141 to EE 5 mcg and 137 to EE 2.5 mcg. Of these, 134 placebo, 143 norethindrone acetate and ethinyl estradiol 1/5, 136 norethindrone acetate/ethinyl estradiol 0.5/2.5, 139 EE 5 mcg and 137 EE 2.5 mcg had a baseline endometrial result. Baseline biopsies were classified as normal (in approximately 95 percent of subjects), or insufficient tissue (in approximately 5 percent of subjects). Follow-up biopsies were obtained in approximately 70 to 80 percent of patients in each arm after 12 and 24 months of therapy. Results for norethindrone acetate and ethinyl estradiol 1/5 and appropriate comparators are shown in Table 5 . Table 5. Endometrial Biopsy Results After 12 and 24 Months of Treatment (CHART Study, 376 to 359) *All patients with endometrial hyperplasia were carried forward for all time points. Endometrial Status Placebo Norethindrone Acetate and Ethinyl Estradiol EE Alone 0.5/2.5 1/5 2.5 mcg 5 mcg Number of Patients Biopsied at Baseline N = 134 N = 136 N = 143 N = 137 N = 139 MONTH 12 (Percent Patients) Patients Biopsied (percent) 113 (84) 103 (74) 110 (77) 100 (73) 114 (82) Insufficient Tissue 30 34 45 20 20 Atrophic Tissue 60 41 41 15 2 Proliferative Tissue 23 28 24 65 91 Endometrial Hyperplasia* 0 0 0 0 1 MONTH 24 (Percent Patients) Patients Biopsied (percent) 94 (70) 99 (73) 102 (71) 89 (65) 107 (77) Insufficient Tissue 35 42 37 23 17 Atrophic Tissue 38 30 33 6 2 Proliferative Tissue 20 27 32 60 86 Endometrial Hyperplasia* 1 0 0 0 2 14.3 Effects on Uterine Bleeding or Spotting in Postmenopausal Women The cumulative incidence of amenorrhea, defined as no bleeding or spotting obtained from participant recall, was evaluated over 12 months for norethindrone acetate and ethinyl estradiol 1/5 and placebo arms. Results are shown in Figure 2 . Figure 2.

2 14.3 Effects on Uterine Bleeding or Spotting in Postmenopausal Women The cumulative incidence of amenorrhea, defined as no bleeding or spotting obtained from participant recall, was evaluated over 12 months for norethindrone acetate and ethinyl estradiol 1/5 and placebo arms. Results are shown in Figure 2 . Figure 2. Participants with Cumulative Amenorrhea Over Time: Intent-to-Treat Population, Last Observation Carried Forward 14.4 Effect on Bone Mineral Density in Postmenopausal Women In the 2 year study, trabecular BMD was assessed at lumbar spine using quantitative computed tomography. A total of 419 postmenopausal primarily Caucasian women, 40 to 64 years of age, with intact uteri and non-osteoporotic bone mineral densities were randomized (1:1:1) to norethindrone acetate and ethinyl estradiol 1/5, norethindrone acetate and ethinyl estradiol 0.5/2.5 or placebo. Approximately 75 percent of the women in each group completed the two-year study. All women received 1000 mg calcium in divided doses. Vitamin D was not supplemented. As shown in Figure 3 , women treated with norethindrone acetate and ethinyl estradiol 1/5 had an average increase of 3.1 percent in lumbar spine BMD from baseline to Month 24. Women treated with placebo had average decreases of –6.3 percent in spinal BMD from baseline to Month 24. The differences in the changes from baseline to Month 24 in the norethindrone acetate and ethinyl estradiol 1/5 group compared with the placebo group was statistically significant. *It should be noted that when measured by QCT, BMD gains and losses are greater than when measured by dual X-ray absorptiometry (DXA). Therefore, the differences in the changes in BMD between the placebo and active drug treated groups will be larger when measured by QCT compared with DXA. Changes in BMD measured by DXA should not be compared with changes in BMD measured by QCT. 14.5 Women’s Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms. WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the "global index". The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years. For those outcomes included in the WHI "global index" that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 6 . These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 6.

ctures. Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 6 . These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 6. Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years 1,2 1 Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. 2 Results are based on centrally adjudicated data. 3 Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. 4 Not included in "global index". 5 Includes metastic and non-metastic breast cancer with the exception of in situ cancer. 6 All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 7 A subset of the events was combined in a "global index" defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. Event Relative Risk CE/MPA vs. Placebo (95 percent nCI 3 ) CE/MPA n = 8,506 Placebo n = 8,102 Absolute Risk per 10,000 Women-Years CHD events 1.23 (0.99 to 1.53) 41 34 Non-fatal MI 1.28 (1.00 to 1.63) 31 25 CHD death 1.10 (0.70 to 1.75) 8 8 All strokes 1.31 (1.03 to 1.68) 33 25 Ischemic stroke Deep vein thrombosis 4 1.44 (1.09 to 1.90) 1.95 (1.43 to 2.67) 26 26 18 13 Pulmonary embolism 2.13 (1.45 to 3.11) 18 8 Invasive breastcancer 5 1.24 (1.01 to 1.54) 41 33 Colorectal cancer Endometrial cancer 4 Cervical cancer 4 0.61 (0.42 to 0.87) 0.81 (0.48 to 1.36) 1.44 (0.47 to 4.42) 10 6 2 16 7 1 Hip fracture Vertebral fractures 4 0.67 (0.47 to 0.96) 0.65 (0.46 to 0.92) 11 11 16 17 Lower arm/wrist fractures 4 0.71 (0.59 to 0.85) 44 62 Total fractures 4 Overall Mortality 3,6 0.76 (0.69 to 0.83) 1.00 (0.83 to 1.19) 152 52 199 52 Global Index 7 1.13 (1.02 to 1.25) 184 165 Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44 to 1.07)] . WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was also stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 7.1 years, are presented in Table 7 . Table 7. Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI ¥ ¥ Adapted from numerous WHI publications. WHI publications can be viewed at www.nblbi.nih.gov/whi. Œ Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. œ Results are based on centrally adjudicated data for an average follow-up of 7.1 years. Ɖ Not included in "global index". * Results are based on an average follow-up of 6.8 years. † All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. ‡ A subset of the events was combined in a "global index" defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.

except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. ‡ A subset of the events was combined in a "global index" defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. Event Relative Risk CE vs Placebo (95 percent nCI Œ ) CE N = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-Years CHD events œ 0.95 (0.78 to 1.16) 54 57 Non-fatal MI œ 0.91 (0.73 to 1.14) 40 42 CHD death œ 1.01 (0.71 to 1.43) 16 16 All strokes œ 1.33 (1.05 to 1.68) 45 33 Ischemic stroke œ 1.55 (1.19 to 2.01) 38 25 Deep vein thrombosis œ Ɖ 1.47 (1.06 to 2.06) 23 15 Pulmonary embolism œ 1.37 (0.90 to 2.07) 14 10 Invasive breast 0.80 (0.62 to 1.04) 28 34 cancer œ Colorectal cancer * 1.08 (0.75 to 1.55) 17 16 Hip fracture œ 0.65 (0.45 to 0.94) 12 19 Vertebral fractures œ Ɖ 0.64 (0.44 to 0.93) 11 18 Lower arm/wrist fractures œ Ɖ 0.58 (0.47 to 0.72) 35 59 Total fractures œ Ɖ 0.71 (0.64 to 0.80) 144 197 Deaths due to other causes * † 1.08 (0.88 to 1.32) 53 50 Overall Mortality œ Ɖ 1.04 (0.88 to 1.22) 79 75 Global Index ‡ 1.02 (0.92 to 1.13) 206 201 For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone were 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. 9 The absolute excess risk of events included in the "global index" was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years (see Table 7 ). Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone therapy increased the risk of ischemic stroke, and this excess was present in all subgroups of women examined 10 (see Table 7 ). Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [HR 0.63 (95 percent CI, 0.36 to 1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46 to 1.11)] . 14.6 Women’s Health Initiative Memory Study The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD.

MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), and Use in Specific Populations ( 8.5 )] . The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), and Use in Specific Populations ( 8.5 )] . When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19 to 2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), and Use in Specific Populations ( 8.5 )] . Figure 5 Figure 6

<table ID="ID517" width="97%" styleCode="Noautorules"><caption> Table 3. Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms per Week -ITT Population, LOCF </caption><col width="26%"/><col width="19%"/><col width="28%"/><col width="26%"/><tfoot><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^&#xE8;Denotes statistical significance at the 0.05 level</paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">[1] The baseline number of moderate to severe vasomotor symptoms (MSVS) is the weekly average number of MSVS during the two week pre-randomization observation period. </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">[2] ANCOVA -Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95 percent CI -Mann-Whitney confidence interval for the difference between means (not stratified by center). </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval 2 randomized women (1 in Placebo and 1 in norethindrone acetate and ethinyl estradiol) did not return diaries. </paragraph></td></tr></tfoot><tbody><tr><td valign="bottom" styleCode=" Toprule Botrule" align="left"><content styleCode="bold"> Visit </content> </td><td styleCode=" Toprule Botrule" align="left"><content styleCode="bold"> Placebo </content> <content styleCode="bold"> (N = 66) </content> </td><td valign="top" styleCode=" Toprule Botrule" align="center"><content styleCode="bold"> Norethindrone Acetate and Ethinyl Estradiol</content> <content styleCode="bold"> 0.5/2.5</content> <content styleCode="bold"> (N = 67) </content> </td><td valign="top" styleCode=" Toprule Botrule" align="center"><content styleCode="bold"> Norethindrone Acetate and Ethinyl Estradiol</content> <content styleCode="bold"><content styleCode="italics"> </content></content><content styleCode="bold"> 1/5 </content> <content styleCode="bold"> (N = 66) </content> </td></tr><tr><td valign="top" align="left"><content styleCode="bold"> Baseline [1] </content> Mean (SD) </td><td valign="top" align="left"> 76.5 (21.4) </td><td align="center"> 77.6 (26.5) </td><td align="center"> 70.0 (16.6) </td></tr><tr><td valign="top" align="left"> </td><td valign="top"/><td/><td/></tr><tr><td valign="top" align="left"><content styleCode="bold"> Week 4 </content> Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) [2] </td><td valign="top" align="left"> 39.4 (27.6) -37.0 (26.6) </td><td align="center"> 30.2 (26.1) -47.4^&#xE8; (26.1) 0.041 (-20.0, -1.0) </td><td align="center"> 20.4 (22.7) -49.6^&#xE8;<sup/>(22.1) &lt;0.001 (-22.0,-6.0) </td></tr><tr><td valign="bottom" align="left"> </td><td valign="bottom"/><td valign="bottom"/><td valign="bottom"/></tr><tr><td valign="bottom" align="left"><content styleCode="bold"> Week 12 </content> Mean (SD) Mean Change from Baseline (SD) </td><td valign="bottom" align="left"> 31.1 (27.0) -45.3 (30.2) </td><td valign="bottom" align="center"> 13.8 (20.4) -63.8^&#xE8; (27.5) </td><td valign="bottom" align="center"> 11.3 (18.9) -58.7^&#xE8; (23.1) </td></tr><tr><td valign="bottom" styleCode=" Botrule" align="left"> p-Value vs.

line (SD) </td><td valign="bottom" align="left"> 31.1 (27.0) -45.3 (30.2) </td><td valign="bottom" align="center"> 13.8 (20.4) -63.8^&#xE8; (27.5) </td><td valign="bottom" align="center"> 11.3 (18.9) -58.7^&#xE8; (23.1) </td></tr><tr><td valign="bottom" styleCode=" Botrule" align="left"> p-Value vs. Placebo (95 percent CI) [2] </td><td valign="bottom" styleCode=" Botrule"/><td valign="bottom" styleCode=" Botrule" align="center"> &lt;0.001 (-27.0, -7.0) </td><td valign="bottom" styleCode=" Botrule" align="center"> &lt;0.001 (-25.0, -5.0) </td></tr></tbody></table>

line (SD) </td><td valign="bottom" align="left"> 31.1 (27.0) -45.3 (30.2) </td><td valign="bottom" align="center"> 13.8 (20.4) -63.8^&#xE8; (27.5) </td><td valign="bottom" align="center"> 11.3 (18.9) -58.7^&#xE8; (23.1) </td></tr><tr><td valign="bottom" styleCode=" Botrule" align="left"> p-Value vs. Placebo (95 percent CI) [2] </td><td valign="bottom" styleCode=" Botrule"/><td valign="bottom" styleCode=" Botrule" align="center"> &lt;0.001 (-27.0, -7.0) </td><td valign="bottom" styleCode=" Botrule" align="center"> &lt;0.001 (-25.0, -5.0) </td></tr></tbody></table> <table ID="ID518" width="97%" styleCode="Noautorules"><caption> Table 4. Mean Change from Baseline in the Daily Severity Score of Moderate to Severe Vasomotor Symptoms per Week -ITT Population, LOCF </caption><col width="26%"/><col width="18%"/><col width="28%"/><col width="26%"/><tfoot><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^&#xA5;Denotes statistical significance at the 0.05 level</paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">[1] The baseline severity of moderate to severe vasomotor symptoms (MSVS) is the daily severity score of MSVS during the two week pre-randomization observation period. </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">[2] ANCOVA -Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95 percent CI -Mann-Whitney confidence interval for the difference between means (not stratified by center). </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval 2 randomized women (1 in Placebo and 1 in norethindrone acetate and ethinyl estradiol) did not return diaries.</paragraph></td></tr></tfoot><tbody><tr><td styleCode=" Toprule Botrule" align="left"><content styleCode="bold"> Visit </content> </td><td valign="top" styleCode=" Toprule Botrule" align="center"><content styleCode="bold"> Placebo </content> <content styleCode="bold"> (N = 66)</content> </td><td valign="top" styleCode=" Toprule Botrule" align="center"><content styleCode="bold"> Norethindrone Acetate and Ethinyl Estradiol</content> <content styleCode="bold"><content styleCode="italics"> </content></content><content styleCode="bold"> 0.5/2.5 </content> <content styleCode="bold"> (N = 67)</content> </td><td valign="top" styleCode=" Toprule Botrule" align="center"><content styleCode="bold"> Norethindrone Acetate and Ethinyl Estradiol</content> <content styleCode="bold"> 1/5 </content> <content styleCode="bold"> (N = 66)</content> </td></tr><tr><td valign="top" align="left"><content styleCode="bold"> Baseline [1] </content> Mean (SD) </td><td align="center"> 2.49 (0.26) </td><td align="center"> 2.48 (0.22) </td><td align="center"> 2.47 (0.23) </td></tr><tr><td valign="top" align="left"> </td><td/><td/><td/></tr><tr><td valign="top" align="left"><content styleCode="bold"> Week 4 </content> Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) [2] </td><td align="center"> 2.13 (0.74) -0.36 (0.68) - </td><td align="center"> 1.88 (0.89) -0.59 (0.83) 0.130 (-0.3, 0.0) </td><td align="center"> 1.45 (1.03) -1.02^&#xA5; (1.06) &lt;0.001 (-0.9, -0.2) </td></tr><tr><td valign="top" align="left"> </td><td/><td/><td/></tr><tr><td valign="top" align="left"><content styleCode="bold"> Week 5 </content> Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) [2] </td><td align="center"> 2.06 (0.79) -0.44 (0.74) </td><td align="center"> 1.68 (0.99) -0.80^&#xA5; (0.94) 0.041 (-0.4, -0.0) </td><td align="center"> 1.23 (1.03) -1.24^&#xA5; (1.07) &lt;0.001 (-1.2, -0.3) </td></tr><tr><td valign="bottom" styleCode=" Botrule" align="left"><content styleCode="bold"> Week 12 </content> Mean (SD) Mean Change from Baseline (SD) p-Value vs.

"> 1.68 (0.99) -0.80^&#xA5; (0.94) 0.041 (-0.4, -0.0) </td><td align="center"> 1.23 (1.03) -1.24^&#xA5; (1.07) &lt;0.001 (-1.2, -0.3) </td></tr><tr><td valign="bottom" styleCode=" Botrule" align="left"><content styleCode="bold"> Week 12 </content> Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) [2] </td><td valign="bottom" styleCode=" Botrule" align="center"> 1.82 (1.03) -0.67 (1.02) - </td><td valign="bottom" styleCode=" Botrule" align="center"> 1.22 (1.11) -1.26^&#xA5; (1.08) 0.002 (-0.9, -0.2) </td><td valign="bottom" styleCode=" Botrule" align="center"> 1.02 (1.16) -1.45^&#xA5; (1.19) &lt;0.001 (-1.4, -0.3) </td></tr></tbody></table> <table ID="ID521" width="100%" styleCode="Noautorules"><caption> Table 5.

Placebo (95 percent CI) [2] </td><td valign="bottom" styleCode=" Botrule" align="center"> 1.82 (1.03) -0.67 (1.02) - </td><td valign="bottom" styleCode=" Botrule" align="center"> 1.22 (1.11) -1.26^&#xA5; (1.08) 0.002 (-0.9, -0.2) </td><td valign="bottom" styleCode=" Botrule" align="center"> 1.02 (1.16) -1.45^&#xA5; (1.19) &lt;0.001 (-1.4, -0.3) </td></tr></tbody></table> <table ID="ID521" width="100%" styleCode="Noautorules"><caption> Table 5. Endometrial Biopsy Results After 12 and 24 Months of Treatment (CHART Study, 376 to 359) </caption><col width="265"/><col width="90"/><col width="82"/><col width="2"/><col width="82"/><col width="2"/><col width="80"/><col width="4"/><col width="101"/><tfoot><tr><td align="left" colspan="9"><paragraph styleCode="Footnote">*All patients with endometrial hyperplasia were carried forward for all time points.</paragraph></td></tr></tfoot><tbody><tr><td valign="top" styleCode=" Toprule" align="center"><content styleCode="bold"> Endometrial Status </content> </td><td valign="top" styleCode=" Toprule" align="center"><content styleCode="bold"> Placebo</content> </td><td colspan="4" valign="top" styleCode=" Toprule Botrule" align="center"><content styleCode="bold"> Norethindrone Acetate and Ethinyl Estradiol</content> </td><td colspan="3" valign="top" styleCode=" Toprule Botrule" align="center"><content styleCode="bold"> EE Alone </content> </td></tr><tr><td valign="top" align="center"> </td><td/><td colspan="2" align="center"><content styleCode="bold"> 0.5/2.5</content> </td><td colspan="2" styleCode=" Toprule" align="center"><content styleCode="bold"> 1/5</content> </td><td colspan="2" align="center"><content styleCode="bold"> 2.5 mcg</content> </td><td align="center"><content styleCode="bold"> 5 mcg</content> </td></tr><tr><td valign="top" styleCode=" Toprule" align="left"><content styleCode="bold"> Number of Patients Biopsied at Baseline </content> </td><td styleCode=" Toprule" align="center"> N = 134 </td><td colspan="2" styleCode=" Toprule" align="center"> N = 136 </td><td colspan="2" styleCode=" Toprule" align="center"> N = 143 </td><td colspan="2" styleCode=" Toprule" align="center"> N = 137 </td><td styleCode=" Toprule" align="center"> N = 139 </td></tr><tr><td valign="bottom" align="left"><content styleCode="bold"> MONTH 12 (Percent Patients) </content> </td><td colspan="8"/></tr><tr><td valign="top" align="left"> Patients Biopsied (percent) </td><td valign="top" align="center"> 113 (84) </td><td colspan="2" valign="top" align="center"> 103 (74) </td><td colspan="2" valign="top" align="center"> 110 (77) </td><td colspan="2" valign="top" align="center"> 100 (73) </td><td valign="top" align="center"> 114 (82) </td></tr><tr><td valign="top" align="left"> Insufficient Tissue </td><td valign="top" align="center"> 30 </td><td colspan="2" valign="top" align="center"> 34 </td><td colspan="2" valign="top" align="center"> 45 </td><td colspan="2" valign="top" align="center"> 20 </td><td valign="top" align="center"> 20 </td></tr><tr><td align="left"> Atrophic Tissue </td><td align="center"> 60 </td><td colspan="2" align="center"> 41 </td><td colspan="2" align="center"> 41 </td><td colspan="2" align="center"> 15 </td><td align="center"> 2 </td></tr><tr><td valign="top" align="left"> Proliferative Tissue </td><td valign="top" align="center"> 23 </td><td colspan="2" valign="top" align="center"> 28 </td><td colspan="2" valign="top" align="center"> 24 </td><td colspan="2" valign="top" align="center"> 65 </td><td valign="top" align="center"> 91 </td></tr><tr><td valign="top" align="left"> Endometrial Hyperplasia* </td><td valign="top" align="center"> 0 </td><td colspan="2" valign="top" align="center"> 0 </td><td colspan="2" valign="top" align="center"> 0 </td><td colspan="2" valign="top" align="center"> 0 </td><td valign="top" align="center"> 1 </td></tr><tr><td valign="bottom" align="left"> </td><td colspan="8"/></tr><tr><td valign="bottom" align="left"

="center"> 0 </td><td colspan="2" valign="top" align="center"> 0 </td><td colspan="2" valign="top" align="center"> 0 </td><td colspan="2" valign="top" align="center"> 0 </td><td valign="top" align="center"> 1 </td></tr><tr><td valign="bottom" align="left"> </td><td colspan="8"/></tr><tr><td valign="bottom" align="left" ><content styleCode="bold"> MONTH 24 (Percent Patients) </content> </td><td colspan="8"/></tr><tr><td valign="top" align="left"> Patients Biopsied (percent) </td><td valign="top" align="center"> 94 (70) </td><td valign="top" align="center"> 99 (73) </td><td colspan="2" valign="top" align="center"> 102 (71) </td><td colspan="2" valign="top" align="center"> 89 (65) </td><td colspan="2" valign="top" align="center"> 107 (77) </td></tr><tr><td valign="top" align="left"> Insufficient Tissue </td><td valign="top" align="center"> 35 </td><td valign="top" align="center"> 42 </td><td colspan="2" valign="top" align="center"> 37 </td><td colspan="2" valign="top" align="center"> 23 </td><td colspan="2" valign="top" align="center"> 17 </td></tr><tr><td align="left"> Atrophic Tissue </td><td align="center"> 38 </td><td align="center"> 30 </td><td colspan="2" align="center"> 33 </td><td colspan="2" align="center"> 6 </td><td colspan="2" align="center"> 2 </td></tr><tr><td valign="top" align="left"> Proliferative Tissue </td><td valign="top" align="center"> 20 </td><td valign="top" align="center"> 27 </td><td colspan="2" valign="top" align="center"> 32 </td><td colspan="2" valign="top" align="center"> 60 </td><td colspan="2" valign="top" align="center"> 86 </td></tr><tr><td styleCode=" Botrule" align="left"> Endometrial Hyperplasia*<sup/> </td><td styleCode=" Botrule" align="center"> 1 </td><td styleCode=" Botrule" align="center"> 0 </td><td colspan="2" styleCode=" Botrule" align="center"> 0 </td><td colspan="2" styleCode=" Botrule" align="center"> 0 </td><td colspan="2" styleCode=" Botrule" align="center"> 2 </td></tr></tbody></table>

yperplasia*<sup/> </td><td styleCode=" Botrule" align="center"> 1 </td><td styleCode=" Botrule" align="center"> 0 </td><td colspan="2" styleCode=" Botrule" align="center"> 0 </td><td colspan="2" styleCode=" Botrule" align="center"> 0 </td><td colspan="2" styleCode=" Botrule" align="center"> 2 </td></tr></tbody></table> <table ID="ID531" width="96%" styleCode="Noautorules"><caption> Table 6. Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years^1,2</caption><col width="24%"/><col width="31%"/><col width="19%"/><col width="25%"/><tfoot><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">¹Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.</paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">²Results are based on centrally adjudicated data. </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">³Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.</paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">⁴Not included in &quot;global index&quot;. </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">⁵Includes metastic and non-metastic breast cancer with the exception of <content styleCode="italics">in situ</content> cancer. </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">⁶All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.</paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">⁷A subset of the events was combined in a &quot;global index&quot; defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.</paragraph></td></tr></tfoot><tbody><tr><td valign="top" styleCode=" Toprule" align="left"> Event </td><td valign="top" styleCode=" Toprule" align="center"> Relative Risk CE/MPA vs.

currence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.</paragraph></td></tr></tfoot><tbody><tr><td valign="top" styleCode=" Toprule" align="left"> Event </td><td valign="top" styleCode=" Toprule" align="center"> Relative Risk CE/MPA vs. Placebo (95 percent nCI³) </td><td valign="top" styleCode=" Toprule Botrule" align="center"> CE/MPA n = 8,506 </td><td valign="top" styleCode=" Toprule Botrule" align="center"> Placebo n = 8,102 </td></tr><tr><td valign="top"/><td valign="top"/><td colspan="2" valign="top" align="center"> Absolute Risk per 10,000 Women-Years </td></tr><tr><td valign="top" styleCode=" Toprule" align="left"> CHD events </td><td valign="top" styleCode=" Toprule" align="center"> 1.23 (0.99 to 1.53) </td><td valign="top" styleCode=" Toprule" align="center"> 41 </td><td valign="top" styleCode=" Toprule" align="center"> 34 </td></tr><tr><td valign="top" align="left"><content styleCode="italics">Non-fatal MI </content> </td><td valign="top" align="center"><content styleCode="italics">1.28 (1.00</content> to<content styleCode="italics"> 1.63) </content> </td><td valign="top" align="center"><content styleCode="italics">31 </content> </td><td valign="top" align="center"><content styleCode="italics">25 </content> </td></tr><tr><td valign="top" align="left"><content styleCode="italics">CHD death </content> </td><td valign="top" align="center"><content styleCode="italics">1.10 (0.70</content> to<content styleCode="italics"> 1.75) </content> </td><td valign="top" align="center"><content styleCode="italics">8 </content> </td><td valign="top" align="center"><content styleCode="italics">8 </content> </td></tr><tr><td valign="top" align="left"> All strokes </td><td valign="top" align="center"> 1.31 (1.03 to 1.68) </td><td valign="top" align="center"> 33 </td><td valign="top" align="center"> 25 </td></tr><tr><td valign="top" align="left"><content styleCode="italics">Ischemic stroke </content> Deep vein thrombosis⁴ </td><td valign="top" align="center"><content styleCode="italics">1.44 (1.09</content> to<content styleCode="italics"> 1.90) </content> 1.95 (1.43 to 2.67) </td><td valign="top" align="center"><content styleCode="italics">26 </content> <content styleCode="italics">26 </content> </td><td valign="top" align="center"><content styleCode="italics">18 </content> <content styleCode="italics">13 </content> </td></tr><tr><td valign="top" align="left"> Pulmonary embolism </td><td valign="top" align="center"> 2.13 (1.45 to 3.11) </td><td valign="top" align="center"> 18 </td><td valign="top" align="center"> 8 </td></tr><tr><td valign="top" align="left"> Invasive breastcancer⁵ </td><td valign="top" align="center"> 1.24 (1.01 to 1.54) </td><td valign="top" align="center"> 41 </td><td valign="top" align="center"> 33 </td></tr><tr><td valign="top" align="left"> Colorectal cancer Endometrial cancer⁴ Cervical cancer⁴ </td><td valign="top" align="center"> 0.61 (0.42 to 0.87) 0.81 (0.48 to 1.36) 1.44 (0.47 to 4.42) </td><td valign="top" align="center"> 10 6 2 </td><td valign="top" align="center"> 16 7 1 </td></tr><tr><td valign="top" align="left"> Hip fracture Vertebral fractures⁴ </td><td valign="top" align="center"> 0.67 (0.47 to 0.96) 0.65 (0.46 to 0.92) </td><td valign="top" align="center"> 11 11 </td><td valign="top" align="center"> 16 17 </td></tr><tr><td valign="top" align="left"> Lower arm/wrist fractures⁴ </td><td valign="top" align="center"> 0.71 (0.59 to 0.85) </td><td valign="top" align="center"> 44 </td><td valign="top" align="center"> 62 </td></tr><tr><td valign="top" align="left"> Total fractures⁴ Overall Mortality^3,6 </td><td valign="top" align="center"> 0.76 (0.69 to 0

fractures⁴ </td><td valign="top" align="center"> 0.71 (0.59 to 0.85) </td><td valign="top" align="center"> 44 </td><td valign="top" align="center"> 62 </td></tr><tr><td valign="top" align="left"> Total fractures⁴ Overall Mortality^3,6 </td><td valign="top" align="center"> 0.76 (0.69 to 0 .83) 1.00 (0.83 to 1.19) </td><td valign="top" align="center"> 152 52 </td><td valign="top" align="center"> 199 52 </td></tr><tr><td valign="top" styleCode=" Botrule" align="left"> Global Index⁷ </td><td valign="top" styleCode=" Botrule" align="center"> 1.13 (1.02 to 1.25) </td><td valign="top" styleCode=" Botrule" align="center"> 184 </td><td valign="top" styleCode=" Botrule" align="center"> 165 </td></tr></tbody></table> <table ID="ID533" width="510" styleCode="Noautorules"><caption> Table 7. Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI^&#xA5;</caption><col width="175"/><col width="5"/><col width="131"/><col width="88"/><col width="15"/><col width="6"/><col width="90"/><tfoot><tr><td align="left" colspan="7"><paragraph styleCode="Footnote"><content styleCode="bold">^&#xA5;</content> Adapted from numerous WHI publications. WHI publications can be viewed at www.nblbi.nih.gov/whi.</paragraph></td></tr><tr><td align="left" colspan="7"><paragraph styleCode="Footnote">^&#x152; Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. </paragraph></td></tr><tr><td align="left" colspan="7"><paragraph styleCode="Footnote"><content styleCode="italics">^&#x153;</content> Results are based on centrally adjudicated data for an average follow-up of 7.1 years.</paragraph></td></tr><tr><td align="left" colspan="7"><paragraph styleCode="Footnote">^&#x189; Not included in &quot;global index&quot;.

ragraph styleCode="Footnote"><content styleCode="italics">^&#x153;</content> Results are based on centrally adjudicated data for an average follow-up of 7.1 years.</paragraph></td></tr><tr><td align="left" colspan="7"><paragraph styleCode="Footnote">^&#x189; Not included in &quot;global index&quot;. </paragraph></td></tr><tr><td align="left" colspan="7"><paragraph styleCode="Footnote">^* Results are based on an average follow-up of 6.8 years.</paragraph></td></tr><tr><td align="left" colspan="7"><paragraph styleCode="Footnote">^&#x2020; All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.</paragraph></td></tr><tr><td align="left" colspan="7"><paragraph styleCode="Footnote">^&#x2021; A subset of the events was combined in a &quot;global index&quot; defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.</paragraph></td></tr></tfoot><tbody><tr><td colspan="2" valign="top" styleCode=" Toprule" align="left"> Event </td><td valign="top" styleCode=" Toprule" align="center"> Relative Risk CE vs Placebo (95 percent nCI^&#x152;) </td><td colspan="2" valign="top" styleCode=" Toprule Botrule" align="center"> CE N = 5,310 </td><td colspan="2" valign="top" styleCode=" Toprule Botrule" align="center"> Placebo n = 5,429 </td></tr><tr><td valign="top" styleCode=" Botrule"/><td colspan="3" valign="top" align="right"> Absolute Risk per 10,000 </td><td colspan="3" valign="top" align="left"> Women-Years </td></tr><tr><td colspan="2" valign="top" align="left"> CHD events^&#x153;<sup/> </td><td valign="top" align="center"> 0.95 (0.78 to 1.16) </td><td colspan="3" valign="top" align="center"> 54 </td><td valign="top" styleCode=" Toprule" align="center"> 57 </td></tr><tr><td colspan="2" valign="top" align="left"><content styleCode="italics">Non-fatal MI</content><content styleCode="italics">^&#x153;</content><sup/> </td><td valign="top" align="center"><content styleCode="italics">0.91 (0.73</content> to<content styleCode="italics"> 1.14) </content> </td><td colspan="3" valign="top" align="center"><content styleCode="italics">40 </content> </td><td valign="top" align="center"><content styleCode="italics">42</content> </td></tr><tr><td colspan="2" valign="top" align="left"><content styleCode="italics">CHD death</content><content styleCode="italics">^&#x153;</content> </td><td valign="top" align="center"><content styleCode="italics">1.01 (0.71</content> to<content styleCode="italics"> 1.43) </content> </td><td colspan="3" valign="top" align="center"><content styleCode="italics">16 </content> </td><td valign="top" align="center"><content styleCode="italics">16 </content> </td></tr><tr><td colspan="2" valign="top" align="left"> All strokes<content styleCode="italics">^&#x153;</content> </td><td valign="top" align="center"> 1.33 (1.05 to 1.68) </td><td colspan="3" valign="top" align="center"> 45 </td><td valign="top" align="center"> 33 </td></tr><tr><td colspan="2" valign="top" align="left"><content styleCode="italics">Ischemic stroke</content><content styleCode="italics">^&#x153;</content><sup/> </td><td valign="top" align="center"><content styleCode="italics">1.55 (1.19</content> to<content styleCode="italics"> 2.01) </content> </td><td colspan="3" valign="top" align="center"><content styleCode="italics">38 </content> </td><td valign="top" align="center"><content styleCode="italics">25 </content> </td></tr><tr><td colspan="2" valign="top" align="left"> Deep vein thrombosis<content styleCode="italics">^&#x153;</content><content styleCode="italics"><sup/></content>^&#x189; </td><td valign="

="italics">38 </content> </td><td valign="top" align="center"><content styleCode="italics">25 </content> </td></tr><tr><td colspan="2" valign="top" align="left"> Deep vein thrombosis<content styleCode="italics">^&#x153;</content><content styleCode="italics"><sup/></content>^&#x189; </td><td valign=" top" align="center"> 1.47 (1.06 to 2.06) </td><td colspan="3" valign="top" align="center"> 23 </td><td valign="top" align="center"> 15 </td></tr><tr><td colspan="2" align="left"> Pulmonary embolism<content styleCode="italics">^&#x153;</content><sup/> </td><td align="center"> 1.37 (0.90 to 2.07) </td><td colspan="3" align="center"> 14 </td><td align="center"> 10 </td></tr><tr><td colspan="2" valign="top" align="left"> Invasive breast </td><td valign="top" align="center"> 0.80 (0.62 to 1.04) </td><td colspan="3" valign="top" align="center"> 28 </td><td valign="top" align="center"> 34 </td></tr><tr><td colspan="2" valign="top" align="left"> cancer<content styleCode="italics">^&#x153;</content><sup/> </td><td colspan="5"/></tr><tr><td colspan="2" align="left"> Colorectal cancer^*<sup/> </td><td align="center"> 1.08 (0.75 to 1.55) </td><td colspan="3" align="center"> 17 </td><td align="center"> 16 </td></tr><tr><td colspan="2" valign="top" align="left"> Hip fracture<content styleCode="italics">^&#x153;</content> </td><td valign="top" align="center"> 0.65 (0.45 to 0.94) </td><td colspan="3" valign="top" align="center"> 12 </td><td valign="top" align="center"> 19 </td></tr><tr><td colspan="2" valign="top" align="left"> Vertebral fractures<content styleCode="italics">^&#x153;</content><content styleCode="italics"><sup/></content>^&#x189; </td><td valign="top" align="center"> 0.64 (0.44 to 0.93) </td><td colspan="3" valign="top" align="center"> 11 </td><td valign="top" align="center"> 18 </td></tr><tr><td colspan="2" valign="top" align="left"> Lower arm/wrist fractures<content styleCode="italics">^&#x153;</content><content styleCode="italics"><sup/></content>^&#x189; </td><td valign="top" align="center"> 0.58 (0.47 to 0.72) </td><td colspan="3" valign="top" align="center"> 35 </td><td valign="top" align="center"> 59 </td></tr><tr><td colspan="2" valign="top" align="left"> Total fractures<content styleCode="italics">^&#x153;</content><content styleCode="italics"><sup/></content>^&#x189; </td><td align="center"> 0.71 (0.64 to 0.80) </td><td colspan="3" align="center"> 144 </td><td align="center"> 197 </td></tr><tr><td colspan="2" valign="top" align="left"> Deaths due to other causes^*<sup/>^&#x2020; </td><td valign="top" align="center"> 1.08 (0.88 to 1.32) </td><td colspan="3" valign="top" align="center"> 53 </td><td valign="top" align="center"> 50 </td></tr><tr><td colspan="2" valign="top" align="left"> Overall Mortality<content styleCode="italics">^&#x153;</content><content styleCode="italics"><sup/></content>^&#x189; </td><td align="center"> 1.04 (0.88 to 1.22) </td><td colspan="3" align="center"> 79 </td><td align="center"> 75 </td></tr><tr><td colspan="2" valign="top" styleCode=" Botrule" align="left"> Global Index^&#x2021;<sup/> </td><td valign="top" styleCode=" Botrule" align="center"> 1.02 (0.92 to 1.13) </td><td colspan="3" valign="top" styleCode=" Botrule" align="center"> 206 </td><td valign="top" styleCode=" Botrule" align="center"> 201 </td></tr></tbody></table>

15 REFERENCES Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA . 2007;297:1465-1477. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med . 2006;166:357-365. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA . 2004;292:1573-1580. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med . 2006;166:772-780. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA . 2003;289:3234-3253. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA . 2006;295:1647-1657. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA . 2003;290:1739-1748. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA . 2004;291:2947-2958. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women's Health Initiative Randomized Trial. J Bone Miner Res . 2006;21:817-828. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation . 2006;113:2425-2434.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Fyavolv 0.5 mg/0.0025 mg are white to off-white, round film-coated tablets, debossed with "F51" on one side and "LU" on the other side, containing 0.5 mg of norethindrone acetate and 0.0025 mg of ethinyl estradiol. Fyavolv 0.5 mg/0.0025 mg are available in bottle of 90 tablets (NDC 68180-827-09) and in a blister (NDC 68180-827-71) containing 28 tablets enclosed in a pouch, such 3 pouches are packed in a carton (NDC 68180-827-73). Fyavolv 1 mg/0.005 mg are blue, round film-coated tablets, debossed with "F52" on one side and "LU" on the other side, containing 1 mg of norethindrone acetate and 0.005 mg of ethinyl estradiol. Fyavolv 1 mg/0.005 mg are available in bottle of 90 tablets (NDC 68180-828-09) and in a blister (NDC 68180-828-71) containing 28 tablets enclosed in a pouch, such 3 pouches are packed in a carton (NDC 68180-828-73). 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION Advise women to read the FDA-approved patient labeling (Patient Information) Vaginal Bleeding Inform postmenopausal women to report any vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions ( 5.2 )] . Possible Serious Adverse Reactions with Estrogen Plus Progestogen Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestogen therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] . Possible Common Adverse Reactions with Estrogen Plus Progestogen Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestogen therapy such as headache, breast pain and tenderness, nausea and vomiting. Distributed by: Lupin Pharmaceuticals, Inc. Naples, FL 34108 United States Manufactured by: Lupin Limited Pithampur (M.P.) - 454 775 India Revised: November 2024 image

Patient Information Fyavolv™ (FYE-uh-volv) (norethindrone acetate and ethinyl estradiol tablets USP) 0.5 mg/0.0025 mg and 1 mg/0.005 mg Read this Patient Information before you start using Fyavolv and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment. What is the most important information I should know about Fyavolv (a combination of estrogen and progestogen)? Do not use estrogens with or without progestogens to prevent heart disease, heart attacks, strokes or dementia (decline of brain function). Using estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. Using estrogens with progestogens may increase your chance of getting dementia, based on a study of women 65 years of age and older. Using estrogen-alone may increase your chance of getting cancer of the uterus (womb). Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia (decline of brain function). Using estrogen-alone may increase your chances of getting strokes or blood clots. Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age and older. Only one estrogen with progestogen product and dose have been shown to increase your chances of getting heart attacks, strokes, breast cancer, blood clots, and dementia. Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. Because other products and doses have not been studied in the same way, it is not known how the use of Fyavolv will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with Fyavolv. What is Fyavolv? Fyavolv is a prescription medicine that contains two kinds of hormones, an estrogen and a progestogen. What is Fyavolv used for? Fyavolv is used after menopause to: • Reduce moderate to severe hot flushes Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes the "change of life" or menopause, the end of monthly menstrual periods. Sometimes both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes "surgical menopause". When estrogen levels begin dropping, some women get very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden intense episodes of heat and sweating ("hot flashes" or "hot flushes"). In some women the symptoms are mild, and they will not need to take estrogens. In other women, symptoms can be more severe. • Help reduce your chances of getting osteoporosis (thin weak bones) If you use Fyavolv only to prevent osteoporosis from menopause, talk with your healthcare provider about whether a different treatment or medicine without estrogens might be better for you. You and your healthcare provider should talk regularly about whether you still need treatment with Fyavolv. Who should not use Fyavolv? Do not use Fyavolv if you have had your uterus (womb) removed (hysterectomy). Fyavolv contains a progestogen to decrease the chance of getting cancer of the uterus (womb). If you do not have a uterus, you do not need a progestogen and you should not use Fyavolv.

need treatment with Fyavolv. Who should not use Fyavolv? Do not use Fyavolv if you have had your uterus (womb) removed (hysterectomy). Fyavolv contains a progestogen to decrease the chance of getting cancer of the uterus (womb). If you do not have a uterus, you do not need a progestogen and you should not use Fyavolv. Do not start using Fyavolv if you: • have any unusual vaginal bleeding. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. • have been diagnosed with a bleeding disorder. • currently have or have had certain cancers . Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use Fyavolv. • had a stroke or heart attack • currently have or have had blood clots • currently have or have had liver problems • are allergic to Fyavolv or any of its ingredients. See the list of ingredients in Fyavolv at the end of this leaflet. Before you use Fyavolv, tell your healthcare provider about all of your medical conditions, including if you: • have any unusual vaginal bleeding Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. • have any other medical conditions that may become worse while you are using Fyavolv. Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, angioedema (swelling of face and tongue), or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. • are going to have surgery or will be on bed rest Your healthcare provider will let you know if you need to stop using Fyavolv. • are pregnant or think you may be pregnant. Fyavolv is not for pregnant women. •are breastfeeding The hormones in Fyavolv can pass into your breast milk. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how Fyavolv works. Some other medicines and food products may increase or decrease the concentrations of the hormones in Fyavolv in the blood. Fyavolv may also affect how your other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine. How should I use Fyavolv? Take Fyavolv exactly as your healthcare provider tells you to take it. Take 1 Fyavolv tablet at the same time each day. You and your healthcare provider should talk regularly (every 3 to 6 months) about the dose you are taking and whether or not you still need treatment with Fyavolv. What are the possible side effects of Fyavolv? Side effects are grouped by how serious they are and how often they happen when you are treated.

e each day. You and your healthcare provider should talk regularly (every 3 to 6 months) about the dose you are taking and whether or not you still need treatment with Fyavolv. What are the possible side effects of Fyavolv? Side effects are grouped by how serious they are and how often they happen when you are treated. Serious, but less common side effects include: Heart attack Stroke Blood clots Breast cancer Cancer of the lining of the uterus (womb) Cancer of the ovary Dementia Gallbladder disease High or low blood calcium levels Changes in vision High blood pressure High levels of fat in your blood Liver problems Changes in your thyroid hormone levels Swelling or fluid retention Cancer changes of endometriosis Enlargement of benign tumors of the uterus ("fibroids") Worsening swelling of face or tongue (angioedema) in women who have a history of angioedema Changes in laboratory test results such as bleeding time and high blood sugar levels Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you: new breast lumps unusual vaginal bleeding changes in vision or speech sudden new severe headaches severe pains in your chest or legs with or without shortness of breath, weakness and fatigue Common side effects of Fyavolv include: headache breast pain irregular vaginal bleeding or spotting stomach or abdominal cramps, bloating hair loss fluid retention vaginal yeast infection These are not all the possible side effects of Fyavolv. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or do not go away. You may report side effects to Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088. What can I do to lower my chances of a serious side effect with Fyavolv? Talk with your healthcare provider regularly about whether you should continue using Fyavolv. If you have a uterus, talk with your healthcare provider about whether Fyavolv is right for you. In general, the addition of a progestogen is recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus (womb). See your healthcare provider right away if you get vaginal bleeding while using Fyavolv. Have a pelvic exam, breast exam and mammogram (breast x-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram (breast x-ray), you may need to have breast exams more often. If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or use tobacco, you may have a higher chance for getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease. How should I store Fyavolv? • Store Fyavolv at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP controlled room temperature]. Keep Fyavolv out of the reach of children. General information about the safe and effective use of Fyavolv. Medicines are sometimes prescribed for conditions that are not mentioned in a Patient Information leaflet. Do not use Fyavolv for conditions for which it was not prescribed. Do not give Fyavolv to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Fyavolv that is written for health professionals. For more information go to www.lupinpharmaceuticals.com or call 1-800-399-2561. What are the ingredients in Fyavolv?

to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Fyavolv that is written for health professionals. For more information go to www.lupinpharmaceuticals.com or call 1-800-399-2561. What are the ingredients in Fyavolv? Active Ingredients: norethindrone acetate and ethinyl estradiol Inactive Ingredients: calcium stearate, corn starch, hypromellose, lactose monohydrate, microcrystalline cellulose, polyethylene glycol 400, titanium dioxide, vitamin E. Each tablet of 1 mg/0.005 mg also contains FD&C Blue No. 2 Aluminum Lake. This Patient Information has been approved by the U.S Food and Drug Administration. Fyavolv™ is a trademark of Lupin Pharmaceuticals, Inc. The other brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products. Distributed by: Lupin Pharmaceuticals, Inc. Naples, FL 34108 United States Manufactured by: Lupin Limited Pithampur (M.P.) - 454 775 India Revised: November 2024 ID#: 278058/278069 image

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (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, including norethindrone acetate and ethinyl estradiol tablets, are contraindicated in women who are over 35 years of age and smoke (see CONTRAINDICATIONS and WARNINGS ).

DESCRIPTION Norethindrone Acetate and Ethinyl Estradiol Tablets, USP are progestogen-estrogen combinations. Each white to off-white tablet contains norethindrone acetate, USP (19-Norpregn-4-en-20-yn-3-one,17-(acetyloxy)-, (17α), 1 mg; ethinyl estradiol 19-Norpregna-1,3,5(10)-triene-20-yne-3,17-diol, (17 α), 20 mcg. Also contains acacia, lactose monohydrate, magnesium stearate, corn starch, sucrose and talc. The structural formulas are as follows: structure1 structure2

CLINICAL PHARMACOLOGY Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation). Pharmacokinetics The pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets have not been characterized; however, the following pharmacokinetic information regarding norethindrone acetate and ethinyl estradiol is taken from the literature. Absorption Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, since the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone (1). Norethindrone acetate and ethinyl estradiol are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol (1 to 3). Distribution Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg (1 to 3). Plasma protein binding of both steroids is extensive (greater than 95%); norethindrone binds to both albumin and sex hormone binding globulin, whereas ethinyl estradiol binds only to albumin (4). Metabolism Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites (5). A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation (6). Excretion Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites (5, 6). Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg) (1 to 3). Special Population Race: The effect of race on the disposition of norethindrone acetate and ethinyl estradiol tablets has not been evaluated. Renal Insufficiency The effect of renal disease on the disposition of norethindrone acetate and ethinyl estradiol tablets has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function. Hepatic Insufficiency The effect of hepatic disease on the disposition of norethindrone acetate and ethinyl estradiol tablets has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function. Drug-Drug Interactions Numerous drug-drug interactions have been reported for oral contraceptives.

ic disease on the disposition of norethindrone acetate and ethinyl estradiol tablets has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function. Drug-Drug Interactions Numerous drug-drug interactions have been reported for oral contraceptives. A summary of these is found under PRECAUTIONS, Drug Interactions.

Pharmacokinetics The pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets have not been characterized; however, the following pharmacokinetic information regarding norethindrone acetate and ethinyl estradiol is taken from the literature.

INDICATIONS AND USAGE Norethindrone acetate and ethinyl estradiol tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception. Oral contraceptives are highly effective. Table I lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates. TABLE 1 LOWEST EXPECTED AND TYPICAL FAILURE RATES DURING THE FIRST YEAR OF CONTINUOUS USE OF A METHOD % Of Women Experiencing an Unintended Pregnancy in the First Year of Continuous Use Method Lowest Expected* Typical** (No contraception) (85) (85) Oral contraceptives 3 combined 0.1 N/A*** progestin only 0.5 N/A*** Diaphragm with spermicidal cream or jelly 6 20 Spermicides alone (foam, creams, gels, vaginal suppositories, and vaginal film) 6 26 Vaginal Sponge nulliparous 9 20 parous 20 40 Implant 0.05 0.05 Injection: depot medroxyprogesterone acetate 0.3 0.3 IUD progesterone T 1.5 2 copper T 380A 0.6 0.8 LNg 20 0.1 0.1 Condom without spermicides female 5 21 male 3 14 Cervical Cap with spermicidal cream or jelly nulliparous 9 20 parous 26 40 Periodic abstinence (all methods) 1 to 9 25 Withdrawal 4 19 Female sterilization 0.5 0.5 Male sterilization 0.1 0.15 Adapted from RA Hatcher et al, Reference 7. *The authors' best guess of the percentage of women expected to experience an accidental pregnancy among couples who initiate a method (not necessarily for the first time) and who use it consistently and correctly during the first year if they do not stop for any other reason. **This term represents “typical” couples who initiate use of a method (not necessarily for the first time), who experience an accidental pregnancy during the first year if they do not stop use for any other reason. ***N/A-Data not available.

<table width="100%"><col width="55%"/><col width="23%"/><col width="20%"/><tbody><tr><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">TABLE 1</content></paragraph><paragraph><content styleCode="bold">LOWEST EXPECTED AND TYPICAL FAILURE RATES DURING THE FIRST YEAR OF CONTINUOUS USE OF A METHOD</content></paragraph><paragraph>% Of Women Experiencing an Unintended Pregnancy in the First Year of Continuous Use</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Method</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Lowest Expected*</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Typical**</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(No contraception)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(85)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(85)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Oral contraceptives</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> combined</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>N/A***</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> progestin only</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>N/A***</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diaphragm with spermicidal cream or jelly</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Spermicides alone (foam, creams, gels, vaginal suppositories, and vaginal film)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vaginal Sponge</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> nulliparous</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> parous</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>40</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Implant</paragraph></td><td align="center" styleCode="Rrule Lrule Botrul

enter" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>40</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Implant</paragraph></td><td align="center" styleCode="Rrule Lrule Botrul e " valign="top"><paragraph>0.05</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.05</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection: depot medroxyprogesterone acetate</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>IUD</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> progesterone T</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> copper T 380A</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> LNg 20</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Condom without spermicides</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> female</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> male</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Cervical Cap with spermicidal cream or jelly</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> nulliparous</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> parous</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>40</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Periodic abstinence (all methods)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 to 9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>

graph>Periodic abstinence (all methods)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 to 9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Withdrawal</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Female sterilization</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Male sterilization</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.15</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Adapted from RA Hatcher et al, Reference 7.</paragraph><paragraph>*The authors&apos; best guess of the percentage of women expected to experience an accidental pregnancy among couples who initiate a method (not necessarily for the first time) and who use it consistently and correctly during the first year if they do not stop for any other reason.</paragraph><paragraph>**This term represents &#x201C;typical&#x201D; couples who initiate use of a method (not necessarily for the first time), who experience an accidental pregnancy during the first year if they do not stop use for any other reason.</paragraph><paragraph>***N/A-Data not available.</paragraph></td></tr></tbody></table>

CONTRAINDICATIONS Oral contraceptives are contraindicated in women who currently have the following conditions: • Thrombophlebitis or thromboembolic disorders • A past history of deep vein thrombophlebitis or thromboembolic disorders • Cerebral vascular or coronary artery disease • Current diagnosis of, or history of, breast cancer, which may be hormone sensitive • Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia • Undiagnosed abnormal genital bleeding • Cholestatic jaundice of pregnancy or jaundice with prior pill use • Hepatic adenomas or carcinomas • Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations (see WARNINGS , RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT ).

WARNINGS The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity, and diabetes. Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined. Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from References 8 and 9 with the author’s permission). For further information, the reader is referred to a text on epidemiological methods. 1. Thromboembolic Disorders and Other Vascular Problems a. Myocardial infarction An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six (10 to 16). The risk is very low under the age of 30. Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases (17). Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 (Table II) among women who use oral contraceptives. Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity (19). In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism (20 to 24). Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS ) Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. b.

insulinism (20 to 24). Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS ) Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. b. Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease (9, 10, 25 to 30). Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization (31). The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped (8). A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives (15, 32). The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions (15, 32). If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four to six weeks after delivery in women who elect not to breastfeed. c. Cerebrovascular disease Oral contraceptives 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 (greater than 35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes (33 to 35). In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension (36). The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension (36). The attributable risk is also greater in older women (9). d. Dose-related risk of vascular disease from oral contraceptives A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease (37 to 39). A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents (20 to 22). A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestin and the nature of the progestin used in the contraceptives. The amount and activity of both hormones should be considered in the choice of an oral contraceptive. Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics.

a balance achieved between doses of estrogen and progestin and the nature of the progestin used in the contraceptives. The amount and activity of both hormones should be considered in the choice of an oral contraceptive. Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular oral contraceptive, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest dose of estrogen which produces satisfactory results for the patient. e. Persistence of risk of vascular disease There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40 to 49 years who had used oral contraceptives for 5 or more years, but this increased risk was not demonstrated in other age groups (14). In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small (40). However, both studies were performed with oral contraceptive formulations containing 50 mcg or higher of estrogens. 2. Estimates of Mortality from Contraceptive Use One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table III). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970’s but not reported until 1983 (41). However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling. Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed (Porter JB, Hunter J, Jick H, et al. Oral contraceptives and nonfatal vascular disease. Obstet Gynecol 1985;66:1-4; and Porter JB, Hershel J, Walker AM. Mortality among oral contraceptive users. Obstet Gynecol 1987;70:29-32), the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.

acceptable means of contraception. Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective. TABLE III ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control and outcome 15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44 No fertility control methods 7 7.4 9.1 14.8 25.7 28.2 Oral contraceptives non-smoker** 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives smoker** 2.2 3.4 6.6 13.5 51.1 117.2 IUD** 0.8 0.8 1 1 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 *Deaths are birth related. **Deaths are method related. Adapted from H.W. Ory, Reference 41. 3. Malignant Neoplasms Breast Cancer Norethindrone acetate and ethinyl estradiol tablets are contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive (see CONTRAINDICATIONS ). 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 ADVERSE REACTIONS , Postmarketing Experience ). Cervical Cancer Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women (42 to 45). However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. 4. Hepatic Neoplasia Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use (46). Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage (47, 48). Studies from Britain have shown an increased risk of developing hepatocellular carcinoma (49 to 51) in long-term (greater than 8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S., and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. 5. 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 norethindrone acetate and ethinyl estradiol tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see CONTRAINDICATIONS ). Norethindrone acetate and ethinyl estradiol tablets can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen. 6. Ocular Lesions There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives.

asabuvir (see CONTRAINDICATIONS ). Norethindrone acetate and ethinyl estradiol tablets can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen. 6. Ocular Lesions There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. 7. Oral Contraceptive Use Before and During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy (52 to 54). Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned (52, 53, 55, 56), when taken inadvertently during early pregnancy. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed. 8. Gallbladder Disease Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens (57, 58). More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal (59 to 61). The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens. 9. Carbohydrate and Lipid Metabolic Effects Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users (23). Oral contraceptives containing greater than 75 mcg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance (62). Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents (23, 63). However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose (64). Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives. A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1a. and 1d. ), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users. 10. Elevated Blood Pressure An increase in blood pressure has been reported in women taking oral contraceptives (65) and this increase is more likely in older oral contraceptive users (66) and with continued use (65). Data from the Royal College of General Practitioners (18) and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens. Women with a history of hypertension or hypertension-related diseases or renal disease (67) should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued.

th a history of hypertension or hypertension-related diseases or renal disease (67) should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives (66), and there is no difference in the occurrence of hypertension among ever and never users (65,67,68). 11. Headache The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. 12. Bleeding Irregularities Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Non-hormonal causes should be considered, and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent. 13. Hereditary Angioedema In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 14. Depression Carefully observe women with a history of depression and discontinue norethindrone acetate and ethinyl estradiol tablets if depression recurs to a serious degree. table

<table width="100%"><col width="98%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/></tr></tbody></table> <table width="100%"><col width="38%"/><col width="10%"/><col width="10%"/><col width="10%"/><col width="10%"/><col width="11%"/><col width="10%"/><tbody><tr><td styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Method of control and outcome</content></paragraph></td><td styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">15 to 19</content></paragraph></td><td styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">20 to 24</content></paragraph></td><td styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">25 to 29</content></paragraph></td><td styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">30 to 34</content></paragraph></td><td styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">35 to 39</content></paragraph></td><td styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">40 to 44</content></paragraph></td></tr><tr><td valign="top"><paragraph>No fertility control methods</paragraph></td><td align="center" valign="top"><paragraph>7</paragraph></td><td align="center" valign="top"><paragraph>7.4</paragraph></td><td align="center" valign="top"><paragraph>9.1</paragraph></td><td align="center" valign="top"><paragraph>14.8</paragraph></td><td align="center" valign="top"><paragraph>25.7</paragraph></td><td align="center" valign="top"><paragraph>28.2</paragraph></td></tr><tr><td valign="top"><paragraph>Oral contraceptives non-smoker**</paragraph></td><td align="center" valign="top"><paragraph>0.3</paragraph></td><td align="center" valign="top"><paragraph>0.5</paragraph></td><td align="center" valign="top"><paragraph>0.9</paragraph></td><td align="center" valign="top"><paragraph>1.9</paragraph></td><td align="center" valign="top"><paragraph>13.8</paragraph></td><td align="center" valign="top"><paragraph>31.6</paragraph></td></tr><tr><td valign="top"><paragraph>Oral contraceptives smoker**</paragraph></td><td align="center" valign="top"><paragraph>2.2</paragraph></td><td align="center" valign="top"><paragraph>3.4</paragraph></td><td align="center" valign="top"><paragraph>6.6</paragraph></td><td align="center" valign="top"><paragraph>13.5</paragraph></td><td align="center" valign="top"><paragraph>51.1</paragraph></td><td align="center" valign="top"><paragraph>117.2</paragraph></td></tr><tr><td valign="top"><paragraph>IUD**</paragraph></td><td align="center" valign="top"><paragraph>0.8</paragraph></td><td align="center" valign="top"><paragraph>0.8</paragraph></td><td align="center" valign="top"><paragraph>1</paragraph></td><td align="center" valign="top"><paragraph>1</paragraph></td><td align="center" valign="top"><paragraph>1.4</paragraph></td><td align="center" valign="top"><paragraph>1.4</paragraph></td></tr><tr><td valign="top"><paragraph>Condom*</paragraph></td><td align="center" valign="top"><paragraph>1.1</paragraph></td><td align="center" valign="top"><paragraph>1.6</paragraph></td><td align="center" valign="top"><paragraph>0.7</paragraph></td><td align="center" valign="top"><paragraph>0.2</paragraph></td><td align="center" valign="top"><paragraph>0.3</paragraph></td><td align="center" valign="top"><paragraph>0.4</paragraph></td></tr><tr><td valign="top"><paragraph>Diaphragm/spermicide*</paragraph></td><td align="center" valign="top"><paragraph>1.9</paragraph></td><td align="center" valign="top"><paragraph>1.2</paragraph></td><td align="center" valign="top">

aph>0.3</paragraph></td><td align="center" valign="top"><paragraph>0.4</paragraph></td></tr><tr><td valign="top"><paragraph>Diaphragm/spermicide*</paragraph></td><td align="center" valign="top"><paragraph>1.9</paragraph></td><td align="center" valign="top"><paragraph>1.2</paragraph></td><td align="center" valign="top"> <paragraph>1.2</paragraph></td><td align="center" valign="top"><paragraph>1.3</paragraph></td><td align="center" valign="top"><paragraph>2.2</paragraph></td><td align="center" valign="top"><paragraph>2.8</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Periodic abstinence*</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2.5</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.6</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.6</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.7</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2.9</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>3.6</paragraph></td></tr><tr><td colspan="7" styleCode="Botrule " valign="top"><paragraph>*Deaths are birth related. **Deaths are method related.</paragraph></td></tr><tr><td colspan="7" styleCode="Botrule " valign="top"><paragraph>Adapted from H.W. Ory, Reference 41.</paragraph></td></tr></tbody></table>

PRECAUTIONS 1. Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted infections. 2. Physical Examination and Follow-Up It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. 3. Lipid Disorders Women who are being treated for hyperlipidemia should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. 4. Liver Function If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function. 5. Fluid Retention Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. 6. Contact Lenses Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. 7. Drug Interactions Effects of Other Drugs on Oral Contraceptives (69) Rifampin: Metabolism of both norethindrone and ethinyl estradiol is increased by rifampin. A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin. Anticonvulsants: Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine, have been shown to increase the metabolism of ethinyl estradiol and/or norethindrone, which could result in a reduction in contraceptive effectiveness. Troglitazone: Administration of troglitazone with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both by approximately 30%, which could result in a reduction in contraceptive effectiveness. Antibiotics: Pregnancy while taking oral contraceptives has been reported when the oral contraceptives were administered with antimicrobials such as ampicillin, tetracycline, and griseofulvin. However, clinical pharmacokinetic studies have not demonstrated any consistent effect of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids. Atorvastatin: Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively. Concomitant Use with HCV Combination Therapy: Liver Enzyme Elevation Co-administeration of norethindrone acetate and ethinyl estradiol tablets with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations (see WARNINGS , RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT ).

on Co-administeration of norethindrone acetate and ethinyl estradiol tablets with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations (see WARNINGS , RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT ). Co-administration of norethindrone acetate and ethinyl estradiol tablets and glecaprevir/pibrentasvir is not recommended due to potential for ALT elevations. Other: Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding has been suggested with phenylbutazone. Effects of Oral Contraceptives on Other Drugs Oral contraceptive combinations containing ethinyl estradiol may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. In addition, oral contraceptives may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with oral contraceptives. 8. Interactions with Laboratory Tests Certain endocrine and liver function tests and blood components may be affected by oral contraceptives: a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability. b. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered. c. Other binding proteins may be elevated in serum. d. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged. e. Triglycerides may be increased. f. Glucose tolerance may be decreased. g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives. 9. Carcinogenesis See WARNINGS section. 10. Pregnancy Discontinue norethindrone acetate and ethinyl estradiol tablets if pregnancy occurs because there is no reason to use COCs in pregnancy. See WARNINGS sections. 11. Lactation Small amounts of oral contraceptive steroids have been identified in human milk, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child. 12. Pediatric Use Safety and efficacy of norethindrone acetate and ethinyl estradiol tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (PATIENT PACKAGE INSERT BRIEF SUMMARY and DETAILED PATIENT PACKAGE INSERT). • Counsel patients that cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs (see BOXED WARNINGS and CONTRAINDICATIONS ). • Counsel patients that the increased risk of venous thromboembolism compared to non-users of CHCs is greatest after initially starting a CHC or restarting (following a 4-week or greater interruption in intake) the same or a different CHC (see WARNINGS ). • Counsel patients that this product does not protect against HIV-infection (AIDS) and other sexually transmitted infections. • Counsel patients to take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event pills are missed (see DOSAGE AND ADMINISTRATION ). • Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs (see PRECAUTIONS ). • Counsel patients who are breastfeeding or who desire to breastfeed that COCs may reduce breast milk production. This is less likely to occur if breastfeeding is well established (see PRECAUTIONS ). • Counsel any patient who starts norethindrone acetate and ethinyl estradiol tablets postpartum, and who has not yet had a period, to use an additional method of contraception until she has taken a white to off-white tablet for 7 consecutive days (see DOSAGE AND ADMINISTRATION ). • Counsel patients that amenorrhea may occur. Pregnancy should be considered in the event of amenorrhea, and should be ruled out if amenorrhea is associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness (see WARNINGS). • Counsel patients with a history of depression that depression may reoccur. Women should contact their healthcare provider if depression occurs (see WARNINGS)

menorrhea, and should be ruled out if amenorrhea is associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness (see WARNINGS). • Counsel patients with a history of depression that depression may reoccur. Women should contact their healthcare provider if depression occurs (see WARNINGS) NON-CONTRACEPTIVE HEALTH BENEFITS The following non-contraceptive health benefits related to the use of oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol (76 to 81). Effects on menses: • Increased menstrual cycle regularity • Decreased blood loss and decreased incidence of iron deficiency anemia • Decreased incidence of dysmenorrhea Effects related to inhibition of ovulation: • Decreased incidence of functional ovarian cysts • Decreased incidence of ectopic pregnancies Effects from long-term use: • Decreased incidence of fibroadenomas and fibrocystic disease of the breast • Decreased incidence of acute pelvic inflammatory disease • Decreased incidence of endometrial cancer • Decreased incidence of ovarian cancer

of functional ovarian cysts • Decreased incidence of ectopic pregnancies Effects from long-term use: • Decreased incidence of fibroadenomas and fibrocystic disease of the breast • Decreased incidence of acute pelvic inflammatory disease • Decreased incidence of endometrial cancer • Decreased incidence of ovarian cancer BRIEF SUMMARY PATIENT PACKAGE INSERT This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted infections. Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. Oral contraceptives, also known as "birth control pills" or "the pill," are taken to prevent pregnancy and, when taken correctly, have a failure rate of about 1% per year when used without missing any pills. The typical failure rate of large numbers of pill users is less than 3% per year when women who miss pills are included. For most women oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably increases the chances of pregnancy. For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be life-threatening or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you: • Smoke • Have high blood pressure, diabetes, high cholesterol • Have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast, jaundice, or malignant or benign liver tumors. You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding. Most side effects of the pill are not serious. The most common side effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea, vomiting, and breakthrough bleeding may subside within the first three months of use. The serious side effects of the pill occur very infrequently, especially if you are in good health and are young. However, you should know that the following medical conditions have been associated with or made worse by the pill: 1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences. 2. Liver tumors, which may rupture and cause severe bleeding. A possible but not definite association has been found with the pill and liver cancer. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer. 3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped. The symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. Notify your doctor or healthcare provider if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics, may decrease oral contraceptive effectiveness. There may be slight increases in the risk of breast cancer among current users of hormonal birth control pills with longer duration of use of 8 years or more.

while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics, may decrease oral contraceptive effectiveness. There may be slight increases in the risk of breast cancer among current users of hormonal birth control pills with longer duration of use of 8 years or more. Some studies have found an increase in the risk of developing cancer of the cervix in women taking the pill, but this finding may be related to differences in sexual behavior or other factors not related to use of the pill. Taking the pill provides some important non-contraceptive benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus. Be sure to discuss any medical condition you may have with your healthcare provider. Your healthcare provider will take a medical and family history and examine you before prescribing oral contraceptives. The physical examination may be delayed to another time if you request it and your healthcare provider believes that it is a good medical practice to postpone it. You should be reexamined at least once a year while taking oral contraceptives. The detailed patient information leaflet gives you further information which you should read and discuss with your healthcare provider. This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted infections such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B and syphilis.

you should read and discuss with your healthcare provider. This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted infections such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B and syphilis. INSTRUCTIONS TO PATIENT TABLET DISPENSER The norethindrone acetate and ethinyl estradiol tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in three rows of seven tablets each with the days of the week appearing above the first row of tablets. Each white to off-white tablet contains 1 mg norethindrone acetate, USP and 0.02 mg ethinyl estradiol, USP. DIRECTIONS To remove a tablet, press down on it with your thumb or finger. The tablet will drop through the back of the tablet dispenser. Do not press with your thumbnail, fingernail, or any other sharp object. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH, DURING THE FIRST 1 TO 3 PACKS OF PILLS. If you do have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn't go away, check with your doctor or clinic. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your birth control pills may not work as well. Use a back-up birth control method (such as condoms or foam) until you check with your doctor or clinic. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or clinic about how to make pill-taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or clinic. BEFORE YOU START TAKING YOUR PILLS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK. IT HAS 21 PILLS: The 21-pill pack has 21 "active" white to off-white pills (with hormones) to take for 3 weeks, followed by 1week without pills. 3. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills (follow the arrows), and 3) the week numbers as shown in the following pictures: 4) the day label strips, if your period starts on a day other than Sunday 1. Pick the day label strip that starts with the first day of your period (this is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins). 2. Place this day label strip on the tablet blister over the area that has the days of the week (starting with Sunday) imprinted in the plastic. Norethindrone acetate and ethinyl estradiol tablets will contain: ALL WHITE TO OFF-WHITE PILLS 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as condoms or foam) to use as a back-up in case you miss pills. An EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. Decide with your doctor or clinic which is the best day for you.

EADY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as condoms or foam) to use as a back-up in case you miss pills. An EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. Decide with your doctor or clinic which is the best day for you. Pick a time of day which will be easy to remember. DAY-1 START: 1. Pick the day label strip that starts with the first day of your period. (This is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins.) 2. Place this day label strip on the tablet dispenser over the area that has the days of the week (starting with Sunday) printed on the plastic. 3. Take the first "active" white to off-white pill of the first pack during the first 24 hours of your period . 4. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. SUNDAY START: 1. Take the first "active" white to off-white pill of the first pack on the Sunday after your period starts , even if you are still bleeding. If your period begins on Sunday, start the pack that same day. 2. Use another method of birth control as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Condoms or foam are good back-up methods of birth control. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: 21 pills: Wait 7 days to start the next pack. You will probably have your period during that week. Be sure that no more than 7 days pass between 21-day packs. WHAT TO DO IF YOU MISS PILLS If you MISS 1 white to off-white "active" pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white to off-white "active" pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or foam) as a back-up method of birth control until you have taken a white to off-white "active" pill every day for 7 days. If you MISS 2 white to off-white "active" pills in a row in THE 3rd WEEK : 1. If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. 3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or foam) as a back-up method of birth control until you have taken a white to off-white "active" pill every day for 7 days. If you MISS 3 OR MORE white to off-white "active" pills in a row (during the first 3 weeks): 1. If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month, but this is expected.

ou are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. 3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or foam) as a back-up method of birth control until you have taken a white to off-white "active" pill every day for 7 days. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE WHITE TO OFF-WHITE "ACTIVE" PILL EACH DAY until you can reach your doctor or clinic. Based on his or her assessment of your medical needs, your doctor or healthcare provider has prescribed this drug for you. Do not give this drug to anyone else. Keep this and all drugs out of the reach of children. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep out of the reach of children. Protect from moisture. blister1

ADVERSE REACTIONS An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section): • Thrombophlebitis • Arterial thromboembolism • Pulmonary embolism • Myocardial infarction • Cerebral hemorrhage • Cerebral thrombosis • Hypertension • Gallbladder disease • Hepatic adenomas or benign liver tumors Post Marketing 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 to 1.12 (Figure 1) (70-74). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 1) (70, 73, 75). 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 to 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 to 10 years of COC use. FIGURE 1: 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. There is evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed: • Mesenteric thrombosis • Retinal thrombosis The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related: • Nausea • Vomiting • Gastrointestinal symptoms (such as abdominal cramps and bloating) • Breakthrough bleeding • Spotting • Change in menstrual flow • Amenorrhea • Temporary infertility after discontinuation of treatment • Edema • Melasma which may persist • Breast changes: tenderness, enlargement, secretion • Change in weight (increase or decrease) • Change in cervical erosion and secretion • Diminution in lactation when given immediately postpartum • Cholestatic jaundice • Migraine • Rash (allergic) • Depression • Reduced tolerance to carbohydrates • Vaginal candidiasis • Change in corneal curvature (steepening) • Intolerance to contact lenses The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted: • Pre-menstrual syndrome • Cataracts • Changes in appetite • Cystitis-like syndrome • Headache • Nervousness • Dizziness • Hirsutism • Loss of scalp hair • Erythema multiforme • Erythema nodosum • Hemorrhagic eruption • Vaginitis • Porphyria • Impaired renal function • Hemolytic uremic syndrome • Budd-Chiari syndrome • Acne • Changes in libido • Colitis figure1

OVERDOSAGE Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females.

DOSAGE AND ADMINISTRATION The tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in three rows of seven tablets each, with the days of the week appearing on the tablet dispenser above the first row of tablets. Note: Each tablet dispenser has been preprinted with the days of the week, starting with Sunday, to facilitate a Sunday-Start regimen. Six different day label strips have been provided with the Detailed Patient & Brief Summary Patient Package Insert in order to accommodate a Day-1 Start regimen. If the patient is using the Day-1 Start regimen, she should place the self-adhesive day label strip that corresponds to her starting day over the preprinted days. Important: The patient should be instructed to use an additional method of protection until after the first week of administration in the initial cycle when utilizing the Sunday-Start regimen. The possibility of ovulation and conception prior to initiation of use should be considered. Dosage and Administration for 21-Day Dosage Regimen To achieve maximum contraceptive effectiveness, norethindrone acetate and ethinyl estradiol tablets must be taken exactly as directed and at intervals not exceeding 24 hours. Norethindrone acetate and ethinyl estradiol tablets provides the patient with a convenient tablet schedule of “3 weeks on-1 week off”. Two dosage regimens are described, one of which may be more convenient or suitable than the other for an individual patient. For the initial cycle of therapy, the patient begins her tablets according to the Day-1 Start or Sunday-Start regimen. With either regimen, the patient takes one tablet daily for 21 consecutive days followed by one week of no tablets. A. Sunday-Start Regimen: The patient begins taking tablets from the top row on the first Sunday after menstrual flow begins. When menstrual flow begins on Sunday, the first tablet is taken on the same day. The last tablet in the dispenser will then be taken on a Saturday, followed by no tablets for a week (7 days). For all subsequent cycles, the patient then begins a new 21-tablet regimen on the eighth day, Sunday, after taking her last tablet. Following this regimen, of 21 days on -7 days off, the patient will start all subsequent cycles on a Sunday. B. Day-1 Regimen: The first day of menstrual flow is Day 1. The patient places the self-adhesive day label strip that corresponds to her starting day over the preprinted days on the tablet dispenser. She starts taking one tablet daily, beginning with the first tablet in the top row. The patient completes her 21-tablet regimen when she has taken the last tablet in the tablet dispenser. She will then take no tablets for a week (7 days). For all subsequent cycles, the patient begins a new 21-tablet regimen on the eighth day after taking her last tablet, again starting with the first tablet in the top row after placing the appropriate day label strip over the preprinted days on the tablet dispenser. Following this regimen of 21 days on-7 days off, the patient will start all subsequent cycles on the same day of the week as the first course. Likewise, the interval of no tablets will always start on the same day of the week. Tablets should be taken regularly with a meal or at bedtime. It should be stressed that efficacy of medication depends on strict adherence to the dosage schedule.

rt all subsequent cycles on the same day of the week as the first course. Likewise, the interval of no tablets will always start on the same day of the week. Tablets should be taken regularly with a meal or at bedtime. It should be stressed that efficacy of medication depends on strict adherence to the dosage schedule. Special Notes on Administration Menstruation usually begins two or three days, but may begin as late as the fourth or fifth day, after discontinuing medication. If spotting occurs while on the usual regimen of one tablet daily, the patient should continue medication without interruption. If the patient forgets to take one or more tablets, the following is suggested: One tablet is missed • take tablet as soon as remembered • take next tablet at the regular time Two consecutive tablets are missed (week 1 or week 2) • take two tablets as soon as remembered • take two tablets the next day • use another birth control method for seven days following the missed tablets Two consecutive tablets are missed (week 3) Sunday-Start Regimen: • take one tablet daily until Sunday • discard remaining tablets • start new pack of tablets immediately (Sunday) • use another birth control method for seven days following the missed tablets Day-1 Start Regimen: • discard remaining tablets • start new pack of tablets that same day • use another birth control method for seven days following the missed tablets Three (or more) consecutive tablets are missed Sunday-Start Regimen: • take one tablet daily until Sunday • discard remaining tablets • start new pack of tablets immediately (Sunday) • use another birth control method for seven days following the missed tablets Day-1 Start Regimen: • discard remaining tablets • start new pack of tablets that same day • use another birth control method for seven days following the missed tablets The possibility of ovulation occurring increases with each successive day that scheduled tablets are missed. While there is little likelihood of ovulation occurring if only one tablet is missed, the possibility of spotting or bleeding is increased. This is particularly likely to occur if two or more consecutive tablets are missed. In the rare case of bleeding which resembles menstruation, the patient should be advised to discontinue medication and then begin taking tablets from a new tablet dispenser on the next Sunday or the first day (Day 1), depending on her regimen. Persistent bleeding which is not controlled by this method indicates the need for reexamination of the patient, at which time nonfunctional causes should be considered. Use of Oral Contraceptives in the Event of a Missed Menstrual Period 1. If the patient has not adhered to the prescribed dosage regimen, the possibility of pregnancy should be considered after the first missed period and oral contraceptives should be withheld until pregnancy has been ruled out. 2. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen. After several months on treatment, bleeding may be reduced to a point of virtual absence. This reduced flow may occur as a result of medication, in which event it is not indicative of pregnancy.

REFERENCES 1. Back DJ, Breckenridge AM, Crawford FE, McIver M, Orme ML’E, Rowe PH and Smith E: Kinetics of norethindrone in women II. Single-dose kinetics. Clin Pharmacol Ther 1978; 24:448-453. 2. Hümpel M, Nieuweboer B, Wendt H and Speck U: Investigations of pharmacokinetics of ethinyloestradiol to specific consideration of a possible first-pass effect in women. Contraception 1979; 19:421-432. 3. Back DJ, Breckenridge AM, Crawford FE, MacIver M, Orme ML’E, Rowe PH and Watts MJ. An investigation of the pharmacokinetics of ethynyl estradiol in women using radioimmunoassay. Contraception 1979; 20:263-273. 4. Hammond GL, Lähteenmäki PLA, Lähteenmäki P and Luukkainen T. Distribution and percentages of non-protein bound contraceptive steroids in human serum. J Steriod Biochem 1982; 17:375-380. 5. Fotherby K. Pharmacokinetics and metabolism of progestins in humans, in Pharmacology of the contraceptive steroids, Goldzieher JW, Fotherby K (eds), Raven Press, Ltd., New York, 1994; 99-126. 6. Goldzieher JW. Pharmacokinetics and metabolism of ethynyl estrogens, in Pharmacology of the contraceptive steroids, Goldzieher JW, Fotherby K (eds), Raven Press Ltd., New York, 1994; 127-151. 7. Hatcher RA, et al. 1998. Contraceptive Technology, Seventeenth Edition. New York: Irvington Publishers. 8. Stadel, B.V.: Oral contraceptives and cardiovascular disease. (Pt. 1). New England Journal of Medicine, 305:612-618, 1981. 9. Stadel, B.V.: Oral contraceptives and cardiovascular disease. (Pt. 2). New England Journal of Medicine , 305:672-677, 1981. 10. Adam, S.A., and M. Thorogood: Oral contraception and myocardial infarction revisited: The effects of new preparations and prescribing patterns. Brit. J. Obstet. and Gynec., 88:838-845, 1981. 11. Mann, J.I., and W.H. Inman: Oral contraceptives and death from myocardial infarction. Brit. Med. J., 2(5965): 245-248, 1975. 12. Mann, J.I., M.P. Vessey, M. Thorogood, and R. Doll: Myocardial infarction in young women with special reference to oral contraceptive practice. Brit. Med. J., 2(5956):241-245, 1975. 13. Royal College of General Practitioners’ Oral Contraception Study: Further analyses of mortality in oral contraceptive users. Lancet, 1:541-546, 1981. 14. Slone, D., S. Shapiro, D.W. Kaufman, L. Rosenberg, O.S. Miettinen, and P.D. Stolley: Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. N.E.J.M., 305: 420-424, 1981. 15. Vessey, M.P.: Female hormones and vascular disease: An epidemiological overview. Brit. J. Fam. Plann., 6:1-12, 1980. 16. Russell-Briefel, R.G., T.M. Ezzati, R. Fulwood, J.A. Perlman, and R.S. Murphy: Cardiovascular risk status and oral contraceptive use, United States, 1976-80. Preventive Medicine, 15:352-362, 1986. 17. Goldbaum, G.M., J.S. Kendrick, G.C. Hogelin, and E.M. Gentry: The relative impact of smoking and oral contraceptive use on women in the United States. J.A.M.A., 258:1339-1342, 1987. 18. Layde, P.M., and V. Beral: Further analyses of mortality in oral contraceptive users: Royal College General Practitioners’ Oral Contraception Study. (Table 5) Lancet, 1:541-546, 1981. 19. Knopp, R.H.: Arteriosclerosis risk: The roles of oral contraceptives and postmenopausal estrogens. J. of Reprod. Med. , 31(9)(Supplement): 913-921, 1986. 20. Krauss, R.M., S. Roy, D.R. Mishell, J. Casagrande, and M.C. Pike: Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: Differential changes in high-density lipoproteins subclasses. Am.

f oral contraceptives and postmenopausal estrogens. J. of Reprod. Med. , 31(9)(Supplement): 913-921, 1986. 20. Krauss, R.M., S. Roy, D.R. Mishell, J. Casagrande, and M.C. Pike: Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: Differential changes in high-density lipoproteins subclasses. Am. J. Obstet. Gyn., 145:446-452, 1983. 21. Wahl, P., C. Walden, R. Knopp, J. Hoover, R. Wallace, G. Heiss, and B. Rifkind: Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol. N.E.J.M., 308:862-867, 1983. 22. Wynn, V., and R. Niththyananthan: The effect of progestin in combined oral contraceptives on serum lipids with special reference to high-density lipoproteins. Am. J. Obstet. and Gyn., 142:766-771, 1982. 23. Wynn, V., and I. Godsland: Effects of oral contraceptives on carbohydrate metabolism. J. Reprod. Medicine, 31 (9)(Supplement): 892-897, 1986. 24. LaRosa, J.C.: Atherosclerotic risk factors in cardiovascular disease. J. Reprod. Med., 31(9) (Supplement): 906-912, 1986. 25. Inman, W.H., and M.P. Vessey: Investigations of death from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. Brit. Med. J., 2(5599): 193-199, 1968. 26. Maguire, M.G., J. Tonascia, P.E. Sartwell, P.D. Stolley, and M.S. Tockman: Increased risk of thrombosis due to oral contraceptives: A further report. Am. J. Epidemiology, 110(2): 188-195, 1979. 27. Pettiti, D.B., J. Wingerd, F. Pellegrin, and S. Ramacharan: Risk of vascular disease in women: Smoking, oral contraceptives, noncontraceptive estrogens, and other factors. J.A.M.A., 242:1150-1154, 1979. 28. Vessey, M.P., and R. Doll: Investigation of relation between use of oral contraceptives and thromboembolic disease. Brit. Med. J., 2(5599): 199-205, 1968. 29. Vessey, M.P., and R. Doll: Investigation of relation between use of oral contraceptives and thromboembolic disease: A further report. Brit. Med. J., 2(5658): 651-657, 1969. 30. Porter, J.B., J.R. Hunter, D.A. Danielson, H. Jick, and A. Stergachis: Oral contraceptives and non-fatal vascular disease: Recent experience. Obstet. and Gyn., 59(3):299-302, 1982. 31. Vessey, M., R. Doll, R. Peto, B. Johnson, and P. Wiggins: A long-term follow-up study of women using different methods of contraception: An interim report. J . Biosocial. Sci., 8:375-427, 1976. 32. Royal College of General Practitioners: Oral contraceptives, venous thrombosis, and varicose veins. J. of Royal College of General Practitioners, 28:393-399, 1978. 33. Collaborative Group for the study of stroke in young women: Oral contraception and increased risk of cerebral ischemia or thrombosis. N.E.J.M., 288:871-878, 1973. 34. Petitti, D.B., and J. Wingerd: Use of oral contraceptives, cigarette smoking, and risk of subarachnoid hemorrhage. Lancet, 2:234-236, 1978. 35. Inman, W.H.: Oral contraceptives and fatal subarachnoid hemorrhage. Brit. Med. J. , 2(6203): 1468-70, 1979. 36. Collaborative Group for the study of stroke in young women: Oral contraceptives and stroke in young women: Associated risk factors. J.A.M.A. , 231:718-722, 1975. 37. Inman, W.H., M.P. Vessey, B. Westerholm, and A. Engelund: Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. Brit. Med. J., 2:203-209, 1970. 38. Meade, T.W., G. Greenberg, and S.G. Thompson: Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 35-mcg oestrogen preparations. Brit. Med. J., 280(6224): 1157-1161, 1980. 39. Kay, C.R.: Progestogens and arterial disease: Evidence from the Royal College of General Practitioners’ study. Amer. J. Obstet. Gyn. , 142:762-765, 1982. 40. Royal College of General Practitioners: Incidence of arterial disease among oral contraceptive users. J. Coll.

ons. Brit. Med. J., 280(6224): 1157-1161, 1980. 39. Kay, C.R.: Progestogens and arterial disease: Evidence from the Royal College of General Practitioners’ study. Amer. J. Obstet. Gyn. , 142:762-765, 1982. 40. Royal College of General Practitioners: Incidence of arterial disease among oral contraceptive users. J. Coll. Gen. Pract. , 33:75-82, 1983. 41. Ory, H.W: Mortality associated with fertility and fertility control: 1983. Family PlanningPerspectives, 15:50-56, 1983. 42. Ory, H., Z. Naib, S.B. Conger, R.A. Hatcher, and C.W. Tyler: Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ. Am. J. Obstet. Gynec. , 124:573-577, 1976. 43. Vessey, M.P., M. Lawless, K. McPherson, D. Yeates: Neoplasia of the cervix uteri and contraception: A possible adverse effect of the pill. Lancet , 2:930, 1983. 44. Brinton, L.A., G.R. Huggins, H.F. Lehman, K. Malli, D.A. Savitz, E. Trapido, J. Rosenthal, and R. Hoover: Long-term use of oral contraceptives and risk of invasive cervical cancer. Int. J. Cancer , 38:339-344, 1986. 45. WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical cancer and combined oral contraceptives. Brit. Med. J ., 290:961-965, 1985. 46. Rooks, J.B., H.W. Ory, K.G. Ishak, L.T. Strauss, J.R. Greenspan, A.P. Hill, and C.W. Tyler: Epidemiology of hepatocellular adenoma: The role of oral contraceptive use. J.A.M.A. , 242:644-648, 1979. 47. Bein, N.N., and H.S. Goldsmith: Recurrent massive hemorrhage from benign hepatic tumors secondary to oral contraceptives. Brit. J. Surg ., 64:433-435, 1977. 48. Klatskin, G.: Hepatic tumors: Possible relationship to use of oral contraceptives. Gastroenterology , 73:386-394, 1977. 49. Henderson, B.E., S. Preston-Martin, H.A. Edmondson, R.L. Peters, and M.C. Pike: Hepatocellular carcinoma and oral contraceptives. Brit. J. Cancer , 48:437-440, 1983. 50. Neuberger, J., D. Forman, R. Doll, and R. Williams: Oral contraceptives and hepatocellular carcinoma. Brit. Med. J. , 292:1355-1357, 1986. 51. Forman, D., T.J. Vincent, and R. Doll: Cancer of the liver and oral contraceptives. Brit. Med. J ., 292: 1357-1361, 1986. 52. Harlap, S., and J. Eldor: Births following oral contraceptive failures. Obstet. Gynec ., 55:447-452, 1980. 53. Savolainen, E., E. Saksela, and L. Saxen: Teratogenic hazards of oral contraceptives analyzed in a national malformation register. Amer. J. Obstet. Gynec. , 140:521-524, 1981. 54. Janerich, D.T., J.M. Piper, and D.M. Glebatis: Oral contraceptives and birth defects. Am. J. Epidemiology , 112:73-79, 1980. 55. Ferencz, C., G.M. Matanoski, P.D. Wilson, J.D. Rubin, C.A. Neill, and R. Gutberlet: Maternal hormone therapy and congenital heart disease. Teratology , 21:225-239, 1980. 56. Rothman, K.J., D.C. Fyler, A. Goldbatt, and M.B. Kreidberg: Exogenous hormones and other drug exposures of children with congenital heart disease. Am. J. Epidemiology , 109:433-439, 1979. 57. Boston Collaborative Drug Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease, and breast tumors. Lancet , 1:1399-1404, 1973. 58. Royal College of General Practitioners: Oral Contraceptives and Health . New York, Pittman, 1974, 100p. 59. Layde, P.M., M.P. Vessey, and D. Yeates: Risk of gallbladder disease: A cohort study of young women attending family planning clinics. J. of Epidemiol. and Comm. Health , 36: 274-278, 1982. 60. Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone disease in an Italian adult female population. Am. J. Epidemiol ., 119:796-805, 1984. 61. Strom, B.L., R.T. Tamragouri, M.L. Morse, E.L. Lazar, S.L. West, P. D. Stolley, and J.K. Jones: Oral contraceptives and other risk factors for gallbladder disease. Clin. Pharmacol. Ther. , 39:335-341, 1986.

Prevalence of gallstone disease in an Italian adult female population. Am. J. Epidemiol ., 119:796-805, 1984. 61. Strom, B.L., R.T. Tamragouri, M.L. Morse, E.L. Lazar, S.L. West, P. D. Stolley, and J.K. Jones: Oral contraceptives and other risk factors for gallbladder disease. Clin. Pharmacol. Ther. , 39:335-341, 1986. 62. Wynn, V., P.W. Adams, I.F. Godsland, J. Melrose, R. Niththyananthan, N.W. Oakley, and A. Seedj: Comparison of effects of different combined oral-contraceptive formulations on carbohydrate and lipid metabolism. Lancet , 1:1045-1049, 1979. 63. Wynn, V.: Effect of progesterone and progestins on carbohydrate metabolism. In Progesterone and Progestin. Edited by C.W. Bardin, E. Milgrom, P. Mauvis-Jarvis. New York, Raven Press , pp. 395-410, 1983. 64. Perlman, J.A., R. G. Roussell-Briefel, T.M. Ezzati, and G. Lieberknecht: Oral glucose tolerance and the potency of oral contraceptive progestogens. J. Chronic Dis. , 38:857- 864, 1985. 65. Royal College of General Practitioners’ Oral Contraception Study: Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet , 1:624, 1977. 66. Fisch, I.R., and J. Frank: Oral contraceptives and blood pressure. J.A.M.A. , 237:2499- 2503, 1977. 67. Laragh, A.J.: Oral contraceptive induced hypertension: Nine years later. Amer. J. Obstet. Gynecol ., 126:141-147, 1976. 68. Ramcharan, S., E. Peritz, F.A. Pellegrin, and W.T. Williams: Incidence of hypertension in the Walnut Creek Contraceptive Drug Study cohort. In Pharmacology of Steroid Contraceptive Drugs. Edited by S. Garattini and H.W. Berendes. New York, Raven Press , pp. 277-288, 1977. (Monographs of the Mario Negri Institute for Pharmacological Research, Milan.) 69. Back DJ, Orme ML’E. Drug interactions, in Pharmacology of the contraceptive steroids. Goldzieher JW, Fotherby K (eds), Raven Press, Ltd., New York, 1994, 407-425. 70. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med . 2002;346(26):2025-2032. 71. Dumeaux V, Fournier A, Lund E, Clavel-Chapelon F. Previous oral contraceptive use and breast cancer risk according to hormone replacement therapy use among postmenopausal women. Cancer Causes Control . 2005;16(5):537-544. 72. Dorjgochoo T, Shu XO, Li HL, et al. Use of oral contraceptives, intrauterine devices and tubal sterilization and cancer risk in a large prospective study, from 1996 to 2006. Int J Cancer . 2009;124(10):2442-2449. 73. Hunter DJ, Colditz GA, Hankinson SE, et al. Oral contraceptive use and breast cancer: a prospective study of young women. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology . 2010;19(10):2496-2502. 74. Vessey M, Yeates D. Oral contraceptive use and cancer. Final report from the Oxford-Family Planning Association contraceptive study. Contraception. 2013; 88(6): 678-683. 75. Morch LS, Skovlund CW, Hannaford PC, Iversen L, Fielding S, Lidegaard O. Contemporary Hormonal Contraception and the Risk of Breast Cancer. N Engl J Med . 2017;377(23):2228-2239. 76. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of ovarian cancer. J.A.M.A. , 249:1596-1599, 1983. 77. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Combination oral contraceptive use and the risk of endometrial cancer. J.A.M.A. , 257:796-800, 1987. 78. Ory, H.W.: Functional ovarian cysts and oral contraceptives: Negative association confirmed surgically. J.A.M.A. , 228:68-69, 1974. 79. Ory, H.W., P. Cole, B. Macmahon, and R.

of Child Health and Human Development: Combination oral contraceptive use and the risk of endometrial cancer. J.A.M.A. , 257:796-800, 1987. 78. Ory, H.W.: Functional ovarian cysts and oral contraceptives: Negative association confirmed surgically. J.A.M.A. , 228:68-69, 1974. 79. Ory, H.W., P. Cole, B. Macmahon, and R. Hoover: Oral contraceptives and reduced risk of benign breast disease. N.E.J.M. , 294:41-422, 1976. 80. Ory, H.W.: The noncontraceptive health benefits from oral contraceptive use. Fam . Plann. Perspectives , 14:182-184, 1982. 81. Ory, H.W., J.D. Forrest, and R. Lincoln: Making Choices: Evaluating the health risks and benefits of birth control methods. New York, The Alan Guttmacher Institute, p.1, 1983. Distributed by: Glenmark Pharmaceuticals Inc., USA Elmwood Park, NJ 07407 Questions? 1 (888) 721-7115 www.glenmarkpharma-us.com May 2025 logo

<table width="100%"><col width="98%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke.</content></paragraph></td></tr></tbody></table>

DETAILED PATIENT PACKAGE INSERT Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted infections. What You Should Know About Oral Contraceptives Any woman who considers using oral contraceptives (the "birth control pill" or "the pill") should understand the benefits and risks of using this form of birth control. This leaflet will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this leaflet is not a replacement for a careful discussion between you and your healthcare provider. You should discuss the information provided in this leaflet with him or her, both when you first start taking the pill and during your revisits. You should also follow your healthcare provider's advice with regard to regular check-ups while you are on the pill. EFFECTIVENESS OF ORAL CONTRACEPTIVES Oral contraceptives or "birth control pills'' or "the pill" are used to prevent pregnancy and are more effective than other non-surgical methods of birth control. When they are taken correctly, the chance of becoming pregnant is less than 1% (1 pregnancy per 100 women per year of use) when used perfectly, without missing any pills. Typical failure rates are actually 3% per year. The chance of becoming pregnant increases with each missed pill during a menstrual cycle. In comparison, typical failure rates for other methods of birth control during the first year of use are as follows: Implant: <1% Male sterilization: <1% Injection: <1% Cervical Cap: 20 to 40% IUD: <1 to 2% Condom alone (male): 14% Diaphragm with spermicides: 20% Condom alone (female): 21% Spermicides alone: 26% Periodic abstinence: 25% Vaginal Sponge: 20 to 40% Withdrawal: 19% Female sterilization: <1% No method: 85% WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. Some women should not use the pill. For example, you should not take the pill if you are pregnant or think you may be pregnant. You should also not use the pill if you have any of the following conditions: • A history of heart attack or stroke • Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes • A history of blood clots in the deep veins of your legs • Chest pain (angina pectoris) • Known or suspected breast cancer • Unexplained vaginal bleeding (until a diagnosis is reached by your doctor) • Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill • Liver tumor (benign or cancerous) • Take any Hepatitis C drug combination containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir.

bleeding (until a diagnosis is reached by your doctor) • Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill • Liver tumor (benign or cancerous) • Take any Hepatitis C drug combination containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. This may increase levels of the liver enzyme “alanine aminotransferase” (ALT) in the blood. Tell your healthcare provider if you have ever had any of these conditions. Your healthcare provider can recommend a safer method of birth control. OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES Tell your healthcare provider if you have: • Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram • Diabetes • Elevated cholesterol or triglycerides • High blood pressure • Migraine or other headaches or epilepsy • Depression • Gallbladder, heart, or kidney disease • History of scanty or irregular menstrual periods Women with any of these conditions should be checked often by their healthcare provider if they choose to use oral contraceptives. Also, be sure to inform your doctor or healthcare provider if you smoke or are on any medications. RISKS OF TAKING ORAL CONTRACEPTIVES 1. Risk of Developing Blood Clots Blood clots and blockage of blood vessels are the most serious side effects of taking oral contraceptives; in particular, a clot in the legs can cause thrombophlebitis, and a clot that travels to the lungs can cause a sudden blocking of the vessel carrying blood to the lungs. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision. If you take oral contraceptives and need elective surgery, need to stay in bed for a prolonged illness, or have recently delivered a baby, you may be at risk of developing blood clots. You should consult your doctor about stopping oral contraceptives three to four weeks before surgery and not taking oral contraceptives for two weeks after surgery or during bed rest. You should also not take oral contraceptives soon after delivery of a baby. It is advisable to wait for at least four weeks after delivery if you are not breastfeeding. If you are breastfeeding, you should wait until you have weaned your child before using the pill. (See also the section on Breastfeeding in GENERAL PRECAUTIONS .) 2. Heart Attacks and Strokes Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these conditions can cause death or disability. Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking and the use of oral contraceptives greatly increase the chances of developing and dying of heart disease. 3. Gallbladder Disease Oral contraceptive users probably have a greater risk than nonusers of having gallbladder disease, although this risk may be related to pills containing high doses of estrogens. 4. Liver Tumors In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, a possible but not definite association has been found with the pill and liver cancers in two studies, in which a few women who developed these very rare cancers were found to have used oral contraceptives for long periods. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer. 5. Risk of Cancer It is not known if hormonal birth control pills cause breast cancer. Some studies, but not all, suggest that there could be a slight increase in the risk of breast cancer among current users with longer duration of use.

are. The chance of developing liver cancer from using the pill is thus even rarer. 5. Risk of Cancer It is not known if hormonal birth control pills cause breast cancer. Some studies, but not all, suggest that there could be a slight increase in the risk of breast cancer among current users with longer duration of use. If you have breast cancer now, or have had it in the past, do not use hormonal birth control because some breast cancers are sensitive to hormones. Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY All methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table. ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control and outcome 15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44 No fertility control methods* 7 7.4 9.1 14.8 25.7 28.2 Oral contraceptives non-smoker** 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives smoker** 2.2 3.4 6.6 13.5 51.1 117.2 IUD** 0.8 0.8 1 1 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 *Deaths are birth related. **Deaths are method related. In the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7 to 26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death was always lower than that associated with pregnancy for any age group, although over the age of 40, the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy (28/100,000 women) in that age group. The suggestion that women over 40 who don't smoke should not take oral contraceptives is based on information from older higher dose pills and on less selective use of pills than is practiced today. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of oral contraceptive use by healthy, non-smoking women over 40 years of age may outweigh the possible risks. However, all women, especially older women, are cautioned to use the lowest dose pill that is effective.

ed today. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of oral contraceptive use by healthy, non-smoking women over 40 years of age may outweigh the possible risks. However, all women, especially older women, are cautioned to use the lowest dose pill that is effective. WARNING SIGNALS If any of these adverse effects occur while you are taking oral contraceptives, call your doctor immediately: • Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung) • Pain in the calf (indicating a possible clot in the leg) • Crushing chest pain or heaviness in the chest (indicating a possible heart attack) • Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke) • Sudden partial or complete loss of vision (indicating a possible clot in the eye) • Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your doctor or healthcare provider to show you how to examine your breasts) • Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor) • Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression) • Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems) SIDE EFFECTS OF ORAL CONTRACEPTIVES 1. Vaginal Bleeding Irregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding which is a flow much like a regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate serious problems. It is important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle or lasts for more than a few days, talk to your doctor or healthcare provider. 2. Contact Lenses If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your doctor or healthcare provider. 3. Fluid Retention Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may raise your blood pressure. If you experience fluid retention, contact your doctor or healthcare provider. 4. Melasma A spotty darkening of the skin is possible, particularly of the face. 5. Other Side Effects Other side effects may include change in appetite, headache, nervousness, depression, dizziness, loss of scalp hair, rash, and vaginal infections. If any of these side effects bother you, call your doctor or healthcare provider. GENERAL PRECAUTIONS 1. Missed Periods and Use of Oral Contraceptives Before or During Early Pregnancy There may be times when you may not menstruate regularly after you have completed taking a cycle of pills. If you have taken your pills regularly and miss one menstrual period, continue taking your pills for the next cycle but be sure to inform your healthcare provider before doing so. If you have not taken the pills daily as instructed and missed a menstrual period, or if you missed two consecutive menstrual periods, you may be pregnant. Check with your healthcare provider immediately to determine whether you are pregnant. Do not continue to take oral contraceptives until you are sure you are not pregnant, but continue to use another method of contraception.

ed a menstrual period, or if you missed two consecutive menstrual periods, you may be pregnant. Check with your healthcare provider immediately to determine whether you are pregnant. Do not continue to take oral contraceptives until you are sure you are not pregnant, but continue to use another method of contraception. There is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects, when taken inadvertently during early pregnancy. Previously, a few studies had reported that oral contraceptives might be associated with birth defects, but these studies have not been confirmed. Nevertheless, oral contraceptives or any other drugs should not be used during pregnancy unless clearly necessary and prescribed by your doctor. You should check with your doctor about risks to your unborn child of any medication taken during pregnancy. 2. While Breastfeeding If you are breastfeeding, consult your doctor before starting oral contraceptives. Some of the drug will be passed on to the child in the milk. A few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition, oral contraceptives may decrease the amount and quality of your milk. If possible, do not use oral contraceptives while breastfeeding. You should use another method of contraception since breastfeeding provides only partial protection from becoming pregnant and this partial protection decreases significantly as you breastfeed for longer periods of time. You should consider starting oral contraceptives only after you have weaned your child completely. 3. Laboratory Tests If you are scheduled for any laboratory tests, tell your doctor you are taking birth control pills. Certain blood tests may be affected by birth control pills. 4. Drug Interactions Certain drugs may interact with birth control pills to make them less effective in preventing pregnancy or cause an increase in breakthrough bleeding. Such drugs include rifampin; drugs used for epilepsy such as barbiturates (for example, phenobarbital), carbamazepine, and phenytoin (Dilantin ® is one brand of this drug); troglitazone; phenylbutazone; and possibly certain antibiotics. You may need to use additional contraception when you take drugs which can make oral contraceptives less effective. Birth control pills interact with certain drugs. These drugs include acetaminophen, clofibric acid, cyclosporine, morphine, prednisolone, salicylic acid, temazepam, and theophylline. You should tell your doctor if you are taking any of these medications. 5. This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted infections such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B and syphilis. INSTRUCTIONS TO PATIENT TABLET DISPENSER The norethindrone acetate and ethinyl estradiol tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in three rows of seven tablets each, with the days of the week appearing above the first row of tablets. Each white to off-white tablet contains 1 mg norethindrone acetate, USP and 0.02 mg ethinyl estradiol, USP. DIRECTIONS To remove a tablet, press down on it with your thumb or finger. The tablet will drop through the back of the tablet dispenser. Do not press with your thumbnail, fingernail, or any other sharp object. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME.

il, fingernail, or any other sharp object. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1 TO 3 PACKS OF PILLS. If you do have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn't go away, check with your doctor or clinic. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your birth control pills may not work as well. Use a back-up birth control method (such as condoms or foam) until you check with your doctor or clinic. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or clinic about how to make pill-taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or clinic. BEFORE YOU START TAKING YOUR PILLS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK IT HAS 21 PILLS: The 21-pill pack has 21 "active" white to off-white pills (with hormones) to take for 3 weeks, followed by 1week without pills. 3. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills (follow the arrows), and 3) the week numbers as shown in the following pictures: 4) the day label strips, if your period starts on a day other than Sunday 1. Pick the day label strip that starts with the first day of your period (this is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins). 2. Place this day label strip on the tablet blister over the area that has the days of the week (starting with Sunday) imprinted in the plastic. Norethindrone acetate and ethinyl estradiol tablets will contain: ALL WHITE TO OFF-WHITE PILLS 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as condoms or foam) to use as a back-up in case you miss pills. An EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. Decide with your doctor or clinic which is the best day for you. Pick a time of day which will be easy to remember. DAY-1 START: 1. Pick the day label strip that starts with the first day of your period. (This is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins.) 2. Place this day label strip on the tablet dispenser over the area that has the days of the week (starting with Sunday) printed on the plastic. 3. Take the first "active" white to off-white pill of the first pack during the first 24 hours of your period . 4. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. SUNDAY START: 1. Take the first "active" white to off-white pill of the first pack on the Sunday after your period starts , even if you are still bleeding. If your period begins on Sunday, start the pack that same day. 2.

back-up method of birth control, since you are starting the pill at the beginning of your period. SUNDAY START: 1. Take the first "active" white to off-white pill of the first pack on the Sunday after your period starts , even if you are still bleeding. If your period begins on Sunday, start the pack that same day. 2. Use another method of birth control as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Condoms or foam are good back-up methods of birth control. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: 21 pills: Wait 7 days to start the next pack. You will probably have your period during that week. Be sure that no more than 7 days pass between 21-day packs. WHAT TO DO IF YOU MISS PILLS If you MISS 1 white to off-white "active" pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white to off-white "active" pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or foam) as a back-up method of birth control until you have taken a white to off-white "active" pill every day for 7 days. If you MISS 2 white to off-white "active" pills in a row in THE 3rd WEEK : 1. If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. 3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or foam) as a back-up method of birth control until you have taken a white to off-white "active" pill every day for 7 days. If you MISS 3 OR MORE white to off-white "active" pills in a row (during the first 3 weeks): 1. If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. 3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or foam) as a back-up method of birth control until you have taken a white to off-white "active" pill every day for 7 days. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE WHITE TO OFF-WHITE "ACTIVE" PILL EACH DAY until you can reach your doctor or clinic. PREGNANCY DUE TO PILL FAILURE The incidence of pill failure resulting in pregnancy is approximately 1% (i.e., one pregnancy per 100 women per year) if taken every day as directed, but more typical failure rates are about 3%.

TAKING ONE WHITE TO OFF-WHITE "ACTIVE" PILL EACH DAY until you can reach your doctor or clinic. PREGNANCY DUE TO PILL FAILURE The incidence of pill failure resulting in pregnancy is approximately 1% (i.e., one pregnancy per 100 women per year) if taken every day as directed, but more typical failure rates are about 3%. If failure does occur, the risk to the fetus is minimal. PREGNANCY AFTER STOPPING THE PILL There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy. There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill. OVERDOSAGE Serious ill effects have not been reported following ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding in females. In case of overdosage, contact your healthcare provider or pharmacist. OTHER INFORMATION Your healthcare provider will take a medical and family history and examine you before prescribing oral contraceptives. The physical examination may be delayed to another time if you request it and your healthcare provider believes that it is a good medical practice to postpone it. You should be reexamined at least once a year. Be sure to inform your healthcare provider if there is a family history of any of the conditions listed previously in this leaflet. Be sure to keep all appointments with your healthcare provider, because this is a time to determine if there are early signs of side effects of oral contraceptive use. Do not use the drug for any condition other than the one for which it was prescribed. This drug has been prescribed specifically for you; do not give it to others who may want birth control pills. HEALTH BENEFITS FROM ORAL CONTRACEPTIVES In addition to preventing pregnancy, use of oral contraceptives may provide certain benefits. They are: • Menstrual cycles may become more regular • Blood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur • Pain or other symptoms during menstruation may be encountered less frequently • Ectopic (tubal) pregnancy may occur less frequently • Noncancerous cysts or lumps in the breast may occur less frequently • Acute pelvic inflammatory disease may occur less frequently • Oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus. If you want more information about birth control pills, ask your doctor or pharmacist. They have a more technical leaflet called the "Physician Insert," which you may wish to read. Remembering to take tablets according to schedule is stressed because of its importance in providing you the greatest degree of protection. MISSED MENSTRUAL PERIODS FOR BOTH DOSAGE REGIMENS At times there may be no menstrual period after a cycle of pills. Therefore, if you miss one menstrual period but have taken the pills exactly as you were supposed to , continue as usual into the next cycle. If you have not taken the pills correctly and miss a menstrual period, you may be pregnant and should stop taking oral contraceptives until your doctor or healthcare provider determines whether or not you are pregnant. Until you can get to your doctor or healthcare provider, use another form of contraception. If two consecutive menstrual periods are missed, you should stop taking pills until it is determined whether or not you are pregnant.

aceptives until your doctor or healthcare provider determines whether or not you are pregnant. Until you can get to your doctor or healthcare provider, use another form of contraception. If two consecutive menstrual periods are missed, you should stop taking pills until it is determined whether or not you are pregnant. Although there does not appear to be any increase in birth defects in newborn babies if you become pregnant while using oral contraceptives, you should discuss the situation with your doctor or healthcare provider. Periodic Examination Your doctor or healthcare provider will take a complete medical and family history before prescribing oral contraceptives. At that time and about once a year thereafter, he or she will generally examine your blood pressure, breasts, abdomen, and pelvic organs (including a Papanicolaou smear, i.e., test for cancer). Keep this and all drugs out of the reach of children. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep out of the reach of children. Protect from moisture. Trademarks are the property of their respective owners. Distributed by: Glenmark Pharmaceuticals Inc., USA Elmwood Park, NJ 07407 Questions? 1 (888) 721-7115 www.glenmarkpharma-us.com May 2025 blister2 logo1

<table width="100%"><col width="98%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke.</content></paragraph></td></tr></tbody></table> <table width="100%"><col width="98%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke.</content></paragraph></td></tr></tbody></table>

of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke.</content></paragraph></td></tr></tbody></table> <table width="100%"><col width="39%"/><col width="10%"/><col width="10%"/><col width="10%"/><col width="10%"/><col width="10%"/><col width="10%"/><tbody><tr><td align="center" colspan="7" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN BY FERTILITY CONTROL METHOD ACCORDING TO AGE</content></paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Method of control and outcome</content></paragraph></td><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">15 to 19</content></paragraph></td><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">20 to 24</content></paragraph></td><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">25 to 29</content></paragraph></td><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">30 to 34</content></paragraph></td><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">35 to 39</content></paragraph></td><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">40 to 44</content></paragraph></td></tr><tr><td valign="top"><paragraph>No fertility control methods*</paragraph></td><td align="center" valign="top"><paragraph>7</paragraph></td><td align="center" valign="top"><paragraph>7.4</paragraph></td><td align="center" valign="top"><paragraph>9.1</paragraph></td><td align="center" valign="top"><paragraph>14.8</paragraph></td><td align="center" valign="top"><paragraph>25.7</paragraph></td><td align="center" valign="top"><paragraph>28.2</paragraph></td></tr><tr><td valign="top"><paragraph>Oral contraceptives non-smoker**</paragraph></td><td align="center" valign="top"><paragraph>0.3</paragraph></td><td align="center" valign="top"><paragraph>0.5</paragraph></td><td align="center" valign="top"><paragraph>0.9</paragraph></td><td align="center" valign="top"><paragraph>1.9</paragraph></td><td align="center" valign="top"><paragraph>13.8</paragraph></td><td align="center" valign="top"><paragraph>31.6</paragraph></td></tr><tr><td valign="top"><paragraph>Oral contraceptives smoker**</paragraph></td><td align="center" valign="top"><paragraph>2.2</paragraph></td><td align="center" valign="top"><paragraph>3.4</paragraph></td><td align="center" valign="top"><paragraph>6.6</paragraph></td><td align="center" valign="top"><paragraph>13.5</paragraph></td><td align="center" valign="top"><paragraph>51.1</paragraph></td><td align="center" valign="top"><paragraph>117.2</paragraph></td></tr><tr><td valign="top"><paragraph>IUD**</paragraph></td><td align="center" valign="top"><paragraph>0.8</paragraph></td><td align="center" valign="top"><paragraph>0.8</paragraph></td><td align="center" valign="top"><paragraph>1</paragraph></td><td align="center" valign="top"><paragraph>1</paragraph></td><td align="center" valign="top"><paragraph>1.4</paragraph></td><td align="center" valign="top"><paragraph>1.4</paragraph></td></tr><tr><td valign="top"><paragraph>Condom*</paragraph></td><td align="center" valign="top"><paragraph>1.1</paragraph></td><td align="center" valign="top"><paragraph>1.6</paragraph></td><td align="center" valign="top"><paragraph>0.7</paragraph></td><td align="center" valign="top"><paragraph>0.2</paragraph></td><td align="center" valign="top"><paragraph>0.3</paragraph></td><td align="center" valign="top"><paragr

aragraph>1.1</paragraph></td><td align="center" valign="top"><paragraph>1.6</paragraph></td><td align="center" valign="top"><paragraph>0.7</paragraph></td><td align="center" valign="top"><paragraph>0.2</paragraph></td><td align="center" valign="top"><paragraph>0.3</paragraph></td><td align="center" valign="top"><paragr aph>0.4</paragraph></td></tr><tr><td valign="top"><paragraph>Diaphragm/spermicide*</paragraph></td><td align="center" valign="top"><paragraph>1.9</paragraph></td><td align="center" valign="top"><paragraph>1.2</paragraph></td><td align="center" valign="top"><paragraph>1.2</paragraph></td><td align="center" valign="top"><paragraph>1.3</paragraph></td><td align="center" valign="top"><paragraph>2.2</paragraph></td><td align="center" valign="top"><paragraph>2.8</paragraph></td></tr><tr><td valign="top"><paragraph>Periodic abstinence*</paragraph></td><td align="center" valign="top"><paragraph>2.5</paragraph></td><td align="center" valign="top"><paragraph>1.6</paragraph></td><td align="center" valign="top"><paragraph>1.6</paragraph></td><td align="center" valign="top"><paragraph>1.7</paragraph></td><td align="center" valign="top"><paragraph>2.9</paragraph></td><td align="center" valign="top"><paragraph>3.6</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/></tr><tr><td colspan="7" styleCode="Botrule " valign="top"><paragraph>*Deaths are birth related.</paragraph><paragraph>**Deaths are method related.</paragraph></td></tr></tbody></table>

Hailey ® 1.5/30 (Each light green to green tablet contains 1.5 mg norethindrone acetate, USP and 30 mcg ethinyl estradiol, USP). PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (PATIENT PACKAGE INSERT BRIEF SUMMARY and DETAILED PATIENT PACKAGE INSERT). • Counsel patients that cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs (see BOXED WARNING and CONTRAINDICATIONS ). • Counsel patients that the increased risk of venous thromboembolism compared to non-users of CHCs is greatest after initially starting a CHC or restarting (following a 4-week or greater interruption in intake) the same or a different CHC (see WARNINGS ). • Counsel patients that this product does not protect against HIV-infection (AIDS) and other sexually transmitted infections. • Counsel patients to take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event pills are missed (see DOSAGE AND ADMINISTRATION ). • Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs (see PRECAUTIONS ). • Counsel patients who are breastfeeding or who desire to breastfeed that COCs may reduce breast milk production. This is less likely to occur if breastfeeding is well established (see PRECAUTIONS ). • Counsel any patient who starts Hailey 1.5/30 postpartum, and who has not yet had a period, to use an additional method of contraception until she has taken a light green to green tablet for 7 consecutive days (see DOSAGE AND ADMINISTRATION ). • Counsel patients that amenorrhea may occur. Pregnancy should be considered in the event of amenorrhea, and should be ruled out if amenorrhea is associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness (see WARNINGS ). • Counsel patients with a history of depression that depression may reoccur. Women should contact their healthcare provider if depression occurs (see WARNINGS ).

orrhea, and should be ruled out if amenorrhea is associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness (see WARNINGS ). • Counsel patients with a history of depression that depression may reoccur. Women should contact their healthcare provider if depression occurs (see WARNINGS ). NON-CONTRACEPTIVE HEALTH BENEFITS The following non-contraceptive health benefits related to the use of oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol (76 to 81). Effects on menses: • Increased menstrual cycle regularity • Decreased blood loss and decreased incidence of iron deficiency anemia • Decreased incidence of dysmenorrhea Effects related to inhibition of ovulation: • Decreased incidence of functional ovarian cysts • Decreased incidence of ectopic pregnancies Effects from long-term use: • Decreased incidence of fibroadenomas and fibrocystic disease of the breast • Decreased incidence of acute pelvic inflammatory disease • Decreased incidence of endometrial cancer • Decreased incidence of ovarian cancer

of functional ovarian cysts • Decreased incidence of ectopic pregnancies Effects from long-term use: • Decreased incidence of fibroadenomas and fibrocystic disease of the breast • Decreased incidence of acute pelvic inflammatory disease • Decreased incidence of endometrial cancer • Decreased incidence of ovarian cancer BRIEF SUMMARY PATIENT PACKAGE INSERT This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted infections. Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. Oral contraceptives, also known as “birth control pills” or “the pill,” are taken to prevent pregnancy and, when taken correctly, have a failure rate of about 1% per year when used without missing any pills. The typical failure rate of large numbers of pill users is less than 3% per year when women who miss pills are included. For most women oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably increases the chances of pregnancy. For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be life-threatening or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you: • Smoke • Have high blood pressure, diabetes, high cholesterol • Have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast, jaundice, or malignant or benign liver tumors. You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding. Most side effects of the pill are not serious. The most common side effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea, vomiting, and breakthrough bleeding may subside within the first three months of use. The serious side effects of the pill occur very infrequently, especially if you are in good health and are young. However, you should know that the following medical conditions have been associated with or made worse by the pill: 1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences. 2. Liver tumors, which may rupture and cause severe bleeding. A possible but not definite association has been found with the pill and liver cancer. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer. 3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped. The symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. Notify your doctor or healthcare provider if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics, may decrease oral contraceptive effectiveness. There may be slight increases in the risk of breast cancer among current users of hormonal birth control pills with longer duration of use of 8 years or more.

while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics, may decrease oral contraceptive effectiveness. There may be slight increases in the risk of breast cancer among current users of hormonal birth control pills with longer duration of use of 8 years or more. Some studies have found an increase in the risk of developing cancer of the cervix in women taking the pill, but this finding may be related to differences in sexual behavior or other factors not related to use of the pill. Taking the pill provides some important non-contraceptive benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus. Be sure to discuss any medical condition you may have with your healthcare provider. Your healthcare provider will take a medical and family history and examine you before prescribing oral contraceptives. The physical examination may be delayed to another time if you request it and your healthcare provider believes that it is a good medical practice to postpone it. You should be reexamined at least once a year while taking oral contraceptives. The detailed patient information leaflet gives you further information which you should read and discuss with your healthcare provider. This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted infections such as Chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B and syphilis. INSTRUCTIONS TO PATIENT TABLET DISPENSER The Hailey 1.5/30 tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in three rows of seven tablets each with the days of the week appearing above the first row of tablets. If your TABLET DISPENSER contains: You are taking: 21 light green to green tablets Hailey 1.5/30 Each light green to green tablet contains 1.5 mg norethindrone acetate and 30 mcg ethinyl estradiol. DIRECTIONS To remove a tablet, press down on it with your thumb or finger. The tablet will drop through the back of the tablet dispenser. Do not press with your thumbnail, fingernail, or any other sharp object. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH, DURING THE FIRST 1 TO 3 PACKS OF PILLS. If you do have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn’t go away, check with your doctor or clinic. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your birth control pills may not work as well. Use a back-up birth control method (such as condoms or foam) until you check with your doctor or clinic. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or clinic about how to make pill-taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or clinic.

ntil you check with your doctor or clinic. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or clinic about how to make pill-taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or clinic. BEFORE YOU START TAKING YOUR PILLS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK TO SEE IF IT HAS 21 PILLS: The 21-Day pill pack has 21 “active” light green to green pills (with hormones) to take for 3 weeks, followed by 1 week without pills. 3. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills (follow the arrows), and 3) the week numbers as shown in the following pictures: Hailey 1.5/30 will contain ALL LIGHT GREEN TO GREEN PILLS. 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as condoms or foam) to use as a back-up in case you miss pills. An EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. Decide with your doctor or clinic which is the best day for you. Pick a time of day which will be easy to remember. DAY-1 START: 1. Pick the day label strip that starts with the first day of your period. (This is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins.) 2. Place this day label strip on the tablet dispenser over the area that has the days of the week (starting with Sunday) printed on the plastic. 3. Take the first “active” light green to green pill of the first pack during the first 24 hours of your period. 4. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. SUNDAY START: 1. Take the first “active” light green to green pill of the first pack on the Sunday after your period starts , even if you are still bleeding. If your period begins on Sunday, start the pack that same day. 2. Use another method of birth control as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Condoms or foam are good back-up methods of birth control. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: 21 pills: Wait 7 days to start the next pack. You will probably have your period during that week. Be sure that no more than 7 days pass between 21 day packs. WHAT TO DO IF YOU MISS PILLS If you MISS 1 light green to green “active” pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 light green to green “active” pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or foam) as a back-up method of birth control until you have taken a light green to green “active” pill every day for 7 days. If you MISS 2 light green to green “active” pills in a row in THE 3rd WEEK: 1. If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday.

have taken a light green to green “active” pill every day for 7 days. If you MISS 2 light green to green “active” pills in a row in THE 3rd WEEK: 1. If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. 3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or foam) as a back-up method of birth control until you have taken a light green to green “active” pill every day for 7 days. If you MISS 3 OR MORE light green to green “active” pills in a row (during the first 3 weeks): 1. If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. 3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or foam) as a back-up method of birth control until you have taken a light green to green “active” pill every day for 7 days. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE LIGHT GREEN TO GREEN “ACTIVE” PILL EACH DAY until you can reach your doctor or clinic. Based on his or her assessment of your medical needs, your doctor or healthcare provider has prescribed this drug for you. Do not give this drug to anyone else. Keep this and all drugs out of the reach of children. Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. blister1

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (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, including Hailey 1.5/30, are contraindicated in women who are over 35 years of age and smoke (see CONTRAINDICATIONS and WARNINGS ). Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke.

DESCRIPTION Hailey ® 1.5/30 (norethindrone acetate and ethinyl estradiol tablets USP) is a progestogen-estrogen combinations. Hailey 1.5/30 (norethindrone acetate and ethinyl estradiol tablets USP) provides a continuous dosage regimen consisting of 21 light green to green oral contraceptive tablets. Each light green to green tablet, for oral administration, contains 1.5 mg norethindrone acetate, USP [(17α)-17-(acetyloxy)-19-norpregn-4-en-20-yn-3-one] and 30 mcg ethinyl estradiol, USP [19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol]. The tablets also contain the following inactive ingredients: acacia, corn starch, D&C Yellow #10, FD&C Blue #1, FD&C Yellow #6, lactose monohydrate, magnesium stearate, sucrose, and talc. The structural formulas are as follows: Norethindrone Acetate, USP Ethinyl Estradiol, USP norethindrone eestructure

CLINICAL PHARMACOLOGY Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation). Pharmacokinetics The pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets have not been characterized; however, the following pharmacokinetic information regarding norethindrone acetate and ethinyl estradiol is taken from the literature. Absorption Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, since the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone (1). Norethindrone acetate and ethinyl estradiol are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol (1 - 3). Distribution Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg (1 - 3). Plasma protein binding of both steroids is extensive (greater than 95%); norethindrone binds to both albumin and sex hormone binding globulin, whereas ethinyl estradiol binds only to albumin (4). Metabolism Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites (5). A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation (6). Excretion Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites (5,6). Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg) (1 - 3). Special Population Race: The effect of race on the disposition of norethindrone acetate and ethinyl estradiol tablets has not been evaluated. Renal Insufficiency The effect of renal disease on the disposition of norethindrone acetate and ethinyl estradiol tablets has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function. Hepatic Insufficiency The effect of hepatic disease on the disposition of norethindrone acetate and ethinyl estradiol tablets has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function. Drug-Drug Interactions Numerous drug-drug interactions have been reported for oral contraceptives.

INDICATIONS AND USAGE Hailey 1.5/30 is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception. Oral contraceptives are highly effective. Table 1 lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates. TABLE 1 LOWEST EXPECTED AND TYPICAL FAILURE RATES DURING THE FIRST YEAR OF CONTINUOUS USE OF A METHOD % Of Women Experiencing an Unintended Pregnancy in the First Year of Continuous Use Method Lowest Expected* Typical** (No contraception) (85) (85) Oral contraceptives Combined progestin only 0.1 0.5 3 N/A*** N/A*** Diaphragm with spermicidal cream or jelly 6 20 Spermicides alone (foam, creams, gels, vaginal suppositories, and vaginal film) 6 26 Vaginal Sponge nulliparous parous 9 20 20 40 Implant 0.05 0.05 Injection: depot medroxyprogesterone acetate 0.3 0.3 IUD progesterone T copper T 380A LNg 20 1.5 0.6 0.1 2 0.8 0.1 Condom without spermicides female male 5 3 21 14 Cervical Cap with spermicidal cream or jelly nulliparous parous 9 26 20 40 Periodic abstinence (all methods) 1 to 9 25 Withdrawal 4 19 Female sterilization 0.5 0.5 Male sterilization 0.1 0.15 Adapted from RA Hatcher et al, Reference 7. *The authors' best guess of the percentage of women expected to experience an accidental pregnancy among couples who initiate a method (not necessarily for the first time) and who use it consistently and correctly during the first year if they do not stop for any other reason. **This term represents “typical” couples who initiate use of a method (not necessarily for the first time), who experience an accidental pregnancy during the first year if they do not stop use for any other reason. ***N/A-Data not available.

<table width="100%"><col width="47%"/><col width="24%"/><col width="27%"/><tbody><tr><td align="center" colspan="3" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">TABLE 1</content></paragraph><paragraph><content styleCode="bold">LOWEST EXPECTED AND TYPICAL FAILURE RATES DURING THE FIRST YEAR</content></paragraph><paragraph><content styleCode="bold">OF CONTINUOUS USE OF A METHOD</content></paragraph></td></tr><tr><td align="center" colspan="3" styleCode="Lrule Botrule " valign="top"><paragraph>% Of Women Experiencing an Unintended Pregnancy in the First Year of Continuous Use</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Method</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>Lowest Expected*</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>Typical**</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>(No contraception)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(85)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(85)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Oral contraceptives Combined progestin only</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 0.1 0.5</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>3 N/A*** N/A***</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Diaphragm with spermicidal cream or jelly</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 6</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 20</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Spermicides alone (foam, creams, gels, vaginal suppositories, and vaginal film)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 6</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 26</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Vaginal Sponge nulliparous parous</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 9 20</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 20 40</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Implant</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>0.05</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>0.05</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Injection: depot medroxyprogesterone acetate</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 0.3</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 0.3</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>IUD progesterone T copper T 380A LNg 20</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 1.5 0.6 0.1</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 2 0.8 0.1</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Condom without spermicides female male </paragraph></td><td align="center" styleCode="

de="Lrule Botrule " valign="top"><paragraph> 1.5 0.6 0.1</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 2 0.8 0.1</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Condom without spermicides female male </paragraph></td><td align="center" styleCode=" Lrule Botrule " valign="top"><paragraph> 5 3</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 21 14</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Cervical Cap with spermicidal cream or jelly nulliparous parous</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 9 26</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> 20 40</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Periodic abstinence (all methods)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>1 to 9</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>25</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Withdrawal</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>19</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Female sterilization</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>0.5</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>0.5</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Male sterilization</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>0.1</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>0.15</paragraph></td></tr><tr><td colspan="3" styleCode="Botrule Lrule " valign="top"><paragraph>Adapted from RA Hatcher et al, Reference 7.</paragraph></td></tr></tbody></table>

WARNINGS The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity, and diabetes. Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined. Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from References 8 and 9 with the author’s permission). For further information, the reader is referred to a text on epidemiological methods. 1. Thromboembolic Disorders and Other Vascular Problems a. Myocardial infarction An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six (10 - 16). The risk is very low under the age of 30. Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases (17). Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 (Table II) among women who use oral contraceptives. Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity (19). In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism (20 - 24). Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS ). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. table2 b.

ism (20 - 24). Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS ). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. table2 b. Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease (9, 10, 25 - 30). Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization (31). The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped (8). A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives (15,32). The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions (15,32). If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four to six weeks after delivery in women who elect not to breastfeed. c. Cerebrovascular disease Oral contraceptives 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 (greater than 35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes (33 - 35). In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension (36). The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension (36). The attributable risk is also greater in older women (9). d. Dose-related risk of vascular disease from oral contraceptives A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease (37 - 39). A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents (20 - 22). A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestin and the nature of the progestin used in the contraceptives. The amount and activity of both hormones should be considered in the choice of an oral contraceptive. Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics.

acceptable means of contraception. Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective. TABLE III ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control and outcome 15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44 No fertility control methods 7 7.4 9.1 14.8 25.7 28.2 Oral contraceptives non-smoker** 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives smoker** 2.2 3.4 6.6 13.5 51.1 117.2 IUD** 0.8 0.8 1 1 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 *Deaths are birth related. **Deaths are method related Adapted from H.W. Ory, Reference 41. 3. Malignant Neoplasms Breast Cancer Norethindrone acetate and ethinyl estradiol tablets are contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive (see CONTRAINDICATIONS ). 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 ADVERSE REACTIONS , Postmarketing Experience). Cervical Cancer Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women (42-45). However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. 4. Hepatic Neoplasia Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use (46). Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage (47,48). Studies from Britain have shown an increased risk of developing hepatocellular carcinoma (49 - 51) in long-term (greater than 8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S., and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. 5. 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 norethindrone acetate and ethinyl estradiol tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see CONTRAINDICATIONS ). Norethindrone acetate and ethinyl estradiol tablets can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen. 6. Ocular Lesions There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives.

asabuvir (see CONTRAINDICATIONS ). Norethindrone acetate and ethinyl estradiol tablets can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen. 6. Ocular Lesions There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. 7. Oral Contraceptive Use Before and During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy (52 to 54). Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned (52,53,55,56), when taken inadvertently during early pregnancy. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed. 8. Gallbladder Disease Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens (57,58). More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal (59 to 61). The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens. 9. Carbohydrate and Lipid Metabolic Effects Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users (23). Oral contraceptives containing greater than 75 mcg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance (62). Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents (23,63). However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose (64). Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives. A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1a. and 1d . ), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users. 10. Elevated Blood Pressure An increase in blood pressure has been reported in women taking oral contraceptives (65) and this increase is more likely in older oral contraceptive users (66) and with continued use (65). Data from the Royal College of General Practitioners (18) and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens. Women with a history of hypertension or hypertension-related diseases or renal disease (67) should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued.

th a history of hypertension or hypertension-related diseases or renal disease (67) should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives (66), and there is no difference in the occurrence of hypertension among ever and never users (65,67,68). 11. Headache The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. 12. Bleeding Irregularities Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Non-hormonal causes should be considered, and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent. 13. Hereditary Angioedema In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 14. Depression Carefully observe women with a history of depression and discontinue Hailey 1.5/30 if depression recurs to a serious degree.

<table width="100%"><col width="98%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/></tr></tbody></table> <table width="100%"><col width="45%"/><col width="9%"/><col width="9%"/><col width="9%"/><col width="9%"/><col width="9%"/><col width="9%"/><thead><tr><th align="center" colspan="7" styleCode="Botrule Toprule " valign="top"><content styleCode="bold">TABLE III</content> <content styleCode="bold">ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS</content> <content styleCode="bold">ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE</content> <content styleCode="bold">WOMEN BY FERTILITY CONTROL METHOD ACCORDING TO AGE</content></th></tr></thead><tbody><tr><td styleCode="Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Method of control and outcome</content></paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph><content styleCode="bold">15 to 19</content></paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph><content styleCode="bold">20 to 24</content></paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph><content styleCode="bold">25 to 29</content></paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph><content styleCode="bold">30 to 34</content></paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph><content styleCode="bold">35 to 39</content></paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph><content styleCode="bold">40 to 44</content></paragraph></td></tr><tr><td valign="top"><paragraph>No fertility control methods</paragraph></td><td valign="top"><paragraph>7</paragraph></td><td valign="top"><paragraph>7.4</paragraph></td><td valign="top"><paragraph>9.1</paragraph></td><td valign="top"><paragraph>14.8</paragraph></td><td valign="top"><paragraph>25.7</paragraph></td><td valign="top"><paragraph>28.2</paragraph></td></tr><tr><td valign="top"><paragraph>Oral contraceptives non-smoker**</paragraph></td><td valign="top"><paragraph>0.3</paragraph></td><td valign="top"><paragraph>0.5</paragraph></td><td valign="top"><paragraph>0.9</paragraph></td><td valign="top"><paragraph>1.9</paragraph></td><td valign="top"><paragraph>13.8</paragraph></td><td valign="top"><paragraph>31.6</paragraph></td></tr><tr><td valign="top"><paragraph>Oral contraceptives smoker**</paragraph></td><td valign="top"><paragraph>2.2</paragraph></td><td valign="top"><paragraph>3.4</paragraph></td><td valign="top"><paragraph>6.6</paragraph></td><td valign="top"><paragraph>13.5</paragraph></td><td valign="top"><paragraph>51.1</paragraph></td><td valign="top"><paragraph>117.2</paragraph></td></tr><tr><td valign="top"><paragraph>IUD**</paragraph></td><td valign="top"><paragraph>0.8</paragraph></td><td valign="top"><paragraph>0.8</paragraph></td><td valign="top"><paragraph>1</paragraph></td><td valign="top"><paragraph>1</paragraph></td><td valign="top"><paragraph>1.4</paragraph></td><td valign="top"><paragraph>1.4</paragraph></td></tr><tr><td valign="top"><paragraph>Condom*</paragraph></td><td valign="top"><paragraph>1.1</paragraph></td><td valign="top"><paragraph>1.6</paragraph></td><td valign="top"><paragraph>0.7</paragraph></td><td valign="top"><paragraph>0.2</paragraph></td><td valign="top"><paragraph>0.3</paragraph></td><td valign="top"><paragraph>0.4</paragraph></td></tr><tr><td valign="top"><paragraph>Diaphragm/spermicide*</paragraph></td><td valign="top"><paragraph>1.9</paragraph></td><td valign="top"><paragraph>1.2</paragraph></td><td valign="top"><paragraph>1.2</paragraph></td><td valign="top"><paragraph>1.3</paragraph></td>

</td><td valign="top"><paragraph>0.4</paragraph></td></tr><tr><td valign="top"><paragraph>Diaphragm/spermicide*</paragraph></td><td valign="top"><paragraph>1.9</paragraph></td><td valign="top"><paragraph>1.2</paragraph></td><td valign="top"><paragraph>1.2</paragraph></td><td valign="top"><paragraph>1.3</paragraph></td> <td valign="top"><paragraph>2.2</paragraph></td><td valign="top"><paragraph>2.8</paragraph></td></tr><tr><td valign="top"><paragraph>Periodic abstinence*</paragraph></td><td valign="top"><paragraph>2.5</paragraph></td><td valign="top"><paragraph>1.6</paragraph></td><td valign="top"><paragraph>1.6</paragraph></td><td valign="top"><paragraph>1.7</paragraph></td><td valign="top"><paragraph>2.9</paragraph></td><td valign="top"><paragraph>3.6</paragraph></td></tr><tr><td colspan="7" valign="top"><paragraph>*Deaths are birth related.</paragraph><paragraph>**Deaths are method related</paragraph></td></tr><tr><td colspan="7" styleCode="Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Adapted from H.W. Ory, Reference 41.</item></list></td></tr></tbody></table>

PRECAUTIONS 1. Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted infections. 2. Physical Examination and Follow-Up It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. 3. Lipid Disorders Women who are being treated for hyperlipidemia should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. 4. Liver Function If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function. 5. Fluid Retention Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. 6. Contact Lenses Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. 7. Drug Interactions Effects of Other Drugs on Oral Contraceptives (69) Rifampin: Metabolism of both norethindrone and ethinyl estradiol is increased by rifampin. A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin. Anticonvulsants: Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine, have been shown to increase the metabolism of ethinyl estradiol and/or norethindrone, which could result in a reduction in contraceptive effectiveness. Troglitazone: Administration of troglitazone with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both by approximately 30%, which could result in a reduction in contraceptive effectiveness. Antibiotics: Pregnancy while taking oral contraceptives has been reported when the oral contraceptives were administered with antimicrobials such as ampicillin, tetracycline, and griseofulvin. However, clinical pharmacokinetic studies have not demonstrated any consistent effect of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids. Atorvastatin: Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively. Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Co-administration of Hailey 1.5/30 with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations (see WARNINGS , RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT ).

bination Therapy – Liver Enzyme Elevation Co-administration of Hailey 1.5/30 with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations (see WARNINGS , RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT ). Co-administration of Hailey 1.5/30 and glecaprevir/pibrentasvir is not recommended due to potential for ALT elevations. Other: Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding has been suggested with phenylbutazone. Effects of Oral Contraceptives on Other Drugs Oral contraceptive combinations containing ethinyl estradiol may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. In addition, oral contraceptives may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with oral contraceptives. 8. Interactions With Laboratory Tests Certain endocrine and liver function tests and blood components may be affected by oral contraceptives: a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability. b. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T 4 by column or by radioimmunoassay. Free T 3 resin uptake is decreased, reflecting the elevated TBG; free T 4 concentration is unaltered. c. Other binding proteins may be elevated in serum. d. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged. e. Triglycerides may be increased. f. Glucose tolerance may be decreased. g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives. 9. Carcinogenesis See WARNINGS section. 10. Pregnancy Discontinue Hailey 1.5/30 if pregnancy occurs because there is no reason to use COCs in pregnancy. See WARNINGS section. 11. Lactation Small amounts of oral contraceptive steroids have been identified in human milk, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child. 12. Pediatric Use Safety and efficacy of norethindrone acetate and ethinyl estradiol tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.

ADVERSE REACTIONS An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section): • Thrombophlebitis • Arterial thromboembolism • Pulmonary embolism • Myocardial infarction • Cerebral hemorrhage • Cerebral thrombosis • Hypertension • Gallbladder disease • Hepatic adenomas or benign liver tumors • Post Marketing 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 to 1.12 (Figure 1) (70-74). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 1) (70, 73, 75). 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 to 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 to 10 years of COC use. FIGURE 1: 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. There is evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed: • Mesenteric thrombosis • Retinal thrombosis The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related: • Nausea • Vomiting • Gastrointestinal symptoms (such as abdominal cramps and bloating) • Breakthrough bleeding • Spotting • Change in menstrual flow • Amenorrhea • Temporary infertility after discontinuation of treatment • Edema • Melasma which may persist • Breast changes: tenderness, enlargement, secretion • Change in weight (increase or decrease) • Change in cervical erosion and secretion • Diminution in lactation when given immediately postpartum • Cholestatic jaundice • Migraine • Rash (allergic) • Depression • Reduced tolerance to carbohydrates • Vaginal candidiasis • Change in corneal curvature (steepening) • Intolerance to contact lenses The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted: • Pre-menstrual syndrome • Cataracts • Changes in appetite • Cystitis-like syndrome • Headache • Nervousness • Dizziness • Hirsutism • Loss of scalp hair • Erythema multiforme • Erythema nodosum • Hemorrhagic eruption • Vaginitis • Porphyria • Impaired renal function • Hemolytic uremic syndrome • Budd-Chiari syndrome • Acne • Changes in libido • Colitis figure1

DOSAGE AND ADMINISTRATION The tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in three rows of seven tablets each, with the days of the week appearing on the tablet dispenser above the first row of tablets. Note: Each tablet dispenser has been preprinted with the days of the week, starting with Sunday, to facilitate a Sunday-Start regimen. Six different day label strips have been provided with the Detailed Patient & Brief Summary Patient Package Insert in order to accommodate a Day-1 Start regimen. If the patient is using the Day-1 Start regimen, she should place the self-adhesive day label strip that corresponds to her starting day over the preprinted days. Important: The patient should be instructed to use an additional method of protection until after the first week of administration in the initial cycle when utilizing the Sunday-Start regimen. The possibility of ovulation and conception prior to initiation of use should be considered. Dosage and Administration for 21-Day Dosage Regimen To achieve maximum contraceptive effectiveness, Hailey 1.5/30 must be taken exactly as directed and at intervals not exceeding 24 hours. Hailey 1.5/30 provides the patient with a convenient tablet schedule of “3 weeks on-1 week off”. Two dosage regimens are described, one of which may be more convenient or suitable than the other for an individual patient. For the initial cycle of therapy, the patient begins her tablets according to the Day-1 Start or Sunday-Start regimen. With either regimen, the patient takes one tablet daily for 21 consecutive days followed by one week of no tablets. A. Sunday-Start Regimen: The patient begins taking tablets from the top row on the first Sunday after menstrual flow begins. When menstrual flow begins on Sunday, the first tablet is taken on the same day. The last tablet in the dispenser will then be taken on a Saturday, followed by no tablets for a week (7 days). For all subsequent cycles, the patient then begins a new 21-tablet regimen on the eighth day, Sunday, after taking her last tablet. Following this regimen, of 21 days on-7 days off, the patient will start all subsequent cycles on a Sunday. B. Day-1 Regimen: The first day of menstrual flow is Day 1. The patient places the self-adhesive day label strip that corresponds to her starting day over the preprinted days on the tablet dispenser. She starts taking one tablet daily, beginning with the first tablet in the top row. The patient completes her 21-tablet regimen when she has taken the last tablet in the tablet dispenser. She will then take no tablets for a week (7 days). For all subsequent cycles, the patient begins a new 21-tablet regimen on the eighth day after taking her last tablet, again starting with the first tablet in the top row after placing the appropriate day label strip over the preprinted days on the tablet dispenser. Following this regimen of 21 days on-7 days off, the patient will start all subsequent cycles on the same day of the week as the first course. Likewise, the interval of no tablets will always start on the same day of the week. Tablets should be taken regularly with a meal or at bedtime. It should be stressed that efficacy of medication depends on strict adherence to the dosage schedule. Special Notes on Administration Menstruation usually begins two or three days, but may begin as late as the fourth or fifth day, after discontinuing medication.

lets should be taken regularly with a meal or at bedtime. It should be stressed that efficacy of medication depends on strict adherence to the dosage schedule. Special Notes on Administration Menstruation usually begins two or three days, but may begin as late as the fourth or fifth day, after discontinuing medication. If spotting occurs while on the usual regimen of one tablet daily, the patient should continue medication without interruption. If the patient forgets to take one or more tablets, the following is suggested: One tablet is missed • take tablet as soon as remembered • take next tablet at the regular time Two consecutive tablets are missed (week 1 or week 2) • take two tablets as soon as remembered • take two tablets the next day • use another birth control method for seven days following the missed tablets Two consecutive tablets are missed (week 3) Sunday-Start Regimen: • take one tablet daily until Sunday • discard remaining tablets • start new pack of tablets immediately (Sunday) • use another birth control method for seven days following the missed tablets Day-1 Start Regimen: • discard remaining tablets • start new pack of tablets that same day • use another birth control method for seven days following the missed tablets Three (or more) consecutive tablets are missed Sunday-Start Regimen: • take one tablet daily until Sunday • discard remaining tablets • start new pack of tablets immediately (Sunday) • use another birth control method for seven days following the missed tablets Day-1 Start Regimen: • discard remaining tablets • start new pack of tablets that same day • use another birth control method for seven days following the missed tablets The possibility of ovulation occurring increases with each successive day that scheduled tablets are missed. While there is little likelihood of ovulation occurring if only one tablet is missed, the possibility of spotting or bleeding is increased. This is particularly likely to occur if two or more consecutive tablets are missed. In the rare case of bleeding which resembles menstruation, the patient should be advised to discontinue medication and then begin taking tablets from a new tablet dispenser on the next Sunday or the first day (Day 1), depending on her regimen. Persistent bleeding which is not controlled by this method indicates the need for reexamination of the patient, at which time nonfunctional causes should be considered. Use of Oral Contraceptives in the Event of a Missed Menstrual Period 1. If the patient has not adhered to the prescribed dosage regimen, the possibility of pregnancy should be considered after the first missed period and oral contraceptives should be withheld until pregnancy has been ruled out. 2. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen. After several months on treatment, bleeding may be reduced to a point of virtual absence. This reduced flow may occur as a result of medication, in which event it is not indicative of pregnancy.

HOW SUPPLIED Hailey ® 1.5/30 is available in blister cards (dispensers), each containing 21 light green to green tablets. Each tablet contains 1.5 mg of norethindrone acetate, USP and 30 mcg of ethinyl estradiol, USP. The tablets are light green to green, round, flat faced beveled edge, uncoated tablets debossed with ‘Y’ on one side and “12” on the other side. Each blister card is packed in a pouch. Each carton (NDC 68462-504-81) contains 3 pouches. Each pouch (NDC 68462-504-79) contains one blister card (NDC 68462- 504-79). Each blister card contains 21 tablets. Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

REFERENCES 1. Back DJ, Breckenridge AM, Crawford FE, McIver M, Orme ML'E, Rowe PH and Smith E: Kinetics of norethindrone in women II. Single-dose kinetics. Clin Pharmacol Ther 1978; 24:448-453. 2. Hümpel M, Nieuweboer B, Wendt H and Speck U: Investigations of pharmacokinetics of ethinyloestradiol to specific consideration of a possible first-pass effect in women. Contraception 1979; 19:421-432. 3. Back DJ, Breckenridge AM, Crawford FE, MacIver M, OrmeML'E, Rowe PH and Watts MJ.An investigation of the pharmacokinetics of ethynylestradiol in women using radioimmunoassay. Contraception 1979; 20:263-273. 4. Hammond GL, Lähteenmäki PLA, Lähteenmäki P and Luukkainen T. Distribution and percentages of non-protein bound contraceptive steroids in human serum. JSteriod Biochem 1982; 17:375-380. 5. Fotherby K.Pharmacokinetics and metabolism of progestins in humans, in Pharmacology of the contraceptive steroids, Goldzieher JW, Fotherby K (eds), Raven Press, Ltd., New York, 1994; 99-126. 6. Goldzieher JW. Pharmacokinetics and metabolism of ethynyl estrogens, in Pharmacology of the contraceptive steroids, Goldzieher JW, Fotherby K (eds), Raven Press Ltd., New York, 1994; 127-151. 7. Hatcher RA,et al. 1998. Contraceptive Technology, Seventeenth Edition. New York: Irvington Publishers. 8. Stadel, B.V.: Oral contraceptives and cardiovascular disease. (Pt. 1). New England Journal of Medicine ,305:612-618, 1981. 9. Stadel, B.V.: Oral contraceptives and cardiovascular disease. (Pt. 2). New England Journal of Medicine , 305:672-677, 1981. 10. Adam, S.A., and M. Thorogood: Oral contraception and myocardial infarction revisited: The effects of new preparations and prescribing patterns. Brit.J.Obstet. and Gynec. ,88:838-845, 1981. 11. Mann,J.I., and W.H. Inman: Oral contraceptives and death from myocardial infarction. Brit. Med. J. ,2(5965): 245-248, 1975. 12. Mann, J.I., M.P. Vessey, M. Thorogood, and R. Doll: Myocardial infarction in young women with special reference to oral contraceptive practice. Brit. Med. J. ,2(5956):241-245, 1975. 13. Royal College of General Practitioners' Oral Contraception Study: Further analyses of mortality in oral contraceptive users. Lancet ,1:541-546, 1981. 14. Slone, D., S. Shapiro, D.W. Kaufman, L. Rosenberg, O.S. Miettinen, and P.D. Stolley: Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. N.E.J.M. ,305:420-424, 1981. 15. Vessey, M.P.: Female hormones and vascular disease: An epidemiological overview. Brit. J. Fam. Plann. ,6:1-12, 1980. 16. Russell-Briefel, R.G., T.M. Ezzati, R. Fulwood, J.A. Perlman, and R.S. Murphy: Cardiovascular risk status and oral contraceptive use, United States, 1976-80. Preventive Medicine ,15:352-362, 1986. 17. Goldbaum, G.M., J.S. Kendrick, G.C. Hogelin, and E.M. Gentry: The relative impact of smoking and oral contraceptive use on women in the United States. J.A.M.A. ,258:1339-1342, 1987. 18. Layde, P.M., and V. Beral: Further analyses of mortality in oral contraceptive users: Royal College General Practitioners' Oral Contraception Study. (Table 5) Lancet ,1:541-546, 1981. 19. Knopp, R.H.: Arteriosclerosis risk: The roles of oral contraceptives and postmenopausal estrogens. J. of Reprod. Med. ,31(9) (Supplement): 913-921, 1986. 20. Krauss, R.M., S. Roy, D.R. Mishell, J. Casagrande, and M.C. Pike: Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: Differential changes in high-density lipoproteins subclasses. Am. J. Obstet.

raceptives and postmenopausal estrogens. J. of Reprod. Med. ,31(9) (Supplement): 913-921, 1986. 20. Krauss, R.M., S. Roy, D.R. Mishell, J. Casagrande, and M.C. Pike: Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: Differential changes in high-density lipoproteins subclasses. Am. J. Obstet. Gyn. ,145:446-452, 1983. 21. Wahl, P., C. Walden, R. Knopp, J. Hoover, R. Wallace, G. Heiss, and B. Rifkind:Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol. N.E.J.M. ,308:862-867, 1983. 22. Wynn, V., and R. Niththyananthan: The effect of progestin in combined oral contraceptives on serum lipids with special reference to high-density lipoproteins. Am. J. Obstet. and Gyn. ,142:766-771, 1982. 23. Wynn, V., and I. Godsland: Effects of oral contraceptives on carbohydrate metabolism. J. Reprod. Medicine ,31 (9) (Supplement): 892-897, 1986. 24. LaRosa, J.C.: Atherosclerotic risk factors in cardiovascular disease. J. Reprod. Med. , 31(9) (Supplement): 906-912, 1986. 25. Inman, W.H., and M.P. Vessey: Investigations of death from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. Brit. Med. J. ,2(5599): 193-199, 1968. 26. Maguire, M.G., J. Tonascia, P.E. Sartwell, P.D. Stolley, and M.S. Tockman: Increased risk of thrombosis due to oral contraceptives: A further report. Am. J. Epidemiology ,110(2): 188-195, 1979. 27. Pettiti, D.B., J. Wingerd, F. Pellegrin, and S. Ramacharan: Risk of vascular disease in women: Smoking, oral contraceptives, noncontraceptive estrogens, and other factors. J.A.M.A. ,242:1150-1154, 1979. 28. Vessey, M.P., and R. Doll: Investigation of relation between use of oral contraceptives and thromboembolic disease. Brit. Med.J. , 2(5599): 199-205, 1968. 29. Vessey, M.P., and R. Doll: Investigation of relation between use of oral contraceptives and thromboembolic disease: A further report. Brit. Med.J. , 2(5658): 651-657, 1969. 30. Porter, J.B., J.R. Hunter, D.A. Danielson, H. Jick, and A. Stergachis: Oral contraceptives and non-fatal vascular disease: Recent experience. Obstet. and Gyn. ,59(3):299-302, 1982. 31. Vessey, M., R. Doll, R. Peto, B. Johnson, and P. Wiggins: A long-term follow-up study of women using different methods of contraception: An interim report. J. Biosocial. Sci. ,8:375-427, 1976. 32. Royal College of General Practitioners: Oral contraceptives, venous thrombosis, and varicose veins. J. of Royal College of General Practitioners ,28:393-399, 1978. 33. Collaborative Group for the study of stroke in young women: Oral contraception and increased risk of cerebral ischemia or thrombosis. N.E.J.M. ,288:871-878, 1973. 34. Petitti, D.B., and J. Wingerd: Use of oral contraceptives, cigarette smoking, and risk of subarachnoid hemorrhage. Lancet ,2:234-236, 1978. 35. Inman, W.H.: Oral contraceptives and fatal subarachnoid hemorrhage. Brit. Med. J. , 2(6203): 1468-70, 1979. 36. Collaborative Group for the study of stroke in young women: Oral contraceptives and stroke in young women: Associated risk factors. J.A.M.A. ,231:718-722, 1975. 37. Inman,W.H., M.P. Vessey, B. Westerholm, and A. Engelund: Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. Brit.Med. J. ,2:203-209, 1970. 38. Meade, T.W., G. Greenberg, and S.G. Thompson: Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 35-mcg oestrogen preparations. Brit. Med. J. , 280(6224): 1157-1161, 1980. 39. Kay, C.R.: Progestogens and arterial disease: Evidence from the Royal College of General Practitioners' study. Amer. J. Obstet. Gyn. ,142:762-765, 1982. 40. Royal College of General Practitioners: Incidence of arterial disease among oral contraceptive users. J. Coll. Gen. Pract.

ed. J. , 280(6224): 1157-1161, 1980. 39. Kay, C.R.: Progestogens and arterial disease: Evidence from the Royal College of General Practitioners' study. Amer. J. Obstet. Gyn. ,142:762-765, 1982. 40. Royal College of General Practitioners: Incidence of arterial disease among oral contraceptive users. J. Coll. Gen. Pract. ,33:75-82, 1983. 41. Ory,H.W:Mortality associated with fertility and fertility control: 1983. Family Planning Perspectives ,15:50-56, 1983. 42. Ory, H., Z. Naib, S.B. Conger, R.A. Hatcher, and C.W. Tyler: Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ. Am. J. Obstet. Gynec ., 124:573-577, 1976. 43. Vessey, M.P., M. Lawless, K. McPherson, D. Yeates: Neoplasia of the cervix uteri and contraception: A possible adverse effect of the pill. Lancet , 2:930, 1983. 44. Brinton, L.A., G.R. Huggins, H.F. Lehman, K. Malli, D.A. Savitz, E. Trapido, J. Rosenthal, and R. Hoover: Long-term use of oral contraceptives and risk of invasive cervical cancer. Int. J. Cancer , 38:339-344, 1986. 45. WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical cancer and combined oral contraceptives. Brit. Med. J. , 290:961-965, 1985. 46. Rooks, J.B., H.W. Ory, K.G. Ishak, L.T. Strauss, J.R. Greenspan, A.P. Hill, and C.W. Tyler: Epidemiology of hepatocellular adenoma: The role of oral contraceptive use. J.A.M.A., 242:644-648, 1979. 47. Bein, N.N., and H.S. Goldsmith: Recurrent massive hemorrhage from benign hepatic tumors secondary to oral contraceptives. Brit. J. Surg., 64:433-435, 1977. 48. Klatskin, G.: Hepatic tumors: Possible relationship to use of oral contraceptives. Gastroenterology , 73:386-394, 1977. 49. Henderson, B.E., S. Preston-Martin, H.A. Edmondson, R.L. Peters, and M.C. Pike: Hepatocellular carcinoma and oral contraceptives. Brit. J. Cancer, 48:437-440, 1983. 50. Neuberger, J., D. Forman, R. Doll, and R. Williams: Oral contraceptives and hepatocellular carcinoma. Brit. Med. J., 292:1355-1357, 1986. 51. Forman, D., T.J. Vincent, and R. Doll: Cancer of the liver and oral contraceptives. Brit. Med. J. , 292: 1357-1361, 1986. 52. Harlap, S., and J. Eldor: Births following oral contraceptive failures. Obstet. Gynec., 55:447-452, 1980. 53. Savolainen, E., E. Saksela, and L. Saxen: Teratogenic hazards of oral contraceptives analyzed in a national malformation register. Amer. J. Obstet. Gynec., 140:521-524, 1981. 54. Janerich, D.T., J.M. Piper, and D.M. Glebatis: Oral contraceptives and birth defects. Am. J. Epidemiology, 112:73-79, 1980. 55. Ferencz, C., G.M. Matanoski, P.D. Wilson, J.D. Rubin, C.A. Neill, and R. Gutberlet: Maternal hormone therapy and congenital heart disease. Teratology , 21:225-239, 1980. 56. Rothman, K.J., D.C. Fyler, A. Goldbatt, and M.B. Kreidberg: Exogenous hormones and other drug exposures of children with congenital heart disease. Am. J. Epidemiology, 109:433-439, 1979. 57. Boston Collaborative Drug Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease, and breast tumors. Lancet, 1:1399-1404, 1973. 58. Royal College of General Practitioners: Oral Contraceptives and Health . New York, Pittman, 1974, 100p. 59. Layde, P.M., M.P. Vessey, and D. Yeates: Risk of gallbladder disease: A cohort study of young women attending family planning clinics. J. of Epidemiol. and Comm. Health, 36: 274-278, 1982. 60. Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone disease in an Italian adult female population. Am. J. Epidemiol., 119:796-805, 1984. 61. Strom, B.L., R.T. Tamragouri, M.L. Morse, E.L. Lazar, S.L. West, P. D. Stolley, and J.K. Jones: Oral contraceptives and other risk factors for gallbladder disease. Clin. Pharmacol. Ther., 39:335-341, 1986. 62. Wynn, V., P.W.

lstone disease in an Italian adult female population. Am. J. Epidemiol., 119:796-805, 1984. 61. Strom, B.L., R.T. Tamragouri, M.L. Morse, E.L. Lazar, S.L. West, P. D. Stolley, and J.K. Jones: Oral contraceptives and other risk factors for gallbladder disease. Clin. Pharmacol. Ther., 39:335-341, 1986. 62. Wynn, V., P.W. Adams, I.F. Godsland, J. Melrose, R. Niththyananthan, N.W. Oakley, and A. Seedj: Comparison of effects of different combined oral-contraceptive formulations on carbohydrate and lipid metabolism. Lancet , 1:1045-1049, 1979. 63. Wynn, V.: Effect of progesterone and progestins on carbohydrate metabolism. In Progesterone and Progestin. Edited by C.W. Bardin, E. Milgrom, P. Mauvis-Jarvis. New York, Raven Press, pp. 395-410, 1983. 64. Perlman, J.A., R. G. Roussell-Briefel, T.M. Ezzati, and G. Lieberknecht: Oral glucose tolerance and the potency of oral contraceptive progestogens. J. Chronic Dis., 38:857- 864, 1985. 65. Royal College of General Practitioners’ Oral Contraception Study: Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet , 1:624, 1977. 66. Fisch, I.R., and J. Frank: Oral contraceptives and blood pressure. J.A.M.A., 237:2499- 2503, 1977. 67. Laragh, A.J.: Oral contraceptive induced hypertension: Nine years later. Amer. J. Obstet. Gynecol., 126:141-147, 1976. 68. Ramcharan, S., E. Peritz, F.A. Pellegrin, and W.T. Williams: Incidence of hypertension in the Walnut Creek Contraceptive Drug Study cohort. In Pharmacology of Steroid Contraceptive Drugs. Edited by S. Garattini and H.W. Berendes. New York, Raven Press , pp. 277-288, 1977. (Monographs of the Mario Negri Institute for Pharmacological Research, Milan.) 69. Back DJ, Orme ML’E. Drug interactions, in Pharmacology of the contraceptive steroids. Goldzieher JW, Fotherby K (eds), Raven Press, Ltd., New York, 1994, 407-425. 70. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346(26):2025-2032. 71. Dumeaux V, Fournier A, Lund E, Clavel-Chapelon F. Previous oral contraceptive use and breast cancer risk according to hormone replacement therapy use among postmenopausal women. Cancer Causes Control. 2005;16(5):537-544. 72. Dorjgochoo T, Shu XO, Li HL, et al. Use of oral contraceptives, intrauterine devices and tubal sterilization and cancer risk in a large prospective study, from 1996 to 2006. Int J Cancer . 2009;124(10):2442-2449. 73. Hunter DJ, Colditz GA, Hankinson SE, et al. Oral contraceptive use and breast cancer: a prospective study of young women. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2010;19(10):2496-2502. 74. Vessey M, Yeates D. Oral contraceptive use and cancer. Final report from the Oxford-Family Planning Association contraceptive study. Contraception. 2013; 88(6): 678-683. 75. Morch LS, Skovlund CW, Hannaford PC, Iversen L, Fielding S, Lidegaard O. Contemporary Hormonal Contraception and the Risk of Breast Cancer. N Engl J Med. 2017;377(23):2228-2239. 76. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of ovarian cancer. J.A.M.A., 249:1596-1599, 1983. 77. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Combination oral contraceptive use and the risk of endometrial cancer. J.A.M.A., 257:796-800, 1987. 78. Ory, H.W.: Functional ovarian cysts and oral contraceptives: Negative association confirmed surgically. J.A.M.A., 228:68-69, 1974. 79. Ory, H.W., P. Cole, B. Macmahon, and R.

te of Child Health and Human Development: Combination oral contraceptive use and the risk of endometrial cancer. J.A.M.A., 257:796-800, 1987. 78. Ory, H.W.: Functional ovarian cysts and oral contraceptives: Negative association confirmed surgically. J.A.M.A., 228:68-69, 1974. 79. Ory, H.W., P. Cole, B. Macmahon, and R. Hoover: Oral contraceptives and reduced risk of benign breast disease. N.E.J.M., 294:41-422, 1976. 80. Ory, H.W.: The noncontraceptive health benefits from oral contraceptive use. Fam. Plann. Perspectives, 14:182-184, 1982. 81. Ory, H.W., J.D. Forrest, and R. Lincoln: Making Choices: Evaluating the health risks and benefits of birth control methods. New York, The Alan Guttmacher Institute, p.1, 1983. Distributed by: Glenmark Pharmaceuticals Inc., USA Elmwood Park, NJ 07407 Questions? 1 (888) 721-7115 www.glenmarkpharma-us.com June 2025 logo

<table width="100%"><col width="98%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke.</content></paragraph></td></tr></tbody></table> <table width="91.36%"><col width="55%"/><col width="34%"/><tbody><tr><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph>If your TABLET DISPENSER contains:</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>You are taking:</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph> 21 light green to green tablets</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Hailey 1.5/30</paragraph></td></tr></tbody></table>

DETAILED PATIENT PACKAGE INSERT Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted infections. What You Should Know About Oral Contraceptives Any woman who considers using oral contraceptives (the “birth control pill” or “the pill”) should understand the benefits and risks of using this form of birth control. This leaflet will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this leaflet is not a replacement for a careful discussion between you and your healthcare provider. You should discuss the information provided in this leaflet with him or her, both when you first start taking the pill and during your revisits. You should also follow your healthcare provider’s advice with regard to regular check-ups while you are on the pill. EFFECTIVENESS OF ORAL CONTRACEPTIVES Oral contraceptives or “birth control pills” or “the pill” are used to prevent pregnancy and are more effective than other non-surgical methods of birth control. When they are taken correctly, the chance of becoming pregnant is less than 1% (1 pregnancy per 100 women per year of use) when used perfectly, without missing any pills. Typical failure rates are actually 3% per year. The chance of becoming pregnant increases with each missed pill during a menstrual cycle. In comparison, typical failure rates for other methods of birth control during the first year of use are as follows: Implant: <1% Injection: <1% IUD: <1 to 2% Diaphragm with spermicides: 20% Spermicides alone: 26% Vaginal Sponge: 20 to 40% Female sterilization: <1% Male sterilization: <1 % Cervical Cap: 20 to 40% Condom alone (male): 14% Condom alone (female): 21% Periodic abstinence: 25% Withdrawal: 19% No method: 85% WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. Some women should not use the pill. For example, you should not take the pill if you are pregnant or think you may be pregnant. You should also not use the pill if you have any of the following conditions: • A history of heart attack or stroke • Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes • A history of blood clots in the deep veins of your legs • Chest pain (angina pectoris) • Known or suspected breast cancer • Unexplained vaginal bleeding (until a diagnosis is reached by your doctor) • Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill • Liver tumor (benign or cancerous) • Take any Hepatitis C drug combination containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir.

are. The chance of developing liver cancer from using the pill is thus even rarer. 5. Risk of Cancer It is not known if hormonal birth control pills cause breast cancer. Some studies, but not all, suggest that there could be a slight increase in the risk of breast cancer among current users with longer duration of use. If you have breast cancer now, or have had it in the past, do not use hormonal birth control because some breast cancers are sensitive to hormones. Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY All methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table. ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control and outcome 15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44 No fertility control methods* 7 7.4 9.1 14.8 25.7 28.2 Oral contraceptives non-smoker** 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives smoker** 2.2 3.4 6.6 13.5 51.1 117.2 IUD** 0.8 0.8 1 1 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 *Deaths are birth related. **Deaths are method related. In the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7 to 26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death was always lower than that associated with pregnancy for any age group, although over the age of 40, the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy (28/100,000 women) in that age group. The suggestion that women over 40 who don’t smoke should not take oral contraceptives is based on information from older higher dose pills and on less selective use of pills than is practiced today. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of oral contraceptive use by healthy, non-smoking women over 40 years of age may outweigh the possible risks. However, all women, especially older women, are cautioned to use the lowest dose pill that is effective.

ed today. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of oral contraceptive use by healthy, non-smoking women over 40 years of age may outweigh the possible risks. However, all women, especially older women, are cautioned to use the lowest dose pill that is effective. WARNING SIGNALS If any of these adverse effects occur while you are taking oral contraceptives, call your doctor immediately: • Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung) • Pain in the calf (indicating a possible clot in the leg) • Crushing chest pain or heaviness in the chest (indicating a possible heart attack) • Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke) • Sudden partial or complete loss of vision (indicating a possible clot in the eye) • Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your doctor or healthcare provider to show you how to examine your breasts) • Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor) • Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression) • Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light-colored bowel movements (indicating possible liver problems) SIDE EFFECTS OF ORAL CONTRACEPTIVES 1. Vaginal Bleeding Irregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding which is a flow much like a regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate serious problems. It is important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle or lasts for more than a few days, talk to your doctor or healthcare provider. 2. Contact Lenses If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your doctor or healthcare provider. 3. Fluid Retention Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may raise your blood pressure. If you experience fluid retention, contact your doctor or healthcare provider. 4. Melasma A spotty darkening of the skin is possible, particularly of the face. 5. Other Side Effects Other side effects may include change in appetite, headache, nervousness, depression, dizziness, loss of scalp hair, rash, and vaginal infections. If any of these side effects bother you, call your doctor or healthcare provider. GENERAL PRECAUTIONS 1. Missed Periods and Use of Oral Contraceptives Before or During Early Pregnancy There may be times when you may not menstruate regularly after you have completed taking a cycle of pills. If you have taken your pills regularly and miss one menstrual period, continue taking your pills for the next cycle but be sure to inform your healthcare provider before doing so. If you have not taken the pills daily as instructed and missed a menstrual period, or if you missed two consecutive menstrual periods, you may be pregnant. Check with your healthcare provider immediately to determine whether you are pregnant. Do not continue to take oral contraceptives until you are sure you are not pregnant, but continue to use another method of contraception.

ed a menstrual period, or if you missed two consecutive menstrual periods, you may be pregnant. Check with your healthcare provider immediately to determine whether you are pregnant. Do not continue to take oral contraceptives until you are sure you are not pregnant, but continue to use another method of contraception. There is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects, when taken inadvertently during early pregnancy. Previously, a few studies had reported that oral contraceptives might be associated with birth defects, but these studies have not been confirmed. Nevertheless, oral contraceptives or any other drugs should not be used during pregnancy unless clearly necessary and prescribed by your doctor. You should check with your doctor about risks to your unborn child of any medication taken during pregnancy. 2. While Breastfeeding If you are breastfeeding, consult your doctor before starting oral contraceptives. Some of the drug will be passed on to the child in the milk. A few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition, oral contraceptives may decrease the amount and quality of your milk. If possible, do not use oral contraceptives while breastfeeding. You should use another method of contraception since breastfeeding provides only partial protection from becoming pregnant and this partial protection decreases significantly as you breastfeed for longer periods of time. You should consider starting oral contraceptives only after you have weaned your child completely. 3. Laboratory Tests If you are scheduled for any laboratory tests, tell your doctor you are taking birth control pills. Certain blood tests may be affected by birth control pills. 4. Drug Interactions Certain drugs may interact with birth control pills to make them less effective in preventing pregnancy or cause an increase in breakthrough bleeding. Such drugs include rifampin; drugs used for epilepsy such as barbiturates (for example, phenobarbital), carbamazepine, and phenytoin (Dilantin ® is one brand of this drug); troglitazone; phenylbutazone; and possibly certain antibiotics. You may need to use additional contraception when you take drugs which can make oral contraceptives less effective. Birth control pills interact with certain drugs. These drugs include acetaminophen, clofibric acid, cyclosporine, morphine, prednisolone, salicylic acid, temazepam, and theophylline. You should tell your doctor if you are taking any of these medications. 5. This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted infections such as Chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. INSTRUCTIONS TO PATIENT TABLET DISPENSER The Hailey 1.5/30 tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in three rows of seven tablets each, with the days of the week appearing above the first row of tablets. If your TABLET DISPENSER contains: You are taking: 21 light green to green tablets Hailey 1.5/30 Each light green to green tablet contains 1.5 mg norethindrone acetate and 30 mcg ethinyl estradiol. DIRECTIONS To remove a tablet, press down on it with your thumb or finger. The tablet will drop through the back of the tablet dispenser. Do not press with your thumbnail, fingernail, or any other sharp object. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2.

l drop through the back of the tablet dispenser. Do not press with your thumbnail, fingernail, or any other sharp object. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1 TO 3 PACKS OF PILLS. If you do have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn’t go away, check with your doctor or clinic. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your birth control pills may not work as well. Use a back-up birth control method (such as condoms or foam) until you check with your doctor or clinic. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or clinic about how to make pill-taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or clinic. BEFORE YOU START TAKING YOUR PILLS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK TO SEE IF IT HAS 21 PILLS: The 21-Day pill pack has 21 “active” light green to green pills (with hormones) to take for 3 weeks, followed by 1 week without pills. 3. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills (follow the arrows), and 3) the week numbers as shown in the following pictures: Hailey 1.5/30 will contain ALL LIGHT GREEN TO GREEN PILLS . 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as condoms or foam) to use as a back-up in case you miss pills. An EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. Decide with your doctor or clinic which is the best day for you. Pick a time of day which will be easy to remember. DAY-1 START: 1. Pick the day label strip that starts with the first day of your period. (This is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins.) 2. Place this day label strip on the tablet dispenser over the area that has the days of the week (starting with Sunday) printed on the plastic. 3. Take the first “active” light green to green pill of the first pack during the first 24 hours of your period. 4. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. SUNDAY START: 1. Take the first “active” light green to green pill of the first pack on the Sunday after your period starts , even if you are still bleeding. If your period begins on Sunday, start the pack that same day. 2. Use another method of birth control as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Condoms or foam are good back-up methods of birth control. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea).

our first pack until the next Sunday (7 days). Condoms or foam are good back-up methods of birth control. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: 21 pills: Wait 7 days to start the next pack. You will probably have your period during that week. Be sure that no more than 7 days pass between 21-day packs. WHAT TO DO IF YOU MISS PILLS If you MISS 1 light green to green “active” pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 light green to green “active” pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or foam) as a back-up method of birth control until you have taken a light green to green “active” pill every day for 7 days. If you MISS 2 light green to green “active” pills in a row in THE 3rd WEEK: 1. If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. 3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or foam) as a back-up method of birth control until you have taken a light green to green “active” pill every day for 7 days. If you MISS 3 OR MORE light green to green “active” pills in a row (during the first 3 weeks): 1. If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. 3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or foam) as a back-up method of birth control until you have taken a light green to green “active” pill every day for 7 days. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE light green to green “ACTIVE” PILL EACH DAY until you can reach your doctor or clinic. PREGNANCY DUE TO PILL FAILURE The incidence of pill failure resulting in pregnancy is approximately 1% (i.e., one pregnancy per 100 women per year) if taken every day as directed, but more typical failure rates are about 3%. If failure does occur, the risk to the fetus is minimal. PREGNANCY AFTER STOPPING THE PILL There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy.

PILL There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy. There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill. OVERDOSAGE Serious ill effects have not been reported following ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding in females. In case of overdosage, contact your healthcare provider or pharmacist. OTHER INFORMATION Your healthcare provider will take a medical and family history and examine you before prescribing oral contraceptives. The physical examination may be delayed to another time if you request it and your healthcare provider believes that it is a good medical practice to postpone it. You should be reexamined at least once a year. Be sure to inform your healthcare provider if there is a family history of any of the conditions listed previously in this leaflet. Be sure to keep all appointments with your healthcare provider, because this is a time to determine if there are early signs of side effects of oral contraceptive use. Do not use the drug for any condition other than the one for which it was prescribed. This drug has been prescribed specifically for you; do not give it to others who may want birth control pills. HEALTH BENEFITS FROM ORAL CONTRACEPTIVES In addition to preventing pregnancy, use of oral contraceptives may provide certain benefits. They are: • Menstrual cycles may become more regular • Blood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur • Pain or other symptoms during menstruation may be encountered less frequently • Ectopic (tubal) pregnancy may occur less frequently • Noncancerous cysts or lumps in the breast may occur less frequently • Acute pelvic inflammatory disease may occur less frequently • Oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus. If you want more information about birth control pills, ask your doctor or pharmacist. They have a more technical leaflet called the “Physician Insert,” which you may wish to read. Remembering to take tablets according to schedule is stressed because of its importance in providing you the greatest degree of protection. MISSED MENSTRUAL PERIODS FOR BOTH DOSAGE REGIMENS At times there may be no menstrual period after a cycle of pills. Therefore, if you miss one menstrual period but have taken the pills exactly as you were supposed to , continue as usual into the next cycle. If you have not taken the pills correctly and miss a menstrual period, you may be pregnant and should stop taking oral contraceptives until your doctor or healthcare provider determines whether or not you are pregnant. Until you can get to your doctor or healthcare provider, use another form of contraception. If two consecutive menstrual periods are missed, you should stop taking pills until it is determined whether or not you are pregnant. Although there does not appear to be any increase in birth defects in newborn babies if you become pregnant while using oral contraceptives, you should discuss the situation with your doctor or healthcare provider. Periodic Examination Your doctor or healthcare provider will take a complete medical and family history before prescribing oral contraceptives.

ny increase in birth defects in newborn babies if you become pregnant while using oral contraceptives, you should discuss the situation with your doctor or healthcare provider. Periodic Examination Your doctor or healthcare provider will take a complete medical and family history before prescribing oral contraceptives. At that time and about once a year thereafter, he or she will generally examine your blood pressure, breasts, abdomen, and pelvic organs (including a Papanicolaou smear, i.e., test for cancer). Keep this and all drugs out of the reach of children. Rx only Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Distributed by: Glenmark Pharmaceuticals Inc., USA Elmwood Park, NJ 07407 Questions? 1 (888) 721-7115 www.glenmarkpharma-us.com June 2025 Trademarks are the property of their respective owners. blister2 logo1

of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke.</content></paragraph></td></tr></tbody></table> <table width="100%"><col width="38%"/><col width="10%"/><col width="10%"/><col width="10%"/><col width="10%"/><col width="10%"/><col width="11%"/><tbody><tr><td align="center" colspan="7" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS</content></paragraph><paragraph><content styleCode="bold">ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE</content></paragraph><paragraph><content styleCode="bold">WOMEN BY FERTILITY CONTROL METHOD ACCORDING TO AGE</content></paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Method of control and outcome</content></paragraph></td><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">15 to 19</content></paragraph></td><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">20 to 24</content></paragraph></td><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">25 to 29</content></paragraph></td><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">30 to 34</content></paragraph></td><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">35 to 39</content></paragraph></td><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">40 to 44</content></paragraph></td></tr><tr><td valign="top"><paragraph>No fertility control methods*</paragraph></td><td valign="top"><paragraph>7</paragraph></td><td valign="top"><paragraph>7.4</paragraph></td><td valign="top"><paragraph>9.1</paragraph></td><td valign="top"><paragraph>14.8</paragraph></td><td valign="top"><paragraph>25.7</paragraph></td><td valign="top"><paragraph>28.2</paragraph></td></tr><tr><td valign="top"><paragraph>Oral contraceptives non-smoker**</paragraph></td><td valign="top"><paragraph>0.3</paragraph></td><td valign="top"><paragraph>0.5</paragraph></td><td valign="top"><paragraph>0.9</paragraph></td><td valign="top"><paragraph>1.9</paragraph></td><td valign="top"><paragraph>13.8</paragraph></td><td valign="top"><paragraph>31.6</paragraph></td></tr><tr><td valign="top"><paragraph>Oral contraceptives smoker**</paragraph></td><td valign="top"><paragraph>2.2</paragraph></td><td valign="top"><paragraph>3.4</paragraph></td><td valign="top"><paragraph>6.6</paragraph></td><td valign="top"><paragraph>13.5</paragraph></td><td valign="top"><paragraph>51.1</paragraph></td><td valign="top"><paragraph>117.2</paragraph></td></tr><tr><td valign="top"><paragraph>IUD**</paragraph></td><td valign="top"><paragraph>0.8</paragraph></td><td valign="top"><paragraph>0.8</paragraph></td><td valign="top"><paragraph>1</paragraph></td><td valign="top"><paragraph>1</paragraph></td><td valign="top"><paragraph>1.4</paragraph></td><td valign="top"><paragraph>1.4</paragraph></td></tr><tr><td valign="top"><paragraph>Condom*</paragraph></td><td valign="top"><paragraph>1.1</paragraph></td><td valign="top"><paragraph>1.6</paragraph></td><td valign="top"><paragraph>0.7</paragraph></td><td valign="top"><paragraph>0.2</paragraph></td><td valign="top"><paragraph>0.3</paragraph></td><td valign="top"><paragraph>0.4</paragraph></td></tr><tr><td valign="top"><paragraph>Diaphragm/spermicide*</paragraph></td><td valign="top"><paragraph>1.9</paragraph></td><td valign="top"><paragraph>1.2</paragraph></td><td valign="top"><paragraph>1.2</paragraph></td><td valign="top"><paragraph>1.3</paragraph></td><td valign="top"><paragraph>2.2</paragraph>

raph></td></tr><tr><td valign="top"><paragraph>Diaphragm/spermicide*</paragraph></td><td valign="top"><paragraph>1.9</paragraph></td><td valign="top"><paragraph>1.2</paragraph></td><td valign="top"><paragraph>1.2</paragraph></td><td valign="top"><paragraph>1.3</paragraph></td><td valign="top"><paragraph>2.2</paragraph> </td><td valign="top"><paragraph>2.8</paragraph></td></tr><tr><td valign="top"><paragraph>Periodic abstinence*</paragraph></td><td valign="top"><paragraph>2.5</paragraph></td><td valign="top"><paragraph>1.6</paragraph></td><td valign="top"><paragraph>1.6</paragraph></td><td valign="top"><paragraph>1.7</paragraph></td><td valign="top"><paragraph>2.9</paragraph></td><td valign="top"><paragraph>3.6</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>*Deaths are birth related.</paragraph><paragraph>**Deaths are method related.</paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/></tr></tbody></table> <table width="87.6%"><col width="62%"/><col width="24%"/><tbody><tr><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph>If your TABLET DISPENSER contains:</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>You are taking:</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>21 light green to green tablets</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Hailey 1.5/30</paragraph></td></tr></tbody></table>