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WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, and BREAST CANCER 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 a dequate 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 Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo [see Warnings and Precautions (5.1) , and Clinical Studies (14.3) ] . The WHI Memory Study (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 (14.4) ] . 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 (14.3 , 14.4) ] . Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of 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 e strogens 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 Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1) , and Clinical Studies (14.3) ] . The WHIMS estrogen plus progestin ancillary study of the 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 (14.4) ] . 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 (14.3 , 14.4) ] .

younger postmenopausal women [see Warnings and Precautions (5.3) , Use in Specific Populations (8.5) , and Clinical Studies (14.4) ] . 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 (14.3 , 14.4) ] . Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2) , and Clinical Studies (14.3) ] . Only 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. Prescribe e strogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, and BREAST CANCER See full prescribing information for complete boxed warning. Estrogen-Alone Therapy There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens (5.2) The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) (5.1) The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of developing 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 The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke and myocardial infarction (MI) (5.1) The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer (5.2) The 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 (5.3) Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia (5.1 , 5.3)

1 INDICATIONS AND USAGE DOTTI is indicated for: DOTTI is an estrogen indicated for: Treatment of moderate to severe vasomotor symptoms due to menopause (1.1) Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause (1.2) Limitations of Use When prescribing solely for the treatment of moderate to severe vaginal atrophy, first consider the use of topical vaginal products. Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure (1.3) Prevention of postmenopausal osteoporosis (1.4) Limitations 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. 1.1 Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause 1.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy Due to Menopause Limitations of Use : When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy, first consider the use of topical vaginal products. 1.3 Treatment of Hypoestrogenism Due to Hypogonadism, Castration, or Primary Ovarian Failure 1.4 Prevention of Postmenopausal Osteoporosis Limitations 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 Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, consider addition of a progestogen to reduce the risk of endometrial cancer. Generally, a woman without a uterus does not need to use a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women who have a history of endometriosis may need a progestogen [see Warnings and Precautions (5.2 , 5.14) ] . 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. Reevaluate postmenopausal women periodically as clinically appropriate to determine whether treatment is still necessary. Start therapy with DOTTI 0.0375 mg/day applied to the skin twice weekly for the treatment of moderate to severe vasomotor symptoms due to menopause or moderate to severe symptoms of vulvar and vaginal atrophy symptoms due to menopause. Dosage adjustment should be guided by the clinical response (2.1 , 2.2 , 2.3) Start therapy with DOTTI 0.025 mg/day for the prevention of postmenopausal osteoporosis (2.4) Place DOTTI on a clean, dry area of the lower abdomen or buttocks. Do not apply DOTTI to the breasts (2.5) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Start therapy with DOTTI 0.0375 mg per day applied to the skin twice weekly. Make dosage adjustments based on the clinical response. Initiate DOTTI at once in a woman not currently taking oral estrogens or in a woman switching from another estradiol transdermal therapy. In women who are currently taking oral estrogens, initiate treatment with DOTTI 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week. Attempts to taper or discontinue DOTTI at 3 to 6 month intervals. Give DOTTI continuously in a woman who does not have an intact uterus. In a woman with an intact uterus, give DOTTI on a cyclic schedule (for example, 3 weeks on DOTTI followed by 1 week off DOTTI). 2.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Start therapy with DOTTI 0.0375 mg per day applied to the skin twice weekly. Dosage adjustment should be guided by the clinical response. Attempts to taper or discontinue DOTTI at 3 to 6 month intervals. In women not currently taking oral estrogens or in women switching from another estradiol transdermal therapy, treatment with DOTTI may be initiated at once. In women who are currently taking oral estrogens, initiate treatment with DOTTI 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week. Give DOTTI continuously in a woman who does not have an intact uterus. In a woman with an intact uterus, give DOTTI on a cyclic schedule (for example, 3 weeks on DOTTI followed by 1 week off DOTTI). 2.3 Hypoestrogenism Due to Hypogonadism, Castration, or Primary Ovarian Failure 2.4 Prevention of Postmenopausal Osteoporosis Start therapy with DOTTI 0.025 mg per day applied to the skin twice weekly. In women not currently taking oral estrogens or in women switching from another estradiol transdermal therapy, treatment with DOTTI may be initiated at once. In women who are currently taking oral estrogens, initiate treatment with DOTTI 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week.

oral estrogens or in women switching from another estradiol transdermal therapy, treatment with DOTTI may be initiated at once. In women who are currently taking oral estrogens, initiate treatment with DOTTI 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week. DOTTI may be given continuously in a woman who does not have an intact uterus. In a woman with an intact uterus, DOTTI may be given on a cyclic schedule (for example, 3 weeks on DOTTI followed by 1 week off DOTTI). 2.5 Application Instructions Place the adhesive side of DOTTI on a clean, dry area of the trunk of the body (including the abdomen or buttocks). Do not apply DOTTI to the breasts. Replace DOTTI twice weekly. Rotate the sites of application, with an interval of at least 1 week allowed between applications to a particular site. Select an area that is not oily, damaged, or irritated. Avoid the waistline, since tight clothing may rub the system off. Apply the system immediately after opening the pouch and removing the protective liner. Press the system firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact, especially around the edges. In the event that a system falls off, reapply the same system or apply a new system to another location. In either case, continue the original treatment schedule. If a woman has forgotten to apply DOTTI, have her apply a new system as soon as possible. Apply the new system on the original treatment schedule. The interruption of treatment in women taking DOTTI might increase the likelihood of breakthrough bleeding, spotting and recurrence of symptoms.

3 DOSAGE FORMS AND STRENGTHS Transdermal system, USP: 0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075 mg/day, and 0.1 mg/day. Transdermal system, USP: 0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075 mg/day, and 0.1 mg/day (3)

4 CONTRAINDICATIONS DOTTI 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, or angioedema, or hypersensitivity to DOTTI Hepatic impairment or disease Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders 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 a 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, or angioedema, or hypersensitivity with DOTTI (4 , 5.15) Hepatic impairment or disease (4 , 5.10) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders (4)

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 stroke and DVT are reported with estrogen-alone therapy. Increased risks of PE, DVT, stroke, and MI are reported with estrogen plus progestin 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-alone substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving daily 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 (14.3) ] . 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 The WHI estrogen plus progestin substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 stokes per 10,000 women-years) [see Clinical Studies (14.3 )] . The increase in risk was demonstrated after the first year and persisted. 1 Immediately discontinue estrogen plus progestogen therapy if a stroke occurs or is suspected. Coronary Heart Disease The WHI estrogen-alone substudy reported no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in women receiving estrogen-alone compared to placebo 2 [see Clinical Studies (14.3) ] . Subgroup analyses of women 50 to 59 years of age, who were less than 10 years since menopause, suggest a reduction (not statistically significant) in CHD events in those women receiving daily CE (0.625 mg)–alone compared to placebo (8 versus 16 per 10,000 women-years). 1 The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) in CHD events in 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 (14.3) ] . 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. 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.

ar 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 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 the HERS, the HERS II, and overall. Venous Thromboembolism In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) 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 3 [see Clinical Studies (14.3) ] . Immediately discontinue estrogen-alone therapy if a VTE occurs or is suspected. The WHI estrogen plus progestin substudy reported a statistically significant 2-fold greater rate of VTE 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 4 [see Clinical Studies (14.3) ] . Immediately discontinue estrogen plus progestogen 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 Endometrial Cancer 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 the use of estrogens for less than 1 year. The greatest risk appears to be associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and 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. 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 with unknown etiology. 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 has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Breast Cancer The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users.

etic estrogens of equivalent estrogen dose. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Breast Cancer 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 (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80) 5 [see Clinical Studies (14.3) ] . 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% 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. 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. 6 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 6 [see Clinical Studies (14.3) ] . Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer with estrogen plus progestin therapy, and a smaller increase in the risk for breast cancer with 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. 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 CE plus MPA versus placebo was 1.58 (95% 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.

estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for CE plus MPA versus placebo was 1.58 (95% 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 to 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-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% 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 (14.4) ] . In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal women 65 to 79 years 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% 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 (14.4) ] . 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% CI, 1.19 to 2.60). Since both ancillary studies were conducted in women aged 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 (14.4) ] . 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 DOTTI, 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 DOTTI pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine.

ccurs, 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 DOTTI 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 DOTTI, 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 estrogens on blood pressure was not seen. 5.9 Exacerbation of Hypertriglyceridemia In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Discontinue DOTTI if pancreatitis occurs. 5.10 Hepatic Impairment and/or 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 DOTTI. 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 estrogens may require increased doses of their thyroid replacement therapy. Monitor thyroid function in these women during treatment with DOTTI to maintain their free thyroid hormone levels in an acceptable range. 5.12 Fluid Retention Estrogens 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-alone therapy, including DOTTI, 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 DOTTI, 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. Consider the addition of progestogen therapy for women known to have residual endometriosis post-hysterectomy. 5.15 Severe Anaphylactic/Anaphylactoid Reactions and Angioedema A few cases of anaphylactic/anaphylactoid reactions are reported in the postmarketing use of DOTTI. Involvement of skin (hives, pruritus, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) are noted.

Anaphylactoid Reactions and Angioedema A few cases of anaphylactic/anaphylactoid reactions are reported in the postmarketing use of DOTTI. Involvement of skin (hives, pruritus, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) are noted. Angioedema involving eye/eyelid, face, larynx, pharynx, tongue and extremity (hands, legs, ankles, and fingers) with or without urticaria requiring medical intervention are reported in the postmarketing use of DOTTI. Angioedema involving the tongue, glottis, or larynx, may result in airway obstruction. Do not give DOTTI to any woman who develops angioedema during treatment with DOTTI. Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy outweigh the risks in such women. 5.16 Exacerbation of Other Conditions Estrogen therapy, including DOTTI, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraines, porphyria, systemic lupus erythematosus, and hepatic hemangiomas. Consider whether the benefits of estrogen therapy outweigh the risks in such women. 5.17 Laboratory Tests Serum follicle-stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy. Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian failure. 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 anti-factor Xa and antithrombin III; decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. Increased thyroid-binding globulin (TBG) 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. 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, and increased triglycerides levels. Impaired glucose tolerance.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in labeling: Cardiovascular Disorders [see Boxed Warning , Warnings and Precautions (5.1) ] Malignant Neoplasms [see Boxed Warning , Warnings and Precautions (5.2) ] The most common adverse reactions (≥10%) with DOTTI are: headache, breast tenderness, nasopharyngitis, sinusitis, sinus headache, upper respiratory tract infection, back pain, depression, and irregular vaginal bleeding or spotting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. There were no clinical trials conducted with DOTTI. DOTTI is bioequivalent to the original formulation of estradiol transdermal system. The following adverse reactions have been reported with the original formulation of estradiol transdermal system therapy: Table 1. Summary of Most Frequently Reported Adverse Reactions Regardless of Relationship Reported at a Frequency ≥5 Percent Estradiol 0.025 mg/day † (N=47) N (%) Estradiol 0.0375 mg/day † (N=130) N (%) Estradiol 0.05 mg/day † (N=103) N (%) Estradiol 0.075 mg/day † (N=46) N (%) Estradiol 0.1 mg/day † (N=132) N (%) Placebo (N=157) N (%) Gastrointestinal disorders Constipation 2 (4.3) 5 (3.8) 4 (3.9) 3 (6.5) 2 (1.5) 4 (2.5) Dyspepsia 4 (8.5) 12 (9.2) 3 (2.9) 2 (4.3) 0 10 (6.4) Nausea 2 (4.3) 8 (6.2) 4 (3.9) 0 7 (5.3) 5 (3.2) General disorders and administration site conditions*** Influenza-like illness 3 (6.4) 6 (4.6) 8 (7.8) 0 3 (2.3) 10 (6.4) Pain NOS* 0 8 (6.2) 0 2 (4.3) 7 (5.3) 7 (4.5) Infections and infestations Influenza 4 (8.5) 4 (3.1) 6 (5.8) 0 10 (7.6) 14 (8.9) Nasopharyngitis 3 (6.4) 16 (12.3) 10 (9.7) 9 (19.6) 11 (8.3) 24 (15.3) Sinusitis NOS* 4 (8.5) 17 (13.1) 13 (12.6) 3 (6.5) 7 (5.3) 16 (10.2) Upper respiratory tract infection NOS* 3 (6.4) 8 (6.2) 11 (10.7) 4 (8.7) 6 (4.5) 9 (5.7) Investigations Weight increased 4 (8.5) 5 (3.8) 2 (1.9) 2 (4.3) 0 3 (1.9) Musculoskeletal and connective tissue disorders Arthralgia 0 11 (8.5) 4 (3.9) 2 (4.3) 5 (3.8) 9 (5.7) Back pain 4 (8.5) 10 (7.7) 9 (8.7) 4 (8.7) 14 (10.6) 10 (6.4) Neck pain 3 (6.4) 4 (3.1) 4 (3.9) 0 6 (4.5) 2 (1.3) Pain in limb 0 10 (7.7) 7 (6.8) 2 (4.3) 6 (4.5) 9 (5.7) Nervous system disorders Headache NOS* 7 (14.9) 35 (26.9) 32 (31.1) 23 (50.0) 34 (25.8) 37 (23.6) Sinus headache 0 12 (9.2) 5 (4.9) 5 (10.9) 2 (1.5) 8 (5.1) Psychiatric disorders Anxiety NEC** 3 (6.4) 5 (3.8) 0 0 2 (1.5) 4 (2.5) Depression 5 (10.6) 4 (3.1) 7 (6.8) 0 4 (3.0) 6 (3.8) Insomnia 3 (6.4) 6 (4.6) 4 (3.9) 2 (4.3) 2 (1.5) 9 (5.7) Reproductive system and breast disorders Breast tenderness 8 (17.0) 10 (7.7) 8 (7.8) 3 (6.5) 17 (12.9) 0 Dysmenorrhea 0 0 0 3 (6.5) 0 0 Intermenstrual bleeding 3 (6.4) 9 (6.9) 6 (5.8) 0 14 (10.6) 7 (4.5) Respiratory, thoracic and mediastinal disorders Sinus congestion 0 4 (3.1) 3 (2.9) 3 (6.5) 6 (4.5) 7 (4.5) Vascular disorders Hot flushes NOS* 3 (6.4) 0 3 (2.9) 0 0 6 (3.8) Hypertension NOS* 2 (4.3) 0 3 (2.9) 0 0 2 (1.3) † Represents milligrams of estradiol delivered daily by each system. * NOS represents not otherwise specified. ** NEC represents not elsewhere classified.

ongestion 0 4 (3.1) 3 (2.9) 3 (6.5) 6 (4.5) 7 (4.5) Vascular disorders Hot flushes NOS* 3 (6.4) 0 3 (2.9) 0 0 6 (3.8) Hypertension NOS* 2 (4.3) 0 3 (2.9) 0 0 2 (1.3) † Represents milligrams of estradiol delivered daily by each system. * NOS represents not otherwise specified. ** NEC represents not elsewhere classified. *** Application site erythema and application site irritation were observed in a small number of patients (3.2% or less of patients across treatment groups). 6.2 Post-marketing Experience The following additional adverse reactions have been identified during post-approval use of DOTTI. 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 Vaginal hemorrhage and abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, uterine leiomyomata, vaginitis, vaginal discharge, ovarian cancer, endometrial hyperplasia, dysmenorrhea. Breast Enlargement, pain, nipple discharge, fibrocystic breast changes, breast cancer. Cardiovascular Deep venous thrombosis, pulmonary embolism, thrombophlebitis. Gastrointestinal Nausea, vomiting, abdominal cramps, bloating, cholelithiasis, liver function tests abnormal, diarrhea. Skin Application site reactions include localized bleeding, bruising, burning, discomfort, dryness, eczema, edema, erythema, erythema multiforme, erythema nodosum, inflammation, irritation, pain, papules and vesicles. Other skin reactions include paresthesia, skin discoloration, skin pigmentation, urticaria, swelling, loss of scalp hair, hirsutism, pruritus, and rash. Eyes Intolerance to contact lenses. Central Nervous System Migraine, dizziness, chorea, nervousness, affect liability, irritability. Miscellaneous Decrease in weight, reduced carbohydrate tolerance, edema, arthralgias, leg cramps, changes in libido, purpura, hypersensitivity, anaphylactic reaction, anaphylactoid reaction, angioedema.

<table width="100%" cellspacing="0" cellpadding="0" border="1"><col width="17pt"/><col/><col/><col/><col/><col/><col/><tbody><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph><content styleCode="bold">Table 1.

<table width="100%" cellspacing="0" cellpadding="0" border="1"><col width="17pt"/><col/><col/><col/><col/><col/><col/><tbody><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph><content styleCode="bold">Table 1. Summary of Most Frequently Reported Adverse Reactions Regardless of Relationship Reported at a Frequency &#x2265;5 Percent </content></paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"/><td styleCode=" Toprule Lrule Rrule"><paragraph>Estradiol 0.025 mg/day^&#x2020; (N=47) N (%)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>Estradiol 0.0375 mg/day^&#x2020; (N=130) N (%)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>Estradiol 0.05 mg/day^&#x2020; (N=103) N (%)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>Estradiol 0.075 mg/day^&#x2020; (N=46) N (%)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>Estradiol 0.1 mg/day^&#x2020; (N=132) N (%)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>Placebo (N=157) N (%)</paragraph></td></tr><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph><content styleCode="bold">Gastrointestinal disorders</content></paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Constipation</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>2 (4.3)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>5 (3.8)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (3.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (6.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>2 (1.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (2.5)</paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Dyspepsia</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (8.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>12 (9.2)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (2.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>2 (4.3)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>10 (6.4)</paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Nausea</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>2 (4.3)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>8 (6.2)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (3.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>7 (5.3)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>5 (3.2)</paragraph></td></tr><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph><content styleCode="bold">General disorders and administration site conditions***</content></paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Influenza-like illness</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (6.4)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>6 (4.6)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>8 (7.8)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (2.3)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>10 (6.4)</paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Pain NOS*</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>8 (6.2)</paragraph></td><td styleCode=" T

aph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>10 (6.4)</paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Pain NOS*</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>8 (6.2)</paragraph></td><td styleCode=" T oprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>2 (4.3)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>7 (5.3)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>7 (4.5)</paragraph></td></tr><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph><content styleCode="bold">Infections and infestations</content></paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Influenza</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (8.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (3.1)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>6 (5.8)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>10 (7.6)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>14 (8.9)</paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Nasopharyngitis</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (6.4)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>16 (12.3)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>10 (9.7)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>9 (19.6)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>11 (8.3)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>24 (15.3)</paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Sinusitis NOS*</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (8.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>17 (13.1)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>13 (12.6)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (6.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>7 (5.3)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>16 (10.2)</paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Upper respiratory tract infection NOS*</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (6.4)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>8 (6.2)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>11 (10.7)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (8.7)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>6 (4.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>9 (5.7)</paragraph></td></tr><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph><content styleCode="bold">Investigations</content></paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Weight increased</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (8.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>5 (3.8)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>2 (1.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>2 (4.3)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (1.9)</paragraph></td></tr><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Arthralgia</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td

r><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Arthralgia</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>11 (8.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (3.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>2 (4.3)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>5 (3.8)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>9 (5.7)</paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Back pain</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (8.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>10 (7.7)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>9 (8.7)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (8.7)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>14 (10.6)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>10 (6.4)</paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Neck pain</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (6.4)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (3.1)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (3.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>6 (4.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>2 (1.3)</paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Pain in limb</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>10 (7.7)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>7 (6.8)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>2 (4.3)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>6 (4.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>9 (5.7)</paragraph></td></tr><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph><content styleCode="bold">Nervous system disorders</content></paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Headache NOS*</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>7 (14.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>35 (26.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>32 (31.1)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>23 (50.0)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>34 (25.8)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>37 (23.6)</paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Sinus headache</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>12 (9.2)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>5 (4.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>5 (10.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>2 (1.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>8 (5.1)</paragraph></td></tr><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph><content styleCode="bold">Psychiatric disorders</content></paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Anxiety NEC**</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (6.4)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>5 (3.8)</paragraph></td><td styleCode=" Toprule Lrule Rrule"

old">Psychiatric disorders</content></paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Anxiety NEC**</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (6.4)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>5 (3.8)</paragraph></td><td styleCode=" Toprule Lrule Rrule" ><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>2 (1.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (2.5)</paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Depression</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>5 (10.6)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (3.1)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>7 (6.8)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (3.0)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>6 (3.8)</paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Insomnia</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (6.4)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>6 (4.6)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (3.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>2 (4.3)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>2 (1.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>9 (5.7)</paragraph></td></tr><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph><content styleCode="bold">Reproductive system and breast disorders</content></paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Breast tenderness</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>8 (17.0)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>10 (7.7)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>8 (7.8)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (6.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>17 (12.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Dysmenorrhea</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (6.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Intermenstrual bleeding</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (6.4)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>9 (6.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>6 (5.8)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>14 (10.6)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>7 (4.5)</paragraph></td></tr><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Sinus congestion</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (3.1)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (2.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (6.5)</paragraph></t

agraph>Sinus congestion</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>4 (3.1)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (2.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (6.5)</paragraph></t d><td styleCode=" Toprule Lrule Rrule"><paragraph>6 (4.5)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>7 (4.5)</paragraph></td></tr><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph><content styleCode="bold">Vascular disorders</content></paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Hot flushes NOS*</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (6.4)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (2.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>6 (3.8)</paragraph></td></tr><tr><td styleCode=" Toprule Lrule Rrule"><paragraph>Hypertension NOS*</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>2 (4.3)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>3 (2.9)</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Toprule Lrule Rrule"><paragraph>2 (1.3)</paragraph></td></tr><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph>^&#x2020; Represents milligrams of estradiol delivered daily by each system.</paragraph></td></tr><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph>* NOS represents not otherwise specified.</paragraph></td></tr><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph>** NEC represents not elsewhere classified.</paragraph></td></tr><tr><td colspan="7" styleCode=" Toprule Lrule Rrule"><paragraph>*** Application site erythema and application site irritation were observed in a small number of patients (3.2% or less of patients across treatment groups).</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS 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 drug metabolism. Inducers of CYP3A4 such as St. John’s wort ( Hypericum perforatum ) preparations, phenobarbital, carbamazepine and rifampin may reduce plasma concentrations of estrogens, 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 plasma concentrations of estrogens and may result in adverse reactions. Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. ( 7 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary DOTTI is not indicated for use in pregnancy. There are no data with the use of DOTTI 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 hormonal contraceptives (estrogen and progestins) 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 are present in human milk and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DOTTI and any potential adverse effects on the breastfed child from DOTTI or from the underlying maternal condition. 8.4 Pediatric Use DOTTI is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration. 8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing DOTTI to determine whether those over 65 years of age differ from younger subjects in their response to DOTTI. The Women’s Health Initiative Studies 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 Warnings and Precautions (5.1) , and Clinical Studies (14.3) ] . 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 Warnings and Precautions (5.1) , and Clinical Studies (14.3) ] . 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-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.3) , and Clinical Studies (14.4) ] . 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 (14.4) ] .

8.1 Pregnancy Risk Summary DOTTI is not indicated for use in pregnancy. There are no data with the use of DOTTI 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 hormonal contraceptives (estrogen and progestins) 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 are present in human milk and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DOTTI and any potential adverse effects on the breastfed child from DOTTI or from the underlying maternal condition.

8.4 Pediatric Use DOTTI is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration.

8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing DOTTI to determine whether those over 65 years of age differ from younger subjects in their response to DOTTI. The Women’s Health Initiative Studies 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 Warnings and Precautions (5.1) , and Clinical Studies (14.3) ] . 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 Warnings and Precautions (5.1) , and Clinical Studies (14.3) ] . 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-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.3) , and Clinical Studies (14.4) ] . 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 (14.4) ] .

10 OVERDOSAGE Overdosage of estrogen 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 DOTTI therapy with institution of appropriate symptomatic care.

11 DESCRIPTION DOTTI (estradiol transdermal system, USP) contains estradiol, USP in a multipolymeric adhesive. The system is designed to release estradiol, USP continuously upon application to intact skin. Five dosage strengths of DOTTI are available to provide nominal in vivo delivery rates of 0.025, 0.0375, 0.05, 0.075, or 0.1 mg of estradiol, USP per day via the skin. Each corresponding system has an active surface area of 1.89, 2.83, 3.78, 5.66, or 7.55 cm 2 and contains 0.314, 0.470, 0.627, 0.940, or 1.253 mg of estradiol USP, respectively. The composition of the systems per unit area is identical. Estradiol, USP is a white to practically white powder, chemically described as estra-1,3,5 (10)- triene-3,17β-diol. The structural formula is: The molecular formula of estradiol, USP is C 18 H 24 0 2 . The molecular weight is 272.39 g/mol. DOTTI is comprised of 3 layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) polyester and ethylene vinyl acetate copolymer film (2) an adhesive formulation containing estradiol USP, acrylic adhesive, silicone adhesive, oleyl alcohol, NF, povidone, USP and dipropylene glycol, and (3) a polyester release liner which is attached to the adhesive surface and must be removed before the system can be used. The active component of the system is estradiol, USP. The remaining components of the system are pharmacologically inactive. FDA approved acceptance criteria for dissolution test specifications differ from USP.

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, 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. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, 2 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 follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. 12.2 Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to DOTTI 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 In a multiple-dose study consisting of 3 consecutive system applications of the original formulation of estradiol transdermal system which was conducted in 17 healthy, postmenopausal women, blood levels of estradiol and estrone were compared following application of these units to sites on the abdomen and buttocks in a crossover fashion. Systems that deliver nominal estradiol doses of approximately 0.0375 mg per day and 0.1 mg per day were applied to abdominal application sites while the 0.1 mg per day doses were also applied to sites on the buttocks. These systems increased estradiol levels above baseline within 4 hours and maintained respective mean levels of 25 and 79 pg/mL above baseline following application to the abdomen; slightly higher mean levels of 88 pg/mL above baseline were observed following application to the buttocks. At the same time, increases in estrone plasma concentrations averaged about 12 and 50 pg/mL, respectively, following application to the abdomen and 61 pg/mL for the buttocks. While plasma concentrations of estradiol and estrone remained slightly above baseline at 12 hours following removal of the systems in this study, results from another study show these levels to return to baseline values within 24 hours following removal of the systems. Figure 1 illustrates the mean plasma concentrations of estradiol at steady-state during application of these patches at 4 different dosages. Figure 1. Steady-State Estradiol Plasma Concentrations for Systems Applied to the Abdomen Nonbaseline-corrected Levels The corresponding pharmacokinetic parameters are summarized in Table 2. Table 2.

the mean plasma concentrations of estradiol at steady-state during application of these patches at 4 different dosages. Figure 1. Steady-State Estradiol Plasma Concentrations for Systems Applied to the Abdomen Nonbaseline-corrected Levels The corresponding pharmacokinetic parameters are summarized in Table 2. Table 2. Steady-State Estradiol Pharmacokinetic Parameters for Systems Applied to the Abdomen (mean ± standard deviation) Nonbaseline-corrected Data* Dosage (mg/day) C max † (pg/mL) C avg ‡ (pg/mL) C min (84 hr) § (pg/mL) 0.0375 46 ± 16 34 ± 10 30 ±10 0.05 83 ± 41 57 ± 23 # 41 ± 11 # 0.075 99 ± 35 72 ± 24 60 ± 24 0.1 133 ± 51 89 ± 38 90 ± 44 0.1 ¶ 145 ± 71 104 ± 52 85 ± 47 *Mean baseline estradiol concentration =11.7 pg/mL. † Peak plasma concentration. ‡ Average plasma concentration. § Minimum plasma concentration at 84 hr. # Measured over 80 hr. ¶ Applied to the buttocks. DOTTI (estradiol transdermal system), the revised formulation with smaller system sizes, was shown to be bioequivalent to the original formulation of estradiol transdermal system, used in the clinical trials. 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 sex hormone-binding globulin (SHBG) and albumin. 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 by Cytochrome 450 isoforms CYP1A2 and CYP3A4. Estradiol undergoes further metabolism to sulfate and glucuronide conjugates. Estradiol and its metabolites are glucuronidated by UGT1A1 and UGT2B7. 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 portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The half-life values calculated after dosing with DOTTI ranged from 5.9 to 7.7 hours. After removal of the transdermal systems, serum concentrations of estradiol and estrone returned to baseline levels within 24 hours. Adhesion Based on combined data from 3 short-term clinical trials consisting of 471 observations, 85% of DOTTI adhered completely to the skin over the 3.5-day wear period. Three percent (3%) of the systems detached and were reapplied or replaced during the 3.5-day wear period. Approximately 80% of the transdermal systems evaluated in these studies were DOTTI 0.05 mg per day.

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, 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. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, 2 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 follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

12.2 Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to DOTTI 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 In a multiple-dose study consisting of 3 consecutive system applications of the original formulation of estradiol transdermal system which was conducted in 17 healthy, postmenopausal women, blood levels of estradiol and estrone were compared following application of these units to sites on the abdomen and buttocks in a crossover fashion. Systems that deliver nominal estradiol doses of approximately 0.0375 mg per day and 0.1 mg per day were applied to abdominal application sites while the 0.1 mg per day doses were also applied to sites on the buttocks. These systems increased estradiol levels above baseline within 4 hours and maintained respective mean levels of 25 and 79 pg/mL above baseline following application to the abdomen; slightly higher mean levels of 88 pg/mL above baseline were observed following application to the buttocks. At the same time, increases in estrone plasma concentrations averaged about 12 and 50 pg/mL, respectively, following application to the abdomen and 61 pg/mL for the buttocks. While plasma concentrations of estradiol and estrone remained slightly above baseline at 12 hours following removal of the systems in this study, results from another study show these levels to return to baseline values within 24 hours following removal of the systems. Figure 1 illustrates the mean plasma concentrations of estradiol at steady-state during application of these patches at 4 different dosages. Figure 1. Steady-State Estradiol Plasma Concentrations for Systems Applied to the Abdomen Nonbaseline-corrected Levels The corresponding pharmacokinetic parameters are summarized in Table 2. Table 2. Steady-State Estradiol Pharmacokinetic Parameters for Systems Applied to the Abdomen (mean ± standard deviation) Nonbaseline-corrected Data* Dosage (mg/day) C max † (pg/mL) C avg ‡ (pg/mL) C min (84 hr) § (pg/mL) 0.0375 46 ± 16 34 ± 10 30 ±10 0.05 83 ± 41 57 ± 23 # 41 ± 11 # 0.075 99 ± 35 72 ± 24 60 ± 24 0.1 133 ± 51 89 ± 38 90 ± 44 0.1 ¶ 145 ± 71 104 ± 52 85 ± 47 *Mean baseline estradiol concentration =11.7 pg/mL. † Peak plasma concentration. ‡ Average plasma concentration. § Minimum plasma concentration at 84 hr. # Measured over 80 hr. ¶ Applied to the buttocks. DOTTI (estradiol transdermal system), the revised formulation with smaller system sizes, was shown to be bioequivalent to the original formulation of estradiol transdermal system, used in the clinical trials. 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 sex hormone-binding globulin (SHBG) and albumin. 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 by Cytochrome 450 isoforms CYP1A2 and CYP3A4. Estradiol undergoes further metabolism to sulfate and glucuronide conjugates. Estradiol and its metabolites are glucuronidated by UGT1A1 and UGT2B7. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite.

iver by Cytochrome 450 isoforms CYP1A2 and CYP3A4. Estradiol undergoes further metabolism to sulfate and glucuronide conjugates. Estradiol and its metabolites are glucuronidated by UGT1A1 and UGT2B7. 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 portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The half-life values calculated after dosing with DOTTI ranged from 5.9 to 7.7 hours. After removal of the transdermal systems, serum concentrations of estradiol and estrone returned to baseline levels within 24 hours. Adhesion Based on combined data from 3 short-term clinical trials consisting of 471 observations, 85% of DOTTI adhered completely to the skin over the 3.5-day wear period. Three percent (3%) of the systems detached and were reapplied or replaced during the 3.5-day wear period. Approximately 80% of the transdermal systems evaluated in these studies were DOTTI 0.05 mg per day.

<table width="100%" cellspacing="0" cellpadding="0" border="1"><col width="17pt"/><col/><col/><col/><tbody><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Table 2. Steady-State Estradiol Pharmacokinetic Parameters for Systems Applied to the Abdomen (mean &#xB1; standard deviation) Nonbaseline-corrected Data*</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dosage (mg/day)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>C_max^&#x2020; (pg/mL)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>C_avg^&#x2021; (pg/mL)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>C_min (84 hr)^&#xA7; (pg/mL)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.0375</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>46 &#xB1; 16</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>34 &#xB1; 10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>30 &#xB1;10</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.05</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>83 &#xB1; 41</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>57 &#xB1; 23^#</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41 &#xB1; 11^#</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.075</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>99 &#xB1; 35</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>72 &#xB1; 24</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>60 &#xB1; 24</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>133 &#xB1; 51</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>89 &#xB1; 38</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>90 &#xB1; 44</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.1^&#xB6;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>145 &#xB1; 71</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>104 &#xB1; 52</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>85 &#xB1; 47</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>*Mean baseline estradiol concentration =11.7 pg/mL.</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^&#x2020;Peak plasma concentration.</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^&#x2021;Average plasma concentration.</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^&#xA7;Minimum plasma concentration at 84 hr.</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^#Measured over 80 hr.</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^&#xB6;Applied to the buttocks.</paragraph></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.

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 In a pharmacokinetic study, DOTTI was shown to be bioequivalent to the original estradiol formulation. In 2 controlled clinical trials with the original estradiol formulation, of 356 women, the 0.075 and 0.1 mg doses were superior to placebo in relieving vasomotor symptoms at Week 4, and maintained efficacy through Weeks 8 and 12 of treatment. In this original study, the 0.0375 and 0.05 mg doses, however, did not differ from placebo until approximately Week 6, therefore, an additional 12-week, placebo-controlled study in 255 women was performed with the original estradiol formulation to establish the efficacy of the lowest dose of 0.0375 mg. The baseline mean daily number of hot flushes in these 255 women was 11.5. Results at Weeks 4, 8, and 12 of treatment are shown in Figure 2. Figure 2. Mean (SD) Change from Baseline in Mean Daily Number of Flushes for Estradiol 0.0375 mg Versus Placebo in a 12-week Trial The 0.0375 mg dose was superior to placebo in reducing both the frequency and severity of vasomotor symptoms at Week 4 and maintained efficacy through Weeks 8 and 12 of treatment. All doses of the original estradiol formulation (0.0375 mg, 0.05 mg, 0.075 mg, and 0.1 mg) are effective for the control of vasomotor symptoms. 14.2 Effects on Bone Mineral Density in Postmenopausal Women Efficacy and safety of the original estradiol formulation in the prevention of postmenopausal osteoporosis have been studied in a 2-year, double-blind, randomized, placebo-controlled, parallel-group study. A total of 261 hysterectomized (161) and non-hysterectomized (100), surgically or naturally menopausal women (within 5 years of menopause), with no evidence of osteoporosis (lumbar spine bone mineral density within 2 standard deviations of average peak bone mass, i.e., at least 0.827 g/cm 2 ) were enrolled in this study; 194 women were randomized to 1 of the 4 doses of the original estradiol formulation (0.1, 0.05, 0.0375, or 0.025 mg/day) and 67 patients to placebo. Over 2 years, study systems were applied to the buttock or the abdomen twice a week. Non-hysterectomized women received oral medroxyprogesterone acetate (2.5 mg/day) throughout the study. The study population comprised naturally (82%) or surgically (18%) menopausal, hysterectomized (61%) or non-hysterectomized (39%) women with a mean age of 52 years (range 27 to 62 years); the mean duration of menopause was 31.7 months (range 2 to 72 months). Two hundred thirty-two (89%) of randomized women (173 on active drug, 59 on placebo) contributed data to the analysis of percent change from baseline in bone mineral density (BMD) of the AP lumbar spine, the primary efficacy variable. Women were given supplemental dietary calcium (1000 mg elemental calcium/day) but no supplemental vitamin D. There was an increase in BMD of the AP lumbar spine in all the original estradiol formulation dose groups; in contrast to this, a decrease in AP lumbar spine BMD was observed in placebo patients. All estradiol doses were significantly superior to placebo (p<0.05) at all time points with the exception of estradiol 0.05 mg/day at 6 months. The highest dose of estradiol was superior to the 3 lower doses. There were no statistically significant differences in pairwise comparisons among the 3 lower doses (See Figure 3). Figure 3.

doses were significantly superior to placebo (p<0.05) at all time points with the exception of estradiol 0.05 mg/day at 6 months. The highest dose of estradiol was superior to the 3 lower doses. There were no statistically significant differences in pairwise comparisons among the 3 lower doses (See Figure 3). Figure 3. Bone Mineral Density-AP Lumbar Spine Least Squares Means of Percentage Change from Baseline All Randomized Patients with at Least One Post-baseline Assessment Available with Last Post-baseline Observation Carried Forward Analysis of percent change from baseline in femoral neck BMD, a secondary efficacy outcome variable, showed qualitatively similar results; all doses of the original estradiol formulation were significantly superior to placebo (p<0.05) at 24 months. The highest estradiol dose was superior to placebo at all time points. A mixture of significant and nonsignificant results were obtained for the lower dose groups at earlier time points. The highest estradiol dose was superior to the 3 lower doses, and there were no significant differences among the 3 lower doses at this skeletal site (See Figure 4). Figure 4. Bone Mineral Density-Femoral Neck Least Squares Means of Percentage Change from Baseline All Randomized Patients with at Least One Post-baseline Assessment Available with Last Post-baseline Observation Carried Forward The mean serum osteocalcin (a marker of bone formation) and urinary excretion of cross-link N-telopeptides of Type 1 collagen (a marker of bone resorption) decreased numerically in most of the active treatment groups relative to baseline. However, the decreases in both markers were inconsistent across treatment groups and the differences between active treatment groups and placebo were not statistically significant. 14.3 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 the 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 causes. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms. WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was 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% White, 15.1% Black, 6.1% Hispanic, 3.6% Other) after an average follow-up of 7.1 years, are presented in Table 3. Table 3. Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI a Event Relative Risk CE vs.

trogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3% White, 15.1% Black, 6.1% Hispanic, 3.6% Other) after an average follow-up of 7.1 years, are presented in Table 3. Table 3. Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI a Event Relative Risk CE vs. Placebo (95% nCI b ) CE n=5,310 Placebo n=5,429 Absolute Risk per 10,000 Women-Years CHD events c 0.95 (0.78 to 1.16) 54 57 Non-fatal MI c 0.91 (0.73 to 1.14) 40 43 CHD death c 1.01 (0.71 to 1.43) 16 16 All strokes c 1.33 (1.05 to 1.68) 45 33 Ischemic stroke c 1.55 (1.19 to 2.01) 38 25 Deep vein thrombosis c,d 1.47 (1.06 to 2.06) 23 15 Pulmonary embolism c 1.37 (0.90 to 2.07) 14 10 Invasive breast cancer c 0.80 (0.62 to 1.04) 28 34 Colorectal cancer e 1.08 (0.75 to 1.55) 17 16 Hip fracture c 0.65 (0.45 to 0.94) 12 19 Vertebral fractures c,d 0.64 (0.44 to 0.93) 11 18 Lower arm/wrist fractures c,d 0.58 (0.47 to 0.72) 35 59 Total fractures c,d 0.71 (0.64 to 0.80) 144 197 Death due to other causes e,f 1.08 (0.88 to 1.32) 53 50 Overall mortality c,d 1.04 (0.88 to 1.22) 79 75 Global Index g 1.02 (0.92 to 1.13) 206 201 a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. c Results are based on centrally adjudicated data for an average follow-up of 7.1 years. d Not included in “global index”. e Results are based on an average follow-up of 6.8 years. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g 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. 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 was 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 nonsignificant 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 3). Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant differences in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined 10 (See Table 3). 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 nonsignificant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95% CI, 0.36 to 1.09)] and overall mortality [HR 0.71 (95% CI, 0.46 to 1.11)]. 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”.

ogen 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 reduction 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% White, 6.8% Black, 5.4% Hispanic, 3.9% Other) are presented in Table 4. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 4. Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years a,b Event Relative Risk CE/MPA vs. Placebo (95% nCI c ) 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 1.44 (1.09 to 1.90) 26 18 Deep vein thrombosis d 1.95 (1.43 to 2.67) 26 13 Pulmonary embolism 2.13 (1.45 to 3.11) 18 8 Invasive breast cancer e 1.24 (1.01 to 1.54) 41 33 Colorectal cancer 0.61 (0.42 to 0.87) 10 16 Endometrial cancer d 0.81 (0.48 to 1.36) 6 7 Cervical cancer d 1.44 (0.47 to 4.42) 2 1 Hip fracture 0.67 (0.47 to 0.96) 11 16 Vertebral fractures d 0.65 (0.46 to 0.92) 11 17 Lower arm/wrist fractures d 0.71 (0.59 to 0.85) 44 62 Total fractures d 0.76 (0.69 to 0.83) 152 199 Overall mortality f 1.00 (0.83 to 1.19) 52 52 Global Index g 1.13 (1.02 to 1.25) 184 165 a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Results are based on centrally adjudicated data. c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. d Not included in “global index”. e Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g 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. 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 [HR 0.69 (95% CI, 0.44 to 1.07)]. 14.4 Women’s Health Initiative Memory Study 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% were age 65 to 69 years of age; 36% were 70 to 74 years of age; 19% 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% 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.

dence 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% 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 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 plus progestin ancillary study enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years of age; 35% were 70 to 74 years of age; 18% were 75 years of age and older) to evaluate the effects of daily 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 was 2.05 (95% 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 AD, VaD, and mixed type (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% 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) ] .

<table width="100%" cellspacing="0" cellpadding="0" border="1"><col width="17pt"/><col/><col/><col/><tbody><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Table 3. Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI^a</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Event</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Relative Risk CE vs.

e"><paragraph><content styleCode="bold">Table 3. Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI^a</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Event</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Relative Risk CE vs. Placebo (95% nCI^b)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>CE n=5,310</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Placebo n=5,429 Absolute Risk per 10,000 Women-Years</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>CHD events^c</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.95 (0.78 to 1.16)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>54</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>57</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Non-fatal MI</content>^c</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">0.91 (0.73 to 1.14)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">40</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">43</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">CHD death</content>^c</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">1.01 (0.71 to 1.43)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">16</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">16</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>All strokes^c</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.33 (1.05 to 1.68)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>45</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>33</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Ischemic stroke</content>^c</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">1.55 (1.19 to 2.01)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">38</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">25</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Deep vein thrombosis^c,d</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.47 (1.06 to 2.06)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>23</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>15</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pulmonary embolism^c</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.37 (0.90 to 2.07)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>14</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Invasive breast cancer^c</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.80 (0.62 to 1.04)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>28</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><

<td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Invasive breast cancer^c</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.80 (0.62 to 1.04)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>28</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">< paragraph>34</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Colorectal cancer^e</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.08 (0.75 to 1.55)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>17</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hip fracture^c</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.65 (0.45 to 0.94)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>12</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>19</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vertebral fractures^c,d</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.64 (0.44 to 0.93)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>18</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Lower arm/wrist fractures^c,d</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.58 (0.47 to 0.72)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>35</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>59</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Total fractures^c,d</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.71 (0.64 to 0.80)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>144</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>197</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Death due to other causes^e,f</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.08 (0.88 to 1.32)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>53</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>50</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Overall mortality^c,d</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.04 (0.88 to 1.22)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>79</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>75</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Global Index^g</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.02 (0.92 to 1.13)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>206</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>201</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^a Adapted from numerous WHI publications.

ph>1.02 (0.92 to 1.13)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>206</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>201</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. </paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. </paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^c Results are based on centrally adjudicated data for an average follow-up of 7.1 years. </paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^d Not included in &#x201C;global index&#x201D;. </paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^e Results are based on an average follow-up of 6.8 years. </paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. </paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^g A subset of the events was combined in a &#x201C;global index&#x201D;, 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></tbody></table> <table width="100%" cellspacing="0" cellpadding="0" border="1"><col width="17pt"/><col/><col/><col/><tbody><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Table 4. Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years^a,b</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Event</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Relative Risk CE/MPA vs.

ble 4. Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years^a,b</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Event</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Relative Risk CE/MPA vs. Placebo (95% nCI^c)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>CE/MPA n=8,506</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Placebo n=8,102 Absolute Risk per 10,000 Women-Years</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>CHD events </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.23 (0.99 to 1.53)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>34</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Non-fatal MI </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">1.28 (1.00 to 1.63)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">31</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">25</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">CHD death </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">1.10 (0.70 to 1.75)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">8</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">8</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>All strokes </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.31 (1.03 to 1.68)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>33</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>25</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Ischemic Stroke </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">1.44 (1.09 to 1.90)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">26</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">18</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Deep vein thrombosis^d</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.95 (1.43 to 2.67)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>26</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pulmonary embolism </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.13 (1.45 to 3.11)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>18</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Invasive breast cancer^e</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.24 (1.01 to 1.54)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>33</paragraph></td></tr><tr><td styleCode=" Botrule Topru

east cancer^e</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.24 (1.01 to 1.54)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>33</paragraph></td></tr><tr><td styleCode=" Botrule Topru le Lrule Rrule"><paragraph>Colorectal cancer </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.61 (0.42 to 0.87)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Endometrial cancer^d</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.81 (0.48 to 1.36)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Cervical cancer^d</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.44 (0.47 to 4.42)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hip fracture </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.67 (0.47 to 0.96)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vertebral fractures^d</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.65 (0.46 to 0.92)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>17</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Lower arm/wrist fractures^d</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.71 (0.59 to 0.85)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>44</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>62</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Total fractures^d</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.76 (0.69 to 0.83)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>152</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>199</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Overall mortality^f</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.00 (0.83 to 1.19)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>52</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>52</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Global Index^g</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.13 (1.02 to 1.25)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>184</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>165</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^a Adapted from numerous WHI publications.

ph>1.13 (1.02 to 1.25)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>184</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>165</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. </paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^b Results are based on centrally adjudicated data. </paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. </paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^d Not included in &#x201C;global index&#x201D;. </paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^e Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. </paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. </paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^g A subset of the events was combined in a &#x201C;global index&#x201D;, 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></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. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006; 166:772-780. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004; 292:1573-1580. 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. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003; 289:3234-3253. 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 DOTTI (estradiol transdermal system, USP), 0.075 mg per day- each 5.66 cm2 system contains 0.940 mg of estradiol USP for nominal* delivery of 0.075 mg of estradiol, USP per day. Patient Calendar Pack of 8 Systems………………………………….NDC 72162-2035-2 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Do not store unpouched. Apply immediately upon removal from the protective pouch. Used transdermal systems still contain active hormone. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504

17 PATIENT COUNSELING INFORMATION Advise women to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ) Vaginal Bleeding Inform postmenopausal women to report any vaginal bleeding to their healthcare providers as soon as possible [see Warnings and Precautions (5.2) ] . Possible Serious Adverse Reactions with Estrogen-Alone Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen-alone 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-Alone Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting. Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 05-2024-03

PATIENT INFORMATION DOTTI (dah ʹ tee) ( estradiol transdermal system) Read this Patient Information before you start using DOTTI 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 DOTTI (an estrogen hormone)? Using estrogen-alone increases your chance of getting cancer of the uterus (womb). Report any unusual vaginal bleeding right away while you are using DOTTI. 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. Do not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline in 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. Do not use estrogens with progestogens to prevent heart disease, heart attacks, strokes, or dementia. 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. Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. 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. Because other products and doses have not been studied in the same way, it is not known how the use of DOTTI will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with DOTTI. What is DOTTI? DOTTI is a prescription medicine patch (transdermal system) that contains the estrogen hormone estradiol. When applied to the skin, estradiol is absorbed through the skin into the bloodstream. What is DOTTI used for? DOTTI is used after menopause to: Reduce moderate to severe hot flashes 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 develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest or sudden intense feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women the symptoms are mild, and they will not need to use estrogens. In other women, symptoms can be more severe. Treat moderate to severe menopausal changes in and around the vagina You and your healthcare provider should talk regularly about whether you still need treatment with DOTTI to control these problems. If you use DOTTI only to treat your menopausal changes in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.

vagina You and your healthcare provider should talk regularly about whether you still need treatment with DOTTI to control these problems. If you use DOTTI only to treat your menopausal changes in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you. Treat certain conditions in women before menopause if their ovaries do not produce enough estrogens naturally Help reduce your chances of getting osteoporosis (thin weak bones) Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use DOTTI to prevent osteoporosis due to 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 should continue treatment with DOTTI. Who should not use DOTTI? Do not start using DOTTI if you: have 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 DOTTI. had a stroke or heart attack currently have or have had blood clots currently have or have had liver problems are allergic to DOTTI or any of the ingredients in it See the list of ingredients in DOTTI at the end of this leaflet. Before you use DOTTI, 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 DOTTI 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); 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 DOTTI. are pregnant or think you may be pregnant. DOTTI is not for pregnant women. are breastfeeding The hormone in DOTTI 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 DOTTI works. DOTTI 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 DOTTI? For detailed instructions, see the step-by-step instructions for using DOTTI at the end of this Patient Information. Use DOTTI exactly as your healthcare provider tells you to use it. DOTTI is for skin use only. Change your DOTTI patch 2 times a week or every 3 to 4 days. Apply your DOTTI patch to a clean, dry area on your lower abdomen. This area must be clean, dry, and free of powder, oil or lotion for your patch to stick to your skin. Apply your DOTTI patch to a different area of your abdomen each time. Do not use the same application site 2 times in the same week. Do not apply DOTTI to your breasts. If you forget to apply a new DOTTI patch, apply a new patch as soon as possible.

nd free of powder, oil or lotion for your patch to stick to your skin. Apply your DOTTI patch to a different area of your abdomen each time. Do not use the same application site 2 times in the same week. Do not apply DOTTI to your breasts. If you forget to apply a new DOTTI patch, apply a new patch as soon as possible. You and your healthcare provider should talk regularly (every 3 to 6 months) about your dose and whether you still need treatment with DOTTI. How to change DOTTI When changing the patch, peel off the used patch slowly from the skin. After removal of DOTTI if any adhesive residue remains on your skin, allow the area to dry for 15 minutes. Then, gently rub the area with oil or lotion to remove the adhesive from your skin. Apply the new patch to a different area of your lower abdomen. This area must be clean, dry, cool and free of powder, oil, or lotion. What are the possible side effects of DOTTI? 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 high blood pressure stroke high levels of fat (triglyceride) in your blood blood clots liver problems breast cancer changes in your thyroid hormone levels cancer of the lining of the uterus (womb) fluid retention cancer of the ovary cancer changes of endometriosis dementia enlargement of benign tumors of the uterus (“fibroids”) high or low blood calcium worsening of swelling of face and tongue (angioedema) in women with a history of angioedema gallbladder disease visual abnormalities 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 swelling of face and tongue with or without red, itchy bumps Common side effects of DOTTI include: headache nausea and vomiting breast pain hair loss irregular vaginal bleeding or spotting fluid retention painful periods vaginal yeast infection stomach or abdominal cramps, bloating redness and/or irritation at patch placement site These are not all the possible side effects of DOTTI. 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 FDA at 1-800-FDA-1088. You may report side effects to Amneal Pharmaceuticals (1-877-835-5472). What can I do to lower my chances of getting a serious side effect with DOTTI? Talk with your healthcare provider regularly about whether you should continue using DOTTI. If you have a uterus, talk to your healthcare provider about whether the addition of a progestogen 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 DOTTI. 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, 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 if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease. How should I store and throw away used DOTTI patches? Store DOTTI at room temperature 68° to 77°F (20° to 25°C) Do not store DOTTI patches outside of their pouches.

use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease. How should I store and throw away used DOTTI patches? Store DOTTI at room temperature 68° to 77°F (20° to 25°C) Do not store DOTTI patches outside of their pouches. Apply immediately upon removal from the protective pouch. Used patches still contain estrogen. To throw away the patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place this container in the trash. Used patches should not be flushed in the toilet. Keep DOTTI and all medicines out of the reach of children. General information about safe and effective use of DOTTI Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use DOTTI for conditions for which it was not prescribed. Do not give DOTTI to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about DOTTI that is written for health professionals. For more information, go to www.amneal.com or call the toll-free number Amneal Pharmaceuticals (1-877-835-5472). What are the ingredients in DOTTI? Active ingredient: estradiol, USP Inactive ingredients: a polyester and ethylene vinyl acetate copolymer film, acrylic and silicone adhesives, oleyl alcohol, NF, povidone, USP, dipropylene glycol and a polyester release liner. Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 05-2024-03 This Patient Information has been approved by the U.S. Food and Drug Administration.

<table width="100%"><col width="17pt"/><col/><tbody><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule">Read this Patient Information before you start using DOTTI 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. </td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What is the most important information I should know about </content><content styleCode="bold">DOTTI (an estrogen hormone)? </content></paragraph><list listType="unordered" styleCode="Disc"><item>Using estrogen-alone increases your chance of getting cancer of the uterus (womb). </item><item>Report any unusual vaginal bleeding right away while you are using DOTTI. 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. </item><item>Do not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function). </item><item>Using estrogen-alone may increase your chances of getting strokes or blood clots. </item><item>Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age and older. </item><item>Do not use estrogens with progestogens to prevent heart disease, heart attacks, strokes, or dementia. </item><item>Using estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. </item><item>Using estrogens with progestogens may increase your chance of getting dementia, based on a study of women 65 years of age and older. </item><item>Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. 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. Because other products and doses have not been studied in the same way, it is not known how the use of DOTTI will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with DOTTI.</item></list></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold">What is</content><content styleCode="bold"> DOTTI? </content>DOTTI is a prescription medicine patch (transdermal system) that contains the estrogen hormone estradiol. When applied to the skin, estradiol is absorbed through the skin into the bloodstream. </td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold">What is </content><content styleCode="bold">DOTTI used for? </content>DOTTI is used after menopause to: <list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Reduce moderate to severe hot flashes </content></item></list><paragraph>Estrogens are hormones made by a woman&#x2019;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 &#x201C;change of life&#x201D; or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place.

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 &#x201C;change of life&#x201D; 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 &#x201C;surgical menopause.&#x201D; </paragraph><paragraph>When estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest or sudden intense feelings of heat and sweating (&#x201C;hot flashes&#x201D; or &#x201C;hot flushes&#x201D;). In some women the symptoms are mild, and they will not need to use estrogens. In other women, symptoms can be more severe.</paragraph><list listType="unordered" styleCode="Disk"><item><content styleCode="bold">Treat moderate to severe menopausal changes in and around the vagina</content></item></list><paragraph>You and your healthcare provider should talk regularly about whether you still need treatment with DOTTI to control these problems. If you use DOTTI only to treat your menopausal changes in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.</paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Treat certain conditions in women before menopause if their ovaries do not produce enough estrogens naturally </content></item><item><content styleCode="bold">Help reduce your chances of getting osteoporosis (thin weak bones) </content></item></list><paragraph>Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use DOTTI to prevent osteoporosis due to 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 should continue treatment with DOTTI.</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Who should not use</content><content styleCode="bold"> DOTTI? Do not start using </content><content styleCode="bold">DOTTI if you: </content></paragraph><list listType="ordered" styleCode="Arabic"><item><content styleCode="bold">have unusual vaginal bleeding </content><paragraph>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. </paragraph></item><item><content styleCode="bold">have been diagnosed with a bleeding disorder</content></item><item><content styleCode="bold">currently have or have had certain cancers </content><paragraph>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 DOTTI.

><item><content styleCode="bold">currently have or have had certain cancers </content><paragraph>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 DOTTI. </paragraph></item><item><content styleCode="bold">had a stroke or heart attack </content></item><item><content styleCode="bold">currently have or have had blood clots </content></item><item><content styleCode="bold">currently have or have had liver problems </content></item><item><content styleCode="bold">are allergic to </content><content styleCode="bold">DOTTI or any of the ingredients in it</content></item></list><paragraph>See the list of ingredients in DOTTI at the end of this leaflet.</paragraph><paragraph><content styleCode="bold">Before you use</content><content styleCode="bold"> DOTTI, tell your healthcare provider about all of your medical conditions, including if you: </content></paragraph><list listType="ordered" styleCode="Arabic"><item><content styleCode="bold">have any unusual vaginal bleeding </content><paragraph>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. </paragraph></item><item><content styleCode="bold">have any other medical conditions that may become worse while you are using DOTTI</content><paragraph>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); problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. </paragraph></item><item><content styleCode="bold">are going to have surgery or will be on bed rest </content><paragraph>Your healthcare provider will let you know if you need to stop using DOTTI. </paragraph></item><item><content styleCode="bold">are pregnant or think you may be pregnant.</content><paragraph>DOTTI is not for pregnant women.</paragraph></item><item><content styleCode="bold">are breastfeeding </content></item></list><paragraph>The hormone in DOTTI can pass into your breast milk. </paragraph><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take,</content> including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how DOTTI works. DOTTI 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.</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">How should I use</content><content styleCode="bold"> DOTTI? </content><content styleCode="bold">For detailed instructions, see the step-by-step instructions for using </content><content styleCode="bold">DOTTI at the end of this Patient Information.</content></paragraph><list listType="unordered" styleCode="Disc"><item>Use DOTTI exactly as your healthcare provider tells you to use it. </item><item>DOTTI is for skin use only. </item><item>Change your DOTTI patch 2 times a week or every 3 to 4 days. </item><item>Apply your DOTTI patch to a clean, dry area on your lower abdomen. This area must be clean, dry, and free of powder, oil or lotion for your patch to stick to your skin. </item><item>Apply your DOTTI patch to a different area of your abdomen each time. Do not use the same application site 2 times in the same week. </item><item>Do not apply DOTTI to your breasts.

on your lower abdomen. This area must be clean, dry, and free of powder, oil or lotion for your patch to stick to your skin. </item><item>Apply your DOTTI patch to a different area of your abdomen each time. Do not use the same application site 2 times in the same week. </item><item>Do not apply DOTTI to your breasts. </item><item>If you forget to apply a new DOTTI patch, apply a new patch as soon as possible. </item><item>You and your healthcare provider should talk regularly (every 3 to 6 months) about your dose and whether you still need treatment with DOTTI. </item></list></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">How to change </content><content styleCode="bold">DOTTI</content></paragraph><list listType="unordered" styleCode="Disc"><item>When changing the patch, peel off the used patch slowly from the skin. </item><item>After removal of DOTTI if any adhesive residue remains on your skin, allow the area to dry for 15 minutes. Then, gently rub the area with oil or lotion to remove the adhesive from your skin. </item><item>Apply the new patch to a different area of your lower abdomen. This area must be clean, dry, cool and free of powder, oil, or lotion.</item></list></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What are the possible side effects of</content><content styleCode="bold"> DOTTI? </content><content styleCode="bold">Side effects are grouped by how serious they are and how often they happen when you are treated.

/td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What are the possible side effects of</content><content styleCode="bold"> DOTTI? </content><content styleCode="bold">Side effects are grouped by how serious they are and how often they happen when you are treated. </content><content styleCode="bold">Serious, but less common side effects include:</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>heart attack </item></list></td><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>high blood pressure</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>stroke</item></list></td><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>high levels of fat (triglyceride) in your blood</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>blood clots</item></list></td><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>liver problems</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>breast cancer</item></list></td><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>changes in your thyroid hormone levels</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>cancer of the lining of the uterus (womb)</item></list></td><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>fluid retention</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>cancer of the ovary</item></list></td><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>cancer changes of endometriosis</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>dementia</item></list></td><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>enlargement of benign tumors of the uterus (&#x201C;fibroids&#x201D;)</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>high or low blood calcium</item></list></td><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>worsening of swelling of face and tongue (angioedema) in women with a history of angioedema</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>gallbladder disease</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>visual abnormalities</item></list></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you: </content></paragraph><list listType="unordered" styleCode="Disc"><item>new breast lumps </item><item>unusual vaginal bleeding </item><item>changes in vision or speech </item><item>sudden new severe headaches </item><item>severe pains in your chest or legs with or without shortness of breath, weakness and fatigue</item><item>swelling of face and tongue with or without red, itchy bumps</item></list><paragraph><content styleCode="bold">Common side effects of DOTTI include:</content></paragraph></t

>sudden new severe headaches </item><item>severe pains in your chest or legs with or without shortness of breath, weakness and fatigue</item><item>swelling of face and tongue with or without red, itchy bumps</item></list><paragraph><content styleCode="bold">Common side effects of DOTTI include:</content></paragraph></t d></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>headache</item></list></td><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item> nausea and vomiting</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>breast pain</item></list></td><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item> hair loss</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>irregular vaginal bleeding or spotting</item></list></td><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item> fluid retention</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>painful periods</item></list></td><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item> vaginal yeast infection</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item>stomach or abdominal cramps, bloating</item></list></td><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item> redness and/or irritation at patch placement site</item></list></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>These are not all the possible side effects of DOTTI.

loating</item></list></td><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disk"><item> redness and/or irritation at patch placement site</item></list></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>These are not all the possible side effects of DOTTI. 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. </paragraph><paragraph>You may report side effects to FDA at 1-800-FDA-1088. You may report side effects to Amneal Pharmaceuticals (1-877-835-5472).</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What can I do to lower my chances of getting a serious side effect with</content><content styleCode="bold"> DOTTI? </content></paragraph><list listType="unordered" styleCode="Disc"><item>Talk with your healthcare provider regularly about whether you should continue using DOTTI. </item><item>If you have a uterus, talk to your healthcare provider about whether the addition of a progestogen 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). </item><item>See your healthcare provider right away if you get vaginal bleeding while using DOTTI. </item><item>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, you may need to have breast exams more often. </item><item>If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. </item></list><paragraph>Ask your healthcare provider for ways to lower your chances for getting heart disease.</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">How should I store and throw away used </content><content styleCode="bold">DOTTI patches? </content></paragraph><list listType="unordered" styleCode="Disc"><item>Store DOTTI at room temperature 68&#xB0; to 77&#xB0;F (20&#xB0; to 25&#xB0;C) </item><item>Do not store DOTTI patches outside of their pouches. Apply immediately upon removal from the protective pouch. </item><item>Used patches still contain estrogen. To throw away the patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place this container in the trash. Used patches should not be flushed in the toilet. </item></list><paragraph><content styleCode="bold">Keep </content><content styleCode="bold">DOTTI and all medicines out of the reach of children. </content><content styleCode="bold">General information about safe and effective use of </content><content styleCode="bold">DOTTI </content>Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use DOTTI for conditions for which it was not prescribed. Do not give DOTTI to other people, even if they have the same symptoms you have. It may harm them.</paragraph><paragraph>You can ask your healthcare provider or pharmacist for information about DOTTI that is written for health professionals. For more information, go to www.amneal.com or call the toll-free number Amneal Pharmaceuticals (1-877-835-5472).</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What are the ingredients in</content><content styleCode="bold"> DOTTI?

th professionals. For more information, go to www.amneal.com or call the toll-free number Amneal Pharmaceuticals (1-877-835-5472).</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What are the ingredients in</content><content styleCode="bold"> DOTTI? </content><content styleCode="bold">Active ingredient:</content> estradiol, USP <content styleCode="bold">Inactive ingredients:</content> a polyester and ethylene vinyl acetate copolymer film, acrylic and silicone adhesives, oleyl alcohol, NF, povidone, USP, dipropylene glycol and a polyester release liner. Distributed by: <content styleCode="bold">Amneal Pharmaceuticals LLC </content>Bridgewater, NJ 08807</paragraph><paragraph>Rev. 05-2024-03</paragraph></td></tr></tbody></table>

INSTRUCTIONS FOR USE DOTTI (dah ʹ tee) (estradiol transdermal system) Read this Instructions for Use before you start using DOTTI 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. 1. Determine Your Schedule for Your Twice-a-Week Application Decide upon which 2 days you will change your patch. Your DOTTI (estradiol transdermal system) individual carton contains a calendar card printed on its inner flap. Mark the 2-day schedule you plan to follow on your carton’s inner flap. Be consistent. If you forget to change your patch on the correct date, apply a new one as soon as you remember. No matter what day this happens, stick to the schedule you have marked on the inner flap of your carton (your calendar card). 2. Where to Apply DOTTI Apply patch to a dry area of the skin of the trunk of the body, including the lower abdomen, or buttocks. Avoid the waistline, since clothing may cause the patch to rub off. Do not apply patch to breasts. When changing your patch, based on your twice-a-week schedule, apply your new patch to a different site. Do not apply a new patch to that same area for at least 1 week. 3. Before You Apply DOTTI Make sure your skin is: Clean (freshly washed), dry and cool. Free of any powder, oil, moisturizer or lotion. Free of cuts or irritations (rashes or other skin problems). 4. How to Apply DOTTI Each patch is individually sealed in a protective pouch. Tear open the pouch at the tear notch (do not use scissors). Remove the patch. Apply the patch immediately after removing from the pouch. Holding the patch with the rigid protective liner facing you, remove half of the liner, which covers the sticky surface of the patch. Avoid touching the sticky side of the patch with your fingers. Using the other half of the rigid protective liner as a handle, apply the sticky side of the patch to the selected area of the abdomen or buttocks. Press the sticky side of the patch firmly into place. Smooth it down. While still holding the sticky side down, fold back the other half of the patch. Grasp an edge of the remaining protective liner and gently pull it off. Avoid touching the sticky side of the patch with your fingers. Press the entire patch firmly into place with the palm of your hand. Continue to apply pressure, with the palm of your hand over the patch, for approximately 10 seconds. Make sure that the patch is properly adhered to your skin. Go over the edges with your finger to ensure good contact around the patch. Note: Showering will not cause your patch to fall off. If your patch falls off reapply it. If you cannot reapply the patch, apply a new patch to another area and continue to follow your original placement schedule. If you stop using your DOTTI patch or forget to apply a new patch as scheduled, you may have spotting, or bleeding, and recurrence of symptoms. 5. Throwing Away Your Used Patch When it is time to change your patch, remove the old patch before you apply a new patch. To throw away the patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place the container in the trash. Used patches should not be flushed in the toilet. This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration. Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 05-2024-03

BOXED WARNING ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of “natural” estrogens results in a different endometrial risk profile than “synthetic” estrogens at equivalent estrogen doses. (See WARNINGS, Malignant neoplasms, Endometrial cancer .) CARDIOVASCULAR AND OTHER RISKS Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. (See WARNINGS, Cardiovascular disorders .) The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical Studies. ) The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy. (See CLINICAL PHARMACOLOGY, Clinical Studies. ) Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

DESCRIPTION Estradiol Tablets USP for oral administration contains 0.5, 1 or 2 mg of micronized estradiol, USP per tablet. Estradiol, USP (17β-estradiol) is a white to practically white powder, chemically described as estra-1,3,5,(10)-triene-3, 17β-diol. The structural formula is: C 18 H 24 O 2 M.W. 272.38 Inactive Ingredients: Colloidal silicon dioxide, corn starch, microcrystalline cellulose, lactose monohydrate, magnesium stearate, and sodium starch glycolate. In addition, the 1 mg also contains FD&C blue no. 1 aluminum lake and D&C red no. 27 aluminum lake. The 2 mg also contains FD&C blue no. 1 aluminum lake and D&C yellow no. 10 aluminum lake. FDA approved dissolution test specifications differ from USP. structure

CLINICAL PHARMACOLOGY 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, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. 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 follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Pharmacokinetics 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 sex hormone binding globulin (SHBG) and albumin. 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 the 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 gut 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. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Special Populations No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment. Drug Interactions 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 drug metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, 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 plasma concentrations of estrogens and may result in side effects.

ions of estrogens, 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 plasma concentrations of estrogens and may result in side effects. Clinical Studies Osteoporosis Most prospective studies of efficacy for this indication have been carried out in white menopausal women, without stratification by other risk factors, and tend to show a universally salutary effect on bone. The results of a two-year, randomized, placebo-controlled, double-blind, dose-ranging study have shown that treatment with 0.5 mg estradiol daily for 23 days (of a 28 day cycle) prevents vertebral bone mass loss in postmenopausal women. When estrogen therapy is discontinued, bone mass declines at a rate comparable to the immediate postmenopausal period. There is no evidence that estrogen replacement therapy restores bone mass to premenopausal levels. Women’s Health Initiative Studies The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

ncer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms. The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 1 below: Table 1: RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHI* Event † Relative Risk CE/MPA vs placebo at 5.2 Years (95% CI ‡ ) Placebo n = 8102 CE/MPA n = 8506 Absolute Risk per 10,000 Women-Years CHD events Non-fatal MI CHD death 1.29 (1.02 to 1.63) 1.32 (1.02 to 1.72) 1.18 (0.70 to 1.97) 30 23 6 37 30 7 Invasive breast cancer § 1.26 (1.00 to 1.59) 30 38 Stroke 1.41 (1.07 to 1.85) 21 29 Pulmonary embolism 2.13 (1.39 to 3.25) 8 16 Colorectal cancer 0.63 (0.43 to 0.92) 16 10 Endometrial cancer 0.83 (0.47 to 1.47) 6 5 Hip fracture 0.66 (0.45 to 0.98) 15 10 Death due to causes other than the events above 0.92 (0.74 to 1.14) 40 37 Global Index † 1.15 (1.03 to 1.28) 151 170 Deep vein thrombosis ¶ 2.07 (1.49 to 2.87) 13 26 Vertebral fractures ¶ 0.66 (0.44 to 0.98) 15 9 Other osteoporotic fractures ¶ 0.77 (0.69 to 0.86) 170 131 * adapted from JAMA, 2002; 288:321-333 † 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, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes ‡ nominal confidence intervals unadjusted for multiple looks and multiple comparisons § includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer ¶ not included in Global Index For those outcomes included in the “global index,” the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 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. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS .) Women’s Health Initiative Memory Study The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo. After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNING and WARNINGS, Dementia .)

INDICATIONS & USAGE Estradiol tablets are indicated in the: 1. Treatment of moderate to severe vasomotor symptoms associated with the menopause. 2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. 3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure. 4. Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease. 5. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only). 6. Prevention of osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. (See CLINICAL PHARMACOLOGY , Clinical Studies. ) The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400 to 800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.

CONTRAINDICATIONS Estrogens should not be used in individuals with any of the following conditions: 1. Undiagnosed abnormal genital bleeding. 2. Known, suspected or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease. 3. Known or suspected estrogen-dependent neoplasia. 4. Active deep vein thrombosis, pulmonary embolism or history of these conditions. 5. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction. 6. Liver dysfunction or disease. 7. Estradiol tablets should not be used in patients with known hypersensitivity to its ingredients. 8. Known or suspected pregnancy. There is no indication for estradiol tablets in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. (See PRECAUTIONS .)

WARNINGS See BOXED WARNINGS. 1. Cardiovascular disorders Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected estrogens should be discontinued immediately. Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. a. Coronary heart disease and stroke In the Women’s Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing . (See CLINICAL PHARMACOLOGY, Clinical Studies .) In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 women-years). The increase in risk was observed in year one and persisted. In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted. In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA (0.625 mg/2.5 mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one 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/MPA group and the placebo group in HERS, HERS II, and overall. Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. b. Venous thromboembolism (VTE) In the Women’s Health Initiative (WHI) study, an increase in VTE has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing. (See CLINICAL PHARMACOLOGY, Clinical Studies .) In the CE/MPA substudy of WHI, a 2 fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted.

p venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2. Malignant neoplasms a. Endometrial cancer The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12- fold 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 one year. The greatest risk appears associated with prolonged use with increased risks of 15- to 24-fold for five to ten years or more and this risk persists for 8 to over 15 years after estrogen therapy is discontinued. Clinical surveillance of all women taking estrogen/progestin combinations is important (see PRECAUTIONS ). Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal 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 progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. b. Breast cancer The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) substudy of CE/MPA (see CLINICAL PHARMACOLOGY , Clinical Studies ). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration. The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy. In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01 to 1.54), and the overall absolute risk was 41 vs 33 cases per 10,000 women-years, for CE/MPA compared with placebo. 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 vs 25 cases per 10,000 women-years, for CE/MPA compared with placebo.

.54), and the overall absolute risk was 41 vs 33 cases per 10,000 women-years, for CE/MPA compared with placebo. 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 vs 25 cases per 10,000 women-years, for CE/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 vs 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA 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. The use of 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. c. Ovarian cancer The WHI estrogen plus progestin substudy reported a statistically non-significant increased 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). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years. 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 to 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. 3. Dementia In the Women’s Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 to 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use . ) It is unknown whether these findings apply to estrogen alone therapy. 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.

men. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use . ) It is unknown whether these findings apply to estrogen alone therapy. 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. Hypercalcemia Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level. 6. Visual abnormalities Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.

PRECAUTIONS A. General Precautions 1. Addition of a progestin when a woman has not had a hysterectomy Studies of the addition of a progestin 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 which may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer. 2. 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 estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use. 3. Hypertriglyceridemia In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. 4. Impaired liver function and past history of cholestatic jaundice Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. 5. Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients 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. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. 6. Fluid retention Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. 7. Hypocalcemia Estrogens should be used with caution in individuals with severe hypocalcemia. 8. Exacerbation of endometriosis Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. 9. Exacerbation of other conditions Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. B. Patient Information Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe estradiol tablets. C. Laboratory Tests Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH).

are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe estradiol tablets. C. Laboratory Tests Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH). (See DOSAGE AND ADMINISTRATION section.) D. Drug/Laboratory Test Interactions 1. 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 betathromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, 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. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). 4. Increased plasma HDL and HDL 2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels. 5. Impaired glucose tolerance. 6. Reduced response to metyrapone test. E. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS .) 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. F. Pregnancy Estradiol tablets should not be used during pregnancy. (See CONTRAINDICATIONS . ) G. Nursing Mothers Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when estradiol is administered to a nursing woman. H. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Large and repeated doses of estrogen over an extended period of time have been shown to accelerate epiphyseal closure, resulting in short adult stature if treatment is initiated before the completion of physiologic puberty in normally developing children. In patients in whom bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended. Estrogen treatment of prepubertal children also induces premature breast development and vaginal cornification, and may potentially induce vaginal bleeding in girls. In boys, estrogen treatment may modify the normal pubertal process. All other physiological and adverse reactions shown to be associated with estrogen treatment of adults could potentially occur in the pediatric population, including thromboembolic disorders and growth stimulation of certain tumors.

bleeding in girls. In boys, estrogen treatment may modify the normal pubertal process. All other physiological and adverse reactions shown to be associated with estrogen treatment of adults could potentially occur in the pediatric population, including thromboembolic disorders and growth stimulation of certain tumors. Therefore, estrogens should only be administered to pediatric patients when clearly indicated and the lowest effective dose should always be utilized. I. Geriatric Use The safety and efficacy of estradiol tablets in geriatric patients has not been established. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greatest frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer’s disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See WARNINGS, Dementia . ) It is unknown whether these findings apply to estrogen alone therapy.

A. General Precautions 1. Addition of a progestin when a woman has not had a hysterectomy Studies of the addition of a progestin 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 which may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer. 2. 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 estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use. 3. Hypertriglyceridemia In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. 4. Impaired liver function and past history of cholestatic jaundice Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. 5. Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients 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. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. 6. Fluid retention Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. 7. Hypocalcemia Estrogens should be used with caution in individuals with severe hypocalcemia. 8. Exacerbation of endometriosis Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. 9. Exacerbation of other conditions Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

C. Laboratory Tests Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH). (See DOSAGE AND ADMINISTRATION section.)

D. Drug/Laboratory Test Interactions 1. 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 betathromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, 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. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). 4. Increased plasma HDL and HDL 2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels. 5. Impaired glucose tolerance. 6. Reduced response to metyrapone test.

E. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS .) 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.

G. Nursing Mothers Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when estradiol is administered to a nursing woman.

H. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Large and repeated doses of estrogen over an extended period of time have been shown to accelerate epiphyseal closure, resulting in short adult stature if treatment is initiated before the completion of physiologic puberty in normally developing children. In patients in whom bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended. Estrogen treatment of prepubertal children also induces premature breast development and vaginal cornification, and may potentially induce vaginal bleeding in girls. In boys, estrogen treatment may modify the normal pubertal process. All other physiological and adverse reactions shown to be associated with estrogen treatment of adults could potentially occur in the pediatric population, including thromboembolic disorders and growth stimulation of certain tumors. Therefore, estrogens should only be administered to pediatric patients when clearly indicated and the lowest effective dose should always be utilized.

I. Geriatric Use The safety and efficacy of estradiol tablets in geriatric patients has not been established. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greatest frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer’s disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See WARNINGS, Dementia . ) It is unknown whether these findings apply to estrogen alone therapy.

ADVERSE REACTIONS See BOXED WARNINGS, WARNINGS , and PRECAUTIONS . The following additional adverse reactions have been reported with estrogen and/or progestin therapy. 1. Genitourinary system Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding, spotting, dysmenorrhea 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 2. Breasts Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer 3. Cardiovascular Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure 4. Gastrointestinal Nausea, vomiting Abdominal cramps, bloating Cholestatic jaundice Increased incidence of gallbladder disease Pancreatitis Enlargement of hepatic hemangiomas 5. Skin Chloasma or melasma that may persist when drug is discontinued Erythema multiforme Erythema nodosum Hemorrhagic eruption Loss of scalp hair Hirsutism Pruritus, rash 6. Eyes Retinal vascular thrombosis Steepening of corneal curvature Intolerance to contact lenses 7. Central Nervous System Headache, migraine, dizziness Mental depression Chorea Nervousness, mood disturbances, irritability Exacerbation of epilepsy Dementia 8. Miscellaneous Increase or decrease in weight Reduced carbohydrate tolerance Aggravation of porphyria Edema Arthralgias; leg cramps Changes in libido Urticaria Angioedema Anaphylactoid/anaphylactic reactions Hypocalcemia Exacerbation of asthma Increased triglycerides To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

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

DOSAGE & ADMINISTRATION When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS ). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. Patients should be started at the lowest dose for the indication. 1. For treatment of moderate to severe vasomotor symptoms, vulval and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible. Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals. The usual initial dosage range is 1 to 2 mg daily of estradiol adjusted as necessary to control presenting symptoms. The minimal effective dose for maintenance therapy should be determined by titration. Administration should be cyclic (e.g., 3 weeks on and 1 week off). 2. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure. Treatment is usually initiated with a dose of 1 to 2 mg daily of estradiol, adjusted as necessary to control presenting symptoms; the minimal effective dose for maintenance therapy should be determined by titration. 3. For treatment of breast cancer, for palliation only, in appropriately selected women and men with metastatic disease. Suggested dosage is 10 mg three times daily for a period of at least three months. 4. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only. Suggested dosage is 1 to 2 mg three times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as by symptomatic improvement of the patient. 5. For prevention of osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. The lowest effective dose of estradiol has not been determined.

HOW SUPPLIED Estradiol Tablets, USP are available as: 0.5 mg: White to off-white, oval, flat-faced, beveled-edge, scored tablet debossed with N and 564on the scored side and plain on the other side, packaged in; bottles of 30 (NDC 68788-8626-3) bottles of 60 (NDC 68788-8626-6) bottles of 90 (NDC 68788-8626-9) bottles of 100 (NDC 68788-8626-1) Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. All trademarks are the property of their respective owners. Distributed by: ANI Pharmaceuticals, Inc. Baudette, MN 56623 Repackaged By: Preferred Pharmaceuticals, Inc. Issued: 04/2024 LB4452-01

PATIENT INFORMATION Estradiol (es″ tra dye′ ol) Tablets, USP Read this PATIENT INFORMATION before you start taking estradiol tablets and read what you get each time you refill estradiol tablets. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT ESTRADIOL TABLETS (AN ESTROGEN HORMONE)? • Estrogens increase the chances of getting cancer of the uterus. Report any unusual vaginal bleeding right away while you are taking estrogens. 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. • Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes. Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may increase your risk of dementia. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol tablets. WHAT ARE ESTRADIOL TABLETS? Estradiol tablets are a medicine that contains estrogen hormones. WHAT IS ESTRADIOL USED FOR? Estradiol is used to: • reduce moderate to severe hot flashes Estrogens are hormones made by a woman's ovaries. Between ages 45 and 55, the ovaries normally stop making estrogens. This leads to a drop in body estrogen levels which 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 the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild, and they will not need estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol. Weight-bearing exercise, like walking or running, and taking calcium with vitamin D supplements may also lower your chances for getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your healthcare provider before starting them. • treat dryness , itching, and burning in or around the vagina, difficulty or burning on urination associated with menopause You and your healthcare provider should talk regularly about whether you still need treatment with estradiol to control these problems. If you use estradiol only to treat your dryness, itching, and burning in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you. • treat certain conditions in which a young woman's ovaries do not produce enough estrogen naturally • treat certain types of abnormal vaginal bleeding due to hormonal imbalance when your doctor has found no serious cause of the bleeding • treat certain cancers in special situations, in men and women • prevent thinning of bones Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break.

certain types of abnormal vaginal bleeding due to hormonal imbalance when your doctor has found no serious cause of the bleeding • treat certain cancers in special situations, in men and women • prevent thinning of bones Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use estradiol 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 should continue with estradiol. WHO SHOULD NOT USE ESTRADIOL? Do not start taking estradiol if you: • have unusual vaginal bleeding which has not been evaluated by your doctor (see BOXED WARNINGS) Unusual vaginal bleeding can be a warning sign of cancer of the uterus, especially if it happens after menopause. Your doctor must find out the cause of the bleeding so that he or she can recommend the proper treatment. Taking estrogens without visiting your doctor can cause you serious harm if your vaginal bleeding is caused by cancer of the uterus. • currently have or have had certain cancers Estrogens may increase the risk of certain types of cancer, including cancer of the breast or uterus. If you have or had cancer, talk with your healthcare provider about whether you should take estradiol. (For certain patients with breast or prostate cancer, estrogens may help.) • had a stroke or heart attack in the past year • currently have or have had blood clots • have or have had liver problems • are allergic to estradiol tablets or any of its ingredients See the end of this leaflet for a list of ingredients in estradiol tablets. • think you may be pregnant Tell your healthcare provider: • if you are breast feeding The hormone in estradiol can pass into your milk • about all of your medical problems Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. • about all the medicines you take This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how estradiol tablets work. Estradiol tablets may also affect how your other medicines work. • if you are going to have surgery or will be on bed rest You may need to stop taking estrogens. HOW SHOULD I TAKE ESTRADIOL TABLETS? 1. Start at the lowest dose and talk to your healthcare provider about how well that doseis working for you. 2. Estrogens should be used at the lowest dose possible for your treatment only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with estradiol. WHAT ARE THE POSSIBLE SIDE EFFECTS OF ESTROGENS? Less common but serious side effects include : • Breast cancer • Cancer of the uterus • Stroke • Heart attack • Blood clots • Dementia • Gallbladder disease • Ovarian cancer These are some of the warning signs of the serious side effects : • Breast lumps • Unusual vaginal bleeding • Dizziness and faintness • Changes in speech • Severe headaches • Chest pain • Shortness of breath • Pains in your legs • Changes in vision • Vomiting Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.

Breast lumps • Unusual vaginal bleeding • Dizziness and faintness • Changes in speech • Severe headaches • Chest pain • Shortness of breath • Pains in your legs • Changes in vision • Vomiting Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you. Common side effects include : • Headache • Breast pain • Irregular vaginal bleeding or spotting • Stomach/abdominal cramps, bloating • Nausea and vomiting • Hair loss Other side effects include : • High blood pressure • Liver problems • High blood sugar • Fluid retention • Enlargement of benign tumors (“fibroids”) of the uterus • A spotty darkening of the skin, particularly on the face • Vaginal yeast infection These are not all the possible side effects of estradiol tablets. For more information, ask your healthcare provider or pharmacist. WHAT CAN I DO TO LOWER MY CHANCES OF A SERIOUS SIDE EFFECT WITH ESTRADIOL? If you use estrogens, you can reduce your risks by doing these things: • Talk with your healthcare provider: • While you are using estrogens, it is important to visit your doctor at least once a year for a check-up. • If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you. • See your healthcare provider right away if you have vaginal bleeding while taking estradiol tablets. • Have a 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 xray), you may need to have more frequent breast examinations. • If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease. • Talk with your healthcare provider regularly about whether you should continue taking estradiol tablets. You and your doctor should reevaluate whether or not you still need estrogens at least every six months. • Be alert for signs of trouble If any of these warning signals (or any other unusual symptoms) happen while you are using estrogens, call your doctor immediately: Abnormal bleeding from the vagina (possible uterine cancer) Pains in the calves or chest, sudden shortness of breath, or coughing blood (possible clot in the legs, or lungs) Severe headache or vomiting, dizziness, faintness, changes in vision or speech, weakness or numbness of an arm or leg (possible clot in the brain or eye) Breast lumps (possible breast cancer; ask your doctor or health professional to show you how to examine your breasts monthly) Yellowing of the skin or eyes (possible liver problem) Pain, swelling, or tenderness in the abdomen (possible gallbladder problem) Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. GENERAL INFORMATION ABOUT SAFE AND EFFECTIVE USE OF ESTRADIOL TABLETS Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take estradiol tablets for conditions for which they were not prescribed. Do not give estradiol tablets to other people, even if they have the same symptoms you have. They may harm them. KEEP ESTRADIOL TABLETS OUT OF THE REACH OF CHILDREN This leaflet provides a summary of the most important information about estradiol tablets. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about estradiol tablets that is written for health professionals. For more information about estradiol, please contact ANI Pharmaceuticals, Inc at 1-855-204-1431 .

rtant information about estradiol tablets. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about estradiol tablets that is written for health professionals. For more information about estradiol, please contact ANI Pharmaceuticals, Inc at 1-855-204-1431 . WHAT ARE THE INGREDIENTS IN ESTRADIOL TABLETS? Inactive Ingredients: Colloidal silicon dioxide, corn starch, microcrystalline cellulose, lactose monohydrate,magnesium stearate,and sodium starch glycolate. In addition, the 1 mg also contains FD&C blue no. 1 aluminum lake and D&C red no. 27 aluminum lake.The 2 mg also contains FD&C blue no. 1 aluminum lake and D&C yellow no. 10 aluminum lake. All trademarks are the property of their respective owners. Distributed by: ANI Pharmaceuticals, Inc. Baudette, MN 56623 Issued: 04/2024 LB4452-01 Repackaged By: Preferred Pharmaceuticals, Inc.

<table cellpadding="0pt" cellspacing="0pt" width="100%"><col width="98%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT ESTRADIOL TABLETS (AN ESTROGEN HORMONE)?</content> </paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Estrogens increase the chances of getting cancer of the uterus. Report any unusual vaginal bleeding right away while you are taking estrogens. 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. </item><item><caption>&#x2022;</caption>Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes.</item></list><paragraph> Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may increase your risk of dementia. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol tablets. </paragraph></td></tr></tbody></table>

INDICATIONS & USAGE Estradiol tablets are indicated in the: Treatment of moderate to severe vasomotor symptoms associated with the menopause. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure. Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only). Prevention of osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. (See CLINICAL PHARMACOLOGY , Clinical Studies. ) The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400 to 800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.

CONTRAINDICATIONS Estrogens should not be used in individuals with any of the following conditions: Undiagnosed abnormal genital bleeding. Known, suspected or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease. Known or suspected estrogen-dependent neoplasia. Active deep vein thrombosis, pulmonary embolism or history of these conditions. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction. Liver dysfunction or disease. Estradiol tablets should not be used in patients with known hypersensitivity to its ingredients. Known or suspected pregnancy. There is no indication for estradiol tablets in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. (See PRECAUTIONS .)

are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe estradiol tablets. C. Laboratory Tests Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH). (See DOSAGE AND ADMINISTRATION section.) D. 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 betathromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, 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. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). Increased plasma HDL and HDL 2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels. Impaired glucose tolerance. Reduced response to metyrapone test. E. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS .) 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. F. Pregnancy Estradiol tablets should not be used during pregnancy. (See CONTRAINDICATIONS . ) G. Nursing Mothers Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when estradiol is administered to a nursing woman. H. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Large and repeated doses of estrogen over an extended period of time have been shown to accelerate epiphyseal closure, resulting in short adult stature if treatment is initiated before the completion of physiologic puberty in normally developing children. In patients in whom bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended. Estrogen treatment of prepubertal children also induces premature breast development and vaginal cornification, and may potentially induce vaginal bleeding in girls. In boys, estrogen treatment may modify the normal pubertal process. All other physiological and adverse reactions shown to be associated with estrogen treatment of adults could potentially occur in the pediatric population, including thromboembolic disorders and growth stimulation of certain tumors.

D. 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 betathromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, 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. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). Increased plasma HDL and HDL 2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels. Impaired glucose tolerance. Reduced response to metyrapone test.

HOW SUPPLIED Estradiol Tablets, USP are available as: 1 mg: Light purple, oval, flat-faced, beveled-edge, scored tablet debossed with N and 565 on the scored side and plain on the other side, packaged in bottles of 30 (NDC 82868-038-30) and 90 (NDC 82868-038-90). Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. All trademarks are the property of their respective owners. Distributed by: ANI Pharmaceuticals, Inc. Baudette, MN 56623 Issued:04/2024 LB4452-01

PATIENT INFORMATION Estradiol (es″ tra dye′ ol) Tablets, USP Read this PATIENT INFORMATION before you start taking estradiol tablets and read what you get each time you refill estradiol tablets. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT ESTRADIOL TABLETS (AN ESTROGEN HORMONE)? Estrogens increase the chances of getting cancer of the uterus. Report any unusual vaginal bleeding right away while you are taking estrogens. 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. Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes. Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may increase your risk of dementia. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol tablets. WHAT ARE ESTRADIOL TABLETS? Estradiol tablets are a medicine that contains estrogen hormones. WHAT IS ESTRADIOL USED FOR? Estradiol is used to: reduce moderate to severe hot flashes Estrogens are hormones made by a woman's ovaries. Between ages 45 and 55, the ovaries normally stop making estrogens. This leads to a drop in body estrogen levels which 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 the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild, and they will not need estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol. Weight-bearing exercise, like walking or running, and taking calcium with vitamin D supplements may also lower your chances for getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your healthcare provider before starting them. treat dryness , itching, and burning in or around the vagina, difficulty or burning on urination associated with menopause You and your healthcare provider should talk regularly about whether you still need treatment with estradiol to control these problems. If you use estradiol only to treat your dryness, itching, and burning in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you. treat certain conditions in which a young woman's ovaries do not produce enough estrogen naturally treat certain types of abnormal vaginal bleeding due to hormonal imbalance when your doctor has found no serious cause of the bleeding treat certain cancers in special situations, in men and women prevent thinning of bones Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break.

reat certain types of abnormal vaginal bleeding due to hormonal imbalance when your doctor has found no serious cause of the bleeding treat certain cancers in special situations, in men and women prevent thinning of bones Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use estradiol 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 should continue with estradiol. WHO SHOULD NOT USE ESTRADIOL? Do not start taking estradiol if you: have unusual vaginal bleeding which has not been evaluated by your doctor (see BOXED WARNINGS) Unusual vaginal bleeding can be a warning sign of cancer of the uterus, especially if it happens after menopause. Your doctor must find out the cause of the bleeding so that he or she can recommend the proper treatment. Taking estrogens without visiting your doctor can cause you serious harm if your vaginal bleeding is caused by cancer of the uterus. currently have or have had certain cancers Estrogens may increase the risk of certain types of cancer, including cancer of the breast or uterus. If you have or had cancer, talk with your healthcare provider about whether you should take estradiol. (For certain patients with breast or prostate cancer, estrogens may help.) had a stroke or heart attack in the past year currently have or have had blood clots have or have had liver problems are allergic to estradiol tablets or any of its ingredients See the end of this leaflet for a list of ingredients in estradiol tablets. think you may be pregnant Tell your healthcare provider: if you are breast feeding The hormone in estradiol can pass into your milk about all of your medical problems Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. about all the medicines you take This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how estradiol tablets work. Estradiol tablets may also affect how your other medicines work. if you are going to have surgery or will be on bed rest You may need to stop taking estrogens. HOW SHOULD I TAKE ESTRADIOL TABLETS? Start at the lowest dose and talk to your healthcare provider about how well that doseis working for you. Estrogens should be used at the lowest dose possible for your treatment only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with estradiol. WHAT ARE THE POSSIBLE SIDE EFFECTS OF ESTROGENS? Less common but serious side effects include : Breast cancer Cancer of the uterus Stroke Heart attack Blood clots Dementia Gallbladder disease Ovarian cancer These are some of the warning signs of the serious side effects : Breast lumps Unusual vaginal bleeding Dizziness and faintness Changes in speech Severe headaches Chest pain Shortness of breath Pains in your legs Changes in vision Vomiting Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.

ous side effects : Breast lumps Unusual vaginal bleeding Dizziness and faintness Changes in speech Severe headaches Chest pain Shortness of breath Pains in your legs Changes in vision Vomiting Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you. Common side effects include : Headache Breast pain Irregular vaginal bleeding or spotting Stomach/abdominal cramps, bloating Nausea and vomiting Hair loss Other side effects include : High blood pressure Liver problems High blood sugar Fluid retention Enlargement of benign tumors (“fibroids”) of the uterus A spotty darkening of the skin, particularly on the face Vaginal yeast infection These are not all the possible side effects of estradiol tablets. For more information, ask your healthcare provider or pharmacist. WHAT CAN I DO TO LOWER MY CHANCES OF A SERIOUS SIDE EFFECT WITH ESTRADIOL? If you use estrogens, you can reduce your risks by doing these things: Talk with your healthcare provider: While you are using estrogens, it is important to visit your doctor at least once a year for a check-up. If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you. See your healthcare provider right away if you have vaginal bleeding while taking estradiol tablets. Have a 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 xray), you may need to have more frequent breast examinations. If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease. Talk with your healthcare provider regularly about whether you should continue taking estradiol tablets. You and your doctor should reevaluate whether or not you still need estrogens at least every six months. Be alert for signs of trouble If any of these warning signals (or any other unusual symptoms) happen while you are using estrogens, call your doctor immediately: Abnormal bleeding from the vagina (possible uterine cancer) Pains in the calves or chest, sudden shortness of breath, or coughing blood (possible clot in the legs, or lungs) Severe headache or vomiting, dizziness, faintness, changes in vision or speech, weakness or numbness of an arm or leg (possible clot in the brain or eye) Breast lumps (possible breast cancer; ask your doctor or health professional to show you how to examine your breasts monthly) Yellowing of the skin or eyes (possible liver problem) Pain, swelling, or tenderness in the abdomen (possible gallbladder problem) Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. GENERAL INFORMATION ABOUT SAFE AND EFFECTIVE USE OF ESTRADIOL TABLETS Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take estradiol tablets for conditions for which they were not prescribed. Do not give estradiol tablets to other people, even if they have the same symptoms you have. They may harm them. KEEP ESTRADIOL TABLETS OUT OF THE REACH OF CHILDREN This leaflet provides a summary of the most important information about estradiol tablets. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about estradiol tablets that is written for health professionals. For more information about estradiol, please contact ANI Pharmaceuticals, Inc at 1-855-204-1431 . WHAT ARE THE INGREDIENTS IN ESTRADIOL TABLETS?

ou would like more information, talk with your healthcare provider or pharmacist. You can ask for information about estradiol tablets that is written for health professionals. For more information about estradiol, please contact ANI Pharmaceuticals, Inc at 1-855-204-1431 . WHAT ARE THE INGREDIENTS IN ESTRADIOL TABLETS? Inactive Ingredients: Colloidal silicon dioxide, corn starch, microcrystalline cellulose, lactose monohydrate,magnesium stearate,and sodium starch glycolate. In addition, the 1 mg also contains FD&C blue no. 1 aluminum lake and D&C red no. 27 aluminum lake.The 2 mg also contains FD&C blue no. 1 aluminum lake and D&C yellow no. 10 aluminum lake. All trademarks are the property of their respective owners. Distributed by: ANI Pharmaceuticals, Inc. Baudette, MN 56623 Issued: 04/2024 LB4452-01

<table cellspacing="0" cellpadding="0" border="0"><tbody><tr><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT ESTRADIOL TABLETS (AN ESTROGEN HORMONE)?</content> <list listType="unordered" styleCode="Disc"><item>Estrogens increase the chances of getting cancer of the uterus. Report any unusual vaginal bleeding right away while you are taking estrogens. 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. </item><item>Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes.</item></list> Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may increase your risk of dementia. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol tablets. </td></tr></tbody></table>

BOXED WARNING ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of “natural” estrogens results in a different endometrial risk profile than “synthetic” estrogens at equivalent estrogen doses (See WARNINGS, Malignant neoplasms, Endometrial cancer ). CARDIOVASCULAR AND OTHER RISKS Estrogens with or without progestins should not be used for the prevention of cardiovascular disease (See WARNINGS, Cardiovascular disorders ). The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo (See CLINICAL PHARMACOLOGY, Clinical Studies ). The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy (See CLINICAL PHARMACOLOGY, Clinical Studies ). Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

DESCRIPTION Estradiol tablets, USP for oral administration contains 0.5, 1 or 2 mg of micronized estradiol, USP per tablet. Estradiol, USP (17β-estradiol) is a white, crystalline solid, chemically described as estra-1,3,5,(10)-triene-3, 17β-diol. The structural formula is: In addition, each tablet for oral administration contains the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. Structure formula.jpg

ncer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms. The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 1 below: Table 1: RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHI 1 Event 2 Relative Risk CE/MPA vs placebo at 5.2 Years (95% CI 3 ) Placebo n = 8102 CE/MPA n = 8506 Absolute Risk per 10,000 Women-Years CHD events Non-fatal MI CHD death 1.29 (1.02 to 1.63) 1.32 (1.02 to 1.72) 1.18 (0.70 to 1.97) 30 23 6 37 30 7 Invasive breast cancer 4 1.26 (1 to 1.59) 30 38 Stroke 1.41 (1.07 to 1.85) 21 29 Pulmonary embolism 2.13 (1.39 to 3.25) 8 16 Colorectal cancer 0.63 (0.43 to 0.92) 16 10 Endometrial cancer 0.83 (0.47 to 1.47) 6 5 Hip fracture 0.66 (0.45 to 0.98) 15 10 Death due to causes other than the events above 0.92 (0.74 to 1.14) 40 37 Global Index 2 1.15 (1.03 to 1.28) 151 170 Deep vein thrombosis 5 2.07 (1.49 to 2.87) 13 26 Vertebral fractures 5 0.66 (0.44 to 0.98) 15 9 Other osteoporotic fractures 5 0.77 (0.69 to 0.86) 170 131 1 adapted from JAMA, 2002; 288:321-333 2 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, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes 3 nominal confidence intervals unadjusted for multiple looks and multiple comparisons 4 includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer 5 not included in Global Index For those outcomes included in the “global index,” the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 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. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality (See BOXED WARNINGS , WARNINGS , and PRECAUTION S). Women’s Health Initiative Memory Study The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo. After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women (See BOXED WARNING and WARNINGS, Dementia ).

Pharmacokinetics 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 sex hormone binding globulin (SHBG) and albumin. 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 the 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 gut 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. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Special Populations No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment. Drug Interactions 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 drug metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, 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 plasma concentrations of estrogens and may result in side effects.

Clinical Studies Osteoporosis Most prospective studies of efficacy for this indication have been carried out in white menopausal women, without stratification by other risk factors, and tend to show a universally salutary effect on bone. The results of a two-year, randomized, placebo-controlled, double-blind, dose-ranging study have shown that treatment with 0.5 mg estradiol daily for 23 days (of a 28 day cycle) prevents vertebral bone mass loss in postmenopausal women. When estrogen therapy is discontinued, bone mass declines at a rate comparable to the immediate postmenopausal period. There is no evidence that estrogen replacement therapy restores bone mass to premenopausal levels. Women’s Health Initiative Studies The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

<table width="100%" styleCode="Noautorules"><col width="42%"/><col width="20%"/><col width="20%"/><col width="18%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Event ²</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Relative Risk</paragraph><paragraph>CE/MPA vs placebo</paragraph><paragraph>at 5.2 Years</paragraph><paragraph>(95% CI ³) </paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Placebo</paragraph><paragraph>n = 8102</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>CE/MPA</paragraph><paragraph>n = 8506</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Absolute Risk per 10,000</paragraph><paragraph>Women-Years</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>CHD events Non-fatal MI CHD death</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.29 (1.02 to 1.63)</paragraph><paragraph>1.32 (1.02 to 1.72)</paragraph><paragraph>1.18 (0.70 to 1.97)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>30</paragraph><paragraph>23</paragraph><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>37</paragraph><paragraph>30</paragraph><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Invasive breast cancer ⁴</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.26 (1 to 1.59)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>30</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>38</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Stroke</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.41 (1.07 to 1.85)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>21</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>29</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Pulmonary embolism</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.13 (1.39 to 3.25)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Colorectal cancer</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.63 (0.43 to 0.92)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Endometrial cancer</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top

lign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Endometrial cancer</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top "><paragraph>0.83 (0.47 to 1.47)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hip fracture</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.66 (0.45 to 0.98)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Death due to causes other than the events above</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.92 (0.74 to 1.14)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>40</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>37</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Global Index ²</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.15 (1.03 to 1.28)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>151</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>170</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Deep vein thrombosis ⁵</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.07 (1.49 to 2.87)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>26</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vertebral fractures ⁵</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.66 (0.44 to 0.98)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Other osteoporotic fractures ⁵</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.77 (0.69 to 0.86)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>170</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>131</paragraph></td></tr></tbody></table>

INDICATIONS AND USAGE Estradiol tablets are indicated in the: Treatment of moderate to severe vasomotor symptoms associated with the menopause. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure. Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only). Prevention of osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate (See CLINICAL PHARMACOLOGY, Clinical Studies ). The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400 to 800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.

CONTRAINDICATIONS Estrogens should not be used in individuals with any of the following conditions: Undiagnosed abnormal genital bleeding. Known, suspected or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease. Known or suspected estrogen-dependent neoplasia. Active deep vein thrombosis, pulmonary embolism or history of these conditions. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction). Liver dysfunction or disease. Estradiol tablets should not be used in patients with known hypersensitivity to its ingredients. Known or suspected pregnancy. There is no indication for estradiol tablets in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy (See PRECAUTIONS ).

WARNINGS See BOXED WARNINGS. 1. Cardiovascular disorders Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected estrogens should be discontinued immediately. Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. a. Coronary heart disease and stroke In the Women’s Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing (See CLINICAL PHARMACOLOGY, Clinical Studies ). In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 women-years). The increase in risk was observed in year one and persisted. In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted. In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA (0.625 mg/2.5 mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one 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/MPA group and the placebo group in HERS, HERS II, and overall. Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. b. Venous thromboembolism (VTE) In the Women’s Health Initiative (WHI) study, an increase in VTE has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing (See CLINICAL PHARMACOLOGY, Clinical Studies ). In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted.

p venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2. Malignant neoplasms a. Endometrial cancer The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold 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 one year. The greatest risk appears associated with prolonged use with increased risks of 15- to 24-fold for five to ten years or more and this risk persists for 8 to over 15 years after estrogen therapy is discontinued. Clinical surveillance of all women taking estrogen/progestin combinations is important (see PRECAUTIONS ). Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal 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 progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. b. Breast cancer The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. 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. 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.: The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)‑alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80].

trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)‑alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80]. Consistent with the Women's Health Initiative (WHI clinical trials), observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy and a smaller, but still 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 the risk with estrogen-alone therapy. However, these studies have not 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. c. Ovarian Cancer The WHI estrogen plus progestin substudy reported a statistically non-significant increased 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, 0.77-3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years. 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. 3. Dementia In the Women’s Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 – 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS.

eing treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 – 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use ). It is unknown whether these findings apply to estrogen alone therapy. 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. Hypercalcemia Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level. 6. Visual abnormalities Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.

PRECAUTIONS A. General 1. Addition of a progestin when a woman has not had a hysterectomy Studies of the addition of a progestin 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 which may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer. 2. 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 estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use. 3. Hypertriglyceridemia In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. 4. Impaired liver function and past history of cholestatic jaundice Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. 5. Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients 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. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. 6. Fluid retention Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. 7. Hypocalcemia Estrogens should be used with caution in individuals with severe hypocalcemia. 8. Exacerbation of endometriosis Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. 9. Exacerbation of other conditions Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. B. Patient Information Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Estradiol Tablets. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762 C.

giomas and should be used with caution in women with these conditions. B. Patient Information Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Estradiol Tablets. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762 C. Laboratory Tests Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH) (See DOSAGE AND ADMINISTRATION section ). D. 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 anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, 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. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). Increased plasma HDL and HDL 2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels. Impaired glucose tolerance. Reduced response to metyrapone test. E. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer (See BOXED WARNINGS , WARNINGS and PRECAUTIONS ). 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. F. Pregnancy Category X Estradiol Tablets should not be used during pregnancy (See CONTRAINDICATIONS ). G. Nursing Mothers Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when estradiol is administered to a nursing woman. H. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Large and repeated doses of estrogen over an extended period of time have been shown to accelerate epiphyseal closure, resulting in short adult stature if treatment is initiated before the completion of physiologic puberty in normally developing children. In patients in whom bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended. Estrogen treatment of prepubertal children also induces premature breast development and vaginal cornification, and may potentially induce vaginal bleeding in girls. In boys, estrogen treatment may modify the normal pubertal process.

riodic monitoring of bone maturation and effects on epiphyseal centers is recommended. Estrogen treatment of prepubertal children also induces premature breast development and vaginal cornification, and may potentially induce vaginal bleeding in girls. In boys, estrogen treatment may modify the normal pubertal process. All other physiological and adverse reactions shown to be associated with estrogen treatment of adults could potentially occur in the pediatric population, including thromboembolic disorders and growth stimulation of certain tumors. Therefore, estrogens should only be administered to pediatric patients when clearly indicated and the lowest effective dose should always be utilized. I. Geriatric Use. The safety and efficacy of estradiol tablets in geriatric patients has not been established. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greatest frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer’s disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70 (See WARNINGS, Dementia ). It is unknown whether these findings apply to estrogen alone therapy.

A. General 1. Addition of a progestin when a woman has not had a hysterectomy Studies of the addition of a progestin 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 which may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer. 2. 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 estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use. 3. Hypertriglyceridemia In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. 4. Impaired liver function and past history of cholestatic jaundice Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. 5. Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients 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. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. 6. Fluid retention Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. 7. Hypocalcemia Estrogens should be used with caution in individuals with severe hypocalcemia. 8. Exacerbation of endometriosis Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. 9. Exacerbation of other conditions Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

B. Patient Information Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Estradiol Tablets. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

C. Laboratory Tests Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH) (See DOSAGE AND ADMINISTRATION section ).

D. 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 anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, 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. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). Increased plasma HDL and HDL 2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels. Impaired glucose tolerance. Reduced response to metyrapone test.

E. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer (See BOXED WARNINGS , WARNINGS and PRECAUTIONS ). 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.

I. Geriatric Use. The safety and efficacy of estradiol tablets in geriatric patients has not been established. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greatest frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer’s disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70 (See WARNINGS, Dementia ). It is unknown whether these findings apply to estrogen alone therapy.

ADVERSE REACTIONS See BOXED WARNINGS , WARNINGS , and PRECAUTIONS . The following additional adverse reactions have been reported with estrogen and/or progestin therapy. 1. Genitourinary system Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding, spotting, dysmenorrhea 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 2. Breasts Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer 3. Cardiovascular Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure 4. Gastrointestinal Nausea, vomiting Abdominal cramps, bloating Cholestatic jaundice Increased incidence of gallbladder disease Pancreatitis Enlargement of hepatic hemangiomas 5. Skin Chloasma or melasma that may persist when drug is discontinued Erythema multiforme Erythema nodosum Hemorrhagic eruption Loss of scalp hair Hirsutism Pruritus, rash 6. Eyes Retinal vascular thrombosis Steepening of corneal curvature Intolerance to contact lenses 7. Central Nervous System Headache, migraine, dizziness Mental depression Chorea Nervousness, mood disturbances, irritability Exacerbation of epilepsy Dementia 8. Miscellaneous Increase or decrease in weight Reduced carbohydrate tolerance Aggravation of porphyria Edema Arthralgias; leg cramps Changes in libido Urticaria Angioedema Anaphylactoid/anaphylactic reactions Hypocalcemia Exacerbation of asthma Increased triglycerides To report SUSPECTED ADVERSE REACTIONS, contact Epic Pharma, LLC at 1-888-374-2791, or the FDA at 1-800-FDA-1088 or www.fda.gov/ medwatch .

DOSAGE AND ADMINISTRATION When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS ). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. Patients should be started at the lowest dose for the indication. 1. For treatment of moderate to severe vasomotor symptoms, vulval and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible. Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals. The usual initial dosage range is 1 to 2 mg daily of estradiol adjusted as necessary to control presenting symptoms. The minimal effective dose for maintenance therapy should be determined by titration. Administration should be cyclic (e.g., 3 weeks on and 1 week off). 2. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure. Treatment is usually initiated with a dose of 1 to 2 mg daily of estradiol, adjusted as necessary to control presenting symptoms; the minimal effective dose for maintenance therapy should be determined by titration. 3. For treatment of breast cancer, for palliation only, in appropriately selected women and men with metastatic disease. Suggested dosage is 10 mg three times daily for a period of at least three months. 4. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only. Suggested dosage is 1 to 2 mg three times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as by symptomatic improvement of the patient. 5. For prevention of osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. The lowest effective dose of estradiol has not been determined.

HOW SUPPLIED Estradiol Tablets, USP, 2 mg are white to off-white, round, convex, bisected tablets, debossed “ Є” above the bisect and “89” below the bisect on one side and plain on the other side. NDC: 70518-2829-00 NDC: 70518-2829-01 PACKAGING: 100 in 1 BOX PACKAGING: 1 in 1 POUCH Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense contents in a tight, light-resistant container as defined in the USP, with a child-resistant closure, as required. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

Patient Information Estradiol Tablets, USP Rx Only Read this PATIENT INFORMATION before you start taking estradiol and read what you get each time you refill estradiol tablets. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT ESTRADIOL TABLETS (AN ESTROGEN HORMONE)? Estrogens increase the chances of getting cancer of the uterus. Report any unusual vaginal bleeding right away while you are taking estrogens. 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. Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes. Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may increase your risk of dementia. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol tablets. WHAT ARE ESTRADIOL TABLETS? Estradiol tablets are medicine that contains estrogen hormones. WHAT IS ESTRADIOL USED FOR? Estradiol is used to: reduce moderate to severe hot flashes Estrogens are hormones made by a woman’s ovaries. Between ages 45 and 55, the ovaries normally stop making estrogens. This leads to a drop in body estrogen levels which 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 the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild, and they will not need estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol. Weight-bearing exercise, like walking or running, and taking calcium with vitamin D supplements may also lower your chances for getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your healthcare provider before starting them. treat dryness, itching, and burning in or around the vagina, difficulty or burning on urination associated with menopause You and your healthcare provider should talk regularly about whether you still need treatment with estradiol to control these problems. If you use estradiol only to treat your dryness, itching, and burning in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you. treat certain conditions in which a young woman’s ovaries do not produce enough estrogen naturally treat certain types of abnormal vaginal bleeding due to hormonal imbalance when your doctor has found no serious cause of the bleeding treat certain cancers in special situations, in men and women prevent thinning of bones Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break.

reat certain types of abnormal vaginal bleeding due to hormonal imbalance when your doctor has found no serious cause of the bleeding treat certain cancers in special situations, in men and women prevent thinning of bones Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use estradiol 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 should continue with estradiol. WHO SHOULD NOT USE ESTRADIOL? Do not start taking estradiol if you: have unusual vaginal bleeding which has not been evaluated by your doctor (see BOXED WARNINGS) Unusual vaginal bleeding can be a warning sign of cancer of the uterus, especially if it happens after menopause. Your doctor must find out the cause of the bleeding so that he or she can recommend the proper treatment. Taking estrogens without visiting your doctor can cause you serious harm if your vaginal bleeding is caused by cancer of the uterus. currently have or have had certain cancers Estrogens may increase the risk of certain types of cancer, including cancer of the breast or uterus. If you have or had cancer, talk with your healthcare provider about whether you should take estradiol. (For certain patients with breast or prostate cancer, estrogens may help.) had a stroke or heart attack in the past year currently have or have had blood clots have or have had liver problems are allergic to estradiol tablets or any of its ingredients See the end of this leaflet for a list of ingredients in estradiol tablets. think you may be pregnant Tell your healthcare provider: if you are breast feeding The hormone in estradiol can pass into your milk about all of your medical problems Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. about all the medicines you take This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how estradiol tablets work. Estradiol tablets may also affect how your other medicines work. if you are going to have surgery or will be on bed rest You may need to stop taking estrogens. HOW SHOULD I TAKE ESTRADIOL TABLETS? Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you. Estrogens should be used at the lowest dose possible for your treatment only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with estradiol. WHAT ARE THE POSSIBLE SIDE EFFECTS OF ESTROGENS? Less common but serious side effects include: Breast cancer Cancer of the uterus Stroke Heart attack Blood clots Dementia Gallbladder disease Ovarian cancer These are some of the warning signs of the serious side effects: Breast lumps Unusual vaginal bleeding Dizziness and faintness Changes in speech Severe headaches Chest pain Shortness of breath Pains in your legs Changes in vision Vomiting Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.

ious side effects: Breast lumps Unusual vaginal bleeding Dizziness and faintness Changes in speech Severe headaches Chest pain Shortness of breath Pains in your legs Changes in vision Vomiting Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you. Common side effects include: Headache Breast pain Irregular vaginal bleeding or spotting Stomach/abdominal cramps, bloating Nausea and vomiting Hair loss Other side effects include: High blood pressure Liver problems High blood sugar Fluid retention Enlargement of benign tumors (“fibroids”) of the uterus A spotty darkening of the skin, particularly on the face Vaginal yeast infection These are not all the possible side effects of estradiol tablets. For more information, ask your healthcare provider or pharmacist. WHAT CAN I DO TO LOWER MY CHANCES OF A SERIOUS SIDE EFFECT WITH ESTRADIOL? If you use estrogens, you can reduce your risks by doing these things: Talk with your healthcare provider: While you are using estrogens, it is important to visit your doctor at least once a year for a check-up. If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you. See your healthcare provider right away if you have vaginal bleeding while taking estradiol tablets. Have a 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 more frequent breast examinations. If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease. Talk with your healthcare provider regularly about whether you should continue taking estradiol tablets. You and your doctor should reevaluate whether or not you still need estrogens at least every six months. Be alert for signs of trouble If any of these warning signals (or any other unusual symptoms) happen while you are using estrogens, call your doctor immediately: Abnormal bleeding from the vagina (possible uterine cancer) Pains in the calves or chest, sudden shortness of breath, or coughing blood (possible clot in the legs, or lungs) Severe headache or vomiting, dizziness, faintness, changes in vision or speech, weakness or numbness of an arm or leg (possible clot in the brain or eye) Breast lumps (possible breast cancer; ask your doctor or health professional to show you how to examine your breasts monthly) Yellowing of the skin or eyes (possible liver problem) Pain, swelling, or tenderness in the abdomen (possible gallbladder problem) Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. GENERAL INFORMATION ABOUT SAFE AND EFFECTIVE USE OF ESTRADIOL TABLETS Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take estradiol tablets for conditions for which they were not prescribed. Do not give estradiol tablets to other people, even if they have the same symptoms you have. They may harm them. KEEP ESTRADIOL TABLETS OUT OF THE REACH OF CHILDREN This leaflet provides a summary of the most important information about estradiol tablets. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about estradiol tablets that is written for health professionals. For more information about estradiol call Epic Pharma, LLC at 1-888-374-2791. WHAT ARE THE INGREDIENTS IN ESTRADIOL TABLETS?

radiol tablets. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about estradiol tablets that is written for health professionals. For more information about estradiol call Epic Pharma, LLC at 1-888-374-2791. WHAT ARE THE INGREDIENTS IN ESTRADIOL TABLETS? Estradiol Tablets USP for oral administration contains 0.5, 1 or 2 mg of estradiol, USP. In addition, each tablet for oral administration contains the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

<table width="100%" styleCode="Noautorules"><colgroup><col width="100%"/></colgroup><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT ESTRADIOL TABLETS (AN ESTROGEN HORMONE)?</content></paragraph><list listType="unordered"><item>Estrogens increase the chances of getting cancer of the uterus.</item></list><paragraph>Report any unusual vaginal bleeding right away while you are taking estrogens. 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.</paragraph><list listType="unordered"><item>Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes.</item></list><paragraph>Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may increase your risk of dementia. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol tablets.</paragraph></td></tr></tbody></table>

BOXED WARNING WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA and BREAST CANCER 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 Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.3)]. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of 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 (14.4)]. 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 (14.3, 14.4). 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. Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia The WHI estrogen plus progestin substudy reported increased risks of pulmonary embolism (PE), DVT, stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.3)]. The 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 (14.4)]. 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 (14.3, 14.4)].

pplies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.4)]. 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 (14.3, 14.4)]. Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.4)]. Only 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. 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. WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA and BREAST CANCER See full prescribing information for complete boxed warning Estrogen-Alone Therapy • There is an increased risk of endometrial cancer in women with a uterus who use unopposed estrogens (5.2) • The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) (5.1) • The WHI Memory Study (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 • The WHI estrogen plus progestin substudy reported increased risks of pulmonary embolism (PE), DVT, stroke, and myocardial infarction (MI) (5.1) • The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer (5.2) • The 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)

1 INDICATIONS AND USAGE Estradiol gel 0.06% is an estrogen indicated for: • Treatment of moderate to severe vasomotor symptoms due to menopause (1.1) • Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause (1.2) 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause 1.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Limitation of Use When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, first consider the use of topical vaginal products.

2 DOSAGE AND ADMINISTRATION Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, consider addition of a progestogen to reduce the risk of endometrial cancer. Generally, a woman without a uterus does not need to use a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women with a history of endometriosis may need a progestogen [see Warnings and Precautions (5.2, 5.14)]. Use estrogen-alone, or in combination with a progestogen at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Reevaluate postmenopausal women periodically as clinically appropriate to determine if treatment is still necessary. Metered- dose pump: Daily administration of estradiol gel 0.06% 1.25 g per day (1 pump depression) to the arm (2.1, 2.2) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Estradiol gel 0.06% 1.25 g per day is the single approved dose for the treatment of moderate to severe vasomotor symptoms due to menopause. The lowest effective dose of estradiol gel 0.06% for this indication has not been determined. Before using the canister for the first time, it must be primed. Remove the large canister cover, and fully depress the pump 5 times Discard the unused gel by thoroughly rinsing down the sink or placing it in the household trash. After priming, the pump is ready to use. The recommended area of application is the arm. Apply a thin layer over the entire arm on the inside and outside from wrist to shoulder. 2.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Estradiol gel 0.06% 1.25 g per day is the single approved dose for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. The lowest effective dose of estradiol gel 0.06% for this indication has not been determined. When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy, first consider the use of topical vaginal products. Before using the canister for the first time, it must be primed. Remove the large canister cover, and fully depress the pump 5 times. Discard the unused gel by thoroughly rinsing down the sink or placing it in the household trash. After priming, the pump is ready to use. The recommended area of application is the arm. Apply a thin layer over the entire arm on the inside and outside from wrist to shoulder.

3 DOSAGE FORMS AND STRENGTHS Estradiol gel 0.06% is an estradiol transdermal gel. One pump depression delivers 1.25 g of gel that contains 0.75 mg estradiol. Gel: 1 pump depression of estradiol gel 0.06% delivers 1.25 g of gel containing 0.75 mg estradiol (3)

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

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, 5.20) 5.1 Cardiovascular Disorders Increased risks of stroke and DVT are reported with estrogen-alone therapy. Increased risks of PE, DVT, stroke and MI are reported with estrogen plus progestin therapy. Immediately discontinue estrogen with or without progestogen 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-alone substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years, respectively). The increase in risk was demonstrated in year 1 and persisted [ see Clinical Studies (14.3) ]. Immediately discontinue estrogen-alone therapy if a stroke occurs or is suspected. Subgroup analysis 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 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 per 10,000 women-years, respectively) [ see Clinical Studies (14.3) ]. 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. Coronary Heart Disease The WHI estrogen-alone substudy reported no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in women receiving estrogen-alone compared to placebo2 [ see Clinical Studies (14.3) ]. 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 women-years). 1 The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) of CHD events 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 (14.3) ]. 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 twenty-one (2,321) women from the original HERS trial agreed to participate in an open-label extension of the original 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 In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) 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 3 [ see Clinical Studies (14.3) ]. Immediately discontinue estrogen-alone therapy if a VTE occurs or is suspected. The WHI estrogen plus progestin substudy reported a statistically significant 2-fold greater rate of VTE 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 persisted4 [ see Clinical Studies (14.3) ]. Immediately discontinue estrogen plus progestogen therapy if a VTE occurs or is suspected. If feasible, discontinue estrogens at least 4 to 6 weeks before any surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 5.2 Malignant Neoplasms Endometrial Cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2-to 12-fold greater than in nonusers, 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 to be associated with prolonged use, with increased risks of 15-to 24-fold for 5 to 10 years or more, and 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 progestin therapy is important. 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 with unknown etiology. 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. Breast Cancer The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users.

lent 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. Breast Cancer 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 (0.625 mg)- alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.8])5 compared to placebo [ see Clinical Studies (14.3) ]. 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 (14.3) ]. 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 6 [ see Clinical Studies (14.3) ]. Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer with 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 therapy has been reported to result in an increase in abnormal mammograms requiring further evaluation. Have all women receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, base the scheduling of mammography examinations on patient age, risk factors, and prior mammogram results. 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 CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24), but it was not statistically significant.

and prior mammogram results. 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 CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24), 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 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-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, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8 [ see Use in Specific Populations (8.5), and Clinical Studies (14.4) ]. In the 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 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8 [see Use in Specific Populations (8.5) , and Clinical Studies (14.4) ]. 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, 1.19-2.60). 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 [ see Use in Specific Populations (8.5) , and Clinical Studies (14.4) ]. 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 estradiol gel 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.

may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including estradiol gel 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 estradiol gel 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 estradiol gel, 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 estrogens 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 estradiol gel if pancreatitis occurs. 5.10 Hepatic Impairment and/or 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 estradiol gel. 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 estrogens may require increased doses of their thyroid replacement therapy. Monitor thyroid function in these women during treatment with estradiol gel to maintain their free thyroid hormone levels in an acceptable range. 5.12 Fluid Retention Estrogens 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-alone therapy, including estradiol gel, 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 estradiol gel, outweigh the risks in 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. Consider the addition of progestogen therapy for women known to have residual endometriosis post-hysterectomy. 5.15 Hereditary Angioedema Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy, including estradiol gel, outweigh the risks in such women.

of progestogen therapy for women known to have residual endometriosis post-hysterectomy. 5.15 Hereditary Angioedema Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy, including estradiol gel, outweigh the risks in such women. 5.16 Exacerbation of Other Conditions Estrogen therapy, including estradiol gel, 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 Alcohol-based Products are Flammable Avoid fire, flame, or smoking until estradiol gel has dried. 5.18 Moisturizer Lotion Application Use of moisturizing lotion one hour after application of estradiol gel significantly increased estradiol absorption [ see Clinical Pharmacology (12.3) ]. 5.19 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 and moderate to severe symptoms of vulvar and vaginal atrophy. 5.20 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 thyroid-binding globulin (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 T3 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. 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 triglyceride levels. • Impaired glucose tolerance.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Cardiovascular Disorders [ see Boxed Warning, and Warnings and Precautions (5.1) ] • Malignant Neoplasms [ see Boxed Warning, and Warnings and Precautions (5.2) ] The most common adverse reactions with estradiol gel (≥5 percent) are headache, flatulence, and breast pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, Encube Ethicals Private Limited at 1-833-285-4151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Estradiol gel was studied in 2 well-controlled, 12-week clinical trials. Incidence of adverse drug reactions ≥5 percent for 1.25 g estradiol gel 0.06% and placebo is given in Table 1. TABLE 1 Incidence of Adverse Drug Reactions ≥5 Percent Occurrence in the Estradiol Gel Treatment Group for the Intent-to-Treat Safety Population in 2 Well-controlled Clinical Studies (Expressed as Percent of Treatment Group ) Body System/ Adverse Drug Reactions Estradiol gel 0.06% 1.25 g /day (n=168) Placebo (n=73) BODY AS A WHOLE Headache 9.5 2.7 DIGESTIVE SYSTEM Flatulence 5.4 4.1 UROGENITAL SYSTEM Breast pain 10.7 8.2 In 2 controlled clinical trials, application site reactions were reported by 0.6 percent of patients who received 1.25 g of estradiol gel. Other skin reactions, such as pruritus and rash, were also noted. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of estradiol gel. 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 Endometrial cancer Breast Pain; tenderness; breast cancer Cardiovascular Deep vein thrombosis; myocardial ischemia; phlebitis Gastrointestinal Nausea; abdominal distension; diarrhea; stomach discomfort Skin Alopecia; rash; pruritus; application site: dryness, pain, discoloration, reaction, rash Eyes Retinal vein occlusion Central nervous system Headache; dizziness; insomnia; hypoesthesia; meningioma; aphasia; bradyphrenia; paresthesia Miscellaneous Drug ineffective; hot flush; arthralgia; night sweats; drug effect decreased; pain in extremity; fatigue; weight increased; pain; hypersensitivity; dyspnea; malignant mesenchymoma; angioedema; hepatitis acute; face edema; accidental exposure; myoclonus; gait disturbance; flushing

<table cellspacing="0" cellpadding="0" border="0"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle"> <content styleCode="bold">Body System/ Adverse Drug Reactions </content></td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold"> Estradiol gel 0.06% 1.25 g /day (n=168)</content></td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold"> Placebo (n=73)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3" align="center" valign="middle"> <content styleCode="bold"> BODY AS A WHOLE</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle"> Headache</td><td styleCode="Rrule" align="center" valign="middle"> 9.5</td><td styleCode="Rrule" align="center" valign="middle"> 2.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="center" valign="middle"> <content styleCode="bold"> DIGESTIVE SYSTEM</content></td><td styleCode="Rrule" align="center" valign="middle"> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle"> Flatulence</td><td styleCode="Rrule" align="center" valign="middle"> 5.4</td><td styleCode="Rrule" align="center" valign="middle"> 4.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="center" valign="middle"> <content styleCode="bold"> UROGENITAL SYSTEM</content></td><td styleCode="Rrule" align="center" valign="middle"> </td></tr><tr><td styleCode="Lrule Rrule" align="center" valign="middle"> Breast pain</td><td styleCode="Rrule" align="center" valign="middle"> 10.7</td><td styleCode="Rrule" align="center" valign="middle"> 8.2</td></tr></tbody></table>

7 DRUG INTERACTIONS 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 drug metabolism. Inducers of CYP3A4, such as St. John's wort ( Hypericum perforatum ) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, 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 plasma concentrations of estrogen and may result in adverse reactions. Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. (7.1)

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Estradiol gel is not indicated for use in pregnancy. There are no data with the use of estradiol gel in pregnant women, however, epidemiologic studies and meta-analysis have not found an increased risk of genital or non-genital birth defects (including cardiac anomalities and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.3 Lactation Estrogens are present in human milk and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breastfeeding is well established. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for estradiol gel and any potential adverse effects on the breastfed child from estradiol gel or from the underlying maternal condition. 8.4 Pediatric Use Estradiol Gel 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 estradiol gel to determine whether those over 65 years of age differ from younger subjects in their response to estradiol gel. The Women's Health Initiative Studies 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 Warnings and Precautions (5.1) and Clinical Studies (14.3) ]. 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 Warnings and Precautions (5.1) and Clinical Studies (14.3) ]. 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-alone or estrogen plus progestin when compared to placebo [ see Warnings and Precautions (5.3), and Clinical Studies (14.4) ]. Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [ see Warnings and Precautions (5.3), and Clinical Studies (14.4) ]

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

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

8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing estradiol gel to determine whether those over 65 years of age differ from younger subjects in their response to estradiol gel. The Women's Health Initiative Studies 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 Warnings and Precautions (5.1) and Clinical Studies (14.3) ]. 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 Warnings and Precautions (5.1) and Clinical Studies (14.3) ]. 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-alone or estrogen plus progestin when compared to placebo [ see Warnings and Precautions (5.3), and Clinical Studies (14.4) ]. Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [ see Warnings and Precautions (5.3), and Clinical Studies (14.4) ]

10 OVERDOSAGE Overdosage of estrogen 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 estradiol gel therapy with institution of appropriate symptomatic care.

11 DESCRIPTION Estradiol gel contains 0.06 percent estradiol in an absorptive hydroalcoholic gel base for topical application. It is a clear, colorless gel, which is odorless when dry. One pump depression of estradiol gel delivers 1.25 g of gel containing 0.75 mg estradiol. Estradiol is a white crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17β-diol. It has an empirical formula of C 18 H 24 O 2 and molecular weight of 272.39. The structural formula is: The active component of the gel is estradiol. The remaining components of the gel (purified water, alcohol (46.12%), trolamine and carbopol 974 P polymer) are pharmacologically inactive. formula

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, 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. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, 2 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. 12.2 Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to estradiol gel 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 Estradiol is transported across intact skin and into the systemic circulation by a passive diffusion process. The rate of diffusion across the stratum corneum is the rate-limiting factor. When estradiol gel is applied to the skin, it dries in 2 to 5 minutes. Estradiol gel 1.25 g (containing 0.75 mg of estradiol) was administered to 24 postmenopausal women once daily on the posterior surface of 1 arm from wrist to shoulder for 14 consecutive days. Mean maximal serum concentrations of estradiol and estrone on Day 14 were 46.4 pg/mL and 64.2 pg/mL, respectively. The time averaged serum estradiol and estrone concentrations over the 24-hour dose interval after administration of 1.25 g estradiol gel on Day 14 are 28.3 pg/mL and 48.6 pg/mL, respectively. Mean concentration-time profiles for unadjusted estradiol and estrone on Day 14 are shown in Figure 1. FIGURE 1 Mean Serum Concentration-time Profiles for Unadjusted Estradiol and Estrone After Multiple-dose Applications of 1.25 g Estradiol gel 0.06% for 14 Days The serum concentrations of estradiol following 2.5 g estradiol gel applications (1.25 g on each arm from wrist to shoulder) appeared to reach steady state after the third daily application. 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 blood largely bound to SHBG and albumin. 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.

sex hormone target organs. Estrogens circulate in blood largely bound to SHBG and albumin. 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. Although the clinical significance has not been determined, estradiol from estradiol gel does not go through first-pass liver metabolism. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The apparent terminal exponential half-life for estradiol was about 36 hours following administration of 1.25 g estradiol gel. Effect of Application Site Washing The effect of application site washing on the serum concentrations of estradiol was determined in 24 healthy postmenopausal women who applied 1.25 g of estradiol gel once daily for 14 consecutive days. Site washing 1 hour after the application resulted in a 22 percent mean decrease in average 24-hour serum concentrations of estradiol. Potential for Estradiol Transfer The effect of estradiol transfer was evaluated in 24 healthy postmenopausal women who topically applied 1.25 g of estradiol gel once daily on the posterior surface of 1 arm from wrist to shoulder for a period of 14 consecutive days. On each day, 1 hour after gel application, a cohort of 24 non-dosed healthy postmenopausal females directly contacted the dosed cohort at the site of gel application for 15 minutes. No change in endogenous mean serum concentrations of estradiol was observed in the non-dosed cohort after direct skin-to-skin contact with subjects administered estradiol gel. Effect of Moisturizer Lotion/Sunscreen on Estradiol Absorption The effect of sunscreen and moisturizer lotion on estradiol absorption from 0.06% estradiol topical gel was evaluated in a randomized, open-label, three-period crossover study in 42 healthy postmenopausal women. The study results showed that repeated daily application of sunscreen for 7 days at 1 hour after the administration of 0.06% estradiol topical gel decreased the mean AUC 0-24h and C max of estradiol by 16%. Repeated daily application of moisturizer lotion for 7 days at 1 hour after the administration of 0.06% estradiol topical gel increased the mean AUC 0-24h and C max of estradiol by 38% and 73%, respectively. The effect of daily application of sunscreen/moisturizer lotion on estradiol absorption, when sunscreen/moisturizer lotion is applied before administration of 0.06% estradiol topical gel, was not studied. e-graph

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, 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. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, 2 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.

12.2 Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to estradiol gel 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 Estradiol is transported across intact skin and into the systemic circulation by a passive diffusion process. The rate of diffusion across the stratum corneum is the rate-limiting factor. When estradiol gel is applied to the skin, it dries in 2 to 5 minutes. Estradiol gel 1.25 g (containing 0.75 mg of estradiol) was administered to 24 postmenopausal women once daily on the posterior surface of 1 arm from wrist to shoulder for 14 consecutive days. Mean maximal serum concentrations of estradiol and estrone on Day 14 were 46.4 pg/mL and 64.2 pg/mL, respectively. The time averaged serum estradiol and estrone concentrations over the 24-hour dose interval after administration of 1.25 g estradiol gel on Day 14 are 28.3 pg/mL and 48.6 pg/mL, respectively. Mean concentration-time profiles for unadjusted estradiol and estrone on Day 14 are shown in Figure 1. FIGURE 1 Mean Serum Concentration-time Profiles for Unadjusted Estradiol and Estrone After Multiple-dose Applications of 1.25 g Estradiol gel 0.06% for 14 Days The serum concentrations of estradiol following 2.5 g estradiol gel applications (1.25 g on each arm from wrist to shoulder) appeared to reach steady state after the third daily application. 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 blood largely bound to SHBG and albumin. 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. Although the clinical significance has not been determined, estradiol from estradiol gel does not go through first-pass liver metabolism. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The apparent terminal exponential half-life for estradiol was about 36 hours following administration of 1.25 g estradiol gel. Effect of Application Site Washing The effect of application site washing on the serum concentrations of estradiol was determined in 24 healthy postmenopausal women who applied 1.25 g of estradiol gel once daily for 14 consecutive days. Site washing 1 hour after the application resulted in a 22 percent mean decrease in average 24-hour serum concentrations of estradiol. Potential for Estradiol Transfer The effect of estradiol transfer was evaluated in 24 healthy postmenopausal women who topically applied 1.25 g of estradiol gel once daily on the posterior surface of 1 arm from wrist to shoulder for a period of 14 consecutive days.

in average 24-hour serum concentrations of estradiol. Potential for Estradiol Transfer The effect of estradiol transfer was evaluated in 24 healthy postmenopausal women who topically applied 1.25 g of estradiol gel once daily on the posterior surface of 1 arm from wrist to shoulder for a period of 14 consecutive days. On each day, 1 hour after gel application, a cohort of 24 non-dosed healthy postmenopausal females directly contacted the dosed cohort at the site of gel application for 15 minutes. No change in endogenous mean serum concentrations of estradiol was observed in the non-dosed cohort after direct skin-to-skin contact with subjects administered estradiol gel. Effect of Moisturizer Lotion/Sunscreen on Estradiol Absorption The effect of sunscreen and moisturizer lotion on estradiol absorption from 0.06% estradiol topical gel was evaluated in a randomized, open-label, three-period crossover study in 42 healthy postmenopausal women. The study results showed that repeated daily application of sunscreen for 7 days at 1 hour after the administration of 0.06% estradiol topical gel decreased the mean AUC 0-24h and C max of estradiol by 16%. Repeated daily application of moisturizer lotion for 7 days at 1 hour after the administration of 0.06% estradiol topical gel increased the mean AUC 0-24h and C max of estradiol by 38% and 73%, respectively. The effect of daily application of sunscreen/moisturizer lotion on estradiol absorption, when sunscreen/moisturizer lotion is applied before administration of 0.06% estradiol topical gel, was not studied. e-graph

14 CLINICAL STUDIES 14.1 Effects on Vasomotor Symptoms in Postmenopausal Women In a placebo-controlled study, 145 postmenopausal women between 29 and 67 years of age (81.4 percent were White) were randomly assigned to receive 1.25 g of estradiol gel (containing 0.75 mg of estradiol) or placebo gel for 12 weeks. Efficacy was assessed at 4 and 12 weeks of treatment. A statistically significant reduction in the frequency and severity of moderate to severe hot flushes was shown at Weeks 4 and 12. (See Table 2) TABLE 2 Mean Change from Baseline in the Number and Severity of Hot Flushes per Day, ITT Population, LOCF Number of Hot Flushes/Day (Moderate to Severe) Severity Score/Day (Mild, Moderate, Severe) Placebo n=73 Estradiol Gel 0.06% 1.25 g n=72 Placebo n=73 Estradiol Gel 0.06% 1.25 g n=72 Baseline Mean (SD) 11.01 (5.66) 10.33 (3.07) 2.30 (0.24) 2.36 (0.29) Week 4* Mean (SD) Mean change from baseline (SD) Diff. vs placebo P value† 5.95 (5.17) -5.06 (4.91) 4.43 (4.13) -5.91 (3.68) 0.85 0.019‡ 2.00 (0.63) - 0.31 (0.62) 1.73 (0.73) -0.63 (0.71) 0.32 0.005‡ Week 12* Mean (SD) Mean change from baseline (SD) Diff. vs placebo P value† 5.17 (6.52) -5.84 (4.52) 2.79 (3.70) -7.55 (3.52) 1.71 0.043‡ 1.76 (0.84) -0.54 (0.84) 1.33 (0.97) -1.03 (0.94) 0.49 <0.001‡ * Primary timepoint. † P values from Elteren's nonparametric test. ‡ Statistically significantly different from placebo. 14.2 Effects on Vulvar and Vaginal Atrophy in Postmenopausal Women Results of the vaginal wall cytology showed a significant (P≤0.001) increase from baseline in the percent of superficial epithelial cells at Week 12 for 1.25 g estradiol gel. In contrast, no significant change from baseline was observed in the placebo group. 14.3 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 causes. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms. WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was 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 50-79; 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 3. TABLE 3 Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHIa Event Relative Risk CE vs.

which included 10,739 women (average 63 years of age, range 50-79; 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 3. TABLE 3 Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHIa Event Relative Risk CE vs. Placebo (95% nCI b ) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-Years CHD events c Non-fatal Mi c CHD death c 0.95 (0.78-1.16) 0.91 (0.73-1.14) 1.01 (0.71-1.43) 54 40 16 57 43 16 All strokesc Ischemic stroke c 1.33 (1.05-1.68) 1.55 (1.19-2.01) 45 38 33 25 Deep vein thrombosis c,d 1.47 (1.06-2.06) 23 15 Pulmonary embolism c 1.37 (0.90-2.07) 14 10 Invasive breast cancer c 0.80 (0.62-1.04) 28 34 Colorectal cancer c 1.08 (0.75-1.55) 17 16 Hip fracture c 0.65 (0.45-0.94) 12 19 Vertebral fractures c,d 0.64 (0.44-0.93) 11 18 Lower arm/wrist fracturesc, d 0.58 (0.47-0.72) 35 59 Total fracturesc, d 0.71 (0.64-0.80) 144 197 Death due to other causes e,f 1.08 (0.88-1.32) 53 50 Overall mortality c,d 1.04 (0.88-1.22) 79 75 Global index g 1.02 (0.92-1.13) 206 201 a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. c Results are based on centrally adjudicated data for an average follow-up of 7.1 years. d Not included in “global index”. e Results are based on an average follow-up of 6.8 years. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g 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, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. 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 was 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 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 3. 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 the 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 risk was present in all subgroups of women examined.10 Timing of 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 [hazard ratio (HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)] . WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early.

, stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)] . 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 reduction 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 50-79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 4. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. TABLE 4 Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years a,b Event Relative Risk CE/MPA vs. Placebo (95% nCI c ) CE/MPA n = 8,506 Placebo n = 8,102 Absolute Risk per 10,000 Women-Years CHD events Non-fatal MI CHD death 1.23 (0.99-1.53) 1.28 (1.00-1.63) 1.10 (0.70-1.75) 41 31 8 34 25 8 All strokes Ischemic stroke 1.31 (1.03-1.68) 1.44 (1.09-1.90) 33 26 25 18 Deep vein thrombosis d 1.95 (1.43-2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive breast cancer e 1.24 (1.01-1.54) 41 33 Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancer d 0.81 (0.48-1.36) 6 7 Cervical cancer d 1.44 (0.47-4.42) 2 1 Hip fracture 0.67 (0.47-0.96) 11 16 Vertebral fractures d 0.65 (0.46-0.92) 11 17 Lower arm/wrist fractures d 0.71 (0.59-0.85) 44 62 Total fractures 0.76 (0.69-0.83) 152 199 Overall mortality f 1.00 (0.83-1.19) 52 52 Global index g 1.13 (1.02-1.25) 184 165 a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Results are based on centrally adjudicated data. c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. d Not included in “global index”. Includes metastatic and non-metastatic breast cancer, with the exception of in-situ breast cancer. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g 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, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. Timing of 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 [HR 0.69 (95 percent CI, 0.441.07)]. 14.4 Women's Health Initiative Memory Study The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 years of age and older (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 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.

y hysterectomized postmenopausal women 65 years of age and older (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 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, 0.83-2.66). 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 the study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed type (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 plus progestin ancillary study 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 daily 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, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in the study included AD, VaD and mixed type (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, 1.19-2.60). 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) ].

<table cellspacing="0" cellpadding="0"><tbody><tr styleCode="Botrule First"><td styleCode="Lrule Rrule" align="justify" valign="middle"/><td styleCode="Rrule" colspan="2" align="center" valign="middle"> <content styleCode="bold"> Number of Hot Flushes/Day (Moderate to Severe)</content></td><td styleCode="Rrule" colspan="2" align="center" valign="middle"> <content styleCode="bold">Severity Score/Day</content> <content styleCode="bold"> (Mild, Moderate, Severe)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="middle"/><td styleCode="Rrule" align="center" valign="middle"> Placebo n=73</td><td styleCode="Rrule" align="center" valign="middle"> Estradiol Gel 0.06% 1.25 g n=72</td><td styleCode="Rrule" align="center" valign="middle"> Placebo n=73</td><td styleCode="Rrule" align="center" valign="middle"> Estradiol Gel 0.06% 1.25 g n=72</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="middle"> <content styleCode="bold">Baseline</content> Mean (SD)</td><td styleCode="Rrule" align="center" valign="middle"> 11.01 (5.66)</td><td styleCode="Rrule" align="center" valign="middle"> 10.33 (3.07) </td><td styleCode="Rrule" align="center" valign="middle"> 2.30 (0.24) </td><td styleCode="Rrule" align="center" valign="middle"> 2.36 (0.29)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="middle"> <content styleCode="bold">Week 4* </content> Mean (SD) Mean change from baseline (SD) Diff. vs placebo <content styleCode="italics">P</content> value&#x2020;</td><td styleCode="Rrule" align="center" valign="middle"> 5.95 (5.17) -5.06 (4.91)</td><td styleCode="Rrule" align="center" valign="middle"> 4.43 (4.13) -5.91 (3.68) 0.85 0.019&#x2021;</td><td styleCode="Rrule" align="center" valign="middle"> 2.00 (0.63) - 0.31 (0.62)</td><td styleCode="Rrule" align="center" valign="middle"> 1.73 (0.73) -0.63 (0.71) 0.32 0.005&#x2021;</td></tr><tr><td styleCode="Lrule Rrule" align="justify" valign="middle"> <content styleCode="bold"> Week 12*</content> Mean (SD) Mean change from baseline (SD) Diff. vs placebo <content styleCode="italics"> P</content> value&#x2020;</td><td styleCode="Rrule" align="justify" valign="middle"> 5.17 (6.52) -5.84 (4.52)</td><td styleCode="Rrule" align="center" valign="middle"> 2.79 (3.70) -7.55 (3.52) 1.71 0.043&#x2021;</td><td styleCode="Rrule" align="center" valign="middle"> 1.76 (0.84) -0.54 (0.84)</td><td styleCode="Rrule" align="center" valign="middle"> 1.33 (0.97) -1.03 (0.94) 0.49 &lt;0.001&#x2021;</td></tr></tbody></table>

52)</td><td styleCode="Rrule" align="center" valign="middle"> 2.79 (3.70) -7.55 (3.52) 1.71 0.043&#x2021;</td><td styleCode="Rrule" align="center" valign="middle"> 1.76 (0.84) -0.54 (0.84)</td><td styleCode="Rrule" align="center" valign="middle"> 1.33 (0.97) -1.03 (0.94) 0.49 &lt;0.001&#x2021;</td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> <content styleCode="bold">Event</content> </td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold">Relative Risk </content> <content styleCode="bold">CE vs.

<table cellspacing="0" cellpadding="0" border="0"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> <content styleCode="bold">Event</content> </td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold">Relative Risk </content> <content styleCode="bold">CE vs. Placebo </content> <content styleCode="bold">(95% nCI^b) </content> </td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold">CE n = 5,310</content></td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold">Placebo n = 5,429 </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> </td><td styleCode="Rrule" align="left" valign="middle"> </td><td styleCode="Rrule" colspan="2" align="center" valign="middle"> <content styleCode="bold">Absolute Risk per 10,000 </content> <content styleCode="bold">Women-Years</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> CHD events^c <content styleCode="italics"> Non-fatal Mi^c</content> <content styleCode="italics"> CHD death^c</content></td><td styleCode="Rrule" align="left" valign="middle"> 0.95 (0.78-1.16) <content styleCode="italics"> 0.91 (0.73-1.14) 1.01 (0.71-1.43)</content></td><td styleCode="Rrule" align="center" valign="middle"> 54 <content styleCode="italics">40 16</content></td><td styleCode="Rrule" align="center" valign="middle"> 57 <content styleCode="italics">43 16</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> All strokesc <content styleCode="italics">Ischemic stroke^c</content></td><td styleCode="Rrule" align="left" valign="middle"> 1.33 (1.05-1.68) <content styleCode="italics">1.55 (1.19-2.01)</content></td><td styleCode="Rrule" align="center" valign="middle"> 45 <content styleCode="italics">38</content></td><td styleCode="Rrule" align="center" valign="middle"> 33 <content styleCode="italics">25</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> Deep vein thrombosis^c,d</td><td styleCode="Rrule" align="center" valign="middle"> 1.47 (1.06-2.06)</td><td styleCode="Rrule" align="center" valign="middle"> 23</td><td styleCode="Rrule" align="center" valign="middle"> 15</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> Pulmonary embolism^c</td><td styleCode="Rrule" align="center" valign="middle"> 1.37 (0.90-2.07)</td><td styleCode="Rrule" align="center" valign="middle"> 14</td><td styleCode="Rrule" align="center" valign="middle"> 10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> Invasive breast cancer^c</td><td styleCode="Rrule" align="left" valign="middle"> 0.80 (0.62-1.04)</td><td styleCode="Rrule" align="center" valign="middle"> 28</td><td styleCode="Rrule" align="center" valign="middle"> 34</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> Colorectal cancer^c</td><td styleCode="Rrule" align="center" valign="middle"> 1.08 (0.75-1.55)</td><td styleCode="Rrule" align="center" valign="middle"> 17</td><td styleCode="Rrule" align="center" valign="middle"> 16</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> Hip fracture^c</td><td styleCode="Rrule" align="left" valign="middle"> 0.65 (0.45-0.94)</td><td styleCode="Rrule" align="center" valign="middle"> 12</td><td styleCode="Rrule" align="center" valign="middle"> 19</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> Vertebral fractures^c,d</td><td styleCode="Rrule" align="center" valign="

ddle"> 0.65 (0.45-0.94)</td><td styleCode="Rrule" align="center" valign="middle"> 12</td><td styleCode="Rrule" align="center" valign="middle"> 19</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> Vertebral fractures^c,d</td><td styleCode="Rrule" align="center" valign=" middle"> 0.64 (0.44-0.93)</td><td styleCode="Rrule" align="center" valign="middle"> 11</td><td styleCode="Rrule" align="center" valign="middle"> 18</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> Lower arm/wrist fracturesc,^d</td><td styleCode="Rrule" align="left" valign="middle"> 0.58 (0.47-0.72)</td><td styleCode="Rrule" align="center" valign="middle"> 35</td><td styleCode="Rrule" align="center" valign="middle"> 59</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> Total fracturesc,^d</td><td styleCode="Rrule" align="center" valign="middle"> 0.71 (0.64-0.80)</td><td styleCode="Rrule" align="center" valign="middle"> 144</td><td styleCode="Rrule" align="center" valign="middle"> 197</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> Death due to other causes^e,f</td><td styleCode="Rrule" align="left" valign="middle"> 1.08 (0.88-1.32)</td><td styleCode="Rrule" align="center" valign="middle"> 53</td><td styleCode="Rrule" align="center" valign="middle"> 50</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> Overall mortality^c,d</td><td styleCode="Rrule" align="left" valign="middle"> 1.04 (0.88-1.22)</td><td styleCode="Rrule" align="center" valign="middle"> 79</td><td styleCode="Rrule" align="center" valign="middle"> 75</td></tr><tr><td styleCode="Lrule Rrule" align="left" valign="middle"> Global index^g</td><td styleCode="Rrule" align="left" valign="middle"> 1.02 (0.92-1.13)</td><td styleCode="Rrule" align="center" valign="middle"> 206</td><td styleCode="Rrule" align="center" valign="middle"> 201</td></tr></tbody></table>

5</td></tr><tr><td styleCode="Lrule Rrule" align="left" valign="middle"> Global index^g</td><td styleCode="Rrule" align="left" valign="middle"> 1.02 (0.92-1.13)</td><td styleCode="Rrule" align="center" valign="middle"> 206</td><td styleCode="Rrule" align="center" valign="middle"> 201</td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="34%"/><col width="24%"/><col width="21%"/><col width="19%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" rowspan="2" align="center" valign="top"><content styleCode="bold">Event</content> </td><td styleCode="Rrule" rowspan="2" align="center" valign="top"><content styleCode="bold">Relative Risk</content> <content styleCode="bold">CE/MPA vs.

l width="19%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" rowspan="2" align="center" valign="top"><content styleCode="bold">Event</content> </td><td styleCode="Rrule" rowspan="2" align="center" valign="top"><content styleCode="bold">Relative Risk</content> <content styleCode="bold">CE/MPA vs. Placebo</content> <content styleCode="bold">(95% nCI^c)</content> </td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">CE/MPA</content> <content styleCode="bold">n = 8,506</content> </td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">Placebo</content> <content styleCode="bold">n = 8,102</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="center" valign="top"><content styleCode="bold">Absolute Risk per 10,000 </content> <content styleCode="bold">Women-Years</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">CHD events <content styleCode="italics"> Non-fatal MI</content> <content styleCode="italics">CHD death</content> </td><td styleCode="Rrule" align="center" valign="top">1.23 (0.99-1.53) <content styleCode="italics">1.28</content><content styleCode="italics">(1.00-1.63)</content> <content styleCode="italics">1.10</content><content styleCode="italics">(0.70-1.75)</content> </td><td styleCode="Rrule" align="center" valign="top">41 <content styleCode="italics">31</content> <content styleCode="italics">8</content> </td><td styleCode="Rrule" align="center" valign="top">34 <content styleCode="italics">25</content> <content styleCode="italics">8</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">All strokes <content styleCode="italics">Ischemic stroke </content> </td><td styleCode="Rrule" align="center" valign="top">1.31 (1.03-1.68) <content styleCode="italics">1.44 (1.09-1.90)</content> </td><td styleCode="Rrule" align="center" valign="top">33 <content styleCode="italics">26</content> </td><td styleCode="Rrule" align="center" valign="top">25 <content styleCode="italics">18</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Deep vein thrombosis^d </td><td styleCode="Rrule" align="center" valign="top">1.95 (1.43-2.67) </td><td styleCode="Rrule" align="center" valign="top">26 </td><td styleCode="Rrule" align="center" valign="top">13 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Pulmonary embolism </td><td styleCode="Rrule" align="center" valign="top">2.13 (1.45-3.11) </td><td styleCode="Rrule" align="center" valign="top">18 </td><td styleCode="Rrule" align="center" valign="top">8 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Invasive breast cancer^e </td><td styleCode="Rrule" align="center" valign="top">1.24 (1.01-1.54) </td><td styleCode="Rrule" align="center" valign="top">41 </td><td styleCode="Rrule" align="center" valign="top">33 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Colorectal cancer </td><td styleCode="Rrule" align="center" valign="top">0.61 (0.42-0.87) </td><td styleCode="Rrule" align="center" valign="top">10 </td><td styleCode="Rrule" align="center" valign="top">16 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Endometrial cancer^d </td><td styleCode="Rrule" align="center" valign="top">0.81 (0.48-1.36) </td><td styleCode="Rrule" align="center" valign="top">6 </td><td styleCode="Rrule" align="center" valign="top">7 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Cervical cancer^d </td><td styleCode="Rrule" align="center" v

lign="center" valign="top">0.81 (0.48-1.36) </td><td styleCode="Rrule" align="center" valign="top">6 </td><td styleCode="Rrule" align="center" valign="top">7 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Cervical cancer^d </td><td styleCode="Rrule" align="center" v align="middle">1.44 (0.47-4.42) </td><td styleCode="Rrule" align="center" valign="top">2 </td><td styleCode="Rrule" align="center" valign="top">1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Hip fracture </td><td styleCode="Rrule" align="center" valign="top">0.67 (0.47-0.96) </td><td styleCode="Rrule" align="center" valign="top">11 </td><td styleCode="Rrule" align="center" valign="top">16 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Vertebral fractures^d </td><td styleCode="Rrule" align="center" valign="top">0.65 (0.46-0.92) </td><td styleCode="Rrule" align="center" valign="top">11 </td><td styleCode="Rrule" align="center" valign="top">17 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Lower arm/wrist fractures^d </td><td styleCode="Rrule" align="center" valign="top">0.71 (0.59-0.85) </td><td styleCode="Rrule" align="center" valign="top">44 </td><td styleCode="Rrule" align="center" valign="top">62 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Total fractures </td><td styleCode="Rrule" align="center" valign="top">0.76 (0.69-0.83) </td><td styleCode="Rrule" align="center" valign="top">152 </td><td styleCode="Rrule" align="center" valign="top">199 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Overall mortality^f </td><td styleCode="Rrule" align="center" valign="top">1.00 (0.83-1.19) </td><td styleCode="Rrule" align="center" valign="top">52 </td><td styleCode="Rrule" align="center" valign="top">52 </td></tr><tr><td styleCode="Lrule Rrule" align="justify" valign="top">Global index^g </td><td styleCode="Rrule" align="center" valign="top">1.13 (1.02-1.25) </td><td styleCode="Rrule" align="center" valign="top">184 </td><td styleCode="Rrule" align="center" valign="top">165 </td></tr></tbody></table>

15 REFERENCES 15 REFERENCES 1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477. 2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357-365. 3. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780. 4. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580. 5. 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. 6. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253. 7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748. 8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958. 9. 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. 10. 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 Estradiol gel is a clear, colorless, hydroalcoholic 0.06 percent estradiol gel supplied in a non-aerosol, metered-dose pump. The pump consists of an LDPE inner liner encased in rigid plastic with a resealable polypropylene cap. Estradiol gel is available in a 50-gram (1.75 oz) size. Each individually packaged 50-gram pump contains 50 grams of gel and can deliver 30 metered 1.25-g doses. NDC: 21922-015-40............................. (50-gram pump) 16.2 Storage and Handling Keep out of reach of children. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION Advise women to read the FDA-approved patient labeling (Patient Information and Instructions for Use) 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-Alone Therapy Inform postmenopausal women of the possible serious adverse reactions of estrogen-alone 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-Alone Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea, and vomiting. Manufactured by: Encube Ethicals Pvt. Ltd. Plot No. C-1, Madkaim Industrial Estate, Madkaim, Post: Mardol, Ponda, Goa - 403 404, India. Distributed by: Encube Ethicals, Inc. 200 Meredith Drive, Suite 202, Durham, NC 27713 USA Revised:03/2026

PATIENT INFORMATION Estradiol Gel 0.06% (es-tra-DYE-ol) (estradiol gel) Read this Patient Information before you start using estradiol gel 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 estradiol gel (an estrogen hormone)? • Using estrogen-alone may increase your chance of getting cancer of the uterus (womb). Report any unusual vaginal bleeding right away while you are using estradiol gel. 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. • Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia (decline in brain function). • Using estrogen-alone may increase yourchances of getting strokes and blood clots. Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age and older. • Do not use estrogens with progestogens to prevent heart disease, heart attack, strokesor dementia. • 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. Only one estrogen-alone product and dose have been shown to increase yourchances of getting strokes, blood clots, and dementia. 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. Because other products and doses have not been studied in the same way, it is not known how the use of estradiol gel will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol gel. What is estradiol gel? Estradiol gel is a prescription medicine gel that containse stradiol ( anestrogenhormone). What is estradiol gel used for? Estradiol gel is used after menopause to:. • Reduce moderate to severe hot flashes 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 the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden intense feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild, and they will not need to use estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol gel. • Treat moderate to severe menopausal changes in and around the vagina You and your healthcare provider should talk regularly about whether you still need treatment with estradiol gel to control these problems.

and your healthcare provider should talk regularly about whether you still need treatment with estradiol gel. • Treat moderate to severe menopausal changes in and around the vagina You and your healthcare provider should talk regularly about whether you still need treatment with estradiol gel to control these problems. If you use estradiol gel only to treat your menopausal changes in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you. Who should not use estradiol gel? Do not start using estradiol gel if you: have 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 cancer, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use estradiol gel. had a stroke or heart attack currently have or have had blood clots currently have or have had liver problems are allergic to estradiol gel or any of its ingredients See the list of ingredients in estradiol gel at the end of this leaflet. Before you use estradiol gel, 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 estradiol gel 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), problems with your heart, liver, thyroid, kidneys, or 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 estradiol gel. are pregnant or think you may be pregnant Estradiol gel is not for pregnant women. are breastfeeding The hormone in estradiol gel 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 estradiol gel works. Estradiol gel 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 a new medicine. How should I use estradiol gel? For detailed instructions, see the step-by-step instructions for using estradiol gel at the end of this Patient Information. Use estradiol gel exactly as your healthcare provider tells you to use it. Estradiol gel is for skin use only. Estradiol gel contains alcohol, which is flammable. Avoid fire, flame or smoking until estradiol gel has dried. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are using and whether you still need treatment with estradiol gel. What are the possible side effects of estradiol gel? Side effects are grouped by how serious they are and how often they happen when you are treated.

nd your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are using and whether you still need treatment with estradiol gel. What are the possible side effects of estradiol gel? 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 • high or low blood calcium • gallbladder disease • worsening of swelling of face and tongue (angioedema) in women with a history of angioedema • visual abnormalities • high blood pressure • liver problems • changes in your thyroid hormone levels • fluid retention • cancer changes of endometriosis • enlargement of benign tumors of the uterus (“fibroids”) • changes in laboratory test results such as bleeding time and high blood sugar 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 swelling of face, lips, and tongue with or without red, itchy bumps Common side effects of estradiol gel include: headache Breast tenderness or pain stomach or abdominal cramps, bloating nausea and vomiting hair loss fluid retention vaginal yeast infection These are not all of the possible side effects of estradiol gel. 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 Encube Ethicals Private Limited at 1-833-285- 4151 to FDA at 1-800-FDA-1088. What can I do to lower my chances of a serious side effect with estradiol gel? Talk with your healthcare provider regularly about whether you should continue using estradiol gel. If you have a uterus, talk with your healthcare provider about whether the addition of a progestogen is right for you. In general, the addition of a progestogen is recommended for women 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 estradiol gel. 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 if you use tobacco, you may have higher chances of getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease. How should I store estradiol gel? Store estradiol gel at room temperature between 68°F to 77°F (20°C to 25°C). Keep estradiol gel and all medicines out of the reach of children. General information about the safe and effective use of estradiol gel Medicines are sometimes prescribed for conditions that are not mentioned in Patient Information leaflets. Do not use estradiol gel for conditions for which it was not prescribed. Do not give estradiol gel to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about estradiol gel that is written for health professionals. For more information, call Encube Ethicals Private Limited at 1-833-285-4151 What are the ingredients in estradiol gel?

people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about estradiol gel that is written for health professionals. For more information, call Encube Ethicals Private Limited at 1-833-285-4151 What are the ingredients in estradiol gel? Active ingredient: estradiol Inactive ingredients: purified water, alcohol (46.12%), trolamine and carbopol 974 P polymer. Instructions for Use Estradiol gel 0.06% (es-tra-DYE-ol) (estradiol gel) Read this Instructions for Use before you start using estradiol gel 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. You will need the following supplies to use estradiol gel: See Figure A. Figure A Estradiol gel is supplied in a metered-dose pump that delivers a measured amount of estradiol to your skin each time you press the pump. Estradiol gel is available in a 50-gram canister Step 1. Priming the estradiol gel pump Before using the estradiol gel pump for the first time, the pump must be primed. The estradiol gel canister contains enough medicine to allow you to prime the pump before you use it for the first time. Remove the large cap from the canister. See Figure B. Figure B Slowly push the pump all the way down 5 times. Do not use any estradiol gel that came out while priming. Wash it down the sink to avoid accidental exposure to others. After priming, the estradiol gel pump is ready to use. One complete press of the pump will give the same amount of estradiol gel each time. Step 2. Applying estradiol gel to your skin • Do not allow other people to apply estradiol gel to your skin for you. • Apply estradiol gel to clean, dry, unbroken skin. Apply estradiol gel after your bath or shower. If you go swimming, try to leave as much time as possible between using your estradiol gel and going swimming. Remove the small cover on the tip of the pump if you have not done so already. See Figure C Figure C To use estradiol gel, press the estradiol gel pump firmly and fully 1 time into the palm of your hand. See Figure D. Figure D Using your hand, apply estradiol gel to the skin of your other arm. See Figure E. Spread the gel as thinly as possible over the entire area on the inside and outside of your arm from your wrist to your shoulder. See Figure F. Do not apply estradiol gel directly to your breasts or in and around your vagina. Do not massage or rub in estradiol gel. Allow the gel to dry for 5 minutes before you get dressed. Step 3. After you use estradiol gel • Place the small cap back on the tip of the pump. Place the large cap over the top of the canister. • Wash your hands right away with soap and water after applying estradiol gel. This will lower the chance that the medicine will spread from your hands to other people. • Do not allow others to make contact with the area of skin where you applied the gel for at least 1 hour after application. • Estradiol gel is flammable until dry. Let estradiol gel dry before smoking or going near an open flame. Step 4. Throwing away used estradiol gel canisters • The estradiol gel 50-gram canister contains enough medicine to allow for priming your canister with up to 5 full pump depressions and delivery of 30 daily doses. After you have first primed your canister and used 30 doses, you will need to throw away the canister. Do not use the canister for more than 30 doses even though the canister may not be completely empty. You may not get the correct dose. This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured by: Encube Ethicals Pvt. Ltd. Plot No.

hrow away the canister. Do not use the canister for more than 30 doses even though the canister may not be completely empty. You may not get the correct dose. This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured by: Encube Ethicals Pvt. Ltd. Plot No. C-1, Madkaim Industrial Estate, Madkaim, Post: Mardol, Ponda, Goa – 403 404, India. Distributed by: Encube Ethicals, Inc . 200 Meredith Drive, Suite 202, Durham, NC 27713 USA Revised: 03/2026 estra container fig-b fig-c fig-d fig EF

<table cellspacing="0" cellpadding="0"><tbody><tr styleCode="First Last"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">What is the most important information I should know about estradiol gel (an estrogen hormone)?</content> &#x2022; Using estrogen-alone may increase your chance of getting cancer of the uterus (womb). Report any unusual vaginal bleeding right away while you are using estradiol gel. 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. &#x2022; Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia (decline in brain function). &#x2022; Using estrogen-alone may increase yourchances of getting strokes and blood clots. Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age and older. &#x2022; Do not use estrogens with progestogens to prevent heart disease, heart attack, strokesor dementia. &#x2022; Using estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. &#x2022; Using estrogens with progestogens may increase your chance of getting dementia, based on a study of women 65 years of age and older. Only one estrogen-alone product and dose have been shown to increase yourchances of getting strokes, blood clots, and dementia. 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. Because other products and doses have not been studied in the same way, it is not known how the use of estradiol gel will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol gel.</td></tr></tbody></table>

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA and BREAST CANCER 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 Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo [see Warnings and Precautions (5.1) , and Clinical Studies (14.3) ] . The WHI Memory Study (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 (14.4) ] . 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 (14.3 , 14.4) ] . 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. Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1) , and Clinical Studies (14.3) ] . The WHIMS estrogen plus progestin ancillary study of the 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 (14.4) ] . 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 (14.3 , 14.4) ] .

younger postmenopausal women [see Warnings and Precautions (5.3) , Use in Specific Populations (8.5) , and Clinical Studies (14.4) ] . 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 (14.3 , 14.4) ] . Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2) , and Clinical Studies (14.3) ] . Only 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. 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. WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, and BREAST CANCER, See full prescribing information for complete boxed warning. Estrogen-Alone Therapy There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens ( 5.2 ) The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) ( 5.1 ) The WHI Memory Study (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 The WHI estrogen plus progestin substudy reported increased risks of stroke, DVT, pulmonary embolism (PE), and myocardial infarction (MI) ( 5.1 ) The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer ( 5.2 ) The 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 )

<table width="100%"><col width="80%" align="left" valign="top"/><col width="20%" align="right" valign="top"/><tbody><tr><td>Warnings and Precautions (<linkHtml href="#S5.2">5.2</linkHtml>)</td><td>12/2023</td></tr></tbody></table>

1 INDICATIONS AND USAGE Climara is indicated for: Climara is an estrogen indicated for: Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause ( 1.1 ) Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause ( 1.2 ) Limitations of Use When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, first consider the use of topical vaginal products. Treatment of Hypoestrogenism due to Hypogonadism, Castration or Primary Ovarian Failure ( 1.3 ) Prevention of Postmenopausal Osteoporosis ( 1.4 ) Limitations 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. 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause 1.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Limitation of Use When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, first consider the use of topical vaginal products. 1.3 Treatment of Hypoestrogenism due to Hypogonadism, Castration, or Primary Ovarian Failure 1.4 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 Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, consider addition of a progestogen to reduce the risk of endometrial cancer. Generally, a woman without a uterus does not need to use a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women who have a history of endometriosis may need a progestogen [see Warnings and Precautions (5.2 , 5.14) ] . Use estrogen-alone, or in combination with a progestogen at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Reevaluate postmenopausal women periodically as clinically appropriate to determine if treatment is still necessary. Start therapy with Climara 0.025 mg per day applied to the skin once-weekly. Dosage adjustment should be guided by the clinical response ( 2.1 ) Place Climara on a clean, dry area of the lower abdomen (below the umbilicus) or upper quadrant of the buttock. Do not apply Climara to the breasts ( 2.5 ) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Start therapy with Climara 0.025 mg per day applied to the skin once weekly. Make dosage adjustments based on the clinical response. Attempt to taper or discontinue Climara at 3 to 6 month intervals. 2.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Start therapy with Climara 0.025 mg per day applied to the skin once weekly. Make dosage adjustments based on the clinical response. Attempt to taper or discontinue Climara at 3 to 6 month intervals. 2.3 Treatment of Hypoestrogenism due to Hypogonadism, Castration, or Primary Ovarian Failure Start therapy with 0.025 mg per day applied to the skin once weekly. Make dose adjustment based on the clinical response.. 2.4 Prevention of Postmenopausal Osteoporosis Start therapy with Climara 0.025 mg per day applied to the skin once weekly. 2.5 Application of the Climara Transdermal System Site Selection Place the adhesive side of Climara on a clean, dry area of the lower abdomen or the upper quadrant of the buttock. Do not apply Climara to or near the breasts. Rotate the sites of application, with an interval of at least 1-week allowed between applications to the same site. Select an area that is not oily, damaged, or irritated. Avoid the waistline, since tight clothing may rub the transdermal system off. Avoid application to areas where sitting would dislodge Climara. Application Apply Climara immediately after opening the pouch and removing the protective liner. Press Climara firmly in place with the fingers for at least 10 seconds, making sure there is good contact, especially around the edges. If the system lifts, apply pressure to maintain adhesion. In the event that a system falls off, reapply it to a different location. If the old system cannot be reapplied, apply a new system for the remainder of the 7-day dosing interval. Wear only one system at any one time during the 7-day dosing interval. Swimming, bathing, or using a sauna while using Climara has not been studied, and these activities may decrease the adhesion of the system and the delivery of estradiol. 2.6 Removal of the Climara Transdermal System Remove Climara carefully and slowly to avoid irritation of the skin.

e during the 7-day dosing interval. Swimming, bathing, or using a sauna while using Climara has not been studied, and these activities may decrease the adhesion of the system and the delivery of estradiol. 2.6 Removal of the Climara Transdermal System Remove Climara carefully and slowly to avoid irritation of the skin. If any adhesive remains on the skin after removal of Climara, allow the area to dry for 15 minutes and then gently rub the area with an oil-based cream or lotion to remove the adhesive residue. Used patches still contain some active hormones. Carefully fold each patch in half so that it sticks to itself before throwing it away.

3 DOSAGE FORMS AND STRENGTHS Climara (estradiol transdermal system), 0.025 mg per day—each 6.5 cm 2 system contains 2 mg of estradiol Climara (estradiol transdermal system), 0.0375 mg per day—each 9.375 cm 2 system contains 2.85 mg of estradiol Climara (estradiol transdermal system), 0.05 mg per day—each 12.5 cm 2 system contains 3.8 mg of estradiol Climara (estradiol transdermal system), 0.060 mg per day—each 15 cm 2 system contains 4.55 mg of estradiol Climara (estradiol transdermal system), 0.075 mg per day—each 18.75 cm 2 system contains 5.7 mg of estradiol Climara (estradiol transdermal system), 0.1 mg per day—each 25.0 cm 2 system contains 7.6 mg of estradiol Transdermal system: 0.025 mg per day, 0.0375 mg per day, 0.05 mg per day, 0.06 mg per day, 0.075 mg per day and 0.1 mg per day ( 3 )

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

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 hormone replacement therapy ( 5.11 , 5.18 ) 5.1 Cardiovascular Disorders Increased risks of stroke and DVT are reported with estrogen-alone therapy. Increased risks of PE, DVT, stroke and MI are reported with estrogen plus progestin 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-alone substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving daily 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 (14.3) ] . 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 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 (14.3) ] . The increase in risk was demonstrated after the first year and persisted. 1 Immediately discontinue estrogen plus progestogen therapy if a stroke occurs or is suspected. Coronary Heart Disease The WHI estrogen-alone substudy reported no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in women receiving estrogen-alone compared to placebo 2 [see Clinical Studies (14.3) ] . 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 daily CE (0.625 mg)-alone compared to placebo (8 versus 16 per 10,000 women-years). 1 The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) of CHD events in 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 (14.3) ] . 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 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 In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) 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 3 [see Clinical Studies (14.3) ] . Immediately discontinue estrogen-alone therapy if a VTE occurs or is suspected. The WHI estrogen plus progestin substudy reported a statistically significant 2-fold greater rate of VTE 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 4 [see Clinical Studies (14.3) ] . Immediately discontinue estrogen plus progestogen 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 Endometrial Cancer 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, and 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. 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 with unknown etiology. 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. Breast Cancer The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users.

lent 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. Breast Cancer 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 (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] 5 [see Clinical Studies (14.3) ] . 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. 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. 6 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 6 [see Clinical Studies (14.3) ] . Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer with estrogen plus progestin therapy, and a smaller increase in the risk for breast cancer with 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. 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 CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24), 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.

ogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24), 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 to 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-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, 0.83-2.66). 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 (14.4) ] . In the 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, 1.21-3.48). 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 (14.4) ] . 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, 1.19-2.60). 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 Use in Specific Populations (8.5) , and Clinical Studies (14.4) ] . 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 Climara 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 Climara pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine.

urs, 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 Climara 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 Climara, 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 estrogens 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 Climara if pancreatitis occurs. 5.10 Hepatic Impairment and/or 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 Climara. 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 estrogens may require increased doses of their thyroid replacement therapy. Monitor thyroid function in these women during treatment with Climara to maintain their free thyroid hormone levels in an acceptable range. 5.12 Fluid Retention Estrogens may cause some degree of fluid retention. Monitor any woman with a condition(s) that might predispose her to fluid retention, such as a cardiac or renal impairment. Discontinue estrogen-alone therapy, including Climara, 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 Climara, 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. Consider the addition of progestogen therapy for women known to have residual endometriosis post-hysterectomy. 5.15 Hereditary Angioedema Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy, including Climara, outweigh the risks in such women. 5.16 Exacerbation of Other Conditions Estrogen therapy, including Climara, 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 such women.

isks in such women. 5.16 Exacerbation of Other Conditions Estrogen therapy, including Climara, 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 such women. 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 and moderate to severe symptoms of vulvar and vaginal atrophy. Laboratory parameters may be useful in guiding Climara dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian failure. 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, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 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. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-l-antitrypsin, ceruloplasmin). Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, and increased triglyceride levels. Impaired glucose tolerance.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning , and Warnings and Precautions (5.1) ] Malignant Neoplasms [see Boxed Warning , and Warnings and Precautions (5.2) ] The most common adverse reactions (≥10 percent) with Climara are: breast pain, upper respiratory tract infections, headaches, abdominal pain, pain, and edema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-84-BAYER (1-888-842-2937) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect pooled data from 5 clinical trials of Climara. A total of 614 women were exposed to Climara for 3 months (193 women at 0.025 mg per day, 201 women at 0.05 mg per day, 194 women at 0.1 mg per day) in randomized, double-blind trials of clinical efficacy versus placebo and versus active comparator. All women were postmenopausal, had a serum estradiol level of less than 20 pg/mL, and a minimum of five moderate to severe hot flushes per week or a minimum of 15 hot flushes per week of any severity at baseline. Included in this table are an additional 25 postmenopausal hysterectomized women exposed to Climara 0.025 mg per day for 6 to 24 months (N=16 at 24 months) in a randomized, double-blind, placebo-controlled study of Climara for the prevention of osteoporosis. Table 1: Treatment-Emergent Adverse Reactions Reported at a Frequency of ≥5 Percent and More Frequent in Women Receiving Climara Climara Body System Adverse Reactions 0.025 mg/day Adverse reactions occurring at rate of ≥5 percent in Climara trials of clinical efficacy versus placebo and versus active comparator; and trial of Climara versus placebo for the prevention of osteoporosis (N=219) 0.05 mg/day Adverse reactions occurring at rate of ≥5 percent in Climara trials of clinical efficacy versus placebo and versus active comparator (N=201) 0.1 mg/day (N=194) Placebo Adverse reactions occurring in placebo group in Climara trial of clinical efficacy versus placebo (N=72) Body as a Whole 21% 39% 37% 29% Headache 5% 18% 13% 10% Pain 1% 8% 11% 7% Back Pain 4% 8% 9% 6% Edema 0.5% 13% 10% 6% Digestive System 9% 21% 29% 18% Abdominal Pain 0% 11% 16% 8% Nausea 1% 5% 6% 3% Flatulence 1% 3% 7% 1% Musculoskeletal System 7% 9% 11% 4% Arthralgia 1% 5% 5% 3% Nervous System 13% 10% 11% 1% Depression 1% 5% 8% 0% Urogenital System 12% 18% 41% 11% Breast Pain 5% 8% 29% 4% Leukorrhea 1% 6% 7% 1% Respiratory System 15% 26% 29% 14% URTI 6% 17% 17% 8% Pharyngitis 0.5% 3% 7% 3% Sinusitis 4% 4% 5% 3% Rhinitis 2% 4% 6% 1% Skin and Appendages 19% 12% 12% 15% Pruritus 0.5% 6% 3% 6% 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Climara. 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.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Climara. 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 bleeding pattern, pelvic pain Breast Breast cancer, breast pain, breast tenderness Cardiovascular Changes in blood pressure, palpitations, hot flashes Gastrointestinal Vomiting, abdominal pain, abdominal distension, nausea Skin Alopecia, hyperhidrosis, night sweats, urticaria, rash Eyes Visual disturbances, contact lens intolerance, Central Nervous System Depression, migraine, paresthesia, dizziness, anxiety, irritability, mood swings, nervousness, insomnia, headache Miscellaneous Fatigue, menopausal symptoms, weight increase, application site reaction, anaphylactic reactions

<table width="85%"><caption>Table 1: Treatment-Emergent Adverse Reactions Reported at a Frequency of &#x2265;5 Percent and More Frequent in Women Receiving Climara</caption><col width="27%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><col width="19%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule"/><th styleCode="Rrule" align="center" colspan="3">Climara</th><th styleCode="Rrule"/></tr><tr><th styleCode="Lrule Rrule">Body System Adverse Reactions</th><th styleCode="Rrule" align="center">0.025 mg/day<footnote>Adverse reactions occurring at rate of &#x2265;5 percent in Climara trials of clinical efficacy versus placebo and versus active comparator; and trial of Climara versus placebo for the prevention of osteoporosis</footnote> (N=219)</th><th styleCode="Rrule">0.05 mg/day<footnote ID="foot12">Adverse reactions occurring at rate of &#x2265;5 percent in Climara trials of clinical efficacy versus placebo and versus active comparator</footnote> (N=201)</th><th styleCode="Rrule">0.1 mg/day<footnoteRef IDREF="foot12"/> (N=194)</th><th styleCode="Rrule">Placebo<footnote>Adverse reactions occurring in placebo group in Climara trial of clinical efficacy versus placebo</footnote> (N=72)</th></tr></thead><tbody><tr><td styleCode="Rrule Lrule"><content styleCode="bold">Body as a Whole</content></td><td styleCode="Rrule">21%</td><td styleCode="Rrule">39%</td><td styleCode="Rrule">37%</td><td styleCode="Rrule">29%</td></tr><tr><td styleCode="Rrule Lrule"> Headache</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">18%</td><td styleCode="Rrule">13%</td><td styleCode="Rrule">10%</td></tr><tr><td styleCode="Rrule Lrule"> Pain</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">11%</td><td styleCode="Rrule">7%</td></tr><tr><td styleCode="Rrule Lrule"> Back Pain</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">9%</td><td styleCode="Rrule">6%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Edema</td><td styleCode="Rrule">0.5%</td><td styleCode="Rrule">13%</td><td styleCode="Rrule">10%</td><td styleCode="Rrule">6%</td></tr><tr><td styleCode="Rrule Lrule"><content styleCode="bold">Digestive System</content></td><td styleCode="Rrule">9%</td><td styleCode="Rrule">21%</td><td styleCode="Rrule">29%</td><td styleCode="Rrule">18%</td></tr><tr><td styleCode="Rrule Lrule"> Abdominal Pain</td><td styleCode="Rrule">0%</td><td styleCode="Rrule">11%</td><td styleCode="Rrule">16%</td><td styleCode="Rrule">8%</td></tr><tr><td styleCode="Rrule Lrule"> Nausea</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Flatulence</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">7%</td><td styleCode="Rrule">1%</td></tr><tr><td styleCode="Rrule Lrule"><content styleCode="bold">Musculoskeletal System</content></td><td styleCode="Rrule">7%</td><td styleCode="Rrule">9%</td><td styleCode="Rrule">11%</td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Arthralgia</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">3%</td></tr><tr><td styleCode="Rrule Lrule"><content styleCode="bold">Nervous Sy

td styleCode="Rrule">11%</td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Arthralgia</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">3%</td></tr><tr><td styleCode="Rrule Lrule"><content styleCode="bold">Nervous Sy stem</content></td><td styleCode="Rrule">13%</td><td styleCode="Rrule">10%</td><td styleCode="Rrule">11%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Depression</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">0%</td></tr><tr><td styleCode="Rrule Lrule"><content styleCode="bold">Urogenital System</content></td><td styleCode="Rrule">12%</td><td styleCode="Rrule">18%</td><td styleCode="Rrule">41%</td><td styleCode="Rrule">11%</td></tr><tr><td styleCode="Rrule Lrule"> Breast Pain</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">29%</td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Leukorrhea</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">7%</td><td styleCode="Rrule">1%</td></tr><tr><td styleCode="Rrule Lrule"><content styleCode="bold">Respiratory System</content></td><td styleCode="Rrule">15%</td><td styleCode="Rrule">26%</td><td styleCode="Rrule">29%</td><td styleCode="Rrule">14%</td></tr><tr><td styleCode="Rrule Lrule"> URTI</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">17%</td><td styleCode="Rrule">17%</td><td styleCode="Rrule">8%</td></tr><tr><td styleCode="Rrule Lrule"> Pharyngitis</td><td styleCode="Rrule">0.5%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">7%</td><td styleCode="Rrule">3%</td></tr><tr><td styleCode="Rrule Lrule"> Sinusitis</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Rhinitis</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">1%</td></tr><tr><td styleCode="Rrule Lrule"><content styleCode="bold">Skin and Appendages</content></td><td styleCode="Rrule">19%</td><td styleCode="Rrule">12%</td><td styleCode="Rrule">12%</td><td styleCode="Rrule">15%</td></tr><tr><td styleCode="Rrule Lrule"> Pruritus</td><td styleCode="Rrule">0.5%</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">6%</td></tr></tbody></table>

7 DRUG INTERACTIONS 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 drug metabolism. Inducers of CYP3A4 such as St. John's wort (hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, 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 plasma concentrations of estrogens and may result in adverse reactions. Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. ( 7 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Climara is not indicated for use in pregnancy. There are no data with the use of Climara 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 hormonal contraceptives (estrogens and progestins) 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 are present in human milk and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Climara and any potential adverse effects on the breastfed child from Climara or from the underlying maternal condition. 8.4 Pediatric Use In general, Climara is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone metabolism and effects on epiphyseal centers is recommended during estrogen administration. 8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Climara to determine whether those over 65 years of age differ from younger subjects in their response to Climara. The Women's Health Initiative Studies 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 (14.3) ] . 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 (14.3) ] . 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-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.3) , and Clinical Studies (14.4) ] . 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 (14.4) ] .

8.1 Pregnancy Risk Summary Climara is not indicated for use in pregnancy. There are no data with the use of Climara 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 hormonal contraceptives (estrogens and progestins) 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.

8.4 Pediatric Use In general, Climara is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone metabolism and effects on epiphyseal centers is recommended during estrogen administration.

8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Climara to determine whether those over 65 years of age differ from younger subjects in their response to Climara. The Women's Health Initiative Studies 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 (14.3) ] . 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 (14.3) ] . 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-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.3) , and Clinical Studies (14.4) ] . 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 (14.4) ] .

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

11 DESCRIPTION Climara (estradiol transdermal system), is designed to release estradiol continuously upon application to intact skin. Six (6.5, 9.375, 12.5, 15, 18.75 and 25 cm 2 ) systems are available to provide nominal in vivo delivery of 0.025, 0.0375, 0.05, 0.06, 0.075 or 0.1 mg respectively of estradiol per day. The period of use is 7 days. Each system has a contact surface area of either 6.5, 9.375, 12.5, 15, 18.75 or 25 cm 2 , and contains 2, 2.85, 3.8, 4.55, 5.7 or 7.6 mg of estradiol USP respectively. The composition of the systems per unit area is identical. Estradiol USP is a white, crystalline powder, chemically described as estra-1,3,5(10)-triene-3, 17β-diol. It has an empirical formula of C 18 H 24 O 2 and molecular weight of 272.38. The structural formula is: The Climara transdermal system comprises three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are: A translucent polyethylene film. An acrylate adhesive matrix containing estradiol USP. A protective liner of siliconized or fluoropolymer-coated polyester film is attached to the adhesive surface and must be removed before the system can be used. The active component of the transdermal system is estradiol. The remaining components of the transdermal system (acrylate copolymer adhesive, fatty acid esters, and polyethylene backing) are pharmacologically inactive. Chemical Structure Image

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. 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. 12.2 Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to Climara 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 Transdermal administration of Climara produces mean serum concentrations of estradiol comparable to those produced by premenopausal women in the early follicular phase of the ovulatory cycle. The pharmacokinetics of estradiol following application of the Climara transdermal system were investigated in 197 healthy postmenopausal women in six studies. In five of the studies, the Climara transdermal system was applied to the abdomen, and in a sixth study, application to the buttocks and abdomen were compared. The Climara transdermal delivery system continuously releases estradiol which is transported across intact skin leading to sustained circulating levels of estradiol during a 7-day treatment period. The systemic availability of estradiol after transdermal administration is about 20 times higher than that after oral administration. This difference is due to the absence of first pass metabolism when estradiol is given by the transdermal route. In a bioavailability study, the Climara 6.5 cm 2 was studied with the Climara 12.5 cm 2 as reference. The mean estradiol levels in serum from the two sizes are shown in Figure 1. Figure 1: Mean Serum 17ß -Estradiol Concentrations versus Time Profile following Application of a 6.5 cm 2 Transdermal System and Application of a 12.5 cm 2 Climara Transdermal System Dose proportionality was demonstrated for the Climara 6.5 cm 2 transdermal system as compared to the Climara 12.5 cm 2 transdermal system in a 2-week crossover study with a 1-week washout period between the two-transdermal systems in 24 postmenopausal women. Dose proportionality was also demonstrated for the Climara transdermal system (12.5 cm 2 and 25 cm 2 ) in a 1-week study conducted in 54 postmenopausal women.

the Climara 12.5 cm 2 transdermal system in a 2-week crossover study with a 1-week washout period between the two-transdermal systems in 24 postmenopausal women. Dose proportionality was also demonstrated for the Climara transdermal system (12.5 cm 2 and 25 cm 2 ) in a 1-week study conducted in 54 postmenopausal women. The mean steady state levels (C avg ) of the estradiol during the application of Climara 25 cm 2 and 12.5 cm 2 on the abdomen were about 80 and 40 pg/mL, respectively. In a 3-week multiple application study in 24 postmenopausal women, the 25 cm 2 Climara transdermal system produced average peak estradiol concentrations (C max ) of approximately 100 pg/mL. Trough values at the end of each wear interval (C min ) were approximately 35 pg/mL. Nearly identical serum curves were seen each week, indicating little or no accumulation of estradiol in the body. Serum estrone peak and trough levels were 60 and 40 pg/mL, respectively. In a single dose, randomized, crossover study conducted to compare the effect of site of application, 38 postmenopausal women wore a single Climara 25 cm 2 transdermal system for 1 week on the abdomen and buttocks. The estradiol serum concentration profiles are shown in Figure 2. Values of C max and C avg were, respectively, 25 percent and 17 percent higher with the buttock application than with the abdomen application. Figure 2: Observed Mean (± SE) Estradiol Serum Concentrations for a One Week Application of the Climara Transdermal System (25 cm 2 ) to the Abdomen and Buttocks of 38 Postmenopausal Women Table 2 provides a summary of estradiol pharmacokinetic parameters determined during evaluation of the Climara transdermal system. Table 2: Pharmacokinetic Summary (Mean Estradiol Values) Climara Delivery Rate Surface Area (cm 2 ) Application Site No. of Subjects Dosing C max (pg/mL) C min (pg/mL) C avg (pg/mL) 0.025 6.5 Abdomen 24 Single 32 17 22 0.05 12.5 Abdomen 102 Single 71 29 41 0.1 25 Abdomen 139 Single 147 60 87 0.1 25 Buttock 38 Single 174 71 106 The relative standard deviation of each pharmacokinetic parameter after application to the abdomen averaged 50 percent, which is indicative of the considerable intersubject variability associated with transdermal drug delivery. The relative standard deviation of each pharmacokinetic parameter after application to the buttock was lower than that after application to the abdomen (for example, for C max 39 percent versus 62 percent, and for C avg 35 percent versus 48 percent). 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. 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. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

sal 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. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Adhesion An open-label study of adhesion potentials of placebo transdermal systems that correspond to the 6.5 cm 2 and 12.5 cm 2 sizes of Climara was conducted in 112 healthy women of 45 to 75 years of age. Each woman applied both transdermal systems weekly, on the upper outer abdomen, for 3 consecutive weeks. It should be noted that lower abdomen and upper quadrant of the buttock are the approved sites of application for Climara. The adhesion assessment was done visually on Days 2, 4, 5, 6, 7 of each week of transdermal system wear. A total of 1,654 adhesion observations were conducted for 333 transdermal systems of each size. Of these observations, approximately 90 percent showed essentially no lift for both the 6.5 cm 2 and 12.5 cm 2 transdermal systems. Of the total number of transdermal systems applied, approximately 5 percent showed complete detachment for each size. Adhesion potentials of the 18.75 cm 2 and 25 cm 2 sizes of transdermal systems (0.075 mg per day and 0.1 mg per day) have not been studied. Figure 1 Figure 2

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. 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.

12.2 Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to Climara 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 Transdermal administration of Climara produces mean serum concentrations of estradiol comparable to those produced by premenopausal women in the early follicular phase of the ovulatory cycle. The pharmacokinetics of estradiol following application of the Climara transdermal system were investigated in 197 healthy postmenopausal women in six studies. In five of the studies, the Climara transdermal system was applied to the abdomen, and in a sixth study, application to the buttocks and abdomen were compared. The Climara transdermal delivery system continuously releases estradiol which is transported across intact skin leading to sustained circulating levels of estradiol during a 7-day treatment period. The systemic availability of estradiol after transdermal administration is about 20 times higher than that after oral administration. This difference is due to the absence of first pass metabolism when estradiol is given by the transdermal route. In a bioavailability study, the Climara 6.5 cm 2 was studied with the Climara 12.5 cm 2 as reference. The mean estradiol levels in serum from the two sizes are shown in Figure 1. Figure 1: Mean Serum 17ß -Estradiol Concentrations versus Time Profile following Application of a 6.5 cm 2 Transdermal System and Application of a 12.5 cm 2 Climara Transdermal System Dose proportionality was demonstrated for the Climara 6.5 cm 2 transdermal system as compared to the Climara 12.5 cm 2 transdermal system in a 2-week crossover study with a 1-week washout period between the two-transdermal systems in 24 postmenopausal women. Dose proportionality was also demonstrated for the Climara transdermal system (12.5 cm 2 and 25 cm 2 ) in a 1-week study conducted in 54 postmenopausal women. The mean steady state levels (C avg ) of the estradiol during the application of Climara 25 cm 2 and 12.5 cm 2 on the abdomen were about 80 and 40 pg/mL, respectively. In a 3-week multiple application study in 24 postmenopausal women, the 25 cm 2 Climara transdermal system produced average peak estradiol concentrations (C max ) of approximately 100 pg/mL. Trough values at the end of each wear interval (C min ) were approximately 35 pg/mL. Nearly identical serum curves were seen each week, indicating little or no accumulation of estradiol in the body. Serum estrone peak and trough levels were 60 and 40 pg/mL, respectively. In a single dose, randomized, crossover study conducted to compare the effect of site of application, 38 postmenopausal women wore a single Climara 25 cm 2 transdermal system for 1 week on the abdomen and buttocks. The estradiol serum concentration profiles are shown in Figure 2. Values of C max and C avg were, respectively, 25 percent and 17 percent higher with the buttock application than with the abdomen application. Figure 2: Observed Mean (± SE) Estradiol Serum Concentrations for a One Week Application of the Climara Transdermal System (25 cm 2 ) to the Abdomen and Buttocks of 38 Postmenopausal Women Table 2 provides a summary of estradiol pharmacokinetic parameters determined during evaluation of the Climara transdermal system. Table 2: Pharmacokinetic Summary (Mean Estradiol Values) Climara Delivery Rate Surface Area (cm 2 ) Application Site No.

em (25 cm 2 ) to the Abdomen and Buttocks of 38 Postmenopausal Women Table 2 provides a summary of estradiol pharmacokinetic parameters determined during evaluation of the Climara transdermal system. Table 2: Pharmacokinetic Summary (Mean Estradiol Values) Climara Delivery Rate Surface Area (cm 2 ) Application Site No. of Subjects Dosing C max (pg/mL) C min (pg/mL) C avg (pg/mL) 0.025 6.5 Abdomen 24 Single 32 17 22 0.05 12.5 Abdomen 102 Single 71 29 41 0.1 25 Abdomen 139 Single 147 60 87 0.1 25 Buttock 38 Single 174 71 106 The relative standard deviation of each pharmacokinetic parameter after application to the abdomen averaged 50 percent, which is indicative of the considerable intersubject variability associated with transdermal drug delivery. The relative standard deviation of each pharmacokinetic parameter after application to the buttock was lower than that after application to the abdomen (for example, for C max 39 percent versus 62 percent, and for C avg 35 percent versus 48 percent). 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. 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. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Adhesion An open-label study of adhesion potentials of placebo transdermal systems that correspond to the 6.5 cm 2 and 12.5 cm 2 sizes of Climara was conducted in 112 healthy women of 45 to 75 years of age. Each woman applied both transdermal systems weekly, on the upper outer abdomen, for 3 consecutive weeks. It should be noted that lower abdomen and upper quadrant of the buttock are the approved sites of application for Climara. The adhesion assessment was done visually on Days 2, 4, 5, 6, 7 of each week of transdermal system wear. A total of 1,654 adhesion observations were conducted for 333 transdermal systems of each size. Of these observations, approximately 90 percent showed essentially no lift for both the 6.5 cm 2 and 12.5 cm 2 transdermal systems. Of the total number of transdermal systems applied, approximately 5 percent showed complete detachment for each size. Adhesion potentials of the 18.75 cm 2 and 25 cm 2 sizes of transdermal systems (0.075 mg per day and 0.1 mg per day) have not been studied. Figure 1 Figure 2

<table width="85%"><caption>Table 2: Pharmacokinetic Summary (Mean Estradiol Values)</caption><col width="12%" align="center" valign="top"/><col width="12%" align="center" valign="top"/><col width="14%" align="center" valign="top"/><col width="12%" align="center" valign="top"/><col width="12%" align="center" valign="top"/><col width="12%" align="center" valign="top"/><col width="12%" align="center" valign="top"/><col width="14%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">Climara Delivery Rate</th><th styleCode="Rrule">Surface Area (cm²)</th><th styleCode="Rrule">Application Site</th><th styleCode="Rrule">No. of Subjects</th><th styleCode="Rrule">Dosing</th><th styleCode="Rrule">C_max (pg/mL)</th><th styleCode="Rrule">C_min (pg/mL)</th><th styleCode="Rrule">C_avg (pg/mL)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">0.025</td><td styleCode="Rrule">6.5</td><td styleCode="Rrule">Abdomen</td><td styleCode="Rrule">24</td><td styleCode="Rrule">Single</td><td styleCode="Rrule">32</td><td styleCode="Rrule">17</td><td styleCode="Rrule">22</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">0.05</td><td styleCode="Rrule">12.5</td><td styleCode="Rrule">Abdomen</td><td styleCode="Rrule">102</td><td styleCode="Rrule">Single</td><td styleCode="Rrule">71</td><td styleCode="Rrule">29</td><td styleCode="Rrule">41</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">0.1</td><td styleCode="Rrule">25</td><td styleCode="Rrule">Abdomen</td><td styleCode="Rrule">139</td><td styleCode="Rrule">Single</td><td styleCode="Rrule">147</td><td styleCode="Rrule">60</td><td styleCode="Rrule">87</td></tr><tr><td styleCode="Lrule Rrule">0.1</td><td styleCode="Rrule">25</td><td styleCode="Rrule">Buttock</td><td styleCode="Rrule">38</td><td styleCode="Rrule">Single</td><td styleCode="Rrule">174</td><td styleCode="Rrule">71</td><td styleCode="Rrule">106</td></tr></tbody></table>

14 CLINICAL STUDIES 14.1 Effects on Vasomotor Symptoms in Postmenopausal Women A study of 214 women 25 to 74 years of age met the qualification criteria and were randomly assigned to one of the three treatment groups: 72 to the 0.05 mg estradiol patch, 70 to the 0.1 mg estradiol patch, and 72 to placebo. Potential participants were postmenopausal women in good general health who experienced vasomotor symptoms. Natural menopause patients had not menstruated for at least 12 months and surgical menopause patients had undergone bilateral oophorectomy at least 4 weeks before evaluation for study entry. In order to enter the 11-week treatment phase of the study, potential participants must have experienced a minimum of five moderate to severe hot flushes per week, or a minimum of 15 hot flushes of any severity per week, for 2 consecutive weeks. Women wore the patches in a cyclical fashion (three weeks on and one week off). During treatment, all women used diaries to record the number and severity of hot flushes. Women were monitored by clinic visits at the end of weeks 1, 3, 7, and 11 and by telephone at the end of weeks 4, 5, 8, and 9. Adequate data for the analysis of efficacy was available from 191 subjects. The results are presented as the mean ± SD number of flushes in each of the 3 treatment weeks of each 4-week cycle. In the 0.05 mg estradiol group, the mean weekly hot flush rate across all treatment cycles decreased from 46 ± 6.5 at baseline to 20 ± 3 (-67 percent). The 0.1 mg estradiol group had a decline in the mean weekly hot flush rate from 52 ± 4.4 at baseline to 16 ± 2.4 (-72 percent). In the placebo group, the mean weekly hot flush rate declined from 53 ± 4.5 at baseline to 46 ± 6.5 (-18.1 percent). Compared with placebo, the 0.05 mg and 0.1 mg estradiol groups showed a statistically significantly larger mean decrease in hot flushes across all treatment cycles (P<0.05). When the response to treatment was analyzed for each of the three cycles of therapy, similar statistically significant differences were observed between both estradiol treatment groups and the placebo group during all treatment cycles. In a double-blind, placebo-controlled, randomized study of 187 women receiving Climara 0.025 mg per day or placebo continuously for up to three 28-day cycles, the Climara 0.025 mg per day dosage was shown to be statistically better than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to severe vasomotor symptoms. Table 3: Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms Intent to Treat (ITT) Treatment Group Statistics Week 4 Week 8 Week 12 E 2 Transdermal System N 82 84 68 Mean -6.45 -7.69 -7.56 SD 4.65 4.76 4.64 Placebo N 83 71 65 Mean -5.11 -5.98 -5.98 SD 7.43 8.63 9.69 p-value <0.002 <0.003 A second active-control trial of 193 randomized women was supportive of the placebo-controlled trial. 14.2 Effects on Bone Mineral Density in Postmenopausal Women A two-year clinical trial enrolled a total of 175 healthy, hysterectomized, postmenopausal, non-osteoporotic (that is, lumbar spine bone mineral density >0.9 gm/cm 2 ) women at 10 study centers in the United States. A total of 129 participating women were allocated to receive active treatment with 4 different doses of estradiol patches (6.5, 12.5, 15, 25 cm 2 ) and 46 participating women were allocated to receive placebo patches.

t is, lumbar spine bone mineral density >0.9 gm/cm 2 ) women at 10 study centers in the United States. A total of 129 participating women were allocated to receive active treatment with 4 different doses of estradiol patches (6.5, 12.5, 15, 25 cm 2 ) and 46 participating women were allocated to receive placebo patches. Seventy-seven percent of the randomized women (100 on active drug and 34 on placebo) contributed data to the analysis of percent change of anterior-posterior (A-P) spine BMD, the primary efficacy variable (see Figure 3 ). A statistically significant overall treatment effect at each timepoint was noted, implying bone preservation for all active treatment groups at all timepoints, as opposed to bone loss for placebo at all timepoints. Figure 3: Mean Percent Change from Baseline in Lumbar Spine (A-P View) Bone Mineral Density By Treatment and Time Last Observation Carried Forward Percent change in BMD of the total hip (see Figure 4 ) was also statistically significantly different from placebo for all active treatment groups. This figure is based on 74 percent of the randomized women (95 on active drug and 34 on placebo). Figure 4 Mean Percent Change from Baseline in Total Hip by Treatment and Time Last Observation Carried Forward Figure 3 Figure 4 14.3 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 causes. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms. WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risk 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 4. Table 4. Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. Event Relative Risk CE vs. Placebo (95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-years CHD events Results are based on centrally adjudicated data for an average follow-up of 7.1 years. 0.95 (0.78-1.16) 54 57 Non-fatal MI 0.91 (0.73-1.14) 40 43 CHD death 1.01 (0.71-1.43) 16 16 All strokes 1.33 (1.05-1.68) 45 33 Ischemic stroke 1.55 (1.19-2.01) 38 25 Deep vein thrombosis , Not included in "global index". 1.47 (1.06-2.06) 23 15 Pulmonary embolism 1.37 (0.9-2.07) 14 10 Invasive breast cancer 0.80 (0.62-1.04) 28 34 Colorectal cancer 1.08 (0.75-1.55) 17 16 Hip fracture 0.65 (0.45-0.94) 12 19 Vertebral fractures , 0.64 (0.44-0.93) 11 18 Lower arm/wrist fractures , 0.58 (0.47-0.72) 35 59 Total fractures , 0.71 (0.64-0.80) 144 197 Death due to causes 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.

ral fractures , 0.64 (0.44-0.93) 11 18 Lower arm/wrist fractures , 0.58 (0.47-0.72) 35 59 Total fractures , 0.71 (0.64-0.80) 144 197 Death due to causes 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. 1.08 (0.88-1.32) 53 50 Overall mortality , 1.04 (0.88-1.22) 79 75 Global Index 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, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. 1.02 (0.92-1.13) 206 201 For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risks per 10,000 women-years in the group treated with CE-alone was 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 4 . 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 the distribution of stroke subtype and severity, including fatal strokes, in women receiving estrogen-alone compared to placebo. Estrogen-alone increased the risk of ischemic stroke, and this excess risk was present in all subgroups of women examined. 10 See Table 4 . Timing of 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 [hazard ratio (HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)] . 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 reduction 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, 6.5 percent Black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 5. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 5: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. , Results are based on centrally adjudicated data. Event Relative Risk CE/MPA vs. placebo (95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

study of WHI at an Average of 5.6 Years Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. , Results are based on centrally adjudicated data. Event Relative Risk CE/MPA vs. placebo (95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ) CE/MPA n = 8,506 Placebo n = 8,102 Absolute Risk per 10,000 Women-years CHD events 1.23 (0.99-1.53) 41 34 Non-fatal MI 1.28 (1.00-1.63) 31 25 CHD death 1.10 (0.70-1.75) 8 8 All strokes 1.31 (1.03-1.68) 33 25 Ischemic stroke 1.44 (1.09-1.90) 26 18 Deep vein thrombosis Not included in "global index". 1.95 (1.43-2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive breast cancer Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. 1.24 (1.01-1.54) 41 33 Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancer 0.81 (0.48-1.36) 6 7 Cervical cancer 1.44 (0.47-4.42) 2 1 Hip fracture 0.67 (0.47-0.96) 11 16 Vertebral fractures 0.65 (0.46-0.92) 11 17 Lower arm/wrist fractures 0.71 (0.59-0.85) 44 62 Total fractures 0.76 (0.69-0.83) 152 199 Overall mortality All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.00 (0.83-1.19) 52 52 Global Index 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, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. 1.13 (1.02-1.25) 184 165 Timing of 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 [HR 0.69 (95 percent CI, 0.44-1.07)]. 14.4 Women's Health Initiative Memory Study 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, 0.83-2.66). 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 the 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 plus progestin ancillary study 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 daily 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, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years.

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, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in the 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, 1.19-2.60). 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) ] .

<table width="80%"><caption>Table 3: Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms Intent to Treat (ITT)</caption><col width="32%" align="left" valign="top"/><col width="17%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">Treatment Group</th><th styleCode="Rrule">Statistics</th><th styleCode="Rrule">Week 4</th><th styleCode="Rrule">Week 8</th><th styleCode="Rrule">Week 12</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Rrule Lrule Botrule" rowspan="3">E₂ Transdermal System</td><td styleCode="Rrule Lrule">N</td><td styleCode="Rrule">82</td><td styleCode="Rrule">84</td><td styleCode="Rrule">68</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule" align="center">Mean</td><td styleCode="Rrule">-6.45</td><td styleCode="Rrule">-7.69</td><td styleCode="Rrule">-7.56</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule" align="center">SD</td><td styleCode="Rrule">4.65</td><td styleCode="Rrule">4.76</td><td styleCode="Rrule">4.64</td></tr><tr styleCode="Botrule"><td rowspan="4" styleCode="Rrule Lrule Botrule">Placebo</td><td styleCode="Rrule">N</td><td styleCode="Rrule">83</td><td styleCode="Rrule">71</td><td styleCode="Rrule">65</td></tr><tr styleCode="Botrule"><td styleCode="Rrule" align="center">Mean</td><td styleCode="Rrule">-5.11</td><td styleCode="Rrule">-5.98</td><td styleCode="Rrule">-5.98</td></tr><tr styleCode="Botrule"><td styleCode="Rrule" align="center">SD</td><td styleCode="Rrule">7.43</td><td styleCode="Rrule">8.63</td><td styleCode="Rrule">9.69</td></tr><tr><td styleCode="Rrule" align="center">p-value</td><td styleCode="Rrule">&lt;0.002</td><td styleCode="Rrule"/><td styleCode="Rrule">&lt;0.003</td></tr></tbody></table>

Botrule"><td styleCode="Rrule" align="center">SD</td><td styleCode="Rrule">7.43</td><td styleCode="Rrule">8.63</td><td styleCode="Rrule">9.69</td></tr><tr><td styleCode="Rrule" align="center">p-value</td><td styleCode="Rrule">&lt;0.002</td><td styleCode="Rrule"/><td styleCode="Rrule">&lt;0.003</td></tr></tbody></table> <table width="90%" ID="table4"><caption>Table 4. Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI<footnote ID="_Ref491268003">Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.</footnote></caption><col width="33%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="22%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2">Event</th><th styleCode="Rrule" rowspan="2">Relative Risk CE vs.

on><col width="33%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="22%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2">Event</th><th styleCode="Rrule" rowspan="2">Relative Risk CE vs. Placebo (95% nCI<footnote>Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.</footnote>)</th><th styleCode="Rrule">CE n = 5,310</th><th styleCode="Rrule">Placebo n = 5,429</th></tr><tr><th styleCode="Rrule" colspan="2" align="center">Absolute Risk per 10,000 Women-years</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Rrule Lrule">CHD events<footnote ID="foot1">Results are based on centrally adjudicated data for an average follow-up of 7.1 years.</footnote></td><td styleCode="Rrule">0.95 (0.78-1.16)</td><td styleCode="Rrule">54</td><td styleCode="Rrule">57</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Non-fatal MI<footnoteRef IDREF="foot1"/></td><td styleCode="Rrule"><content styleCode="italics">0.91 (0.73-1.14)</content></td><td styleCode="Rrule"><content styleCode="italics">40</content></td><td styleCode="Rrule"><content styleCode="italics">43</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> <content styleCode="italics">CHD death</content><footnoteRef IDREF="foot1"/></td><td styleCode="Rrule"><content styleCode="italics">1.01 (0.71-1.43)</content></td><td styleCode="Rrule"><content styleCode="italics">16</content></td><td styleCode="Rrule"><content styleCode="italics">16</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">All strokes<footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">1.33 (1.05-1.68)</td><td styleCode="Rrule">45</td><td styleCode="Rrule">33</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"><content styleCode="italics"> Ischemic stroke</content><footnoteRef IDREF="foot1"/></td><td styleCode="Rrule"><content styleCode="italics">1.55 (1.19-2.01)</content></td><td styleCode="Rrule"><content styleCode="italics">38</content></td><td styleCode="Rrule"><content styleCode="italics">25</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Deep vein thrombosis<footnoteRef IDREF="foot1"/>^,<footnote ID="foot2">Not included in &quot;global index&quot;.</footnote></td><td styleCode="Rrule">1.47 (1.06-2.06)</td><td styleCode="Rrule">23</td><td styleCode="Rrule">15</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Pulmonary embolism<footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">1.37 (0.9-2.07)</td><td styleCode="Rrule">14</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Invasive breast cancer<footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">0.80 (0.62-1.04)</td><td styleCode="Rrule">28</td><td styleCode="Rrule">34</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Colorectal cancer<footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">1.08 (0.75-1.55)</td><td styleCode="Rrule">17</td><td styleCode="Rrule">16</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hip fracture<footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">0.65 (0.45-0.94)</td><td styleCode="Rrule">12</td><td styleCode="Rrule">19</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Vertebral fractures<footnoteRef IDREF="foot1"/>^,<footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">0.64 (0.44-0.93)</td><td styleCode="Rrule">11</td><td styleCode="Rrule">18</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Lower arm/wrist fractures<footnoteRef IDREF="foot1"/>^,<footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">0.58 (0.47-0.72)</td><td styleCode="Rrule">35</td><td styleCode="Rrule">59</td></tr><tr

styleCode="Rrule">11</td><td styleCode="Rrule">18</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Lower arm/wrist fractures<footnoteRef IDREF="foot1"/>^,<footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">0.58 (0.47-0.72)</td><td styleCode="Rrule">35</td><td styleCode="Rrule">59</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Total fractures<footnoteRef IDREF="foot1"/>^,<footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">0.71 (0.64-0.80)</td><td styleCode="Rrule">144</td><td styleCode="Rrule">197</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Death due to causes<footnote>Results are based on an average follow-up of 6.8 years.</footnote>^,<footnote>All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.</footnote></td><td styleCode="Rrule Lrule">1.08 (0.88-1.32)</td><td styleCode="Rrule">53</td><td styleCode="Rrule">50</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Overall mortality<footnoteRef IDREF="foot1"/>^,<footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">1.04 (0.88-1.22)</td><td styleCode="Rrule">79</td><td styleCode="Rrule">75</td></tr><tr><td styleCode="Rrule Lrule"><paragraph>Global Index<footnote>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, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes.</footnote></paragraph></td><td styleCode="Rrule">1.02 (0.92-1.13)</td><td styleCode="Rrule">206</td><td styleCode="Rrule">201</td></tr></tbody></table>

arliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes.</footnote></paragraph></td><td styleCode="Rrule">1.02 (0.92-1.13)</td><td styleCode="Rrule">206</td><td styleCode="Rrule">201</td></tr></tbody></table> <table width="90%"><caption>Table 5: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years <footnote>Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.</footnote>^,<footnote> Results are based on centrally adjudicated data.</footnote></caption><col width="35%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2">Event</th><th styleCode="Rrule" rowspan="2">Relative Risk CE/MPA vs. placebo (95% nCI<footnote>Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.</footnote>)</th><th styleCode="Rrule">CE/MPA n = 8,506</th><th styleCode="Rrule">Placebo n = 8,102</th></tr><tr><th styleCode="Rrule" colspan="2" align="center">Absolute Risk per 10,000 Women-years</th></tr></thead><tbody><tr><td styleCode="Rrule Lrule">CHD events</td><td styleCode="Rrule">1.23 (0.99-1.53)</td><td styleCode="Rrule">41</td><td styleCode="Rrule">34</td></tr><tr><td styleCode="Rrule Lrule"> <content styleCode="italics"> Non-fatal MI</content></td><td styleCode="Rrule"><content styleCode="italics">1.28 (1.00-1.63)</content></td><td styleCode="Rrule"><content styleCode="italics">31</content></td><td styleCode="Rrule"><content styleCode="italics">25</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> <content styleCode="italics">CHD death</content></td><td styleCode="Rrule"><content styleCode="italics">1.10 (0.70-1.75)</content></td><td styleCode="Rrule"><content styleCode="italics">8</content></td><td styleCode="Rrule"><content styleCode="italics">8</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">All strokes</td><td styleCode="Rrule">1.31 (1.03-1.68)</td><td styleCode="Rrule">33</td><td styleCode="Rrule">25</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> <content styleCode="italics">Ischemic stroke</content></td><td styleCode="Rrule"><content styleCode="italics">1.44 (1.09-1.90)</content></td><td styleCode="Rrule"><content styleCode="italics">26</content></td><td styleCode="Rrule"><content styleCode="italics">18</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Deep vein thrombosis<footnote ID="_Ref371672455">Not included in &quot;global index&quot;.

lics">1.44 (1.09-1.90)</content></td><td styleCode="Rrule"><content styleCode="italics">26</content></td><td styleCode="Rrule"><content styleCode="italics">18</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Deep vein thrombosis<footnote ID="_Ref371672455">Not included in &quot;global index&quot;. </footnote></td><td styleCode="Rrule">1.95 (1.43-2.67)</td><td styleCode="Rrule">26</td><td styleCode="Rrule">13</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Pulmonary embolism</td><td styleCode="Rrule">2.13 (1.45-3.11)</td><td styleCode="Rrule">18</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Invasive breast cancer<footnote ID="_Ref371672465">Includes metastatic and non-metastatic breast cancer, with the exception of <content styleCode="italics">in situ</content> breast cancer.</footnote></td><td styleCode="Rrule">1.24 (1.01-1.54)</td><td styleCode="Rrule">41</td><td styleCode="Rrule">33</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Colorectal cancer</td><td styleCode="Rrule">0.61 (0.42-0.87)</td><td styleCode="Rrule">10</td><td styleCode="Rrule">16</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Endometrial cancer<footnoteRef IDREF="_Ref371672455"/></td><td styleCode="Rrule">0.81 (0.48-1.36)</td><td styleCode="Rrule">6</td><td styleCode="Rrule ">7</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Cervical cancer<footnoteRef IDREF="_Ref371672455"/></td><td styleCode="Rrule">1.44 (0.47-4.42)</td><td styleCode="Rrule">2</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hip fracture</td><td styleCode="Rrule">0.67 (0.47-0.96)</td><td styleCode="Rrule">11</td><td styleCode="Rrule">16</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Vertebral fractures<footnoteRef IDREF="_Ref371672455"/></td><td styleCode="Rrule">0.65 (0.46-0.92)</td><td styleCode="Rrule">11</td><td styleCode="Rrule">17</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Lower arm/wrist fractures<footnoteRef IDREF="_Ref371672455"/></td><td styleCode="Rrule">0.71 (0.59-0.85)</td><td styleCode="Rrule">44</td><td styleCode="Rrule">62</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Total fractures<footnoteRef IDREF="_Ref371672455"/></td><td styleCode="Rrule">0.76 (0.69-0.83)</td><td styleCode="Rrule">152</td><td styleCode="Rrule">199</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Overall mortality<footnote ID="_Ref371672686">All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.</footnote></td><td styleCode="Rrule">1.00 (0.83-1.19)</td><td styleCode="Rrule">52</td><td styleCode="Rrule">52</td></tr><tr><td styleCode="Rrule Lrule">Global Index <footnote ID="_Ref371672697">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, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes.</footnote></td><td styleCode="Rrule">1.13 (1.02-1.25)</td><td styleCode="Rrule">184</td><td styleCode="Rrule">165</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. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580. 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. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253. 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 Climara (estradiol transdermal system), 0.025 mg per day — each 6.5 cm 2 system contains 2 mg of estradiol USP Individual Carton of 4 systems NDC 50419-454-04 Climara (estradiol transdermal system), 0.0375 mg per day — each 9.375 cm 2 system contains 2.85 mg of estradiol USP Individual Carton of 4 systems NDC 50419-456-04 Climara (estradiol transdermal system), 0.05 mg per day — each 12.5 cm 2 system contains 3.8 mg of estradiol USP Individual Carton of 4 systems NDC 50419-451-04 Climara (estradiol transdermal system), 0.06 mg per day — each 15 cm 2 system contains 4.55 mg of estradiol USP Individual Carton of 4 systems NDC 50419-459-04 Climara (estradiol transdermal system), 0.075 mg per day — each 18.75 cm 2 system contains 5.7 mg of estradiol USP Individual Carton of 4 systems NDC 50419-453-04 Climara (estradiol transdermal system), 0.1 mg per day — each 25 cm 2 system contains 7.6 mg of estradiol USP Individual Carton of 4 systems NDC 50419-452-04 16.2 Storage and Handling Store at 20°C to 25°C (66°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Do not store above 86°F (30°C). Do not store unpouched. Apply immediately upon removal from the protective pouch. Used transdermal systems still contain active hormone. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet.

16.2 Storage and Handling Store at 20°C to 25°C (66°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Do not store above 86°F (30°C). Do not store unpouched. Apply immediately upon removal from the protective pouch. Used transdermal systems still contain active hormone. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet.

17 PATIENT COUNSELING INFORMATION Advise women to read the FDA-approved patient labeling (Patient Information and Instructions for Use) Vaginal Bleeding Inform postmenopausal women to report any vaginal bleeding to their healthcare provider as soon as possible [see Warning and Precautions (5.2) ] . Possible Serious Adverse Reactions with Estrogen-Alone Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen-alone 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-Alone Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting.

Patient Information Climara (Klī-mâr-uh) (estradiol transdermal system) Read this Patient Information before you start using Climara 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 Climara (an estrogen hormone)? Using estrogen-alone may increase your chance of getting cancer of the uterus (womb). Report any unusual vaginal bleeding right away while you are using Climara. 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. Do not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline in 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 age 65 years of age and older. Do not use estrogens with progestogens to prevent heart disease, heart attacks, strokes or dementia. 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 age 65 years of age and older. Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. 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. Because other products and doses have not been studied in the same way, it is not known how the use of Climara will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with Climara. What is Climara? Climara is a prescription medicine patch (transdermal system) that contains estradiol (an estrogen hormone). What is Climara used for? The Climara is used after menopause to: Reduce moderate to severe hot flashes 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 develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden intense feelings of heat and sweating ("hot flashes" or "hot flushes"). In some women, the symptoms are mild, and they will not need to use estrogens. In other women, symptoms can be more severe. Treat moderate to severe menopausal changes in and around the vagina You and your healthcare provider should talk regularly about whether you still need treatment with Climara to control these problems. If you use Climara only to treat your menopausal changes in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.

na You and your healthcare provider should talk regularly about whether you still need treatment with Climara to control these problems. If you use Climara only to treat your menopausal changes in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you. Treat certain conditions in women before menopause if their ovaries do not produce enough estrogens naturally Help reduce your chances of getting osteoporosis (thin weak bones) Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use Climara only to prevent osteoporosis due to 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 Climara. Who should not use Climara? Do not start using Climara if you: have 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 chance 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 Climara. had a stroke or heart attack currently have or have had blood clots currently have or have had liver problems are allergic to Climara or any of the ingredients in it. See the list of ingredients in Climara at the end of this leaflet. Before you use Climara, 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 Climara 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 Climara. are pregnant or think you may be pregnant. Climara is not for pregnant women. are breastfeeding The hormone in Climara 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 Climara works. Climara 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 Climara? For detailed instructions, see the step-by-step instructions for using Climara at the end of this Patient Information. Use Climara exactly as your healthcare provider tells you to use it. Climara is for skin use only. Change your Climara patch 1 time each week or every 7 days. Apply your Climara patch to a clean, dry area on your lower abdomen or buttocks. This area must be clean, dry, and free of powder, oil or lotion for your patch to stick to your skin. Apply your Climara patch to a different area of your abdomen or your buttocks each time. Do not use the same application site 2 times in the same week. Do not apply Climara to your breasts.

r lower abdomen or buttocks. This area must be clean, dry, and free of powder, oil or lotion for your patch to stick to your skin. Apply your Climara patch to a different area of your abdomen or your buttocks each time. Do not use the same application site 2 times in the same week. Do not apply Climara to your breasts. If you forget to apply a new Climara patch, apply a new patch as soon as possible. You and your healthcare provider should talk regularly (every 3 to 6 months) about the dose you are using and whether you still need treatment with Climara. How to Change Climara When changing Climara, peel off the used patch slowly from the skin. After removal of Climara if any adhesive residue remains on your skin, allow the area to dry for 15 minutes. Then, gently rub the area with an oil-based cream or lotion to remove the adhesive from your skin. Apply the new patch to a different area of your abdomen or buttocks. This area must be clean, dry, and free of powder, oil or lotion. Do not use the same site again for at least 1 week after removal of an old patch. What are the possible side effects of Climara? 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 high or low blood calcium gallbladder disease visual abnormalities high blood pressure high levels of fat (triglyceride) in your blood liver problems changes in your thyroid hormone levels fluid retention cancer changes of endometriosis enlargement of benign tumors of the uterus ("fibroids") worsening of swelling of face and tongue (angioedema) in women with a history of angioedema 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 Climara include: headache breast tenderness or pain irregular vaginal bleeding or spotting stomach or abdominal cramps, bloating nausea and vomiting hair loss fluid retention vaginal yeast infection redness and/or irritation at the patch placement site These are not all the possible side effects of Climara. 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 FDA at 1-800-FDA-1088. You may report side effects to Bayer Healthcare Pharmaceuticals at 1-888-842-2937. What can I do to lower my chances of a serious side effect with Climara? Talk with your healthcare provider regularly about whether you should continue using Climara. If you have a uterus, talk with your healthcare provider about whether the addition of a progestogen is right for you. In general, the addition of a progestogen is generally 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 Climara. 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, 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 if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease.

mal mammogram, 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 if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease. How should I store and throw away used Climara? Store Climara at room temperature 68°F to 77°F (20°C to 25°C). Do not store Climara patches outside of their pouches. Apply immediately upon removal from the protective pouch. Used patches still contain estrogen. To throw away the patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place this container in the trash. Used patches should not be flushed in the toilet. Keep Climara and all medicines out of the reach of children. General information about the safe and effective use of Climara. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use Climara for conditions for which it was not prescribed. Do not give Climara to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about Climara that is written for health professionals. For more information, go to www.climara.com or call Bayer HealthCare Pharmaceuticals Inc at 1-888-842-2937. What are the ingredients in Climara? Active ingredient: estradiol Inactive ingredient: acrylate copolymer adhesive, fatty acid esters, and polyethylene backing.

<table width="100%" styleCode="Noautorules"><col width="100%" align="left" valign="top"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">What is the most important information I should know about Climara (an estrogen hormone)?</content></paragraph><list listType="unordered" styleCode="disc"><item>Using estrogen-alone may increase your chance of getting cancer of the uterus (womb).</item><item>Report any unusual vaginal bleeding right away while you are using Climara. 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.</item><item>Do not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function).</item><item>Using estrogen-alone may increase your chances of getting strokes or blood clots.</item><item>Using estrogen-alone may increase your chance of getting dementia, based on a study of women age 65 years of age and older.</item><item>Do not use estrogens with progestogens to prevent heart disease, heart attacks, strokes or dementia.</item><item>Using estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. </item><item>Using estrogens with progestogens may increase your chance of getting dementia, based on a study of women age 65 years of age and older.</item><item>Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. 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. Because other products and doses have not been studied in the same way, it is not known how the use of Climara will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with Climara.</item></list></td></tr></tbody></table>

, and dementia. Because other products and doses have not been studied in the same way, it is not known how the use of Climara will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with Climara.</item></list></td></tr></tbody></table> <table width="100%" styleCode="Noautorules"><col width="50%" align="left" valign="top"/><col width="50%" align="left" valign="top"/><tbody><tr><td><list styleCode="disc" listType="unordered"><item>heart attack</item><item>stroke</item><item>blood clots</item><item>breast cancer</item><item>cancer of the lining of the uterus (womb)</item><item>cancer of the ovary</item><item>dementia</item><item>high or low blood calcium</item><item>gallbladder disease</item><item>visual abnormalities</item><item>high blood pressure</item></list></td><td><list styleCode="disc" listType="unordered"><item>high levels of fat (triglyceride) in your blood</item><item>liver problems</item><item>changes in your thyroid hormone levels</item><item>fluid retention</item><item>cancer changes of endometriosis</item><item>enlargement of benign tumors of the uterus (&quot;fibroids&quot;)</item><item>worsening of swelling of face and tongue (angioedema) in women with a history of angioedema </item></list></td></tr></tbody></table> <table width="100%" styleCode="Noautorules"><col width="50%" align="left" valign="top"/><col width="50%" align="left" valign="top"/><tbody><tr><td><list listType="unordered" styleCode="disc"><item>headache</item><item>breast tenderness or pain</item><item>irregular vaginal bleeding or spotting</item><item>stomach or abdominal cramps, bloating</item><item>nausea and vomiting</item></list></td><td><list listType="unordered" styleCode="disc"><item>hair loss</item><item>fluid retention</item><item>vaginal yeast infection</item><item>redness and/or irritation at the patch placement site</item></list></td></tr></tbody></table>

INSTRUCTIONS FOR USE Climara (Klī-mâr-uh) (estradiol transdermal system) Read this Patient Information before you start using Climara 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. You will need the following supplies: See Figure A Figure A Step 1: Pick the days you will change your Climara. You will need to change your patch 1 time each week or every 7 days. Step 2. Remove the Climara patch from the pouch. Remove patch from its protective pouch by tearing at the notch (do not use scissors). See Figure B Do not remove your patch from the protective pouch until you are ready to apply it. Figure B Step 3. Remove the adhesive liner. See Figure C You will see that Climara is an oval shaped clear patch that is attached to a thick, hard-plastic adhesive liner and covered by a clear, plastic film. See Figure C To apply your patch you must first remove the protective, clear plastic film that is attached to the clear thicker plastic backing. See Figure D There is a silver foil-sticker attached to the inside of the pouch. Do not remove the silver foil sticker from the pouch. See Figure E Figure C Figure D Figure E Step 4. Placing the patch on your skin. Apply the sticky side of the patch to 1 of the areas of skin shown below. See Figure F and Figure G Do not touch the sticky side of the patch with your fingers. Figure F Figure G Note: Avoid the waistline, since clothing and belts may cause the patch to be rubbed off. Do not apply Climara to your breasts. Only apply Climara to skin that is clean, dry, and free of any powder, oil, or lotion. Do not apply the patch to injured, burned, or irritated skin, or areas with skin conditions (such as birth marks, tattoos, or that is very hairy). Step 5. Press the patch firmly onto your skin. Press the patch firmly in place with your fingers for at least 10 seconds Rub the edges of the patch to make sure that it will stick to your skin. ( See Figure H ) Figure H Note: Contact with water while you are swimming, using a sauna, bathing, or showering may cause the patch to fall off. If your patch falls off reapply it. If you cannot reapply the patch, apply a new patch to another area (See Figures F and G ), and continue to follow your original application schedule. If you stop using your Climara patch or forget to apply a new patch as scheduled, you may have spotting, or bleeding, and your symptoms may come back. Step 6: Throwing away your used patch. When it is time to change your patch, remove the old patch before you apply a new patch. To throw away the patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place this container in the trash. Do not flush used patches in the toilet. This Patient Information and Instructions for Use have been approved by the U.S Food and Drug Administration. Revised: 9/2021 © 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981 Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H

<table width="100%" styleCode="Noautorules"><col width="33%" valign="middle" align="center"/><col width="33%" valign="middle" align="center"/><col width="34%" valign="middle" align="center"/><tbody><tr><td><renderMultiMedia referencedObject="MM9" ID="FigC"/></td><td><renderMultiMedia referencedObject="MM10" ID="FigD"/></td><td><renderMultiMedia referencedObject="MM11" ID="FigE"/></td></tr><tr><td><content styleCode="bold">Figure C</content></td><td><content styleCode="bold">Figure D</content></td><td><content styleCode="bold">Figure E</content></td></tr></tbody></table> <table width="100%" styleCode="Noautorules"><col width="51%" valign="middle" align="center"/><col width="49%" valign="middle" align="center"/><tbody><tr><td><renderMultiMedia referencedObject="MM12" ID="FigF"/></td><td><renderMultiMedia referencedObject="MM13" ID="FigG"/></td></tr><tr><td><content styleCode="bold">Figure F</content></td><td><content styleCode="bold">Figure G</content></td></tr></tbody></table>