------DOSAGE AND ADMINISTRATION------HIGHLIGHTS OF PRESCRIBING INFORMATION One (1) gram intravaginally daily for one week followed by 1 gram intravaginally twice a week. (2.2) These highlights do not include all the information needed to use Synthetic Conjugated , A Vaginal Cream safely and effectively. ------DOSAGE FORMS AND STRENGTHS------See full prescribing information for Synthetic , A • 30 gram tube of cream (3) Vaginal Cream. • Each gram of cream contains 0.625 mg synthetic conjugated (synthetic conjugated estrogens, A) Vaginal Cream estrogens, A (3) Initial U.S. Approval: 1999 ------CONTRAINDICATIONS------­ WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR • Undiagnosed abnormal genital bleeding (4) DISORDERS AND PROBABLE DEMENTIA FOR • Known, suspected, or history of breast cancer (4, 5.3) ALONE THERAPY • Known or suspected estrogen-dependent neoplasia (4, 5.3) See full prescribing information for complete boxed warning. • ● There is an increased risk of endometrial cancer in a woman with a Active deep vein thrombosis, pulmonary embolism, or history of these uterus who uses unopposed estrogens (5.3) conditions (4, 5.2) • ● Estrogen-alone therapy should not be used for the prevention of Active arterial thromboembolic disease (for example, stroke and cardiovascular disease or dementia (5.2, 5.4) myocardial infarction) or a history of these conditions (4, 5.2) • ● The Women’s Health Initiative (WHI) estrogen-alone substudy Known liver dysfunction or disease (4, 5.10) reported increased risks of stroke and deep vein thrombosis (5.2) • Known or suspected pregnancy (4, 8.1) ● The Women’s Health Initiative Memory Study (WHIMS) estrogen------WARNINGS AND PRECAUTIONS------alone ancillary study of WHI reported an increased risk of probable • Estrogens increase the risk of gallbladder disease (5.5) dementia in postmenopausal women 65 years of age and older (5.4) • Discontinue estrogen if severe hypercalcemia, loss of vision, severe WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER hypertriglyceridemia, or cholestatic jaundice occurs (5.6, 5.7, 5.10, 5.11) AND PROBABLE DEMENTIA FOR ESTROGEN PLUS PROGESTIN • Monitor thyroid function in women on thyroid hormone replacement THERAPY (5.12, 5.19) See full prescribing information for complete boxed warning. ------ADVERSE REACTIONS------● Estrogen plus progestin therapy should not be used for the prevention Most common adverse reactions (> 3 percent) are: headache, vulvovaginal of cardiovascular disease or dementia (5.2, 5.4) infection, upper respiratory tract infection and hot flush. (6.1, 14.1) ● The WHI estrogen plus progestin substudy reported increased risks of To report SUSPECTED ADVERSE REACTIONS, contact Duramed stroke, deep vein thrombosis, pulmonary embolism, myocardial Pharmaceuticals at 1-800-227-7522 or FDA at 1-800-FDA-1088 or infarction (5.2) www.fda.gov/medwatch. ● The WHI estrogen plus progestin substudy reported increased risks of ------DRUG INTERACTIONS------invasive breast cancer (5.3) Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism. ● The WHIMS estrogen plus progestin ancillary study of WHI reported (7) an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.4) ------USE IN SPECIFIC POPULATIONS------• Nursing Women: Estrogen administration to nursing women has been ------INDICATIONS AND USAGE------shown to decrease the quantity and quality of breast milk (8.3) Synthetic Conjugated Estrogens, A, Vaginal Cream is a mixture of estrogens • Geriatric Use: An increased risk of probable dementia in women over 65 indicated for: years of age was reported in the Women’s Health Initiative Memory • Treatment of Moderate to Severe Vaginal Dryness, a Symptom of ancillary studies of the Women’s Health Initiative (5.4, 8.5) Vulvar and Vaginal Atrophy, due to Menopause (1.1) See 17 for PATIENT COUNSELING INFORMATION and FDA- • Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar Approved Patient Labeling and Vaginal Atrophy, due to Menopause (1.2) Revised:11/2008

______FULL PRESCRIBING INFORMATION: CONTENTS* 5.13 Fluid Retention 5.14 Hypocalcemia BOXED WARNING 5.15 Exacerbation of Endometriosis 1 INDICATIONS AND USAGE 5.16 Exacerbation of Other Conditions 1.1 Treatment of Moderate to Severe Vaginal Dryness, a Symptom 5.17 Effect on Barrier Contraception of Vulvar and Vaginal Atrophy, due to Menopause 5.18 Laboratory Test 1.2 Treatment of Moderate to Severe Dyspareunia, a Symptom of 5.19 Drug and Laboratory Test Interactions Vulvar and Vaginal Atrophy, due to Menopause 6. ADVERSE REACTIONS 2 DOSAGE AND ADMINISTRATION 6.1 Clinical Study Experience 2.1 General Dosing Information 7. DRUG INTERACTIONS 2.2 Recommended Dosing 7.1 Metabolic Interactions 3 DOSAGE FORMS AND STRENGTHS 8. USE IN SPECIFIC POPULATIONS 4 CONTRAINDICATIONS 8.1 Pregnancy 8.3 Nursing Mothers 5 WARNINGS AND PRECAUTIONS 8.4 Pediatric Use 5.1 Risks from Systemic Absorption 8.5 Geriatric Use 5.2 Cardiovascular Disorders 8.6 Renal Impairment 5.3 Malignant Neoplasms 8.7 Hepatic Impairment 5.4 Probable Dementia 8.8 Gender 5.5 Gallbladder Disease 8.9 Race 5.6 Hypercalcemia 5.7 Visual Abnormalities 10. OVERDOSAGE 5.8 Addition of a Progestin When a Woman Has Not Had a 11. DESCRIPTION Hysterectomy 5.9 Elevated Blood Pressure 12. CLINICAL PHARMACOLOGY 5.10 Hypertriglyceridemia 12.1 Mechanism of Action 5.11 Hepatic Impairment and/or Past History of Cholestatic 12.2 Pharmacodynamics Jaundice 12.3 Pharmacokinetics 5.12 Hypothyroidism 13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 17.2 Possible Serious Adverse Reactions with Estrogens 17.3 Possible Less Serious but Common Adverse Reactions 14. CLINICAL STUDIES with Estrogens 14.1 Effects on Vulvar and Vaginal Atrophy 17.4 Instructions for Use of Vaginal Applicator 14.2 Women’s Health Initiative Studies 17.5 FDA-Approved Patient Labeling 14.3 Women’s Health Initiative Memory Study 15 REFERENCES * Sections or subsections omitted from the full prescribing information 16. HOW SUPPLIED/STORAGE AND HANDLING are not listed. 17. PATIENT COUNSELING INFORMATION 17.1 Vaginal Bleeding ______

FULL PRESCRIBING INFORMATION Synthetic Conjugated Estrogens, A Vaginal Cream is indicated for:

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR 1.1 Treatment of Moderate to Severe Vaginal Dryness, a Symptom of DISORDERS AND PROBABLE DEMENTIA FOR ESTROGEN­ Vulvar and Vaginal Atrophy, due to Menopause. ALONE THERAPY 1.2 Treatment of Moderate to Severe Dyspareunia, a Symptom of ENDOMETRIAL CANCER Vulvar and Vaginal atrophy, due to Menopause.

2. DOSAGE AND ADMINISTRATION There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen 2.1 General Dosing Information therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic Generally, when estrogen is prescribed for a postmenopausal woman with a measures, including directed or random endometrial sampling when uterus, a progestin should also be considered to reduce the risk of indicated, should be undertaken to rule out malignancy in endometrial cancer. postmenopausal women with undiagnosed persistent or recurring A woman without a uterus does not need a progestin. In some cases, abnormal genital bleeding [see Warnings and Precautions (5.3)]. however, hysterectomized women with a history of endometriosis may need CARDIOVASCULAR DISORDERS AND PROBABLE DEMENTIA a progestin [see Warnings and Precautions (5.3, 5.15)]. Use of estrogen-alone, or in combination with a progestin, should be with Estrogen-alone therapy should not be used for the prevention of the lowest effective dose and for the shortest duration consistent with cardiovascular disease or dementia [see Warnings and Precautions (5.2, treatment goals and risks for the individual woman. Postmenopausal women 5.4), and Clinical Studies (14.2, 14.3)]. should be re-evaluated periodically as clinically appropriate to determine if The Women’s Health Initiative (WHI) estrogen-alone substudy reported treatment is still necessary. increased risks of stroke and deep vein thrombosis (DVT) in 2.2. Recommended Dosing postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg], relative Synthetic Conjugated Estrogens, A Vaginal Cream 1 gram is administered to placebo [see Warnings and Precautions (5.2) and Clinical Studies intravaginally daily for one week followed by 1 gram administered (14.2)]. intravaginally twice weekly. The Women’s Health Initiative Memory Study (WHIMS) estrogen-alone 3. DOSAGE FORM AND STRENGTH ancillary study of the WHI, reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older Synthetic Conjugated Estrogens, A Vaginal Cream contains synthetic during 5.2 years of treatment with daily CE (0.625 mg) alone, relative to conjugated estrogens, A 0.625 mg per gram in a nonliquifying cream base. placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.4), Use in 4. CONTRAINDICATIONS Specific Populations (8.5) and Clinical Studies (14.3)]. Synthetic Conjugated Estrogens, A Vaginal Cream therapy should not be In the absence of comparable data, these risks should be assumed to be used in women with any of the following conditions: similar for other doses of CE and other dosage forms of estrogens. • Undiagnosed abnormal genital bleeding Estrogens with or without progestins should be prescribed at the lowest • Known, suspected, or history of breast cancer effective doses and for the shortest duration consistent with treatment • Known or suspected estrogen-dependent neoplasia goals and risks for the individual woman. • Active deep vein thrombosis, pulmonary embolism or history of these conditions WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER • Active arterial thromboembolic disease (for example, stroke and AND PROBABLE DEMENTIA FOR ESTROGEN PLUS PROGESTIN myocardial infarction) or a history of these conditions THERAPY • Known liver dysfunction or disease • Known or suspected pregnancy Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.2, 5. WARNINGS AND PRECAUTIONS 5.4), and Clinical Studies (14.2, 14.3)]. 5.1 Risks from Systemic Absorption The WHI estrogen plus progestin substudy reported increased risks of Systemic absorption occurs with the use of Synthetic Conjugated Estrogens, DVT, pulmonary embolism, stroke and myocardial infarction in A Vaginal Cream. The warnings, precautions, and adverse reactions postmenopausal women (50 to 79 years of age) during 5.6 years of associated with oral synthetic conjugated estrogens, A treatment should be treatment with daily oral CE (0.625 mg) combined with taken into account. medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.2), and Clinical Studies (14.2)]. 5.2 Cardiovascular Disorders The WHI estrogen plus progestin substudy also demonstrated an An increased risk of stroke and deep vein thrombosis (DVT) has been increased risk of invasive breast cancer [see Warnings and Precautions reported with estrogen-alone therapy. An increased risk of pulmonary (5.3), and Clinical Studies (14.2)]. embolism, DVT, stroke, and myocardial infarction has been reported with estrogen plus progestin therapy. Should any of these occur or be suspected, The WHIMS estrogen plus progestin ancillary study of the WHI, estrogens with or without progestins should be discontinued immediately. reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), Risk factors for arterial vascular disease (for example, hypertension, relative to placebo. It is unknown whether this finding applies to younger diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or postmenopausal women [see Warnings and Precautions (5.4), Use in venous thromboembolism (for example, personal history of venous Specific Populations (8.5) and Clinical Studies (14.3)]. thromboembolism [VTE], obesity, and systemic lupus erythematosus) should be managed appropriately. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA therapy and other combinations Stroke and dosage forms of estrogens and progestins. In the Women's Health Initiative (WHI) estrogen-alone substudy, a Estrogens with or without progestins should be prescribed at the lowest statistically significant increased risk of stroke was reported in women 50 to effective doses and for the shortest duration consistent with treatment 79 years of age receiving daily CE (0.625 mg) compared to women in the goals and risks for the individual woman. same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted [see 1. INDICATIONS AND USAGE Clinical Studies (14.2)]. Should a stroke occur or be suspected, estrogens should be discontinued immediately. Clinical surveillance of all women taking estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including Subgroup analyses of women 50 to 59 years of age suggest no increased risk directed or random endometrial sampling when indicated, should be of stroke for those women receiving CE (0.625 mg) versus those receiving 1 undertaken to rule out malignancy in postmenopausal women with placebo (18 versus 21 per 10,000 women-years). undiagnosed persistent or recurring abnormal genital bleeding. In the WHI estrogen plus progestin substudy, a statistically significant There is no evidence that the use of natural estrogens results in a different increased risk of stroke was reported in all women receiving daily CE (0.625 endometrial risk profile than synthetic estrogens of equivalent estrogen mg) plus MPA (2.5 mg) compared to placebo (33 versus 25 per 10,000 dose. Adding a progestin to estrogen therapy in postmenopausal women has women-years) [see Clinical Studies (14.2)]. The increase in risk was 1 been shown to reduce the risk of endometrial hyperplasia, which may be a demonstrated after the first year and persisted. precursor to endometrial cancer. Coronary Heart Disease Breast Cancer In the WHI estrogen-alone substudy, no overall effect on coronary heart The most important randomized clinical trial providing information about disease (CHD) events (defined as nonfatal myocardial infarction [MI], silent breast cancer in estrogen-alone users is the Women's Health Initiative MI, or CHD death) was reported in women receiving estrogen-alone 2 (WHI) substudy of daily CE (0.625mg). In the WHI estrogen-alone compared to placebo [see Clinical Studies (14.2)]. substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg) was not associated with an increased risk of invasive breast cancer (relative risk Subgroup analyses of women 50 to 59 years of age suggest a statistically non­ 5 significant reduction in CHD events (CE 0.625 mg compared to placebo) in [RR] 0.80) [see Clinical Studies (14. 2)]. women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).1 The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily In the WHI estrogen plus progestin substudy, there was a statistically non­ CE (0.625mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the significant increased risk of CHD events in women receiving daily CE estrogen plus progestin substudy reported an increased risk of breast cancer (0.625mg) plus MPA (2.5mg) compared to women receiving placebo (41 1 in women who took daily CE plus MPA. In this substudy, prior use of versus 34 per 10,000 women-years). An increase in relative risk was estrogen-alone or estrogen plus progestin therapy was reported by 26 demonstrated in year 1, and a trend toward decreasing relative risk was percent of the women. The relative risk of invasive breast cancer was 1.24, reported in years 2 through 5 [see Clinical Studies (14.2)]. and the absolute risk was 41 versus 33 cases per 10,000 women-years for 6 In postmenopausal women with documented heart disease (n = 2,763), estrogen plus progestin compared with placebo. Among women who average age 66.7 years), in a controlled clinical trial of secondary prevention reported prior use of hormone therapy, the relative risk of invasive breast of cardiovascular disease(Heart and Estrogen/Progestin Replacement Study cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) women-years, for estrogen plus progestin compared with placebo. Among demonstrated no cardiovascular benefit. During an average follow-up of 4.1 women who reported no prior use of hormone therapy, the relative risk of years, treatment with CE plus MPA did not reduce the overall rate of CHD invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 events in postmenopausal women with established coronary heart disease. cases per 10,000 women-years for estrogen plus progestin compared with There were more CHD events in the CE plus MPA-treated group than in the placebo. In the same substudy, invasive breast cancers were larger and placebo group in year 1, but not during subsequent years. Two thousand, three diagnosed at a more advanced stage in the CE (0.625) plus MPA (2.5mg) hundred and twenty-one (2,321) women from the original HERS trial agreed group compared with the placebo group. Metastatic disease was rare, with to participate in an open label extension of HERS, HERS II. Average follow- no apparent difference between the two groups. Other prognostic factors, up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. such as histologic subtype, grade and hormone receptor status did not differ Rates of CHD events were comparable among women in the CE (0.625mg) between the groups [see Clinical Studies (14.2)]. plus MPA (2.5mg) group and the placebo group in HERS, HERS II, and overall. Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin Venous Thromboembolism (VTE) therapy, and a smaller increased risk for estrogen-alone therapy, after In the WHI estrogen-alone substudy, the risk of VTE (DVT and pulmonary several years of use. The risk increased with duration of use, and appeared embolism [PE]), was increased for women receiving daily CE (0.625 mg) to return to baseline over about 5 years after stopping treatment (only the compared to placebo (30 versus 22 per 10,000 women-years), although only observational studies have substantial data on risk after stopping). the increased risk of DVT reached statistical significance (23 versus 15 per Observational studies also suggest that the risk of breast cancer was greater, 10,000 women years). The increase in VTE risk was demonstrated during the and became apparent earlier, with estrogen plus progestin therapy as first 2 years3 [see Clinical Studies (14.2)]. Should a VTE occur or be compared to estrogen-alone therapy. However, these studies have not suspected, estrogens should be discontinued immediately. generally found significant variation in the risk of breast cancer among different estrogens or among different estrogen plus progestin combinations, In the WHI estrogen plus progestin substudy, a statistically significant 2-fold doses, or routes of administration. greater rate of VTE was reported in women receiving daily CE (0.625mg) plus MPA(2.5mg) compared to women receiving placebo (35 vs. 17 per The use of estrogen-alone and estrogen plus progestin therapy has been 10,000 women-years). Statistically significant increases in risk for both DVT reported to result in an increase in abnormal mammograms requiring further (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women- evaluation. years) were also demonstrated. The increase in VTE risk was observed during 4 All women should receive yearly breast examinations by a healthcare the first year and persisted [See Clinical Studies (14.2)]. Should a VTE occur provider and perform monthly breast self-examinations. In addition, or be suspected, estrogens should be discontinued immediately. mammography examinations should be scheduled based on patient age, risk If feasible, estrogens should be discontinued at least 4 to 6 weeks before factors, and prior mammogram results. surgery of the type associated with an increased risk of thromboembolism, or Ovarian Cancer during periods of prolonged immobilization. The WHI estrogen plus progestin substudy reported a statistically non­ 5.3 Malignant Neoplasms significant increased risk of ovarian cancer. After an average follow-up of Endometrial Cancer 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent nCI 0.77-3.24). The absolute risk for CE plus An increased risk of endometrial cancer has been reported with the use of MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7 In unopposed estrogen therapy in a woman with a uterus. The reported some epidemiologic studies, the use of estrogen-only products, in particular endometrial cancer risk among unopposed estrogen users is about 2- to 12­ for 5 or more years, has been associated with an increased risk of ovarian fold greater than in non-users, and appears dependent on duration of treatment cancer. However, the duration of exposure associated with increased risk is and on estrogen dose. Most studies show no significant increased risk not consistent across all epidemiologic studies and some report no associated with use of estrogens for less than 1 year. The greatest risk appears association. 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. 5.4 Probable Dementia Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the In the estrogen-alone Women's Health Initiative Memory Study (WHIMS), an increased TBG by making more thyroid hormone, thus maintaining free T4 ancillary study of WHI, a population of 2,947 hysterectomized women 65 to and T3 serum concentrations in the normal range. Women dependent on 79 years of age was randomized to daily CE (0.625mg) or placebo. In the thyroid hormone replacement therapy who are also receiving estrogens may WHIMS estrogen plus progestin ancillary study, a population of 4,532 require increased doses of their thyroid hormone replacement therapy. These postmenopausal women 65 to 79 years of age was randomized to daily CE women should have their thyroid function monitored in order to maintain (0.625mg) plus MPA (2.5mg) or placebo. their free thyroid hormone levels in an acceptable range. In the WHIMS estrogen-alone ancillary study, after an average follow-up of 5.13 Fluid Retention 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 Estrogens may cause some degree of fluid retention. Women with probable dementia for CE-alone vs. placebo was 1.49 (95 percent CI 0.83­ conditions that might be influenced by this factor, such as a cardiac or renal 2.66). The absolute risk of probable dementia for CE alone vs. placebo was 37 dysfunction, warrant careful observation when estrogens are prescribed. versus 25 cases per 10,000 women-years8 [see Use in Specific Populations (8.5) and Clinical Studies (14.3)]. 5.14 Hypocalcemia In the WHIMS estrogen plus progestin ancillary study, after an average Estrogens should be used with caution in women with hypoparathyroidism follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in as estrogen-induced hypocalcemia may occur. the placebo group were diagnosed with probable dementia. The relative risk of 5.15 Exacerbation of Endometriosis 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 A few cases of malignant transformation of residual endometrial implants placebo was 45 versus 22 cases per 10,000 women-years8 [see Use in Specific have been reported in women treated post-hysterectomy with estrogen-alone Populations (8.5) and Clinical Studies (14.3)]. therapy. For women known to have residual endometriosis post- hysterectomy, the addition of progestin should be considered. 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 5.16 Exacerbation of Other Conditions percent nCI 1.19-2.60). Since both substudies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, women8 [see Use in Specific Populations (8.5) and Clinical Studies 14.3)]. epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these 5.5 Gallbladder Disease conditions. A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in 5.17 Effects on Barrier Contraception postmenopausal women receiving estrogens has been reported. No studies have been conducted to determine the potential for Synthetic 5.6 Hypercalcemia Conjugated Estrogens, A Vaginal Cream to weaken and contribute to the failure of condoms, diaphragms, or cervical caps made of latex or rubber. Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug 5.18 Laboratory Test Interactions should be stopped and appropriate measures taken to reduce the serum calcium level. Serum follicle stimulating hormone and levels have not been shown to be useful in the management of moderate to severe symptoms of 5.7 Visual Abnormalities vulvar and vaginal atrophy. Retinal vascular thrombosis has been reported in women receiving estrogens. 5.19 Drug/Laboratory Test Interactions Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Accelerated prothrombin time, partial thromboplastin time, and platelet If examination reveals papilledema or retinal vascular lesions, estrogens aggregation time; increased platelet count; increased factors II, VII antigen, should be permanently discontinued. VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and 5.8 Addition of a Progestin When a Woman Has Not Had a antithrombin III, decreased antithrombin III activity; increased levels of Hysterectomy fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 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 Increased thyroid-binding globulin (TBG) levels leading to increased reported a lowered incidence of endometrial hyperplasia than would be circulating total thyroid hormone levels as measured by protein-bound induced by estrogen treatment alone. Endometrial hyperplasia may be a iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by precursor to endometrial cancer. radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid There are, however, possible risks that may be associated with the use of replacement therapy may require higher doses of thyroid hormone. progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG) and sex hormone binding globulin 5.9 Elevated Blood Pressure (SHBG), leading to increased total circulating corticosteroids and sex In a small number of case reports, substantial increases in blood pressure have , respectively. Free hormone concentrations, such as and been attributed to idiosyncratic reactions to estrogens. In a large, randomized, estradiol, may be decreased. Other plasma proteins may be increased placebo-controlled clinical trial, a generalized effect of estrogens on blood (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). pressure was not seen. Increased plasma HDL and HDL2 cholesterol sub-fraction concentrations, 5.10 Hypertriglyceridemia reduced LDL cholesterol concentration, increased triglycerides levels. In women with pre-existing hypertriglyceridemia, estrogen therapy may be Impaired glucose tolerance. associated with elevations of plasma triglycerides leading to pancreatitis. 6. ADVERSE REACTIONS Consider discontinuation of treatment if pancreatitis develops. 6.1 Clinical Study Experience 5.11 Hepatic Impairment and/or Past History of Cholestatic Jaundice Because clinical trials are conducted under widely varying conditions, Estrogens may be poorly metabolized in women with impaired liver function. adverse reaction rates observed in the clinical trials of a drug cannot be For women with a history of cholestatic jaundice associated with past estrogen directly compared to rates in the clinical trials of another drug and may not use or with pregnancy, caution should be exercised and in the case of reflect the rates observed in practice. recurrence, medication should be discontinued. 5.12 Hypothyroidism The adverse reactions that occurred in at least 3 percent of Synthetic In the Women’s Health Initiative Memory Study (WHIMS) of Conjugated Estrogens, A Vaginal Cream 1g- and placebo-treated postmenopausal women 65 to 79 years of age, there was an increased risk of postmenopausal women in a 12-week, randomized, double-blind, placebo- developing probable dementia in the estrogen-alone and the estrogen plus controlled trial are shown in Table 1. progestin groups when compared to placebo [see Clinical Studies (14.3)]. Table 1: Incidence of Treatment-Emergent Adverse Reactions with Since both substudies were conducted in women 65 to 79 years of age, it is Greater than 3 percent Occurrence by Body System (Safety Cohort) unknown whether these findings apply to younger postmenopausal women8 MedDra System Organ Class 1 g SCE, A 1g Placebo [see Clinical Studies (14.3)]. and Preferred Term Vaginal Cream (N=150) (N=155) 8.6 Renal Impairment n % n % The effect of renal impairment on Synthetic Conjugated Estrogens, A Infections and Infestations Vaginal Cream pharmacokinetics has not been studied. Vulvovaginal Mycotic Infection 7 4.7 5 3.2 8.7 Hepatic Impairment Upper Respiratory Tract 7 4.7 7 4.5 Infection The effect of hepatic impairment on Synthetic Conjugated Estrogens, A Nervous System Disorders Vaginal Cream pharmacokinetics has not been studied. Headache 6 4.0 0 0 8.8 Gender Vascular Disorders Synthetic Conjugated Estrogens, A Vaginal Cream is indicated for use in Hot Flush 5 3.3 2 1.3 women only. . 8.9 Race 7. DRUG INTERACTIONS No studies were done to determine the effect of race on the No formal drug interactions studies have been conducted for Synthetic pharmacokinetics of Synthetic Conjugated Estrogens, A Vaginal Cream. Conjugated Estrogens, A Vaginal Cream. 10. OVERDOSAGE 7.1 Metabolic Interactions Overdosage of estrogen may cause nausea and vomiting, breast tenderness, In vitro and in vivo studies have shown that estrogens are metabolized dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding in partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or women. Treatment of overdose consists of discontinuation of Synthetic inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of Conjugated Estrogens, A Vaginal Cream with institution of appropriate CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), symptomatic care. phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic 11. DESCRIPTION effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir Each gram of Synthetic Conjugated Estrogens, A Vaginal Cream contains and grapefruit juice may increase plasma concentrations of estrogens and may 0.625 mg of synthetic conjugated estrogens, A in a non-liquefying base result in adverse reactions. containing: benzyl alcohol, cetyl alcohol, cetyl esters wax, glycerin, glyceryl monostearate, light mineral oil, methyl stearate, propylene glycol 8. USE IN SPECIFIC POPULATIONS monostearate, sodium hydroxide, sodium lauryl sulfate, sodium phosphate 8.1 Pregnancy dibasic anhydrous, water and white wax. Synthetic Conjugated Estrogens, A Vaginal Cream should not be used during Synthetic conjugated estrogens, A, is the active ingredient in Synthetic pregnancy [see Contraindications (4)]. There appears to be little or no Conjugated Estrogens, A Vaginal Cream and is a blend of nine (9) synthetic increased risk of birth defects in children born to women who have used . The estrogenic substances are sodium sulfate, estrogens and progestins as an oral contraceptive inadvertently during early sodium sulfate, sodium 17α-dihydroequilin sulfate, sodium 17α­ pregnancy. , sodium 17α-dihydroequilin sulfate, sodium 17β­ dihydroequilenin sulfate, sodium 17β-dihydroequilenin sulfate, sodium 8.3 Nursing Mothers sulfate and sodium 17β-estradiol sulfate. Synthetic Conjugated Estrogens, A Vaginal Cream, should not be use during The structural formulae for these estrogens are: lactation. Estrogen administration to nursing mothers has been shown to O O decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the breast milk of mothers receiving estrogens. Caution should be exercised when Synthetic Conjugated Estrogens A, Vaginal Cream is administered to a nursing woman. NaO SO NaO3SO 3 C H NaO S C18H21NaO5S 18 21 5 8.4 Pediatric Use 372.42 372.42 Sodium Sodium Equilin Sulfate Synthetic Conjugated Estrogens, A Vaginal Cream is not indicated in OH OH children. Clinical studies have not been conducted in the pediatric population. 8.5 Geriatric Use

NaO3SO C18H21NaO5S There have not been sufficient numbers of geriatric women involved in NaO3SO 372.42 C18H21NaO5S clinical studies utilizing Synthetic Conjugated Estrogens, A Vaginal Cream to 372.42 determine whether those over 65 years of age differ from younger subjects in Sodium 17α-Dihydroequilin Sulfate Sodium 17β-Dihydroequilin their response to synthetic conjugated estrogens, A. Sulfate The Women’s Health Initiative Study OH OH In the Women's Health Initiative (WHI) estrogen-alone substudy, there was a higher relative risk (daily CE [0.625mg] versus placebo) of stroke in women greater than 65 years of age [see Clinical Studies (14.2)]. NaO SO 3 C H NaO S NaO3SO 18 23 5 C18H23NaO5S 374.44 In the WHI estrogen plus progestin substudy, there was a higher relative risk 374.44 of nonfatal stroke and invasive breast cancer in women greater than 65years of Sodium 17α-Estradiol Sulfate Sodium 17β-Estradiol Sulfate age [see Clinical Studies (14.2)].

The Women’s Health Initiative Memory Study O OH Tmax (hr) 8.3 8.9 10.1 (%CV) (132.6) (67.8) (45.4)

AUC0-24 (pg.hr/mL) 560.7 139.7 65.4 (%CV) (60.7) (43.3) (108.5)

NaO3SO Day 27 C H NaO S 18 17 5 NaO3SO 368.39 C H NaO S 18 19 5 Cmax (pg/mL) 24.0 7.9 5.5 370.41 Sodium Equilenin Sulfate Sodium 17α-Dihydroequilenin (%CV) (47.8) (92.4) (125.4) OH Tmax (hr) 12.0 12.3 10.5 (%CV) (72.7) (80.1) (40.0)

AUC0-24 (pg.hr/mL) 293.8 92.5 27.3 (%CV) (46.3) (89.1) (135.8)

NaO3SO CV = coefficient of variation C18H19NaO5S 370.41 Sodium 17β-Dihydroequilenin The plasma concentration versus time profile for BA free estrone, BA free Sulfate estradiol and free equilin at Day 27 following the recommended dosing regimen of 1 gm Synthetic Conjugated Estrogens, A Vaginal Cream is presented in Figure 1. 12. CLINICAL PHARMACOLOGY Figure 1: Pharmacokinetic Profiles of BA free Estrone, BA free 12.1 Mechanism of Action Estradiol and free Equilin after Day 27 for Twice Weekly Dosing of 1g dose of SCE-A Vaginal Cream Endogenous estrogens are largely responsible for the development and 35 maintenance of the female reproductive system and secondary sexual BA Free Estrone characteristics. Although circulating estrogens exist in a dynamic equilibrium 30 BA Free Estradiol of metabolic interconversions, estradiol is the principal intracellular human Free Equilin estrogen and is substantially more potent than its metabolites, estrone and 25 at the receptor level. 20 The primary source of estrogen in normally cycling adult women is the 15 ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen 10 is produced by conversion of , secreted by the adrenal cortex, Plasma Concentration (pg/mL) to estrone by peripheral tissues. Thus, estrone and the sulfate-conjugated 5 form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. 0 0 12 24 36 48 Estrogens act through binding to nuclear receptors in estrogen-responsive Time (hour) tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Distribution Circulating estrogens modulate the pituitary secretion of the , The distribution of exogenous estrogens is similar to that of endogenous luteinizing hormone (LH) and follicle-stimulating hormone (FSH), through a estrogens. Estrogens are widely distributed in the body and are generally negative feedback mechanism. Estrogens act to reduce the elevated levels of found in higher concentrations in the sex hormone target organs. Estrogens these hormones in postmenopausal women. circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. 12.2 Pharmacodynamics Metabolism Currently, there are no pharmacodynamic data known for Synthetic Conjugated Estrogens, A Vaginal Cream. Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic 12.3 Pharmacokinetics interconversions. These transformations take place mainly in the liver. The Absorption vaginal delivery of estrogens circumvents first-pass metabolism. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which Pharmacokinetic parameters for baseline-adjusted (BA) free estrone, baseline is the major urinary metabolite. Estrogens also undergo enterohepatic adjusted free estradiol, and free equilin at Day 1, Day 7 and Day 27 following recirculation via sulfate and glucuronide conjugation in the liver, biliary the recommended dosing regimen of 1 gm Synthetic Conjugated Estrogens, A secretion of conjugates into the intestine, and hydrolysis in the intestine Vaginal Cream are presented in Table 2. The decline in plasma concentrations followed by reabsorption. In postmenopausal women, a significant from Day 1 to Day 27 [see Clinical Pharmacology, Excretion (12.4)] suggests proportion of the circulating estrogens exist as sulfate conjugates, especially that there is very little to no systemic accumulation during this dosing interval estrone sulfate, which serves as a circulating reservoir for the formation of for Synthetic Conjugated Estrogens, A Vaginal Cream. more active estrogens. Excretion Table 2: Pharmacokinetic parameters for baseline-adjusted free After the recommended dosing application of Synthetic Conjugated estrone, baseline-adjusted free estradiol, and free equilin at Day 1, Estrogens, A Vaginal Cream, the mean half-lives at steady-state were 22.1 Day 7 and Day 27 following the recommended dosing regimen of 1 hr for baseline-adjusted free estradiol, 34.1 hr for baseline-adjusted free gm Synthetic Conjugated Estrogens, A Vaginal Cream. estrone, and 15.7 hr for free equilin.

BA Estrone BA Estradiol Equilin Specific Populations Day 1 No pharmacokinetic studies were conducted in specific populations, including patients with renal or hepatic impairment. Cmax (pg/mL) 74.4 16.1 14.3 (%CV) (87.7) (84.8) (92.3) 13. NONCLINICAL TOXICOLOGY Tmax (hr) 6.8 6.6 6.0 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility (%CV) (74.1) (61.7) (64.8)

AUC0-24 (pg.hr/mL) 622.7 131.6 94.9 Long-term continuous administration of natural and synthetic estrogens in (%CV) (64.4) (56.9) (93.4) certain animal species increases the frequency of carcinomas of the breast, Day 7 uterus, cervix, vagina, testis, and liver. C (pg/mL) 38.5 12.7 7.4 max 14. CLINICAL STUDIES (%CV) (60.1) (100.3) (60.5) 14.1 Effects on Vulvar and Vaginal Atrophy pulmonary embolism (PE), endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. The A 12-week prospective, randomized, double blind, placebo-controlled study did not evaluate the effects of CE or CE plus MPA on menopausal multicenter study was conducted to evaluate the efficacy and safety of symptoms. Synthetic Conjugated Estrogens, A Vaginal Cream in the treatment of moderate to severe symptoms of vulvar and vaginal atrophy in 275 (mean age WHI Estrogen-Alone Substudy = 59.9 years) naturally or surgically postmenopausal women between 42 and 76 years of age who at baseline had < 5% superficial cells on a vaginal smear, The WHI estrogen-alone substudy was stopped early because an increased a vaginal pH >5.0, and who identified their most bothersome moderate to risk of stroke was observed and it was deemed that no further information severe symptom of vulvar and vaginal atrophy from among five symptoms would be obtained regarding the risks and benefits of estrogen-alone therapy (vaginal dryness, vaginal soreness, vaginal irritation/itching, pain during in predetermined primary endpoints. intercourse, bleeding after intercourse). The majority (86.5%) of the women Results of the estrogen-alone substudy, which included 10,739 women were Caucasian (n=238), 6.5% were Hispanic (n=18), 5.4% were Black (average age of 63 years, range 50 to 79; 75.3 percent White, 15.1 percent (n=15) and 0.7% were Asian (n=2). All patients were assessed for Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up improvement in the mean change from baseline to Week 12 for the co-primary of 7.1 years are presented in Table 4. efficacy variables of: most bothersome symptom (MBS) of vulvar and vaginal atrophy (defined as the individual moderate to severe symptom that had been Table 4: Relative And Absolute Risk Seen In The Estrogen-Alone identified by the patient as most bothersome to her at baseline); percentage of Substudy Of WHI vaginal superficial cells and percentage of vaginal parabasal cells on a vaginal Event Relative Risk CE Placebo smear, and vaginal pH. CE vs. Placebo n = 5,310 n = 5,429

In this study, a statistically significant mean reduction in severity between (95% nCIa) baseline and week 12 for the group treated with 1g Synthetic Conjugated Absolute Risk per 10,000 Estrogens, A Vaginal Cream compared to placebo was observed for the Women-Years symptoms of vaginal dryness and pain during intercourse when they were CHD eventsb 0.95 (0.78-1.16) 54 57 selected as the MBS (see Table 3). Nonfatal MIb 0.91 (0.73-1.14) 40 43 b CHD death 1.01 (0.71- 1.43) 16 16 b Table 3 Change from Baseline to Week 12 in the Severity of Vaginal All Stroke 1.33 (1.05-1.68) 45 33 Dryness and Pain with Intercourse, Symptoms That Were Self- Ischemicb 1.55 (1.19-2.01 38 25 Identified at Baseline by the Postmenopausal Study Patient as her Deep vein thrombosisb,c 1.47 (1.06-2.06) 23 15 Most Bothersome Symptom Pulmonary embolismb 1.37 (0.90-2.07) 14 10 Most Bothersome Symptom at SCE, A Placebo Invasive breast cancerb 0.80 (0.62-1.04) 28 34 Baseline Vaginal Cream Colorectal cancerd 1.08 (0.75-1.55) 17 16 1 gram Hip fractureb 0.65 (0.45-0.94) 12 19 twice weekly Vertebral fracturesb,c 0.64 (0.44-0.93) 11 18 Lower arm/wrist 0.58 (0.47-0.72) 35 59 Vaginal Dryness fracturesb,c n 60 72 Total fracturesb,c 0.71 (0.64-0.80) 144 197 Death due to other 1.08 (0.88-1.32) 53 50 Baseline Severity* 2.58 2.47 causesd,e Overall mortality b,c 1.04 (0.88-1. 22) 79 75 Least Square Mean Change from f Baseline (SE) -1.65 (0.144) -1.17 (0.130) Global index 1.02 (0.92-1.13) 206 201 aNominal confidence intervals unadjusted for multiple looks and multiple p-value versus Placebo 0.0016 NA comparisons bResults are based on centrally adjudicated data for an average follow-up of Pain With Intercourse 7.1 years cNot included in “Global Index” N 45 41 dResults are based on an average follow-up of 6.8 years e Baseline Severity * 2.71 2.76 All deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease Least Square Mean Change from fA subset of the events was combined in a “global index”, defined as the Baseline (SE) -1.75 (0.208) -0.82 (0.233) earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other p-value versus Placebo 0.0002 NA causes SCE = synthetic conjugated estrogens For those outcomes included in the WHI “global index” that reached *severity was scored on a scale of 0 to 3 (0=none, 1=mild, 2=moderate and statistical significance, the absolute excess risk per 10,000 women-years in 3=severe) the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was7 fewer hip fractures 9. The In addition, Synthetic Conjugated Estrogens, A Vaginal Cream 1g increased absolute excess risk of events included in the “global index” was a non­ superficial cells by a mean of 25.9 percent as compared to 3.8 percent for significant 5 events per 10,000 women-years. There was no difference placebo (statistically significant). A corresponding statistically significant between the groups in terms of all-cause mortality [see Boxed Warnings, mean reduction from baseline in parabasal cells (36.3 percent for Synthetic and Warnings and Precautions (5)]. Conjugated Estrogens, A Vaginal Cream and 5.7 percent for placebo) was observed at week 12. The mean reduction between baseline and week 12 in No overall difference for primary CHD events (nonfatal MI, silent MI and the pH was 1.47 in the Synthetic Conjugated Estrogens, A Vaginal Cream CHD death) and invasive breast cancer incidence in women receiving CE- group and 0.30 in the placebo group (statistically significant). alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 14.2 Women’s Health Initiative Studies years1 (see Table 3). The Women’s Health Initiative (WHI) enrolled approximately 27,000 Centrally adjudicated results for stroke events from the estrogen-alone predominantly healthy postmenopausal women in two substudies to assess the substudy, after an average follow-up of 7.1 years, reported no significant risks and benefits of daily oral CE (0.625mg)-alone or in combination with difference in distribution of stroke subtype or severity, including fatal MPA (2.5mg) compared to placebo in the prevention of certain chronic strokes, in women receiving CE-alone compared to placebo. Estrogen-alone diseases. The primary endpoint was the incidence of coronary heart disease increased the risk for ischemic stroke, and this excess risk was present in all [(CHD) defined as nonfatal myocardial infarction (MI), silent MI and CHD subgroups of women examined (see Table 4). 10 death], with invasive breast cancer as the primary adverse outcome, with invasive breast cancer as the primary adverse outcome. A “global index” Timing of the initiation of estrogen therapy relative to the start of included the earliest occurrence of CHD, invasive breast cancer, stroke, menopause may affect the overall risk benefit profile. The WHI estrogen­ alone substudy stratified by age showed in women 50-59 years of age, a non­ After an average follow-up of 5.2 years, the relative risk of probable significant trend toward reduced risk for CHD [HR 0.63 (95 percent CI 0.36- dementia for CE-alone versus placebo was 1.49 (95 percent CI 0.83-2.66). 1.09)] and overall mortality [ HR 0.71 (95 percent CI 0.46 – 1.11)]. 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 WHI Estrogen Plus Progestin Substudy this study included Alzheimer’s disease (AD), vascular dementia (VaD) and The WHI estrogen plus progestin substudy was also stopped early. According mixed types (having features of both AD and VaD). The most common to the predefined stopping rule, after an average follow-up of 5.6 years of classification of probable dementia in the treatment and placebo groups was treatment, the increased risk of breast cancer and cardiovascular events AD. Since the ancillary study was conducted in women 65 to 79 years of exceeded the specified benefits included in the “global index.” The absolute age it is unknown whether these findings apply to younger postmenopausal excess risk of events included in the “global index” was 19 per 10,000 women [see Warnings and Precautions (5.4) and Use in Specific women-years. Populations (8.5)]. For those outcomes included in the WHI “global index” that reached The WHIMS estrogen plus progestin ancillary study enrolled 4,532 statistical significance after 5.6 years of follow-up, the absolute excess risks predominantly healthy postmenopausal women 65 years of age and older per 10,000 women- years in the group treated with CE plus MPA were 7 more (47 percent, age 65 to 69 years; 35 percent, 70 to 74 years; 18 percent, 75 CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast years of age and older) to evaluate the effects of daily CE (0.625 mg) plus cancers, while the absolute risk reductions per 10,000 women-years were 6 MPA (2.5 mg) on the incidence of probable dementia (primary outcome) fewer colorectal cancers and 5 fewer hip fractures. compared to placebo. Results of the estrogen-plus-progestin substudy, which included 16,608 After an average follow-up of 4 years, the relative risk of probable dementia women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 for CE (0.625) plus MPA (2.5mg) versus placebo was 2.05 (95 percent CI percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 1.21-3.48). The absolute risk of probable dementia for CE (0.625) plus MPA 5 below. These results reflect centrally adjudicated data after an average (2.5mg) versus placebo was 45 versus 22 per 10,000 women–years. follow-up of 5.6 years. Probable dementia as defined in this study included Alzheimer’s disease, vascular dementia and mixed types (having features of both AD and VaD). Table 5. Relative And Absolute Risk Seen in the Estrogen Plus Progestin The most common classification of probable dementia in both the treatment Substudy of WHI at an Average of 5.6 Yearsa and placebo groups was AD. The most common classification of probable dementia in the treatment group and placebo group was AD. Since the Event Relative Risk CE/MPA Placebo ancillary study was conducted in women 65 to 79 years of age, it is CE/MPA vs. n = 8,506 n = 8,102 unknown whether these findings apply to younger postmenopausal women Placebo [see Warnings and Precautions (5.4) and Use in Specific Population (8.5)]. (95% nCIb) When data from the two populations were pooled as planned in the WHIMS Absolute Risk per 10,000 protocol, the reported overall relative risk for probable dementia was 1.76 Women-Years (95 percent CI 1.19-2.60). Differences between groups became apparent in CHD events 1.23 (0.99-1.53) 41 34 the first year of treatment. It is unknown whether these findings apply to Non-fatal MIb 1.28 (1.00-1.63) 31 25 younger postmenopausal women [see Warnings and Precautions (5.4) and CHD death 1.10 (0.70-1.75) 8 8 Use in Specific Populations (8.5)]. All strokes 1.31 (1.03-1.68) 33 25 Ischemic stroke 1.44 (1.09 -1.90) 26 18 15. REFERENCES Deep vein thrombosisc 1.95 (1.43 – 2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 1. Rossouw, JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. Invasive breast cancerd 1.24 (1.01-1.54) 41 33 2007;297:1465-1477. Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancerc 0.81 (0.48-1.36) 6 7 2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Cervical cancerc 1.44 (0.47-4.42) 2 1 Disease. Arch Int Med. 2006;166:357-365. Hip fractureb 0.67 (0.47-0.96) 11 16 Vertebral fracturesc 0.65 (0.46-0.92) 11 17 3. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780. Lower arm/wrist 0.71 (0.59-0.85) 44 62 c fractures 4. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Total fracturesc 0.76 (0.69-0.83) 152 199 Thrombosis. JAMA. 2004;292:1573-1580. Overall Mortalityce 1.00 (0.83-1.19) 52 52 Global Indexf 1.13(1.02-1.25) 184 165 5. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast a Results are based on centrally adjudicated data. Cancer and Mammography Screening in Postmenopausal Women b Nominal confidence intervals unadjusted for multiple looks and multiple With Hysterectomy. JAMA. 2006;295:1647-1657. comparisons. 6. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast c Not included in Global Index Cancer and Mammography in Healthy Postmenopausal Women. d Includes metastatic and non-metastatic breast cancer, with the exception of in JAMA. 2003;289:3234-3253. situ cancer eAll deaths, except from breast or colorectal cancer, definite/probable CHD, 7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic PE or cerebrovascular disease cancers and Associated Diagnostic Procedures. JAMA. fA subset of the events was combined in a “global index” defined as the 2003;290:1739-1748. earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary 8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of embolism, colorectal cancer, hip fracture, or death due to other causes. Probable Dementia and Mild Cognitive Impairment in Postmenopausal Timing of the initiation of estrogen therapy relative to the start of menopause Women. 2004;291:2947-2958. may affect the overall risk benefit profile. The WHI estrogen plus progestin 9. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of substudy stratified by age showed in women 50-59 years of age, a non­ Fractures and BMD in Postmenopausal Women With Hysterectomy: significant trend toward reduced risk for overall mortality [HR 0.69 (95 Results From the Women’s Health Initiative Randomized Trial. J Bone percent CI 0.44 – 1.07)]. Miner Res. 2006;21:817-828. 14.3 Women’s Health Initiative Memory Study 10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in The estrogen-alone Women’s Health Initiative Memory Study (WHIMS), an the Women’s Health Initiative. Circulation. 2006;113:2425-2434. ancillary study of WHI, enrolled 2,947 predominantly healthy

hysterectomized postmenopausal women 65 years to 79 years of age and older (45 percent, age 65 to 69 years; 36 percent, 70 to 74 years; 19 percent, 75 16. HOW SUPPLIED/STORAGE AND HANDLING years of age and older) to evaluate the effects of daily CE (0.625 mg) on the incidence of probable dementia (primary outcome) compared to placebo. Synthetic Conjugated Estrogens, A (synthetic conjugated estrogens, A) Vaginal Cream 0.625 mg/g is available in a tube containing 30 g cream with eight (8) re-usable applicators: What is Synthetic Conjugated Estrogens, A Vaginal Cream? NDC 51285-586-30 Synthetic Conjugated Estrogens, A Vaginal Cream is a medicine that contains a mixture of synthetic estrogens. Store at 20-25ºC (68-77ºF); excursions are permitted to 15-30°C (59-86°F). Do not freeze. What is Synthetic Conjugated Estrogens, A Vaginal Cream used for? 17. PATIENT COUNSELING INFORMATION Synthetic Conjugated Estrogens, A Vaginal Cream is used after menopause to: See 17.4 for FDA-Approved Patient Labeling • Treat dryness in and around the vagina caused by 17.1 Vaginal Bleeding menopausal changes of the vagina Inform postmenopausal women of the importance of reporting vaginal • Treat painful intercourse caused by menopausal changes of bleeding to their healthcare provider as soon as possible [see Warnings and the vagina Precautions (5.3)]. You and your healthcare provider should talk regularly about whether you 17.2 Possible Serious Adverse Reactions with Estrogens still need treatment with Synthetic Conjugated Estrogens, A Vaginal Cream Inform postmenopausal women of possible serious adverse reactions of to control these problems. estrogen therapy including Cardiovascular Disorders, Malignant Neoplasms, Who should not use Synthetic Conjugated Estrogens, A Vaginal and Probable Dementia [see Warnings and Precautions (5.2, 5.3, 5.4)]. Cream? 17.3 Possible Less Serious But Common Adverse Reactions with Do not start using Synthetic Conjugated Estrogens, A Vaginal Cream if you: Estrogens • Have unusual vaginal bleeding Inform postmenopausal women of possible less serious but common adverse • Currently have or have had certain cancers reactions of estrogen therapy such as headache, breast pain and tenderness, Estrogens may increase the chances of getting certain types of nausea and vomiting. cancers, including cancer of the breast or uterus. If you have or 17.4 Instructions for Use of Vaginal Applicator have had cancer, talk with your healthcare provider about whether you should use Synthetic Conjugated Estrogens, A 1. Remove cap from tube. Vaginal Cream. • Had a stroke or heart attack 2. Screw nozzle end of applicator onto tube. • Currently have or have had blood clots 3. Gently squeeze tube from the bottom to force sufficient cream into the • Currently have or have had liver problems applicator to the marked stopping point on the applicator as a guide to • Are allergic to Synthetic Conjugated Estrogens, A Vaginal measure the correct dose. Cream or any of its ingredients

4. Unscrew applicator from tube. See the end of this leaflet for a list of ingredients in Synthetic 5. Lie on back with knees drawn up. To deliver medication, gently insert Conjugated Estrogens, A Vaginal Cream. applicator deeply into vagina and press plunger downward to its original position. • Think you may be pregnant TO CLEANSE APPLICATOR: Pull plunger to remove it from barrel. Wash Tell your healthcare provider: with mild soap and warm water. • If you have any unusual vaginal bleeding. DO NOT BOIL OR USE HOT WATER. 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 the cause. 17.5 FDA-Approved Patient Labeling • About all of your medical problems. PATIENT INFORMATION Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), Synthetic Conjugated Estrogens, A Vaginal Cream epilepsy (seizures), diabetes, migraine, endometriosis, lupus, or problems with your heart, liver, thyroid, kidneys, or have high Read this PATIENT INFORMATION before you start using Synthetic calcium levels in your blood. Conjugated Estrogens, A Vaginal Cream and read what you get each time you • About all the medicines you take. refill your Synthetic Conjugated Estrogens, A Vaginal Cream Prescription. This includes prescription and nonprescription medicines, There may be new information. This information does not take the place of vitamins, and herbal supplements. Some medicines may affect talking to your healthcare provider about your menopausal symptoms and how Synthetic Conjugated Estrogens, A Vaginal Cream works. their treatment. Synthetic Conjugated Estrogens, A Vaginal Cream may also WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD affect how your other medicines work. KNOW ABOUT Synthetic Conjugated Estrogens, A Vaginal Cream • If you are going to have surgery or will be on bed rest. (SYNTHETIC ESTROGEN MIXTURE)? You may need to stop using Synthetic Conjugated Estrogens, A Vaginal Cream. • Estrogens increase the chances of getting cancer of the uterus. • If you are breast feeding. The hormones in Synthetic Conjugated Estrogens, A Vaginal • Report any unusual vaginal bleeding right away while you are taking Cream can pass into your milk. Synthetic Conjugated Estrogens, A Vaginal Cream. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). How should I use Synthetic Conjugated Estrogens, A Vaginal Cream Your healthcare provider should check any unusual vaginal bleeding to Synthetic Conjugated Estrogens, A is a cream that you place in your vagina find out the cause. with an applicator. • Do not use estrogens with or without progestins to prevent heart disease, 1. Take the dose recommended by your health care provider and talk to heart attacks, strokes or dementia. him or her about how well that dose is working for you. 2. Estrogens should be used at the lowest dose possible for your • Using estrogens with our without progestins may increase your chances treatment only as long as needed. You and your healthcare provider of getting heart attacks, strokes, breast cancer, and blood clots. Using should talk regularly (for example, every 3 to 6 months) about the dose estrogens, with or without progestins may increase your risk of dementia you are taking and whether you still need treatment with Synthetic based on a study of women age 65 years or older. You and your Conjugated Estrogens, A Vaginal Cream. healthcare provider should talk regularly about whether you still need treatment with Synthetic Conjugated Estrogens, A Vaginal Cream. INSTRUCTIONS FOR USE 1. Remove cap from tube. reduce the chance of getting cancer of the uterus. See your 2. Screw nozzle end of applicator onto tube. healthcare provider right away if you get vaginal bleeding while taking Synthetic Conjugated Estrogens, A Vaginal Cream. 3. Gently squeeze tube from the bottom to force sufficient cream into • Have a pelvic exam, breast exam and mammogram (breast X- the applicator to the marked stopping point on the applicator as a ray) every year unless your healthcare provider tells you guide to measure the correct dose. something else. If members of your family have had breast 4. Unscrew applicator from tube. cancer or if you have ever had breast lumps or an abnormal 5. Lie on back with knees drawn up. To deliver medication, gently mammogram, you may need to have breast exams more often. insert applicator deeply into vagina and press plunger downward to • If you have high blood pressure, high cholesterol (fat in the its original position. blood), diabetes, are overweight, or if you use tobacco, you may TO CLEANSE APPLICATOR: Pull plunger to remove it from barrel. have higher chances for getting heart disease. Ask your Wash with mild soap and warm water. healthcare provider for ways to lower your chances for getting heart disease. DO NOT BOIL OR USE HOT WATER. General information about safe and effective use of Synthetic What are the possible side effects of Synthetic Conjugated Estrogens, A Conjugated Estrogens, A Vaginal Cream. Vaginal Cream? Medicines are sometimes prescribed for conditions that are not mentioned in Synthetic Conjugated Estrogens, A Vaginal Cream is only used in and around patient information leaflets. Do not use Synthetic Conjugated Estrogens, A the vagina; however, the risks associated with oral estrogens should be taken Vaginal Cream for conditions for which it was not prescribed. Do not give into account. Synthetic Conjugated Estrogens, A Vaginal Cream to other people, even if they have the same symptoms you have. It may harm them. Keep Synthetic Side effects are grouped by how serious they are and how often they Conjugated Estrogens, A Vaginal Cream out of the reach of children. happen when you are treated. It is not known whether or not Synthetic Conjugated Estrogens, A Vaginal Serious but less common side effects include: Cream can weaken or contribute to the failure of condoms, diaphragms, or • Breast cancer cervical caps made of latex or rubber. • Cancer of the uterus This leaflet provides a summary of the most important information about • Stroke • Heart attack Synthetic Conjugated Estrogens, A Vaginal Cream. If you would like more • Blood clots information, talk with your healthcare provider or pharmacist. You can ask • Dementia for information about Synthetic Conjugated Estrogens, A Vaginal Cream • Gallbladder disease that is written for health professionals. You can get more information by • Ovarian cancer calling the toll free number 1-800-227-7522. • High blood pressure • Liver problems • High blood sugar What are the inactive ingredients in Synthetic Conjugated Estrogens, A • Enlargement of benign tumors of the uterus (“fibroids”) Vaginal Cream?

Some of the warning signs of these serious side effects include: The ingredients are: benzyl alcohol, cetyl alcohol, cetyl esters wax, glycerin, • Breast lumps glyceryl monostearate, light mineral oil, methyl stearate, propylene glycol • Unusual vaginal bleeding monostearate, sodium hydroxide, sodium lauryl sulfate, sodium phosphate • Dizziness and faintness dibasic anhydrous, water, and white wax. • Changes in speech Store at 20-25ºC (68-77ºF); excursions are permitted to 15-30°C (59­ • Severe headaches 86°F). Do not freeze. • Chest pain • Shortness of breath • Pains in your legs Mfd. by DPT Laboratories, Inc. • Changes in vision San Antonio, TX 78209 • Vomiting for Duramed Pharmaceuticals, Inc. • Yellowing of skin, eyes, or nail beds Subsidiary of Barr Pharmaceuticals, Inc. Pomona, New York 10970 Call your healthcare provider right away if you get any of these warning signs, Issued: November 2008 or any other unusual symptom that concerns you.

Less serious but common side effects include: • Headache • Breast pain • Irregular vaginal bleeding or spotting • Stomach/abdominal cramps, bloating • Nausea and vomiting • Hair loss • Fluid retention • Vaginal yeast infection • Reactions from inserting Synthetic Conjugated Estrogens, A Vaginal Cream, such as vaginal burning, irritation, and itching

These are not all the possible side effects of Synthetic Conjugated Estrogens, A Vaginal Cream. For more information, ask your healthcare provider or pharmacist. What can I do to lower my chances of a serious side effect with Synthetic Conjugated Estrogens, A™ Vaginal Cream? • Talk with your healthcare provider regularly about whether you should continue using Synthetic Conjugated Estrogens, A Vaginal Cream. • If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you. The addition of a progestin is generally recommended for women with a uterus to