Estradiol

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions ( 5.1 )] Malignant Neoplasms [see Boxed Warning, Warnings and Precautions ( 5.2 )] The most common adverse reactions (≥ 10 percent) with estradiol transdermal system are upper respiratory tract infections, pain, arthralgia, and leukorrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 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. Estradiol transdermal system was investigated in a 2-year double blind, placebo-controlled, multicenter study in the United States. A total of 417 postmenopausal women (208 women on estradiol transdermal system, 209 on placebo) 60 to 80 years old, with an intact uterus were enrolled in the study. At 24 months, 189 women remained in the estradiol transdermal system group and 186 remained in the placebo group. Adverse events with an incidence of ≥5 percent in the estradiol transdermal system 0.014 mg group and greater than those reported in the placebo group are listed in Table 1. Table 1: Summary of Most Frequently Reported Treatment Emergent Adverse Reactions (≥5 percent) by Treatment Groups Body System Adverse Reactions Estradiol Transdermal System 0.014 mg/day (N=208) Placebo (N=209) Body as a Whole Abdominal Pain Accidental Injury Infection Pain 95 (46%) 17 (8%) 29 (14%) 11 (5%) 26 (13%) 100 (48%) 17 (8%) 23 (11%) 10 (5%) 26 (12%) Cardiovascular 20 (10%) 19 (9%) Digestive System Constipation Dyspepsia 52 (25%) 11 (5%) 11 (5%) 44 (21%) 6 (3%) 9 (4%) Metabolic and Nutritional Disorders 25 (12%) 22 (11%) Musculoskeletal System Arthralgia Arthritis Myalgia 54 (26%) 24 (12%) 11 (5%) 10 (5%) 51 (24%) 13 (6%) 15 (7%) 6 (3%) Nervous System Dizziness 30 (14%) 11 (5%) 23 (11%) 6 (3%) Respiratory System Bronchitis Upper Respiratory Infection 62 (30%) 12 (6%) 33 (16%) 67 (32%) 9 (4%) 35 (17%) Skin and Appendages Application Site Reaction Breast Pain 50 (24%) 18 (9%) 10 (5%) 54 (26%) 18 (9%) 8 (4%) Urogenital System Cervical Polyps Leukorrhea 66 (32%) 13 (6%) 22 (11%) 40 (19%) 4 (2%) 3 (1%) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of the other estradiol transdermal systems and the estradiol transdermal system, 0.014 mg/day. 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 Edema, fatigue, menopausal symptoms, weight increased, application site reaction, anaphylactic reactions

4 CONTRAINDICATIONS Estradiol transdermal system 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 estradiol transdermal system 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 estradiol transdermal system ( 4 ) Hepatic impairment or disease ( 4 , 5.10 ) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 )

11 DESCRIPTION Estradiol transdermal system, USP is designed to provide nominal in vivo delivery of 0.014 mg of estradiol per day continuously upon application to intact skin. The period of use is 7 days. The transdermal system has a contact surface area of 3.9 cm 2 , and contains 0.982 mg of estradiol USP. Estradiol USP is a white, crystalline powder, chemically described as estra-1,3,5(10)-triene-3, 17ß-diol. It has an empirical formula of C 18 H 24 O 2 and molecular weight of 272.38. The structural formula is: The estradiol transdermal system, USP comprises three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are: 1. a translucent polyethylene film. 2. an acrylate adhesive matrix containing estradiol USP. 3. A protective liner of silicon coated polyester film is attached to the adhesive surface and must be removed before the transdermal system can be used. Cross Section of the System: Estradiol transdermal system, USP is packaged with additional pieces of protective film above and below the system within each pouch. These are discarded at the time of use. The active component of the transdermal system is estradiol USP. The remaining components of the transdermal system (acrylic adhesive, colloidal silicon dioxide, ethyl oleate, glyceryl monolaurate, isopropyl myristate, povidone, and polyethylene backing) are pharmacologically inactive. FDA approved drug release test specifications differ from USP. Estradiol Transdermal System, 14 mcg/day Estradiol Transdermal System, 14 mcg/ day

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 take 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. Apply estradiol transdermal system once-weekly to the lower abdomen. Do not apply estradiol transdermal system to the breast. ( 2.1 ) 2.1 Prevention of Postmenopausal Osteoporosis Apply estradiol transdermal system 0.014 mg per day to a clean dry area of the lower abdomen once weekly. 2.2 Application of the Estradiol Transdermal System Site Selection Place the adhesive side of estradiol transdermal system on a clean, dry area of the lower abdomen or the upper quadrant of the buttock. Do not apply estradiol transdermal system to or near the breasts. Rotate the sites of application with an interval of at least 1-week allowed between applications to a 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 estradiol transdermal system. Application Apply estradiol transdermal system immediately after opening the pouch and removing the protective liner. Press estradiol transdermal system 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 estradiol transdermal system has not been studied, and these activities may decrease the adhesion of the system and the delivery of estradiol. 2.3 Removal of the Estradiol Transdermal System Remove estradiol transdermal system carefully and slowly to avoid irritation of the skin. If any adhesive remains on the skin after removal of estradiol transdermal system, 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.

1 INDICATIONS AND USAGE Estradiol transdermal system is indicated for: Estradiol transdermal system is an estrogen indicated for: Prevention of Postmenopausal Osteoporosis ( 1.1 ) 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 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.

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

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 )

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 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 estradiol transdermal system 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 The bioavailability of estradiol following application of an estradiol transdermal system, relative to that of a transdermal system delivering 0.025 mg per day, was investigated in 18 healthy postmenopausal women, mean age 66 years (range 60 to 80 years). The mean serum estradiol concentrations upon administration of the two patches to the lower abdomen are shown in Figure 1. Transdermal administration of estradiol transdermal system produced geometric mean serum concentration (C avg ) of estradiol of 13.7 pg/mL. No patches failed to adhere during the one week application period of both transdermal systems. Following application of the estradiol transdermal system to the abdomen, it is estimated to provide an average nominal in-vivo daily delivery of 0.014 mg estradiol per day. The estradiol 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. Figure 1: Mean Uncorrected Serum 17ß-Estradiol Concentrations vs. Time Profile Following Application of the Estradiol Transdermal System, 0.014 mg/day and the Estradiol Transdermal System, 6.5 cm 2 Table 2 provides a summary of estradiol pharmacokinetic parameters determined during evaluation of the estradiol transdermal system using baseline uncorrected serum concentrations . Table 2: Summary of Estradiol Pharmacokinetic Parameters (Abdomen Application) Product Estradiol Daily Delivery Rate, mg/day AUC (0-t last ) pg•h/mL C max pg/mL C avg pg/mL T max h C min pg/mL Estradiol transdermal system 0.014 2296 20.6 13.7 42 12.6 Estradiol transdermal system 6.5 cm 2 0.025 4151 37.2 24.7 42 20.4 Pharmacokinetic parameters are expressed in geometric means except for the T max which represents the median estimate and the C min which is expressed as the arithmetic mean. The estimated estradiol daily delivery rate for estradiol transdermal system, 6.5 cm 2 is quoted from its labeling. 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. In the clinical study with 208 patients on estradiol transdermal system, SHBG concentration (mean ± SD) remained essentially unchanged over the 2 year period (baseline 45.1 ± 20.1 nmol/L, 24-month visit 46.4 ± 20.9 nmol/L). 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 In an estradiol transdermal system pharmacokinetic study with 18 postmenopausal women, no patches failed to adhere during the one week application period. Estradiol Transdermal System, 14 mcg/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, 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 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 estradiol transdermal system 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 The bioavailability of estradiol following application of an estradiol transdermal system, relative to that of a transdermal system delivering 0.025 mg per day, was investigated in 18 healthy postmenopausal women, mean age 66 years (range 60 to 80 years). The mean serum estradiol concentrations upon administration of the two patches to the lower abdomen are shown in Figure 1. Transdermal administration of estradiol transdermal system produced geometric mean serum concentration (C avg ) of estradiol of 13.7 pg/mL. No patches failed to adhere during the one week application period of both transdermal systems. Following application of the estradiol transdermal system to the abdomen, it is estimated to provide an average nominal in-vivo daily delivery of 0.014 mg estradiol per day. The estradiol 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. Figure 1: Mean Uncorrected Serum 17ß-Estradiol Concentrations vs. Time Profile Following Application of the Estradiol Transdermal System, 0.014 mg/day and the Estradiol Transdermal System, 6.5 cm 2 Table 2 provides a summary of estradiol pharmacokinetic parameters determined during evaluation of the estradiol transdermal system using baseline uncorrected serum concentrations . Table 2: Summary of Estradiol Pharmacokinetic Parameters (Abdomen Application) Product Estradiol Daily Delivery Rate, mg/day AUC (0-t last ) pg•h/mL C max pg/mL C avg pg/mL T max h C min pg/mL Estradiol transdermal system 0.014 2296 20.6 13.7 42 12.6 Estradiol transdermal system 6.5 cm 2 0.025 4151 37.2 24.7 42 20.4 Pharmacokinetic parameters are expressed in geometric means except for the T max which represents the median estimate and the C min which is expressed as the arithmetic mean. The estimated estradiol daily delivery rate for estradiol transdermal system, 6.5 cm 2 is quoted from its labeling. 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. In the clinical study with 208 patients on estradiol transdermal system, SHBG concentration (mean ± SD) remained essentially unchanged over the 2 year period (baseline 45.1 ± 20.1 nmol/L, 24-month visit 46.4 ± 20.9 nmol/L). 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 In an estradiol transdermal system pharmacokinetic study with 18 postmenopausal women, no patches failed to adhere during the one week application period.

20230421

1

3 DOSAGE FORMS AND STRENGTHS Estradiol Transdermal System, USP 0.014 mg per day - each 3.9 cm 2 system contains 0.982 mg of estradiol USP. Transdermal system 0.014 mg per day ( 3 )

estradiol estradiol ESTRADIOL ESTRADIOL SILICON DIOXIDE ETHYL OLEATE ISOPROPYL MYRISTATE GLYCERYL LAURATE POVIDONE 2-ETHYLHEXYL ACRYLATE 2-HYDROXYETHYL ACRYLATE GLYCIDYL METHACRYLATE

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 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.

ANDA204379

Estradiol

estradiol

68382-323

HUMAN PRESCRIPTION DRUG

TRANSDERMAL

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 using estradiol transdermal system for the prevention of postmenopausal osteoporosis.

PACKAGE LABEL PRINCIPAL DISPLAY PANEL NDC 68382- 323 -04 Estradiol Transdermal System, USP 0.014 mg/day Apply one transdermal system per week. For Transdermal Use Only Contents: 4 Transdermal Systems Rx Only zydus Pharmaceuticals USA Estradiol Transdermal System, USP 0.014mg/day

RECENT MAJOR CHANGES Boxed Warning 09/2021

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.

14 CLINICAL STUDIES 14.1 Effects on Bone Mineral Density in Postmenopausal Women The efficacy of estradiol transdermal system in the prevention of postmenopausal osteoporosis was investigated in a 2-year double blind, placebo-controlled, multicenter study in the United States. A total of 417 postmenopausal women, 60 to 80 years of age, with an intact uterus were enrolled in the study. All participants received supplemental calcium and vitamin D. At the lumbar spine estradiol transdermal system increased BMD by 2.3 percent after 1 year and 3 percent after 2 years compared with a 0.5 percent increase after 1 and 2 years of treatment with placebo. At the hip estradiol transdermal system increased BMD by 0.9 percent after one year and 0.84 percent after two years compared with a mean decrease of 0.22 percent after 1 year and 0.71 percent after 2 years of placebo treatment. The changes in BMD from baseline were statistically significantly (p <0.001) greater during treatment with estradiol transdermal system than during treatment with placebo for both the spine and hip after 1 and 2 years (Table 3). Table 3: Mean Percent BMD Change from Baseline in Lumbar Spine and Total Hip (Full Analysis Set) Lumbar spine Total hip Time points Estradiol Transdermal System N a = 208 Placebo N a = 209 p-value Time points Estradiol Transdermal System N a = 208 Placebo N a = 209 p-value 12-month Endpoint n b = 189 n b = 186 <0.001 12-month Endpoint n b = 189 n b = 184 <0.001 +2.29 +0.51 +0.90 -0.22 24-month Endpoint n b = 189 n b = 186 <0.001 24-month Endpoint n b = 189 n b = 185 <0.001 +2.99 +0.54 +0.84 -0.71 a) N = total number of patients. b) n = number of patients with data available for each variable. The BMD data of the study were analyzed according to baseline estradiol levels of the patients. Overall, estimated treatment effects on lumbar spine and total hip BMD after 2 years were approximately twice as large in the subgroup with baseline estradiol levels < 5 pg/mL than in the subgroup with baseline estradiol levels ≥ 5 pg/mL (Table 4). Table 4: Mean Percent Change in Lumbar Spine and Total Hip BMD at 24 months by Subgroups of Baseline Estradiol Level (< 5 pg/mL, 5 pg/mL) Lumbar spine Total hip Baseline estradiol levels Estradiol Transdermal System Placebo Treatment difference Estradiol Transdermal System Placebo Treatment difference < 5 pg/mL n a = 101 n a = 97 n a = 101 n a = 96 +3.50 +0.29 3.21 +1.04 -1.09 2.13 (p < 0.001) (p < 0.001) ≥ 5 pg/mL n a = 88 n a = 89 n a = 88 n a = 89 +2.40 +0.81 1.59 +0.61 -0.31 0.92 (p = 0.002) (p = 0.045) a) n = number of patients with data available for each variable 14.2 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 5. Table 5: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI a Event b 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 (0.78-1.16) 54 57 Non-fatal MI c 0.91 (0.73-1.14) 40 43 CHD death c 1.01 (0.71-1.43) 16 16 All strokes c 1.33 (1.05-1.68) 45 33 Ischemic stroke c 1.55 (1.19-2.01) 38 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 0.8 (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 fractures c,d 0.58 (0.47-0.72) 35 59 Total fractures c,d 0.71 (0.64-0.80) 144 197 Death due to 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 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 5. 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 5. 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 6. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 6: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years 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 1.31 (1.03-1.68) 33 25 Ischemic stroke 1.44 (1.09-1.90) 26 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 d 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". 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, 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 0.44-1.07)] . 14.3 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 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 )] .

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.

8.5 Geriatric Use A total of 417 postmenopausal women 61 to 79 years old, with an intact uterus, participated in the osteoporosis trial. More than 50 percent of women receiving study drug, were 65 years of age or older. Efficacy in older (≥ 65 years of age) and younger (<65 years of age) postmenopausal women in the osteoporosis treatment trial was comparable both at 12 and 24 months. Safety in older (≥ 65 years of age) and younger (<65 years of age) postmenopausal women in the osteoporosis treatment trial was also comparable throughout the study. 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 ( 14.2 )] . 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 ( 14.2 )] . 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 ( 14.3 )] . 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 ( 14.3 )].

8.2 Lactation Risk Summary Estrogens are present in human milk and can reduce milk production in breast-feeding females. 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 estradiol transdermal system and any potential adverse effects on the breastfed child from estradiol transdermal system or from the underlying maternal condition.

8.4 Pediatric Use Estradiol transdermal system is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.

8.1 Pregnancy Risk Summary Estradiol transdermal system is not indicated for use in pregnancy. There are no data with the use of estradiol transdermal system in pregnant women, however, epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Estradiol transdermal system is not indicated for use in pregnancy. There are no data with the use of estradiol transdermal system in pregnant women, however, epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital 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 females. 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 estradiol transdermal system and any potential adverse effects on the breastfed child from estradiol transdermal system or from the underlying maternal condition. 8.4 Pediatric Use Estradiol transdermal system is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population. 8.5 Geriatric Use A total of 417 postmenopausal women 61 to 79 years old, with an intact uterus, participated in the osteoporosis trial. More than 50 percent of women receiving study drug, were 65 years of age or older. Efficacy in older (≥ 65 years of age) and younger (<65 years of age) postmenopausal women in the osteoporosis treatment trial was comparable both at 12 and 24 months. Safety in older (≥ 65 years of age) and younger (<65 years of age) postmenopausal women in the osteoporosis treatment trial was also comparable throughout the study. 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 ( 14.2 )] . 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 ( 14.2 )] . 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 ( 14.3 )] . 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 ( 14.3 )].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Estradiol Transdermal System, USP 0.014 mg per day — each 3.9 cm 2 system contains 0.982 mg of estradiol USP Individual Carton of 4 systems NDC 68382-323-04 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°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 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° to 25°C (68° to 77°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 child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet.

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 ( 14.2 ) ]. 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 ( 14.3 ) ]. 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 ( 14.2 , 14.3 )] . 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 ( 14.2 ) ]. 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 ( 14.3 ) ]. 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 ( 14.2 , 14.3 )] . 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 ( 14.2 ) ]. 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 )