Estradiol Transdermal System

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Cardiovascular Disorders [see Boxed Warning, and Warnings and Precautions ( 5.1 )] • Malignant Neoplasms [see Boxed Warning, and Warnings and Precautions ( 5.2 )] The most common adverse reactions (≥10 percent) with the Estradiol Transdermal System are: breast pain, upper respiratory tract infections, headaches, abdominal pain, pain, and edema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-84-BAYER (1-888-842-2937) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The Estradiol Transdermal System 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect pooled data from 5 clinical trials of the Estradiol Transdermal System. A total of 614 women were exposed to the Estradiol Transdermal System for 3 months (193 women at 0.025 mg per day, 201 women at 0.05 mg per day, 194 women at 0.1 mg per day) in randomized, double-blind trials of clinical efficacy versus placebo and versus active comparator. All women were postmenopausal, had a serum estradiol level of less than 20 pg/mL, and a minimum of five moderate to severe hot flushes per week or a minimum of 15 hot flushes per week of any severity at baseline. Included in this table are an additional 25 postmenopausal hysterectomized women exposed to the Estradiol Transdermal System 0.025 mg per day for 6 to 24 months (N=16 at 24 months) in a randomized, double-blind, placebo-controlled study of the Estradiol Transdermal System for the prevention of osteoporosis. Table 1: Treatment-Emergent Adverse Reactions Reported at a Frequency of ≥5 Percent and More Frequent in Women Receiving the Estradiol Transdermal System The Estradiol Transdermal System Body System Adverse Reactions 0.025 mg/day Adverse reactions occurring at rate of ≥5 percent in the Estradiol Transdermal System trials of clinical efficacy versus placebo and versus active comparator; and trial of the Estradiol Transdermal System versus placebo for the prevention of osteoporosis (N=219) 0.05 mg/day Adverse reactions occurring at rate of ≥5 percent in the Estradiol Transdermal System trials of clinical efficacy versus placebo and versus active comparator (N=201) 0.1 mg/day (N=194) Placebo Adverse reactions occurring in placebo group in the Estradiol Transdermal System trial of clinical efficacy versus placebo. (N=72) Body as a Whole Headache Pain Back Pain Edema 21% 5% 1% 4% 0.5% 39% 18% 8% 8% 13% 37% 13% 11% 9% 10% 29% 10% 7% 6% 6% Digestive System Abdominal Pain Nausea Flatulence 9% 0% 1% 1% 21% 11% 5% 3% 29% 16% 6% 7% 18% 8% 3% 1% Musculoskeletal System Arthralgia 7% 1% 9% 5% 11% 5% 4% 3% Nervous System Depression 13% 1% 10% 5% 11% 8% 1% 0% Urogenital System Breast Pain Leukorrhea 12% 5% 1% 18% 8% 6% 41% 29% 7% 11% 4% 1% Respiratory System URTI Pharyngitis Sinusitis Rhinitis 15% 6% 0.5% 4% 2% 26% 17% 3% 4% 4% 29% 17% 7% 5% 6% 14% 8% 3% 3% 1% Skin and Appendages Pruritus 19% 0.5% 12% 6% 12% 3% 15% 6% The Estradiol Transdermal System 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of the Estradiol Transdermal System. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Genitourinary System Changes in bleeding pattern, pelvic pain Breast Breast cancer, breast pain, breast tenderness Cardiovascular Changes in blood pressure, palpitations, hot flashes Gastrointestinal Vomiting, abdominal pain, abdominal distension, nausea Skin Alopecia, hyperhidrosis, night sweats, urticaria, rash Eyes Visual disturbances, contact lens intolerance, Central Nervous System Depression, migraine, paresthesia, dizziness, anxiety, irritability, mood swings, nervousness, insomnia, headache Miscellaneous Fatigue, menopausal symptoms, weight increase, application site reaction, anaphylactic reactions

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

2 DOSAGE AND ADMINISTRATION Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, consider addition of a progestogen to reduce the risk of endometrial cancer. Generally, a woman without a uterus does not need to use a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women who have a history of endometriosis may need a progestogen [see Warnings and Precautions ( 5.2 , 5.14 )] . Use estrogen-alone, or in combination with a progestogen at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Reevaluate postmenopausal women periodically as clinically appropriate to determine if treatment is still necessary. • Start therapy with the Estradiol Transdermal System 0.025 mg per day applied to the skin once-weekly. Dosage adjustment should be guided by the clinical response ( 2.1 ) • Place the Estradiol Transdermal System on a clean, dry area of the lower abdomen (below the umbilicus) or upper quadrant of the buttock. Do not apply the Estradiol Transdermal System to the breasts ( 2.5 ) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Start therapy with Estradiol Transdermal System 0.025 mg per day applied to the skin once weekly. Make dosage adjustments based on the clinical response. Attempt to taper or discontinue Estradiol Transdermal System at 3 to 6 month intervals. 2.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Start therapy with Estradiol Transdermal System 0.025 mg per day applied to the skin once weekly. Make dosage adjustments based on the clinical response. Attempt to taper or discontinue Estradiol Transdermal System at 3 to 6 month intervals. 2.3 Treatment of Hypoestrogenism due to Hypogonadism, Castration, or Primary Ovarian Failure Start therapy with 0.025 mg per day applied to the skin once weekly. Make dose adjustment based on the clinical response. 2.4 Prevention of Postmenopausal Osteoporosis Start therapy with Estradiol Transdermal System 0.025 mg per day applied to the skin once weekly. 2.5 Application of the Estradiol Transdermal System 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 the same site. • Select an area that is not oily, damaged, or irritated. Avoid the waistline, since tight clothing may rub the transdermal system off. • Avoid application to areas where sitting would dislodge 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. 2.6 Removal of the Estradiol Transdermal System 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 The Estradiol Transdermal System is indicated for: 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause [Enter Generic Section here] 1.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Limitation of Use When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, first consider the use of topical vaginal products. 1.3 Treatment of Hypoestrogenism due to Hypogonadism, Castration, or Primary Ovarian Failure [Enter Generic Section here] 1.4 Prevention of Postmenopausal Osteoporosis Limitation of Use When prescribing solely for the prevention of postmenopausal osteoporosis, first consider the use of non-estrogen medications. Consider estrogen therapy only for women at significant risk of osteoporosis

10 OVERDOSAGE Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding in women. Treatment of overdose consists of discontinuation of the 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 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 the 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 Transdermal administration of the Estradiol Transdermal System produces mean serum concentrations of estradiol comparable to those produced by premenopausal women in the early follicular phase of the ovulatory cycle. The pharmacokinetics of estradiol following application of the Estradiol Transdermal System transdermal system were investigated in 197 healthy postmenopausal women in six studies. In five of the studies, the Estradiol Transdermal System transdermal system was applied to the abdomen, and in a sixth study, application to the buttocks and abdomen were compared. The Estradiol Transdermal System transdermal delivery system continuously releases estradiol which is transported across intact skin leading to sustained circulating levels of estradiol during a 7-day treatment period. The systemic availability of estradiol after transdermal administration is about 20 times higher than that after oral administration. This difference is due to the absence of first pass metabolism when estradiol is given by the transdermal route. In a bioavailability study, the Estradiol Transdermal System 6.5 cm 2 was studied with the Estradiol Transdermal System 12.5 cm 2 as reference. The mean estradiol levels in serum from the two sizes are shown in Figure 1. Figure 1: Mean Serum 17ß -Estradiol Concentrations versus Time Profile following Application of a 6.5 cm2 Estradiol Transdermal System and Application of a 12.5 cm2 Estradiol Transdermal System Transdermal System Dose proportionality was demonstrated for the Estradiol Transdermal System 6.5 cm 2 as compared to the Estradiol Transdermal System 12.5 cm 2 in a 2-week crossover study with a 1-week washout period between the two-transdermal systems in 24 postmenopausal women. Dose proportionality was also demonstrated for the Estradiol Transdermal System (12.5 cm 2 and 25 cm 2 ) in a 1-week study conducted in 54 postmenopausal women. The mean steady state levels (C avg ) of the estradiol during the application of the Estradiol Transdermal System 25 cm 2 and 12.5 cm 2 on the abdomen were about 80 and 40 pg/mL, respectively. In a 3-week multiple application study in 24 postmenopausal women, the 25 cm 2 Estradiol Transdermal System produced average peak estradiol concentrations (C max ) of approximately 100 pg/mL. Trough values at the end of each wear interval (C min ) were approximately 35 pg/mL. Nearly identical serum curves were seen each week, indicating little or no accumulation of estradiol in the body. Serum estrone peak and trough levels were 60 and 40 pg/mL, respectively. In a single dose, randomized, crossover study conducted to compare the effect of site of application, 38 postmenopausal women wore a single Estradiol Transdermal System 25 cm 2 transdermal system for 1 week on the abdomen and buttocks. The estradiol serum concentration profiles are shown in Figure 2. Values of C max and C avg were, respectively, 25 percent and 17 percent higher with the buttock application than with the abdomen application. Figure 2: Observed Mean (± SE) Estradiol Serum Concentrations for a One Week Application of the Estradiol Transdermal System Transdermal System (25 cm2 ) to the Abdomen and Buttocks of 38 Postmenopausal Women Table 2 provides a summary of estradiol pharmacokinetic parameters determined during evaluation of the Estradiol Transdermal System transdermal system. Table 2: Pharmacokinetic Summary (Mean Estradiol Values) Estradiol Transdermal System Delivery Rate Surface Area (cm 2 ) Application Site No. of Subjects Dosing C max (pg/mL) C min (pg/mL) C avg (pg/mL) 0.025 6.5 Abdomen 24 Single 32 17 22 0.05 12.5 Abdomen 102 Single 71 29 41 0.1 25 Abdomen 139 Single 147 60 87 0.1 25 Buttock 38 Single 174 71 106 The relative standard deviation of each pharmacokinetic parameter after application to the abdomen averaged 50 percent, which is indicative of the considerable intersubject variability associated with transdermal drug delivery. The relative standard deviation of each pharmacokinetic parameter after application to the buttock was lower than that after application to the abdomen (for example, for C max 39 percent versus 62 percent, and for C avg 35 percent versus 48 percent). Fig 1 Fig 2 Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Adhesion An open-label study of adhesion potentials of placebo transdermal systems that correspond to the 6.5 cm 2 and 12.5 cm 2 sizes of the Estradiol Transdermal System was conducted in 112 healthy women of 45 to 75 years of age. Each woman applied both transdermal systems weekly, on the upper outer abdomen, for 3 consecutive weeks. It should be noted that lower abdomen and upper quadrant of the buttock are the approved sites of application for the Estradiol Transdermal System. The adhesion assessment was done visually on Days 2, 4, 5, 6, 7 of each week of transdermal system wear. A total of 1,654 adhesion observations were conducted for 333 transdermal systems of each size. Of these observations, approximately 90 percent showed essentially no lift for both the 6.5 cm 2 and 12.5 cm 2 transdermal systems. Of the total number of transdermal systems applied, approximately 5 percent showed complete detachment for each size. Adhesion potentials of the 18.75 cm 2 and 25 cm 2 sizes of transdermal systems (0.075 mg per day and 0.1 mg per day) have not been studied.

12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

12.2 Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to the 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 Transdermal administration of the Estradiol Transdermal System produces mean serum concentrations of estradiol comparable to those produced by premenopausal women in the early follicular phase of the ovulatory cycle. The pharmacokinetics of estradiol following application of the Estradiol Transdermal System transdermal system were investigated in 197 healthy postmenopausal women in six studies. In five of the studies, the Estradiol Transdermal System transdermal system was applied to the abdomen, and in a sixth study, application to the buttocks and abdomen were compared. The Estradiol Transdermal System transdermal delivery system continuously releases estradiol which is transported across intact skin leading to sustained circulating levels of estradiol during a 7-day treatment period. The systemic availability of estradiol after transdermal administration is about 20 times higher than that after oral administration. This difference is due to the absence of first pass metabolism when estradiol is given by the transdermal route. In a bioavailability study, the Estradiol Transdermal System 6.5 cm 2 was studied with the Estradiol Transdermal System 12.5 cm 2 as reference. The mean estradiol levels in serum from the two sizes are shown in Figure 1. Figure 1: Mean Serum 17ß -Estradiol Concentrations versus Time Profile following Application of a 6.5 cm2 Estradiol Transdermal System and Application of a 12.5 cm2 Estradiol Transdermal System Transdermal System Dose proportionality was demonstrated for the Estradiol Transdermal System 6.5 cm 2 as compared to the Estradiol Transdermal System 12.5 cm 2 in a 2-week crossover study with a 1-week washout period between the two-transdermal systems in 24 postmenopausal women. Dose proportionality was also demonstrated for the Estradiol Transdermal System (12.5 cm 2 and 25 cm 2 ) in a 1-week study conducted in 54 postmenopausal women. The mean steady state levels (C avg ) of the estradiol during the application of the Estradiol Transdermal System 25 cm 2 and 12.5 cm 2 on the abdomen were about 80 and 40 pg/mL, respectively. In a 3-week multiple application study in 24 postmenopausal women, the 25 cm 2 Estradiol Transdermal System produced average peak estradiol concentrations (C max ) of approximately 100 pg/mL. Trough values at the end of each wear interval (C min ) were approximately 35 pg/mL. Nearly identical serum curves were seen each week, indicating little or no accumulation of estradiol in the body. Serum estrone peak and trough levels were 60 and 40 pg/mL, respectively. In a single dose, randomized, crossover study conducted to compare the effect of site of application, 38 postmenopausal women wore a single Estradiol Transdermal System 25 cm 2 transdermal system for 1 week on the abdomen and buttocks. The estradiol serum concentration profiles are shown in Figure 2. Values of C max and C avg were, respectively, 25 percent and 17 percent higher with the buttock application than with the abdomen application. Figure 2: Observed Mean (± SE) Estradiol Serum Concentrations for a One Week Application of the Estradiol Transdermal System Transdermal System (25 cm2 ) to the Abdomen and Buttocks of 38 Postmenopausal Women Table 2 provides a summary of estradiol pharmacokinetic parameters determined during evaluation of the Estradiol Transdermal System transdermal system. Table 2: Pharmacokinetic Summary (Mean Estradiol Values) Estradiol Transdermal System Delivery Rate Surface Area (cm 2 ) Application Site No. of Subjects Dosing C max (pg/mL) C min (pg/mL) C avg (pg/mL) 0.025 6.5 Abdomen 24 Single 32 17 22 0.05 12.5 Abdomen 102 Single 71 29 41 0.1 25 Abdomen 139 Single 147 60 87 0.1 25 Buttock 38 Single 174 71 106 The relative standard deviation of each pharmacokinetic parameter after application to the abdomen averaged 50 percent, which is indicative of the considerable intersubject variability associated with transdermal drug delivery. The relative standard deviation of each pharmacokinetic parameter after application to the buttock was lower than that after application to the abdomen (for example, for C max 39 percent versus 62 percent, and for C avg 35 percent versus 48 percent). Fig 1 Fig 2 Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Adhesion An open-label study of adhesion potentials of placebo transdermal systems that correspond to the 6.5 cm 2 and 12.5 cm 2 sizes of the Estradiol Transdermal System was conducted in 112 healthy women of 45 to 75 years of age. Each woman applied both transdermal systems weekly, on the upper outer abdomen, for 3 consecutive weeks. It should be noted that lower abdomen and upper quadrant of the buttock are the approved sites of application for the Estradiol Transdermal System. The adhesion assessment was done visually on Days 2, 4, 5, 6, 7 of each week of transdermal system wear. A total of 1,654 adhesion observations were conducted for 333 transdermal systems of each size. Of these observations, approximately 90 percent showed essentially no lift for both the 6.5 cm 2 and 12.5 cm 2 transdermal systems. Of the total number of transdermal systems applied, approximately 5 percent showed complete detachment for each size. Adhesion potentials of the 18.75 cm 2 and 25 cm 2 sizes of transdermal systems (0.075 mg per day and 0.1 mg per day) have not been studied.

20231208

7

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

Estradiol Transdermal System Estradiol ESTRADIOL ESTRADIOL Estradiol Transdermal System Estradiol ESTRADIOL ESTRADIOL Estradiol Transdermal System Estradiol ESTRADIOL ESTRADIOL Estradiol Transdermal System Estradiol ESTRADIOL ESTRADIOL Estradiol Transdermal System Estradiol ESTRADIOL ESTRADIOL Estradiol Transdermal System Estradiol ESTRADIOL ESTRADIOL

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.

NDA020375

Estradiol Transdermal System

Estradiol

0781-7134

HUMAN PRESCRIPTION DRUG

TRANSDERMAL

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL • NDC 0781-7119-54 4 transdermal systems Estradiol Transdermal System 0.025 mg/day Contents: Each 6.5 cm2 system contains 2 mg estradiol USP to provide 0.025 mg of estradiol per day. The inactive components are acrylate copolymer adhesive, fatty acid esters, and polyethylene backing. For transdermal use only. Keep this and all drugs out of the reach of children. Rx only 0.025 Patch

Warnings and Precautions ( 5.2 ) 12/2023

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 Vasomotor Symptoms in Postmenopausal Women A study of 214 women 25 to 74 years of age met the qualification criteria and were randomly assigned to one of the three treatment groups: 72 to the 0.05 mg estradiol patch, 70 to the 0.1 mg estradiol patch, and 72 to placebo. Potential participants were postmenopausal women in good general health who experienced vasomotor symptoms. Natural menopause patients had not menstruated for at least 12 months and surgical menopause patients had undergone bilateral oophorectomy at least 4 weeks before evaluation for study entry. In order to enter the 11-week treatment phase of the study, potential participants must have experienced a minimum of five moderate to severe hot flushes per week, or a minimum of 15 hot flushes of any severity per week, for 2 consecutive weeks. Women wore the patches in a cyclical fashion (three weeks on and one week off). During treatment, all women used diaries to record the number and severity of hot flushes. Women were monitored by clinic visits at the end of weeks 1, 3, 7, and 11 and by telephone at the end of weeks 4, 5, 8, and 9. Adequate data for the analysis of efficacy was available from 191 subjects. The results are presented as the mean ± SD number of flushes in each of the 3 treatment weeks of each 4-week cycle. In the 0.05 mg estradiol group, the mean weekly hot flush rate across all treatment cycles decreased from 46 ± 6.5 at baseline to 20 ± 3 (-67 percent). The 0.1 mg estradiol group had a decline in the mean weekly hot flush rate from 52 ± 4.4 at baseline to 16 ± 2.4 (-72 percent). In the placebo group, the mean weekly hot flush rate declined from 53 ± 4.5 at baseline to 46 ± 6.5 (-18.1 percent). Compared with placebo, the 0.05 mg and 0.1 mg estradiol groups showed a statistically significantly larger mean decrease in hot flushes across all treatment cycles (P<0.05). When the response to treatment was analyzed for each of the three cycles of therapy, similar statistically significant differences were observed between both estradiol treatment groups and the placebo group during all treatment cycles. In a double-blind, placebo-controlled, randomized study of 187 women receiving estradiol 0.025 mg per day or placebo continuously for up to three 28-day cycles, the estradiol 0.025 mg per day dosage was shown to be statistically better than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to severe vasomotor symptoms. Table 3: Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms Intent to Treat (ITT) Treatment Group Statistics Week 4 Week 8 Week 12 E 2 Transdermal System N 82 84 68 Mean -6.45 -7.69 -7.56 SD 4.65 4.76 4.64 Placebo N 83 71 65 Mean -5.11 -5.98 -5.98 SD 7.43 8.63 9.69 p-value <0.002 <0.003 A second active-control trial of 193 randomized women was supportive of the placebo-controlled trial. 14.2 Effects on Bone Mineral Density in Postmenopausal Women A two-year clinical trial enrolled a total of 175 healthy, hysterectomized, postmenopausal, non-osteoporotic (that is, lumbar spine bone mineral density >0.9 gm/cm 2 ) women at 10 study centers in the United States. A total of 129 participating women were allocated to receive active treatment with 4 different doses of estradiol patches (6.5, 12.5, 15, 25 cm 2 ) and 46 participating women were allocated to receive placebo patches. Seventy-seven percent of the randomized women (100 on active drug and 34 on placebo) contributed data to the analysis of percent change of anterior-posterior (A-P) spine BMD, the primary efficacy variable (see Figure 3). A statistically significant overall treatment effect at each timepoint was noted, implying bone preservation for all active treatment groups at all timepoints, as opposed to bone loss for placebo at all timepoints. Figure 3: Mean Percent Change from Baseline in Lumbar Spine (A-P View) Bone Mineral Density By Treatment and Time Last Observation Carried Forward Figure 3: Mean Percent Change from Baseline in Lumbar Spine (A-P View) Bone Mineral Density By Treatment and Time Last Observation Carried Forward Percent change in BMD of the total hip (see Figure 4) was also statistically significantly different from placebo for all active treatment groups. This figure is based on 74 percent of the randomized women (95 on active drug and 34 on placebo). Figure 4: Mean Percent Change from Baseline in Total Hip by Treatment and Time Last Observation Carried Forward fig 3 fig 4 14.3 Women's Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms. WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risk and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79: 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 7.1 years, are presented in Table 4. Table 4: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi Event Relative Risk CE vs. Placebo (95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-years CHD events 0.95 (0.78-1.16) 54 57 Non-fatal MIc 0.91 (0.73-1.14) 40 43 CHD death Results are based on centrally adjudicated data for an average follow-up of 7.1 years. 1.01 (0.71-1.43) 16 16 All strokes 1.33 (1.05-1.68) 45 33 Ischemic stroke 1.55 (1.19-2.01) 38 25 Deep vein thrombosis , Not included in "global index". 1.47 (1.06-2.06) 23 15 Pulmonary embolism 1.37 (0.9-2.07) 14 10 Invasive breast cancer 0.80 (0.62-1.04) 28 34 Colorectal cancer 1.08 (0.75-1.55) 17 16 Hip fracture 0.65 (0.45-0.94) 12 19 Vertebral fractures , 0.64 (0.44-0.93) 11 18 Lower arm/wrist fractures , 0.58 (0.47-0.72) 35 59 Total fractures , 0.71 (0.64-0.80) 144 197 Death due to causes Results are based on an average follow-up of 6.8 years. , All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.08 (0.88-1.32) 53 50 Overall mortality , 1.04 (0.88-1.22) 79 75 Global Index A subset of the events was combined in a "global index", defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. 1.02 (0.92-1.13) 206 201 For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risks per 10,000 women-years in the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. 9 The absolute excess risk of events included in the "global index" was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years. See Table 4. Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in the distribution of stroke subtype and severity, including fatal strokes, in women receiving estrogen-alone compared to placebo. Estrogen-alone increased the risk of ischemic stroke, and this excess risk was present in all subgroups of women examined. 10 See Table 4. Timing of initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk-benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)] . WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the "global index". The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reduction per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.5 percent Black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 5 . These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 5: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. Results are based on centrally adjudicated data. Event Relative Risk CE/MPA vs. placebo (95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ) CE/MPA n = 8,506 Placebo n = 8,102 Absolute Risk per 10,000 Women-years CHD events 1.23 (0.99-1.53) 41 34 Non-fatal MI 1.28 (1.00-1.63) 31 25 CHD death 1.10 (0.70-1.75) 8 8 All strokes 1.31 (1.03-1.68) 33 25 Ischemic stroke 1.44 (1.09-1.90) 26 18 Deep vein thrombosis Not included in "global index". 1.95 (1.43-2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive breast cancer Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. 1.24 (1.01-1.54) 41 33 Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancer 0.81 (0.48-1.36) 6 7 Cervical cancer 1.44 (0.47-4.42) 2 1 Hip fracture 0.67 (0.47-0.96) 11 16 Vertebral fractures 0.65 (0.46-0.92) 11 17 Lower arm/wrist fractures 0.71 (0.59-0.85) 44 62 Total fractures 0.76 (0.69-0.83) 152 199 Overall mortality All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.00 (0.83-1.19) 52 52 Global Index A subset of the events was combined in a "global index", defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. 1.13 (1.02-1.25) 184 165 Timing of initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44-1.07)] . 14.4 Women's Health Initiative Memory Study The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in the study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), and Use in Specific Populations ( 8.5 )] . The WHIMS estrogen plus progestin ancillary study enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years of age; and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. Probable dementia 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 1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA . 2007;297:1465-1477. 2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357-365. 3. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780. 4. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580. 5. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA. 2006;295:1647-1657. 6. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253. 7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748. 8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958. 9. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women's Health Initiative Randomized Trial. J Bone Miner Res. 2006;21:817-828. 10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation. 2006;113:2425-2434.

8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing the Estradiol Transdermal System to determine whether those over 65 years of age differ from younger subjects in their response to the Estradiol Transdermal System. The Women’s Health Initiative Studies In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies ( 14.3 )] . In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies ( 14.3 )] . The Women’s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.4 )] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.4 )] .

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

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

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary the Estradiol Transdermal System is not indicated for use in pregnancy. There are no data with the use of the Estradiol Transdermal System in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary Estrogens are present in human milk and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for the Estradiol Transdermal System and any potential adverse effects on the breastfed child from the Estradiol Transdermal System or from the underlying maternal condition. 8.4 Pediatric Use In general, the Estradiol Transdermal System is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone metabolism and effects on epiphyseal centers is recommended during estrogen administration. 8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing the Estradiol Transdermal System to determine whether those over 65 years of age differ from younger subjects in their response to the Estradiol Transdermal System. The Women’s Health Initiative Studies In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies ( 14.3 )] . In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies ( 14.3 )] . The Women’s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.4 )] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.4 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Estradiol Transdermal System, 0.025 mg/day — each 6.5 cm 2 system contains 2 mg of estradiol USP Individual Carton of 4 systems NDC 0781-7119-54 Estradiol Transdermal System, 0.0375 mg/day — each 9.375 cm 2 system contains 2.85 mg of estradiol USP Individual Carton of 4 systems NDC 0781-7122-54 Estradiol Transdermal System, 0.05 mg/day — each 12.5 cm 2 system contains 3.8 mg of estradiol USP Individual Carton of 4 systems ………………NDC 0781-7133-54 Estradiol Transdermal System, 0.06 mg/day — each 15 cm 2 system contains 4.55 mg of estradiol USP Individual Carton of 4 systems NDC 0781-7134-54 Estradiol Transdermal System, 0.075 mg/day — each 18.75 cm 2 system contains 5.7 mg of estradiol USP Individual Carton of 4 systems……………… NDC 0781-7136-54 Estradiol Transdermal System, 0.1 mg/day — each 25 cm 2 system contains 7.6 mg of estradiol USP Individual Carton of 4 systems ……………….NDC 0781-7104-54 16.2 Storage and Handling Store at 20°C to 25°C (66°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Do not store above 86°F (30°C). Do not store unpouched. Apply immediately upon removal from the protective pouch. Used transdermal systems still contain active hormone. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet.

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA and BREAST CANCER Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated to rule out malignancy in postmenopausal women with undiagnosed, persistent or recurring abnormal genital bleeding [see Warnings and Precautions ( 5.2 )] . Cardiovascular Disorders and Probable Dementia The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo [see Warnings and Precautions ( 5.1 ), and Clinical Studies ( 14.3 )] . The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.4 )] . Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions ( 5.1 , 5.3 ), and Clinical Studies ( 14.3 , 14.4 )] . Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions ( 5.1 ), and Clinical Studies ( 14.3 )] . The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), Use in Specific Populations (8.5), and Clinical Studies ( 14.4 )] . Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions ( 5.1 , 5.3 ), and Clinical Studies ( 14.3 , 14.4 )] . Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies ( 14.3 )] . Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA and BREAST CANCER See full prescribing information for complete boxed warning. Estrogen-Alone Therapy 1. There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens ( 5.2 ) 2. The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) ( 5.1 ) 3. 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 ) 4. 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 ) •