Estradiol

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in labeling: Cardiovascular Disorders [see Boxed Warnings and Warnings and Precautions ( 5.1 )] Malignant Neoplasms [see Boxed Warnings and Warnings and Precautions ( 5.2 )] The most common adverse reactions (greater than or equal to 5 percent) with Estradiol Transdermal System are: headache, breast tenderness, back pain, pain in limb, nasopharyngitis, dyspepsia, nausea, sinusitis, and intermenstrual bleeding ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Noven at 1-800-455-8070 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. There were no clinical trials conducted with ESTRADIOL TRANSDERMAL SYSTEM. ESTRADIOL TRANSDERMAL SYSTEM is bioequivalent to Vivelle ® . The following adverse reactions are reported with Vivelle therapy: Table 1: Summary of Most Frequently Reported Adverse Reactions (Vivelle versus Placebo) Regardless of Relationship Reported at a Frequency ≥ 5 Percent †Represents milligrams of estradiol delivered daily by each system *NOS represents not otherwise specified **NEC represents not elsewhere classified ***Application site erythema and application site irritation were observed in 3.2% or less of patients across treatment groups. Vivelle 0.025 mg/ day† (N=47) N (%) Vivelle 0.0375 mg/ day† (N=130) N (%) Vivelle 0.05 mg/ day† (N=103) N (%) Vivelle 0.075 mg/ day† (N=46) N (%) Vivelle 0.1 mg/ day† (N=132) N (%) Placebo (N=157) N (%) Gastrointestinal disorders Constipation 2 (4.3) 5 (3.8) 4 (3.9) 3 (6.5) 2 (1.5) 4 (2.5) Dyspepsia 4 (8.5) 12 (9.2) 3 (2.9) 2 (4.3) 0 10 (6.4) Nausea 2 (4.3) 8 (6.2) 4 (3.9) 0 7 (5.3) 5 (3.2) General disorders and administration site conditions *** Influenza-like illness 3 (6.4) 6 (4.6) 8 (7.8) 0 3 (2.3) 10 (6.4) Pain NOS * 0 8 (6.2) 0 2 (4.3) 7 (5.3) 7 (4.5) Infections and infestations Influenza 4 (8.5) 4 (3.1) 6 (5.8) 0 10 (7.6) 14 (8.9) Nasopharyngitis 3 (6.4) 16 (12.3) 10 (9.7) 9 (19.6) 11 (8.3) 24 (15.3) Sinusitis NOS * 4 (8.5) 17 (13.1) 13 (12.6) 3 (6.5) 7 (5.3) 16 (10.2) Upper respiratory tract infection NOS * 3 (6.4) 8 (6.2) 11 (10.7) 4 (8.7) 6 (4.5) 9 (5.7) Investigations Weight increased 4 (8.5) 5 (3.8) 2 (1.9) 2 (4.3) 0 3 (1.9) Musculoskeletal and connective tissue disorders Arthralgia 0 11 (8.5) 4 (3.9) 2 (4.3) 5 (3.8) 9 (5.7) Back pain 4 (8.5) 10 (7.7) 9 (8.7) 4 (8.7) 14 (10.6) 10 (6.4) Neck pain 3 (6.4) 4 (3.1) 4 (3.9) 0 6 (4.5) 2 (1.3) Pain in limb 0 10 (7.7) 7 (6.8) 2 (4.3) 6 (4.5) 9 (5.7) Nervous system disorders Headache NOS * 7 (14.9) 35 (26.9) 32 (31.1) 23 (50.0) 34 (25.8) 37 (23.6) Sinus headache 0 12 (9.2) 5 (4.9) 5 (10.9) 2 (1.5) 8 (5.1) Psychiatric disorders Anxiety NEC ** 3 (6.4) 5 (3.8) 0 0 2 (1.5) 4 (2.5) Depression 5 (10.6) 4 (3.1) 7 (6.8) 0 4 (3.0) 6 (3.8) Insomnia 3 (6.4) 6 (4.6) 4 (3.9) 2 (4.3) 2 (1.5) 9 (5.7) Reproductive system and breast disorders Breast tenderness 8 (17.0) 10 (7.7) 8 (7.8) 3 (6.5) 17 (12.9) 0 Dysmenorrhea 0 0 0 3 (6.5) 0 0 Intermenstrual bleeding 3 (6.4) 9 (6.9) 6 (5.8) 0 14 (10.6) 7 (4.5) Respiratory, thoracic and mediastinal disorders Sinus congestion 0 4 (3.1) 3 (2.9) 3 (6.5) 6 (4.5) 7 (4.5) Vascular disorders Hot flushes NOS * 3 (6.4) 0 3 (2.9) 0 0 6 (3.8) Hypertension NOS * 2 (4.3) 0 3 (2.9) 0 0 2 (1.3) During the clinical pharmacology studies with ESTRADIOL TRANSDERMAL SYSTEM, 35 percent or less of subjects experienced barely perceptible erythema. No transdermal systems were removed due to irritation. Three subjects (2.2 percent) reported mild discomfort while wearing ESTRADIOL TRANSDERMAL SYSTEM (N=136). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of 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. Breast Breast enlargement Cardiovascular Palpitations, angina unstable Gastrointestinal Hemorrhage, diarrhea Skin Application site reactions, erythema, rash, hyperhidrosis, pruritis, urticaria Central Nervous System Dizziness, paresthesia, migraine, mood swings, emotional disorder, irritability, nervousness Miscellaneous Portal vein thrombosis, dyspnea, malaise, fatigue, peripheral edema, muscle spasms, paresthesia oral, swollen tongue, lip swelling, pharyngeal edema

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 a history of breast cancer [See Warnings and Precautions ( 5.2 )] . Estrogen-dependent neoplasia [See Warnings and Precautions ( 5.2 )] . Active DVT, PE, or a history of these conditions [See Warnings and Precautions ( 5.1 )] . Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions [See Warnings and Precautions ( 5.2 )] . 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, 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 contains estradiol in a multipolymeric adhesive. The system is designed to release estradiol continuously upon application to intact skin. Five dosage strengths of ESTRADIOL TRANSDERMAL SYSTEM are available to provide nominal in vivo delivery rates of 0.025, 0.0375, 0.05, 0.075, or 0.1 mg of estradiol per day via the skin. Each corresponding system has an active surface area of 1.65, 2.48, 3.30, 4.95, or 6.6 cm 2 and contains 0.41, 0.62, 0.83, 1.24, or 1.65 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. The structural formula is The molecular formula of estradiol is C 18 H 24 O 2 . The molecular weight is 272.39 ESTRADIOL TRANSDERMAL SYSTEM is comprised of three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a polyolefin laminate backing (2) an adhesive formulation containing estradiol, acrylic adhesive, silicone adhesive, oleyl alcohol, NF, povidone, USP and dipropylene glycol, and (3) a polyester release liner which is attached to the adhesive surface and must be removed before the system can be used. The active component of the system is estradiol. The remaining components of the system are pharmacologically inactive. chemical structure layers

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 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 of 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 ESTRADIOL TRANSDERMAL SYSTEM 0.0375 mg per day applied to the skin twice weekly for the treatment of moderate to severe vasomotor symptoms due to menopause. Dosage adjustment should be guided by the clinical response ( 2.1 ) Start therapy with ESTRADIOL TRANSDERMAL SYSTEM 0.025 mg per day applied to the skin twice weekly for the prevention of postmenopausal osteoporosis. The dose may be adjusted as necessary ( 2.2 ) Place ESTRADIOL TRANSDERMAL SYSTEM on a clean, dry area on the lower abdomen (below the umbilicus) or buttocks. Do not apply ESTRADIOL TRANSDERMAL SYSTEM to the breasts ( 2.3 ) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Start therapy with ESTRADIOL TRANSDERMAL SYSTEM 0.0375 mg per day applied to the skin twice weekly. Make dosage adjustments based on clinical response. Therapy should be started at the lowest effective dose and the shortest duration consistent with the treatment goals. Attempts to taper or discontinue the medication at 3 to 6 month intervals. 2.2 Prevention of Postmenopausal Osteoporosis due to Menopause 2.3 Application Instructions Place the adhesive side of ESTRADIOL TRANSDERMAL SYSTEM on a clean, dry area on the lower abdomen (below the umbilicus) or buttocks. Do not apply ESTRADIOL TRANSDERMAL SYSTEM to the breasts. Replace ESTRADIOL TRANSDERMAL SYSTEM twice weekly (every 3-4 days). Rotate the sites of application, with an interval of at least 1 week allowed between applications to a particular site. Select an area for application that is not oily, damaged, or irritated. Avoid the waistline, since tight clothing may rub the system off. Apply the system immediately after opening the pouch and removing the protective liner. Press the system firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact with the skin, especially around the edges. In the event that a system falls off, reapply the same system or apply a new system to another location. If a woman has forgotten to apply ESTRADIOL TRANSDERMAL SYSTEM, have her apply a new system as soon as possible. Apply the new system on the original treatment schedule. The interruption of treatment in women taking ESTRADIOL TRANSDERMAL SYSTEM might increase the likelihood of breakthrough bleeding, spotting and recurrence of symptoms.

1 INDICATIONS AND USAGE ESTRADIOL TRANSDERMAL SYSTEM is an estrogen indicated for: Treatment of moderate to severe vasomotor symptoms due to menopause ( 1.1 ) Prevention of postmenopausal osteoporosis ( 1.2 ) Limitation of Use When prescribing solely for the treatment of postmenopausal osteoporosis, first consider the use of non-estrogen medications. Consider estrogen therapy only for women at significant risk of osteoporosis. 1.1 Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause 1.2 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 may occur 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 metabolism and decrease or increase the estrogen plasma concentration. ( 7.1 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen responsive tissues. To date, 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 concentrations 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 In a single-dose, two way-crossover clinical study conducted in 96 healthy, non-smoking postmenopausal women under fed condition, ESTRADIOL TRANSDERMAL SYSTEM (0.1 mg per day) was bioequivalent to Vivelle (0.1 mg per day) based on estradiol exposure (AUC 0-84 ) and estradiol peak concentration (C max ) following a single-dose on the lower abdomen for 84 hours. Estradiol pharmacokinetics were characterized in a separate open-label, single-center, randomized, single-dose, three-way crossover study conducted in 36 healthy, non-smoking postmenopausal women (aged 40 to 65 years). ESTRADIOL TRANSDERMAL SYSTEM delivering nominal estradiol of approximately 0.025 mg, 0.05 mg, and 0.1 mg per day were applied to the lower abdomen under fed state in a crossover fashion for 84 hours. The mean estradiol pharmacokinetics parameters are summarized in Table 2 . AUC and C max are dose proportional from 0.025 mg to 0.1 mg per day. Table 2: Mean (SD) Serum Pharmacokinetic Parameters of Baseline-Uncorrected Estradiol following a Single Dose of ESTRADIOL TRANSDERMAL SYSTEM (N=36) a Median (minimum-maximum) Parameter 0.1 mg/day 0.05 mg/day 0.025 mg/day AUC 84 (pg·hr/mL) 5875 (1857) 3057 (980) 1763 (600) AUC 120 (pg·hr/mL) 6252 (1938) 3320 (1038) 1979 (648) C max (pg/mL) 117 (39.3) 56.6 (17.6) 30.3 (11.1) T max (hr) a 24.0 (8-60) 24.0 (8-60) 36.0 (8-84) Figure 1 illustrates the mean baseline-uncorrected estradiol serum concentrations of ESTRADIOL TRANSDERMAL SYSTEM at three different strengths. Figure 1: Mean Baseline-Uncorrected Estradiol Serum Concentration-Time Profiles Following a Single Dose of ESTRADIOL TRANSDERMAL SYSTEM 0.1 mg per day (Treatment A), 0.05 mg per day (Treatment B), and 0.025 mg per day (Treatment C) (N=36) Distribution No specific investigation of the tissue distribution of estradiol absorbed from ESTRADIOL TRANSDERMAL SYSTEM in humans has been conducted. The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The mean half-life values of estradiol calculated from treatment groups in the bioequivalence study and dose-proportionality study after dosing with the ESTRADIOL TRANSDERMAL SYSTEM ranged from 6.2 to 7.9 hours. After removal of the transdermal systems, serum concentrations of estradiol and estrone returned to baseline concentrations within 24 hours. Adhesion and Adhesive Residue Based on combined data from bioequivalence and dose proportionality studies consisting of 208 ESTRADIOL TRANSDERMAL SYSTEM observations, approximately 98 percent of the observations had an adhesion score of 0 (i.e., the skin adhesion rate was greater than or equal to 90 percent) over the 84-hour wear period. One woman had a complete detachment during the wear period. Approximately 65 percent of the transdermal systems evaluated in these studies were with ESTRADIOL TRANSDERMAL SYSTEM 0.1 mg per day (6.6 cm 2 active surface area). After removal of ESTRADIOL TRANSDERMAL SYSTEM, women had either no adhesive residue (score of 0) or light adhesive residue (score of 1). No woman had medium adhesive residue. Of the 208 ESTRADIOL TRANSDERMAL SYSTEM observations, 54 percent had light adhesive residue and 46 percent had no adhesive residue. figure1

12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen responsive tissues. To date, 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 concentrations 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 In a single-dose, two way-crossover clinical study conducted in 96 healthy, non-smoking postmenopausal women under fed condition, ESTRADIOL TRANSDERMAL SYSTEM (0.1 mg per day) was bioequivalent to Vivelle (0.1 mg per day) based on estradiol exposure (AUC 0-84 ) and estradiol peak concentration (C max ) following a single-dose on the lower abdomen for 84 hours. Estradiol pharmacokinetics were characterized in a separate open-label, single-center, randomized, single-dose, three-way crossover study conducted in 36 healthy, non-smoking postmenopausal women (aged 40 to 65 years). ESTRADIOL TRANSDERMAL SYSTEM delivering nominal estradiol of approximately 0.025 mg, 0.05 mg, and 0.1 mg per day were applied to the lower abdomen under fed state in a crossover fashion for 84 hours. The mean estradiol pharmacokinetics parameters are summarized in Table 2 . AUC and C max are dose proportional from 0.025 mg to 0.1 mg per day. Table 2: Mean (SD) Serum Pharmacokinetic Parameters of Baseline-Uncorrected Estradiol following a Single Dose of ESTRADIOL TRANSDERMAL SYSTEM (N=36) a Median (minimum-maximum) Parameter 0.1 mg/day 0.05 mg/day 0.025 mg/day AUC 84 (pg·hr/mL) 5875 (1857) 3057 (980) 1763 (600) AUC 120 (pg·hr/mL) 6252 (1938) 3320 (1038) 1979 (648) C max (pg/mL) 117 (39.3) 56.6 (17.6) 30.3 (11.1) T max (hr) a 24.0 (8-60) 24.0 (8-60) 36.0 (8-84) Figure 1 illustrates the mean baseline-uncorrected estradiol serum concentrations of ESTRADIOL TRANSDERMAL SYSTEM at three different strengths. Figure 1: Mean Baseline-Uncorrected Estradiol Serum Concentration-Time Profiles Following a Single Dose of ESTRADIOL TRANSDERMAL SYSTEM 0.1 mg per day (Treatment A), 0.05 mg per day (Treatment B), and 0.025 mg per day (Treatment C) (N=36) Distribution No specific investigation of the tissue distribution of estradiol absorbed from ESTRADIOL TRANSDERMAL SYSTEM in humans has been conducted. The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The mean half-life values of estradiol calculated from treatment groups in the bioequivalence study and dose-proportionality study after dosing with the ESTRADIOL TRANSDERMAL SYSTEM ranged from 6.2 to 7.9 hours. After removal of the transdermal systems, serum concentrations of estradiol and estrone returned to baseline concentrations within 24 hours. Adhesion and Adhesive Residue Based on combined data from bioequivalence and dose proportionality studies consisting of 208 ESTRADIOL TRANSDERMAL SYSTEM observations, approximately 98 percent of the observations had an adhesion score of 0 (i.e., the skin adhesion rate was greater than or equal to 90 percent) over the 84-hour wear period. One woman had a complete detachment during the wear period. Approximately 65 percent of the transdermal systems evaluated in these studies were with ESTRADIOL TRANSDERMAL SYSTEM 0.1 mg per day (6.6 cm 2 active surface area). After removal of ESTRADIOL TRANSDERMAL SYSTEM, women had either no adhesive residue (score of 0) or light adhesive residue (score of 1). No woman had medium adhesive residue. Of the 208 ESTRADIOL TRANSDERMAL SYSTEM observations, 54 percent had light adhesive residue and 46 percent had no adhesive residue. figure1

20211202

4

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

Estradiol estradiol ESTRADIOL ESTRADIOL DIPROPYLENE GLYCOL OLEYL ALCOHOL POVIDONE K30 Estradiol estradiol ESTRADIOL ESTRADIOL DIPROPYLENE GLYCOL OLEYL ALCOHOL POVIDONE K30 Estradiol estradiol ESTRADIOL ESTRADIOL DIPROPYLENE GLYCOL OLEYL ALCOHOL POVIDONE K30 Estradiol estradiol ESTRADIOL ESTRADIOL DIPROPYLENE GLYCOL OLEYL ALCOHOL POVIDONE K30 Estradiol estradiol ESTRADIOL ESTRADIOL DIPROPYLENE GLYCOL OLEYL ALCOHOL POVIDONE K30

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.

NDA203752

Estradiol

estradiol

68968-3437

HUMAN PRESCRIPTION DRUG

TRANSDERMAL

PRINCIPAL DISPLAY PANEL - NDC: 68968-3425-8 - 0.025 mg 8-count Carton Label 0.025 mg 8-count Carton Label

Boxed Warning 10/2021

17 PATIENT COUNSELING INFORMATION Advice women to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ). Vaginal Bleeding Inform postmenopausal women to report unusual vaginal bleeding to their healthcare providers as soon as possible [see Warnings and Precautions ( 5.2 )] Possible Serious Adverse Reactions with Estrogen–Alone Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] . Possible Common Adverse Reactions with Estrogen–Alone Therapy Inform postmenopausal women of less serious but common adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting.

INSTRUCTIONS FOR USE ESTRADIOL TRANSDERMAL SYSTEM Read this PATIENT INFORMATION before you start using ESTRADIOL TRANSDERMAL SYSTEM and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment. You will need the following supplies (See Figure A ) Figure A Step 1: Pick the days you will change your patch. You will need to change your patch 2 times a week or every 3 to 4 days. Use the calendar printed inside your carton to choose the 2 days you will change your patch (See Figure B ). Remember to change your patch on the same 2 days you marked on your calendar. If you forget to change your patch on the correct date, apply a new patch as soon as you remember, and continue to follow your original schedule Figure B Step 2. Remove the ESTRADIOL TRANSDERMAL SYSTEM patch from the pouch. Remove the patch from its protective pouch by tearing at the notch ( do not use scissors, See Figure C ). Do not remove your patch from the protective pouch until you are ready to apply it Figure C Step 3. Remove half of the adhesive liner (See Figure D ). Figure D Step 4. Placing the patch on your skin. Hold the part of the patch that still has the adhesive liner on it Avoid touching the sticky half of the patch with your fingers Apply the exposed sticky half of the patch to 1 of the areas of skin shown below (See Figures E and F ) Note: Avoid the waistline, since clothing and belts may cause the patch to be rubbed off Do not apply the patch to your breasts Only apply the patch to skin that is clean, dry, and free of any powder, oil, or lotion You should not apply the patch to injured, burned, or irritated skin, or areas with skin conditions (such as birth marks, tattoos, or that is very hairy) Step 5: Press the patch firmly onto your skin. Remove the remaining half of the adhesive liner and press the entire patch into place with the palm of your hand for 10 seconds Rub the edges of the patch with your fingers to make sure that it will stick to your skin (See Figure G ) Figure G Note: Showering will not cause your patch to fall off If your patch falls off reapply it. If you cannot reapply the patch, apply a new patch to another area (See Figures D and E ) and continue to follow your original placement schedule If you stop using your ESTRADIOL TRANSDERMAL SYSTEM patch or forget to apply a new patch as scheduled, you may have spotting, or bleeding, and recurrence of symptoms Step 6: Throwing away your used patch. When it is time to change your patch, remove the old patch before you apply a new patch To throw away the patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place this container in the trash. Used patches should not be flushed in the toilet This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration. Distributed by: Grove Pharmaceuticals Miami, FL 33186 Approved 10/2021 Vivelle ® is a registered trademark of Novartis Corporation. 102631-2 Figure A Figure B Figure C Figure D Figure E, F Figure G

14 CLINICAL STUDIES 14.1 Effects on Vasomotor Symptoms in Postmenopausal Women There have been no efficacy and safety trials conducted with ESTRADIOL TRANSDERMAL SYSTEM. In a pharmacokinetic study, ESTRADIOL TRANSDERMAL SYSTEM was shown to be bioequivalent to Vivelle. In two controlled clinical trials with Vivelle, in a total of 356 subjects, the 0.075 and 0.1 mg doses were superior to placebo in relieving vasomotor symptoms at Weeks 4, 8 and 12 of treatment. In these studies, the 0.0375 and 0.05 mg doses did not differ from placebo at Week 4, therefore, a third 12-week placebo-controlled study in 255 subjects was performed with Vivelle to establish the efficacy of the lowest dose of 0.0375 mg. The baseline mean daily number of hot flushes in these 255 subjects was 11.5. Results at Weeks 4, 8, and 12 of treatment are shown in Figure 2 . Figure 2: Mean (SD) change from baseline in mean daily number of hot flushes for Vivelle 0.0375 mg versus Placebo in a 12 week trial. The 0.0375 mg dose was superior to placebo in reducing both the frequency and severity of vasomotor symptoms at Weeks 4, 8 and 12 of treatment. figure2 14.2 Effects on Bone Mineral Density in Postmenopausal Women There have been no bone efficacy and safety trials conducted with ESTRADIOL TRANSDERMAL SYSTEM. In a pharmacokinetic study, ESTRADIOL TRANSDERMAL SYSTEM was shown to be bioequivalent to Vivelle. Efficacy and safety of Vivelle in the prevention of postmenopausal osteoporosis have been studied in a 2-year double-blind, randomized, placebo-controlled, parallel group study. A total of 261 hysterectomized (161) and non-hysterectomized (100), surgically or naturally menopausal women (within 5 years of menopause), with no evidence of osteoporosis (lumbar spine bone mineral density within 2 standard deviations of average peak bone mass, i.e., ≥0.0827 g/cm 2 ) were enrolled in this study; 194 patients were randomized to one of the four doses of Vivelle (0.1, 0.05, 0.0375, or 0.025 mg/day) and 67 patients to placebo. Over 2 years, study systems were applied to the buttock or the abdomen twice a week. Non-hysterectomized women received oral medroxyprogesterone acetate (2.5 mg/day) throughout the study. The study population comprised naturally (82 percent) or surgically (18 percent) menopausal, hysterectomized (61 percent) or non-hysterectomized (39 percent) women with a mean age of 52.0 years (range 27 to 62 years); the mean duration of menopause was 31.7 months (range 2 to 72 months). Two hundred thirty-two (89 percent) randomized subjects (173 on active drug, 59 on placebo) contributed data to the analysis of percent change from baseline in bone mineral density (BMD) of the AP lumbar spine, the primary efficacy variable. Patients were given supplemental dietary calcium (100 mg elemental calcium/day) but no supplemental vitamin D. There was an increase in BMD of the AP lumbar spine in all Vivelle dose groups; in contrast to this, a decrease in AP lumbar spine BMD was observed in placebo patients. All Vivelle doses were significantly superior to placebo (p<0.05) at all time points with the exception of Vivelle 0.05 mg/day at 6 months. The highest dose of Vivelle was superior to the three lower doses. There were no statistically significant differences in pairwise comparisons among the three lower doses (See Figure 3 ). Figure 3: Bone mineral density – AP Lumbar spine Least squares means of percentage change from baseline All randomized patients with at least one post-baseline assessment available with last post-baseline observation carried forward Analysis of percent change from baseline in femoral neck BMD, a secondary efficacy outcome variable, showed qualitatively similar results; all doses of Vivelle were significantly superior to placebo (p<0.05) at 24 months. The highest Vivelle dose was superior to placebo at all time points. A mixture of significant and non-significant results were obtained for the lower dose groups at earlier time points. The highest Vivelle dose was superior to the three lower doses, and there were no significant differences among the three lower doses at this skeletal site (see Figure 4 ). Figure 4: Bone mineral density - Femoral neck Least squares means of percentage change from baseline All randomized patients with at least one post-baseline assessment available with last post-baseline observation carried forward figure3 figure4 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 cause. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms. WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow- up of 7.1 years are presented in Table 3 . Table 3: Relative and Absolute Risk Seen in the Estrogen Alone Substudy of WHI a 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, PE, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. Event Relative Risk CE vs. Placebo (95% nCI b ) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-Years CHD events c Non-fatal MI c CHD death c 0.95 (0.78–1.16) 0.91 (0.73–1.14) 1.01 (0.71–1.43) 54 40 16 57 43 16 All Strokes c Ischemic stroke c 1.33 (1.15–1.68) 1.55 (1.19–2.01) 45 38 33 25 Deep vein thrombosis c,d 1.47 (1.06–2.06) 23 15 Pulmonary embolism c 1.37 (0.90–2.07) 14 10 Invasive breast cancer c 0.80 (0.62–1.04) 28 34 Colorectal cancer e 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 other causes e,f 1.08 (0.88–1.32) 53 50 Overall mortality c,d 1.04 (0.88–1.22) 79 75 Global Index g 1.02 (0.92–1.13) 206 201 For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. 9 The absolute excess risk of events included in the “global index” was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared to placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years. Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant differences in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined. 10 Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [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, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 4 . These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 4: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years a,b 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. Event Relative Risk CE/MPA vs. Placebo (95% nCI c ) CE/MPA (n = 8,506) Placebo (n = 8,102) Absolute Risk per 10,000 Women-Years CHD events Non-fatal MI CHD death 1.23 (0.99–1.53) 1.28 (1.00–1.63) 1.10 (0.70–1.75) 41 31 8 34 25 8 All strokes Ischemic stroke 1.31 (1.03–1.68) 1.44 (1.09–1.90) 33 26 25 18 Deep vein thrombosis d 1.95 (1.43–2.67) 26 13 Pulmonary embolism 2.13 (1.45–3.11) 18 8 Invasive breast cancer e 1.24 (1.01–1.54) 41 33 Colorectal cancer 0.61 (0.42–0.87) 10 16 Endometrial cancer d 0.81 (0.48–1.36) 6 7 Cervical cancer d 1.44 (0.47–4.42) 2 1 Hip fracture 0.67 (0.47–0.96) 11 16 Vertebral fractures d 0.65 (0.46–0.92) 11 17 Lower arm/wrist fractures d 0.71 (0.59–0.85) 44 62 Total fractures 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 Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified for 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 (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.5 )] . The WHIMS estrogen plus progestin ancillary study enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21- 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.5 )] . When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 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 There have not been sufficient numbers of geriatric women involved in clinical studies utilizing ESTRADIOL TRANSDERMAL SYSTEM to determine whether those over 65 years of age differ from younger subjects in their response to 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 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 ( 14.3 )] .

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 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 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 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 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 There have not been sufficient numbers of geriatric women involved in clinical studies utilizing ESTRADIOL TRANSDERMAL SYSTEM to determine whether those over 65 years of age differ from younger subjects in their response to 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 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 ( 14.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ESTRADIOL TRANSDERMAL SYSTEM, 0.025 mg per day - each 1.65 cm 2 system contains 0.41 mg of estradiol USP for nominal* delivery of 0.025 mg of estradiol per day. Patient Calendar Pack of 8 Systems…………………………………..NDC 68968-3425-8 ESTRADIOL TRANSDERMAL SYSTEM, 0.0375 mg per day - each 2.48 cm 2 system contains 0.62 mg of estradiol USP for nominal* delivery of 0.0375 mg of estradiol per day. Patient Calendar Pack of 8 Systems…………………………………..NDC 68968-3437-8 ESTRADIOL TRANSDERMAL SYSTEM, 0.05 mg per day - each 3.3 cm 2 system contains 0.83 mg of estradiol USP for nominal* delivery of 0.05 mg of estradiol per day. Patient Calendar Pack of 8 Systems………………………………….NDC 68968-3450-8 ESTRADIOL TRANSDERMAL SYSTEM, 0.075 mg per day - each 4.95 cm 2 system contains 1.24 mg of estradiol USP for nominal* delivery of 0.075 mg of estradiol per day. Patient Calendar Pack of 8 Systems………………………………….NDC 68968-3475-8 ESTRADIOL TRANSDERMAL SYSTEM, 0.1 mg per day - each 6.6 cm 2 system contains 1.65 mg of estradiol USP for nominal* delivery of 0.1 mg of estradiol per day. Patient Calendar Pack of 8 Systems………………………………….NDC 68968-3410-8 *See Description 16.2 Storage and Handling Store at room temperature 68°F to 77°F (20°C to 25°C); excursions permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature] Do not store unpouched. Apply immediately upon removal from the protective pouch. Used transdermal systems still contain active hormone. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet.

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER, AND PROBABLE DEMENTIA Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions ( 5.2 )] . Cardiovascular Disorders and Probable Dementia The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo [see Warnings and Precautions ( 5.1 ), and Clinical Studies ( 14.3 )] . The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or 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 route 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 or 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, BREAST CANCER, and PROBABLE DEMENTIA 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 DVT, pulmonary embolism (PE), stroke, and myocardial infarction (MI) ( 5.1 ) The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer ( 5.2 ) The WHIMS estrogen plus progestin ancillary study of WHI reported an increased risk of 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 )