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

Treatment of Hypoestrogenism due to Hypogonadism, Castration or Primary Ovarian Failure ( 1.3 ) Prevention of Postmenopausal Osteoporosis ( 1.4 ) Limitations of Use When prescribing solely for the prevention of postmenopausal osteoporosis, first consider the use of non-estrogen medications.

Consider estrogen therapy only for women at significant risk of osteoporosis.

1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause 1.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Limitation of Use When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, first consider the use of topical vaginal products.

1.3 Treatment of Hypoestrogenism due to Hypogonadism, Castration, or Primary Ovarian Failure 1.4 Prevention of Postmenopausal Osteoporosis Limitation of Use When prescribing solely for the prevention of postmenopausal osteoporosis, first consider the use of non-estrogen medications.

Consider estrogen therapy only for women at significant risk of osteoporosis.

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 Estradiol Transdermal System are breast pain, upper respiratory tract infections, headaches, abdominal pain, pain, and edema.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc.

at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect pooled data from 5 clinical trials of Estradiol Transdermal System.

A total of 614 women were exposed to 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 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 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 Estradiol Transdermal System a) Adverse reactions occurring at rate of ≥5 percent in Estradiol Transdermal System trials of clinical efficacy versus placebo and versus active comparator; and trial of Estradiol Transdermal System versus placebo for the prevention of osteoporosis b) Adverse reactions occurring at rate of ≥5 percent in Estradiol Transdermal System trials of clinical efficacy versus placebo and versus active comparator c) Adverse reactions occurring in placebo group in Estradiol Transdermal System trial of clinical efficacy versus placebo Estradiol Transdermal System Body System Adverse Reactions 0.025 mg/day a (N=219) 0.05 mg/day b (N=201) 0.1 mg/day b (N=194) Placebo c (N=72) Body as a Whole 21% 39% 37% 29% Headache 5% 18% 13% 10% Pain 1% 8% 11% 7% Back Pain 4% 8% 9% 6% Edema 0.5% 13% 10% 6% Digestive System 9% 21% 29% 18% Abdominal Pain 0% 11% 16% 8% Nausea 1% 5% 6% 3% Flatulence 1% 3% 7% 1% Musculoskeletal System 7% 9% 11% 4% Arthralgia 1% 5% 5% 3% Nervous System 13% 10% 11% 1% Depression 1% 5% 8% 0% Urogenital System 12% 18% 41% 11% Breast Pain 5% 8% 29% 4% Leukorrhea 1% 6% 7% 1% Respiratory System 15% 26% 29% 14% URTI 6% 17% 17% 8% Pharyngitis 0.5% 3% 7% 3% Sinusitis 4% 4% 5% 3% Rhinitis 2% 4% 6% 1% Skin and Appendages 19% 12% 12% 15% Pruritus 0.5% 6% 3% 6% 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of 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