Estradiol

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)] . Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)] . The most common adverse reactions (incidence >5 percent and greater than placebo) in any estradiol treatment group are metrorrhagia, breast tenderness, vaginal mycosis, nasopharyngitis, and upper respiratory tract infection (6.1). To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Estradiol was studied at doses of 0.25, 0.5 and 1.0 gram per day in a 12-week, double-blind, placebo-controlled study that included a total of 495 postmenopausal women (86.5 percent Caucasian). The adverse reactions that occurred at a rate greater than 5 percent and greater than placebo in any of the treatment groups are summarized in Table 1. Table 1: Number (%) of Subjects with Common Adverse Reactions* in a 12-Week Placebo-Controlled Study of estradiol Estradiol Placebo SYSTEM ORGAN CLASS Preferred Term 0.25 grams/day N=122 n (%) 0.5 grams/ day N=123 n (%) 1.0 gram/day N=125 n (%) N=125 n (%) INFECTIONS & INFESTATIONS Nasopharyngitis 7(5.7) 5(4.1) 6(4.8) 5(4.0) Upper Respiratory Tract Infection 7(5.7) 3(2.4) 2(1.6) 2(1.6) Vaginal mycosis 1(0.8) 3(2.4) 8(6.4) 4(3.2) REPRODUCTIVE SYSTEM & BREAST DISORDERS Breast Tenderness 3(2.5) 7(5.7) 11(8.8) 2(1.6) Metrorrhagia 5(4.1) 7(5.7) 12(9.6) 2(1.6) *Adverse reactions reported by >5 percent of patients in any treatment group. In a 12-week placebo-controlled study of estradiol, application site reactions were seen in <1 percent of participating women. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of estradiol. 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 Amenorrhea, dysmenorrhea, ovarian cyst, vaginal discharge Breasts Gynecomastia Cardiovascular Palpitations, ventricular extrasystoles Gastrointestinal Flatulence Skin Rash pruritic, urticaria Eyes Retinal vein occlusion Central Nervous System Tremor Miscellaneous Arthralgia, application site rash, asthenia, chest discomfort, fatigue, feeling abnormal, heart rate increased, insomnia, malaise, muscle spasms, pain in extremity, weight increased.

4 CONTRAINDICATIONS Estradiol is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding [see Warning and Precautions (5.2)] Breast cancer or history of breast cancer [see Warning and Precautions (5.2)] Estrogen-dependent neoplasia [see Warning and Precautions (5.2)] Active DVT, PE, or history of these conditions [see Warning and Precautions (5.1)] Active arterial thromboembolic disease (e.g. stroke and MI), or a history of these conditions [see Warning and Precautions (5.1)] Known anaphylactic reaction, angioedema, or hypersensitivity to estradiol Hepatic impairment or disease Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Undiagnosed abnormal genital bleeding (4) Breast cancer or a history of breast cancer (4, 5.2) Estrogen-dependent neoplasia (4, 5.2) Active DVT, PE, or history of these conditions (4, 5.1) Active arterial thromboembolic disease (e.g., stroke and MI), or history of these conditions (4, 5.1) Known anaphylactic reaction, angioedema, or hypersensitivity to estradiol (4) Hepatic impairment or disease (4, 5.10) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders (4)

11 DESCRIPTION Estradiol Gel, 0.1% is a clear, colorless smooth gel, free from visible particulate matter. It is designed to deliver sustained circulating concentrations of estradiol when applied once daily to the skin. The gel is applied to a small area (200 cm 2 ) of the thigh in a thin layer. Estradiol gel is available in five doses of 0.25, 0.5, 0.75, 1.0, and 1.25 grams for topical application (corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively). The active component of the topical gel is estradiol. Estradiol is a white crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17ß-diol. It has an empirical formula of C 18 H 24 O 2 and molecular weight of 272.39. The structural formula is: The remaining components of the gel (carbomer, alcohol [62%], propylene glycol, purified water, and trolamine) are pharmacologically inactive. estradiol-structure

2 DOSAGE & 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 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 whether treatment is still necessary. Daily administration of 0.25 to 1.25 grams of estradiol to the right or left upper thigh on alternating days. Women should be started with the lowest effective dose and the dose should be evaluated periodically (2). 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Start therapy with the 0.25 grams applied once daily on the skin of either the right or left upper thigh. Adjust the dose up to a maximum of 1.25 grams, as needed. The application surface area should be about 5 by 7 inches (approximately the size of two palm prints). The entire contents of a unit dose packet should be applied each day. To avoid potential skin irritation, apply estradiol to the right or left upper thigh on alternating days. Do not apply estradiol on the face, breasts, or irritated skin or in or around the vagina. Allow gel to dry after application before dressing. Do not wash the application site within 1 hour after applying estradiol. Avoid contact of the gel with eyes. Wash hands after application.

1 INDICATIONS & USAGE 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Estradiol is an estrogen indicated for the treatment of moderate to severe vasomotor symptoms due to menopause (1.1).

10 OVERDOSAGE Overdosage of estrogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding in women. Treatment of overdose consists of discontinuation of estradiol 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 result in adverse reactions. Inducers and 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 estradiol 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 Estradiol diffuses across intact skin and into the systemic circulation by a passive absorption process, with diffusion across the stratum corneum being the rate-limiting factor. In a 14-day, Phase 1, multiple-dose study, estradiol demonstrated linear and approximately dose-proportional estradiol pharmacokinetics at steady state for both AUC0-24 and C max following once daily dosing to the skin of either the right or left upper thigh (Table 2). Table 2: Mean (%CV) Pharmacokinetic Parameters for Estradiol (uncorrected for baseline) on Day 14 Following Multiple Daily Doses of Estradiol 0.1% Parameter (units) Estradiol 0.25 grams Estradiol 0.5 grams Estradiol 1.0 gram AUC 0-24 (pg•h/mL) 236 (94) 504 (149) 732 (81) C max (pg/mL) 14.7 (84) 28.4 (139) 51.5 (86) C avg (pg/mL) 9.8 (92) 21 (148) 30.5 (81) t max * (h) 16 (0, 72) 10 (0, 72) 8 (0, 48) E2:E1 ratio 0.42 0.65 0.65 *Median (Min, Max). Steady-state serum concentration of estradiol are achieved by day 12 following daily application of estradiol to the skin of the upper thigh. The mean (SD) serum estradiol levels following once daily dosing at day 14 are shown in Figure 1. Figure 1: Mean (SD) Serum Estradiol Concentrations (Values Uncorrected for Baseline) on Day 14 Following Multiple Daily Doses of estradiol 0.1% The effect of sunscreens and other topical lotions on the systemic exposure of estradiol has not been evaluated. Studies conducted using topical estrogen gel approved products have shown that sunscreens have the potential for changing the systemic exposure of topically applied estrogen gels. 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. Although the clinical significance has not been determined , estradiol from estradiol does not undergo first pass metabolism and provides estradiol to estrone ratios at steady state in the range of 0.42 to 0.65. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The apparent terminal half-life for estradiol was about 10 hours following administration of estradiol. Potential for Estradiol Transfer The effect of estradiol transfer was evaluated in healthy postmenopausal women who topically applied 1.0 gram of estradiol (single dose) on one thigh. One and 8 hours after gel application, they engaged in direct thigh-to-arm contact with a partner for 15 minutes. While some elevation of estradiol levels over baseline was seen in the male subjects, the degree of transferability in this study was inconclusive. Effects of Washing The effect of application site washing on skin surface levels and serum concentrations of estradiol was determined in 16 healthy postmenopausal women after application of 1.0 gram of estradiol to a 200 cm 2 area on the thigh. Washing the application site with soap and water 1 hour after application removed all detectable amounts of estradiol from the surface of the skin, and resulted in a 30 to 38 percent decrease in the mean total 24-hour exposure to estradiol. figure-one

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 estradiol 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 Estradiol diffuses across intact skin and into the systemic circulation by a passive absorption process, with diffusion across the stratum corneum being the rate-limiting factor. In a 14-day, Phase 1, multiple-dose study, estradiol demonstrated linear and approximately dose-proportional estradiol pharmacokinetics at steady state for both AUC0-24 and C max following once daily dosing to the skin of either the right or left upper thigh (Table 2). Table 2: Mean (%CV) Pharmacokinetic Parameters for Estradiol (uncorrected for baseline) on Day 14 Following Multiple Daily Doses of Estradiol 0.1% Parameter (units) Estradiol 0.25 grams Estradiol 0.5 grams Estradiol 1.0 gram AUC 0-24 (pg•h/mL) 236 (94) 504 (149) 732 (81) C max (pg/mL) 14.7 (84) 28.4 (139) 51.5 (86) C avg (pg/mL) 9.8 (92) 21 (148) 30.5 (81) t max * (h) 16 (0, 72) 10 (0, 72) 8 (0, 48) E2:E1 ratio 0.42 0.65 0.65 *Median (Min, Max). Steady-state serum concentration of estradiol are achieved by day 12 following daily application of estradiol to the skin of the upper thigh. The mean (SD) serum estradiol levels following once daily dosing at day 14 are shown in Figure 1. Figure 1: Mean (SD) Serum Estradiol Concentrations (Values Uncorrected for Baseline) on Day 14 Following Multiple Daily Doses of estradiol 0.1% The effect of sunscreens and other topical lotions on the systemic exposure of estradiol has not been evaluated. Studies conducted using topical estrogen gel approved products have shown that sunscreens have the potential for changing the systemic exposure of topically applied estrogen gels. 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. Although the clinical significance has not been determined , estradiol from estradiol does not undergo first pass metabolism and provides estradiol to estrone ratios at steady state in the range of 0.42 to 0.65. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The apparent terminal half-life for estradiol was about 10 hours following administration of estradiol. Potential for Estradiol Transfer The effect of estradiol transfer was evaluated in healthy postmenopausal women who topically applied 1.0 gram of estradiol (single dose) on one thigh. One and 8 hours after gel application, they engaged in direct thigh-to-arm contact with a partner for 15 minutes. While some elevation of estradiol levels over baseline was seen in the male subjects, the degree of transferability in this study was inconclusive. Effects of Washing The effect of application site washing on skin surface levels and serum concentrations of estradiol was determined in 16 healthy postmenopausal women after application of 1.0 gram of estradiol to a 200 cm 2 area on the thigh. Washing the application site with soap and water 1 hour after application removed all detectable amounts of estradiol from the surface of the skin, and resulted in a 30 to 38 percent decrease in the mean total 24-hour exposure to estradiol. figure-one

20230830

1

3 DOSAGE FORMS & STRENGTHS Estradiol Gel, 0.1% is available in five doses of 0.25, 0.5, 0.75, 1.0, and 1.25 grams for transdermal application (corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively). Estradiol is a clear, colorless smooth gel, free from visible particulate matter. Gel: 0.25, 0.5, 0.75, 1.0, and 1.25 gram-filled single-dose foil packets containing 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively (3)

Estradiol Estradiol ESTRADIOL ESTRADIOL CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) ALCOHOL PROPYLENE GLYCOL WATER TROLAMINE Estradiol Estradiol ESTRADIOL ESTRADIOL CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) ALCOHOL PROPYLENE GLYCOL WATER TROLAMINE Estradiol Estradiol ESTRADIOL ESTRADIOL CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) ALCOHOL PROPYLENE GLYCOL WATER TROLAMINE Estradiol Estradiol ESTRADIOL ESTRADIOL CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) ALCOHOL PROPYLENE GLYCOL WATER TROLAMINE Estradiol Estradiol ESTRADIOL ESTRADIOL CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) ALCOHOL PROPYLENE GLYCOL WATER TROLAMINE

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.

ANDA217610

Estradiol

Estradiol

70954-532

HUMAN PRESCRIPTION DRUG

TOPICAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Estradiol Gel, 0.1% - 0.25 mg/packet - Carton - NDC 70954-531-20 Estradiol Gel, 0.1% - 0.5 mg/packet - Carton - NDC 70954-530-20 Estradiol Gel, 0.1% - 0.75 mg/packet - Carton - NDC 70954-532-20 Estradiol Gel, 0.1% - 1 .0 mg/packet - Carton - NDC 70954-533-20 Estradiol Gel, 0.1% - 1 .25 mg/packet - Carton - NDC 70954-534-20 Estradiol Gel, 0.1% - 0.25 mg/packet - Pouch- NDC 70954-531-10 Estradiol Gel, 0.1% - 0.5 mg/packet - Pouch- NDC 70954-530-10 Estradiol Gel, 0.1% - 0.75 mg/packet - Pouch- NDC 70954-532-10 Estradiol Gel, 0.1% - 1.0 mg/packet - Pouch- NDC 70954-533-10 Estradiol Gel, 0.1% - 1.25 mg/packet - Pouch- NDC 70954-534-10 carton-1 carton-2 carton-3 carton-4 carton-5 pouch-1 pouch-2 pouch-3 pouch-4 pouch-5

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 Warnings and Precautions (5.2)] . Unintentional Secondary Exposure to Estradiol gel Inform women about the possibility of secondary exposure to estradiol gel Apply estradiol gel as directed and keep children from contacting exposed application site(s). If direct contact with the application site occurs, wash the contact area thoroughly with soap and water. Look for signs of unexpected sexual development, such as breast mass or increased breast size in prepubertal children. If signs of unintentional secondary exposure are noticed: Have the child(ren) evaluated by a healthcare provider. Have women contact their healthcare provider to discuss the appropriate use and handling of estradiol gel when around children. Pets may also be unintentionally exposed to estradiol gel if above precautions are not followed. 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 Less Serious but Common Adverse Reactions with Estrogen-Alone Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headaches, breast pain and tenderness, nausea and vomiting. Trademarks are the property of their respective owners. Distributed by: ANI Pharmaceuticals, Inc. Baudette, MN 56623 Issued: 05/2023 LB4497-01

14 CLINICAL STUDIES 14.1 Effects on Vasomotor Symptoms in Postmenopausal Women A randomized, double-blind, placebo-controlled trial evaluated the efficacy of 12-week treatment with three different daily doses of estradiol for vasomotor symptoms in 495 postmenopausal women (86.5 percent White; 10.1 percent Black) between 34 and 89 years of age (mean age 54.6) who had at least 50 moderate to severe hot flushes per week at baseline (2 week period prior to treatment). Women applied placebo, estradiol 0.25 grams (0.25 mg estradiol), estradiol 0.5 grams (0.5 mg estradiol) or estradiol 1.0 gram (1.0 mg estradiol) once daily to the thigh. Reductions in both the median daily frequency and the median daily severity of moderate to severe hot flushes were statistically significant for the 0.5 grams per day and the 1.0 gram per day estradiol doses when compared to placebo at week 4. Statistically significant reductions in both the median daily frequency and the median daily severity of moderate to severe hot flushes for the estradiol 0.25 grams per day dose when compared to placebo were delayed to week 7. There were statistically significant reductions in median daily frequency and severity of hot flushes for all three estradiol doses (0.25 grams per day, 0.5 grams per day and 1.0 gram per day) compared to placebo at week 12. See Table 3 for results. Table 3: Summary of Change From Baseline in the Median Daily Frequency and Severity of Hot Flushes during Estradiol Treatment (ITT Population) Estradiol Placebo Evaluation 0.25 grams/day N=121 0.5 grams/day N=119 1.0 gram/day N=124 N=124 Frequency of Daily Hot Flushes Baseline Median 9.72 9.24 9.64 9.32 Median Change: Week 4 p-value† -5.00 0.132 -5.73 0.011 -7.20 <0.001 -3.63 Median Change: Week 7 p-value† -6.62 <0.001 -7.14 <0.001 -7.71 <0.001 -4.37 Median Change: Week 12 p-value† -6.88 <0.001 -7.29 <0.001 -8.35 <0.001 -4.48 Severity of Daily Hot Flushes Baseline Median 2.52 2.51 2.52 2.54 Median Change: Week 4 p-value† -0.07 0.283 -0.18 <0.001 -0.47 <0.001 -0.04 Median Change: Week 7 p-value† -0.24 <0.001 -0.46 <0.001 -1.06 <0.001 -0.06 Median Change: Week 12 p-value† -0.33 0.021 -0.56 0.002 -1.69 <0.001 -0.13 †p-values from the van Elteren’s test stratified by pooled center, comparison in median change was significant if p<0.05. 14.2 Women’s Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other 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 4. 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 nonsignificant 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 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 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 reductions 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 5. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. 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)] . table-4 table-5 14.3 Women's Health Initiative Memory Study The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 year 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 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. 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 studies utilizing estradiol to determine whether those over 65 years of age differ from younger subjects in their response to estradiol. 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 Warnings and Precautions (5.1) and Clinical Studies (14.2)] . In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Warnings and Precautions (5.1, 5.2), and Clinical Studies (14.2)] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.3), and Clinical Studies (14.3)] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions (5.3), and Clinical Studies (14.3)].

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

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

8.1 Pregnancy Risk Summary Estradiol is not indicated for use in pregnant women. There are no data with the use of estradiol 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 (estrogen 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 is not indicated for use in pregnant women. There are no data with the use of estradiol 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 (estrogen 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 and any potential adverse effects on the breastfed child from estradiol or from the underlying maternal condition. 8.4 Pediatric Use Estradiol 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 studies utilizing estradiol to determine whether those over 65 years of age differ from younger subjects in their response to estradiol. 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 Warnings and Precautions (5.1) and Clinical Studies (14.2)] . In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Warnings and Precautions (5.1, 5.2), and Clinical Studies (14.2)] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.3), and Clinical Studies (14.3)] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions (5.3), and Clinical Studies (14.3)].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Estradiol Gel, 0.1% is a clear, colorless smooth gel, free from visible particulate matter, supplied in single-dose foil packets of 0.25, 0.5, 0.75, 1.0, and 1.25 grams, corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively. NDC 70954-531-20, carton of 30 packets, 0.25 mg estradiol per single-dose foil packet NDC 70954-530-20, carton of 30 packets, 0.5 mg estradiol per single-dose foil packet NDC 70954-532-20, carton of 30 packets, 0.75 mg estradiol per single-dose foil packet NDC 70954-533-20, carton of 30 packets, 1.0 mg estradiol per single-dose foil packet NDC 70954-534-20, carton of 30 packets, 1.25 mg estradiol per single-dose foil packet Keep out of the reach of children. 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F). Excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature].

BOXED WARNING WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA and BREAST CANCER Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2)]. Cardiovascular Disorders and Probable Dementia The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.2)]. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.3)]. Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.2, 14.3)]. Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia The WHI estrogen plus progestin substudy reported increased risks of pulmonary embolism (PE), DVT, stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.2)] . The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.3)]. Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.2, 14.3)]. Breast Cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.2)] . Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA and BREAST CANCER See full prescribing information for complete boxed warning. Estrogen-Alone Therapy There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens (5.2) The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) (5.1) The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3) Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia (5.1, 5.3) Estrogen Plus Progestin Therapy The WHI estrogen plus progestin substudy reported increased risks of pulmonary embolism (PE), DVT, stroke, and myocardial infarction (MI) (5.1) The WHI estrogen plus progestin study 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)