1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause

2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause

ELESTRIN is applied once daily to the upper arm for the treatment of moderate to severe vasomotor symptoms due to menopause using a metered-dose pump which delivers 0.87 grams of estradiol gel (0.52 mg estradiol) per actuation (1 pump).

Start therapy with one pump per day (0.87 grams per day, which contains 0.52 mg of estradiol).

Make dosage adjustments based on clinical response.

5.1 Cardiovascular Disorders

Increased risk of stroke and DVT are reported with estrogen-alone therapy.

Increased risk of PE, DVT, stroke and MI are reported with estrogen plus progestin therapy. Immediately discontinue estrogen with or without progestin therapy if any of these occur or is suspected.

Manage appropriately any risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus).

5.2 Malignant Neoplasms

5.3 Probable Dementia

In the WHI Memory Study (WHIMS) estrogen-alone ancillary study, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.

After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. 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-years8 [see Use in Specific Populations (8.5), and Clinical Studies (14.3)].

In the WHIMS estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.

After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95% CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8 [see Use in Specific Populations (8.5), and Clinical Studies (14.3)].

When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI, 1.19-2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see Use in Specific Populations (8.5), and Clinical Studies (14.3)].

5.4 Gallbladder Disease

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

5.5 Hypercalcemia

Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including ELESTRIN if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level.

5.6 Visual Abnormalities

Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue ELESTRIN pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Discontinue estrogens, including ELESTRIN, if examination reveals papilledema or retinal vascular lesions.

5.7 Addition of a Progestin When a Woman Has Not Had a Hysterectomy

Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.

5.8 Elevated Blood Pressure

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen.

5.9 Exacerbation of Hypertriglyceridemia

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of ELESTRIN if pancreatitis occurs.

5.10 Hepatic Impairment and/or Past History of Cholestatic Jaundice

Estrogens may be poorly metabolized in women with hepatic impairment. Exercise caution in any woman with a history of cholestatic jaundice associated with past estrogen use or with pregnancy. In the case of recurrence of cholestatic jaundice, discontinued ELESTRIN.

5.11 Exacerbation of Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. Monitor thyroid function in these women during treatment with ELESTRIN to maintain their free thyroid hormone levels in an acceptable range.

5.12 Fluid Retention

Estrogens may cause some degree of fluid retention. Monitor any woman with a condition(s) that might predispose her to fluid retention, such as cardiac or renal impairment. Discontinue estrogen-alone therapy, including ELESTRIN, with evidence of medically concerning fluid retention.

5.13 Hypocalcemia

Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy, including ELESTRIN, outweigh the risks in such women.

5.14 Exacerbation of Endometriosis

A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. Consider the addition of a progestin for women known to have residual endometriosis post-hysterectomy.

5.15 Hereditary Angioedema

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy outweigh the risks in such women.

5.16 Exacerbation of Other Conditions

Estrogen therapy, including ELESTRIN, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas. Consider whether the benefits of estrogen therapy outweigh the risks in such women.

5.17 Photosensitivity or Photoallergy

Increased sensitivity to direct exposure to the sun on areas of ELESTRIN application has not been evaluated.

5.18 Sunscreen Application

Estradiol absorption was increased when sunscreen was applied 10 minutes before ELESTRIN application. Do not apply sunscreen to the application site of ELESTRIN until at least 25 minutes after the application of ELESTRIN.

Concomitant application of sunscreen and ELESTRIN to the same application site for 7 or more days may increase estradiol absorption. Avoid applying sunscreen to the area of ELESTRIN application for an extended period of 7 or more days [see Clinical Pharmacology, Pharmacokinetics (12.3)].

5.19 Miscellaneous

Alcohol based gels, including ELESTRIN, are potentially flammable. Avoid fire, flame, or smoking until ELESTRIN has dried.

5.20 Laboratory Tests

Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms.

5.21 Drug-Laboratory Test Interactions

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Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

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Increased thyroid binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.

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Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

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Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, and increased triglycerides levels.

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Impaired glucose tolerance.

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.

ELESTRIN was studied in a placebo-controlled trial that included a total of 484 postmenopausal women. The adverse reactions that occurred at a rate greater than 5 percent in any of the treatment groups are summarized in Table 1.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ELESTRIN. 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 vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea; increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer.

Breasts

Tenderness; enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.

Cardiovascular

Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure.

Gastrointestinal

Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas.

Skin

Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash.

Eyes

Retinal vascular thrombosis, intolerance to contact lenses.

Central Nervous System

Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia.

Miscellaneous

Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgias; leg cramps; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides.

8.1 Pregnancy

Risk Summary

ELESTRIN is not indicated for use in pregnancy. There are no data with the use of ELESTRIN in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies or limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy. Animal studies to evaluate embryo/fetal toxicity were not conducted with ELESTRIN.

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 breast-feeding should be considered along with the mother’s clinical need for ELESTRIN and any potential adverse effects on the breast-fed child from ELESTRIN or from the underlying maternal condition.

8.4 Pediatric Use

ELESTRIN is not indicated 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 ELESTRIN to determine whether those over 65 years of age differ from younger subjects in their response to ELESTRIN.

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 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 ELESTRIN 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

Steady-state serum concentrations of estradiol are achieved in approximately 3 days following daily application of ELESTRIN to the upper arm.

Pharmacokinetic parameters for estradiol on Day 14 following daily application of 0.87 g or 1.7 g of ELESTRIN are summarized in Table 2. Dose dependent PK parameters for ELESTRIN 0.87 g and 1.7 g indicated the dose and serum estradiol (E2) concentrations to be linearly related but not dose-proportional (i.e., doubling in dose led to a 2.5- to 3.0-fold increase in PK parameters). The nominal mean delivery rates of estradiol using the baseline-adjusted average serum concentrations from pharmacokinetic studies using 0.87 g per day and 1.7 g per day are 0.0125 mg per day and 0.0375 mg per day, respectively.

TABLE 2 - Summary of Unadjusted PK Parameters for Estradiol after 14 Days of Dosing

* Tmax shown as median (range) † E2:E1 (estradiol:estrone) ratio
Pharmacokinetic Parameter	0.87 g ELESTRIN (0.52 mg/d Estradiol) Mean	1.7 g ELESTRIN (1.04 mg/d Estradiol) Mean
AUC0-24 (pg’hr/mL)	335.2	940.2
Cmax (pg/mL)	21.6	66.7
Cave (pg/mL)	15.4	39.2
Cmin (pg/mL)	9.4	21.1
Tmax (h)*	18 (1 - 20)	4 (1 - 20)
Fluctuation Index	0.80	1.16
E2:E1† ratio	0.53	0.98

Mean concentrations of estradiol over a 24-hour period on Day 14 are shown in Figure 1.

Based on the Cave values at steady state, the E2:E1 ratio was 0.53 for the 0.87 g and 0.98 for the 1.7 g doses. The significance of this finding is that the 1.7 g dose produced an E2:E1 ratio of a premenopausal woman. The 1.7 g dose of ELESTRIN reached the goal of restoring the E2:E1 ratio (~1.0) to that observed in premenopausal women in the early follicular phase of the menstrual cycle.

Application of sunscreen 10 minutes before application of ELESTRIN increased the exposure to estradiol by approximately 55 percent. No significant change in estradiol exposure was observed when sunscreen was applied 25 minutes after application of ELESTRIN. In the same study, prolonged (7 days) concomitant application of sunscreen to the site of ELESTRIN application increased exposure to estradiol by about 2-fold, regardless of whether it was applied before or after application of ELESTRIN.

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.

14.1 Effects on Vasomotor Symptoms in Postmenopausal Women

A randomized, double-blind, placebo-controlled clinical trial evaluated the efficacy of 12-week treatment with three different daily doses of ELESTRIN for the treatment of vasomotor symptoms in 484 postmenopausal women between 28 and 74 years of age (mean 54 years; 83-88 percent Caucasian per group) who had at least 60 moderate-to-severe hot flushes per week at baseline. At baseline, mean hot flushes is 13 per day, mean serum estradiol is 11.2-13.2 pg/mL, and prior hormone/estrogen therapy is 75.7-84.5 percent. Participants applied placebo, 1.7 g (1.04 mg estradiol), or 2.6 g (1.56 mg estradiol) once daily to the upper arm. The study was amended to identify the lowest effective dose of ELESTRIN and limit the number of women exposed to the 2.6 g dose. After the study amendment, ELESTRIN 0.87 g (0.52 mg estradiol) was added and the 2.6 g was discontinued from further enrollment. Reduction in both the frequency and severity of moderate to severe hot flushes was statistically significant for the ELESTRIN 1.7 g per day dose compared to placebo at week 4. Statistically significant reductions in both the frequency and severity of moderate to severe hot flushes when compared to placebo were delayed for the ELESTRIN 0.87 g per day dose to week 5. Both the 0.87 g per day and 1.7 g per day doses were statistically significant compared to placebo at week 12. Statistically significant reductions in the frequency and severity of daily moderate-to-severe hot flush rate compared to placebo were noted beginning at week 3 for the 1.7 g per day ELESTRIN treatment (data on file). The reductions in frequency and severity are shown in Table 3.

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.

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 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 the 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 cases per 10,000 women-years. Probable dementia as defined in the study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5)].

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3), and Use in Specific Populations (8.5)].

16.1 How Supplied

Elestrin (estradiol gel) 0.06% in a colorless, non-staining hydroalcoholic gel supplied in a non-aerosol, metered-dose pump container constructed of polypropylene. The drug product is contained within a collapsible inner liner/bag consisting of an inner and outer layer of low density polyethylene with a resealable polypropylene cap. Each pump container holds 35 g of gel and is capable of delivering 26 g of gel as 30 metered doses. Each metered dose delivers 0.87 g of gel which contains 0.52 mg of estradiol.

NDC 0037-4801-70.....Carton containing two ELESTRIN 35 g pump containers.

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].