Estradiol

Approved 24 Aug 2023TransdermalGel

The FDA lists this product in 60 strengths and forms.

Indications

1.1Treatment of Moderate to Severe Vasomotor

Symptoms due to Menopause Estradiol gel is an estrogen indicated for the treatment of moderate to severe vasomotor symptoms due to menopause (1.1).

Contraindications

Estradiol gel 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 gel 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 gel (4) Hepatic impairment or disease (4, 5.10) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders (4)

Warnings and precautions

WARNINGS AND PRECAUTIONS

5.1Cardiovascular Disorders

Increased risks 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 progestogen therapy if any of these occur or are suspected. Manage appropriately any risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus).

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5.2Malignant Neoplasms Endometrial Cancer

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2-to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risk of 15-to 24-fold for 5 to 10 years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women using estrogen-alone or estrogen plus progestogen therapy is important. 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 with unknown etiology. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose.

Adding a progestogen to postmenopausal estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Breast Cancer The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] compared to placebo 5 [see Clinical Studies (14.2)] .

After a mean follow-up of 5.6 years, the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg) reported an increased risk of invasive breast cancer in women who took daily CE plus MPA compared to placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo.

Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo.

In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare, with no

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 gel treatment group are metrorrhagia, breast tenderness, vaginal mycosis, nasopharyngitis, and upper respiratory tract infection (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Northstar RxLLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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 gel 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 Gel Estradiol Gel 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 gel, application site reactions were seen in <1 percent of participating women.

6.2Postmarketing Experience

The following adverse reactions have been identified during post-approval use of estradiol gel. 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.

Estradiol

Indications

1.1Treatment of Moderate to Severe Vasomotor

Contraindications

Warnings and precautions

5.1Cardiovascular Disorders

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5.2Malignant Neoplasms Endometrial Cancer

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

Composition

Strengths and forms

Official product information

At a glance

Guidelines