Estradiol Transdermal
FDA Drug Information • Also known as: Estradiol
- Brand Names
- Estradiol
- Drug Class
- Estrogen [EPC]
- Route
- TOPICAL
- Dosage Form
- GEL
- Product Type
- HUMAN PRESCRIPTION DRUG
⚠ Boxed Warning (Black Box)
WARNING: ENDOMETRIAL CANCER WITH UNOPPOSED ESTROGEN IN WOMEN WITH A UTERUS There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen-only 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 menopausal women abnormal genital bleeding of unknown etiology [see Warnings and Precautions (5.2) ] . WARNING: ENDOMETRIAL CANCER WITH UNOPPOSED ESTROGEN IN WOMEN WITH A UTERUS See full prescribing information for complete boxed warning. There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens (5.2)
Description
11 DESCRIPTION Estradiol gel 0.1%, is a clear, colorless gel, which is odorless when dry. It is designed to deliver sustained circulating concentrations of estradiol, USP 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, and 1.25 grams for topical application (corresponding to 0.25, 0.5, 0.75, 1, and 1.25 mg estradiol USP, respectively). The active component of the topical gel is estradiol USP, an estrogen. Estradiol, USP 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 272.38. The structural formula is: The remaining components of the gel (carbomer homopolymer type B, ethyl alcohol 95%, propylene glycol, purified water, and trolamine) are pharmacologically inactive. Estradiol gel, 0.1% contains 55% w/w alcohol. Structural Formula
What Is Estradiol Transdermal Used For?
1 INDICATIONS AND USAGE Estradiol gel, 0.1% is an estrogen indicated for the treatment of moderate to severe vasomotor symptoms due to menopause (1.1) . 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Daily administration of 0.25 to 1.25 grams of estradiol gel, 0.1% 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 Important Use Information The timing of estradiol gel, 0.1% initiation can affect the overall benefit-risk profile. Consider initiating estradiol gel, 0.1% in women <60 years old or <10 years since menopause onset [see Warnings and Precautions (5) , Use in Specific Populations (8.5) and Clinical Studies (14) ] . When estrogen is prescribed for a menopausal woman with a uterus, the addition of a progestogen has been shown to reduce the risk of endometrial cancer. There are possible risks associated with the use of progestogens plus estrogens that differ from those of estrogen-alone regimens. See prescribing information for progestogens indicated for the prevention of endometrial hyperplasia in non-hysterectomized menopausal women receiving estrogens [see Warnings and Precautions (5.2 , 5.3) ] . Generally, a woman without a uterus, does not need to use a progestogen with estrogen therapy. In some cases, however, hysterectomized women with a history of endometriosis may benefit from the addition of a progestogen [see Warnings and Precautions (5.13) ] . 2.2 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 gel, 0.1% to the right or left upper thigh on alternating days. Do not apply estradiol gel, 0.1% 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 gel, 0.1%. Avoid contact of the gel with eyes. Wash hands after application.
Side Effects (Adverse Reactions)
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 gel treatment group are metrorrhagia, breast tenderness, vaginal mycosis, nasopharyngitis, and upper respiratory tract infection (6.1) . To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 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 gel was studied at doses of 0.25, 0.5 and 1 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 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. 6.2 Postmarketing 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
Drug Interactions
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) .
Contraindications
4 CONTRAINDICATIONS Estradiol gel is contraindicated in women with any of the following conditions: Abnormal genital bleeding of unknown etiology [see Warning and Precautions (5.2) ] Current 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 (for example, stroke or 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 [see Warnings and Precautions (5.9) ] 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 , 5.9) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders (4)
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Estradiol gel is not indicated for use in pregnant women. There are no data with the use of estradiol gel 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.
Overdosage
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 gel therapy with institution of appropriate symptomatic care.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Estradiol gel, 0.1% is a clear, colorless, smooth, opalescent gel free from lumps and foreign matter filled in single-dose foil packets of 0.25, 0.5, 0.75, 1, and 1.25 grams, corresponding to 0.25, 0.5, 0.75, 1, and 1.25 mg estradiol USP, respectively. NDC 69238-2452-3, carton of 30 packets, 0.25 mg estradiol, USP per single-dose foil packet NDC 69238-2451-3, carton of 30 packets, 0.5 mg estradiol, USP per single-dose foil packet NDC 69238-2450-3, carton of 30 packets, 0.75 mg estradiol, USP per single-dose foil packet NDC 69238-2449-3, carton of 30 packets, 1 mg estradiol, USP per single-dose foil packet NDC 69238-2448-3, carton of 30 packets, 1.25 mg estradiol, USP 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 between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature.]
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.