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ESTRADIOL .75 mg/1.25g Gel — NDC 21922-015-40 (Billing 21922-0015-40)

by Encube Ethicals, Inc. · 1 BOTTLE, PUMP in 1 CARTON / 50 g in 1 BOTTLE, PUMP

This is a package of ESTRADIOL .75 mg/1.25g Gel from Encube Ethicals, Inc., marketed since May 2026 and currently FDA-listed. It is this product's only package size.

NDC 21922-0015-40
🏷️ FDA NDC (as labeled) 21922-015-40 billing pads the product segment with a zero
Rx only Generic On market Non-controlled ⇄ Compare with another NDC
🗂️ FDA directory synced Oct 1, 2026 · this listing last changed Jul 24, 2026 · sources: openFDA · FDA label (DailyMed) · FDA Orange & Purple Book · First Databank · CMS NADAC, ASP, Medicare & Medicaid · RxNorm
📋 All sources & update times →

This page is curated, coded, and maintained by

Compiled from public FDA, CMS, DailyMed, NADAC, and related drug data sources. Editorial policy

⚠️
Other active recalls for Estradiol (different manufacturers) — 4 · tap to view
These affect other manufacturers’ products for the same ingredient — not necessarily the exact NDC on this page.
Class II · May 12, 2026 — Defective Container; packets were found to be either empty or partially full. (ANI Pharmaceuticals, Inc.) · FDA recall D-0543-2026
Class III · May 16, 2024 — Failed Impurities/Degradation Specifications. (Zydus Pharmaceuticals (USA) Inc) · FDA recall D-0543-2024
Class III · May 16, 2024 — Failed Impurities/Degradation Specifications. (Zydus Pharmaceuticals (USA) Inc) · FDA recall D-0542-2024
Class III · Feb 21, 2023 — Failed Content Uniformity Specifications: The Spray Content Uniformity (SCU) requirement for Standard Deviation did not meet the requirement at the 18-month stability time point. (Padagis US LLC) · FDA recall D-0464-2023
Each entry is an official FDA enforcement report — look up any recall number in the FDA recall database ↗

Identity & classification

Regulatory identifiers FDA, NLM and CMS codes for this package

FDA NDC (as labeled) 21922-015-40
Product NDC 21922-015
11-digit billing NDC 21922001540
RxCUI 226597
UNII 4TI98Z838E
UPC 0321922015409
Application # ANDA218214
SPL Set ID 54f108d6-ddd2-4276-8508-2c8e16a65fb2
Established class (EPC) Estrogen
Mechanism of action Estrogen Receptor Agonists
Chemical class Estradiol Congeners
DEA schedule Non-controlled
Marketing category ANDA
Marketing status On market
FDA listing status Listed (active directory)
Marketing start 2026-05-13
Route TRANSDERMAL
Dosage form GEL
Substance ESTRADIOL
TE code (Orange Book) AB · RLD · RS
Quick answers
  • RxCUI (RxNorm): 226597
Why two NDCs? The FDA registers this code as 21922-015-40 — a 5-3-2 layout, and that's what's printed on the package and shown on DailyMed. For insurance claims, every NDC is standardized to a uniform 11-digit 5-4-2 format by adding a zero to the product segment → 21922-0015-40. Same drug, same package — only the format differs.
Where does this data come from?
Identifiers from the FDA openFDA NDC Directory and Structured Product Labeling; RxCUI from RxNorm (NLM); GPI from Medi-Span; GCN / HIC / AHFS / legend from First Databank.

RxNorm drug class

This medicine belongs to the Radioactive Diagnostic Agent class.

Pharmacologic class Radioactive Diagnostic Agent, Estrogen
Drug family (ATC) Natural and semisynthetic estrogens, plain, Progestogens and estrogens, sequential preparations
How it works Positron Emitting Activity, Estrogen Receptor Agonists
Where does this data come from?
Therapeutic classes from RxNorm RxClass (U.S. National Library of Medicine) — Established Pharmacologic Class (FDA), ATC drug family (WHO) and mechanism of action, matched by this product’s RxCUI.

Clinical

📗 Our plain-language guide HelloPharmacist
  • It's an estrogen used mainly for menopause symptoms like hot flashes and vaginal dryness. Some patches are also used for low estrogen from ovarian problems or to prevent osteoporos...
  • That depends on the form. Patches go on the skin once or twice a week depending on the brand, and the injection goes into a muscle. Use the lowest dose that works for the shortest...
  • Headache, breast tenderness, spotting or irregular bleeding, cold-like symptoms and skin irritation where a patch sits are the most common. Tell your doctor if they bother you or d...
  • Get urgent help for chest pain, sudden weakness or trouble speaking, a swollen painful leg, sudden shortness of breath or sudden vision changes. These could be a stroke or blood cl...
📖 Read our full Estradiol guide →
5
Nutrient depletion considerations

Estradiol may be associated with lower levels of 5 nutrients — worth a chat with your pharmacist, not a cause for alarm.

🧪 Full Estradiol nutrient depletion report →
An association is not a deficiency. Educational only — don't start or stop anything without professional guidance.
Where does this data come from?
Plain-language summary from MedlinePlus (U.S. National Library of Medicine); supplement & herbal interactions and nutrient depletion data from the Natural Medicines database; our full guide is HelloPharmacist editorial content.

Pricing

A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.

Price systemPer gPer package
Retail pharmacies payNADAC · weekly Not in the retail survey — common for institutional, discontinued, or low-volume packs.
Medicaid paysCMS SDUD · 12 mo No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data.
Medicare drug plans payPart D · Q2 2026 $3.04 $152.14 / 50 g
Where does this data come from?
NADAC (National Average Drug Acquisition Cost) is the CMS weekly pharmacy-acquisition-cost survey — what pharmacies pay. ASP (Average Sales Price) is the CMS Medicare Part B drug-payment file, published quarterly. Medicaid pays is computed by us from CMS State Drug Utilization Data (total reimbursed ÷ units, trailing 12 months) — gross of rebates and inclusive of dispensing fees, so it reflects what Medicaid paid, not an acquisition cost. Medicare drug plans pay is the median negotiated point-of-sale unit cost across plans listing this NDC in the CMS quarterly Prescription Drug Plan pricing files, before rebates. The VA pays is the federal contract price (FSS, and the statutory Big 4 ceiling where listed) from the VA National Acquisition Center pharmaceutical price file. All are free public government data; each measures a different payer, so the figures are not directly comparable.

Packaging — all sizes for this product

Package NDCDescription Marketing startMarketing endStatus
21922-0015-40 You're viewing this Main listing 1 BOTTLE, PUMP in 1 CARTON / 50 g in 1 BOTTLE, PUMP 2026-05-13 — Active

Therapeutic equivalents

ProductLabelerPackNADAC/unitTEStatusPrice vs. this
Estradiol .75 mg/1.25g 70954-0646-10 ANI 50 g $3.387 AB Availability likely —
Estradiol .75 mg/1.25g 73473-0308-50 Solaris 1 bottle $3.387 AB Availability likely —
Elestrin .52 mg/.87g 00037-4801-70 Viatris 2 bottles $3.609 — Availability likely —
EstroGel .75 mg/1.25g 17139-0617-40 ASCEND 50 g — AB FDA listed —
Estradiol .75 mg/1.25gthis 21922-0015-40 Encube 1 bottle — AB FDA listed —
About this product: this is a generic version of the medicine. FDA equivalence ratings are shown when available, and other versions are listed above, least expensive first.
Where does this data come from?
Equivalents are other NDCs of the same ingredient, form and route from the openFDA NDC Directory, ranked least-expensive-first by NADAC. Therapeutic-equivalence (AB) ratings come from the FDA Orange Book; biologics use the FDA Purple Book for biosimilar & interchangeable status.

Availability & generic status

🏛️
2026
On the market since
May 2026
📍
2026
Currently FDA-listed
listed with the FDA
🔓
·
Generic on the market
this product is a generic
✅This is a generic drug

This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.

Where does this data come from?
Patents and exclusivity from the FDA Orange Book (small-molecule drugs), refreshed from public FDA data. Generic launch timing is an estimate, not a guarantee.

Inactive Ingredients / Excipients

Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.

Loading inactive ingredients from the official FDA label in the background. No external source is being called by this page request.
Where does this data come from?
Source: official FDA Structured Product Labeling (SPL) via DailyMed and the openFDA label index. Structured IACT rows and label-wide narrative are kept separate; availability and product-level specificity depend on the submitted label.

Inactive ingredient FAQ

Are inactive ingredients the same for every manufacturer?
No. Inactive ingredients can differ by manufacturer, dosage form, strength, and package / product version.
Why might an inactive ingredient be missing?
Some SPLs do not provide a complete structured inactive-ingredient list, and older or unusual labels may only include the information in narrative text.
Can inactive ingredients matter?
Yes. They can matter for allergies, intolerances, dyes, gluten / lactose concerns, preservatives, and formulation differences — but confirm with a pharmacist or the manufacturer when it’s clinically important.

Manufacturer & labeler

LabelerEncube Ethicals, Inc.
Application holderENCUBE ETHICALS PRIVATE LTD
FDA applicationANDA218214 (ANDA)
Labeler code21922
First marketedMay 2026
Product typeHuman Prescription Drug
Portfolio77 products on file
The labeler markets the product; the application holder owns the FDA approval. They’re often the same company but can differ (e.g. a repackager or an authorized generic). A mailing address / phone appears here when the manufacturer includes it in the product’s FDA label (not all do).
Where does this data come from?
Labeler, application holder and registered establishment from the FDA openFDA NDC Directory and Drugs@FDA; address/contact from the product’s FDA label.

Full prescribing information FDA SPL

The complete FDA label for this product — the official prescribing information, verbatim, section by section. Very long sections are excerpted here and marked; the full text is on DailyMed (linked in the sources below). Jump with a chip, search within the label, or expand everything.
🚨 Boxed Warning 🎯 Indications and Usage ⏱️ Dosage and Administration 💊 Dosage Forms and Strengths ⛔ Contraindications ⚠️ Warnings and Cautions 🤒 Adverse Reactions 🔄 Drug Interactions 👥 Use in Specific Populations 🤰 Pregnancy 🧒 Pediatric Use 🧓 Geriatric Use 🆘 Overdosage 🧬 Clinical Pharmacology 🧬 Mechanism of Action 📦 How Supplied / Storage and Handling 📋 Description 💬 Information for Patients 🍼 Nursing Mothers 🧬 Pharmacokinetics 🧬 Pharmacodynamics 🔬 Clinical Studies 🧪 Nonclinical Toxicology 📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 📚 References 📄 Patient Package Insert 📄 Package Label / Principal Display Panel
🚨 Boxed Warning ~3 min read ▾

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 (14.3)]. 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 (14.4)]. 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 (14.3, 14.4). 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 (14.3)].

The WHIMS estrogen plus progestin ancillary study of 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 (14.4)]. 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 (14.3, 14.4)].

Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.4)]. 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.

W… [Excerpted — this section continues on DailyMed.]

🎯 Indications and Usage 96 words ▾

1 INDICATIONS AND USAGE Estradiol gel 0.06% 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)

1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause

1.2Treatment 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.

⏱️ Dosage and Administration ~2 min read ▾

2 DOSAGE AND 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 to use a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women with 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 if treatment is still necessary. Metered- dose pump: Daily administration of estradiol gel 0.06% 1.25 g per day (1 pump depression) to the arm (2.1, 2.2)

2.1Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Estradiol gel 0.06% 1.25 g per day is the single approved dose for the treatment of moderate to severe vasomotor symptoms due to menopause. The lowest effective dose of estradiol gel 0.06% for this indication has not been determined. Before using the canister for the first time, it must be primed.

Remove the large canister cover, and fully depress the pump 5 times Discard the unused gel by thoroughly rinsing down the sink or placing it in the household trash. After priming, the pump is ready to use. The recommended area of application is the arm.

Apply a thin layer over the entire arm on the inside and outside from wrist to shoulder.

2.2Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Estradiol gel 0.06% 1.25 g per day is the single approved dose for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. The lowest effective dose of estradiol gel 0.06% for this indication has not been determined. When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy, first consider the use of topical vaginal products.

Before using the canister for the first time, it must be primed. Remove the large canister cover, and fully depress the pump 5 times. Discard the unused gel by thoroughly rinsing down the sink or placing it in the household trash.

After priming, the pump is ready to use. The recommended area of application is the arm. Apply a thin layer over the entire arm on the inside and outside from wrist to shoulder.

💊 Dosage Forms and Strengths 44 words ▾

3 DOSAGE FORMS AND STRENGTHS Estradiol gel 0.06% is an estradiol transdermal gel. One pump depression delivers 1.25 g of gel that contains 0.75 mg estradiol. Gel: 1 pump depression of estradiol gel 0.06% delivers 1.25 g of gel containing 0.75 mg estradiol (3)

⛔ Contraindications 202 words ▾

4 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 a 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. • Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. • Undiagnosed abnormal genital bleeding (4, 5.2) • 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 (for example, stroke or MI), or a 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 Cautions ~3 min read ▾

5 WARNINGS AND PRECAUTIONS • Estrogens increase the risk of gallbladder disease (5.4) • Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.5, 5.6, 5.9, 5.10) • Monitor thyroid function in women on thyroid replacement therapy (5.11, 5.20)

5.1Cardiovascular Disorders Increased risks of stroke and DVT are reported with estrogen-alone therapy. Increased risks of PE, DVT, stroke and MI are reported with estrogen plus progestin therapy. Immediately discontinue estrogen with or without progestogen if any of these occur or are 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). Stroke The WHI estrogen-alone substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years, respectively).

The increase in risk was demonstrated in year 1 and persisted [ see Clinical Studies (14.3) ]. Immediately discontinue estrogen-alone therapy if a stroke occurs or is suspected. Subgroup analysis of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).

1 The WHI estrogen plus progestin substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years, respectively) [ see Clinical Studies (14.3) ]. The increase in risk was demonstrated after the first year and persisted.1 Immediately discontinue estrogen with or without progestogen therapy if a stroke occurs or is suspected. Coronary Heart Disease The WHI estrogen-alone substudy reported no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in women receiving estrogen-alone compared to placebo2 [ see Clinical Studies (14.3) ].

Subgroup analyses of women 50 to 59 years of age, who were less than 10 years since menopause, suggest a reduction (not statistically significant) of CHD events in those women receiving CE (0.625 mg)- alone compared to placebo) (8 versus 16 per 10,000 women-years). 1 The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) of CHD events in those women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [ see Clinical Studies (14.3) ].

In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established CHD. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years.

Two thousand, three hundred twenty-one (2,321) women from the original HERS trial agreed to participate in an open-label extension of the original HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS,… [Excerpted — this section continues on DailyMed.]

🤒 Adverse Reactions ~2 min read ▾

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 with estradiol gel (≥5 percent) are headache, flatulence, and breast pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, Encube Ethicals Private Limited at 1-833-285-4151 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 clinical practice. Estradiol gel was studied in 2 well-controlled, 12-week clinical trials. Incidence of adverse drug reactions ≥5 percent for 1.25 g estradiol gel 0.06% and placebo is given in Table 1.

TABLE 1 Incidence of Adverse Drug Reactions ≥5 Percent Occurrence in the Estradiol Gel Treatment Group for the Intent-to-Treat Safety Population in 2 Well-controlled Clinical Studies (Expressed as Percent of Treatment Group ) Body System/ Adverse Drug Reactions Estradiol gel 0.06% 1.25 g /day (n=168) Placebo (n=73) BODY AS A WHOLE Headache 9.5

2.7DIGESTIVE SYSTEM Flatulence 5.4

4.1UROGENITAL SYSTEM Breast pain 10.7

8.2In 2 controlled clinical trials, application site reactions were reported by 0.6 percent of patients who received 1.25 g of estradiol gel. Other skin reactions, such as pruritus and rash, were also noted.

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 Endometrial cancer Breast Pain; tenderness; breast cancer Cardiovascular Deep vein thrombosis; myocardial ischemia; phlebitis Gastrointestinal Nausea; abdominal distension; diarrhea; stomach discomfort Skin Alopecia; rash; pruritus; application site: dryness, pain, discoloration, reaction, rash Eyes Retinal vein occlusion Central nervous system Headache; dizziness; insomnia; hypoesthesia; meningioma; aphasia; bradyphrenia; paresthesia Miscellaneous Drug ineffective; hot flush; arthralgia; night sweats; drug effect decreased; pain in extremity; fatigue; weight increased; pain; hypersensitivity; dyspnea; malignant mesenchymoma; angioedema; hepatitis acute; face edema; accidental exposure; myoclonus; gait disturbance; flushing

🔄 Drug Interactions 114 words ▾

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 estrogen and may result in adverse reactions. Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration.

(7.1)

👥 Use in Specific Populations ~2 min read ▾

8 USE IN SPECIFIC POPULATIONS

8.1Pregnancy Risk Summary Estradiol gel is not indicated for use in pregnancy. There are no data with the use of estradiol gel in pregnant women, however, epidemiologic studies and meta-analysis have not found an increased risk of genital or non-genital birth defects (including cardiac anomalities and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.3Lactation 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 breastfeeding is well established. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for estradiol gel and any potential adverse effects on the breastfed child from estradiol gel or from the underlying maternal condition.

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

8.5Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing estradiol gel to determine whether those over 65 years of age differ from younger subjects in their response to estradiol gel. 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 (14.3) ]. 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) and Clinical Studies (14.3) ].

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 (14.4) ]. 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 Warnings and Precautions (5.3), and Clinical Studies (14.4) ]

🤰 Pregnancy 92 words ▾

8.1Pregnancy Risk Summary Estradiol gel is not indicated for use in pregnancy. There are no data with the use of estradiol gel in pregnant women, however, epidemiologic studies and meta-analysis have not found an increased risk of genital or non-genital birth defects (including cardiac anomalities and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

🧒 Pediatric Use 23 words ▾

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

🧓 Geriatric Use 218 words ▾

8.5Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing estradiol gel to determine whether those over 65 years of age differ from younger subjects in their response to estradiol gel. 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 (14.3) ]. 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) and Clinical Studies (14.3) ].

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 (14.4) ]. 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 Warnings and Precautions (5.3), and Clinical Studies (14.4) ]

🆘 Overdosage 39 words ▾

10 OVERDOSAGE Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of estradiol gel therapy with institution of appropriate symptomatic care.

🧬 Clinical Pharmacology ~3 min read ▾

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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, 2 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.

12.2Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to estradiol gel 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.

12.3Pharmacokinetics Absorption Estradiol is transported across intact skin and into the systemic circulation by a passive diffusion process. The rate of diffusion across the stratum corneum is the rate-limiting factor. When estradiol gel is applied to the skin, it dries in 2 to 5 minutes.

Estradiol gel 1.25 g (containing 0.75 mg of estradiol) was administered to 24 postmenopausal women once daily on the posterior surface of 1 arm from wrist to shoulder for 14 consecutive days. Mean maximal serum concentrations of estradiol and estrone on Day 14 were 46.4 pg/mL and 64.2 pg/mL, respectively. The time averaged serum estradiol and estrone concentrations over the 24-hour dose interval after administration of 1.25 g estradiol gel on Day 14 are 28.3 pg/mL and 48.6 pg/mL, respectively.

Mean concentration-time profiles for unadjusted estradiol and estrone on Day 14 are shown in Figure 1. FIGURE 1 Mean Serum Concentration-time Profiles for Unadjusted Estradiol and Estrone After Multiple-dose Applications of 1.25 g Estradiol gel 0.06% for 14 Days The serum concentrations of estradiol following 2.5 g estradiol gel applications (1.25 g on each arm from wrist to shoulder) appeared to reach steady state after the third daily application. 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 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 clini… [Excerpted — this section continues on DailyMed.]

🧬 Mechanism of Action 185 words ▾

12.1Mechanism 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, 2 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.

📦 How Supplied / Storage and Handling 105 words ▾

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1How Supplied Estradiol gel is a clear, colorless, hydroalcoholic 0.06 percent estradiol gel supplied in a non-aerosol, metered-dose pump. The pump consists of an LDPE inner liner encased in rigid plastic with a resealable polypropylene cap. Estradiol gel is available in a 50-gram (1.75 oz) size.

Each individually packaged 50-gram pump contains 50 grams of gel and can deliver 30 metered 1.25-g doses. NDC: 21922-015-40............................. (50-gram pump)

16.2Storage and Handling Keep out of reach of children. 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].

📋 Description 102 words ▾

11 DESCRIPTION Estradiol gel contains 0.06 percent estradiol in an absorptive hydroalcoholic gel base for topical application. It is a clear, colorless gel, which is odorless when dry. One pump depression of estradiol gel delivers 1.25 g of gel containing 0.75 mg estradiol.

Estradiol is a white crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17β-diol. It has an empirical formula of C 18 H 24 O 2 and molecular weight of 272.39. The structural formula is: The active component of the gel is estradiol.

The remaining components of the gel (purified water, alcohol (46.12%), trolamine and carbopol 974 P polymer) are pharmacologically inactive. formula

💬 Information for Patients 145 words ▾

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) ]. Possible Serious Adverse Reactions with Estrogen-Alone Therapy Inform postmenopausal women of the 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 Common Adverse Reactions with Estrogen-Alone Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea, and vomiting. Manufactured by: Encube Ethicals Pvt. Ltd.

Plot No. C-1, Madkaim Industrial Estate, Madkaim, Post: Mardol, Ponda, Goa - 403 404, India. Distributed by: Encube Ethicals, Inc.

200 Meredith Drive, Suite 202, Durham, NC 27713 USA Revised:03/2026

🍼 Nursing Mothers 71 words ▾

8.3Lactation 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 breastfeeding is well established. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for estradiol gel and any potential adverse effects on the breastfed child from estradiol gel or from the underlying maternal condition.

🧬 Pharmacokinetics ~3 min read ▾

12.3Pharmacokinetics Absorption Estradiol is transported across intact skin and into the systemic circulation by a passive diffusion process. The rate of diffusion across the stratum corneum is the rate-limiting factor. When estradiol gel is applied to the skin, it dries in 2 to 5 minutes.

Estradiol gel 1.25 g (containing 0.75 mg of estradiol) was administered to 24 postmenopausal women once daily on the posterior surface of 1 arm from wrist to shoulder for 14 consecutive days. Mean maximal serum concentrations of estradiol and estrone on Day 14 were 46.4 pg/mL and 64.2 pg/mL, respectively. The time averaged serum estradiol and estrone concentrations over the 24-hour dose interval after administration of 1.25 g estradiol gel on Day 14 are 28.3 pg/mL and 48.6 pg/mL, respectively.

Mean concentration-time profiles for unadjusted estradiol and estrone on Day 14 are shown in Figure 1. FIGURE 1 Mean Serum Concentration-time Profiles for Unadjusted Estradiol and Estrone After Multiple-dose Applications of 1.25 g Estradiol gel 0.06% for 14 Days The serum concentrations of estradiol following 2.5 g estradiol gel applications (1.25 g on each arm from wrist to shoulder) appeared to reach steady state after the third daily application. 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 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 gel does not go through first-pass liver metabolism.

Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The apparent terminal exponential half-life for estradiol was about 36 hours following administration of 1.25 g estradiol gel. Effect of Application Site Washing The effect of application site washing on the serum concentrations of estradiol was determined in 24 healthy postmenopausal women who applied 1.25 g of estradiol gel once daily for 14 consecutive days.

Site washing 1 hour after the application resulted in a 22 percent mean decrease in average 24-hour serum concentrations of estradiol. Potential for Estradiol Transfer The effect of estradiol transfer was evaluated in 24 healthy postmenopausal women who topically applied 1.25 g of estradiol gel once daily on the posterior surface of 1 arm from wrist to shoulder for a period of 14 consecutive days. On each day, 1 hour after gel application, a cohort of 24 non-dosed healthy postmenopausal females directly contacted the dosed cohort at the site of gel application for 15 minutes.

No change in endogenous mean serum concentrations of estradiol was observed in the non-dosed cohort after direct skin-to-skin contact with subjects administered estradiol gel. Effect of Moisturizer Lotion/Sunscreen on Estradiol Absorption The effect of sunscreen and moisturizer lotion on estradiol absorption from 0.06% estradiol topical gel was evaluated in a randomized, open-label, three-period crossover study in 42 healthy postmenopausal women. The study results showed that… [Excerpted — this section continues on DailyMed.]

🧬 Pharmacodynamics 44 words ▾

12.2Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to estradiol gel 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.

🔬 Clinical Studies ~3 min read ▾

14 CLINICAL STUDIES

14.1Effects on Vasomotor Symptoms in Postmenopausal Women In a placebo-controlled study, 145 postmenopausal women between 29 and 67 years of age (81.4 percent were White) were randomly assigned to receive 1.25 g of estradiol gel (containing 0.75 mg of estradiol) or placebo gel for 12 weeks. Efficacy was assessed at 4 and 12 weeks of treatment. A statistically significant reduction in the frequency and severity of moderate to severe hot flushes was shown at Weeks 4 and 12.

(See Table 2) TABLE 2 Mean Change from Baseline in the Number and Severity of Hot Flushes per Day, ITT Population, LOCF Number of Hot Flushes/Day (Moderate to Severe) Severity Score/Day (Mild, Moderate, Severe) Placebo n=73 Estradiol Gel 0.06% 1.25 g n=72 Placebo n=73 Estradiol Gel 0.06% 1.25 g n=72 Baseline Mean (SD) 11.01 (5.66) 10.33 (3.07) 2.30 (0.24) 2.36 (0.29) Week 4* Mean (SD) Mean change from baseline (SD) Diff. vs placebo P value† 5.95 (5.17) -5.06 (4.91) 4.43 (4.13) -5.91 (3.68) 0.85 0.019‡ 2.00 (0.63) - 0.31 (0.62) 1.73 (0.73) -0.63 (0.71) 0.32 0.005‡ Week 12* Mean (SD) Mean change from baseline (SD) Diff. vs placebo P value† 5.17 (6.52) -5.84 (4.52) 2.79 (3.70) -7.55 (3.52) 1.71 0.043‡ 1.76 (0.84) -0.54 (0.84) 1.33 (0.97) -1.03 (0.94) 0.49 <0.001‡ * Primary timepoint. † P values from Elteren's nonparametric test. ‡ Statistically significantly different from placebo.

14.2Effects on Vulvar and Vaginal Atrophy in Postmenopausal Women Results of the vaginal wall cytology showed a significant (P≤0.001) increase from baseline in the percent of superficial epithelial cells at Week 12 for 1.25 g estradiol gel. In contrast, no significant change from baseline was observed in the placebo group.

14.3Women'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 causes.

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 50-79; 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 3.

TABLE 3 Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHIa Event Relative Risk CE vs. Placebo (95% nCI b ) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-Years CHD events c Non-fatal Mi c CHD death c 0.95 (0.78-1.16) 0.91 (0.73-1.14) 1.01 (0.71-1.43) 54 40 16 57 43 16 All strokesc Ischemic stroke c 1.33 (1.05-1.68) 1.55 (1.19-2.01) 45 38 33 25 Deep vein thrombosis c,d 1.47 (1.06-2.06) 23 15 Pulmonary embolism c 1.37 (0.90-2.07) 14 10 Invasive breast cancer c 0.80 (0.62-1.04) 28 34 Colorectal cancer c 1.08 (0.75-1.55) 17 16 Hip fracture c 0.65 (0.45-0.94) 12 19 Vertebral fractures c,d 0.64 (0.44-0.93) 11 18 Lower arm/wrist fracturesc, d 0.58 (0.47-0.72) 35 59 Total fracturesc, d 0.71 (0.64-0.80) 144 197 Death due to other causes e,f 1.08 (0.88-1.32) 53 50 Overall mortality c,d 1.04 (0.88-1.22) 79 75 Global index g 1.02 (0.92-1.13) 206 201 a Adapted from numerous WHI publications.

WHI publications can be viewed at www.nhlbi.nih.… [Excerpted — this section continues on DailyMed.]

🧪 Nonclinical Toxicology 35 words ▾

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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.

📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 32 words ▾

13.1Carcinogenesis, 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.

📚 References 214 words ▾

15 REFERENCES 15 REFERENCES 1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause.

JAMA. 2007;297:1465-1477. 2.

Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med.

2006;166:357-365. 3. Curb JD, et al.

Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780.

4. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis.

JAMA. 2004;292:1573-1580. 5.

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. 6. Chlebowski RT, et al.

Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253.

7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures.

JAMA. 2003;290:1739-1748. 8.

Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA.

2004;291:2947-2958. 9. 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.

📄 Patient Package Insert ~3 min read ▾

PATIENT INFORMATION Estradiol Gel 0.06% (es-tra-DYE-ol) (estradiol gel) Read this Patient Information before you start using estradiol gel and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment What is the most important information I should know about estradiol gel (an estrogen hormone)? • Using estrogen-alone may increase your chance of getting cancer of the uterus (womb).

Report any unusual vaginal bleeding right away while you are using estradiol gel. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. • Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia (decline in brain function). • Using estrogen-alone may increase yourchances of getting strokes and blood clots.

Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age and older. • Do not use estrogens with progestogens to prevent heart disease, heart attack, strokesor dementia. • Using estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. • Using estrogens with progestogens may increase your chance of getting dementia, based on a study of women 65 years of age and older. Only one estrogen-alone product and dose have been shown to increase yourchances of getting strokes, blood clots, and dementia.

Only one estrogen with progestogen product and dose have been shown to increase your chances of getting heart attacks, strokes, breast cancer, blood clots, and dementia. Because other products and doses have not been studied in the same way, it is not known how the use of estradiol gel will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol gel.

What is estradiol gel? Estradiol gel is a prescription medicine gel that containse stradiol ( anestrogenhormone). What is estradiol gel used for?

Estradiol gel is used after menopause to:. • Reduce moderate to severe hot flashes Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual periods).

Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause.” When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden intense feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild, and they will not need to use estrogens.

In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol gel. • Treat moderate to severe menopausal changes in and around the vagina You and your healthcare provider should talk regularly about whether you still need treatment with estradiol gel to control these problems. If you use estradiol gel only to treat your menopausal changes in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.

Who should not use estradiol gel? Do not start using estradiol gel if you: have unusual vaginal bleeding Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. have been diagnosed with a bleeding disorder currently have or have had certain cancers Estrogens may increase the chances of getting certain types of cancer, including cancer o… [Excerpted — this section continues on DailyMed.]

📄 Package Label / Principal Display Panel 22 words ▾

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 21922-015-40 Estradiol Gel 0.06% For Topical Use Only. A multiple-dose pump containing 50 grams (1.75 oz) carton

Source: FDA Structured Product Labeling, mirrored from DailyMed / openFDA. Prefer the government’s original formatting? View this label on DailyMed ↗

Medicare Part D spend CMS · PART D · 2026 (Q1)

Medicare Part D (outpatient prescription) spending for Estradiol — the program that covers self-administered drugs. 17 manufacturers.
⚠️ Drug-level data: CMS publishes Part D spending by drug, not by NDC — these figures combine every manufacturer, strength and package size sold under the name Estradiol. That’s a different level of aggregation than the Medicaid card above, which is specific to this exact 11-digit NDC (pack size included), so the two aren’t directly comparable.
Period
Total Part D spend
$65.73M
Claims incl. refills
1.4M
Beneficiaries
1.2M
Spend / beneficiary
$56.27
Spend / claim
$46.97
Trend by period
💵 About the dollar figures: spending is what Part D plans paid before confidential manufacturer rebates, so the program’s real net cost is lower. A blank patient count means fewer than 11 people — CMS hides counts that small to protect privacy. Source: CMS Medicare Quarterly Part D Spending by Drug (data.cms.gov), updated quarterly.

About this NDC listing & data coverage

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What data is (and isn’t) available for this NDC — tap to expand
NDC identity (package / product / labeler codes) ✓ Available
Labeler ✓ Available
Product & package description ✓ Available
Marketing category & status ✓ Available
Active ingredient / dosage form / route ✓ Available
FDA label (SPL via DailyMed) ✓ Available
Package photos — Not published for this NDC No photo available yet for this listing.
Inactive ingredients (structured) — Not published for this NDC The labeler did not submit a structured excipient list, or no SPL is available.
NADAC pharmacy acquisition price (CMS) — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey.
Orange Book / therapeutic-equivalence data ✓ Available
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Medicaid utilization (CMS SDUD) — Not published for this NDC CMS reports utilization only for NDCs with Medicaid claims above its privacy threshold.
“Not published” reflects what the public FDA / CMS / NLM sources provide for this exact package code — it is a property of the data feeds, not a judgment about the product.

Questions about this listing

Why is there no price listed?
The pricing shown on our NDC pages comes from CMS NADAC, a voluntary survey of retail community pharmacy invoices. CMS does not publish a NADAC for every NDC — packages outside the retail survey (institutional and hospital products, bulk packages, discontinued items, and many OTC items) may never receive one. A missing price reflects the survey's scope, not this product's actual cost, and does not mean the product is free or unavailable.
Is the NDC printed on the package the same as the 11-digit billing NDC?
Yes, they identify this exact package in different formats. The form printed on the packaging and shown on DailyMed is the one the FDA registered. Insurance claims use a fixed 11-digit 5-4-2 format, so the short segment is padded with a leading zero and the dashes are dropped. The Identity section at the top of this page lists each form of this code.
Is this package still being marketed?
Yes, per the latest FDA NDC Directory data on this page: this package is listed as actively marketed, with no marketing end date reported by Encube Ethicals, Inc.. Listing status can change — the directory data on this page refreshes weekly.
Who lists this product with the FDA?
Encube Ethicals, Inc. is the labeler of record for this NDC — the company under whose FDA-assigned code the package is listed. The labeler may be the manufacturer itself or a distributor marketing the product under its own code.
Do I need a prescription for this product?
This NDC is listed with FDA as a prescription product, so it is dispensed under a prescriber's order. Your pharmacist can tell you whether any over-the-counter forms of the same medication exist.
This page identifies an FDA-listed package (the NDC) and reports public regulatory and pricing data about the listing. It is reference information, not a medical recommendation — talk to your pharmacist or prescriber about your own medication.
Where does this data come from?
Listing facts (marketing category, packager status, marketing dates) from the FDA openFDA NDC Directory; label availability from DailyMed; pricing coverage from CMS NADAC; equivalence scope from the FDA Orange Book.
← 21922-0011-05 · Encube 21922-0016-04 · Encube →
For educational and professional reference only — not medical advice. Pricing reflects published NADAC and CMS ASP (free public data) and may differ from your acquisition cost; always verify before billing or dispensing.