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Estradiol Gel .5 mg/.5g Gel, 30 packets — NDC 21922-0087-52 package photo
Label image from the product's FDA listing (DailyMed) — may show a different pack size or an older label revision.

Estradiol Gel .5 mg/.5g Gel, 30 packets — NDC 21922-087-52 (Billing 21922-0087-52)

by Encube Ethicals, Inc. · 30 PACKET in 1 CARTON / .5 g in 1 PACKET

This is a package of 30 packets of Estradiol Gel .5 mg/.5g Gel from Encube Ethicals, Inc., marketed since Mar 2025 and currently FDA-listed; retail pharmacies pay about $0.9548 per packet (NADAC). It is this product's only package size.

NDC 21922-0087-52
🏷️ FDA NDC (as labeled) 21922-087-52 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) 21922-087-52
Product NDC 21922-087
11-digit billing NDC 21922008752
NCPDP billing unit EA — each (per item)
RxCUI 2619677, 2619679, 2619681, 2619683, 2619685
UNII 4TI98Z838E
Application # ANDA218507
SPL Set ID d4a3606f-83b2-45df-bc77-faebfa796f9a
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 2025-03-10
Route TOPICAL
Dosage form GEL
Substance ESTRADIOL
TE code (Orange Book) AB · RLD · RS

Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification

GPI-14 24000035004040
GCN Seq No 060493
GCN 26659
HICL code 001421
Ingredient (HICL) Estradiol
HIC1 code G
Therapeutic class — broad (HIC1) Female Genital System
HIC2 code G1
Therapeutic class — intermediate (HIC2) Estrogens
HIC3 code G1A
Therapeutic class — specific (HIC3) Estrogenic Agents
AHFS code 68:16.04.00
AHFS class Estrogens
FDB label name ESTRADIOL 0.1% (0.5MG) GEL PKT
FDB brand name Estradiol
Legend status F — Federal legend — prescription drug or device
Quick answers
  • GSN (GCN sequence number): 060493
  • GCN: 26659
  • GPI-14 (Medi-Span): 24000035004040
  • HICL (First Databank): 001421
  • AHFS class code: 68:16.04.00
  • RxCUI (RxNorm): 2619677
Why two NDCs? The FDA registers this code as 21922-087-52 — 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 → 21922-0087-52. 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

Label name ESTRADIOL 0.1% (0.5MG) GEL PKT Ingredient Estradiol
📖 What it is MedlinePlus · NLM

Estradiol topical may be used for the following: to treat and prevent hot flushes (hot flashes; sudden strong feelings of heat and sweating) in women who are experiencing menopause (change of life; the end of monthly menstrual periods). to treat vaginal dryness, itching, and burning Estradiol is in a class of medications called estrogen hormones. It works by replacing estrogen that is normally produced by the body.

Read the full MedlinePlus article ↗
📗 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 eaPer package
Retail pharmacies payNADAC · weekly $0.955 $28.64 / 30 packets
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 · quarterly No Part D plan price is available for this NDC in our data.
NADAC price history (per ea) — tap or hover for the price & month
Dec 2025 Mar 2026 Jun 2026 Sep 2026 $1.837 $0.955
▼ Down 48% over the last 10 months.
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
21922-0087-52 You're viewing this Main listing 30 PACKET in 1 CARTON / .5 g in 1 PACKET 2025-03-10 — Active

Therapeutic equivalents

ProductLabelerPackNADAC/unitTEStatusPrice vs. this
Estradiol .5 mg/.5g 13811-0091-32 Trigen 30 packets $0.955 AB Availability likely —
Estradiol Gel .5 mg/.5gthis 21922-0087-52 Encube 30 packets $0.955 AB Availability likely —
Estradiol .5 mg/.5g 45802-0202-30 Padagis 30 packets $0.955 AB Availability likely —
Estradiol .5 mg/.5g 69238-2451-03 Amneal 30 packets $0.955 AB Availability likely —
Estradiol .5 mg/.5g 70700-0144-35 Xiromed, 30 packets $0.955 AB Availability likely —
Estradiol .5 mg/.5g 70954-0530-20 ANI 30 packets $0.955 AB Availability likely —
Estradiol .5 mg/.5g 72603-0242-30 NorthStar 30 packets $0.955 AB Availability likely —
Divigel .5 mg/.5g 68025-0066-07 Vertical 7 packets — AB FDA listed —
Estradiol .5 mg/.5g 72162-2291-03 Bryant 30 packets — 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

🏛️
2025
On the market since
Mar 2025
📍
2026
Currently FDA-listed
1 year listed
🔓
·
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.

💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.

  • UNII 3K9958V90M
    A liquid solvent derived from fermentation or chemical synthesis. In medicines, alcohol dissolves active ingredients, helps preserve the product, and improves how the body absorbs certain drugs.
  • UNII HHT01ZNK31
    Carbomer Homopolymer Type B is a synthetic polymer made from acrylic acid. It absorbs water and forms a gel, so it's used in medicines as a thickener, suspending agent, and to help create a smooth texture in creams, gels, and lotions.
  • UNII 6DC9Q167V3
    Propylene glycol is a clear liquid derived from petroleum or vegetable sources. It acts as a solvent, humectant, and preservative in medicines, helping dissolve active ingredients and maintain product stability.
  • UNII 9O3K93S3TK
    Trolamine is an alkaline compound used as a pH buffer and emulsifier in medicines. It helps neutralize acids, stabilize formulations, and enable mixing of oil and water-based ingredients.
  • UNII 059QF0KO0R
    Water is a liquid solvent that dissolves and mixes ingredients together in liquid medicines, syrups, and injections. It helps distribute the active drug evenly throughout the product.

5 inactive ingredients listed in the exact product block matched to this NDC.

Where does this data come from?
Data sourced from official FDA Structured Product Labeling (SPL) via DailyMed — ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.

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 applicationANDA218507 (ANDA)
Labeler code21922
First marketedMar 2025
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 🧬 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 ( 14.2 )]. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo.

It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.3 )] . Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions ( 5.1 , 5.3 ), and Clinical Studies ( 14.2 , 14.3 )]. Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI.

Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile.

Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia The WHI estrogen plus progestin substudy reported increased risks of pulmonary embolism (PE), DVT, stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions ( 5.1 ), and Clinical Studies ( 14.2 )].

The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.3 )] . Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions ( 5.1 , 5.3 ), and Clinical Studies ( 14.2 , 14.3 )].

Breast Cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions ( 5.2 ), and Clinical Studies ( 14.2 )]. Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia, and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen p… [Excerpted — this section continues on DailyMed.]

🎯 Indications and Usage 37 words ▾

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 ~1 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 a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women who have a history of endometriosis may need a progestogen [see Warnings and Precautions ( 5.2 , 5.14 )] .

Use estrogen-alone, or in combination with a progestogen, at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Reevaluate postmenopausal women periodically as clinically appropriate to determine whether treatment is still necessary. Daily administration of 0.25 to 1.25 grams of estradiol 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 ).

2.1Treatment 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.

💊 Dosage Forms and Strengths 72 words ▾

3 DOSAGE FORMS AND STRENGTHS Estradiol gel 0.1% is available in five doses of 0.25, 0.5, 0.75, 1.0, and 1.25 grams for transdermal application (corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol respectively). Estradiol gel 0.1% is a clear, colorless gel, which is odorless when dry. Gel: 0.25, 0.5, 0.75, 1.0, and 1.25 gram-filled single-dose foil packets containing 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively ( 3 ).

⛔ Contraindications ~1 min read ▾

4 CONTRAINDICATIONS Estradiol gel 0.1% 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 0.1% • 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 0.1% ( 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 , 5.22 )

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). 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 strokes per 10,000 women-years, respectively).

The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies ( 14.2 )]. Immediately discontinue estrogen-alone therapy if a stroke occurs or is suspected. Subgroup analyses 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 ( 14.2 )]. The increase in risk was demonstrated after the first year and persisted. 1 Immediately discontinue estrogen plus 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 placebo 2 [see Clinical Studies ( 14.2 )]. 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 daily 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 ( 14.2 )]. 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 coronary heart disease. 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 and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of 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 (0.625 mg) plus MPA (2.5 mg) group an… [Excerpted — this section continues on DailyMed.]

🤒 Adverse Reactions ~2 min read ▾

6 ADVERSE REACTIONS The most common adverse reactions (incidence ＞5 percent and greater than placebo) in any estradiol gel 0.1% treatment group are metrorrhagia, breast tenderness, vaginal mycosis, nasopharyngitis, and upper respiratory tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Pvt. Ltd.

1-833-285-4151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . The most common adverse reactions (incidence ＞5 percent and greater than placebo) in any estradiol gel 0.1% treatment group are metrorrhagia, breast tenderness, vaginal mycosis, nasopharyngitis, and upper respiratory tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Pvt.

Ltd. 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 practice. Estradiol gel 0.1% 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 0.1% Estradiol Gel 0.1% 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 Upper Respiratory Tract Infection Vaginal mycosis 7 (5.7) 7 (5.7) 1 (0.8) 5 (4.1) 3 (2.4) 3 (2.4) 6 (4.8) 2 (1.6) 8 (6.4) 5 (4.0) 2 (1.6) 4 (3.2) REPRODUCTIVE SYSTEM & BREAST DISORDERS Breast Tenderness Metrorrhagia 3 (2.5) 5 (4.1) 7 (5.7) 7 (5.7) 11 (8.8) 12 (9.6) 2 (1.6) 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 0.1%, 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 0.1%. 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 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 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 ).

👥 Use in Specific Populations ~2 min read ▾

8 USE IN SPECIFIC POPULATIONS

8.1Pregnancy Risk Summary Estradiol gel 0.1% is not indicated for use in pregnant women. There are no data with the use of estradiol gel 0.1% in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2Lactation Risk Summary Estrogens are present in human milk and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for estradiol gel 0.1% and any potential adverse effects on the breastfed child from estradiol gel 0.1% or from the underlying maternal condition.

8.4Pediatric Use Estradiol gel 0.1% 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 studies utilizing estradiol gel 0.1% to determine whether those over 65 years of age differ from younger subjects in their response to estradiol gel 0.1%. The Women's Health Initiative Studies In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Warnings and Precautions ( 5.1 ) and Clinical Studies ( 14.2 )] . In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Warnings and Precautions ( 5.1 , 5.2 ), and Clinical Studies ( 14.2 )] .

The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.3 )] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.3 )] .

🤰 Pregnancy 95 words ▾

8.1Pregnancy Risk Summary Estradiol gel 0.1% is not indicated for use in pregnant women. There are no data with the use of estradiol gel 0.1% 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.

🧒 Pediatric Use 24 words ▾

8.4Pediatric Use Estradiol gel 0.1% is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.

🧓 Geriatric Use ~1 min read ▾

8.5Geriatric Use There have not been sufficient numbers of geriatric women involved in studies utilizing estradiol gel 0.1% to determine whether those over 65 years of age differ from younger subjects in their response to estradiol gel 0.1%. The Women's Health Initiative Studies In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Warnings and Precautions ( 5.1 ) and Clinical Studies ( 14.2 )] . In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Warnings and Precautions ( 5.1 , 5.2 ), and Clinical Studies ( 14.2 )] .

The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.3 )] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.3 )] .

🆘 Overdosage 39 words ▾

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 0.1% 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, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues.

To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism.

Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

12.2Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to estradiol gel 0.1% 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 diffuses across intact skin and into the systemic circulation by a passive absorption process, with diffusion across the stratum corneum being the rate-limiting factor. In a 14-day, Phase 1, multiple-dose study, estradiol gel 0.1% demonstrated linear and approximately dose-proportional pharmacokinetics at steady state for both AUC 0-24 and C max following once daily dosing to the skin of either the right or left upper thigh (Table 2). Table 2: Mean (%CV) Pharmacokinetic Parameters for Estradiol (uncorrected for baseline) on Day 14 Following Multiple Daily Doses of Estradiol gel 0.1% Parameter (units) Estradiol Gel 0.1% 0.25 grams Estradiol Gel 0.1% 0.5 grams Estradiol Gel 0.1% 1.0 gram AUC 0-24 (pgh/mL) 236 (94) 504 (149) 732 (81) C max (pg/mL) 14.7 (84) 28.4 (139) 51.5 (86) C avg (pg/mL) 9.8 (92) 21 (148) 30.5 (81) t max * (h) 16 (0,72) 10 (0,72) 8 (0,48) E2:E1 ratio 0.42 0.65 0.65 *Median (Min, Max).

Steady-state serum concentration of estradiol are achieved by day 12 following daily application of estradiol gel 0.1% to the skin of the upper thigh. The mean (SD) serum estradiol levels following once daily dosing at day 14 are shown in Figure 1. Figure 1: Mean (SD) Serum Estradiol Concentrations (Values Uncorrected for Baseline) on Day 14 Following Multiple Daily Doses of estradiol gel 0.1% Figure 1 The effect of sunscreens and other topical lotions on the systemic exposure of estradiol gel 0.1% has not been evaluated.

Studies conducted using topical estrogen gel approved products have shown that sunscreens have the potential for changing the systemic exposure of topically applied estrogen gels. Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs.

Estrogens circulate in the blood largely bound to SHBG and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions.

These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens… [Excerpted — this section continues on DailyMed.]

🧬 Mechanism of Action 188 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, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues.

To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism.

Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

📦 How Supplied / Storage and Handling 140 words ▾

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1How Supplied Estradiol gel 0.1% is a clear, colorless, smooth, opalescent gel supplied in single-dose foil packets of 0.25, 0.5, 0.75, 1.0, and 1.25 grams, corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively. NDC 21922-086-52, carton of 30 packets, 0.25 mg estradiol per single-dose foil packet NDC 21922-087-52, carton of 30 packets, 0.5 mg estradiol per single-dose foil packet NDC 21922-088-52, carton of 30 packets, 0.75 mg estradiol per single-dose foil packet NDC 21922-089-52, carton of 30 packets, 1.0 mg estradiol per single-dose foil packet NDC 21922-090-52, carton of 30 packets, 1.25 mg estradiol per single-dose foil packet Keep out of the reach of children.

16.2Storage and Handling Store at 20°C to 25°C (68°F to 77°F). Excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.]

📋 Description 144 words ▾

11 DESCRIPTION Estradiol gel 0.1percent, is a clear, colorless gel, which is odorless when dry. It is designed to deliver sustained circulating concentrations of estradiol when applied once daily to the skin. The gel is applied to a small area (200 cm2) of the thigh in a thin layer.

Estradiol gel 0.1% is available in five doses of 0.25, 0.5, 0.75, 1.0, and 1.25 grams for topical application (corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively). The active component of the topical gel is estradiol. Estradiol is a white crystalline powder, chemically described as estra-1,3, 5(10)-triene-3,17ß-diol.

It has an empirical formula of C 18 H 24 O 2 and molecular weight of 272.39. The structural formula is: The remaining components of the gel alcohol 59.61% v/v, carbopol 974 P polymer, propylene glycol, purified water, and trolamine 99% are pharmacologically inactive. str

💬 Information for Patients ~1 min read ▾

17 PATIENT COUNSELING INFORMATION Advise women to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Vaginal Bleeding Inform postmenopausal women to report any vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions ( 5.2 )] . Unintentional Secondary Exposure to estradiol gel 0.1% Inform women about the possibility of secondary exposure to estradiol gel 0.1%: • Apply estradiol gel 0.1% as directed and keep children from contacting exposed application site(s).

If direct contact with the application site occurs, wash the contact area thoroughly with soap and water. • Look for signs of unexpected sexual development, such as breast mass or increased breast size in prepubertal children. • If signs of unintentional secondary exposure are noticed: • Have the child(ren) evaluated by a healthcare provider. • Have women contact their healthcare provider to discuss the appropriate use and handling of Estradiol gel 0.1% when around children. • Pets may also be unintentionally exposed to estradiol gel 0.1% if above precautions are not followed.

Possible Serious Adverse Reactions with Estrogen-Alone Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] . Possible Less Serious but Common Adverse Reactions with Estrogen-Alone Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headaches, breast pain and tenderness, nausea and vomiting.

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: 03/2025

🧬 Pharmacokinetics ~3 min read ▾

12.3Pharmacokinetics Absorption Estradiol diffuses across intact skin and into the systemic circulation by a passive absorption process, with diffusion across the stratum corneum being the rate-limiting factor. In a 14-day, Phase 1, multiple-dose study, estradiol gel 0.1% demonstrated linear and approximately dose-proportional pharmacokinetics at steady state for both AUC 0-24 and C max following once daily dosing to the skin of either the right or left upper thigh (Table 2). Table 2: Mean (%CV) Pharmacokinetic Parameters for Estradiol (uncorrected for baseline) on Day 14 Following Multiple Daily Doses of Estradiol gel 0.1% Parameter (units) Estradiol Gel 0.1% 0.25 grams Estradiol Gel 0.1% 0.5 grams Estradiol Gel 0.1% 1.0 gram AUC 0-24 (pgh/mL) 236 (94) 504 (149) 732 (81) C max (pg/mL) 14.7 (84) 28.4 (139) 51.5 (86) C avg (pg/mL) 9.8 (92) 21 (148) 30.5 (81) t max * (h) 16 (0,72) 10 (0,72) 8 (0,48) E2:E1 ratio 0.42 0.65 0.65 *Median (Min, Max).

Steady-state serum concentration of estradiol are achieved by day 12 following daily application of estradiol gel 0.1% to the skin of the upper thigh. The mean (SD) serum estradiol levels following once daily dosing at day 14 are shown in Figure 1. Figure 1: Mean (SD) Serum Estradiol Concentrations (Values Uncorrected for Baseline) on Day 14 Following Multiple Daily Doses of estradiol gel 0.1% Figure 1 The effect of sunscreens and other topical lotions on the systemic exposure of estradiol gel 0.1% has not been evaluated.

Studies conducted using topical estrogen gel approved products have shown that sunscreens have the potential for changing the systemic exposure of topically applied estrogen gels. Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs.

Estrogens circulate in the blood largely bound to SHBG and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions.

These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption.

In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Although the clinical significance has not been determined , estradiol from estradiol gel 0.1% does not undergo first pass metabolism and provides estradiol to estrone ratios at steady state in the range of 0.42 to 0.65. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

The apparent terminal half-life for estradiol was about 10 hours following administration of estradiol gel 0.1%. Potential for Estradiol Transfer The effect of estradiol transfer was evaluated in healthy postmenopausal women who topically applied 1.0 gram of estradiol gel 0.1% (single dose) on one thigh. One and 8 hours after gel application, they engaged in direct thigh-to-arm contact with a partner for 15 minutes.

While some elevation of estradiol levels over baseline was seen in the male subjects, the degree of transferability in this study was inconclusive. Effects of Washing The effect of application site washing on skin surface levels and serum concentrations of estradiol was determined in 16 healthy postmenopausal women after application of 1.0 gram of estradiol gel 0.1% to a 200 cm2 area on the thigh. Washing the application site with soap and water 1 hour after application removed all detectable a… [Excerpted — this section continues on DailyMed.]

🧬 Pharmacodynamics 45 words ▾

12.2Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to estradiol gel 0.1% 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 A randomized, double-blind, placebo-controlled trial evaluated the efficacy of 12-week treatment with three different daily doses of estradiol gel 0.1% for vasomotor symptoms in 495 postmenopausal women (86.5 percent White; 10.1 percent Black) between 34 and 89 years of age (mean age 54.6) who had at least 50 moderate to severe hot flushes per week at baseline (2-week period prior to treatment). Women applied placebo, estradiol gel 0.1% 0.25 grams (0.25 mg), estradiol gel 0.1% 0.5 grams (0.5 mg estradiol) or estradiol gel 0.1% 1.0 gram (1.0 mg estradiol) once daily to the thigh.

Reductions in both the median daily frequency and the median daily severity of moderate to severe hot flushes were statistically significant for the 0.5 grams per day and the 1.0 gram per day estradiol gel 0.1% doses when compared to placebo at week 4. Statistically significant reductions in both the median daily frequency and the median daily severity of moderate to severe hot flushes for the estradiol gel 0.1% 0.25 grams per day dose when compared to placebo were delayed to week 7. There were statistically significant reductions in median daily frequency and severity of hot flushes for all three estradiol gel 0.1% doses (0.25 grams per day, 0.5 grams per day and 1.0 gram per day) compared to placebo at week 12.

See Table 3 for results. Table 3: Summary of Change From Baseline in the Median Daily Frequency and Severity of Hot Flushes during estradiol gel 0.1% Treatment (ITT Population) Estradiol Gel, 0.1% Placebo Evaluation 0.25 grams/day N=121 0.5 grams/day N=119 1.0 gram/day N=124 N=124 Frequency of Daily Hot Flushes Baseline Median 9.72 9.24 9.64

9.32Median Change: Week 4 p-value† -5.00 0.132 -5.73 0.011 -7.20 <0.001 -3.63 Median Change: Week 7 p-value† -6.62 <0.001 -7.14 <0.001 -7.71 <0.001 -4.37 Median Change: Week 12 p-value† -6.88 <0.001 -7.29 <0.001 -8.35 <0.001 -4.48 Severity of Daily Hot Flushes Baseline Median 2.52 2.51 2.52

2.54Median Change: Week 4 p-value† -0.07 0.283 -0.18 <0.001 -0.47 <0.001 -0.04 Median Change: Week 7 p-value† 0.24 0 <0.001 -0.46 <0.001 -1.06 <0.001

0.06Median Change: Week 12 p-value† -0.33 0.021 -0.56 0.002 -1.69 <0.001 -0.13 †p-values from the van Elteren's test stratified by pooled center; comparison in median change was significant if p <0.05.

14.2Women's Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause.

These substudies did not evaluate the effects of CE- alone or CE plus MPA on menopausal symptoms. WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 7.1 years are presented in Table 4.

Table 4: Relative And Absolute Risk Seen In The Estrogen-Alone Substudy of WHIa Event Relative Risk CE vs. Placebo (95% nCIb) CE n=5,310 Placebo n=5,429 Absolute Risk per 10,000 Women-Years Absolute Risk per 10,000 Women-Years CHD eventsc Nonfatal MIc CHD deathc 0.95 (0.78 – 1.16) 0.91 (0.73 – 1.14) 1.01 (0.7… [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 ~1 min read ▾

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 PATIENT INFORMATION ESTRADIOL GEL 0.1% (es-tra-DYE-ole) Read this Patient Information leaflet before you start using estradiol gel 0.1% 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 0.1% (AN ESTROGEN HORMONE)? Using estrogen-alone increases your chance of getting cancer of the uterus (womb). Report any unusual vaginal bleeding right away while you are using estradiol gel 0.1%.

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 of brain function) Using estrogen-alone may increase your chances of getting strokes or 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 attacks, strokes or 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 or older Only one estrogen-alone product and dose have been shown to increase your chances 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 0.1% will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol gel 0.1%.

What is estradiol gel 0.1%? Estradiol gel 0.1% is a prescription medicine that contains estradiol (an estrogen hormone). Estradiol gel 0.1% is a clear, colorless, smooth gel that is odorless when dry.

When applied to the skin, estradiol is absorbed through the skin into the bloodstream. What is estradiol gel 0.1% used for? Estradiol gel 0.1% 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 to 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 estrogens. In other women, symptoms can be more severe.

Who should not use estradiol gel 0.1%? Do not start using estradiol gel 0.1% if you: • have any 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 cancers, including cancer of the breast or uterus (womb).

If you have or have had cancer, talk with your healthcare provider about whether you should use estradiol gel 0.1%. • had a stroke or heart attack • currently have or have had blood clots • currently have or have had liver problems • are allergic to estradiol gel 0.1%… [Excerpted — this section continues on DailyMed.]

📄 Package Label / Principal Display Panel 103 words ▾

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 21922- 086 -52 Estradiol Gel, 0.1% 0.25 mg 0.25 g gel provides 0.25 mg estradiol/packet 30 Packets NDC 21922- 087 -52 Estradiol Gel, 0.1% 0.5 mg 0.5 g gel provides 0.5 mg estradiol/packet 30 Packets NDC 21922- 088 -52 Estradiol Gel, 0.1% 0.75 mg 0.75 g gel provides 0.75 mg estradiol/packet 30 Packets NDC 21922- 089 -52 Estradiol Gel, 0.1% 1 mg 1 g gel provides 1 mg estradiol/packet 30 Packets NDC 21922- 090 -52 Estradiol Gel, 0.1% 1.25 mg 1.25 g gel provides 1.25 mg estradiol/packet 30 Packets 0-25 c 0-5-c 0-75 c 1 c 1-25 c

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 (matched by generic name) — 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. CMS lists 17 products for this generic; we show the highest-spend one. 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.

Reported adverse events (FAERS)

Read carefully: FAERS reports are voluntary and unverified. Counts are not incidence, do not establish causation, are subject to reporting bias, and cannot be used to compare one drug to another. Shown for signal context only. Reports for Estradiol Gel (this brand).

Top reported reactions

Nausea2,776
Headache2,754
Fatigue2,750
Pain2,006
Diarrhoea1,891
Breast Cancer Female1,709
Dizziness1,646

Reporter sex

0 reports

Serious outcomes

Disabling1,212
Death886
Reports over time (by year) — tap or hover for the count & year
2019 2021 2023 2026 5,234 2,827
Most recent year is provisional (FAERS lags ~3 months).
Where does this data come from?
Adverse-event reports from the FDA Adverse Event Reporting System (FAERS) via openFDA. FAERS reports are voluntary and unverified — counts are not incidence and don’t establish causation.
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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.