Estradiol Vaginal Inserts 10 ug Tablet, Film Coated — NDC 59651-439-08 (Billing 59651-0439-08)
This is a package of Estradiol Vaginal Inserts 10 ug Tablet, Film Coated from Aurobindo Pharma Limited, marketed since Aug 2024 and currently FDA-listed; retail pharmacies pay about $5.52 per unit (NADAC). It is the main listing for this product, which comes in 2 package sizes.
Other active recalls for Estradiol (different manufacturers) — 4 · tap to view
Identity & classification
Regulatory identifiers FDA, NLM and CMS codes for this package
Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification
- GSN (GCN sequence number): 065966
- GCN: 28107
- GPI-14 (Medi-Span): 55350020000310
- HICL (First Databank): 001421
- AHFS class code: 68:16.04.00
- RxCUI (RxNorm): 884707
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
- RxNorm (NLM RxNav) · catalog refreshed Oct 1, 2026
- Medi-Span GPI (licensed)
- First Databank (licensed) · refreshed Oct 1, 2026
RxNorm drug class
This medicine belongs to the Radioactive Diagnostic Agent class.
Where does this data come from?
- RxClass (NLM) · catalog refreshed Oct 1, 2026
Clinical
- 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...
Patient education
Supplement & herbal interactions
Some supplements/herbs that may interact with Estradiol — tap one for details:
Estradiol may be associated with lower levels of 5 nutrients — worth a chat with your pharmacist, not a cause for alarm.
Where does this data come from?
- MedlinePlus (NLM) · refreshed Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Ask a licensed pharmacist directly — free, answered by our team.
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 system | Per ea | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $5.518 | $44.14 / 8 tablet |
| Medicaid paysCMS SDUD · 12 mo | $7.04 | $56.29 / 8 tablet |
| Medicare drug plans payPart D · quarterly | No Part D plan price is available for this NDC in our data. | |
Where does this data come from?
- CMS NADAC weekly file · file of Sep 30, 2026
- CMS ASP pricing files · refreshed Sep 20, 2026
- CMS Medicaid State Drug Utilization Data · through Q1 2026
- CMS Part D plan pricing files · refreshed Sep 24, 2026
- VA National Acquisition Center price file
Packaging — all sizes for this product
| Package NDC | Description | Per unit | Per pack | Marketing start | Marketing end | Status |
|---|---|---|---|---|---|---|
| 59651-0439-08 You're viewing this Main listing | 8 APPLICATOR in 1 CARTON / 1 TABLET, FILM COATED in 1 APPLICATOR | $5.52 / ea | $44.14 | 2024-08-02 | — | Active |
| 59651-0439-18 59651-439-18 | 18 APPLICATOR in 1 CARTON / 1 TABLET, FILM COATED in 1 APPLICATOR | $5.52 / ea | $99.32 | 2024-08-02 | — | Active |
This pack has the lowest per-ea cost of the 2 priced pack sizes ($5.52 NADAC).
In Medicaid, this is the most-dispensed pack of this product — about 87% of fills over the last four reported quarters. See all packs ↓
Pack size FAQ
What quantity is in this package?
What NDC number is used to bill for this package of Estradiol Vaginal Inserts 10 ug Tablet, Film Coated?
Prices are the latest CMS NADAC pharmacy acquisition cost per NDC; per-pack figures are per-unit × pack quantity, shown only when the pack is denominated in the same measure NADAC prices.
Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Estradiol 10 ug 00093-3223-08 | Teva | 8 inserts | $5.518 | AB | Availability likely | — |
| Estradiol Vaginal Inserts 10 ugthis 59651-0439-08 | Aurobindo | 1 tablet | $5.518 | AB | Availability likely | — |
| Yuvafem 10 ug 65162-0226-21 | Amneal | 8 tablets | $5.518 | AB | Availability likely | — |
| Estradiol Vaginal Inserts 10 ug 68462-0711-71 | Glenmark | 1 tablet | $5.518 | AB | Availability likely | — |
| Estradiol Vaginal Inserts 10 ug 72603-0874-08 | NorthStar | 1 tablet | $5.518 | AB | Availability likely | — |
| Vagifem 10 ug 00169-5176-03 | Novo | 8 inserts | $20.325 | AB | Availability likely | +268% |
| Yuvafem 10 ug 42291-0962-08 | AvKARE | 8 tablets | — | AB | FDA listed | — |
| Estradiol 10 ug 53746-0226-21 | Amneal | 8 inserts | — | AB | FDA listed | — |
| Estradiol 10 ug 63629-8803-01 | Bryant | 8 inserts | — | AB | FDA listed | — |
| Estradiol 10 ug 63629-8804-01 | Bryant | 18 inserts | — | AB | FDA listed | — |
| Imvexxy 10 ug 68308-0748-00 | Mayne | 2 inserts | — | AB | Discontinued | — |
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA Orange Book · refreshed Oct 3, 2026
- CMS NADAC weekly file · file of Sep 30, 2026
Availability & generic status
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?
- FDA Orange Book · refreshed Oct 3, 2026
What it looks like
Where does this data come from?
- FDA label on DailyMed · label index refreshed Oct 1, 2026
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 B1QE5P712K
Hypromellose 2208 is a plant-derived thickening agent that dissolves in water. It's used as a binder to help hold tablet ingredients together and as a coating on pills to control how quickly the medicine releases in your body.
-
UNII 36SFW2JZ0W
Hypromellose 2910 is a plant-based thickening agent derived from cellulose. In medicines, it forms a protective coating on tablets or capsules and controls how quickly the drug dissolves and releases into your body.
-
UNII EWQ57Q8I5X
Lactose monohydrate is a natural sugar derived from milk. It serves as a filler and binder in tablets and capsules, helping create the proper size, texture, and consistency of the medicine.
-
UNII 70097M6I30
Magnesium stearate is a salt made from magnesium and stearic acid, a fatty substance. It's used in tablets and capsules as a lubricant and glidant to help ingredients flow smoothly during manufacturing and prevent sticking.
-
UNII O8232NY3SJ
A plant-based carbohydrate derived from corn kernels. It acts as a filler to add bulk, a binder to hold ingredients together, and a disintegrant to help the tablet break apart in your stomach for absorption.
5 inactive ingredients listed in the exact product block matched to this NDC.
Where does this data come from?
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.- FDA label on DailyMed · label index refreshed Oct 1, 2026
- FDA openFDA NDC Directory · synced Oct 1, 2026
Inactive ingredient FAQ
Are inactive ingredients the same for every manufacturer?
Why might an inactive ingredient be missing?
Can inactive ingredients matter?
Manufacturer & labeler
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- Drugs@FDA
Full prescribing information FDA SPL
🚨 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 (5.3) ] .
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 (5.2) , 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 (5.4) , 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 (5.2 , 5.4) , 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 (5.2) , 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 (5.4) , 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 (5.2 , 5.4) , 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 (5.3) , 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 plus progestogen products… [Excerpted — this section continues on DailyMed.]
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Estradiol vaginal inserts are an estrogen indicated for the treatment of atrophic vaginitis due to menopause ( 1.1 )
1.1Treatment of Atrophic Vaginitis due to Menopause .
⏱️ Dosage and Administration ▾
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 (5.3 , 5.15) ] .
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. Administer estradiol vaginal inserts intravaginally: 1 insert daily for 2 weeks, followed by 1 insert twice weekly (for example, Tuesday and Friday) ( 2.1 )
2.1Treatment of Atrophic Vaginitis due to Menopause Administer estradiol vaginal inserts intravaginally using the supplied applicator: 1 insert daily for 2 weeks, followed by 1 insert twice weekly (for example, Tuesday and Friday).
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Estradiol vaginal inserts, USP are round, white to off-white, film-coated tablet debossed with “S” on one side and “10” on other side containing 10 mcg of estradiol. Each vaginal insert is 6 mm in diameter and is administered in a disposable applicator. Vaginal Insert: One 10 mcg vaginal insert contains 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS Estradiol is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.3) ]. Breast cancer or a history of breast cancer [see Warnings and Precautions (5.3) ]. Estrogen-dependent neoplasia [see Warnings and Precautions (5.3) ].
Active DVT, PE, or history of these conditions [see Warnings and Precautions (5.2) ]. Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions [see Warnings and Precautions (5.2) ]. Known anaphylactic reaction, or angioedema, or hypersensitivity to estradiol [see Warnings and Precautions (5.16) ] .
Hepatic impairment or disease. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. Undiagnosed abnormal genital bleeding ( 4 , 5.3 ) Breast cancer or a history of breast cancer ( 4 , 5.3 ) Estrogen-dependent neoplasia ( 4 , 5.3 ) Active DVT, PE, or history of these conditions ( 4 , 5.2 ) Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions ( 4 , 5.2 ) Known anaphylactic reaction, angioedema, or hypersensitivity to estradiol ( 4 , 5.16 ) Hepatic impairment or disease ( 4 , 5.11 ) Protein C, protein S, or antithrombin deficient, or other known thrombophilic disorders ( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Estrogens increase the risk of gallbladder disease ( 5.5 ) Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs ( 5.6 , 5.7 , 5.10 , 5.11 ) The estradiol vaginal inserts applicator may cause vaginal abrasion ( 5.18 ) Monitor thyroid function in women on thyroid replacement therapy ( 5.12 , 5.19 )
5.1Risks from Systemic Absorption Estradiol vaginal inserts are intended only for vaginal administration. Systemic absorption occurs with the use of estradiol. The warnings, precautions, and adverse reactions associated with the use of systemic estrogen-alone therapy should be taken into account.
5.2Cardiovascular 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 therapy 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 (14.2) ]. 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 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 placebo 2 [see Clinical Studies (14.2) ]. Subgroup analysis of women 50 to 59 years of age, who were less than 10 years since menopause, suggests 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 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 CHD. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not… [Excerpted — this section continues on DailyMed.]
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning , Warnings and Precautions (5.2) ] Malignant Neoplasms [see Boxed Warning , Warnings and Precautions (5.3) ] The most common adverse reactions (incidence ≥5 percent) with estradiol are: back pain, vulvovaginal pruritus, vulvovaginal mycotic infection and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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. In a 12-month randomized, double-blind, parallel group, placebo-controlled study, a total of 309 postmenopausal women were randomized to receive either placebo or estradiol 10 mcg inserts. Adverse reactions with an incidence of ≥5 percent in the estradiol 10 mcg group and greater than those reported in the placebo group are listed in Table 1.
N = Total number of women in study. n = Number of women who experienced adverse reactions. Table 1: Treatment-Emergent Adverse Reactions Reported at a Frequency of ≥ 5 Percent in Women Receiving Estradiol 10 mcg Body System Adverse Reaction Treatment Number (%) of Women Placebo N = 103 n (%) Estradiol N = 205 n (%) Body As A Whole Back Pain 2 (2) 14 (7) Digestive System Diarrhea 0 11 (5) Urogenital System Vulvovaginal Mycotic Infection 3 (3) 17 (8) Vulvovaginal Pruritus 2 (2) 16 (8)
6.2Postmarketing Experience The following adverse reactions have been identified during post-approval use of estradiol 10 mcg. 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. Gastrointestinal disorders Diarrhea General disorders and administration site conditions Drug ineffective Immune system disorders Hypersensitivity Investigations Blood estrogen increased Weight increased Metabolism and nutrition disorders Fluid retention Neoplasms benign and malignant Breast cancer Endometrial cancer Psychiatric disorders Depression Insomnia Central Nervous System Aggravated migraine Reproductive system and breast disorders Endometrial hyperplasia Vulvovaginal burning sensation Vulvovaginal pain Genital pruritus Vulvovaginal rash Vulvovaginal swelling Vaginismus Vaginal ulceration Skin and subcutaneous tissue disorders Rash Rash erythematous Rash pruritic Urticaria Vascular disorders Deep vein thrombosis
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS In-vitro and in-vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St.
John’s wort ( Hypericum perforatum ) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may 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 ▾
8 USE IN SPECIFIC POPULATIONS
8.1Pregnancy Risk Summary Estradiol is not indicated for use in pregnancy. There are no data with the use of estradiol 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 (estrogens 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 females. 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 and any potential adverse effects on the breastfed child from estradiol or from the underlying maternal condition.
8.4Pediatric Use Estradiol 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 to determine whether those over 65 years of age differ from younger subjects in their response to estradiol. 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 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 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 (5.4) , 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 (5.4) , and Clinical Studies (14.3) ].
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary Estradiol is not indicated for use in pregnancy. There are no data with the use of estradiol 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 (estrogens 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 ▾
8.4Pediatric Use Estradiol is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.
🧓 Geriatric Use ▾
8.5Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing estradiol to determine whether those over 65 years of age differ from younger subjects in their response to estradiol. 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 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 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 (5.4) , 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 (5.4) , and Clinical Studies (14.3) ].
🆘 Overdosage ▾
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 therapy with institution of appropriate symptomatic care.
🧬 Clinical Pharmacology ▾
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, 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 concentration does not predict an individual woman’s therapeutic response to estradiol 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 Estrogen drug products are well absorbed through the skin, mucous membranes, and the gastrointestinal tract. The vaginal delivery of estrogens circumvents first-pass metabolism. In a single-center, randomized, open-label, multiple-dose study conducted in 29 patients, estradiol 10 mcg demonstrated a mean estradiol (E2) C ave at Day 83 of 5.5 pg/mL after 12 weeks of treatment (see Table 2).
Table 2: Arithmetic Means of Estradiol (E2), Estrone (E1), and Estrone Sulfate (E1S) PK Parameters Following Multiple Doses a of Estradiol 10 mcg Uncorrected for baseline, N=29 a Patients received vaginal inserts as a once daily intravaginal treatment for the first 2 weeks and a twice weekly intravaginal maintenance for the following 10 weeks. b CV: Coefficient of Variance for both AUC 0-24 and C ave(0-24) E2 E1 E1S AUC 0-24 (h.pg/mL) C ave (0-24) (pg/mL) %CV b AUC 0-24 (h.pg/mL) C ave (0-24) (pg/mL) %CV b AUC 0-24 (h.pg/mL) C ave (0-24) (pg/mL) %CV b Day 1 242.08 10.09 33.02 485.21 20.22 44.86 5158.32 214.93
53.57Day 14 176.49 7.35 43.69 496.14 20.67 30.88 6323.41 263.48
50.07Day 83 132.04 5.50 59.69 411.08 17.13 39.58 3804.65 158.53
49.76Distribution 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 the 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 gut followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and su… [Excerpted — this section continues on DailyMed.]
🧬 Mechanism of Action ▾
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, 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 ▾
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1How Supplied Each Estradiol Vaginal Inserts USP, 10 mcg, is round, white to off-white, film-coated tablet debossed with “S” on one side and “10” on other side, contained in a disposable, single-use applicator, packaged in a blister pack. Cartons contain 8 or 18 applicators with inset inserts. Estradiol vaginal inserts USP, 10 mcg 8 applicators: NDC 59651-439-08 18 applicators: NDC 59651-439-18 Keep out of reach of children.
16.2Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Do not refrigerate.
📋 Description ▾
11 DESCRIPTION Estradiol vaginal inserts USP, 10 mcg are round, white to off-white, film-coated tablets debossed with “S” on one side and “10” on other side containing 10.3 mcg of estradiol hemihydrate USP equivalent to 10 mcg of estradiol USP. Each insert of estradiol vaginal inserts USP, 10 mcg contains the following excipients: corn starch, hypromellose, lactose monohydrate and magnesium stearate. Each estradiol vaginal inserts, USP is 6 mm in diameter and is placed in a disposable applicator.
Each insert-filled applicator is packaged separately in a blister pack. Estradiol vaginal inserts, USP are used intravaginally. When the insert comes in contact with the vaginal mucosa, estradiol is released into the vagina.
Estradiol hemihydrate is a white or creamy white, small crystals or crystalline powder, chemically described as estra-1,3,5 (10)-triene-3,17β-diol. The chemical formula is C 18 H 24 O 2 • ½ H 2 O with a molecular weight of 281.4. The structural formula is: FDA approved IVR method and acceptance criteria differs from the USP IVR method and acceptance criteria str
💬 Information for Patients ▾
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 (5.3) ]. 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 (5.2 , 5.3 , 5.4) ].
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. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India Revised: 09/2025
🧬 Pharmacokinetics ▾
12.3Pharmacokinetics Absorption Estrogen drug products are well absorbed through the skin, mucous membranes, and the gastrointestinal tract. The vaginal delivery of estrogens circumvents first-pass metabolism. In a single-center, randomized, open-label, multiple-dose study conducted in 29 patients, estradiol 10 mcg demonstrated a mean estradiol (E2) C ave at Day 83 of 5.5 pg/mL after 12 weeks of treatment (see Table 2).
Table 2: Arithmetic Means of Estradiol (E2), Estrone (E1), and Estrone Sulfate (E1S) PK Parameters Following Multiple Doses a of Estradiol 10 mcg Uncorrected for baseline, N=29 a Patients received vaginal inserts as a once daily intravaginal treatment for the first 2 weeks and a twice weekly intravaginal maintenance for the following 10 weeks. b CV: Coefficient of Variance for both AUC 0-24 and C ave(0-24) E2 E1 E1S AUC 0-24 (h.pg/mL) C ave (0-24) (pg/mL) %CV b AUC 0-24 (h.pg/mL) C ave (0-24) (pg/mL) %CV b AUC 0-24 (h.pg/mL) C ave (0-24) (pg/mL) %CV b Day 1 242.08 10.09 33.02 485.21 20.22 44.86 5158.32 214.93
53.57Day 14 176.49 7.35 43.69 496.14 20.67 30.88 6323.41 263.48
50.07Day 83 132.04 5.50 59.69 411.08 17.13 39.58 3804.65 158.53
49.76Distribution 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 the 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 gut followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
🧬 Pharmacodynamics ▾
12.2Pharmacodynamics Generally, a serum concentration does not predict an individual woman’s therapeutic response to estradiol 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 ▾
14 CLINICAL STUDIES
14.1Effects on Atrophic Vaginitis in Postmenopausal Women A 12-month double-blind, randomized, parallel group, placebo-controlled multicenter study was conducted in the U.S. and Canada to evaluate the efficacy and safety of estradiol 10 mcg in the treatment of atrophic vaginitis in 309 postmenopausal women between 46 and 81 years of age (mean 57.6 years of age) who at baseline identified their most bothersome symptom of atrophic vaginitis from among six symptoms (vaginal dryness, vaginal and/or vulvar irritation/itching, vaginal soreness, dysuria, dyspareunia and vaginal bleeding associated with intercourse).
Women inserted one insert intravaginally each day for 14 days, then one insert twice weekly for the remaining 50 weeks. The majority (92.9 percent) of the women were Caucasian (n=287), 3.2 percent were Black (n=10), 1.6 percent were Asian (n=5) and 2.2 percent were Other (n=7). All participants were assessed for improvement in the mean change from baseline to Week 12 for co-primary efficacy variables of: a composite of most bothersome symptoms of atrophic vaginitis; percentage of vaginal superficial cells and percentage of vaginal parabasal cells on a vaginal smear; and vaginal pH.
Relief of Vaginal Symptoms Estradiol 10 mcg was statistically superior to placebo in reducing the severity of a composite score of most bothersome symptoms associated with atrophic vaginitis at Week 12 (see Table 3). Table 3: Mean Change from Baseline to Week 12 in a Composite Score of Most Bothersome Symptoms Compared to Placebo – ITT Population a Placebo Estradiol 10 mcg ITT Population a N 93 190 Baseline mean composite score 2.29
2.35Change from baseline at Week 12 (LOCF) -0.84 -1.20 p-value versus Placebo --- 0.002 a All randomized subjects who received at least one dose of study drug and had at least one post-baseline evaluation. Also demonstrated for estradiol 10 mcg compared to placebo was a statistically significant increase in the percentage of superficial cells at Week 12 (13.2 percent compared to 3.8 percent for matching placebo, p<0.001), a statistically significant decrease in parabasal cells at Week 12 (-37.0 percent compared to -9.3 percent for matching placebo, p<0.001), and a statistically significant mean reduction between baseline and Week 12 in vaginal pH score (-1.3 compared to -0.4 for matching placebo, p<0.001).
Endometrial safety was assessed by endometrial biopsy at the screening and final study visit. Of the 172 women in the estradiol 10 mcg group who had a biopsy performed at end of study, 92 women had endometrial tissue that was atrophic or inactive and 73 women had no tissue or tissue insufficient for diagnosis. There was one case of adenocarcinoma grade 2 and one case of complex hyperplasia without atypia.
Three women exhibited polyps (two atrophic polyps and one adenomyomatus type polyp) and two others had adenomyosis and an atypical epithelial proliferation. Endometrial safety of estradiol 10 mcg was additionally evaluated in a second, 12 month, open-label, multicenter safety study. Of the 297 women who had a biopsy performed at end of study, 183 women had endometrial tissue that was atrophic or inactive and 111 women had no tissue or tissue insufficient for diagnosis.
There was one case of complex hyperplasia without atypia. Two women exhibited polyps.
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… [Excerpted — this section continues on DailyMed.]
🧪 Nonclinical Toxicology ▾
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 ▾
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 ▾
15 REFERENCES Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA .
2007; 297:1465-1477. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease.
Arch Int Med . 2006; 166:357-365. Curb JD, et al.
Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006; 166:772-780.
Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA.
2004; 292:1573-1580. 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. Chlebowski RT, et al.
Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003; 289:3234-3253.
Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic cancers and Associated Diagnostic Procedures. JAMA.
2003; 290:1739-1748. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women.
JAMA . 2004; 291:2947-2958. 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.
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 ▾
PATIENT INFORMATION Estradiol (es″ tra dye′ ol) Vaginal Inserts, USP Read this Patient Information before you start using estradiol vaginal inserts 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 vaginal inserts (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 vaginal inserts. 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 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 attack, strokes or dementia. Using estrogens with progestogens may increase your chances of getting blood clots, strokes, heart attacks, or breast cancer.
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 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 vaginal inserts will affect your chances of these conditions.
You and your healthcare provider should talk regularly about whether you still need treatment with estradiol vaginal inserts. What is estradiol vaginal insert? Estradiol vaginal insert is a prescription medicine that contains estradiol (an estrogen hormone) in a vaginal insert.
What is estradiol vaginal insert used for? Estradiol vaginal insert is used after menopause to: 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 vaginal insert to control these problems. Who should not use estradiol vaginal inserts?
Do not start using estradiol vaginal inserts 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 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 vaginal inserts. had a stroke or heart attack currently have or have had blood clots currently have or have had liver problems are allergic to estradiol vaginal inserts or any of the ingredients in it.
See the list of ingredients in estradiol vaginal inserts at the end of this leaflet. Before you use estradiol vaginal inserts, tell your healthcare provider about all of your medical conditions, including 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 any other medical conditions that may become worse while you are using estradiol vaginal inserts Your healthcare provider may need to check you more carefully if you have certain conditions, such as… [Excerpted — this section continues on DailyMed.]
📄 Package Label / Principal Display Panel ▾
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 10 mcg (8 vaginal inserts) NDC 59651-439-08 Estradiol Vaginal Inserts, USP 10 mcg Rx only 8 vaginal inserts AUROBINDO PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 10 mcg (8 Inserts)