Estradiol .25 mg/.25g Gel, 30 packets
Other active recalls for Estradiol (different manufacturers) — 4 · tap to view
🆔 Identity & classification
Where does this data come from?
🏷️ RxNorm drug class
This medicine belongs to the Radioactive Diagnostic Agent class.
Where does this data come from?
🏭 Manufacturer & labeler
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🩺 Clinical
- Estradiol is a form of estrogen — the main hormone your ovaries produce. It's most commonly prescribed to relieve moderate to severe menopausal symptoms like hot flashes and vagina...
- Apply your patch to clean, dry skin — typically on your lower abdomen. Don't put it on your breasts or the same spot two patches in a row. Climara and Menostar are changed once a w...
- Yes, and it's important to be aware of them. Estradiol — especially when combined with a progestogen — can raise the risk of blood clots, stroke, and breast cancer. Women with a ut...
- Are there serious risks I need to know about?
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?
Ask a licensed pharmacist directly — free, answered by our team.
🧪 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.
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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.
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UNII 4Q93RCW27E
A synthetic polymer made from acrylic acid that's crosslinked for stability. It acts as a thickener and gelling agent in creams and gels, helping the medicine spread evenly and maintain its texture.
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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.
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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.
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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.
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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?
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💲 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 | $0.864 | $25.91 / 30 packets |
| Medicaid paysCMS SDUD · 12 mo | $1.65 | $49.59 / 30 packets |
| Medicare drug plans payPart D · Q2 2026 | $3.26 | $97.81 / 30 packets |
Where does this data come from?
🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Estradiol .25 mg/.25g 13811-0090-32 | Trigen | 30 packets | $0.864 | AB | Availability likely | — |
| Estradiol Gel .25 mg/.25g 21922-0086-52 | Encube | 30 packets | $0.864 | AB | Availability likely | — |
| Estradiol .25 mg/.25g 45802-0134-30 | Padagis | 30 packets | $0.864 | AB | Availability likely | — |
| Estradiol .25 mg/.25g 69238-2452-03 | Amneal | 30 packets | $0.864 | AB | Availability likely | — |
| Estradiol .25 mg/.25g 70700-0143-35 | Xiromed, | 30 packets | $0.864 | AB | Availability likely | — |
| Estradiol .25 mg/.25g 70954-0531-20 | ANI | 30 packets | $0.864 | AB | Availability likely | — |
| Estradiol .25 mg/.25gthis 72603-0241-30 | NorthStar | 30 packets | $0.864 | AB | Availability likely | — |
| Divigel .25 mg/.25g 68025-0065-07 | Vertical | 7 packets | — | AB | FDA listed | — |
| Estradiol .25 mg/.25g 72162-2290-03 | Bryant | 30 packets | — | AB | FDA listed | — |
Where does this data come from?
⏳ 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?
🗺️ Medicaid utilization & spend
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 72603-0241-30 You're viewing this | 30 PACKET in 1 CARTON (72603-241-30) / .25 g in 1 PACKET (72603-241-01) | 2023-12-18 | Active |
📄 Full prescribing information FDA SPL
🚨 Boxed Warning ▾
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 plus progestogen products is not known.…
🎯 Indications and Usage ▾
1 INDICATIONS & USAGE
1.1Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Estradiol gel is an estrogen indicated for the treatment of moderate to severe vasomotor symptoms due to menopause (1.1).
⏱️ Dosage and Administration ▾
2 DOSAGE & 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 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 to the right or left upper thigh on alternating days. Do not apply estradiol gel 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. Avoid contact of the gel with eyes.
Wash hands after application.
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS & 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 is a clear, colorless smooth gel, free from visible particulate matter. 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 ▾
4 CONTRAINDICATIONS Estradiol gel is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding [see Warning and Precautions (5.2)] Breast cancer or history of breast cancer [see Warning and Precautions (5.2)] Estrogen-dependent neoplasia [see Warning and Precautions (5.2)] Active DVT, PE, or history of these conditions [see Warning and Precautions (5.1)] Active arterial thromboembolic disease (e.g. stroke and MI), or a history of these conditions [see Warning and Precautions (5.1)] Known anaphylactic reaction, angioedema, or hypersensitivity to estradiol gel Hepatic impairment or disease Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Undiagnosed abnormal genital bleeding (4) Breast cancer or a history of breast cancer (4, 5.2) Estrogen-dependent neoplasia (4, 5.2) Active DVT, PE, or history of these conditions (4, 5.1) Active arterial thromboembolic disease (e.g., stroke and MI), or history of these conditions (4, 5.1) Known anaphylactic reaction, angioedema, or hypersensitivity to estradiol gel (4) Hepatic impairment or disease (4, 5.10) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders (4)
⚠️ Warnings ▾
5 WARNINGS AND PRECAUTIONS WARNINGS AND PRECAUTIONS
5.1Cardiovascular Disorders Increased risks of stroke and DVT are reported with estrogen-alone therapy. Increased risk of PE, DVT, stroke and MI are reported with estrogen plus progestin therapy. Immediately discontinue estrogen with or without progestogen therapy if any of these occur or are suspected.
Manage appropriately any risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus). 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 and the placebo group in HERS, HERS II, and overall. Venous Thromboembolism In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although…
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)] . Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)] . The most common adverse reactions (incidence >5 percent and greater than placebo) in any estradiol gel treatment group are metrorrhagia, breast tenderness, vaginal mycosis, nasopharyngitis, and upper respiratory tract infection (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Northstar RxLLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Estradiol gel was studied at doses of 0.25, 0.5 and 1.0 gram per day in a 12-week, double-blind, placebo-controlled study that included a total of 495 postmenopausal women (86.5 percent Caucasian). The adverse reactions that occurred at a rate greater than 5 percent and greater than placebo in any of the treatment groups are summarized in Table 1.
Table 1: Number (%) of Subjects with Common Adverse Reactions* in a 12-Week Placebo-Controlled Study of Estradiol Gel Estradiol Gel Placebo SYSTEM ORGAN CLASS Preferred Term 0.25 grams/day N=122 n (%) 0.5 grams/ day N=123 n (%) 1.0 gram/day N=125 n (%) N=125 n (%) INFECTIONS & INFESTATIONS Nasopharyngitis 7(5.7) 5(4.1) 6(4.8) 5(4.0) Upper Respiratory Tract Infection 7(5.7) 3(2.4) 2(1.6) 2(1.6) Vaginal mycosis 1(0.8) 3(2.4) 8(6.4) 4(3.2) REPRODUCTIVE SYSTEM & BREAST DISORDERS Breast Tenderness 3(2.5) 7(5.7) 11(8.8) 2(1.6) Metrorrhagia 5(4.1) 7(5.7) 12(9.6) 2(1.6) *Adverse reactions reported by >5 percent of patients in any treatment group.
In a 12-week placebo-controlled study of estradiol gel, application site reactions were seen in <1 percent of participating women.
6.2Postmarketing Experience The following adverse reactions have been identified during post-approval use of estradiol gel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Genitourinary System Amenorrhea, dysmenorrhea, ovarian cyst, vaginal discharge Breasts Gynecomastia Cardiovascular Palpitations, ventricular extrasystoles Gastrointestinal Flatulence Skin Rash pruritic, urticaria Eyes Retinal vein occlusion Central Nervous System Tremor Miscellaneous Arthralgia, application site rash, asthenia, chest discomfort, fatigue, feeling abnormal, heart rate increased, insomnia, malaise, muscle spasms, pain in extremity, weight increased.
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St.
John's wort ( Hypericum perforatum ) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice, may increase plasma concentrations of estrogens and result in adverse reactions. Inducers and inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration (7).
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS USE IN SPECIFIC POPULATIONS
8.1Pregnancy Risk Summary Estradiol gel is not indicated for use in pregnant women. There are no data with the use of estradiol gel in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
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 and any potential adverse effects on the breastfed child from estradiol gel or from the underlying maternal condition.
8.4Pediatric Use Estradiol gel is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.
8.5Geriatric Use There have not been sufficient numbers of geriatric women involved in studies utilizing estradiol gel to determine whether those over 65 years of age differ from younger subjects in their response to estradiol gel. The Women's Health Initiative Studies In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Warnings and Precautions (5.1) and Clinical Studies (14.2)] . 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 ▾
8.1Pregnancy Risk Summary Estradiol gel is not indicated for use in pregnant women. There are no data with the use of estradiol gel in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
🧒 Pediatric Use ▾
8.4Pediatric Use Estradiol gel is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.
🧓 Geriatric Use ▾
8.5Geriatric Use There have not been sufficient numbers of geriatric women involved in studies utilizing estradiol gel to determine whether those over 65 years of age differ from younger subjects in their response to estradiol gel. The Women's Health Initiative Studies In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Warnings and Precautions (5.1) and Clinical Studies (14.2)] . 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 ▾
10 OVERDOSAGE Overdosage of estrogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding in women. Treatment of overdose consists of discontinuation of estradiol gel therapy with institution of appropriate symptomatic care.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY 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 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 demonstrated linear and approximately dose-proportional estradiol pharmacokinetics at steady state for both AUC0-24 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 0.25 grams Estradiol Gel 0.5 grams Estradiol Gel 1.0 gram AUC 0-24 (pg•h/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 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% The effect of sunscreens and other topical lotions on the systemic exposure of estradiol gel 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 unde…
🧬 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, 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 ▾
16 HOW SUPPLIED/STORAGE AND HANDLING HOW SUPPLIED/STORAGE AND HANDLING
16.1How Supplied Estradiol Gel, 0.1% is a clear, colorless smooth gel, free from visible particulate matter, 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 72603-241-30, carton of 30 packets, 0.25 mg estradiol per single-dose foil packet (NDC 72603-241-01) NDC 72603-242-30, carton of 30 packets, 0.5 mg estradiol per single-dose foil packet (NDC 72603-242-01) NDC 72603-243-30, carton of 30 packets, 0.75 mg estradiol per single-dose foil packet (NDC 72603-243-01) NDC 72603-244-30, carton of 30 packets, 1.0 mg estradiol per single-dose foil packet (NDC 72603-244-01) NDC 72603-245-30, carton of 30 packets, 1.25 mg estradiol per single-dose foil packet (NDC 72603-245-01) Keep out of the 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].
📋 Description ▾
11 DESCRIPTION Estradiol Gel, 0.1% is a clear, colorless smooth gel, free from visible particulate matter. 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 cm 2 ) of the thigh in a thin layer.
Estradiol gel 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 (carbomer, alcohol [62%], propylene glycol, purified water, and trolamine) are pharmacologically inactive. estradiol-structure
💬 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 (5.2)] . Unintentional Secondary Exposure to Estradiol gel Inform women about the possibility of secondary exposure to estradiol gel Apply estradiol gel 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 when around children. Pets may also be unintentionally exposed to estradiol gel 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. Trademarks are the property of their respective owners. Manufactured for: Northstar Rx LLC Memphis, TN 38141 Manufactured by: Novitium Pharma LLC East Windsor, NJ 08520 Rev.
09/2024 LB4679-02