Estradiol

Introduction Overview

Generic Name

estradiol

Brand Name

Yuvafem

Dosage Form

vaginal tablet (vaginal insert)

Drug Class

Estrogens; Miscellaneous vaginal agents

Pharmacokinetics

Absorption:
Yuvafem delivers estradiol vaginally, allowing absorption directly through the vaginal mucosa. Vaginal administration circumvents the first-pass hepatic metabolism typical of oral estrogens, resulting in measurable but relatively low systemic estradiol levels. In a multiple-dose pharmacokinetic study involving postmenopausal women, estradiol concentration (Cave) at steady state after 12 weeks of treatment was approximately 5.5 pg/mL, substantially lower than systemic exposures seen with oral estrogen therapies. Absorption kinetics demonstrate consistent plasma estradiol and its metabolites (estrone and estrone sulfate) with repeated dosing, achieving relatively stable plasma concentrations reflecting steady-state exposure.

Distribution:
Estradiol, both endogenous and exogenous, is widely distributed throughout the body, with higher concentrations in estrogen target tissues such as reproductive organs. In plasma, estradiol predominantly binds to sex hormone-binding globulin (SHBG) and albumin, which regulate its bioavailability and distribution. The distribution profile of vaginally administered estradiol is similar to that of endogenous hormone, with systemic exposure generally limited but sufficient for local therapeutic effects. The pharmacokinetic profile confirms limited systemic distribution but highlights the potential for systemic exposure, necessitating awareness of systemic estrogenic effects.

Metabolism:
Estradiol undergoes extensive metabolism primarily in the liver through reversible interconversion with estrone and subsequent conversion to estriol, which is the major urinary metabolite. Additional pathways include conjugation reactions resulting in sulfate and glucuronide derivatives that enter enterohepatic recirculation, contributing to prolonged estrogen availability. In postmenopausal women, estrone sulfate serves as a circulating reservoir, facilitating conversion back to active estradiol. Vaginal delivery limits first-pass metabolism but metabolic pathways remain operative once estradiol enters systemic circulation.

Elimination:
The metabolic breakdown products of estradiol, including estrone, estriol, and their conjugates, are primarily excreted via urine. Biliary excretion via bile and feces occurs through conjugated metabolites undergoing enterohepatic recirculation. The elimination half-life of estradiol after vaginal administration is consistent with endogenous hormone turnover. The elimination pattern supports sustained local estrogen effects with low systemic accumulation, which is clinically relevant for minimizing systemic adverse effects.

Dosage Forms

Available Dosage Forms:
Yuvafem is supplied as a vaginal insert (tablet), white to off-white, small, round, biconvex, film-coated vaginal tablets with a diameter of 6 mm. Each insert contains 10 mcg of estradiol (equivalent to 10.3 mcg estradiol hemihydrate). The vaginal insert is contained within a disposable, single-use applicator.

Dosages for Adults and Adolescents:
The recommended dosing regimen for postmenopausal women to treat moderate to severe symptoms of vulvar and vaginal atrophy is one vaginal insert daily for the initial 2 weeks, followed by maintenance dosing with one insert twice weekly, spaced several days apart (e.g., Tuesday and Friday). Dosage adjustments should be individualized based on symptom severity and clinical response.

Specific Patient Populations:
Yuvafem is intended for use in postmenopausal women. It is not indicated for pediatric use, and safety and efficacy have not been established in this population. Use in geriatric women has not been extensively studied; however, given systemic absorption, caution is warranted due to higher risks of cardiovascular and neoplastic adverse events in older women. Women with a uterus should be assessed for the need for adjunct progestogen therapy to reduce endometrial cancer risk.

Packaging:
Yuvafem is supplied in cartons containing either 8 or 18 individually blister-packaged applicators with vaginal inserts.

Mechanism Of Action

Yuvafem contains estradiol, the principal and most biologically active form of endogenous estrogen. Estradiol exerts its effects primarily through specific binding to estrogen receptors (ERs) located in the nuclei of estrogen-responsive cells, notably ER-alpha and ER-beta, which are distributed variably across target tissues. Upon hormone binding, the estradiol-receptor complex undergoes conformational changes allowing it to bind estrogen response elements on DNA, modulating transcription of estrogen-responsive genes.

In the vaginal epithelium and underlying connective tissue, estradiol promotes proliferation, vascularization, and maintenance of mucosal integrity and lubrication by increasing glycogen content and epithelial cell maturation. It counteracts the vaginal atrophy that occurs after menopause due to estrogen deficiency by restoring thickness, elasticity, and hydration of the vaginal mucosa.

Estradiol also exerts systemic endocrine effects by feedback inhibition of hypothalamic-pituitary axis gonadotropins (LH and FSH), which modulate endogenous hormonal homeostasis. This fine regulation supports the therapeutic benefits of estradiol in menopausal hormone therapy while necessitating vigilance for systemic estrogen effects.

Compared to other estrogenic therapies, vaginal administration of estradiol via Yuvafem achieves targeted local therapy with lower systemic exposure, reducing risks associated with oral estrogens. Clinical studies confirm that Yuvafem improves vaginal atrophy symptoms effectively while maintaining a favorable safety profile related to its mechanistic targeting of estrogen receptors in urogenital tissues.

Pharmacological Actions

Replacement therapy for estrogen deficiency in postmenopausal women to treat vaginal atrophy symptoms.
Local estrogenic stimulation of vaginal epithelium resulting in restoration of mucosal thickness and function.
Modulation of gene expression via nuclear estrogen receptors leading to proliferation and differentiation of vaginal epithelial cells.
Negative feedback on pituitary gonadotropin secretion, reducing elevated LH and FSH levels in postmenopausal women.
Improvement of vaginal pH and reduction of parabasal cells enhancing vaginal microbiota and mucosal health.
Amelioration of vulvovaginal symptoms including dryness, itching, soreness, and dyspareunia.
Reduction of urinary symptoms associated with atrophic urethritis and vaginal atrophy.
Lower systemic estrogen exposure compared to oral estrogens, reducing systemic side effects burden.
Limited hepatic first-pass metabolism due to vaginal administration route.
Potential effects on lipid metabolism and coagulation proteins as part of systemic estrogen actions.

Therapeutic Or Clinical Uses

Treatment of moderate to severe vulvar and vaginal atrophy in postmenopausal women.
Alleviation of symptoms such as vaginal dryness, irritation, itching, soreness, dyspareunia, and dysuria related to estrogen deficiency.
Management of atrophic vaginitis resulting from menopause to improve quality of life.
Adjunct therapy in women with hypoestrogenism induced by hypogonadism, castration, or primary ovarian failure when appropriate.
Local hormone replacement to minimize systemic exposure in symptomatic postmenopausal women.
Reduction of vaginal pH and restoration of vaginal flora balance to prevent recurrent infections.
Supportive therapy in women with urogenital symptoms related to menopause.
Improvement of vaginal mucosal integrity to decrease susceptibility to trauma and infections.
Alternative to systemic estrogen therapy in women contraindicated for oral estrogen use.
Potential reduction in urinary tract infections and irritative symptoms associated with mucosal atrophy.

Side Or Adverse Effects

Back pain reported in approximately 7% of patients in clinical trials.
Vulvovaginal pruritus (itching) experienced by around 8% of users.
Vulvovaginal mycotic infections reported in approximately 8% of women.
Diarrhea occurring in about 5% of treated women.
Headache, including migraine exacerbation.
Breast pain and tenderness.
Irregular vaginal bleeding or spotting.
Stomach or abdominal cramps and bloating.
Nausea and vomiting.
Hair loss (alopecia).
Fluid retention leading to edema.
Vaginal yeast infections noted as local adverse effects.
Rare reports of hypersensitivity reactions including rash, urticaria, and angioedema.
Risk of venous thromboembolism including deep vein thrombosis and pulmonary embolism.
Potential increased risk of endometrial hyperplasia, malignancy when used without progestogen in women with uterus.

Precautions

Use the lowest effective dose for the shortest duration consistent with treatment goals.
Monitor for any vaginal bleeding and evaluate promptly to exclude endometrial pathology.
Consider adding a progestogen in women with intact uterus to reduce risk of endometrial hyperplasia or cancer.
Discontinue immediately if signs or symptoms of thromboembolism, stroke, myocardial infarction, or liver dysfunction develop.
Exercise caution in women with a history of cardiovascular disease, thrombophilia, or hepatic impairment.
Monitor blood pressure regularly due to possible elevations.
Track triglyceride levels in patients with hypertriglyceridemia history to prevent pancreatitis.
Be vigilant for exacerbation of asthma, epilepsy, diabetes, migraine, lupus erythematosus, and porphyria.
Use cautiously in women with history of gallbladder disease due to increased risk of gallstones.
Adjust thyroid hormone replacement therapy in women concurrently treated for hypothyroidism.
Assess hereditary angioedema history carefully before use due to potential symptom exacerbation.
Avoid use during prolonged immobilization or prior to major surgery associated with thromboembolism risk.
Evaluate liver function periodically with clinical and laboratory tests.
Avoid use in pregnancy and lactation unless clearly indicated with risk-benefit assessment.
Advise patients on proper vaginal insertion technique to minimize local irritation or abrasion.

Warnings

Increased risk of endometrial cancer in women with a uterus using unopposed estrogen therapy.
Elevated risk of cardiovascular disorders including stroke, deep vein thrombosis, pulmonary embolism, and myocardial infarction.
Potential increased risk of probable dementia in postmenopausal women aged 65 and older.
Do not use estrogen alone or with progestogen for prevention of cardiovascular disease or dementia.
Increased risk of invasive breast cancer with combined estrogen plus progestogen therapy.
Discontinue estrogen therapy if visual disturbances or significant hypercalcemia occur.
Increased risk of gallbladder disease requiring surgery in postmenopausal women.
Risk of venous thromboembolism; caution advised with history or risk factors for thromboembolic events.
Possible exacerbation of existing conditions including asthma, epilepsy, diabetes, migraine, lupus.
Discontinue therapy if signs of hepatic dysfunction such as cholestatic jaundice develop.
Monitor for local vaginal irritation; vaginal abrasions secondary to applicator use have been reported.
Evaluate breast health regularly including mammography and clinical examinations.
Inform patients of serious adverse effects including thrombotic events and malignancies.
Use cautiously in women with a history of endometriosis as malignant transformation risks exist.
Avoid use in women with known hypersensitivity to estradiol or any ingredient of Yuvafem.

Contraindication

Known or suspected estrogen-dependent neoplasia including breast cancer.
Undiagnosed abnormal genital bleeding.
Active or history of deep vein thrombosis or pulmonary embolism.
Active or history of arterial thromboembolic disease such as stroke or myocardial infarction.
Known hypersensitivity to estradiol or any component of the formulation.
Severe hepatic impairment or active liver disease.
Known thrombophilic disorders including deficiencies of protein C, protein S, or antithrombin.
Pregnancy and lactation.
Known or suspected malignancies of the breast or reproductive tract.
Women with unexplained vaginal bleeding until diagnosis is established.
History of hypersensitivity reactions including anaphylaxis or angioedema attributed to estrogens.
Use in pediatric patients as safety and efficacy have not been established.
Women with current or past history of malignant tumors sensitive to estrogens.
Contraindicated in patients with severe hypertriglyceridemia.
Women with conditions that could be exacerbated by estrogens such as porphyria or systemic lupus erythematosus.

Drug Interactions

Inducers of CYP3A4 such as rifampin, carbamazepine, phenobarbital, and St. John's wort may decrease estradiol plasma concentrations, reducing efficacy.
Inhibitors of CYP3A4 including erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice may increase estradiol plasma levels, heightening the risk of adverse effects.
Concurrent use with thyroid hormone replacement therapy may require dose adjustments due to increased thyroid-binding globulin induced by estrogens.
Estrogens may alter coagulation factors and interact with anticoagulants affecting bleeding risk.
Potential interactions with corticosteroids and other hormone therapies due to changes in binding proteins like corticosteroid-binding globulin and sex hormone-binding globulin.
Estrogens can influence glucose tolerance; caution advised with antidiabetic medications.
Concomitant use with drugs affecting lipid metabolism may alter lipid profiles.
Estrogens may affect the metabolism and plasma levels of cyclosporine.
Drugs affecting liver enzyme activity may alter estrogen levels and potentially therapeutic outcomes.
Potential interaction with medications metabolized by CYP3A4 mandates careful monitoring.
Drug interactions may change the bleeding profile and therapeutic response of estrogen therapy.
Careful evaluation of all concomitant medications is recommended before or during Yuvafem therapy.
Patients should be advised to report any new medications or supplements to their healthcare provider.
Pharmacokinetic interactions might affect both the efficacy and safety of Yuvafem.
Combination with other estrogenic compounds can potentiate estrogenic effects and side effects.

Preparations Of The Drug

Yuvafem vaginal insert: white to off-white, round, biconvex, film-coated vaginal tablets, 6 mm diameter.
Each insert contains 10 mcg estradiol (10.3 mcg estradiol hemihydrate).
Supplied in a disposable, single-use applicator for intravaginal administration.
Available in cartons containing 8 or 18 applicator-insert units, individually blister-packaged.
Formulation excipients include corn starch, hypromellose, lactose monohydrate, magnesium stearate.
Film coating consists of hypromellose and polyethylene glycol (PEG).
Storage conditions recommend room temperature between 20°C to 25°C (68°F to 77°F).
Do not refrigerate; protect from excessive heat or moisture.
Each unit dose is designed for once-daily insertion initially; maintenance dosing twice weekly.
Packaging specifications ensure sterility and stability of the product until use.
Blister packs facilitate individual dosing adherence and product protection.
Provided with detailed patient instructions and applicator use guidelines.
Manufactured and distributed by Amneal Pharmaceuticals LLC.
NDC for 8-count carton: 65162-226-21; NDC for 18-count carton: 65162-226-23.
Proper disposal of used applicators and inserts is advised as per healthcare guidance.