Estradiol Vaginal Insert

The following serious adverse reactions are discussed elsewhere in the labeling:

Clinical 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 vaginal 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.

In a 12-week, randomized, double-blind, placebo-controlled study, 138 postmenopausal women were randomized to receive either placebo or estradiol 25 mcg vaginal inserts. Adverse reactions with an incidence of ≥ 5 percent in the estradiol 25 mcg group and greater than those reported in the placebo group are listed in Table 2.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of estradiol 25 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.

Genitourinary System

Endometrial cancer, endometrial hyperplasia, vaginal irritation, vaginal pain, vaginismus, vaginal ulceration

Breast

Breast cancer

Cardiovascular

Deep vein thrombosis

Gastrointestinal

Diarrhea

Skin

Urticaria, erythematous or pruritic rash, genital pruritus

Central Nervous System

Aggravated migraine, depression, insomnia

Miscellaneous

Fluid retention, weight increase, drug ineffectiveness, hypersensitivity, blood estrogen increase

Additional postmarketing adverse reactions have been reported in patients receiving other forms of hormone therapy.

Mechanism 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.

Pharmacodynamics

Currently, there are no pharmacodynamic data known for estradiol.

Pharmacokinetics

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, parallel group study conducted in 58 patients, estradiol 10 mcg and 25 mcg demonstrated a mean estradiol (E2) Cave at Day 83 of 5.5 pg/mL and 11.59 pg/mL, respectively after 12 weeks of treatment (see Tables 3 and 4).

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 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.

Use in Specific Populations

No pharmacokinetic studies were conducted in specific populations, including patients with renal or hepatic impairment.

Carcinogenesis, 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.

How Supplied

Estradiol Vaginal Inserts USP, 10 mcg, are white to off-white, round, film-coated, unscored, biconvex inserts, debossed with "TV" on one side and "T5" on the other side. Each insert is 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 0093-3223-08

18 applicators: NDC 0093-3223-97

Keep out of reach of children

Storage and Handling

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Do not refrigerate.

ESTRADIOL (es tra DYE ole) vaginal ring is an insert that contains a female hormone. This medicine helps relieve symptoms of vaginal irritation and dryness that occurs in some women during menopause. This medicine can also help relieve hot flashes.

This drug also comes in other forms, including Topical emulsion, Topical gel, Topical solution, spray, Oral tablet, Vaginal tablet, Vaginal cream, Injectable solution, Transdermal patch, ... more

This drug can cause serious side effects. See which side effects you should report to your doctor right away.

Know how to use your medication, and learn what might happen if you miss a dose.

Talk to your healthcare provider if you have any of these conditions.

Know what to watch for and get tips for reducing your risks while taking this drug.

Do not take this medicine with any of the following medications:

• aromatase inhibitors like aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole

This medicine may also interact with the following medications:

• carbamazepine
• certain antibiotics used to treat infections
• certain barbiturates used for inducing sleep or treating seizures
• grapefruit juice
• medicines for fungus infections like itraconazole and ketoconazole
• raloxifene or tamoxifen
• rifabutin, rifampin, or rifapentine
• ritonavir
• St. John's Wort