PROGYNOVA

Valerate (also known as E2V) is a pro-drug ester of Estradiol, a naturally occurring hormone that circulates endogenously within the human body.

Estradiol is the most potent form of all mammalian estrogenic steroids and acts as the major female sex hormone.

As a pro-drug of estradiol, estradiol acetate therefore has the same downstream effects within the body through binding to the Estrogen Receptor (ER) including ERα and ERβ subtypes, which are located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain.

Estradiol is commonly produced with an ester side-chain as endogenous estradiol has very low oral bioavailability on its own (2-10%).

First-pass metabolism by the gut and the liver quickly degrades the estradiol molecule before it gets a chance to enter systemic circulation and exert its estrogenic effects 9.

Esterification of estradiol aims to improves absorption and bioavailability after oral administration (such as with Estradiol valerate) or to sustain release from depot intramuscular injections (such as with Estradiol Cypionate) through improved lipophilicity.

Following absorption, the esters are cleaved, resulting in the release of endogenous estradiol, or 17β-estradiol.

Ester pro-drugs of estradiol are therefore considered to be bioidentical forms of estrogen 12.

Estradiol valerate is commercially available as an intramuscular injection as the product Delestrogen and is indicated for the treatment of moderate to severe vasomotor symptoms and vulvovaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure, and for the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).

Estradiol valerate is also available in combination with Dienogest as the commercially available product Natazia used for the prevention of pregnancy and for the treatment of heavy menstrual bleeding.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70-500 mcg of estradiol daily, depending on the phase of the menstrual cycle.

However, after menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues.

Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women Label.

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.

Because of the difference in potency between estradiol and estrone, menopause (and a change in primary hormone from estradiol to estrone) is associated with a number of symptoms associated with this reduction in potency and in estrogenic effects.

These include hot flashes, vaginal dryness, mood changes, irregular menses, chills, and sleeping problems.

Administration of synthetic and bioidentical forms of estrogen, such as estradiol valerate, has shown to improve these menopausal symptoms.

Estradiol valerate is commercially available as an intramuscular injection as the product Delestrogen and is indicated for the treatment of moderate to severe vasomotor symptoms and vulvovaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure, and for the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).

Estradiol valerate is also available in combination with Dienogest as the commercially available product Natazia used for the prevention of pregnancy and for the treatment of heavy menstrual bleeding.

Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain.

Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ).

Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects 11.

Estrogen receptor Agonist Estrogen receptor beta Agonist Nuclear receptor subfamily 1 group I member 2 Agonist.

When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks Label.

After oral administration of estradiol valerate, cleavage to 17β-estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage.

This gives rise to estradiol and its metabolites, estrone and other metabolites.

Maximum serum estradiol concentrations of 73.3 pg/mL are reached at a median of approximately 6 hours (range: 1.5–12 hours) and the area under the estradiol concentration curve was 1301 pg-h/mL after single ingestion of a tablet containing 3 mg estradiol valerate under fasted condition on Day of the 28-day sequential regimen.

Exogenous estrogens are metabolized using the same mechanism as endogenous estrogens.

Estrogens are partially metabolized by cytochrome

Hover over products below to view reaction partners Estradiol valerate Estradiol.

Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

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There have been no reports of serious ill effects from overdose, including ingestion by children.

Overdosage may cause withdrawal bleeding in females and nausea.

• A high risk of arterial or venous thrombotic diseases.

• Smoke, if over age 35.

• Have deep vein thrombosis or pulmonary embolism, now or in the past.

• Have cerebrovascular disease.

• Have coronary artery disease.

• Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation).

• Have inherited or acquired hypercoagulopathies.

• Have uncontrolled hypertension.

• Have diabetes mellitus with vascular disease.

• Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35.

• Undiagnosed abnormal uterine bleeding.

• Current diagnosis of, or history of, breast cancer, which may be hormone sensitive.

• Liver tumors, benign or malignant, or liver disease ).

• Breast cancer.

• Liver tumors or liver disease.

• Take one tablet daily by mouth at the same time every day.

• Tablets must be taken in the order directed on the blister pack.

• Do not skip or delay intake by more than 12 hours. 2.1 How to Take Natazia To achieve maximum contraceptive effectiveness, Natazia must be taken exactly as directed.

Take one tablet by mouth at the same time every day. Tablets must be taken in the order directed on the blister pack.

Tablets should not be skipped or intake delayed by more than 12 hours.

For patient instructions for missed pills, see FDA-Approved Patient Labeling. 2.2 How to Start Natazia Instruct the patient to begin taking Natazia on Day of her menstrual cycle (that is, the first day of her menstrual bleeding).

Instruct the patient to use a non-hormonal contraceptive as back-up during the first 9 days.

For postpartum women who do not breastfeed or after a second trimester abortion, start Natazia no earlier than 4 weeks postpartum due to the increased risk of thromboembolism.

If the patient starts on

Natazia postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken Natazia for 9 consecutive days.

The possibility of ovulation and conception prior to initiation of medication should also be considered.

• Another pill.

• Vaginal ring.

• Instruct her to take the first dark yellow pill on the first day of her withdrawal bleed.

She should not continue taking the pills from her previous birth control pack.

If she does not have a withdrawal bleed, rule out pregnancy before starting Natazia.

• If she previously used a vaginal ring or transdermal patch, she should start using Natazia on the day the ring or patch is removed.

• Instruct the patient to use a non-hormonal back-up method such as a condom or spermicide for the first 9 days.

• Progestin-only pill.

• Intrauterine system.

• Instruct her to take the first dark yellow pill on the day she would have taken her next progestin-only pill or on the day of removal of her implant or intrauterine system or on the day when she would have had her next injection.

• Instruct the patient to use a non-hormonal back-up method such as a condom or spermicide for the first 9 days. 2.3 Advice in case of Gastrointestinal Disturbances In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken.

If vomiting or diarrhea occurs within 3-4 hours after taking a colored tablet, this can be regarded as a missed tablet.

Natazia (estradiol valerate and estradiol valerate/dienogest) tablets are available in packages of three blister packs (NDC 50419-409-03).

The active and inert film-coated tablets are rounded with biconvex faces, one side is embossed with a regular hexagon shape with the letters DD or DJ or DH or DN or DT.

• 2 round biconvex dark yellow film-coated tablets with embossed “DD” in a regular hexagon on one side each containing 3 mg estradiol valerate.

• 5 round biconvex medium red film-coated tablets with embossed “DJ” in a regular hexagon on one side each containing 2 mg estradiol valerate and 2 mg dienogest.

• 17 round biconvex light yellow film-coated tablets with embossed “DH” in a regular hexagon on one side each containing 2 mg estradiol valerate and 3 mg dienogest.

• 2 round biconvex dark red film-coated tablets with embossed “DN” in a regular hexagon on one side each containing 1 mg estradiol valerate.

• 2 white round biconvex white film-coated tablets with embossed “DT” in a regular hexagon on one side (inert) 16.2 Storage Store at 25º C (77º F); excursions permitted to 15–30 o C (59–86 o F) .

Risk Summary There is no reason to use COCs in pregnancy Discontinue Natazia if pregnancy occurs.

Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to COCs prior to 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 to 4 percent and to 20 percent, respectively.

Safety and efficacy of

Natazia have been established in women of reproductive age.

Efficacy is expected to be the same for postpubertal adolescents under the age of and for users 18 years and older.

Use of this product before menarche is not indicated.

Natazia has not been studied in postmenopausal women and is not indicated in this population.