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Trade Names:
Alora
- Transdermal System 0.77 mg
- Transdermal System 1.5 mg
- Transdermal System 2.3 mg
- Transdermal System 3.1 mg

Trade Names:
Climara
- Transdermal System 2 mg
- Transdermal System 2.85 mg
- Transdermal System 3.8 mg
- Transdermal System 4.55 mg
- Transdermal System 5.7 mg
- Transdermal System 7.6 mg

Trade Names:
Esclim
- Transdermal System 5 mg
- Transdermal System 7.5 mg
- Transdermal System 10 mg
- Transdermal System 15 mg
- Transdermal System 20 mg

Trade Names:
Estrace
- Tablets 0.5 mg micronized estradiol
- Tablets 1 mg micronized estradiol
- Tablets 2 mg micronized estradiol

Trade Names:
Estraderm
- Transdermal System 4 mg
- Transdermal System 8 mg

Trade Names:
Estrasorb
- Topical Emulsion 2.5 mg estradiol hemihydrate/g

Trade Names:
Estring
- Ring 2 mg

Trade Names:
Gynodiol
- Tablets 0.5 mg micronized estradiol
- Tablets 1 mg micronized estradiol
- Tablets 1.5 mg micronized estradiol
- Tablets 2 mg micronized estradiol

Trade Names:
Vivelle
- Transdermal System 3.28 mg
- Transdermal System 4.33 mg
- Transdermal System 6.57 mg
- Transdermal System 8.66 mg

Trade Names:
Vivelle-Dot
- Transdermal System 0.39 mg
- Transdermal System 0.585 mg
- Transdermal System 0.78 mg
- Transdermal System 1.17 mg
- Transdermal System 1.56 mg

Trade Names:
Delestrogen
- Injection 10 mg/mL
- Injection 20 mg/mL
- Injection 40 mg/mL

Trade Names:
Depo-Estradiol
- Injection 5 mg/mL

Mechanism of Action

Pharmacology

Promotes growth and development of female reproductive system and secondary sex characteristics; affects release of pituitary gonadotropins; inhibits ovulation and prevents postpartum breast engorgement; conserves calcium and phosphorous and encourages bone formation; overrides stimulatory effects of testosterone.

Pharmacokinetics

Absorption

Well absorbed through the skin, mucous membranes, and GI tract.

Distribution

Approximately 80% is bound to sex hormone-binding globulin; most of the rest is loosely bound to albumin, and approximately 20% is unbound. Crosses the placenta.

Metabolism

Orally administered estradiol undergoes first-pass effect. Metabolic conversion occurs primarily in the liver but also at local target tissue sites. Also undergoes enterohepatic recirculation.

Elimination

A certain portion is excreted in the bile and then reabsorbed from the intestine. Excreted in the urine as conjugates.

Indications and Usage

Management of moderate to severe vasomotor symptoms associated with menopause, female hypogonadism, female castration, primary ovarian failure, postpartum breast engorgement, and atrophic conditions caused by deficient endogenous estrogen production; atrophic urethritis; palliative treatment of metastatic breast or prostate cancer in selected women and men; prevention and treatment of osteoporosis; abnormal uterine bleeding caused by hormonal imbalance in the absence of organic pathology and only when associated with a hypoplastic or atrophic endometrium.

Contraindications

Breast cancer (except in patients being treated for metastatic disease); estrogen-dependent neoplasia; undiagnosed abnormal genital bleeding; thrombophlebitis or thromboembolic disorders associated with previous estrogen use; known or suspected pregnancy; active deep vein thrombosis, pulmonary embolism, or history of these conditions; active or recent (eg, within past year) arterial thromboembolic disease (eg, MI, stroke); liver dysfunction or disease.

Dosage and Administration

PO 10 mg 3 times daily for 3 mo or more.

PO 1 mg 3 times daily.

PO 1 to 2 mg/day. Adjust to control symptoms.

IM 10 to 20 mg every 4 wk given cyclically.

IM 1.5 to 2 mg every mo given cyclically.

PO 0.05 mg once to 3 times daily during first 2 wk of theoretical menstrual cycle given cyclically.

PO 0.5 mg/day (3 wk on, 1 wk off). Transdermal 0.025 to 0.1 mg. Start with 0.025 mg system applied to skin twice/wk and adjust dose as necessary to control symptoms.

PO 1 to 2 mg 3 times daily.

IM 30 mg or more every 1 to 2 wk.

PO 0.15 to 2 mg/day.

PO 1 to 2 mg/day, adjust to control symptoms; cyclic therapy recommended. Transdermal 0.025 to 0.1 mg. Start with 0.025 mg system applied to skin once or twice/wk and adjust dose as necessary to control symptoms. Topical Application of two 1.74-g pouches/day ( Estrasorb ).

IM 10 to 20 mg every 4 wk.

IM 1 to 5 mg every 3 to 4 wk.

Start at lowest dose. Press into an oval and insert as deeply as possible into the upper 1/3 of the vaginal vault. The ring is to remain in place continuously for 3 mo, then removed and, if appropriate, replaced by a new ring. If the ring is removed or falls out during the 90-day treatment, rinse it in lukewarm water and reinsert.

PO 1 to 2 mg/day; adjust to control symptoms; cyclic therapy recommended. Transdermal 0.025 to 0.1 mg. Start with 0.025 mg system applied to skin twice weekly and adjust dose as necessary to control symptoms. Give continuously in women without intact uterus; otherwise give cyclically. Intravaginal Insert 2 to 4 g/day for 1 to 2 wk. Ring Start at lowest dose. Press into an oval and insert as deeply as possible into the upper 1/3 of the vaginal vault. The ring is to remain in place continuously for 3 mo, then removed and, if appropriate, replaced by a new ring. If the ring is removed or falls out during the 90-day treatment, rinse it in lukewarm water and reinsert.

IM 10 to 20 mg every 4 wk.

IM 1 to 1.5 mg every 3 to 4 wk.

General Advice

• Administer prescribed dose without regard to meals. Administer with food if GI upset occurs.

• Open pouch; remove protective liner from patch, and immediately apply patch to clean, dry skin on lower abdomen or upper quadrant of buttock. Do not apply patch to breasts; skin areas that are oily, damaged, or irritated, which have had powder, lotion, or moisturizer applied, or where clothing or sitting could dislodge patch.
• Press firmly with palm of hand for approximately 10 sec. Be sure good contact is made, especially at edges. If patch falls off, attempt to reapply. Apply new patch to different site if necessary.
• Rotate application sites so that no site is used more than once a week.

• Remove vaginal ring from protective pouch; press opposite sides of ring together and have patient insert into the vagina. If patient has difficulty inserting ring, health care provider can insert ring. If patient feels discomfort gently push ring further into the vagina.

• Emulsion is applied once daily in the morning, while in a comfortable seated position, to skin on both legs that is clean, dry, and not irritated.
• Cut or tear first pouch at notches indicated near the top of the pouch; push the entire contents from the bottom of the pouch through the neck of the pouch to the left thigh. Have patient use 1 or both hands to rub the emulsion into the entire left thigh and calf for 3 min until thoroughly absorbed; have patient rub any excess emulsion remaining on hands on the buttocks. Repeat this process using the second pouch and the right thigh and calf, including rubbing any remaining emulsion on the hands on the buttocks. Have patient wash hands with soap and water to remove any residual medication.
• Instruct patient to allow application areas to dry thoroughly before covering with clothing to avoid transfer to other individuals.

• For IM administration only. Not for intradermal, subcutaneous, or IV administration.
• Inspect solution visually before administration. Do not administer if solution is cloudy, discolored, or contains particulate matter. Crystals may form if solution is stored at low temperature but will dissolve readily when solution is warmed.
• Administer prescribed dose by deep IM injection into upper outer quadrant of gluteal muscle.

Storage/Stability

Store tablets at controlled room temperature (59° to 86°F).

Store patches at controlled room temperature (59° to 86°F). Do not remove from pouch until just immediately before application.

Store vaginal ring at controlled room temperature (59° to 86°F). Do not remove ring from pouch until immediately before insertion.

Store pouches at controlled room temperature (59° to 86°F).

Store injection at controlled room temperature (68° to 77°F).

Drug Interactions

Estrogens may reduce the effect of anticoagulants.

Estradiol may alter effects and increase toxicity of these agents.

May decrease estradiol concentration.

An increase in the pharmacologic and toxicologic effects of corticosteroids may occur.

May increase plasma concentrations of estrogens.

Loss of seizure control or decreased estrogenic effects may occur.

Increased serum thyroxine-binding globulin concentrations; thyroid hormone requirements may need to be increased.

Laboratory Test Interactions

Endocrine and LFT results may be affected; possible decreased PT and increased platelet aggreability; decreased antithrombin III activity; increased thyroid-binding globulin and total T ₄ ; impaired glucose tolerance; decreased serum folate concentration; increased serum triglyceride and phospholipid concentrations; increased corticosteroid binding globulin and sex-hormone binding globulin; increased plasma HDL concentrations; reduced LDL cholesterol concentrations; increased triglyceride levels; reduced response to metyrapone test.

Adverse Reactions

Cardiovascular

Thrombosis; thrombophlebitis; MI; elevated BP; pulmonary embolism; stroke.

CNS

Headache; migraine; dizziness; depression; insomnia; anxiety; emotional lability; chorea; nervousness; mood disturbance; irritability; somnolence; exacerbation of epilepsy.

Dermatologic

Chloasma; melasma; erythema nodosum or multiforme; scalp hair loss; hirsutism; urticaria; dermatitis; skin hypertrophy; pruritus; hemorrhagic eruption.

EENT

Intolerance to contact lenses; retinal vascular thrombosis; steepening of corneal curvature.

GI

Nausea; vomiting; abdominal cramps; bloating; colitis; acute pancreatitis; diarrhea; dyspepsia; flatulence; gastritis; gastroenteritis; enlarged abdomen; hemorrhoids; increased incidence of gallbladder disease.

Genitourinary

Increased risk of endometrial carcinoma; breakthrough bleeding; dysmenorrhea; amenorrhea; vaginal candidiasis; premenstrual-like syndrome; increased size of uterine fibromyomata; hemolytic uremic syndrome; UTI; vaginitis; vaginal discomfort/pain; cystitis; dysuria; genital pruritus; urinary incontinence; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia.

Hepatic

Cholestatic jaundice.

Metabolic

Hyperglycemia; hypercalcemia.

Respiratory

Upper respiratory tract infection; sinusitis; rhinitis; pharyngitis; flu-like symptoms; allergy; bronchitis; chest pain.

Miscellaneous

Pain at injection site; redness and irritation at site of transdermal system; increase/decrease in weight; reduced carbohydrate tolerance; edema; changes in libido; breast tenderness; acute intermittent porphyria; vaginal bleeding; hypersensitivity reactions; back pain; arthritis; arthralgia; hot flushes; leg edema; otitis media; toothache; breast enlargement and pain; nipple discharge; galactorrhea; fibrocystic breast changes; breast cancer; increased triglycerides.

Precautions

Pregnancy

Category X .

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established.

Hepatic Function

Metabolism may be impaired; use drug with caution.

Special Risk Patients

Because asthma, diabetes melitis, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas may be exacerbated by estrogens, use with caution.

Tartrazine Sensitivity

Some products contain tartrazine, which may cause allergic reaction in susceptible patients.

Breast cancer

Estrogen has been associated with an increased risk of breast cancer.

Calcium and phosphorus metabolism

Use drug with caution in patients with metabolic bone diseases.

Diabetic patient

Monitor blood sugar in diabetic patient when drug is started or dose is changed. Report significant changes to health care provider.

Glucose intolerance

BP increases during estrogen replacement therapy usually return to normal upon discontinuation of the drug. BP should be monitored during estrogen use. Elevation of BP in previously normotensive or hypertensive patients should be evaluated and estrogen therapy may have to be stopped. A worsening of glucose tolerance has been observed.

Endometriosis

May be exacerbated with administration of estrogens.

Fluid retention

Use drug with careful observation when conditions that might be affected by this factor are present (eg, asthma, cardiac or renal function impairment, epilepsy).

Gallbladder disease

Risk of gallbladder disease may increase in women receiving postmenopausal estrogens.

Hypercoagulability

Estrogen therapy may promote hypercoagulability, primarily related to decreased antithrombin activity.

Hypothyroidism

Estrogen administration may lead to increased thyroid-binding globulin (TBG) levels.

Induction of malignant neoplasms

May increase risk of endometrial or other carcinomas (endometrial, breast).

Familial hyperlipoproteinemia

May be associated with massive elevations of plasma triglycerides.

Surgery/Immobilization

Consider discontinuing therapy during periods of prolonged immobilization and, if possible, 4 to 6 wk before surgery that is associated with an increased risk of thromboembolic disease.

Uterine leiomyomata

Pre-existing uterine leiomyomata may increase in size during estrogen use.

Tapering/Withdrawal

Ensure that attempts are made every 3 to 6 mo to discontinue therapy or reduce the dose of medication.

Unopposed estrogen administration (eg, without progesterone)

Increases risk of uterine cancer. Therefore, when using estrogens on long-term basis in a woman with intact uterus, consider cyclic therapy with progesterone (eg, estrogen on days 1 to 25 of mo with progesterone added for last 12 days) or daily coadministration of estrogen plus progesterone on daily basis. In a woman without uterus, use of cyclic therapy and/or therapy with progesterone is not necessary.

Visual abnormalities

Retinal vascular thrombosis has been reported in patients receiving estrogen.

Overdosage

Symptoms

Nausea, withdrawal bleeding in women.

Patient Information

• Advise patient to review patient information leaflet before starting therapy and with each refill.
• Instruct patient to take (or use) as prescribed and not to change the dose or stop taking unless advised by health care provider.
• Advise patient taking tablets that medication can be taken without regard to meals, but to take with food if GI upset occurs.
• Instruct diabetic patient to monitor blood glucose more frequently when drug is started or dose is changed and to inform health care provider of significant changes in readings.
• Review the following nonhormonal modalities that help prevent osteoporosis: 1,500 mg/day of calcium, vitamin D supplementation, exercise.
• Instruct patient to report the following symptoms to health care provider: pain in groin or calves, sharp chest pain or sudden shortness of breath, abnormal vaginal bleeding, breast lumps, sudden severe headache, dizziness or fainting, vision or speech problems, weakness or numbness of arms or legs, severe abdominal pain or swelling, yellowing of skin or eyes, severe depression.
• Teach patient proper method of breast self-examination.
• Advise patient that follow-up visits and examinations, including Pap smear, at least once a year will be required to monitor therapy and to keep appointments.

• Transdermal system
• Advise patient not to apply patch to breasts, or to skin areas that are oily, damaged, or irritated, which have had powder, moisturizer, or lotion applied, or to where clothing or sitting could dislodge patch.
• Teach patient proper procedure for applying patch as follows: open pouch, remove protective liner from patch, and immediately apply patch to clean, dry skin on lower abdomen or upper quadrant of buttock. Press firmly with palm of hand for approximately 10 sec. Be sure good contact is made, especially at edges.
• Advise patient that if patch falls off, it should be reapplied to a different site. If patch cannot be reapplied, instruct patient to apply a new patch at a different site but to continue to follow the original dosing scheduled.
• Teach patient proper procedure for changing patch as follows: slowly peel off used patch, fold in half, and discard in trash. Apply new patch at different site. Instruct patient to rotate application sites so that no site is used more than once a week.
• Advise patient that if scheduled patch change is missed to remove the old patch and apply a new patch to a different site but to continue to follow the original application schedule.
• Advise patient to notify health care provider if skin irritation or persistent redness or itching occur at application site.

• Estradiol ring
• Teach patient proper procedure for inserting or replacing ring as follows: wash hands before and after insertion; remove vaginal ring from protective pouch, press opposite sides of ring together, and insert into the vagina. If patient has difficulty inserting ring, health care provider can insert it. If ring causes discomfort, gently push it further into the vagina.
• Advise patient that the ring should not be felt when in place, nor should it interfere with sexual intercourse; repositioning the ring should result in resolution of any abnormal sensation. Advise patient to notify health care provider if repositioning ring does not resolve abnormal sensations.
• Advise patient that if ring is totally expelled from vagina, to clean the it in warm water and reinsert.
• Remind patient that ring should be removed and replaced by a new ring every 3 mo in order to maintain beneficial effects.

• Topical Emulsion
• Advise patient to apply emulsion qd in the morning to skin on both legs that is clean and dry.
• Caution patient not to apply emulsion to any skin area that appears to be red or irritated.
• Teach patient proper procedure for applying emulsion as follows: cut or tear first pouch at notches indicated near the top of the pouch; while in a comfortable seated position push the entire contents from the bottom of the pouch through the neck of the pouch onto the left thigh; using 1 or both hands, rub the emulsion into the entire left thigh and calf for 3 min until thoroughly absorbed; rub any excess emulsion remaining on hands on the buttocks; repeat this process using the second pouch and the right thigh and calf including rubbing any remaining emulsion on the hands on the buttocks; wash hands with soap and water to remove any residual medication.
• Instruct patient to allow application areas to dry thoroughly before covering with clothing to avoid transfer to other individuals.
• Advise patient that if application of the emulsion in the morning is missed, to apply it as soon as remembered and to never apply the emulsion more than once each day.

• Injection
• Advise patient that medication will be prepared and administered by a health care professional in a medical setting on a scheduled basis.