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Drugs reference index «Estrogens, Conjugated or Esterified»

Estrogens, Conjugated or Esterified

Pronunciation: (ES-troe-jenz KON-joo-GAY-ted es-TER-i-fide)Class: Estrogens Esterified Estrogen

Trade Names:Menest- Tablets 0.3 mg- Tablets 0.625 mg- Tablets 1.25 mg- Tablets 2.5 mg

Conjugated Estrogen

Trade Names:Estrace- Cream, vaginal 0.1 mg per g

Trade Names:Estring- Ring, vaginal 2 mg

Trade Names:Femring- Ring, vaginal 0.05 mg/day- Ring, vaginal 0.1 mg/day

Trade Names:Premarin- Cream, vaginal 0.625 mg- Tablets 0.3 mg- Tablets 0.45 mg- Tablets 0.625 mg- Tablets 0.9 mg- Tablets 1.25 mg

Trade Names:Premarin IV- Injection 25 mg

Trade Names:Vagifem- Tablets, vaginal 25 mcg

C.E.S. (Canada)

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 phosphorus and encourages bone formation; overrides stimulatory effects of testosterone.

Pharmacokinetics

Absorption

Well absorbed from GI tract. The tablets slowly release the drug over several hours. Conjugated estrogens are water-soluble and well-absorbed through the skin, mucous membranes, and GI tract after release from the drug formulation.

Vagifem

C max is 50 pg/mL over a 12-wk course without accumulation.

Vaginal ring

T max is 0.5 to 1 h, then declines to a relatively constant rate for the following 90 days.

Distribution

Bound to sex hormone–binding globulin and albumin. Widely distributed and generally found in higher concentration in the sex hormone target organs. Crosses the placenta.

Metabolism

Partially metabolized by CYP3A4. Metabolized in the liver and undergoes enterohepatic recirculation. Estradiol is converted reversibly to estrone, and both can be converted to estriol (major urinary metabolite).

Elimination

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

Vaginal ring

The mean percent excreted in the 24-h urine as estradiol 4 and 12 wk after application is 5% and 8%, respectively, of the daily released amount.

Special Populations

Renal Function Impairment

Pharmacokinetics have not been studied.

Hepatic Function Impairment

Pharmacokinetics have not been studied.

Indications and Usage

Conjugated or esterified estrogens

Treatment of moderate to severe vasomotor symptoms associated with menopause; treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause; treatment of hypoestrogenism caused by hypogonadism, female castration, or primary ovarian failure; palliative treatment of metastatic breast cancer in selected women and men; palliative treatment of advanced androgen-dependent carcinoma of the prostate.

Conjugated estrogens

Prevention of postmenopausal osteoporosis.

Conjugated estrogens, parenteral form

Short-term treatment of abnormal uterine bleeding caused by hormonal imbalance in the absence of organic pathology.

Estrace vaginal cream, Premarin vaginal cream

Treatment of vulvar and vaginal atrophy.

Estring

Treatment of moderate to severe urogenital symptoms caused by postmenopausal atrophy of the vagina (eg, burning, dryness, dyspareunia, pruritus) and/or the lower urinary tract (urinary urgency and dysuria).

Femring

Treatment of moderate to severe vasomotor symptoms associated with menopause; treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause.

Premarin vaginal cream

Treatment of atrophic vaginitis and kraurosis vulvae.

Vagifem

Treatment of atopic vaginitis.

Contraindications

Breast cancer (except in patients being treated for metastatic disease); estrogen-dependent neoplasia; undiagnosed abnormal genital bleeding; known or suspected pregnancy; active deep vein thrombosis, pulmonary embolism, or a history of these conditions; active or recent (within past year) arterial thromboembolic disease (eg, MI, stroke); liver dysfunction or disease; hypersensitivity to any component of the product.

Dosage and Administration

Abnormal Uterine BleedingAdults

IV / IM

Conjugated estrogens

25 mg; may repeat in 6 to 12 h.

Atopic VaginitisAdults

Vaginal

Tablet

Insert 1 tablet vaginally once daily for 2 wk. Maintenance treatment is 1 tablet inserted vaginally twice weekly.

Intravaginal

Premarin vaginal cream

0.5 g in a cycle of 21 days of therapy daily followed by 7 days of no therapy.

Breast CancerAdults

PO

Conjugated estrogens

10 mg 3 times daily for 3 mo or more.

Female Castration, Primary Ovarian FailureAdults

PO

Conjugated estrogens

0.3 to 1.25 mg/day, cyclically (3 wk on estrogen, 1 wk off).

Esterified estrogens

1.25 mg/day cyclically (3 wk on estrogen, 1 wk off).

Female HypogonadismAdults

PO

Conjugated estrogens

0.3 to 0.625 mg/day, cyclically (3 wk on estrogen, 1 wk off).

Esterified estrogens

2.5 to 7.5 mg/day in divided doses for 20 days, followed by 10-day rest period. If bleeding does not occur at the end of this schedule, the schedule is repeated.

Kraurosis VulvaeAdults

Intravaginal

Premarin vaginal cream

0.5 g in a cycle of 21 days of therapy daily followed by 7 days of no therapy.

Postmenopausal OsteoporosisAdults

PO

Conjugated estrogens

Start with 0.3 mg daily and adjust dose based on individual clinical and bone mineral density responses. May be given continuously or in cyclical regimen (eg, 25 days on drug followed by 5 days off drug).

Prostatic CarcinomaAdults

PO

Conjugated estrogens

1.25 to 2.5 mg 3 times daily.

Urogenital Symptoms Caused by Postmenopausal Atrophy of the Vagina and/or Lower Urinary TractAdults Estring

Vaginal ring Insert 1 ring as deeply as possible into upper one-third of vaginal vault. Ring is to remain in place for 90 days, after which it is to be removed and replaced by a new ring if necessary. The need to continue treatment should be assessed at 3- or 6-mo intervals.

Vasomotor SymptomsAdults Conjugated estrogen

PO Start with 0.3 mg daily and adjust dose based on individual patient response. May be given continuously or in cyclical regimen (eg, 25 days on drug followed by 5 days off drug).

Esterified estrogens

PO 1.25 mg/day.

Femring

Vaginal ring Start with vaginal ring delivering estradiol 0.05 mg/day inserted into the vagina. It should remain in place for 90 days, then removed and replace with a new vaginal ring if needed.

Vulvar and Vaginal Atrophy SymptomsAdults Conjugated estrogens

PO Start with 0.3 mg daily and adjust dose based on individual patient response. May be given continuously or in cyclical regimen (eg, 25 days on drug followed by 5 days off drug).

Estrace vaginal cream

Intravaginal Usual dose range is 2 to 4 g daily for 1 to 2 wk, then gradually reduce to 50% of the initial dose for a similar period. A maintenance dosage of 1 g 1 to 3 times weekly may be used after restoration of the vaginal mucosa has been achieved.

Esterified estrogens

Intravaginal 0.3 to 1.25 mg or more daily, depending on tissue response. Administer cyclically.

Premarin vaginal cream

Intravaginal 0.5 g twice weekly (eg, Monday and Thursday) as a continuous regimen or in a cycle of 21 days of therapy daily followed by 7 days of no therapy.

Femring vaginal ring

Intravaginal Start with vaginal ring delivering estradiol 0.05 mg/day inserted into the vagina. It should remain in place for 90 days, then be removed and replaced with a new vaginal ring if needed.

General Advice

  • Administer parenteral form immediately after reconstitution.
  • Do not shake parenteral form vigorously.
  • To clean vaginal applicator, remove plunger from barrel and wash with mild soap and warm water. Do not boil or use hot water.
Conjugated estrogens
  • Administer IM injection deeply into muscle.
  • Administer IV injection slowly to avoid flushing.
  • Infusion of conjugated estrogen with other agents is not recommended. Solution is compatible with normal saline, dextrose, and invert sugar solutions. It is not compatible with any solution with acidic pH.
  • Using the supplied applicator, gently insert vaginal tablet into the vagina as far as it can comfortably inserted without force.
  • Estrace vaginal cream has a calibrated plastic applicator for delivery. Do not separate plunger from the applicator.
  • Conjugated estrogen IV is not compatible with protein hydrolysate, ascorbic acid, or any solution with an acid pH.
  • Vaginal ring
  • To insert, press the ring into an oval and place in the upper one-third of the vaginal vault. The exact position is not critical.
  • If there is discomfort, the ring is probably not far enough inside. The ring should gently be pushed farther into the vagina.
  • Some women have experienced moving or gliding of the vaginal ring within the vagina. Instances of expulsion have been reported. If this occurs, Estring can be rinsed in lukewarm water and reinserted.
  • The ring may be removed by hooking a finger through the ring and pulling it out.
Esterified estrogens
  • Administer as prescribed without regard to meals.
  • Administer with food if GI upset occurs.

Storage/Stability

Injection

Store vials for parenteral administration in refrigerator, at 36° to 46°F.

Tablets, Premarin , vaginal cream, vaginal tablets

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

Estring , Femring

Store at 59° to 86°F.

Estrace vaginal cream

Store at room temperature. Protect from temperatures exceeding 104°F.

Drug Interactions

Barrier contraceptives (eg, latex condoms)

Premarin vaginal cream may weaken latex condoms, which may contribute to the failure of condoms, diaphragms, or cervical caps made of latex or rubber.

Corticosteroids (eg, prednisone)

Increased pharmacologic and toxicologic effects of corticosteroids may occur.

Hydantoins (eg, phenytoin)

Loss of seizure control or decreased estrogenic effects may occur.

Inducers of CYP3A4 (eg, barbiturates [eg, phenobarbital], bosentan, carbamazepine, modafinil, rifampin, St. John's wort, topiramate)

May reduce plasma estrogens, resulting in a decrease in therapeutic effects and changes in uterine bleeding profile.

Inhibitors of CYP3A4 (eg, azole antifungal agents [eg, itraconazole, ketoconazole], grapefruit juice, macrolide antibiotics [eg, clarithromycin, erythromycin], ritonavir)

May elevate estrogen plasma levels, resulting in increased adverse reactions.

Thyroid hormones (eg, levothyroxine)

Serum-free thyroxine concentrations may be decreased, increasing serum thyrotropin concentrations and the need for thyroid hormone.

Laboratory Test Interactions

Increased thyroid-binding globulin and total T4; impaired glucose tolerance; decreased serum folate concentration; accelerated PT, partial thromboplastin, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta thromboglubulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity; other serum-binding proteins may be elevated (eg, corticosteroid-binding globulin, sex hormone–binding globulin); other plasma proteins may be increase (eg, ceruloplasmin); reduced response to metyrapone test; increased plasma HDL and HDL 2 cholesterol subfraction concentrations; reduced LDL cholesterol concentrations; increased triglyceride levels. Serum follicle-stimulating hormone and estradiol levels have not been shown to be useful in the management of moderate to severe symptoms of vulvar and vaginal atrophy.

Adverse Reactions

Cardiovascular

Vasodilatation (5%); migraine (1% to 3%); deep vein thrombosis (DVT), increased BP, MI, pulmonary embolism, stroke, thrombophlebitis (postmarketing).

CNS

Headache (32%); asthenia (8%); insomnia (4%); anxiety (1% to 3%); changes in libido, decreased libido, dementia, depression, dizziness, irritability, mood disturbance, nervousness (postmarketing).

Dermatologic

Dermatitis, skin atrophy (1% to 3%); chloasma, hirsutism, loss of scalp hair, pruritus, rash, urticaria (postmarketing).

EENT

Pharyngitis (5%); otitis media (1% to 3%); abnormal bleeding, intolerance of contact lenses, retinal vascular thrombosis (postmarketing).

GI

Abdominal pain (17%); abdominal distension, diarrhea, flatulence (7%); dyspepsia (3% to 5%); nausea (3%); gastritis, hemorrhoids, toothache, tooth disorder (1% to 3%); abdominal cramps, bloating, bowel obstruction, enlarged abdomen, gallbladder disease, pruritus ani, vomiting (postmarketing).

Genitourinary

Breast tenderness, vaginal candidiasis (11%); intermenstrual bleeding (10%); breast pain, genital moniliasis, leucorrhea, UTI (7%); asymptomatic genital bacterial growth, genital pruritus, vaginitis (6%); vaginal discomfort/pain, vaginal hemorrhage (5%); hematuria (3% to 5%); cystitis, dysuria, genital eruption, urinary incontinence, urogenital pruritus (1% to 3%); abnormal uterine bleeding/spotting, adherence of vaginal ring to vaginal wall, breast cancer, breast discharge, breast engorgement, breast enlargement, change in cervical secretion, cystitis-like syndrome, dysmenorrhea/pelvic pain, endometrial cancer, endometrial hyperplasia, fibrocystic breast changes, genital edema, gynecomastia in males, increased size of uterine leiomyomata, micturition frequency, precocious puberty, urethral disorder, vulval disorder, vulvovaginal discomfort (postmarketing).

Metabolic-Nutritional

Decreased or increased weight, glucose intolerance, increased triglycerides (postmarketing).

Musculoskeletal

Arthralgia, back pain (14%); myalgia (9%); leg cramps (7%); arthritis (4%); skeletal pain (2%); arthropathy (postmarketing).

Respiratory

Upper respiratory tract infection (11%); cough (5%); sinusitis (4%); bronchitis (3% to 5%); syncope (1% to 3%); exacerbation of asthma (postmarketing).

Miscellaneous

Infection (23%); pain (20%); accidental injury (12%); allergy (4%); family stress, flu-like symptoms, hot flushes (3%); chest pain, leg edema (1% to 3%); anaphylactic reactions, edema, hypersensitivity, toxic shock syndrome with vaginal ring (postmarketing).

Precautions

Warnings

CV and other risks

Do not use estrogens with or without progestins for prevention of CV disease. The Women's Health Initiative (WHI) study reported increased risk of MI, stoke, invasive breast cancer, pulmonary emboli, and DVT in postmenopausal women 50 to 79 yr of age during 5.6 yr of treatment with oral conjugated estrogens 0.625 mg combined with medroxyprogesterone acetate 2.5 mg compared with placebo.

Dementia

A subsidiary of WHI, the WHI Memory Study, reported increased risk of developing probable dementia in postmenopausal women 65 yr of age and older during 4 yr of treatment with oral conjugated estrogens plus medroxyprogesterone acetate compared with placebo. It is unknown if this finding applies to younger postmenopausal women or women taking estrogen alone.

Endometrial cancer

Close clinical surveillance of all women taking estrogens is important. The use of unopposed estrogen in women with intact uteri has been associated with an increase risk of endometrial cancer. Undertake diagnostic measures, including endometrial sampling when indicated, to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

Monitor

Monitor BP at beginning of therapy and at regular intervals during treatment. Periodically monitor thyroid function. Monitor blood glucose levels in diabetic patients. Monitor blood glucose more frequently in patients with diabetes when therapy is started and the dose is changed.

Baseline examinations

Ensure that breast, abdominal, and pelvic examination, and Pap smear have been completed and documented before starting therapy and annually thereafter during prolonged therapy.

Pregnancy

Contraindicated in pregnancy.

Vagifem

Category X .

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established.

Elderly

Estring

There have not been sufficient numbers of elderly patients involved in studies to determine whether those older than 65 yr of age differ in response from younger subjects. Use with caution, usually starting at the low end of the dosage range, because of the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapy.

Hepatic Function

Metabolism may be impaired; use drug with caution.

Special Risk Patients

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

Breast cancer

Estrogen and estrogen/progestin therapy in postmenopausal women has been associated with an increased risk of breast cancer. The increased risk is apparent after several years of treatment.

Calcium/Phosphorus metabolism

Use drug with caution in patients with metabolic bone diseases.

Elevated BP

BP elevation may occur. Assess BP at beginning of therapy and periodically during treatment.

Endometrial hyperplasia

A higher incidence of endometrial hyperplasia was reported in women receiving continuous estrogen alone compared with those receiving coadministration of a progestin. Endometrial hyperplasia may be a precursor to endometrial cancer.

Endometriosis

May be exacerbated by estrogens.

Fluid retention

Because estrogens may cause fluid retention, carefully monitor patients with conditions influenced by fluid retention (eg, asthma, cardiac dysfunction, epilepsy, renal function impairment).

Gallbladder disease

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

Glucose intolerance

Impaired glucose tolerance may occur.

Hepatic adenoma

Consider the possibility in patients with abdominal mass, abdominal pain and tenderness, or hypovolemic shock.

Hypercalcemia

Severe hypercalcemia in patients with breast cancer and bone metastases may occur.

Hypertriglyceridemia

In patients with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations in plasma triglycerides, leading to pancreatitis and other complications.

Hypocalcemia

Use with caution.

Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin levels. Ensure that thyroid function is periodically monitored in patients with hypothyroidism and that thyroid-replacement dose is adjusted, if necessary, to maintain free thyroid levels in an acceptable range.

Induction of malignant neoplasms

May increase risk of endometrial or other carcinomas.

Ovarian cancer

Estrogen plus progestogen has been reported to increase the risk of cancer. Use of estrogen alone for long duration, more that 10 yr, has been associated with increased risk of ovarian cancer.

Surgery/Immobilization

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

Tapering/Withdrawal

Attempts should be made every 3 to 6 mo to discontinue therapy or reduce the dose of medication.

Toxic shock syndrome

Has been reported.

Unopposed estrogen administration (eg, without progesterone)

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

Vaginal irritation

Estradiol vaginal ring may not be suitable for women with narrow, short, or stenosed vaginas, or conditions that make the vagina more susceptible to irritation or ulceration.

Visual abnormalities

Retinal vascular thrombosis may occur, leading to diplopia, loss of vision, migraine, or sudden onset of proptosis.

Overdosage

Symptoms

Abdominal pain, breast tenderness, drowsiness/fatigue, nausea, vomiting, withdrawal bleeding.

Patient Information

  • Advise patient to review patient information leaflet before starting therapy and with each refill.
  • Advise patient that medication can be taken without regard to meals, but to take with food if GI upset occurs.
  • Instruct patient with diabetes 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 nonhormonal modalities that help prevent osteoporosis: calcium 1,500 mg/day, vitamin D supplementation, exercise.
  • Caution patient that this medication must not be taken during pregnancy or when pregnancy is possible. Advise patient to use reliable form of birth control while taking this drug.
  • Advise patient regarding importance of smoking cessation or reduction of intake to less than 15 cigarettes/day because of risk of CV complications.
  • Teach patient proper method of performing breast self-examination.
  • Instruct patient to report abnormal vaginal bleeding, breast lumps, dizziness or fainting, pain in groin or calves, severe abdominal pain, severe depression, sharp chest pain or sudden shortness of breath, sudden severe headache, vision or speech problems, weakness or numbness in arm or leg, or yellowing of skin or eyes to health care provider.
  • Remind patient to have Pap smear every 6 to 12 mo while undergoing therapy.
  • Inform patient that it may take 2 to 3 wk to feel the full effects of the estradiol vaginal ring in relieving vaginal and urinary symptoms and to contact health care provider if symptoms persist more than a few weeks.
  • Instruct patient to contact health care provider if, after insertion of the vaginal ring, vaginal secretions are associated with a bad odor or vaginal discomfort or itching.
  • Instruct patient that after 90 days there will not be enough estradiol in the vaginal ring to maintain its full effect and, if health care provider determines that there is a need to continue therapy, to remove the ring at that time and replace it with a new ring.
  • Instruct patient to remove the estradiol vaginal ring and immediately contact health care provider if experiencing diarrhea, dizziness, faintness, fever, muscle pain, nausea, a sunburn-rash on face or body, or vomiting.

Copyright © 2009 Wolters Kluwer Health.

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