Estropipate

( Piperazine Estrone Sulfate )

Pronunciation: ES-troe-PIP-ate
Class: Estrogens

Trade Names

Estropipate
- Tablets Sodium estrone sulfate 0.625 mg
- Tablets Sodium estrone sulfate 1.25 mg
- Tablets Sodium estrone sulfate 2.5 mg

Pharmacology

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

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Well absorbed from the GI tract.

Distribution

Largely bound to sex hormone–binding globulin and albumin. Crosses the placenta.

Metabolism

Undergoes first-pass metabolism. Metabolic conversion occurs primarily in the liver but also at local target tissue sites. Also undergoes enterohepatic recirculation.

Metabolized partially by CYP3A4.

Elimination

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

Indications and Usage

Treatment of moderate to severe vasomotor, vulval, and vaginal atrophy symptoms associated with menopause; treatment of hypoestrogenism caused by castration, hypogonadism, or primary ovarian failure.

Contraindications

Active deep vein thrombosis, pulmonary embolism, or history of these conditions; active or recent (ie, within past year) arterial thromboembolic disease (eg, stroke, MI); hypersensitivity to any component of the product; known or suspected estrogen-dependent neoplasia; known or suspected pregnancy; known, suspected, or history of breast cancer; liver dysfunction or disease; undiagnosed abnormal genital bleeding.

Dosage and Administration

Dosage is calculated as estrone sulfate.

Vasomotor Symptoms, Vulval and Vaginal Atrophy
Adults

PO 0.625 to 5 mg/day given cyclically.

Female Hypogonadism, Female Castration, Primary Ovarian Failure
Adults

PO 1.25 to 7.5 mg/day for 3 wk, followed by 8- to 10-day drug-free period.

Storage/Stability

Store below 77°F.

Drug Interactions

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.

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.

Thyroid hormones (eg, levothyroxine)

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

Laboratory Test Interactions

Accelerated PT, partial thromboplastin, and platelet aggregation time; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; decreased serum folate concentration; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; increased platelet count; increased plasma HDL and HDL 2 cholesterol subfraction concentrations; increased plasminogen antigen and activity; other serum-binding proteins may be elevated (eg, corticosteroid-binding globulin, sex hormone–binding globulin); increased thyroid-binding globulin and total T4; impaired glucose-tolerance; increased triglyceride levels; other plasma proteins may be increased (eg, ceruloplasmin); reduced LDL cholesterol concentrations; reduced response to metyrapone test.

Adverse Reactions

Cardiovascular

Deep and superficial venous thrombosis; increased BP; MI; pulmonary embolism; stroke; thrombophlebitis.

CNS

Changes in libido; chorea; dementia; dizziness; exacerbation of epilepsy; headache; irritability; mental depression; migraine; mood disturbances; nervousness.

Dermatologic

Chloasma or melasma; erythema multiforme; erythema nodosum; hemorrhagic eruption; hirsutism; loss of scalp hair; pruritus; rash; urticaria.

EENT

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

GI

Abdominal cramps; bloating; gallbladder disease; nausea; pancreatitis; vomiting.

Genitourinary

Abnormal withdrawal bleeding or flow; breakthrough bleeding; breast cancer; breast enlargement, pain, and tenderness; change in amount of cervical secretion; changes in cervical ectropion; changes in vaginal bleeding pattern; dysmenorrhea; endometrial cancer; exacerbation of endometriosis; fibrocystic breast changes; galactorrhea; increase in size of uterine leiomyomata; nipple discharge; ovarian cancer; spotting; vaginal candidiasis; vaginitis.

Hepatic

Cholestatic jaundice; enlargement of hepatic hemangiomas.

Hypersensitivity

Anaphylactic/anaphylactoid reactions; angioedema.

Metabolic-Nutritional

Changes in triglycerides; decrease or increase in weight; exacerbation of diabetes mellitus; hypercalcemia; hypocalcemia; reduced carbohydrate tolerance.

Musculoskeletal

Arthralgia; leg cramps.

Respiratory

Exacerbation of asthma.

Miscellaneous

Aggravation of porphyria; edema.

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 deep vein thrombosis, invasive breast cancer, MI, pulmonary emboli, and stroke in postmenopausal women 50 to 79 yr of age during 5 yr of treatment with oral conjugated estrogens 0.625 mg combined with medroxyprogesterone acetate 2.5 mg compared with placebo.

Dementia

A substudy 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 increased 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 blood pressure at regular intervals.


Pregnancy

Category X .

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established.

Hepatic Function

Metabolism may be impaired; use drug with caution.

Carcinogenesis

Long-term continuous administration of estrogen has shown an increased risk of breast, endometrial, and ovarian cancer.

Endometriosis

May be exacerbated.

Fluid retention

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

Gallbladder disease

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

Hypocalcemia

Use with caution in patients with severe hypocalcemia.

Hypercalcemia

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

Hypertension

Substantial increases in BP have been attributed to idiosyncratic reactions to estrogens.

Hypertriglyceridemia

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

Induction of malignant neoplasms

May increase risk of endometrial or other carcinomas.

Ovarian cancer

Estrogen plus progestin may increase the risk of ovarian cancer. Data are conflicting as to whether estrogen alone increases the risk of ovarian cancer.

Special risk patients

Because estrogens may cause exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, or hepatic hemangiomas, use with caution.

Visual abnormalities

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

Overdosage

Symptoms

Nausea, vomiting, withdrawal bleeding in women.

Patient Information

  • 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.
  • Instruct patient to report these symptoms to health care provider: 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 of arms or legs; yellowing of skin or eyes.
  • Advise patient to stop smoking or to reduce number of cigarettes smoked to less than 15/day because of increased risk of CV complications.
  • Remind patient to have Pap smear every 6 to 12 mo while undergoing therapy.
  • Teach patient proper method of breast self-examination.

Copyright © 2009 Wolters Kluwer Health.

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