Estropipate

Pronunciation

(ES troe pih pate)

U.S. Brand Names

Ogen®; Ortho-Est®

Synonyms

Ortho Est; Piperazine Estrone Sulfate

Generic Available

Yes

Canadian Brand Names

Ogen®

Use

Treatment of moderate to severe vasomotor symptoms associated with menopause; treatment of vulvar and vaginal atrophy; hypoestrogenism (due to hypogonadism, castration, or primary ovarian failure); osteoporosis (prophylaxis, in women at significant risk only)

Pregnancy Risk Factor

Pregnancy Implications

Increased risk of fetal reproductive tract disorders and other birth defects; do not use during pregnancy.

Lactation

Enters breast milk/use caution

Contraindications

Hypersensitivity to estrogens or any component of the formulation; undiagnosed abnormal vaginal bleeding; history of or current thrombophlebitis or venous thromboembolic disorders (including DVT, PE); active or recent (within 1 year) arterial thromboembolic disease (eg, stroke, MI); carcinoma of the breast, except in appropriately selected patients being treated for metastatic disease; estrogen-dependent tumor; hepatic dysfunction or disease; pregnancy

Warnings/Precautions

Cardiovascular-related considerations: Estrogens with or without progestin should not be used to prevent coronary heart disease. Use caution with cardiovascular disease or dysfunction. May increase the risks of hypertension, myocardial infarction (MI), stroke, pulmonary emboli (PE), and deep vein thrombosis; incidence of these effects was shown to be significantly increased in postmenopausal women using conjugated equine estrogens (CEE) in combination with medroxyprogesterone acetate (MPA). Nonfatal MI, PE, and thrombophlebitis have also been reported in males taking high doses of CEE (eg, for prostate cancer). Estrogen compounds are generally associated with lipid effects such as increased HDL-cholesterol and decreased LDL-cholesterol. Triglycerides may also be increased; use with caution in patients with familial defects of lipoprotein metabolism. Whenever possible, estrogens should be discontinued at least 4-6 weeks prior to surgeries associated with an increased risk of thromboembolism or during periods of prolonged immobilization.

Neurological considerations: The risk of dementia may be increased in postmenopausal women; increased incidence was observed in women 65 years of age taking CEE in combination with MPA.

Cancer-related considerations: Unopposed estrogens may increase the risk of endometrial carcinoma in postmenopausal women. Estrogens may increase the risk of breast cancer. An increased risk of invasive breast cancer was observed in postmenopausal women using CEE in combination with MPA; a smaller increase in risk was seen with estrogen therapy alone in observational studies. An increase in abnormal mammograms has also been reported with estrogen and progestin therapy. Estrogen use may lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs.

Estrogens may cause retinal vascular thrombosis; discontinue permanently if papilledema or retinal vascular lesions are observed on examination. Use with caution in patients with diseases which may be exacerbated by fluid retention, including asthma, epilepsy, migraine, diabetes or renal dysfunction. Use with caution in patients with a history of severe hypocalcemia, SLE, hepatic hemangiomas, porphyria, endometriosis, and gallbladder disease. Use caution with history of cholestatic jaundice associated with past estrogen use or pregnancy. Safety and efficacy in pediatric patients have not been established. Prior to puberty, estrogens may cause premature closure of the epiphyses, premature breast development in girls or gynecomastia in boys. Vaginal bleeding and vaginal cornification may also be induced in girls.

Before prescribing estrogen therapy to postmenopausal women, the risks and benefits must be weighed for each patient. Women should be informed of these risks and benefits, as well as possible effects of progestin when added to estrogen therapy. Estrogens with or without progestin should be used for shortest duration possible consistent with treatment goals. Conduct periodic risk:benefit assessments.

When used solely for prevention of osteoporosis in women at significant risk, nonestrogen treatment options should be considered. When used solely for the treatment of vulvar and vaginal atrophy, topical vaginal products should be considered.

Adverse Reactions

Frequency not defined.

Cardiovascular: Edema, hypertension, venous thromboembolism

Central nervous system: Dizziness, headache, mental depression, migraine

Dermatologic: Chloasma, erythema multiforme, erythema nodosum, hemorrhagic eruption, hirsutism, loss of scalp hair, melasma

Endocrine & metabolic: Breast enlargement, breast tenderness, libido (changes in), increased thyroid-binding globulin, increased total thyroid hormone (T4), increased serum triglycerides/phospholipids, increased HDL-cholesterol, decreased LDL-cholesterol, impaired glucose tolerance, hypercalcemia

Gastrointestinal: Abdominal cramps, bloating, cholecystitis, cholelithiasis, gallbladder disease, nausea, pancreatitis, vomiting, weight gain/loss

Genitourinary: Alterations in frequency and flow of menses, changes in cervical secretions, endometrial cancer, increased size of uterine leiomyomata, vaginal candidiasis

Hematologic: Aggravation of porphyria, decreased antithrombin III and antifactor Xa, increased levels of fibrinogen, increased platelet aggregability and platelet count; increased prothrombin and factors VII, VIII, IX, X

Hepatic: Cholestatic jaundice

Neuromuscular & skeletal: Chorea

Ocular: Intolerance to contact lenses, steeping of corneal curvature

Respiratory: Pulmonary thromboembolism

Miscellaneous: Carbohydrate intolerance

Overdosage/Toxicology

Toxicity is unlikely following single exposures of excessive doses, any treatment following emesis and charcoal administration should be supportive and symptomatic. Effects noted after large doses include headache, nausea, and vomiting. Bleeding may occur in females.

Drug Interactions

Based on estrone: Substrate of CYP1A2 (major), 2B6 (minor), 2C8/9 (minor), 2E1 (minor), 3A4 (major)

Anticoagulants: Increase potential for thromboembolic events

Corticosteroids: Estrogens may enhance the effects of hydrocortisone and prednisone.

CYP1A2 inducers: May decrease the levels/effects of estrogens. Example inducers include aminoglutethimide, carbamazepine, phenobarbital, and rifampin.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of estrogens. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

Ethanol/Nutrition/Herb Interactions

Ethanol: Routine use increases estrogen level and risk of breast cancer; avoid ethanol. Ethanol may also increase the risk of osteoporosis.

Food: Folic acid absorption may be decreased.

Herb/Nutraceutical: St John's wort may decrease levels. Avoid black cohosh, dong quai (has estrogenic activity). Avoid red clover, saw palmetto, ginseng (due to potential hormonal effects).

Stability

Tablet: Store below 25°C (77°F)

Mechanism of Action

Estrogens are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estradiol is the principle intracellular human estrogen and is more potent than estrone and estriol at the receptor level; it is the primary estrogen secreted prior to menopause. In males and following menopause in females, estrone and estrone sulfate are more highly produced. Estrogens modulate the pituitary secretion of gonadotropins, luteinizing hormone, and follicle-stimulating hormone through a negative feedback system; estrogen replacement reduces elevated levels of these hormones. Estropipate is prepared from purified crystalline estrone that has been solubilized as the sulfate and stabilized with piperazine.

Pharmacodynamics/Kinetics

Absorption: Well absorbed

Metabolism: Hepatic and in target tissues; first-pass effect

Dosage

Adults:

Oral:

Moderate to severe vasomotor symptoms associated with menopause: Usual dosage range: 0.75-6 mg estropipate daily; use the lowest dose and regimen that will control symptoms, and discontinue as soon as possible. Attempt to discontinue or taper medication at 3- to 6-month intervals. If a patient with vasomotor symptoms has not menstruated within the last 2 months, start the cyclic administration arbitrarily. If the patient has menstruated, start cyclic administration on day 5 of bleeding.

Female hypogonadism: 1.5-9 mg estropipate daily for the first 3 weeks, followed by a rest period of 8-10 days; use the lowest dose and regimen that will control symptoms. Repeat if bleeding does not occur by the end of the rest period. The duration of therapy necessary to product the withdrawal bleeding will vary according to the responsiveness of the endometrium. If satisfactory withdrawal bleeding does not occur, give an oral progestin in addition to estrogen during the third week of the cycle.

Female castration or primary ovarian failure: 1.5-9 mg estropipate daily for the first 3 weeks of a theoretical cycle, followed by a rest period of 8-10 days; use the lowest dose and regimen that will control symptoms

Osteoporosis prophylaxis: 0.75 mg estropipate daily for 25 days of a 31-day cycle

Atrophic vaginitis or kraurosis vulvae: 0.75-6 mg estropipate daily; administer cyclically. Use the lowest dose and regimen that will control symptoms; discontinue as soon as possible.

Elderly: Refer to Adults dosing. A higher incidence of stroke and invasive breast cancer were observed in women >75 years in a WHI substudy using conjugated equine estrogen.

Dosing adjustment in hepatic impairment:

Mild to moderate liver impairment: Dosage reduction of estrogens is recommended

Severe liver impairment: Not recommended

Monitoring Parameters

Yearly physical examination that includes blood pressure and Papanicolaou smear, breast exam, mammogram. Monitor for signs of endometrial cancer in female patients with uterus. Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding.

Menopausal symptoms: Assess need for therapy at 3- to 6-month intervals

Prevention of osteoporosis: Bone density measurement

Test Interactions

Pathologist should be advised of estrogen/progesterone therapy when specimens are submitted. Reduced response to metyrapone test.

Dietary Considerations

Ensure adequate calcium and vitamin D intake when used for the prevention of osteoporosis.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy without consulting prescriber. Take as prescribed at same time each day; maintain prescribed schedule. Avoid alcohol (ethanol may increase the risk of osteoporosis). Annual gynecologic and breast exams are important. If taking for prevention of osteoporosis, ask prescriber about calcium and vitamin D intake, and weight-bearing exercises. If you have diabetes, monitor glucose levels closely (may impair glucose tolerance). May cause nausea or vomiting (small, frequent meals may help); abdominal pain, difficult/painful menstrual cycles; dizziness or mental depression; rash; headache; or breast pain or increased/decreased libido. Report significant swelling of extremities; sudden acute pain in legs or calves, chest or abdomen; shortness of breath; severe headache or vomiting; sudden blindness; weakness or numbness of arm or leg; unusual vaginal bleeding; yellowing of skin or eyes; or unusual bruising or bleeding. You may become intolerant to wearing contact lenses, notify prescriber if this occurs. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. This drug may cause severe fetal defects and should not be used during pregnancy. Consult prescriber for appropriate contraceptive measures. Consult prescriber if breast-feeding.

Additional Information

The use of estrogens for the prevention of other chronic diseases, as well as their potential negative effects on women's health, has been debated. Data published from the Women's Health Initiative (WHI) has provided some additional insight on this controversial topic. In the WHI, one arm of the study compared postmenopausal women with an intact uterus using CEE 0.625 mg in combination with MPA 2.5 mg daily, versus placebo. This arm of the study was stopped in 2002. In March, 2004, it was announced that the arm of the study comparing placebo to CEE alone in postmenopausal women without a uterus was ended.

Based on preliminary findings, the FDA has requested labeling changes be made to estrogen products used in postmenopausal women. The updates include information from the Women's Health Initiative Memory Study (WHIMS) as well as information collected from the completed CEE/MPA arm of the WHI study. Complete analysis of the WHI data is forthcoming, and will include all information collected through February, 2004.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May rarely cause anxiety or depression

Mental Health: Effects on Psychiatric Treatment

None reported

Dosage Forms

Tablet: 0.625 mg [estropipate 0.75 mg]; 1.25 mg [estropipate 1.5 mg]; 2.5 mg [estropipate 3 mg]

Ogen®: 0.625 mg [estropipate 0.75 mg]; 1.25 mg [estropipate 1.5 mg]; 2.5 mg [estropipate 3 mg]

Ortho-Est®: 0.625 mg [estropipate 0.75 mg]; 1.25 mg [estropipate 1.5 mg]

References

Shumaker SA, Legault C, Rapp SR, et al, "WHIMS Investigators. Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women: The Women's Health Initiative Memory Study: A Randomized Controlled Trial," JAMA , 2003, 289(20):2651-62.

U.S. Food and Drug Administration, Department of Health and Human Services, "FDA Approves New Labels for Estrogen and Estrogen with Progestin Therapies for Postmenopausal Women Following Review of Women's Health Initiative Data," January 8, 2003. Available at: http://www.fda.gov/medwatch/SAFETY/2003/safety03.htm#prempr. Accessed January 9, 2003.

"Writing Group for the Women's Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principle Results From the Women's Health Initiative Randomized Controlled Trial," JAMA , 2002, 288:321-33.

International Brand Names

Genoral® (AU); Harmogen® (GB, IE); Ogen® (AU, CA, ID, MX)

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