Estropipate

Estropipate is a form of estrogen. Estrogen is a female sex hormone necessary for many processes in the body.

Estropipate is used to treat symptoms of menopause such as hot flashes, and vaginal dryness, burning, and irritation. It is also used to prevent osteoporosis.

Estropipate may also be used for purposes other than those listed in this medication guide.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about estropipate, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about estropipate. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using estropipate.

Review Date: October 4, 2017

Estropipate tablets are indicated in the:

1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.

2. Treatment of moderate to severe symptoms of vulval and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.

3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.

4. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate.

The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.

Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing oral contraceptives by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.

• Ortho-Est 0.625 [DSC]
• Ortho-Est 1.25 [DSC]

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Reduced response to metyrapone test.

Routine physical examination that includes blood pressure and Papanicolaou smear, breast exam, mammogram. Monitor for signs of endometrial cancer in female patients with a uterus. Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal genital bleeding. Monitor for loss of vision, sudden onset of proptosis, diplopia, migraine; signs and symptoms of thromboembolic disorders; glycemic control in patients with diabetes; lipid profiles in patients being treated for hyperlipidemias; thyroid function in patients on thyroid hormone replacement therapy.

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

Prevention of osteoporosis: Bone density measurement

Note: Monitoring of FSH and serum estradiol is not useful when managing vasomotor symptoms associated with menopause or vulvar and vaginal atrophy.

Applies to estropipate: oral tablet

Gastrointestinal

Gastrointestinal effects are common and most often include nausea and vomiting. Some studies have demonstrated a 2 to 4 fold increase in gallbladder disease in postmenopausal women taking estrogen therapy.[Ref]

Cases of oral pigmentation and ischemic colitis have been reported rarely.[Ref]

Oncologic

A number of studies have suggested that the risk of endometrial carcinoma is removed (or delayed) by the administration of progestins in combination with estrogen therapy.

The increased risk of breast cancer due to use of estrogens is controversial. Several studies have suggested that long-term estrogen therapy may be associated with a slightly increased risk of breast cancer. Meta analysis of 51 studies (epidemiological data) supports a modest risk increase associated with long-term hormone replacement therapy (HRT).

One study of Swedish women has reported that a 10% increase in the relative risk of breast cancer may occur and that the risk is related to increasing duration of estrogen therapy. In that study, women with more than nine years of estrogen use had a 70% greater relative risk of breast cancer than controls. That study, however, examined use of a variety of estrogen preparations of which estradiol was the most frequently prescribed. In addition, women who took progestins did not demonstrate a decreased risk of breast cancer and may even have been at higher risk.

The Toronto Breast Cancer Study has reported that women who receive unopposed conjugated estrogens for less than 15 years are not at increased risk of breast cancer. In that study, an increase in the risk of breast cancer for women who used conjugated estrogens for more than 15 years was not ruled out.

The Case-Control Surveillance Study has reported that there is "no evidence that the use of unopposed conjugated estrogens increases the risk of breast cancer, even after long duration of use or long latent intervals, but the possibility of a modest increase (less than a doubling) could not be excluded."

Follow-up to the Nurses' Health Study of 1992 concluded, however, that there is an increased risk of breast cancer in women taking estrogen replacement therapy and that the risk is not reduced by concurrent use of progestins. (In that study, greater risk was associated with advanced age and prolonged duration of hormonal therapy.)

A study of middle-aged women in the Puget Sound area concluded that "on the whole, the use of estrogen with progestin HRT [hormone replacement therapy] does not appear to be associated with an increased risk of breast cancer in middle-aged women."

A prospective cohort study (11 years) of 37,105 women by Gapstur et al evaluated the histology of the breast cancer in women who ever used HRT. No association was found between duration of ever HRT use and the incidence of ductal carcinoma in situ or invasive ductal/lobular carcinoma. The duration of ever HRT use was associated with risk of invasive carcinoma with a favorable prognosis (relative risk (RR) = 1.81, 95% confidence interval (CI), 1.07 to 3.07 for HRT use less than or equal to 5yrs and RR = 2.65, CI, 1.32 to 5.23 for HRT use > 5yrs, p = 0.005). The relative risk of invasive carcinoma with a favorable prognosis for current users (adjusted for age and other risk factors) was 4.42, CI, 2.00 to 9.76 for less than or equal to 5yrs and 2.63, CI, 1.18 to 5.89 for > 5yrs). Risk of invasive ductal or lobular carcinoma for current users less than or equal to 5yrs was RR = 1.38, CI, 1.03 to 1.85.[Ref]

Use of unopposed estrogen therapy has been associated with an increased risk of endometrial cancer in patients with an intact uterus and less persuasively, with an increased risk of breast cancer.[Ref]

Cardiovascular

Studies suggest that unopposed estrogen therapy may decrease the risk of coronary heart disease by as much as 35%. Combination therapy with a progestin may also decrease coronary risk. However, the extent of risk reduction with combination therapy has not been determined. Data are available that suggest combination therapy does not reduce the overall rate of coronary heart disease in postmenopausal women with established coronary disease.[Ref]

The reported effects of estrogens on cardiovascular activity are variable. Alterations in lipid profiles in treated women are thought to be responsible for reducing cardiovascular risks. Data suggest estrogen use may increase blood pressure, particularly in patients receiving high doses, decrease blood pressure, or result in no change. In addition, noncontraceptive use of estrogens in young women (particularly smokers) may substantially increase the risk of nonfatal myocardial infarction. Other studies have concluded that no increased risk of myocardial infarction exists.[Ref]

Metabolic

Metabolic effects include generally favorable alterations in plasma lipid profiles. Specifically, increased HDL and decreased cholesterol and LDL levels occur. Estrogen therapy may lead to increased serum triglyceride levels resulting in pancreatitis in patients with familial lipoprotein metabolic defects.

Metabolic adverse effects such as hypercalcemia have occurred in patients with breast cancer and bone metastases administered estrogens.[Ref]

Endocrine

Endocrine side effects with estrogen use may result in increased levels of thyroxin-binding globulin, leading to an increase in total thyroid serum levels and a decrease in resin uptake of T3. Free thyroid hormone levels remain unchanged. Other endocrine effects include decreased fasting plasma glucose.[Ref]

General

Close observation of patients who may be particularly sensitive to fluid retention because of underlying asthma, epilepsy, migraine, heart disease, and renal dysfunction is recommended.[Ref]

Estrogens may cause some degree of fluid retention and mastodynia. Alterations in libido have occurred.[Ref]

Hepatic

Many of the reports of hepatic tumors have occurred in women taking long-term oral contraceptives. However, some tumors have been reported in women taking isolated estrogen therapy.[Ref]

Rare cases of focal nodular hyperplasia, liver cell adenomas, hepatic hemangiomas and well-differentiated hepatocellular carcinomas have been reported in association with estrogen therapy. Aggravation of porphyria has been reported.[Ref]

Hematologic

Hypercoagulability has been reported in women taking estrogens, although the clinical significance of such hypercoagulability in postmenopausal women taking estrogens has not been determined.[Ref]

Hypersensitivity

Hypersensitivity reactions including anaphylaxis have been reported in association with estrogens and the dyes contained in some conjugated estrogen formulations.[Ref]

Other

Estrogen therapy may cause a two-fold increase in risk of "fibrocystic breast disease".[Ref]

Psychiatric

Psychiatric side effects associated with estrogen therapy include cases of rapid mood cycling in patients with severe depression.[Ref]

Nervous system

Nervous system side effects include migraine, dizziness, and mental depression.[Ref]

Genitourinary

Estrogens may cause abnormal uterine bleeding (which must be carefully distinguished from bleeding related to endometrial carcinoma). In addition, estrogens may increase the size of preexisting uterine leiomyomata.

Several cases of pseudoincontinence (excessive vaginal discharge perceived by patients as urinary incontinence) have been reported in premenopausal who have undergone hysterectomy-oophorectomy and received post-operative estrogens.[Ref]

Ocular

Ocular side effects of estrogen therapy include alterations in corneal curvature and contact lens discomfort.[Ref]

Dermatologic

Dermatologic effects include chloasma or melasma, which may not resolve following discontinuation of estrogen therapy. Scalp hair loss, hirsutism, erythema nodosum, and hemorrhagic eruptions have occurred.[Ref]

Some side effects of estropipate may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Dose depends on the presence or absence of an intact uterus.

Recommendations with intact uterus:

Regimen 1 (Continuous Unopposed Estrogen Therapy):

0.625 mg orally once a day.

Regimen 2 (Cyclic Combined Estrogen-Progestin Therapy):

0.625 mg orally once a day for 25 days AND Medroxyprogesterone acetate 5 to 10 mg orally once a day for 10 to 14 days of the cycle.

Regimen 3 (Continuous Combined Estrogen-Progestin Therapy):

0.625 mg orally once a day AND Medroxyprogesterone acetate 2.5 mg orally once a day.

Recommendation following hysterectomy:

0.625 mg orally once a day.

In addition to hormonal therapy, adequate calcium intake is important for postmenopausal women who require treatment or prevention of osteoporosis. The average diet of older American women contains 400 to 600 mg of calcium per day. The optimal intake suggested is 1500 mg per day. If dietary intake is insufficient to achieve 1500 mg per day, dietary supplementation may be useful in women who have no contraindication to calcium supplementation.

Long-term therapy (for more than 5 years) is generally necessary in order to obtain substantive benefits in reducing the risk of bone fracture. Maximal benefits are obtained if estrogen therapy is initiated as soon after menopause as possible. The optimal duration of therapy has not been definitively determined.

Dose depends on the presence or absence of an intact uterus.

Recommendations with intact uterus:

Regimen 1 (Continuous Unopposed Estrogen Therapy):

0.625 mg to 5 mg orally once a day.

Regimen 2 (Cyclic Combined Estrogen-Progestin Therapy):

0.625 mg to 5 mg orally once a day for 25 days AND Medroxyprogesterone acetate 5 to 10 mg orally once a day for 10 to 14 days of the cycle.

Regimen 3 (Continuous Combined Estrogen-Progestin Therapy):

0.625 mg to 5 mg orally once a day AND Medroxyprogesterone acetate 2.5 mg orally once a day.

Recommendation following hysterectomy:

0.625 mg to 5 mg orally once a day.

Many women may require higher dosages during the initiation of therapy. The dosage of estropipate should be adjusted to the minimum dose that will achieve the desired clinical effect.

In general, the duration of hormone therapy for the treatment of postmenopausal symptoms should be limited. Treatment for one to five years is generally sufficient. However, long-term therapy (for the treatment/prophylaxis of osteoporosis and for risk reduction of cardiovascular disease) may be considered during the time in which the patient is being treated for postmenopausal symptoms.

Dose depends on the presence or absence of an intact uterus.

Recommendations with intact uterus:

Regimen 1 (Continuous Unopposed Estrogen Therapy):

0.625 mg to 5 mg orally once a day.

Regimen 2 (Cyclic Combined Estrogen-Progestin Therapy):

0.625 mg to 5 mg orally once a day for 25 days AND Medroxyprogesterone acetate 5 to 10 mg orally once a day for 10 to 14 days of the cycle.

Regimen 3 (Continuous Combined Estrogen-Progestin Therapy):

0.625 mg to 5 mg orally once a day AND Medroxyprogesterone acetate 2.5 mg orally once a day.

Recommendation following hysterectomy:

0.625 mg to 5 mg orally once a day.

Many women may require higher dosages during the initiation of therapy. The dosage of estropipate should be adjusted to the minimum dose that will achieve the desired clinical effect.

In general, the duration of hormone therapy for the treatment of postmenopausal symptoms like atrophic vaginitis, kraurosis vulvae, or atrophic urethritis should be limited. Treatment for one to five years is generally sufficient.