Estropipate, Esterified Estrogens

Steroidal estrogens.106 107 108

Use of estrogens alone in postmenopausal women generally is referred to as estrogen replacement therapy (ERT); use of estrogens in combination with progestins usually is referred to as hormone replacement therapy (HRT) or postmenopausal hormone therapy.b

Estrogen Replacement Therapy

Management of moderate to severe vasomotor symptoms associated with menopause.106 107 108 Esterified estrogens also is used in fixed combination with methyltestosterone in women who do not respond adequately to estrogens alone;108 FDA is reevaluating this combination.100 101

Management of vulvar and vaginal atrophy associated with menopause.106 107 If estrogens are used solely for this indication, consider use of topical vaginal preparations.106 107

Osteoporosis

Prevention of postmenopausal osteoporosis.106 Used adjunctively with other measures (e.g., diet, calcium, vitamin D, weight-bearing exercise, physical therapy) to retard further bone loss and progression of osteoporosis in postmenopausal women.106

Estrogens are effective for prevention of osteoporosis but are associated with a number of adverse effects.106 If prevention of postmenopausal osteoporosis is the sole indication for therapy, consider alternative therapy (e.g., alendronate, raloxifene, risedronate).106

Has been effective in the treatment of osteoporosis in postmenopausal women. Formerly recommended as first-line therapy; however, recommendations on appropriate use of HRT have been revised based on WHI study findings. (See Boxed Warning.) Evaluate risks and benefits of long-term HRT use in the management of osteoporosis, taking into account the increased risk of breast cancer and cardiovascular disease, availability of other pharmacologic modalities (e.g., alendronate, calcitonin, calcium, raloxifene, risedronate, vitamin D), and life-style factors that can be modified.

Has been used in a limited number of anorexic women with chronic amenorrhea to reduce calcium loss† and, thereby, reduce risk of osteoporosis.

Corticosteroid-induced Osteoporosis

Has been used to prevent bone loss in postmenopausal women receiving low- to moderate-dose corticosteroid therapy†.

Hypoestrogenism

Treatment of hypoestrogenism secondary to hypogonadism, castration, or primary ovarian failure.106 107

Metastatic Breast Carcinoma

Palliative treatment of metastatic breast cancer in selected women and men.107 One of several second-line agents.a

Prostate Carcinoma

Palliative treatment of advanced androgen-dependent prostate carcinoma.107

Cardiovascular Risk Reduction†

ERT or HRT does not decrease the incidence of cardiovascular disease.106 107 108 AHA, American College of Obstetricians and Gynecologists, FDA, and manufacturers recommend that hormone therapy not be used to prevent heart disease in healthy women (primary prevention) or to protect women with preexisting heart disease (secondary prevention).

Alzheimer’s Disease

Prior use of HRT, but not current HRT unless such use exceeds 10 years, associated with reduced risk of Alzheimer’s disease†. Estrogens have not been shown to prevent progression of Alzheimer’s disease, and American Academy of Neurology recommends that estrogens not be used for treatment of Alzheimer’s disease.

Initiation of ERT or HRT in women ≥65 years of age not associated with an improvement in cognitive function. Some women receiving ERT or HRT (specifically conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily or conjugated estrogens 0.625 mg daily) experience detrimental effects. Incidence of probable dementia in women receiving ERT or HRT was higher than that in women receiving placebo. Use of ERT or HRT to prevent dementia or cognitive decline in women ≥65 years of age is not recommended.

Postpartum Breast Engorgement

Used in the past for prevention of postpartum breast engorgement†; FDA has withdrawn approval of estrogen-containing drugs for this indication, since estrogens have not been shown to be safe for this use.b (See Lactation under Cautions.)

Pregnancy

Not effective for any purpose during pregnancy; use contraindicated in pregnant women.106 107 108 (See Pregnancy under Cautions.)

Contraindications

• Undiagnosed abnormal genital bleeding.106 107 108

• Known or suspected breast cancer or history of breast cancer (except when used for palliative treatment of metastatic disease in appropriately selected individuals).106 107 108

• Known or suspected estrogen-dependent neoplasia.106 107 108

• Active DVT or pulmonary embolism; history of DVT or pulmonary embolism.106 107 108

• Active or recent (within past year) arterial thromboembolic disease (e.g., stroke, MI).106 107 108 b

• Liver disease or impairment.106 107 108

• Known or suspected pregnancy.106 107 108

• Known hypersensitivity to the drug or any ingredient in the formulation.106 107 108

Warnings/Precautions

Warnings

Estrogen/progestin therapy associated with increased risk of MI, stroke, DVT, and pulmonary embolism.106 107 108 c Estrogen therapy associated with increased risk of stroke and DVT.c (See Boxed Warning.) Discontinue estrogens immediately if any of these events occur or are suspected.106 107 108 Use of ERT or HRT is not advised in women with a history of stroke or transient ischemic attacks. (See Contraindications under Cautions.)

Appropriately manage risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, obesity) and/or venous thromboembolism (personal or family history of venous thromboembolism, obesity, systemic lupus erythematosus).106 107 108 (See Contraindications under Cautions.)

Discontinue estrogens, whenever feasible, at least 4–6 weeks prior to surgery that is associated with an increased risk of thromboembolism or during prolonged immobilization.106 107 108

Use of unopposed estrogen therapy in women who have a uterus is associated with increased risk of endometrial cancer.106 107 108 Clinical surveillance and evaluation are essential.106 107 108 Perform diagnostic tests to rule out malignancy in women with undiagnosed, persistent or recurring abnormal vaginal bleeding.106 107 108

Incidence of endometrial hyperplasia is reduced substantially when progestins are used concomitantly.106 107 108

HRT associated with an increased risk of breast cancer.106 107 108

All postmenopausal women should receive yearly breast examinations by a clinician and perform monthly self-examinations.106 107 108 Schedule periodic mammography based on patient age and risk factors.106 107 108

ERT or HRT in women ≥65 years of age has been associated with increased risk of developing probable dementia.106 107 108 Whether these findings apply to younger women is unknown.106 107 108 (See Alzheimer’s Disease under Uses.)

ERT associated with increased risk of gallbladder disease requiring surgery.106 107 108

Estrogens may cause severe hypercalcemia in patients with breast cancer and bone metastases.106 107 108 Discontinue the drug and initiate appropriate therapy to reduce serum calcium concentrations if hypercalcemia occurs.106 107 108

Retinal thrombosis reported.106 107 108 Discontinue pending examination if sudden partial or complete loss of vision, or sudden onset of proptosis, diplopia, or migraine occurs.106 107 108 Discontinue estrogen if papilledema or retinal vascular lesions noted on examination.106 107 108

General Precautions

Rarely, substantial increases in BP attributed to idiosyncratic reactions to estrogen.106 107 108 ERT generally is not associated with elevated BP.106 107 108 Monitor BP at regular intervals.106 107 108

Estrogen therapy may be associated with increases in plasma triglyceride concentrations resulting in pancreatitis in women with increased serum lipids.106 107 108

Estrogens may cause some degree of fluid retention; use with caution and careful monitoring in patients with conditions that might be aggravated by fluid retention (e.g., cardiac or renal impairment).106 107 108

Use with caution in patients with severe hypocalcemia.106 107 108

Long-term estrogen therapy associated with increased incidence of ovarian cancer in some epidemiologic studies.106 107 108 Other studies did not show a clinically important association.106 107 108

Estrogens may exacerbate endometriosis.106 107 108

Malignant transformation of residual endometrial implants reported rarely in women receiving unopposed estrogen following hysterectomy.106 107 108 Consider the addition of progestin in women with residual endometriosis following hysterectomy.106 107 108

Estrogens may exacerbate asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas; use with caution in patients with these conditions.106 107 108

When esterified estrogens is used in fixed combination with methyltestosterone or estrogens are used in conjunction with a progestin, consider the precautions, cautions, and contraindications of the concomitant agent.106 107 108

Specific Populations

Category X.106 107 108 (See Contraindications under Cautions.)

In utero exposure of females to diethylstilbestrol (DES [no longer commercially available in US]) is associated with increased risk of vaginal adenosis, squamous cell dysplasia of the cervix, and clear-cell vaginal cancer in later life.b

In utero exposure of males to DES is associated with an increased risk of genital abnormalities and possibly testicular cancer later in life.b

Women who receive DES during pregnancy may be at increased risk of breast cancer; causal relationship unproven.b

Administration of estrogens to nursing women has been associated with decreased amounts and lower quality of milk.106 107 108 Detectable amounts of estrogens have been identified in milk of women receiving these drugs.106 107 108 Caution advised.106 107 108

Estrogen therapy has been used for induction of puberty in adolescents with some forms of pubertal delay.b Safety and efficacy of estrogens in children not otherwise established.106 107 108

Use estrogen therapy with caution and careful monitoring if bone growth is not yet complete, since estrogens may cause premature epiphyseal closure.b

Insufficient experience with esterified estrogens in fixed combination with methyltestosterone (Estratest, Estratest HS) in geriatric patients to determine whether geriatric patients respond differently than younger women.108 Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential concomitant disease and drug therapy.108

Possible increased risk of developing probable dementia in women ≥65 years of age.106 107 108 (See Dementia under Cautions.)

Estrogens may be poorly metabolized in patients with hepatic impairment.106 107 108 (See Contraindications under Cautions.)

Caution advised in patients with a history of cholestatic jaundice associated with previous estrogen use or with pregnancy; discontinue if jaundice recurs.106 107 108

Use with caution.106 107 108 (See Fluid Retention under Cautions.)

Common Adverse Effects

Vaginal hemorrhage, vaginal moniliasis.106 107 108

Storage

Oral

<30°C.106 108

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Most preparations containing androgenic anabolic steroid hormones are subject to control under the Federal Controlled Substances Act of 1970, as amended by the Anabolic Steroids Control Act of 1990 and 2004, as schedule III (C-III) drugs.102 104 However, manufacturers of certain preparations containing androgenic anabolic steroids (principally combinations that also include estrogens) have applied for and obtained for their product(s) an exemption from the record-keeping and other regulatory requirements of the Federal Controlled Substances Act.103 105 Because regulatory requirements for a given preparation containing an androgenic anabolic steroid may be subject to change under the provisions of the Act, contact the manufacturer when specific clarification about a preparation’s status is required.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name