Estrogens, Conjugated

Drug class: Antineoplastic Agents

Usage of Estrogens, Conjugated

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. Another therapeutic option involves use of estrogens in combination with an estrogen agonist-antagonist; this combination referred to as a tissue-selective estrogen complex (TSEC).

ERT

Management of moderate to severe vasomotor symptoms associated with menopause.

Management of severe vaginal dryness, pain with sexual intercourse, and vulvar and vaginal atrophy associated with menopause. If used solely for this indication, consider use of topical vaginal preparations.

Osteoporosis

Prevention of osteoporosis. 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.

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

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† [off-label] 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† [off-label].

Hypoestrogenism

Treatment of hypoestrogenism secondary to hypogonadism, castration, or primary ovarian failure. Used for induction of puberty in adolescents with pubertal delay due to hypogonadism.

Metastatic Breast Carcinoma

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

Prostate Carcinoma

Palliative treatment of advanced androgen-dependent prostate carcinoma.

Abnormal Uterine Bleeding

Treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology.

Cardiovascular Risk Reduction† [off-label]

ERT or HRT does not decrease the incidence of cardiovascular disease. 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† [off-label]. Estrogens have not been shown to prevent progression of Alzheimer’s disease; 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 experience detrimental effects. Incidence of probable dementia in women receiving ERT or HRT was higher than that in women receiving placebo. (See Boxed Warning.) 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† [off-label]; FDA has withdrawn approval of estrogen-containing drugs for this indication, since estrogens have not been shown to be safe for this use. (See Lactation under Cautions.)

Pregnancy

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

Relate drugs

How to use Estrogens, Conjugated

General

  • A progestin generally is added to estrogen therapy (HRT) in women with an intact uterus. Addition of a progestin for ≥10 days per cycle of estrogen or daily with estrogen reduces incidence of endometrial hyperplasia and attendant risk of endometrial carcinoma in women with an intact uterus.
  • As an alternative to progestin, use of Bazedoxifene (an estrogen agonist-antagonist) in fixed combination with conjugated estrogens reduces risk of endometrial hyperplasia.
  • ERT is appropriate in women who have undergone a hysterectomy (to avoid unnecessary exposure to progestins).

    • Administration

    Conjugated estrogens USP usually administered orally; may also administer intravaginally or by deep IM or slow IV injection.

    Administer synthetic conjugated estrogens A and synthetic conjugated estrogens B orally.

    Estrogen therapy generally is administered in a continuous daily dosage regimen or, alternatively, in a cyclic regimen. When administered cyclically, estrogen usually is given once daily for 3 weeks followed by 1 week without the drug or once daily for 25 days followed by 5 days off; regimen is repeated as necessary.

    When parenteral administration of conjugated estrogens USP is required, IV injection is preferred because of the more rapid response compared with IM injection.

    Oral Administration

    Oral preparations containing medroxyprogesterone acetate in combination with conjugated estrogens USP as monophasic or biphasic regimens are commercially available in a mnemonic dispensing package to aid user in complying with the prescribed dosage schedule.

    Oral preparation containing bazedoxifene acetate in fixed combination with conjugated estrogens is commercially available in a 30-day package including 2 blister packs of 15 tablets each.

    IV Administration

    For solution and drug compatibility information, see Compatibility under Stability.

    Administer by direct IV injection.

    Reconstitution

    Reconstitute vial containing 25 mg of conjugated estrogens USP with 5 mL of sterile water for injection. Do not shake vigorously. Administer immediately after reconstitution.

    Rate of Administration

    Administer slowly (to avoid flushing reaction).

    IM Administration

    Administer by deep IM injection.

    Reconstitution

    Reconstitute vial containing 25 mg of conjugated estrogens USP with 5 mL of sterile water for injection. Do not shake vigorously. Administer immediately after reconstitution.

    Vaginal Administration

    Administer intravaginally as a vaginal cream.

    Dosage

    Individualize dosage according to the condition being treated and the tolerance and therapeutic response of the patient.

    To minimize risk of adverse effects, use the lowest possible effective dosage. Because of the potential increased risk of cardiovascular events, breast cancer, and venous thromboembolic events, limit estrogen, estrogen/progestin, or conjugated estrogens in fixed combination with bazedoxifene to the lowest effective doses and shortest duration of therapy consistent with treatment goals and risks for the individual woman.

    Periodically reevaluate use of estrogen, estrogen/progestin, or conjugated estrogens in fixed combination with bazedoxifene (i.e., at 3- to 6-month intervals).

    Pediatric Patients

    Hypoestrogenism Oral

    Conjugated estrogens USP: 0.15 mg daily may induce breast development. Increase dosage at 6- to 12-month intervals to achieve appropriate bone age advancement and epiphyseal closure.

    Conjugated estrogens USP: 0.625 mg daily (with progestins) sufficient to induce artificial cyclic menses and to maintain bone mineral density (BMD) after skeletal maturity.

    Adults

    Estrogen Replacement Therapy Vasomotor Symptoms Oral

    Conjugated estrogens USP: Initially, 0.3 mg daily continuously or in cyclic regimen (25 days on, 5 days off). Adjust dosage based on patient response.

    Synthetic conjugated estrogens A: Initially, 0.45 mg daily. May increase dosage up to 1.25 mg daily.

    Synthetic conjugated estrogens B: Initially, 0.3 mg daily. May increase dosage up to 1.25 mg daily. Adjust dosage based on patient response.

    Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro), monophasic regimen: Initially, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily. Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily.

    Conjugated estrogens USP with medroxyprogesterone acetate (Premphase), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; medroxyprogesterone acetate 5 mg daily on days 15–28 of the cycle.

    Conjugated estrogens in fixed combination with bazedoxifene acetate: Conjugated estrogens 0.45 mg with bazedoxifene 20 mg once daily.

    Vulvar and Vaginal Atrophy Oral

    Conjugated estrogens USP: Initially, 0.3 mg daily continuously or in cyclic regimen (25 days on, 5 days off). Adjust dosage based on patient response.

    Synthetic conjugated estrogens A: 0.3 mg daily.

    Synthetic conjugated estrogens B: 0.3 mg daily.

    Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro), monophasic regimen: Initially, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily. Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily.

    Conjugated estrogens USP with medroxyprogesterone acetate (Premphase), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; medroxyprogesterone acetate 5 mg daily on days 15–28 of the cycle.

    Vaginal

    Conjugated estrogens USP: 0.5–2 g daily in cyclic regimen (3 weeks on, 1 week off).

    Osteoporosis Prevention in Postmenopausal Women Oral

    Conjugated estrogens USP: Initially, 0.3 mg daily continuously or in cyclic regimen (25 days on, 5 days off). Adjust dosage based on clinical and BMD response.

    Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro), monophasic regimen: Initially, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily. Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily. Adjust dosage based on clinical and BMD response.

    Conjugated estrogens USP with medroxyprogesterone acetate (Premphase), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; medroxyprogesterone acetate 5 mg daily on days 15–28 of the cycle.

    Conjugated estrogens in fixed combination with bazedoxifene acetate: Conjugated estrogens 0.45 mg with bazedoxifene 20 mg once daily.

    Hypoestrogenism Female Hypogonadism Oral

    Conjugated estrogens USP: 0.3–0.625 mg daily in a cyclic regimen (3 weeks on, 1 week off). Adjust dosage based on symptom severity and endometrial responsiveness.

    Female Castration or Primary Ovarian Failure Oral

    Conjugated estrogens USP: 1.25 mg daily in a cyclic regimen. Adjust dosage based on symptom severity and clinical response.

    Metastatic Breast Carcinoma Oral

    Conjugated estrogens USP: 10 mg 3 times daily for ≥3 months.

    Prostate Carcinoma Oral

    Conjugated estrogens USP: 1.25–2.5 mg 3 times daily.

    Abnormal Uterine Bleeding IV or IM

    Conjugated estrogens USP: 25 mg; can repeat dose in 6–12 hours.

    Warnings

    Contraindications

  • Undiagnosed abnormal genital bleeding.
  • Known or suspected breast cancer or history of breast cancer (except when used for palliative treatment of metastatic disease in appropriately selected individuals).
  • Known or suspected estrogen-dependent neoplasia.
  • Active DVT or pulmonary embolism; history of DVT or pulmonary embolism.
  • Active or recent (within past year) arterial thromboembolic disease (e.g., stroke, MI).
  • Liver disease or impairment.
  • Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders.
  • Known or suspected pregnancy.
  • Known hypersensitivity to estrogen or any ingredient in the formulation.

    • Warnings/Precautions

    Warnings

    Cardiovascular Disorders

    Estrogen/progestin therapy associated with increased risk of MI, stroke, DVT, and pulmonary embolism. Estrogen therapy associated with increased risk of stroke and DVT. (See Boxed Warning.) Discontinue estrogens immediately if any of these events occur or are suspected. 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). (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.

    Endometrial Cancer

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

    Incidence of endometrial hyperplasia is reduced substantially when progestins are used concomitantly. Concomitant use of estrogen agonist/antagonist bazedoxifene also reduces risk of endometrial hyperplasia associated with conjugated estrogens.

    Breast Cancer

    HRT associated with increased risk of breast cancer or increase in abnormal mammograms requiring further evaluation.

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

    Dementia

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

    Gallbladder Disease

    ERT associated with increased risk of gallbladder disease requiring surgery.

    Hypercalcemia

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

    Ocular Effects

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

    General Precautions

    Elevated BP

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

    Hypertriglyceridemia

    Estrogen therapy may be associated with increases in plasma triglyceride concentrations resulting in pancreatitis in women with increased serum lipids. Consider discontinuance of therapy if pancreatitis occurs.

    Fluid Retention

    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).

    Hypocalcemia

    Use with caution in patients with hypoparathyroidism since estrogen-induced hypocalcemia may occur.

    Hereditary Angioedema

    Estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

    Ovarian Cancer

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

    Endometriosis

    Estrogens may exacerbate endometriosis.

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

    Other Conditions

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

    Precautions Specific to Vaginal Administration

    Exposure to conjugated estrogens USP vaginal cream may weaken latex condoms. Consider the potential for the cream to weaken and contribute to protective failure of latex or rubber condoms, diaphragms, or cervical caps.

    Use of Fixed Combinations

    When a progestin is used in conjunction with estrogen therapy, consider the cautions, precautions, and contraindications associated with progestin therapy.

    When bazedoxifene is used in combination with conjugated estrogens, consider the usual cautions, precautions, contraindications, and interactions associated with bazedoxifene. Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug in the fixed combination.

    Specific Populations

    Pregnancy

    Category X. (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.

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

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

    Lactation

    Administration of estrogens to nursing women has been associated with decreased amounts and lower quality of milk. Detectable amounts of estrogens have been identified in milk of women receiving these drugs. Caution advised. Conjugated estrogens/bazedoxifene in fixed combination not recommended for use in nursing women.

    Pediatric Use

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

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

    Estrogen therapy in prepubertal girls induces premature breast development and vaginal cornification and may induce vaginal bleeding. Estrogen therapy in boys may modify the normal pubertal process.

    Geriatric Use

    No substantial differences in safety in women ≥65 years of age compared with younger women; increased incidence of stroke and invasive breast cancer reported in women≥75 years of age compared with younger women.

    Conjugated estrogens/bazedoxifene in fixed combination not recommended for use in women ≥75 years of age.

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

    Clinical studies of estrogens alone or in combination with a progestin did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.

    Hepatic Impairment

    Estrogens may be poorly metabolized in patients with hepatic impairment. (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.

    Renal Impairment

    Use with caution. (See Fluid Retention under Cautions.)

    Common Adverse Effects

    Abdominal pain, asthenia, flatulence, leg cramps, pruritus, vaginal hemorrhage, vaginitis, vaginal moniliasis.

    What other drugs will affect Estrogens, Conjugated

    Appears to be metabolized partially by CYP3A4.

    Drugs Affecting Hepatic Microsomal Enzymes

    CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma estrogen concentrations).

    CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma estrogen concentrations).

    Specific Drugs and Foods

    Drug or Food

    Interaction

    Comments

    Anticoagulants, oral

    Possible decreased anticoagulant action

    Monitor; increase warfarin dosage if required

    Antifungals, azoles (itraconazole, ketoconazole)

    Possible increased plasma estrogen concentrations; increased potential for adverse effects

    Carbamazepine

    Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding

    Corticosteroids (hydrocortisone)

    Enhanced anti-inflammatory effects in patients with chronic inflammatory skin disease

    Observe for signs of excessive corticosteroid effects; adjust corticosteroid dosage when initiating or discontinuing estrogen

    Grapefruit juice

    Possible increased plasma estrogen concentrations; increased potential for adverse effects

    Macrolide antibiotics (clarithromycin, erythromycin)

    Possible increased plasma estrogen concentrations; increased potential for adverse effects

    Medroxyprogesterone

    Interaction unlikely

    Phenobarbital

    Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding

    Rifampin

    Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding

    Ritonavir

    Possible increased plasma estrogen concentrations; increased potential for adverse effects

    St. John’s wort (Hypericum perforatum)

    Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding

    Thyroid agents

    Increased thyroid-binding globulin concentrations

    Increased dosages of thyroid replacement agents may be needed; monitor thyroid function

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