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Estrogens, Conjugated

Class: Estrogens
ATC Class: G03CA57
VA Class: HS300
Brands: Cenestin, Duavee, Enjuvia, Premarin, Premphase, Prempro

Warning(s)

  • Estrogens increase the risk of endometrial cancer in postmenopausal women.101 104 105 106 107 121 (See Endometrial Cancer under Cautions.)

  • Do not use estrogens with or without progestins for prevention of cardiovascular disease101 104 105 106 107 121 (see Cardiovascular Risk Reduction under Uses and Cardiovascular Disorders under Cautions) or dementia (see Alzheimer’s Disease under Uses).101 104 105 107

  • The Women’s Health Initiative (WHI) study of estrogen alone reported increased risks of stroke and DVT in postmenopausal women receiving approximately 7 years of therapy with conjugated estrogens 0.625 mg daily.101 104 105 107

  • The WHI study of estrogen plus progestin reported increased risks of MI, stroke, invasive breast cancer, pulmonary embolism, and DVT in postmenopausal women receiving ≥5 years of therapy with conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily.101 104 105 106 107

  • The WHI Memory Study (WHIMS) reported increased risk of developing probable dementia in postmenopausal women ≥65 years of age receiving long-term therapy (4–5 years) with conjugated estrogens in conjunction with medroxyprogesterone acetate or conjugated estrogens alone.101 104 105 107 Not known whether this finding also applies to younger postmenopausal women.101 104 105 107

  • Other dosages of conjugated estrogens with medroxyprogesterone and other combinations or dosage forms of estrogens with progestin not studied in WHI trials; in the absence of comparable data, assume risks are similar.101 104 105 107

  • Prescribe estrogens (with or without progestins) at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman.101 104 105 106 107

Introduction

Mixture of estrogens available either as preparations that meet current official USP standards (i.e., conjugated estrogens USP)101 105 107 108 109 or as nonofficial preparations (i.e., synthetic conjugated estrogens A and synthetic conjugated estrogens B, which are prepared synthetically from plant sources).106 108 109 121 122

Uses for 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. b 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).263

ERT

Management of moderate to severe vasomotor symptoms associated with menopause.101 106 107 121 262 266

Management of severe vaginal dryness, pain with sexual intercourse, and vulvar and vaginal atrophy associated with menopause.101 105 106 107 266 If used solely for this indication, consider use of topical vaginal preparations.101 105 106 107 266

Osteoporosis

Prevention of osteoporosis.100 101 107 262 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.100 101 107

Estrogens are effective for prevention of osteoporosis but are associated with a number of adverse effects.100 101 107 If prevention of postmenopausal osteoporosis is the sole indication for therapy, consider alternative therapy (e.g., alendronate, raloxifene, risedronate).101 107 112

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.101 107

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.101 Used for induction of puberty in adolescents with pubertal delay due to hypogonadism.101

Metastatic Breast Carcinoma

Palliative treatment of metastatic breast cancer in selected women and men.101 One of several second-line agents.a

Prostate Carcinoma

Palliative treatment of advanced androgen-dependent prostate carcinoma.101

Abnormal Uterine Bleeding

Treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology.104

Cardiovascular Risk Reduction

ERT or HRT does not decrease the incidence of cardiovascular disease.101 105 106 107 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; 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; FDA has withdrawn approval of estrogen-containing drugs for this indication, since estrogens have not been shown to be safe for this use.110 (See Lactation under Cautions.)

Pregnancy

Not effective for any purpose during pregnancy; use contraindicated in pregnant women.101 104 105 106 107 121 (See Pregnancy under Cautions.)

Estrogens, Conjugated Dosage and Administration

General

  • A progestin generally is added to estrogen therapy (HRT) in women with an intact uterus.101 104 105 107 121 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.101 104 105 107 121

  • As an alternative to progestin, use of bazedoxifene (an estrogen agonist-antagonist) in fixed combination with conjugated estrogens reduces risk of endometrial hyperplasia.261 262 263

  • ERT is appropriate in women who have undergone a hysterectomy (to avoid unnecessary exposure to progestins).101 104 105 107 121

Administration

Conjugated estrogens USP usually administered orally; may also administer intravaginally or by deep IM or slow IV injection.101 104 105 107

Administer synthetic conjugated estrogens A and synthetic conjugated estrogens B orally.106 121

Estrogen therapy generally is administered in a continuous daily dosage regimen or, alternatively, in a cyclic regimen.101 105 107 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.101 105

When parenteral administration of conjugated estrogens USP is required, IV injection is preferred because of the more rapid response compared with IM injection.104

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.107

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.262

IV Administration

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

Administer by direct IV injection.104

Reconstitution

Reconstitute vial containing 25 mg of conjugated estrogens USP with 5 mL of sterile water for injection.104 Do not shake vigorously.104 Administer immediately after reconstitution.104

Rate of Administration

Administer slowly (to avoid flushing reaction).104

IM Administration

Administer by deep IM injection.104

Reconstitution

Reconstitute vial containing 25 mg of conjugated estrogens USP with 5 mL of sterile water for injection.104 Do not shake vigorously.104 Administer immediately after reconstitution.104

Vaginal Administration

Administer intravaginally as a vaginal cream.105

Dosage

Individualize dosage according to the condition being treated and the tolerance and therapeutic response of the patient.101 104 105 106 107 121

To minimize risk of adverse effects, use the lowest possible effective dosage.101 104 105 106 107 121 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.101 104 105 107 121 262

Periodically reevaluate use of estrogen, estrogen/progestin, or conjugated estrogens in fixed combination with bazedoxifene (i.e., at 3- to 6-month intervals).101 104 105 107 121 262

Pediatric Patients

Hypoestrogenism
Oral

Conjugated estrogens USP: 0.15 mg daily may induce breast development.101 Increase dosage at 6- to 12-month intervals to achieve appropriate bone age advancement and epiphyseal closure.101

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.101

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).101 Adjust dosage based on patient response.101

Synthetic conjugated estrogens A: Initially, 0.45 mg daily.106 May increase dosage up to 1.25 mg daily.106

Synthetic conjugated estrogens B: Initially, 0.3 mg daily.121 266 May increase dosage up to 1.25 mg daily.266 Adjust dosage based on patient response.121 266

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.107 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.107

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.107

Conjugated estrogens in fixed combination with bazedoxifene acetate: Conjugated estrogens 0.45 mg with bazedoxifene 20 mg once daily.262

Vulvar and Vaginal Atrophy
Oral

Conjugated estrogens USP: Initially, 0.3 mg daily continuously or in cyclic regimen (25 days on, 5 days off).101 Adjust dosage based on patient response.101

Synthetic conjugated estrogens A: 0.3 mg daily.106

Synthetic conjugated estrogens B: 0.3 mg daily.266

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.107 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.107

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.107

Vaginal

Conjugated estrogens USP: 0.5–2 g daily in cyclic regimen (3 weeks on, 1 week off).105

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).101 Adjust dosage based on clinical and BMD response.101

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.107 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.107 Adjust dosage based on clinical and BMD response.107

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.107

Conjugated estrogens in fixed combination with bazedoxifene acetate: Conjugated estrogens 0.45 mg with bazedoxifene 20 mg once daily.262

Hypoestrogenism
Female Hypogonadism
Oral

Conjugated estrogens USP: 0.3–0.625 mg daily in a cyclic regimen (3 weeks on, 1 week off).101 Adjust dosage based on symptom severity and endometrial responsiveness.101

Female Castration or Primary Ovarian Failure
Oral

Conjugated estrogens USP: 1.25 mg daily in a cyclic regimen.101 Adjust dosage based on symptom severity and clinical response.101

Metastatic Breast Carcinoma
Oral

Conjugated estrogens USP: 10 mg 3 times daily for ≥3 months.101

Prostate Carcinoma
Oral

Conjugated estrogens USP: 1.25–2.5 mg 3 times daily.101

Abnormal Uterine Bleeding
IV or IM

Conjugated estrogens USP: 25 mg; can repeat dose in 6–12 hours.104

Cautions for Estrogens, Conjugated

Contraindications

Warnings/Precautions

Warnings

Cardiovascular Disorders

Estrogen/progestin therapy associated with increased risk of MI, stroke, DVT, and pulmonary embolism.101 104 105 106 107 112 113 114 121 Estrogen therapy associated with increased risk of stroke and DVT.101 104 105 107 262 (See Boxed Warning.) Discontinue estrogens immediately if any of these events occur or are suspected.101 104 105 106 107 121 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).101 104 105 106 107 121 (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.101 104 105 106 107 121 262

Endometrial Cancer

Use of unopposed estrogen therapy in women who have a uterus is associated with increased risk of endometrial cancer.101 104 105 106 107 121 262 Clinical surveillance and evaluation are essential.101 104 105 106 107 121 Perform diagnostic tests to rule out malignancy in women with undiagnosed, persistent or recurring abnormal vaginal bleeding.101 104 105 106 107 121

Incidence of endometrial hyperplasia is reduced substantially when progestins are used concomitantly.101 104 105 106 107 121 Concomitant use of estrogen agonist/antagonist bazedoxifene also reduces risk of endometrial hyperplasia associated with conjugated estrogens.262

Breast Cancer

HRT associated with increased risk of breast cancer101 104 105 106 107 112 113 114 121 or increase in abnormal mammograms requiring further evaluation.262

All postmenopausal women should receive yearly breast examinations by a clinician and perform monthly self-examinations.101 104 105 106 107 121 262 Schedule periodic mammography based on patient age and risk factors.101 104 105 106 107 121 262

Dementia

ERT or HRT in women ≥65 years of age has been associated with increased risk of developing probable dementia.101 104 105 107 121 262 Whether these findings apply to younger women is unknown.101 104 105 107 121 (See Alzheimer’s Disease under Uses.)

Gallbladder Disease

ERT associated with increased risk of gallbladder disease requiring surgery.101 104 105 106 107 121 262

Hypercalcemia

Estrogens may cause severe hypercalcemia in patients with breast cancer and bone metastases.101 104 105 106 107 121 Discontinue the drug and initiate appropriate therapy to reduce serum calcium concentrations if hypercalcemia occurs.101 104 105 106 107 121

Ocular Effects

Retinal thrombosis reported.101 104 105 106 107 121 262 Discontinue pending examination if sudden partial or complete loss of vision or sudden onset of proptosis, diplopia, or migraine occurs.101 104 105 107 121 262 Discontinue estrogens if papilledema or retinal vascular lesions noted on examination.101 104 105 106 107 104 105 121 262

General Precautions

Elevated BP

Rarely, substantial increases in BP attributed to idiosyncratic reactions to estrogen.101 104 105 106 107 121 262 ERT generally is not associated with elevated BP.101 104 105 107 121 Monitor BP at regular intervals.101 104 105 106 107 121

Hypertriglyceridemia

Estrogen therapy may be associated with increases in plasma triglyceride concentrations resulting in pancreatitis in women with increased serum lipids.101 104 105 106 107 121 262 Consider discontinuance of therapy if pancreatitis occurs.262 264 265 266

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).101 104 105 106 107 121 262

Hypocalcemia

Use with caution in patients with hypoparathyroidism since estrogen-induced hypocalcemia may occur.101 104 105 106 107 121 262 264 265 266

Hereditary Angioedema

Estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.262 264 265 266 267

Ovarian Cancer

Long-term estrogen therapy associated with increased incidence of ovarian cancer in some epidemiologic studies.101 104 105 106 107 121 262 Other studies did not show a clinically important association.101 104 105 106 107 121 262

Endometriosis

Estrogens may exacerbate endometriosis.101 104 105 106 107 121

Malignant transformation of residual endometrial implants reported rarely in women receiving unopposed estrogen following hysterectomy.101 104 105 107 Consider the addition of progestin in women with residual endometriosis following hysterectomy.101 104 105 107 121

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.101 104 105 107 121 262

Precautions Specific to Vaginal Administration

Exposure to conjugated estrogens USP vaginal cream may weaken latex condoms.105 Consider the potential for the cream to weaken and contribute to protective failure of latex or rubber condoms, diaphragms, or cervical caps.105

Use of Fixed Combinations

When a progestin is used in conjunction with estrogen therapy, consider the cautions, precautions, and contraindications associated with progestin therapy.107 a

When bazedoxifene is used in combination with conjugated estrogens, consider the usual cautions, precautions, contraindications, and interactions associated with bazedoxifene.262 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.262

Specific Populations

Pregnancy

Category X.101 104 105 106 107 121 262 (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

Lactation

Administration of estrogens to nursing women has been associated with decreased amounts and lower quality of milk.101 104 105 106 107 121 262 Detectable amounts of estrogens have been identified in milk of women receiving these drugs.101 104 105 106 107 121 262 Caution advised.101 104 105 106 107 121 Conjugated estrogens/bazedoxifene in fixed combination not recommended for use in nursing women.262

Pediatric Use

Estrogen therapy has been used for induction of puberty in adolescents with some forms of pubertal delay.101 Safety and efficacy of estrogens in children not otherwise established.101 104 105 107 121

Use estrogen therapy with caution and careful monitoring if bone growth is not yet complete, since estrogens may cause premature epiphyseal closure.101

Estrogen therapy in prepubertal girls induces premature breast development and vaginal cornification and may induce vaginal bleeding.101 Estrogen therapy in boys may modify the normal pubertal process.101

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.101 104 105 107

Conjugated estrogens/bazedoxifene in fixed combination not recommended for use in women ≥75 years of age.262

Possible increased risk of developing probable dementia in women ≥65 years of age. (See Dementia under Cautions.)101 104 105 107

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.101 104 105 107

Hepatic Impairment

Estrogens may be poorly metabolized in patients with hepatic impairment.101 104 105 106 107 121 (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.101 104 105 106 107 121

Renal Impairment

Use with caution.101 104 105 107 121 (See Fluid Retention under Cautions.)

Common Adverse Effects

Abdominal pain, asthenia, flatulence, leg cramps, pruritus, vaginal hemorrhage, vaginitis, vaginal moniliasis.101 107

Interactions for Estrogens, Conjugated

Appears to be metabolized partially by CYP3A4.101 104 105 106 107 121

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma estrogen concentrations).101 104 105 106 107 121

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma estrogen concentrations).101 104 105 106 107 121

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Anticoagulants, oral

Possible decreased anticoagulant actionb

Monitor; increase warfarin dosage if requiredb

Antifungals, azoles (itraconazole, ketoconazole)

Possible increased plasma estrogen concentrations; increased potential for adverse effects101 104 105 106 107 121

Carbamazepine

Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding101 104 105 106 107 121

Corticosteroids (hydrocortisone)

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

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

Grapefruit juice

Possible increased plasma estrogen concentrations; increased potential for adverse effects101 104 105 106 107 121

Macrolide antibiotics (clarithromycin, erythromycin)

Possible increased plasma estrogen concentrations; increased potential for adverse effects101 104 105 106 107 121

Medroxyprogesterone

Interaction unlikely101 106 107

Phenobarbital

Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding101 104 105 106 107 121

Rifampin

Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding101 104 105 106 107 121

Ritonavir

Possible increased plasma estrogen concentrations; increased potential for adverse effects101 104 105 106 107 121

St. John’s wort (Hypericum perforatum)

Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding101 104 105 106 107 121

Thyroid agents

Increased thyroid-binding globulin concentrations101 104 105 106 107 121

Increased dosages of thyroid replacement agents may be needed; monitor thyroid function101 104 105 106 107 121

Estrogens, Conjugated Pharmacokinetics

Absorption

Bioavailability

Conjugated estrogens are well absorbed through mucous membranes and from the GI tract.101 104 105 106 107 121

Food

Conjugated estrogens USP: High-fat meal does not affect extent of oral absorption.107

Synthetic conjugated estrogens A: Effect of food unknown.106

Synthetic conjugated estrogens B: Effects of food unknown.121

Distribution

Extent

Widely distributed; highest concentrations found in sex hormone target organs.101 104 105 106 107 121

Plasma Protein Binding

50–80%.b

Elimination

Metabolism

Metabolized in the liver; the kidney, gonads, and muscle tissue involved to some extent.b Estrogens metabolized partially by CYP3A4.101 104 105 106 107 121

Extensive metabolic conversion takes place in the liver (e.g., estradiol converted to estrone, both converted to estriol).101 104 105 106 107 121

Estrogens undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption.101 104 105 106 107 121

Elimination Route

Estrogens and their metabolites excreted mainly in urine.101 104 106 107 121

Half-life

Conjugated estrogens: 10–28 hours.101 106 107

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).101 106 107 121

Parenteral

Powder for Injection

2–8°C.104

Vaginal

Cream

20–25°C (may be exposed to 15–30°C).105

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Stated to be incompatible with protein hydrolysate, ascorbic acid, or any solution with an acid pH.104

Solution Compatibility104

Compatible

Dextrose solutions

Invert sugar solutions

Sodium chloride 0.9%

Drug Compatibility
Y-Site CompatibilityHID

Compatible

Heparin sodium with hydrocortisone sodium succinate

Potassium chloride

Vitamin B complex with C

Actions

  • Conjugated estrogens USP is a mixture of conjugated equine estrogens obtained from natural sources and occurring as the sodium salts of the water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mare’s urine.101 It is a mixture of sodium estrone sulfate and sodium equilin sulfate that also contains 17α-dihydroequilin, 17α-estradiol, 17β-dihydroequilin, equilenin, 17α-dihydroequilenin, 17β-dihydroequilenin, δ8,9-dehydroestrone, and 17β-estradiol.101

  • Synthetic conjugated estrogens A is a mixture of conjugated estrogens prepared synthetically from plant sources (i.e., soy and yams).106 It contains the sodium salts of water-soluble estrogen sulfates blended into a 9-component mixture of estrone sulfate and sodium equilin sulfate as well as the concomitant components 17α-dihydroequilin, 17α-estradiol, 17β-dihydroequilin, 17α-dihydroequilenin, 17β-dihydroequilenin, equilenin, and 17β-estradiol as sodium sulfate conjugates.106

  • Synthetic conjugated estrogens B is a mixture of conjugated estrogens prepared synthetically from plant sources.121 122 It contains the sodium salts of water-soluble estrogen sulfates blended into a 10-component mixture of estrone sulfate and sodium equilin sulfate as well as the concomitant components 17α-dihydroequilin, 17α-estradiol, 17β-dihydroequilin, 17α-dihydroequilenin, 17β-dihydroequilenin, equilenin, 17β-estradiol, and δ8,9-dehydroestrone as sodium sulfate conjugates.121 This mixture contains the 10 estrogenic substances present in currently available commercial preparations of conjugated estrogens USP.121

  • Exogenous estrogens elicit, to varying degrees, all the pharmacologic responses usually produced by endogenous estrogens.a

Advice to Patients

  • Importance of providing patient a copy of the manufacturer’s patient information.101 104 105 106 107 121

  • Risk of cancer of the uterus in postmenopausal women.101 104 105 106 107 121 Importance of reporting any unusual vaginal bleeding to clinicians.101 104 105 106 107 121

  • Risk of MI, stroke, breast cancer, and venous thromboembolism.101 104 105 106 107 121 Importance of not using estrogens to prevent heart disease, MI, or strokes.101 104 105 106 107 121

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.101 104 105 106 107 121

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as concomitant illnesses.101 104 105 106 107 121

  • Importance of informing patients of other important precautionary information.101 104 105 106 107 121 (See Cautions.)

Preparations

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.

Conjugated Estrogens USP

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

0.3 mg

Premarin

Pfizer

0.45 mg

Premarin

Pfizer

0.625 mg

Premarin

Pfizer

0.9 mg

Premarin

Pfizer

1.25 mg

Premarin

Pfizer

Parenteral

For injection

25 mg

Premarin Intravenous

Pfizer

Vaginal

Cream

0.0625%

Premarin

Pfizer

Conjugated Estrogens Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

0.45 mg with Bazedoxifene Acetate 20 mg (of bazedoxifene)

Duavee

Pfizer

Tablets, monophasic regimen

0.3 mg with Medroxyprogesterone acetate 1.5 mg (28 tablets)

Prempro

Pfizer

0.45 mg with Medroxyprogesterone acetate 1.5 mg (28 tablets)

Prempro

Pfizer

0.625 mg with Medroxyprogesterone Acetate 2.5 mg (28 tablets)

Prempro

Pfizer

0.625 mg with Medroxyprogesterone Acetate 5 mg (28 tablets)

Prempro

Pfizer

Tablets, biphasic regimen

0.625 mg (14 tablets Premarin) and 0.625 mg with Medroxyprogesterone Acetate 5 mg (14 tablets)

Premphase

Pfizer

Conjugated Estrogens A, Synthetic

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

0.3 mg

Cenestin

Teva

0.45 mg

Cenestin

Teva

0.625 mg

Cenestin

Teva

0.9 mg

Cenestin

Teva

1.25 mg

Cenestin

Teva

Conjugated Estrogens B, Synthetic

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

0.3 mg

Enjuvia

Teva

0.45 mg

Enjuvia

Teva

0.625 mg

Enjuvia

Teva

0.9 mg

Enjuvia

Teva

1.25 mg

Enjuvia

Teva

AHFS DI Essentials. © Copyright 2016, Selected Revisions February 29, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. National Institutes of Health. Osteoporosis. JAMA. 1984; 252:799-802. [IDIS 188217] [PubMed 6748181]

101. Wyeth. Premarin (conjugated estrogens) USP tablets prescribing information. Philadelphia, PA; 2007 Jan..

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