Estropipate, Esterified Estrogens

Class: Estrogens
ATC Class: G03CA07
VA Class: HS300
CAS Number: 7280-37-7
Brands: Estratest, Estratest H.S., Menest, Ogen, Ortho-Est

Warning(s)

  • Estrogens increase the risk of endometrial cancer in postmenopausal women.106 107 108 (See Endometrial Cancer under Cautions.)

  • Do not use estrogens with or without progestins for prevention of cardiovascular disease106 107 108 (See Cardiovascular Risk Reduction under Uses and Cardiovascular Disorders under Cautions) or dementia (See Alzheimer’s Disease under Uses).c

  • 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.c

  • 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.106 107 108 c

  • The WHI Memory Study (WHIMS) reported increased risk of developing probable dementia in postmenopausal women ≥65 years of age receiving long-term (4–5 years) therapy with conjugated estrogens in conjunction with medroxyprogesterone acetate or conjugated estrogen alone.106 107 108 c Not known whether this finding also applies to younger postmenopausal women.106 107 108

  • 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.106 107 108

  • 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.106 107 108

Introduction

Steroidal estrogens.106 107 108

Uses for Estropipate, Esterified Estrogens

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.)

Estropipate, Esterified Estrogens Dosage and Administration

General

  • A progestin generally is added to estrogen therapy (HRT) in women with an intact uterus.a Addition of a progestin for ≥10 days per cycle of estrogen administration or daily with estrogen reduces incidence of endometrial hyperplasia and attendant risk of endometrial carcinoma in women with an intact uterus.a

ERT is appropriate in women who have undergone a hysterectomy (avoids unnecessary exposure to progestins).106 107 108

Administration

Administer estropipate and esterified estrogens orally.106 107 108

Estrogen therapy generally is administered in a continuous daily dosage regimen or, alternatively, in a cyclic regimen.106 107 108 When administered cyclically, estrogen usually is given once daily for 3 weeks followed by 1 week without the drug; regimen is repeated as necessary.106 107 108

Oral Administration

Administer orally one or more times daily.106 107 108

When estropipate or esterified estrogens is used for management of vasomotor symptoms, initiate treatment at any time in women who have not menstruated within the previous 2 months; if patient is menstruating, start cyclic administration on day 5 of cycle.106 107

Dosage

Individualize dosage according to the condition being treated and the tolerance and therapeutic response of the patient.106 107 108

To minimize risk of adverse effects, use the lowest possible effective dosage.106 107 108 c Because of the potential increased risk of cardiovascular events, breast cancer, and venous thromboembolic events, limit estrogen and estrogen/progestin therapy to the lowest effective doses and shortest duration of therapy consistent with treatment goals and risks for the individual woman.106 107 108

Periodically reevaluate estrogen and estrogen/progestin therapy (i.e., at 3- to 6-month intervals).106 107 108

Adults

Estrogen Replacement Therapy
Vasomotor Symptoms
Oral

Estropipate: 0.75–6 mg daily in a cyclic regimen.106

Esterified estrogens: 1.25 mg daily in a cyclic regimen.107

Esterified estrogens in fixed combination with methyltestosterone: Esterified estrogens 0.625 mg with methyltestosterone 1.25 mg daily in a cyclic regimen (3 weeks on, 1 week off).108 Alternatively, esterified estrogens 1.25 mg with methyltestosterone 2.5 mg daily in a cyclic regimen.108

Vulvar and Vaginal Atrophy
Oral

Estropipate: 0.75–6 mg daily in a cyclic regimen.106

Esterified estrogens: 0.3–≥1.25 mg daily in a cyclic regimen.107

Osteoporosis
Prevention in Postmenopausal Women
Oral

Estropipate: 0.75 mg daily in a cyclic regimen (25 days on, 6 days off).106

Hypoestrogenism
Female Hypogonadism
Oral

Estropipate: 1.5–9 mg daily for 3 weeks followed by 8–10 days without the drug; if menstruation does not occur by the end of the 8- to 10-day drug-free period, repeat the same dosage schedule.106 Number of courses required to induce menstruation varies depending on endometrial responsiveness.106 If satisfactory withdrawal bleeding does not occur, may administer an oral progestin concomitantly during the third week of the cycle.106

Esterified estrogens: 2.5–7.5 mg daily in divided doses for 20 days, followed by 10 days without the drug.107 Number of courses required to induce menstruation varies depending on endometrial responsiveness.107 If menstruation does not occur by the end of the first complete cycle, repeat the same dosage schedule.107 If menstruation occurs before the end of the 10-day drug-free period, initiate estrogen-progestin regimen with esterified estrogens 2.5–7.5 mg given daily in divided doses for 20 days; administer oral progestin during the last 5 days of esterified estrogens administration.107 If menstruation begins before the estrogen-progestin regimen is completed, discontinue therapy and then reinstitute on the fifth day of menstruation.107

Female Castration or Primary Ovarian Failure
Oral

Estropipate: 1.5–9 mg daily for 3 weeks, followed by 8–10 days without the drug.106 Adjust dosage according to severity of symptoms and therapeutic response.106

Esterified estrogens: 1.25 mg daily in a cyclic regimen.107 Adjust dosage according to severity of symptoms and therapeutic response.107

Metastatic Breast Carcinoma
Oral

Esterified estrogens: 10 mg 3 times daily for ≥3 months.107

Prostate Carcinoma
Oral

Esterified estrogens: 1.25–2.5 mg 3 times daily.107

Cautions for Estropipate, Esterified Estrogens

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

Cardiovascular Disorders

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

Endometrial Cancer

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

Breast Cancer

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

Dementia

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.)

Gallbladder Disease

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

Hypercalcemia

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

Ocular Effects

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

Elevated BP

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

Hypertriglyceridemia

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

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).106 107 108

Hypocalcemia

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

Ovarian Cancer

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

Endometriosis

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

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.106 107 108

Combination Therapy

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

Pregnancy

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

Lactation

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

Pediatric Use

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

Geriatric Use

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.)

Hepatic Impairment

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

Renal Impairment

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

Common Adverse Effects

Vaginal hemorrhage, vaginal moniliasis.106 107 108

Interactions for Estropipate, Esterified Estrogens

Appears to be metabolized partially by CYP3A4.106 107 108

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma estrogen concentrations).106 107 108

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma estrogen concentrations).106 107 108

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 effects106 107 108

Carbamazepine

Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding106 107 108

Corticosteroids (hydrocortisone)

Enhanced anti-inflammatory effects of hydrocortisone 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 effects106 107 108

Macrolide antibiotics (clarithromycin, erythromycin)

Possible increased plasma estrogen concentrations; increased potential for adverse effects106 107 108

Phenobarbital

Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding106 107 108

Rifampin

Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding106 107 108

Ritonavir

Possible increased plasma estrogen concentrations; increased potential for adverse effects106 107 108

St. John’s wort (Hypericum perforatum)

Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding106 107 108

Thyroid agents

Increased thyroid-binding globulin concentrations106 107 108

Increased dosages of thyroid replacement agents may be needed; monitor thyroid function106 107 108

Estropipate, Esterified Estrogens Pharmacokinetics

Absorption

Bioavailability

Estrogens are well absorbed from the GI tract.106 107 108

Distribution

Extent

Widely distributed;b highest concentrations found in sex hormone target organs.106 107 108

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 CYP3A4.106 107 108

Extensive metabolic conversion (i.e., estradiol converted to estrone, both converted to estriol) takes place in the liver.106 107 108

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.106 107 108

Elimination Route

Estrogens and their metabolites are excreted mainly in urine.106 107 108

Stability

Storage

Oral

Tablets

<30°C.106 108

Actions

  • Estropipate is estrone solubilized as the sulfate and stabilized with piperazine.106

  • Esterified estrogens is a mixture of the sodium salts of the sulfate esters of the estrogenic substances excreted by pregnant mares.107

  • 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.106 107 108

  • Risk of cancer of the uterus in postmenopausal women.106 107 108 Importance of reporting any unusual vaginal bleeding to clinicians.106 107 108

  • Risk of MI, stroke, breast cancer, and venous thromboembolism.106 107 108 Importance of not using estrogens to prevent heart disease, MI, or strokes.106 107 108

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.106 107 108

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.106 107 108

  • Importance of informing patients of other important precautionary information.106 107 108 (See Cautions.)

Preparations

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

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

Estropipate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

0.75 mg*

Estropipate Tablets

Ogen (scored)

Pfizer

Ortho-Est (scored)

Sun Pharmaceuticals

1.5 mg*

Estropipate Tablets

Ogen (scored)

Pfizer

Ortho-Est (scored)

Sun Pharmaceuticals

Estropipate Tablets

3 mg*

Estropipate Tablets

Ogen (scored)

Pfizer

Esterified Estrogens

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

0.3 mg

Menest

Monarch

0.625 mg

Menest

Monarch

1.25 mg

Menest

Monarch

2.5 mg

Menest

Monarch

Esterified Estrogens Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

0.625 mg with Methyltestosterone 1.25 mg

Covaryx H.S. (with parabens, povidone, and propylene glycol)

Centrix

1.25 mg with Methyltestosterone 2.5 mg

Covaryx (with parabens, povidone, and propylene glycol)

Centrix

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 2, 2012. 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

100. Food and Drug Administration. Certain estrogen-androgen combinations drugs; drugs for human use; drug efficacy study implementation; amendment and opportunity for hearing. [Docket nos. 78N-0377 and 98P-1041; DESI 7661] Fed Regist. 2003; 68:17953-7.

101. Food and Drug Administration. FDA revises finding on estrogen/androgen combination products in the treatment of hot flashes. FDA Talk Paper . Rockville, MD; 2003 Apr 10. Correction. 2003 Apr 11. From the FDA web site. Accessed 2003 Jun 9.

102. Drug Enforcement Administration (DEA), Department of Justice. Schedules of controlled substances: anabolic steroids. Final rule. [21 CFR Part 1308] Fed Regist. 1991; 56:5753-4.

103. Drug Enforcement Administration (DEA), Department of Justice. Schedules of controlled substances: exempt anabolic products. Final rule. [21 CFR Part 1308] Fed Regist. 1992; 57:55090-1.

104. Drug Enforcement Administration (DEA), Department of Justice. Implementation of the Anabolic Steroid Control Act of 2004. Fed Regist. 2005; 241:74653-8.

105. Drug Enforcement Administration (DEA), Office of Diversion Control. Exempt Anabolic Steroids (December 31, 2003). From the DEA web site.

106. Pfizer. Ogen (estropipate) tablets prescribing information. New York, NY; 2005 Nov.

107. Monarch Pharmaceuticals. Menest (esterified estrogens) tablets prescribing information. Bristol, TN; 2005 Jun.

108. Solvay Pharmaceuticals Inc. Estratest and Estratest H.S. (esterified estrogens and methyltestosterone) tablets prescribing information. Marietta, GA; 2005 Jan.

a. AHFS drug information 2007. McEvoy GK, ed. Estropipate Estrogens, Esterified. Bethesda, MD: American Society of Health-System Pharmacists; 2007:3105-7.

b. AHFS drug information 2004. McEvoy GK, ed. Estrogens General Statement. Bethesda, MD: American Society of Health-System Pharmacists; 2004:2949-57.

c. Kenwood Therapeutics. Elestrin (estradiol) gel prescribing information. Fairfield, NJ; 2006 Dec.

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