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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(ES troe jenz KON joo gate ed/EE kwine & me DROKS ee proe JES te rone)
Generic Available (U.S.)
No
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Use: Labeled Indications
Women with an intact uterus: Treatment of moderate-to-severe vasomotor symptoms associated with menopause; treatment of moderate-to-severe vulvar and vaginal atrophy due to menopause; postmenopausal osteoporosis (prophylaxis)
Pregnancy Considerations
See individual agents; use of this combination is contraindicated during pregnancy
Lactation
Enters breast milk/use caution
Breast-Feeding Considerations
See individual agents.
Contraindications
Angioedema or anaphylactic reaction to estrogens or any component of the formulation; undiagnosed abnormal vaginal bleeding; DVT or PE (current or history of); active or history of arterial thromboembolic disease (eg, stroke, MI); carcinoma of the breast (known, suspected or history of); estrogen-dependent tumor; hepatic dysfunction or disease; known protein C, protein S, antithrombin deficiency or other known thrombophilic disorders; pregnancy
Warnings/Precautions
Boxed warnings:
• Breast cancer: See “Concerns related to adverse effects” below.
• Cardiovascular disease: See “Disease-related concerns” below.
• Dementia: See “Concerns related to adverse effects” below.
• Endometrial carcinoma: See “Concerns related to adverse effects” below.
• Risks vs benefits: See “Other warnings/precautions” below.
Concerns related to adverse effects:
• Anaphylaxis/angioedema: Anaphylaxis requiring emergency medical management has been reported within minutes to hours of taking conjugated estrogen (CE) and medroxyprogesterone acetate (MPA) tablets. Angioedema involving the face, feet, hands, larynx, and tongue has also been reported. Exogenous estrogens may exacerbate symptoms in women with hereditary angioedema.
• Breast cancer: [U.S. Boxed Warning]: Based on data from the Women's Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in postmenopausal women using conjugated estrogens (CE) in combination with medroxyprogesterone acetate (MPA). This risk may be associated with duration of use and declines once combined therapy is discontinued (Chlebowski, 2009). The risk of invasive breast cancer was decreased in postmenopausal women with a hysterectomy using CE only, regardless of weight. However, the risk was not significantly decreased in women at high risk for breast cancer (family history of breast cancer, personal history of benign breast disease) (Anderson, 2012). An increase in abnormal mammogram findings has also been reported with estrogen alone or in combination with progestin therapy. Estrogen use may also lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs. Use is contraindicated in patients with known or suspected breast cancer.
• Dementia: [U.S. Boxed Warning]: Estrogens with or without progestin should not be used to prevent dementia. In the Women's Health Initiative Memory Study (WHIMS), an increased incidence of dementia was observed in women ≥65 years of age taking CE alone or in combination with MPA.
• Endometrial carcinoma: [U.S. Boxed Warning]: The use of unopposed estrogen in women with an intact uterus is associated with an increased risk of endometrial cancer. The addition of a progestin to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer. Adequate diagnostic measures, including endometrial sampling if indicated, should be performed to rule out malignancy in postmenopausal women with undiagnosed abnormal vaginal bleeding. Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestin in women with residual endometriosis posthysterectomy.
• Inherited thrombophilia: Women with inherited thrombophilias (eg, protein C or S deficiency) may have increased risk of venous thromboembolism (DeSancho, 2010; van Vlijmen, 2011). Use is contraindicated in women with protein C, protein S, antithrombin deficiency, or other known thrombophilic disorders.
• Lipid effects: Estrogen compounds are generally associated with lipid effects such as increased HDL-cholesterol and decreased LDL-cholesterol. Triglycerides may also be increased; use with caution in patients with familial defects of lipoprotein metabolism. Discontinue if pancreatitis occurs.
• Ovarian cancer: Postmenopausal estrogen therapy and combined estrogen/progesterone therapy may increase the risk of ovarian cancer; however, the absolute risk to an individual woman is small. Although results from various studies are not consistent, risk does not appear to be significantly associated with the duration, route, or dose of therapy. In one study, the risk decreased after 2 years following discontinuation of therapy (Mørch, 2009). Although the risk of ovarian cancer is rare, women who are at an increased risk (eg, family history) should be counseled about the association (NAMS, 2012).
• Retinal vascular thrombosis: Estrogens may cause retinal vascular thrombosis; discontinue if migraine, loss of vision, proptosis, diplopia, or other visual disturbances occur; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.
Disease-related concerns:
• Asthma: Use caution in patients with asthma; may exacerbate disease.
• Carbohydrate intolerance: May have adverse effects on glucose tolerance; use caution in women with diabetes.
• Cardiovascular disease: [U.S. Boxed Warning]: Estrogens with or without progestin should not be used to prevent cardiovascular disease. Using data from the Women's Health Initiative (WHI) studies, an increased risk of deep vein thrombosis (DVT) and stroke has been reported with CE and an increased risk of DVT, stroke, pulmonary emboli (PE) and myocardial infarction (MI) has been reported with CE with MPA in postmenopausal women. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of venous thromboembolism (VTE). Risk factors should be managed appropriately; discontinue use if adverse cardiovascular events occur or are suspected.
• Diseases exacerbated by fluid retention: Use with caution in patients with diseases which may be exacerbated by fluid retention, including cardiac or renal dysfunction.
• Epilepsy: Use caution with epilepsy; may exacerbate disease.
• Gallbladder disease: Use of postmenopausal estrogen may be associated with an increased risk of gallbladder disease requiring surgery.
• Hepatic dysfunction: Estrogens are poorly metabolized in patients with hepatic dysfunction. Use caution with a history of cholestatic jaundice associated with prior estrogen use or pregnancy. Discontinue if jaundice develops or if acute or chronic hepatic disturbances occur. Use is contraindicated with hepatic disease.
• Hepatic hemangiomas: Use with caution in patients with hepatic hemangiomas; may exacerbate disease.
• Hypocalcemia: Use with caution in patients with severe hypocalcemia.
• Migraine: Use caution with migraine; may exacerbate disease.
• Porphyria: Use with caution in patients with porphyria; may exacerbate disease.
• SLE: Use with caution in patients with SLE; may exacerbate disease.
Concurrent drug therapy issues:
• Thyroid replacement therapy: Estrogens may increase thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels. Women on thyroid replacement therapy may require higher doses of thyroid hormone while receiving estrogens.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children. Prior to puberty, estrogens may cause premature closure of the epiphyses, premature breast development in girls, or gynecomastia in boys. Vaginal bleeding and vaginal cornification may also be induced in girls.
• Surgical patients: Whenever possible, should be discontinued at least 4-6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
Other warnings/precautions:
• Osteoporosis use: For use only in women at significant risk of osteoporosis and for who other nonestrogen medications are not considered appropriate.
• Risks vs benefits: [U.S. Boxed Warning]: Estrogens with or without progestin should be used for the shortest duration possible at the lowest effective dose consistent with treatment goals. Before prescribing estrogen therapy to postmenopausal women, the risks and benefits must be weighed for each patient. Women should be informed of these risks and benefits, as well as possible effects of progestin when added to estrogen therapy. Patients should be reevaluated as clinically appropriate to determine if treatment is still necessary. Available data related to treatment risks are from Women's Health Initiative (WHI) studies, which evaluated oral CE 0.625 mg with or without MPA 2.5 mg relative to placebo in postmenopausal women. Other combinations and dosage forms of estrogens and progestins were not studied. Outcomes reported from clinical trials using CE with or without MPA should be assumed to be similar for other doses and other dosage forms of estrogens and progestins until comparable data becomes available.
• Vulvar and vaginal atrophy use: When used solely for the treatment of vulvar and vaginal atrophy, topical vaginal products should be considered.
Adverse Reactions
>10%:
Central nervous system: Headache (28% to 37%), pain (11% to 13%), depression (6% to 11%)
Endocrine & metabolic: Breast pain (32% to 38%), dysmenorrhea (5% to 13%)
Gastrointestinal: Abdominal pain (16% to 23%), nausea (9% to 11%)
Neuromuscular & skeletal: Back pain (13% to 16%)
Respiratory: Pharyngitis (11% to 13%)
Miscellaneous: Infection (16% to 18%), flu-like syndrome (10% to 13%)
1% to 10%:
Cardiovascular: Peripheral edema (3% to 4%)
Central nervous system: Dizziness (3% to 5%)
Dermatologic: Pruritus (5% to 10%), rash (4% to 6%)
Endocrine & metabolic: Leukorrhea (5% to 9%)
Gastrointestinal: Flatulence (8% to 9%), diarrhea (5% to 6%), dyspepsia (5% to 6%)
Genitourinary: Vaginitis (5% to 7%), cervical changes (4% to 5%), pelvic pain (4 to 5%), vaginal hemorrhage (1% to 3%)
Neuromuscular & skeletal: Weakness (6% to 10%), arthralgia (7% to 9%), leg cramps (3% to 5%), hypertonia (3% to 4%)
Respiratory: Sinusitis (7% to 8%), rhinitis (6% to 8%)
Postmarketing and/or case reports (adverse reactions reported with this combination; also see individual monographs): Abnormal uterine bleeding, acne, amenorrhea, anaphylactoid/anaphylactic reactions, angioedema, anxiety, appetite changes, asthma exacerbation, bloating, breast cancer, breast enlargement breast tenderness, cervical secretion changes, chloasma, cholestatic jaundice, chorea exacerbation, contact lens intolerance, dementia, DVT, edema, endometrial cancer, endometrial hyperplasia, epilepsy exacerbation, erythema multiforme, erythema nodosum, fibrocytic breast changes, galactorrhea, gallbladder disease, glucose intolerance, hirsutism, hypersensitivity, hypertension, irritability, libido changes, melasma, MI, migraine, mood disturbance, nipple discharge, ovarian cancer, pancreatitis, PE, retinal vascular thrombosis, scalp hair loss, stroke, superficial venous thrombosis, thrombophlebitis, triglycerides increased, urticaria, uterine leiomyomata (increase in size), vaginal candidiasis, vomiting, weight changes
Metabolism/Transport Effects
Refer to individual components.
Drug Interactions
Acitretin: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Given the potential for progestin-only preparations to fail to prevent pregnancy during acitretin therapy, such products should not be relied upon. Alternative, nonhormonal forms of contraception must be employed during acitretin therapy. Risk D: Consider therapy modification
Aminoglutethimide: May increase the metabolism of Progestins. Management: Progestin-containing contraceptives are not recommended; consider the use of alternative, nonhormonal contraceptives. Risk D: Consider therapy modification
Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Risk X: Avoid combination
Aprepitant: May decrease the serum concentration of Contraceptives (Progestins). Management: Alternative or additional methods of contraception should be used both during treatment with aprepitant or fosaprepitant and for at least one month following the last aprepitant/fosaprepitant dose. Risk D: Consider therapy modification
ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double aripiprazole dose when initiating concomitant therapy with a CYP3A4 inducer (e.g., carbamazepine). Monitor response and adjust aripiprazole dose as clinically indicated. If CYP3A4 inducer is discontinued, reduce aripiprazole dose to 10-15 mg/day. Risk D: Consider therapy modification
Artemether: May decrease the serum concentration of Contraceptives (Progestins). Management: Consider the use of an alternative (i.e., non-hormonal) means of contraception in all women of childbearing potential who are using artemether. Risk D: Consider therapy modification
Ascorbic Acid: May increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
Axitinib: CYP3A4 Inducers (Weakly to Moderately Effective) may decrease the serum concentration of Axitinib. Risk X: Avoid combination
Barbiturates: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. Risk D: Consider therapy modification
Benzodiazepines (metabolized by oxidation): Contraceptives (Progestins) may increase the serum concentration of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Bexarotene: May decrease the serum concentration of Contraceptives (Progestins). Management: Women of childbearing potential receiving bexarotene should use two reliable forms of contraception (including at least one nonhormonal form). Risk D: Consider therapy modification
Bexarotene (Systemic): May decrease the serum concentration of Contraceptives (Progestins). Management: Women of childbearing potential receiving bexarotene should use two reliable forms of contraception (including at least one nonhormonal form). Risk D: Consider therapy modification
Bile Acid Sequestrants: May decrease the serum concentration of Contraceptives (Progestins). Management: Administer oral progestin-containing contraceptives at least 1-4 hours prior to or 4-6 hours after administration of a bile acid sequestrant. Risk D: Consider therapy modification
Boceprevir: May increase the serum concentration of Contraceptives (Progestins). Management: Do not rely on systemic hormonal contraceptives for contraception during treatment with boceprevir. Patients receiving combination regimens containing ribavirin should use two alternative effective means of contraception. Risk D: Consider therapy modification
Bosentan: May decrease the serum concentration of Contraceptives (Progestins). Management: Use an alternative (i.e., non-hormonal) means of contraception for all women of childbearing potential who are using bosentan, and do not rely on hormonal contraceptives alone. Risk D: Consider therapy modification
CarBAMazepine: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. Risk D: Consider therapy modification
Chenodiol: Estrogen Derivatives may diminish the therapeutic effect of Chenodiol. Management: Monitor clinical response to chenodiol closely when used together with any estrogen derivative. Risk C: Monitor therapy
Clobazam: May decrease the serum concentration of Contraceptives (Progestins). Risk D: Consider therapy modification
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy
Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapy
CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Cyproterone: May decrease the serum concentration of CYP2E1 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Felbamate: May decrease the serum concentration of Contraceptives (Progestins). Management: Contraceptive failure is possible. Use of an alternative, nonhormonal method of contraception is recommended. Risk D: Consider therapy modification
Fosaprepitant: May decrease the serum concentration of Contraceptives (Progestins). The active metabolite aprepitant is likely responsible for this effect. Management: Alternative or additional methods of contraception should be used both during treatment with aprepitant or fosaprepitant and for at least one month following the last aprepitant/fosaprepitant dose. Risk D: Consider therapy modification
Fosphenytoin: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Risk D: Consider therapy modification
Griseofulvin: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Risk X: Avoid combination
Herbs (Estrogenic Properties): May enhance the adverse/toxic effect of Estrogen Derivatives. Risk C: Monitor therapy
Herbs (Progestogenic Properties) (eg, Bloodroot, Yucca): May enhance the adverse/toxic effect of Progestins. Risk C: Monitor therapy
LamoTRIgine: May decrease the serum concentration of Contraceptives (Progestins). Management: Women using progestin-only “minipill” products may be at risk for contraceptive failure; it is unclear if other progestin-containing products would be significantly impacted. Alternative, non-hormonal, means of contraception are recommended. Risk D: Consider therapy modification
Mycophenolate: May decrease the serum concentration of Contraceptives (Progestins). Management: Use of an additional or alternative (nonhormonal) method of contraception should be considered. Risk D: Consider therapy modification
Nevirapine: May decrease the serum concentration of Contraceptives (Progestins). Management: Instruct patients receiving nevirapine to use an alternative or additional nonhormonal contraceptive. Nevirapine product labeling however suggests that depo-medroxyprogesterone acetate may be used as a sole method of contraception. Risk D: Consider therapy modification
OXcarbazepine: May decrease the serum concentration of Contraceptives (Progestins). Management: Contraceptive failure is possible. Use of an additional or alternative, nonhormonal method of contraception is recommended. Risk D: Consider therapy modification
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Phenytoin: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Risk D: Consider therapy modification
Prucalopride: May decrease the serum concentration of Contraceptives (Progestins). Risk D: Consider therapy modification
Retinoic Acid Derivatives: May diminish the therapeutic effect of Contraceptives (Progestins). Retinoic Acid Derivatives may decrease the serum concentration of Contraceptives (Progestins). Management: Two forms of effective contraception should be used in patients receiving retinoic acid derivatives. Particularly, microdosed progesterone-only preparations may be inadequately effective. Risk D: Consider therapy modification
Rifamycin Derivatives: May decrease the serum concentration of Contraceptives (Progestins). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Risk D: Consider therapy modification
ROPINIRole: Estrogen Derivatives may increase the serum concentration of ROPINIRole. Risk C: Monitor therapy
Saxagliptin: CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Risk C: Monitor therapy
Selegiline: Contraceptives (Progestins) may increase the serum concentration of Selegiline. Risk C: Monitor therapy
Somatropin: Estrogen Derivatives may diminish the therapeutic effect of Somatropin. Shown to be a concern with oral hormone replacement therapy in postmenopausal women. Management: Monitor for reduced growth hormone efficacy. A larger somatropin dose may be required to reach treatment goal. This interaction does not appear to apply to non-orally administered estrogens (e.g., transdermal, vaginal ring). Risk D: Consider therapy modification
St Johns Wort: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Consider using a product other than St John's wort. Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Risk D: Consider therapy modification
Telaprevir: May decrease the serum concentration of Contraceptives (Progestins). Management: Two different nonhormonal forms of contraception are required for women of childbearing potential taking telaprevir. Hormonal contraceptives may be less effective during concurrent telaprevir and for up to 2 weeks after telaprevir discontinuation. Risk D: Consider therapy modification
Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Risk C: Monitor therapy
Tipranavir: Estrogen Derivatives may enhance the dermatologic adverse effect of Tipranavir. The combination of tipranavir/ritonavir and ethinyl estradiol/norethindrone was associated with a high incidence of skin rash. Tipranavir may decrease the serum concentration of Estrogen Derivatives. Management: Women using hormonal contraceptives should consider alternative, non-hormonal forms of contraception. Risk D: Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Topiramate: May decrease the serum concentration of Contraceptives (Progestins). Management: Caution patients that this combination may be associated with reduced contraceptive effectiveness. Consider adding an additional (non-hormonal) contraceptive method. Risk D: Consider therapy modification
Tranexamic Acid: Contraceptives (Progestins) may enhance the thrombogenic effect of Tranexamic Acid. Management: Ensure that the potential benefits of concurrent therapy outweigh the increased risk of potential thrombosis that accompanies use of tranexamic acid with hormonal contraceptives. Risk D: Consider therapy modification
Ursodiol: Estrogen Derivatives may diminish the therapeutic effect of Ursodiol. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Contraceptives (Progestins) may diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Management: When possible, concomitant hormonal contraceptives and coumarin derivatives should be avoided in order to eliminate the risk of thromboembolic disorders. Consider using an alternative, nonhormonal contraceptive. Risk D: Consider therapy modification
Voriconazole: May increase the serum concentration of Contraceptives (Progestins). Contraceptives (Progestins) may increase the serum concentration of Voriconazole. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (routine use increases estrogen plasma concentrations and risk of breast cancer). Ethanol may also increase the risk of osteoporosis.
Food: Folic acid absorption may be decreased.
Herb/Nutraceutical: St John's wort may decrease levels. Avoid black cohosh, dong quai (has estrogenic activity). Avoid red clover, saw palmetto, ginseng (due to potential hormonal effects).
Storage
Store at room temperature 20°C to 25°C (68°F to 77°F).
Mechanism of Action
Conjugated estrogens contain a mixture of estrone sulfate, equilin sulfate, 17 alpha-dihydroequilin, 17 alpha-estradiol, and 17 beta-dihydroequilin. Estrogens are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estradiol is the principle intracellular human estrogen and is more potent than estrone and estriol at the receptor level; it is the primary estrogen secreted prior to menopause. Following menopause, estrone and estrone sulfate are more highly produced. Estrogens modulate the pituitary secretion of gonadotropins, luteinizing hormone, and follicle-stimulating hormone through a negative feedback system; estrogen replacement reduces elevated levels of these hormones in postmenopausal women.
MPA inhibits gonadotropin production which then prevents follicular maturation and ovulation. In women with adequate estrogen, MPA transforms a proliferative endometrium into a secretory endometrium; when administered with conjugated estrogens, reduces the incidence of endometrial hyperplasia and risk of adenocarcinoma.
Pharmacodynamics/Kinetics
See individual agents.
Dosage
Oral: Adults:
Treatment of moderate-to-severe vasomotor symptoms associated with menopause; treatment of vulvar and vaginal atrophy due to menopause in women with a uterus; osteoporosis prophylaxis in females with an intact uterus (Note: The lowest dose that will control symptoms should be used; medication should be discontinued as soon as possible):
Premphase®: One maroon conjugated estrogen 0.625 mg tablet daily on days 1 through 14 and 1 light blue conjugated estrogen 0.625 mg/MPA 5 mg tablet daily on days 15 through 28
Prempro®: One conjugated estrogen/MPA tablet once daily; maximum dose: 1 conjugated estrogen 0.625 mg/MPA 5 mg tablet daily
Elderly: Refer to adult dosing; a higher incidence of stroke and invasive breast cancer was observed in women >75 years in a WHI substudy.
Monitoring Parameters
Routine physical examination that includes blood pressure and Papanicolaou smear, breast exam, mammogram. Monitor for signs of endometrial cancer. Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding. Monitor for loss of vision, sudden onset of proptosis, diplopia, migraine; signs and symptoms of thromboembolic disorders; glycemic control in patients with diabetes; lipid profiles in patients being treated for hyperlipidemias; thyroid function in patients on thyroid hormone replacement therapy.
Menopausal symptoms: Assess need for therapy at 3- to 6-month intervals
Prevention of osteoporosis: Bone density measurement
Test Interactions
Pathologist should be advised of estrogen/progesterone therapy when specimens are submitted. Reduced response to metyrapone test.
Dietary Considerations
Administration with food decreases nausea, administer with food. Ensure adequate calcium and vitamin D intake when used for the prevention of osteoporosis.
Patient Education
See individual agents.
Geriatric Considerations
Before prescribing estrogen therapy to postmenopausal women, the risks and benefits must be weighed for each patient. Women should be informed of these risks and benefits, as well as possible side effects and the return of menstrual bleeding (when cycled with a progestin), and be involved in the decision to prescribe. A higher incidence of stroke and invasive breast cancer was observed in women >75 years in a WHI substudy.
Cardiovascular Considerations
It is important to recognize that estrogens may induce or worsen hypertension. These problems are less severe with lower doses. Furthermore, estrogens may precipitate thromboembolic events, particularly in women who smoke. It is important that patients on long-term estrogens undergo monitoring of blood pressure and avoid cigarette use.
Conjugated estrogens (alone or in combination with a progestin) should not be used to prevent coronary heart disease. The HERS trial found that women with coronary disease derived no cardiovascular protection compared to those treated with placebo. In the Women's Health Initiative trial, a conjugated estrogen/progestin combination did not offer protection against heart disease. No cardiovascular benefits were seen; in fact, more coronary heart disease was observed in the treatment group. Substantial evidence suggests that estrogen therapy increases bone mineralization and therefore may be of added benefit in patients with osteoporosis. Estrogen also has a favorable effect on lipids (decreases total cholesterol and LDL, increases HDL) but increases triglycerides. Therapy should be initiated after careful evaluation of risk:benefit for therapy.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness, headache, depression, insomnia, nervousness, irritability, and mood disturbances
Mental Health: Effects on Psychiatric Treatment
Barbiturates and carbamazepine may decrease the effects of estrogens; estrogens may affect metabolism of benzodiazepines; monitor for clinical effect. The Women's Health Initiative (WHI) Memory Study reported an increased risk of developing dementia in postmenopausal women ≥65 years of age during 4 years of treatment with oral conjugated equine estrogens and medroxyprogesterone acetate relative to placebo (1.8% vs 0.9%). Relative risk was 2.05 (95% CI 1.21-3.48). Therefore, estrogens and progestins should not be used for the prevention of dementia. The WHI also reported an increased risk of stroke (29 vs 21 per 10,000 women-years) compared to women receiving placebo. The increase in risk was observed after the first year and persisted. May cause hypertriglyceridemia; monitor in patients receiving antipsychotics especially clozapine, olanzapine, and quetiapine.
Nursing: Physical Assessment/Monitoring
See individual agents.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Premphase® [therapy pack contains 2 separate tablet formulations]: Conjugated estrogens 0.625 mg [14 maroon tablets] and conjugated estrogen 0.625 mg/medroxyprogesterone acetate 5 mg [14 light blue tablets] (28s)
Prempro®:
0.3/1.5: Conjugated estrogens 0.3 mg and medroxyprogesterone acetate 1.5 mg (28s)
0.45/1.5: Conjugated estrogens 0.45 mg and medroxyprogesterone acetate 1.5 mg (28s)
0.625/2.5: Conjugated estrogens 0.625 mg and medroxyprogesterone acetate 2.5 mg (28s)
0.625/5: Conjugated estrogens 0.625 mg and medroxyprogesterone acetate 5 mg (28s)
Pricing: U.S. (www.drugstore.com)
Tablets (Premphase)
0.625-5 mg (28): $79.99
Tablets (Prempro)
0.3-1.5 mg (28): $85.99
0.45-1.5 mg (28): $85.99
0.625-5 mg (28): $85.99
References
Anderson GL, Chlebowski RT, Aragaki AK, et al, "Conjugated Equine Oestrogen and Breast Cancer Incidence and Mortality in Postmenopausal Women With Hysterectomy: Extended Follow-Up of the Women's Health Initiative Randomised Placebo-Controlled Trial," Lancet Oncol, 2012 [epub ahead of print].
Anderson GL, Limacher M, Assaf AR, et al, "Effects of Conjugated Equine Estrogen In Postmenopausal Women With Hysterectomy: The Women's Health Initiative Randomized Controlled Trial." JAMA, 2004, 291(14):1701-12.
Chlebowski RT, Kuller LH, Prentice RL, et al, "Breast Cancer After Use of Estrogen Plus Progestin in Postmenopausal Women," N Engl J Med, 2009, 360(6):573-87.
DeSancho MT, Dorff T, and Rand JH, "Thrombophilia and the Risk of Thromboembolic Events In Women on Oral Contraceptives and Hormone Replacement Therapy," Blood Coagul Fibrinolysis, 2010, 21(6):534-8.
Grodstein F, Stampfer MJ, Colditz GA, et al, “Postmenopausal Hormone Therapy and Mortality,” N Engl J Med, 1997, 336(25):1769-75.
Hsia J, Langer RD, Manson JE, et al, "Conjugated Equine Estrogens and Coronary Heart Disease: The Women's Health Initiative," Arch Intern Med, 2006, 166(3):357-65.
Hulley S, Grady D, Bush T, et al, “Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group,” JAMA, 1998, 280(7):605-13.
Mørch LS, Løkkegaard E, Andreasen AH, et al, “Hormone Therapy and Ovarian Cancer,” JAMA, 2009, 302(3):298-305.
North American Menopause Society [NAMS], "The 2012 Hormone Therapy Position Statement of The North American Menopause Society," Menopause, 2012, 19(3):257-71.
Rossouw JE, Anderson GL, Prentice RL, et al, “Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principle Results From the Women's Health Initiative Randomized Controlled Trial,”JAMA, 2002, 288(3):321-33.
Shumaker SA, Legault C, Rapp SR, et al, “Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women: The Women's Health Initiative Memory Study: A Randomized Controlled Trial,” JAMA, 2003, 289(20):2651-62.
U.S. Food and Drug Administration, Department of Health and Human Services, “WHIMS Study on Estrogen/Progestin,” May 27, 2003. Available at http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm135318.htm
van Vlijmen EF, Veeger NJ, Middeldorp S, et al, "Thrombotic Risk During Oral Contraceptive Use and Pregnancy in Women With Factor V Leiden or Prothrombin Mutation: A Rational Approach to Contraception," Blood, 2011, 118(8):2055-61.
Wassertheil-Smoller S, Hendrix S, Limacher M, et al, “Effect of Estrogen Plus Progestin on Stroke in Postmenopausal Women: The Women's Health Initiative: A Randomized Trial,” JAMA, 2003, 289:2673-84.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
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