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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.
Medication Safety Issues
Sound-alike/look-alike issues:
Premphase® may be confused with Prempro™
Prempro™ may be confused with Premphase®
Pronunciation
(ES troe jenz KON joo gate ed/EE kwine & me DROKS ee proe JES te rone)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Women with an intact uterus: Treatment of moderate-to-severe vasomotor symptoms associated with menopause; treatment of atrophic vaginitis; 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
Hypersensitivity to conjugated estrogens, medroxyprogesterone (MPA), or any component of the formulation; undiagnosed abnormal vaginal bleeding; history of or current thrombophlebitis or venous thromboembolic disorders (including DVT, PE); active or recent (within 1 year) arterial thromboembolic disease (eg, stroke, MI); carcinoma of the breast; estrogen-dependent tumor; hepatic dysfunction or disease; pregnancy
Warnings/Precautions
Boxed warnings:
• Cardiovascular disease: See “Disease-related concerns” below.
• Dementia: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Breast cancer: Estrogens may increase the risk of breast cancer. An increased risk of invasive breast cancer was observed in postmenopausal women using CEE in combination with MPA; a smaller increase in risk was seen with estrogen therapy alone in observational studies. An increase in abnormal mammograms has also been reported with estrogen and progestin therapy. Estrogen use may lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs.
• Dementia: [U.S. Boxed Warning]: The risk of dementia may be increased in postmenopausal women; increased incidence was observed in women ?65 years of age taking CEE alone or in combination with MPA.
• Endometrial cancer: Unopposed estrogens may increase the risk of endometrial carcinoma in postmenopausal women. Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with estrogen only therapy.
• 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.
• 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.
• Retinal vascular thrombosis: Estrogens may cause retinal vascular thrombosis; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.
Disease-related concerns:
• Cardiovascular disease: [U.S. Boxed Warning]: Estrogens with or without progestin should not be used to prevent coronary heart disease. Use caution with cardiovascular disease or dysfunction. May increase the risks of hypertension, myocardial infarction (MI), stroke, pulmonary emboli (PE), and deep vein thrombosis; incidence of these effects was shown to be significantly increased in postmenopausal women using conjugated equine estrogens (CEE) in combination with medroxyprogesterone acetate (MPA). Nonfatal MI, PE, and thrombophlebitis have also been reported in males taking high doses of CEE (eg, for prostate cancer).
• Cholestatic jaundice: Use caution with history of cholestatic jaundice associated with past estrogen use or pregnancy.
• Diseases exacerbated by fluid retention: Use with caution in patients with diseases which may be exacerbated by fluid retention, including asthma, epilepsy, migraine, diabetes, or renal dysfunction.
• Gallbladder disease: Use with caution in patients with gallbladder disease.
• Hepatic hemangiomas: Use with caution in patients with hepatic hemangiomas.
• Hypocalcemia: Use with caution in patients with severe hypocalcemia.
• Porphyria: Use with caution in patients with porphyria.
• SLE: Use with caution in patients with SLE.
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 weeks prior to and for 2 weeks following elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
Other warnings/precautions:
• Osteoporosis use: When used solely for the prevention of osteoporosis in women at significant risk, nonestrogen treatment options should be considered.
• Risks vs. benefits: 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. Estrogens with or without progestin should be used for shortest duration possible consistent with treatment goals. Conduct periodic risk:benefit assessments.
• 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 (8% 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%), 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%)
Additional adverse effects reported with conjugated estrogens and/or progestins: Abdominal cramps, acne, abnormal uterine bleeding, aggravation of porphyria, amenorrhea, anaphylactoid reactions, anaphylaxis, antifactor Xa decreased, antithrombin III decreased, appetite changes, bloating, breast enlargement, breast tenderness, cerebral embolism, cerebral thrombosis, chloasma, cholestatic jaundice, cholecystitis, cholelithiasis, chorea, contact lens intolerance, cystitis-like syndrome, decreased carbohydrate tolerance, dizziness; factors VII, VIII, IX, X, XII, VII-X complex, and II-VII-X complex increased; endometrial hyperplasia, erythema multiforme, erythema nodosum, galactorrhea, hemorrhagic eruption, fatigue, fibrinogen increased, impaired glucose tolerance, HDL-cholesterol increased, hirsutism, hypertension, increase in size of uterine leiomyomata, gallbladder disease, insomnia, LDL-cholesterol decreased, libido changes, loss of scalp hair, melasma, migraine, nervousness, optic neuritis, pancreatitis, platelet aggregability and platelet count increased, premenstrual like syndrome, PT and PTT accelerated, pulmonary embolism, pyrexia, retinal thrombosis, somnolence, steepening of corneal curvature, thrombophlebitis, thyroid-binding globulin increased, total thyroid hormone (T4) increased, triglycerides increased, urticaria, vaginal candidiasis, vomiting, weight gain/loss
Metabolism/Transport Effects
Based on estradiol and estrone: Substrate of CYP1A2 (major), 2A6 (minor), 2B6 (minor), 2C9 (minor), 2C19 (minor), 2D6 (minor), 2E1 (minor), 3A4 (major); Inhibits CYP1A2 (weak), 2C8 (weak); Induces CYP3A4 (weak)
Medroxyprogesterone: Substrate of CYP3A4 (major); Induces CYP3A4 (weak)
Drug Interactions
Acitretin: May diminish the therapeutic effect of Contraceptive (Progestins). Contraceptive failure is possible. Risk X: Avoid combination
Aminoglutethimide: May increase the metabolism of Progestins. 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 Contraceptive (Progestins). Risk D: Consider therapy modification
Artemether: May decrease the serum concentration of Contraceptive (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
Barbiturates: May diminish the therapeutic effect of Contraceptive (Progestins). Contraceptive failure is possible. Risk D: Consider therapy modification
Bosentan: May decrease the serum concentration of Contraceptive (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 Contraceptive (Progestins). Contraceptive failure is possible. Risk D: Consider therapy modification
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
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Fosaprepitant: May decrease the serum concentration of Contraceptive (Progestins). The active metabolite aprepitant is likely responsible for this effect. Risk D: Consider therapy modification
Griseofulvin: May diminish the therapeutic effect of Contraceptive (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 Contraceptive (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
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Phenytoin: May diminish the therapeutic effect of Contraceptive (Progestins). Contraceptive failure is possible. Risk D: Consider therapy modification
Rifamycin Derivatives: May decrease the serum concentration of Contraceptive (Progestins). Contraceptive failure is possible. 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
Somatropin: Estrogen Derivatives may diminish the therapeutic effect of Somatropin. Shown to be a concern with oral hormone replacement therapy in postmenopausal women. Risk D: Consider therapy modification
St Johns Wort: May diminish the therapeutic effect of Contraceptive (Progestins). Contraceptive failure is possible. 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. Risk D: Consider therapy modification
Topiramate: May decrease the serum concentration of Contraceptive (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: Contraceptive (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
Vitamin K Antagonists (eg, warfarin): Contraceptive (Progestins) may diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Risk D: Consider therapy modification
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 or treatment of atrophic vaginitis in females with an intact uterus. (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 one light blue conjugated estrogen 0.625 mg/MPA 5 mg tablet daily on days 15 through 28; re-evaluate patients at 3- and 6-month intervals to determine if treatment is still necessary; monitor patients for signs of endometrial cancer; rule out malignancy if unexplained vaginal bleeding occurs
Prempro™: One conjugated estrogen 0.3 mg/MPA 1.5 mg tablet daily; re-evaluate at 3-and 6-month intervals to determine if therapy is still needed; dose may be increased to a maximum of one conjugated estrogen 0.625 mg/MPA 5 mg tablet daily in patients with bleeding or spotting, once malignancy has been ruled out
Osteoporosis prophylaxis in females with an intact uterus:
Premphase®: One maroon conjugated estrogen 0.625 tablet daily on days 1 through 14 and one light blue conjugated estrogen 0.625 mg/MPA 5 mg tablet daily on days 15 through 28; monitor patients for signs of endometrial cancer; rule out malignancy if unexplained vaginal bleeding occurs
Prempro™: One conjugated estrogen 0.3 mg/MPA 1.5 mg tablet daily; dose may be increased to one conjugated estrogen 0.625 mg/MPA 5 mg tablet daily; in patients with bleeding or spotting, once malignancy has been ruled out
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
Yearly 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. Oral therapy may be more convenient for vaginal atrophy and urinary incontinence.
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): $69.99
Tablets (Prempro)
0.45-1.5 mg (28): $70.36
0.625-2.5 mg (28): $64.99
0.625-5 mg (28): $67.99
References
Grodstein F, Stampfer MJ, Colditz GA, et al, “Postmenopausal Hormone Therapy and Mortality,” N Engl J Med, 1997, 336(25):1769-75.
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.
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 S, Legault C, Thal L, 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, 289:2651-62.
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.
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 December 2009
Content last modified December 2009
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