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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:
Enjuvia™ may be confused with Januvia™
Pronunciation
(ES troe jenz, KON joo gate ed, bee, sin THET ik)
U.S. Brand Names
Generic Available
No
Pharmacologic Category
Use: Labeled Indications
Treatment of moderate-to-severe vasomotor symptoms of menopause; treatment of vulvar and vaginal atrophy associated with menopause; treatment of moderate-to-severe vaginal dryness and pain with intercourse associated with menopause
Pregnancy Considerations
Use during pregnancy is contraindicated.
Lactation
Enters breast milk/use caution
Breast-Feeding Considerations
The AAP considers ethinyl estradiol, an estrogen derivative, to be “usually compatible” with breast-feeding. Estrogen has been shown to decrease the quantity and quality of human milk. Use only if clearly needed. Monitor the growth of the infant closely.
Contraindications
Hypersensitivity to estrogens 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.
• Endometrial carcinoma: 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 conjugated equine estrogens (CEE) in combination with medroxyprogesterone acetate (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 carcinoma: [U.S. Boxed Warning]: 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. Consider adding a progestin in women with residual endometriosis posthysterectomy.
• 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 CEE in combination with 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, estrogens 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:
• 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.
• Vaginal dryness/atrophy: When used solely for the treatment of vaginal dryness and pain with intercourse, or vulvar and vaginal atrophy, topical vaginal products should be considered.
Adverse Reactions
>10%:
Central nervous system: Headache (15% to 25%), pain (10% to 19%)
Endocrine & metabolic: Breast pain (up to 14%)
Gastrointestinal: Abdominal pain (4% to 15%), nausea (7% to 12%)
1% to 10%:
Central nervous system: Dizziness (1% to 7%)
Endocrine & metabolic: Dysmenorrhea (1% to 8%)
Gastrointestinal: Flatulence (4% to 7%)
Genitourinary: Vaginitis (2% to 7%)
Neuromuscular & skeletal: Paresthesia (up to 6%)
Respiratory: Bronchitis (up to 7%), rhinitis (4% to 7%), sinusitis (3% to 7%)
Miscellaneous: Flu-like syndrome (4% to 7%)
In addition, the following have been reported with estrogen and/or progestin therapy:
Cardiovascular: Edema, hypertension, MI, stroke, venous thromboembolism
Central nervous system: Epilepsy exacerbation, irritability, mental depression, migraine, mood disturbances, nervousness
Dermatologic: Angioedema, chloasma, erythema multiforme, erythema nodosum, hemorrhagic eruption, hirsutism, loss of scalp hair, melasma, pruritus, rash, urticaria
Endocrine & metabolic: Breast cancer, breast enlargement, breast tenderness, HDL-cholesterol increased, hyper-/hypocalcemia, impaired glucose tolerance, LDL-cholesterol decreased, libido (changes in), serum triglycerides/phospholipids increased, thyroid-binding globulin increased, total thyroid hormone (T4) increased
Gastrointestinal: Abdominal cramps, bloating, cholecystitis, cholelithiasis, gallbladder disease, pancreatitis, weight gain/loss
Genitourinary: Alterations in frequency and flow of menses, changes in cervical secretions, endometrial cancer, endometrial hyperplasia, increased size of uterine leiomyomata, vaginal candidiasis
Hematologic: Aggravation of porphyria; antithrombin III and antifactor Xa decreased; fibrinogen levels increased; platelet aggregability and platelet count increased; prothrombin and factors VII, VIII, IX, X increased
Hepatic: Cholestatic jaundice, hepatic hemangiomas enlarged
Local: Thrombophlebitis
Neuromuscular & skeletal: Arthralgias, chorea, leg cramps
Ocular: Contact lens intolerance, corneal curvature steepening, retinal vascular thrombosis
Respiratory: Asthma exacerbation, pulmonary thromboembolism
Miscellaneous: Anaphylactoid/anaphylactic reactions, carbohydrate intolerance
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); Induces CYP3A4 (weak)
Drug Interactions
Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Risk X: Avoid combination
Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). 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
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Herbs (Estrogenic Properties): May enhance the adverse/toxic effect of Estrogen Derivatives. Risk C: Monitor therapy
Ropinirole: Estrogen Derivatives may increase the serum concentration of Ropinirole. 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
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
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (routine use increases estrogen plasma concentrations and risk of breast cancer).
Food: Grapefruit juice may increase estrogen plasma concentrations, leading to increased adverse effects.
Herb/Nutraceutical: St John's wort may decrease levels. Herbs with estrogenic properties may enhance the adverse/toxic effect of estrogen derivatives; examples include alfalfa, black cohosh, bloodroot, hops, kudzu, licorice, red clover, saw palmetto, soybean, thyme, wild yam, and yucca.
Storage
Store at room temperature of 25°C (77°F).
Mechanism of Action
Conjugated B/synthetic estrogens contain a mixture of 10 synthetic estrogen substances, including sodium estrone sulfate, sodium equilin sulfate, sodium 17-alpha-dihydroequilin, sodium 17-alpha-estradiol, and sodium 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.
Pharmacodynamics/Kinetics
Absorption: Well absorbed over a period of several hours
Protein-binding: Sex hormone-binding globulin (SHBG) and albumin
Metabolism: Hepatic via CYP3A4; estradiol is converted to estrone and estriol; also undergoes enterohepatic recirculation; estrone sulfate is the main metabolite in postmenopausal women
Half-life elimination: Conjugated estrone: 8-20 hours; conjugated equilin: 5-17 hours
Excretion: Urine (primarily estriol, also as estradiol, estrone, and conjugates)
Dosage
The lowest dose that will control symptoms should be used; medication should be discontinued as soon as possible. Oral:
Adults:
Moderate-to-severe vasomotor symptoms associated with menopause: 0.3 mg/day; may be titrated up to 1.25 mg/day. Attempts to discontinue medication should be made at 3- to 6-month intervals.
Vaginal dryness/vulvar and vaginal atrophy associated with menopause: 0.3 mg/day. Attempts to discontinue medication should be made at 3- to 6-month intervals.
Elderly: A higher incidence of stroke and invasive breast cancer were observed in women >75 years in a WHI substudy using conjugated equine estrogen.
Monitoring Parameters
Yearly physical examination that may include blood pressure and Papanicolaou smear, breast exam, mammogram. Monitor for signs of endometrial cancer in female patients with uterus. 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.
Test Interactions
Pathologist should be advised of estrogen/progesterone therapy when specimens are submitted. Reduced response to metyrapone test observed with conjugated estrogens (equine).
Patient Education
Do not take any new medication during therapy without consulting prescriber. Take exactly as directed. Routine use of alcohol may increase estrogen level and risk of breast cancer. Annual gynecologic and regular self-breast exams are important. If you have diabetes, monitor glucose levels closely (may impair glucose tolerance). You may experience nausea, vomiting or abdominal pain (small, frequent meals may help); dizziness or mental depression (use caution when driving); rash; hair loss; headache; or breast pain, increased/decreased libido, or enlargement/tenderness of breasts. difficult/painful menstrual cycles. Report significant swelling of extremities; sudden acute pain in legs or calves, chest, or abdomen; shortness of breath; severe headache or vomiting; sudden blindness; weakness or numbness of arm or leg; unusual vaginal bleeding; yellowing of skin or eyes; unusual bruising or bleeding; any alteration or decrease in mental alertness or acuity; or other persistent adverse reactions. You may become intolerant to wearing contact lenses, notify prescriber if this occurs. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant while taking this medication. Consult prescriber for appropriate contraceptive measures. This medication may cause fetal defects and should not be used during pregnancy. Consult prescriber if breast-feeding.
Geriatric Considerations
Enjuvia™ has not been studied in an elderly population. 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 of age in a WHI substudy. Oral therapy may be more convenient for vaginal atrophy and urinary incontinence.
Additional Information
Not biologically equivalent to conjugated estrogens from equine source. Contains 10 unique estrogenic compounds (equine source contains at least 10 active estrogenic compounds).
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, irritability, depression, mood disturbances, and nervousness
Mental Health: Effects on Psychiatric Treatment
The risk of dementia may be increased in postmenopausal women. Increased incidence of dementia was observed in women ?65 years of age who were taking conjugated equine estrogens alone or in combination with medroxyprogesterone acetate. May increase triglycerides; combined use with clozapine, olanzapine, and quetiapine may produce an additive risk. Nausea is common; combined use with lithium, valproic acid, carbamazepine, and SSRIs may produce an additive risk. Carbamazepine and St John's wort may reduce the effectiveness or estrogens.
Nursing: Physical Assessment/Monitoring
Assess potential for interactions with other pharmacological agents or herbal products patient may be taking (eg, increased potential for decreased levels/effects or increased potential for toxicity or thrombolic events). Assess results of annual gynecological exam, therapeutic effectiveness, need for continued treatment, and adverse effects (eg, thromboembolism, hypertension, edema, CNS changes) on a regular basis during therapy. Note: 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 and periodic assessment of risk:benefit should be made. Caution patients with diabetes to monitor glucose levels closely (may impair glucose tolerance). Teach patient proper use, possible side effects/appropriate interventions, and adverse symptoms to report. Remind patient about the importance of frequent self-breast exams and the need for annual gynecological exam. Pregnancy risk factor X: Determine that patient is not pregnant before starting therapy. Do not give to females of childbearing age unless patient is capable of complying with contraceptive use. Advise patient about contraceptive measures as appropriate.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Enjuvia™: 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, 1.25 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Enjuvia)
0.3 mg (30): $60.98
0.45 mg (100): $181.64
0.625 mg (100): $182.51
0.9 mg (100): $180.60
1.25 mg (100): $181.64
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.
Lexi-Comp.com
Last full review/revision October 2009
Content last modified October 2009
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