|
This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or
standards of non-Merck sources.
Special Alerts
Transdermal Patches: Risk of Burns During MRI - March 2009
The U.S. Food and Drug Administration (FDA) has issued a public health advisory regarding the risk of burns associated with the use of transdermal medication patches containing aluminum or other metals during MRI screening. The package labeling for certain metal-containing patches includes a warning related to the risk of burns if the patches are not removed prior to MRI procedures. However, not all transdermal medication patches with metallic backings have this warning in the labeling. Although metal materials are present in certain patches, it may not be visible. The FDA is currently reviewing the components of all transdermal medication systems to ensure that proper warnings are present in the labeling of those patches that do contain metal materials. In the interim, the FDA recommends that healthcare professionals who refer patients to have an MRI procedure should identify patients who are wearing a transdermal medication patch prior to the scan. Those patients who are wearing a transdermal medication patch should be advised on the proper removal of the patch prior to the procedure as well as reapplication following the scan.
Additional information can be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm111493.htm
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:
Alora® may be confused with Aldara®
Elestrin™ may be confused with alosetron
Estraderm® may be confused with Testoderm®
International issues:
Vivelle®: Brand name for ethinyl estradiol and norgestimate in Austria
Estring® may be confused with Estrena® [Finland]
Estrena® [Finland] may be confused with estrone in the U.S.
Transdermal patch may contain conducting metal (eg, aluminum); remove patch prior to MRI.
Pronunciation
(es tra DYE ole)
U.S. Brand Names
Index Terms
Generic Available
Yes: Oral tablet, patch, valerate oil for injection
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Treatment of moderate-to-severe vasomotor symptoms associated with menopause; treatment of vulvar and vaginal atrophy; hypoestrogenism (due to hypogonadism, castration, or primary ovarian failure); prostatic cancer (palliation), breast cancer (palliation), osteoporosis (prophylaxis); abnormal uterine bleeding due to hormonal imbalance; postmenopausal urogenital symptoms of the lower urinary tract (urinary urgency, dysuria)
Pregnancy Risk Factor
X
Pregnancy Considerations
Estrogens are not indicated for use during pregnancy or immediately postpartum. Increased risk of fetal reproductive tract disorders and other birth defects have been observed with diethylstilbestrol (DES). In general, the use of estrogen and progestin as in combination hormonal contraceptives have not been associated with teratogenic effects when inadvertently taken early in pregnancy. These products are not intended to be used during pregnancy.
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 estradiol 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, except in appropriately selected patients being treated for metastatic disease; estrogen-dependent tumor; hepatic dysfunction or disease; porphyria; 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.
• Risks vs benefits: See “Other warnings/precautions” 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 with an intact uterus. Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding. The use of a progestin should be considered when administering estrogens to postmenopausal women with an intact uterus. 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; use is contraindicated with certain products.
• 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.
Dosage form specific issues:
• Topical emulsion, gel, spray: Absorption of the topical emulsion (Estrasorb™) and topical gel (Elestrin™) is increased by application of sunscreen; do not apply sunscreen within close proximity of estradiol. When sunscreen is applied ~1 hour prior to the topical spray (Evamist™), no change in absorption was observed (estradiol absorption was decreased when sunscreen is applied 1 hour after Evamist™). Application of Divigel® or EstroGel® with sunscreen has not been evaluated.
• Transdermal patch: May contain conducting metal (eg, aluminum); remove patch prior to MRI.
• Vaginal ring: Use may not be appropriate in women with narrow vagina, vaginal stenosis, vaginal infections, cervical prolapse, rectoceles, cystoceles, or other conditions which may increase the risk of vaginal irritation, ulceration, or increase the risk of expulsion. Ring should be removed in case of ulceration, erosion, or adherence to vaginal wall; do not reinsert until healing is complete. Ensure proper vaginal placement of the ring to avoid inadvertent urinary bladder insertion.
Other warnings/precautions:
• Osteoporosis use: When used solely for prevention of osteoporosis in women at significant risk, nonestrogen treatment options should be considered.
• Risks vs. benefits: [U.S. Boxed Warning]: Estrogens with or without progestin should be used for 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. 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. Use caution applying topical products to severely atrophic vaginal mucosa.
Adverse Reactions
Frequency not defined. Some adverse reactions observed with estrogen and/or progestin combination therapy.
Cardiovascular: Chest pain, DVT, edema, hypertension, MI, stroke, syncope, venous thromboembolism
Central nervous system: Anxiety, dementia, dizziness, epilepsy exacerbation, headache, insomnia, irritability, mental depression, migraine, mood disturbances, nervousness
Dermatologic: Angioedema, chloasma, dermatitis, erythema multiforme, erythema nodosum, hemorrhagic eruption, hirsutism, loss of scalp hair, melasma, rash, pruritus, urticaria
Endocrine & metabolic: Breast cancer, breast enlargement, breast pain, breast tenderness, fibrocystic breast changes, HDL-cholesterol increased, galactorrhea, glucose intolerance, hot flashes, hypocalcemia, LDL-cholesterol decreased, libido changes, nipple pain, serum triglycerides/phospholipids increased, thyroid-binding globulin increased, total thyroid hormone (T4) increased
Gastrointestinal: Abdominal cramps, abdominal distension, abdominal pain, bloating, cholecystitis, cholelithiasis, diarrhea, dyspepsia, flatulence, gallbladder disease, gastritis, nausea, pancreatitis, vomiting, weight gain/loss
Genitourinary: Alterations in frequency and flow of menses, cervical secretion changes, cystitis, dysmenorrhea, dysuria, endometrial cancer, endometrial hyperplasia, genital eruption, metrorrhagia, ovarian cancer, Pap smear suspicious, urinary tract infection, uterine leiomyomata size increased, leukorrhea, uterine pain, urinary incontinence, urogenital eruption/pruritus, vaginal candidiasis, vaginal discharge, vaginal moniliasis, vaginitis
Vaginal: Trauma from applicator insertion may occur in women with severely atrophic vaginal mucosa; skin hypertrophy, vaginal discomfort, vaginal hemorrhage, vaginal pain
Hematologic: Aggravation of porphyria, antithrombin III and antifactor Xa decreased, fibrinogen levels increased, platelet aggregability increased, platelet count increased, prothrombin increased; factors VII, VIII, IX, X increased
Hepatic: Cholestatic jaundice, hepatic hemangioma enlargement
Local: Thrombophlebitis
Gel, spray: Application site reaction
Transdermal patches: Burning, erythema, irritation
Neuromuscular & skeletal: Arthralgia, arthritis, back pain, chorea, leg cramps, muscle cramps, skeletal pain
Ocular: Blindness, contact lens intolerance, corneal curvature steepening, retinal vascular thrombosis, vision abnormal
Respiratory: Asthma exacerbation, pulmonary thromboembolism
Miscellaneous: Anaphylactoid/anaphylactic reactions
Postmarketing and/or case reports: Liver function tests increased (rare), leg pain
Vaginal ring: Bowel obstruction, ring adherence to vaginal wall, toxic shock syndrome
Metabolism/Transport Effects
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)
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
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
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
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
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
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 level 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. 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, yucca.
Mechanism of Action
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: Oral, topical: Well absorbed
Protein binding: 37% to sex hormone-binding globulin; 61% to albumin
Metabolism: Hepatic via oxidation and conjugation in GI tract; hydroxylated via CYP3A4 to metabolites; first-pass effect; enterohepatic recirculation; reversibly converted to estrone and estriol
Excretion: Primarily urine (as metabolites estrone and estriol); feces (small amounts)
Dosage
All dosage needs to be adjusted based upon the patient's response
Oral:
Prostate cancer (androgen-dependent, inoperable, progressing): 10 mg 3 times/day for at least 3 months
Breast cancer (inoperable, progressing in appropriately selected patients): 10 mg 3 times/day for at least 3 months
Osteoporosis prophylaxis in postmenopausal females: 0.5 mg/day in a cyclic regimen (3 weeks on and 1 week off)
Female hypoestrogenism (due to hypogonadism, castration, or primary ovarian failure): 1-2 mg/day; titrate as necessary to control symptoms using minimal effective dose for maintenance therapy
Moderate-to-severe vasomotor symptoms associated with menopause: 1-2 mg/day, adjusted as necessary to limit symptoms; administration should be cyclic (3 weeks on, 1 week off). Patients should be re-evaluated at 3- to 6-month intervals to determine if treatment is still necessary.
I.M.:
Prostate cancer: Valerate: ?30 mg or more every 1-2 weeks
Moderate-to-severe vasomotor symptoms associated with menopause:
Cypionate: 1-5 mg every 3-4 weeks
Valerate: 10-20 mg every 4 weeks
Female hypoestrogenism (due to hypogonadism):
Cypionate: 1.5-2 mg monthly
Valerate: 10-20 mg every 4 weeks
Topical:
Emulsion: Moderate-to-severe vasomotor symptoms associated with menopause: 3.84 g applied once daily in the morning
Gel:
Moderate-to-severe vasomotor symptoms associated with menopause:
Divigel®: 0.25 g/day; adjust dose based on patient response. Dosing range: 0.25-1 g/day
Elestrin™: 0.87g/day applied at the same time each day
EstroGel®: 1.25 g/day applied at the same time each day
Vulvar and vaginal atrophy:
Elestrin™: 0.87g/day applied at the same time each day
EstroGel®: 1.25 g/day applied at the same time each day
Spray: Moderate-to-severe vasomotor symptoms associated with menopause (Evamist™): Initial: One spray (1.53 mg) per day. Adjust dose based on patient response. Dosing range: 1-3 sprays per day.
Transdermal: Indicated dose may be used continuously in patients without an intact uterus. May be given continuously or cyclically (3 weeks on, 1 week off) in patients with an intact uterus (exception - Menostar®, see specific dosing instructions). When changing patients from oral to transdermal therapy, start transdermal patch 1 week after discontinuing oral hormone (may begin sooner if symptoms reappear within 1 week):
Once-weekly patch:
Moderate-to-severe vasomotor symptoms associated with menopause, vulvar and vaginal atrophy associated with menopause, female hypoestrogenism (Climara®): Apply 0.025 mg/day patch once weekly. Adjust dose as necessary to control symptoms. Patients should be re-evaluated at 3- to 6-month intervals to determine if treatment is still necessary.
Osteoporosis prophylaxis in postmenopausal women:
Climara®: Apply patch once weekly; minimum effective dose 0.025 mg/day; adjust response to therapy by biochemical markers and bone mineral density
Menostar®: Apply patch once weekly. In women with a uterus, also administer a progestin for 14 days every 6-12 months
Twice-weekly patch:
Moderate-to-severe vasomotor symptoms associated with menopause, vulvar/vaginal atrophy, female hypogonadism: Titrate to lowest dose possible to control symptoms, adjusting initial dose after the first month of therapy; re-evaluate therapy at 3- to 6-month intervals to taper or discontinue medication:
Alora®, Estraderm®, Vivelle-Dot®: Apply 0.05 mg patch twice weekly
Vivelle®: Apply 0.0375 mg patch twice weekly
Prevention of osteoporosis in postmenopausal women:
Alora®, Vivelle®, Vivelle-Dot®: Apply 0.025 mg patch twice weekly, increase dose as necessary
Estraderm®: Apply 0.05 mg patch twice weekly
Vaginal cream: Vulvar and vaginal atrophy: Insert 2-4 g/day intravaginally for 2 weeks, then gradually reduce to 1/2 the initial dose for 2 weeks, followed by a maintenance dose of 1 g 1-3 times/week
Vaginal ring:
Postmenopausal vaginal atrophy, urogenital symptoms: Estring®: 2 mg intravaginally; following insertion, ring should remain in place for 90 days
Moderate-to-severe vasomotor symptoms associated with menopause; vulvar/vaginal atrophy: Femring®: 0.05 mg intravaginally; following insertion, ring should remain in place for 3 months; dose may be increased to 0.1 mg if needed
Vaginal tablets: Atrophic vaginitis: Vagifem®: Initial: Insert 1 tablet once daily for 2 weeks; maintenance: Insert 1 tablet twice weekly; attempts to discontinue or taper medication should be made at 3- to 6-month intervals
Dosing adjustment in hepatic impairment:
Mild-to-moderate liver impairment: Dosage reduction of estrogens is recommended
Severe liver impairment: Not recommended
Administration: I.M.
Injection for intramuscular administration only.
Administration: Topical
Emulsion: Apply to clean dry skin while in a sitting position. Contents of two pouches (total 3.48 g) are to be applied individually, once daily in the morning. Apply contents of first pouch to left thigh, massage into skin of left thigh and calf until thoroughly absorbed (~3 minutes). Apply excess from both hands to the buttocks. Apply contents of second pouch to the right thigh, massage into skin of right thigh and calf until thoroughly absorbed (~3 minutes). Apply excess from both hands to buttocks. Wash hands with soap and water. Allow skin to dry before covering legs with clothing. Do not apply to other areas of body. Do not apply to red or irritated skin.
Gel: Apply to clean, dry, unbroken skin at the same time each day. Allow to dry for 5 minutes prior to dressing. Gel is flammable; avoid fire or flame until dry. After application, wash hands with soap and water. Prior to the first use, pump must be primed. Do not apply gel to breast.
Divigel®: Apply entire contents of packet to right or left upper thigh each day (alternate sites). Do not apply to face, breasts, vaginal area or irritated skin. Apply over an area ~5x7 inches. Do not wash application site for 1 hour. Allow gel to dry before dressing
Elestrin™: Apply to upper arm and shoulder area using two fingers to spread gel. Apply after bath or shower; allow at least 2 hours between applying gel and going swimming. Wait at least 25 minutes before applying sunscreen to application area. Do not apply sunscreen to application area for ?7 days (may increase absorption of gel).
EstroGel®: Apply gel to the arm, from the wrist to the shoulder. Spread gel as thinly as possible over one arm.
Spray: Evamist™: Prior to first use, prime pump by spraying 3 sprays with the cover on. To administer dose, hold container upright and vertical and rest the plastic cone flat against the skin while spraying. Spray to the inner surface of the forearm, starting near the elbow. If more than one spray is needed, apply to adjacent but not overlapping areas. Apply at the same time each day. Allow spray to dry for ~2 minutes. Do not wash application site for 30 minutes. Apply to clean, dry, unbroken skin. Do not apply to skin other than that of the forearm. Solution contained in the spray is flammable; avoid fire, flame, or smoking until spray has dried. If needed, sunscreen should be applied ~1 hour prior to application of Evamist™.
Transdermal patch: Aerosol topical corticosteroids applied under the patch may reduce allergic reactions. Do not apply transdermal system to breasts, but place on trunk of body (preferably abdomen). Rotate application sites allowing a 1-week interval between applications at a particular site. Do not apply to oily, damaged or irritated skin; avoid waistline or other areas where tight clothing may rub the patch off. Apply patch immediately after removing from protective pouch. In general, if patch falls off, the same patch may be reapplied or a new system may be used for the remainder of the dosing interval. Swimming, bathing, or showering are not expected to affect use of the patch. Note the following exceptions:
Estraderm®: Do not apply to an area exposed to direct sunlight.
Menostar®: Swimming, bathing, or wearing patch while in a sauna have not been studied; adhesion of patch may be decreased or delivery of estradiol may be affected. Remove patch slowly after use to avoid skin irritation. If any adhesive remains on the skin after removal, first allow skin to dry for 15 minutes, then gently rub area with an oil-based cream or lotion. If patch falls off, a new patch should be applied for the remainder of the dosing interval.
Administration: Other
Vaginal ring: Exact positioning is not critical for efficacy; however, patient should not feel anything once inserted. In case of discomfort, ring should be pushed further into vagina. If ring is expelled prior to 90 days, it may be rinsed off and reinserted. Ensure proper vaginal placement of the ring to avoid inadvertent urinary bladder insertion. If vaginal infection develops, Estring® should be removed; reinsert only after infection has been appropriately treated. Femring® may remain in place during local treatment of a vaginal infection.
Vaginal tablet: Insert tablet with supplied applicator at the same time each day. Once inserted, depress plunger until a click is heard, then remove applicator and discard. If tablet comes out of applicator prior to insertion, do not replace; use a new tablet filled applicator instead.
Monitoring Parameters
Routine physical examination that includes 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.
When using Menostar® in a woman with a uterus, endometrial sampling is recommended at yearly intervals or when clinically indicated.
Menopausal symptoms: Assess need for therapy at 3- to 6-month intervals
Prevention of osteoporosis: Bone density measurement
Reference Range
Children: <10 pg/mL (SI: <37 pmol/L)
Male: 10-50 pg/mL (SI: 37-184 pmol/L)
Female:
Premenopausal: 30-400 pg/mL (SI: 110-1468 pmol/L)
Postmenopausal: 0-30 pg/mL (SI: 0-110 pmol/L)
Test Interactions
Pathologist should be advised of estrogen/progesterone therapy when specimens are submitted. Reduced response to metyrapone test.
Dietary Considerations
Ensure adequate calcium and vitamin D intake when used for the prevention of osteoporosis.
Patient Education
Do not take any new prescription or OTC medications or herbal products during therapy without consulting prescriber. Follow directions for timing and application of your prescription (see product insert or consult prescriber). Wash hands thoroughly prior to and following application; do not apply topical agent to damaged, reddened, or irritated skin; do not allow agent to come in contact with face or eyes. 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, enlargement/tenderness of breasts, or difficult/painful menstrual cycles. Report unusual swelling of extremities; sudden acute pain in legs or calves, chest, or abdomen; shortness of breath; severe headache or vomiting; sudden blindness or change in visual acuity; weakness or numbness of arm or leg; unusual vaginal bleeding; yellowing of skin or eyes; unusual bruising or bleeding; skin rash; 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
Before prescribing estrogen therapy to postmenopausal women, the risks and benefits must be weighed for each patient. Data in women ?80 years are minimal and it is unclear if the reduced risk is applicable to women in this age group. 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. 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.
Several observational trials evaluating the use of estrogen in primary prevention of coronary artery disease in women found a decrease in cardiovascular events. However, a recent trial (HERS) found that women with coronary disease derived no cardiovascular protection compared to those treated with placebo. 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
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
Assess potential for interactions with other pharmacological agents or herbal products patient may be taking (eg, increased or decreased levels/effects of estradiol or increased potential for toxicity or thrombolic events). Assess results of annual gynecological exam, therapeutic effectiveness (dependent on rationale for use), need for continued therapy, 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 and application (according to formulation), 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. [DSC] = Discontinued product
Cream, vaginal:
Estrace®: 0.1 mg/g (42.5 g)
Emulsion, topical, as hemihydrate:
Estrasorb™: 2.5 mg/g (56s) [each pouch contains 4.35 mg estradiol hemihydrate; contents of two pouches delivers estradiol 0.05 mg/day]
Gel, topical:
Divigel®: 0.1% (0.25 g) [delivers estradiol 0.25 mg/packet]; (0.5 g) [delivers 0.5 mg estradiol/packet]; (1 g) [delivers estradiol 1 mg/packet]
Elestrin™: 0.06% (144 g) [delivers estradiol 0.52 mg/0.87 g; 100 actuations]
EstroGel®: 0.06% (50 g) [delivers estradiol 0.75 mg/1.25 g; 32 actuations; contains ethanol]
Injection, oil, as cypionate:
Depo®-Estradiol: 5 mg/mL (5 mL) [contains chlorobutanol, cottonseed oil]
Injection, oil, as valerate: 10 mg/mL (5 mL); 20 mg/mL (5 mL); 40 mg/mL (5 mL)
Delestrogen®:
10 mg/mL (5 mL) [contains chlorobutanol, sesame oil]
20 mg/mL (5 mL) [contains benzyl alcohol, castor oil]
40 mg/mL (5 mL) [contains benzyl alcohol, castor oil]
Ring, vaginal, as base:
Estring®: 2 mg (1s) [total estradiol 2 mg; releases 7.5 mcg/day over 90 days]
Ring, vaginal, as acetate:
Femring®: 0.05 mg/day (1s) [total estradiol 12.4 mg; releases 0.05 mg/day over 3 months]; 0.1 mg/day (1s) [total estradiol 24.8 mg; releases 0.1 mg/day over 3 months]
Solution, topical [spray]:
Evamist™: 1.53 mg/spray (8.1 mL) [contains 56 sprays after priming; contains ethanol]
Tablet, oral, as acetate:
Femtrace®: 0.45 mg, 0.9 mg, 1.8 mg
Tablet, oral, micronized: 0.5 mg, 1 mg, 2 mg
Estrace®: 0.5 mg, 1 mg, 2 mg [2 mg tablets contain tartrazine]
Gynodiol®: 0.5 mg [DSC], 1 mg [DSC], 1.5 mg [DSC], 2 mg [DSC]
Tablet, vaginal, as base:
Vagifem®: 25 mcg
Transdermal system: 0.025 mg/24 hours (4s) [once-weekly patch]; 0.0375 mg/24 hours (4s) [once-weekly patch]; 0.05 mg/24 hours (4s) [once-weekly patch]; 0.06 mg/24 hours (4s) [once-weekly patch]; 0.075 mg/24 hours [once-weekly patch]; 0.1 mg/24 hours (4s) [once-weekly patch]
Alora® [twice-weekly patch]:
0.025 mg/24 hours (8s) [9 cm2, total estradiol 0.77 mg]
0.05 mg/24 hours (8s, 24s [DSC]) [18 cm2, total estradiol 1.5 mg]
0.075 mg/24 hours (8s) [27 cm2, total estradiol 2.3 mg]
0.1 mg/24 hours (8s) [36 cm2, total estradiol 3.1 mg]
Climara® [once-weekly patch]:
0.025 mg/24 hours (4s) [6.5 cm2, total estradiol 2.04 mg]
0.0375 mg/24 hours (4s) [9.375 cm2, total estradiol 2.85 mg]
0.05 mg/24 hours (4s) [12.5 cm2, total estradiol 3.8 mg]
0.06 mg/24 hours (4s) [15 cm2, total estradiol 4.55 mg]
0.075 mg/24 hours (4s) [18.75 cm2, total estradiol 5.7 mg]
0.1 mg/24 hours (4s) [25 cm2, total estradiol 7.6 mg]
Estraderm® [twice-weekly patch]:
0.05 mg/24 hours (8s) [10 cm2, total estradiol 4 mg]
0.1 mg/24 hours (8s) [20 cm2, total estradiol 8 mg]
Menostar® [once-weekly patch]: 0.014 mg/24 hours (4s) [3.25 cm2, total estradiol 1 mg]
Vivelle® [twice-weekly patch]:
0.05 mg/24 hours (8s) [14.5 cm2, total estradiol 4.33 mg] [DSC]
0.1 mg/24 hours (8s) [29 cm2, total estradiol 8.66 mg] [DSC]
Vivelle-Dot® [twice-weekly patch]:
0.025 mg/day (24s) [2.5 cm2, total estradiol 0.39 mg]
0.0375 mg/day (24s) [3.75 cm2, total estradiol 0.585 mg]
0.05 mg/day (24s) [5 cm2, total estradiol 0.78 mg]
0.075 mg/day (24s) [7.5 cm2, total estradiol 1.17 mg]
0.1 mg/day (24s) [10 cm2, total estradiol 1.56 mg]
Pricing: U.S. (www.drugstore.com)
Cream (Estrace)
0.1 mg/g (42.5): $126.77
Emulsion (Estrasorb)
4.35 mg/1.74 g (10.44): $16.95
Gel (Divigel)
0.25 mg/0.25gm (30): $77.36
0.5mg/0.5gm (1): $72.99
Gel (Elestrin)
0.52 MG/0.87 GM (0.06%) (144): $155.71
Gel (Estrogel)
0.75 MG/1.25 GM (0.06%) (50): $75.15
Oil (Delestrogen)
10 mg/mL (5): $79.99
20 mg/mL (5): $111.99
40 mg/mL (5): $177.99
Oil (Depo-Estradiol)
5 mg/mL (5): $48.29
Patch weekly (Climara)
0.025 mg/24 hrs (4): $75.58
0.0375 mg/24 hrs (4): $69.05
0.05 mg/24 hrs (4): $75.58
0.06 mg/24 hrs (4): $69.05
0.075 mg/24 hrs (4): $69.05
0.1 mg/24 hrs (4): $75.58
Patch weekly (Estradiol)
0.025 mg/24 hrs (4): $36.99
0.0375 mg/24 hrs (4): $39.35
0.05 mg/24 hrs (4): $36.99
0.06 mg/24 hrs (4): $39.99
0.075 mg/24 hrs (4): $35.99
0.1 mg/24 hrs (4): $35.99
Patch weekly (Menostar)
14 mcg/24 hrs (4): $73.18
Patch, twice-weekly (Alora)
0.05 mg/24 hrs (8): $58.41
0.075 mg/24 hrs (8): $49.60
0.1 mg/24 hrs (8): $60.65
Patch, twice-weekly (Estraderm)
0.05 mg/24 hrs (8): $60.37
0.1 mg/24 hrs (8): $65.94
Patch, twice-weekly (Vivelle)
0.05 mg/24 hrs (8): $49.99
Patch, twice-weekly (Vivelle-Dot)
0.025 mg/24 hrs (8): $61.53
0.0375 mg/24 hrs (8): $56.76
0.05 mg/24 hrs (8): $57.99
0.075 mg/24 hrs (8): $60.35
0.1 mg/24 hrs (8): $65.93
Ring (Estring)
2 mg (1): $187.42
Ring (Femring)
0.05 mg/24 hrs (1): $166.60
0.1 mg/24 hrs (1): $184.78
Solution (Evamist)
1.53 mg/spray (8.1): $107.99
Tablets (Estrace)
0.5 mg (30): $61.80
1 mg (30): $64.14
2 mg (30): $74.16
Tablets (Estradiol)
0.5 mg (30): $13.99
1 mg (30): $11.99
2 mg (90): $17.99
Tablets (Femtrace)
0.45 mg (100): $178.01
0.9 mg (100): $173.06
1.8 mg (100): $216.51
Tablets (Gynodiol)
0.5 mg (30): $9.99
1 mg (30): $18.99
1.5 mg (30): $22.99
2 mg (30): $15.99
Tablets (Vagifem)
25 mcg (8): $52.99
25 mcg (18): $127.19
References
American College of Physicians, “Guidelines for Counseling Postmenopausal Women About Preventive Hormone Therapy,” Ann Intern Med, 1992, 117(12):1038-41.
Belchetz PE, “Hormone Treatment for Postmenopausal Women,” N Engl J Med, 1994, 330(15):1062-71.
Ettinger B, Friedman GD, Bush T, et al, “Reduced Mortality Associated With Long-Term Postmenopausal Estrogen Therapy,” Obstet Gynecol, 1996, 87(1):6-12.
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 SA, Legault C, Rapp SR, et al, “WHIMS Investigators. 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.
Stallard S, Litherland JC, Cordiner CM, et al, “Effect of Hormone Replacement Therapy on the Pathological Stage of Breast Cancer: Population Based, Cross Sectional Study,” BMJ, 2000, 320(7231):348-9.
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.
International Brand Names
Lexi-Comp.com
Last full review/revision September 2009
|
