Brand and Other Names:Activella, CombiPatch, more...Lopreeza, Mimvey
- Classes: Estrogens/Progestins-HRT
Dosing & Uses
Dosage Forms & Strengths
patch, extended release
- 0.05mg/0.25mg per 24 hr
- 0.05mg/0.14mg per 24 hr
Menopause & Vasomotor Symptoms
Oral tablets: 1 tablet PO qDay
Patch: Apply 1 patch to lower abdomen continuously, changed 2 times a week
Alternative patch regimen: 1 estradiol patch (0.05 mg/d) days 1-14, changed 2 times a week; then 1 patch on days 15-28, changed 2 times a week
- Activella, Lopreeza, Mimvey (1 mg/0.5 mg or 0.5 mg/0.1 mg): Treatment of moderate-to-severe vasomotor symptoms due to menopause in patients with an intact uterus, and for prevention of osteoporosis in postmenopausal women with an intact uterus
- Activella, Lopreeza. Mimvey (1 mg/0.5 mg): Treatment of moderate-to-severe symptoms of valvar/vaginal atrophy due to menopause
- CombiPatch: Treatment of moderate to severe vasomotor symptoms in menopause, vulvar/vaginal atrophy; treatment of hypoestrogenisms due to hypogonadism, castration, or primary ovarian failure
Serious - Use Alternative
Significant - Monitor Closely
Change in menstrual flow
Frequency Not Defined
Change in weight
Deep vein thrombosis
Fallopian tube cyst
Gall bladder disorder
Black Box Warnings
- Estrogens with and without progestins should not be used to prevent cardiovascular disease
- Estrogens plus progestins: Women’s Health Initiative (WHI) Estrogen Plus Progestin substudy reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis (DVT) in postmenopausal women (aged 50-79 yr) during 5.6 yr of treatment with daily PO conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) compared with placebo
- Estrogens alone: The estrogen alone substudy of the WHI Study reported increased risks of stroke and DVT in postmenopausal women (aged 50-79 yr) during 6.8 yr of treatment w/ oral conjugated estrogens (0.625 mg/day) alone compared with placebo
- Estrogens with and without progestins should not be used to prevent dementia
- Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI study, reported increased risk of developing probable dementia in postmenopausal women aged 65 yr or older during 4 yr of treatment with daily CE 0.625 mg combined with MPA 2.5 mg, compared with placebo
- Estrogens alone: A substudy of the WHIMS reported an increased risk of developing probable dementia in postmenopausal women aged 65 yr or older during 5.2 yr of treatment with conjugated estrogens 0.625 mg alone compared with placebo
- Unknown whether these findings apply to younger postmenopausal women
- The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer
- In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins
- Because of these risks, estrogens with or without progestins should be prescribed at lowest effective dose and for shortest duration consistent with treatment goals and individual risks
- Estrogens alone: There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens
- Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer
Hypersensitivity, including anaphylaxis or angioedema to estrogen/progestins Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders
Current/history of: DVT/PE, arterial thromboembolic disease, breast cancer, liver disease/tumours
Undiagnosed abnormal vaginal bleeding
Jaundice with previous oral contraceptive use
History of pruritus gravidarum, pemphigoid gestationis, deterioration of otosclerosis or idiopathic jaundice during pregnancy
Untreated endometrial hyperplasia
Caution in patients with bone mineral density changes, current/history of depression, DM, HTN, hyperlipidemia, hypertriglyceridemia, obesity, endometriosis, family history of breast cancer & DVT/PE, smoking, epilepsy, migraine, renal/cardiac impairment
Discontinue if the following develop: jaundice, visual problems, 4-6 wk before major surgery, any symptoms of VTE, massive BP increase, unusually severe migraines or first-time migraines, depression
Increased risk of post-op thromboembolic complications
Conditions exacerbated by fluid retention (eg, asthma, migraine, cardiac/renal dysfunction, epilepsy)
History of migraine with aura
In some epidemiologic studies, use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer; however, duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association
Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases; if hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce serum calcium levels
Angioedema involving eye/eyelid, face, larynx, pharynx, tongue and extremity (hands, legs, ankles, and fingers) with or without urticaria requiring medical intervention has occurred in postmarketing; women who develop angioedema anytime during course of treatment should not receive it again; exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema
Cases of anaphylactic/ anaphylactoid reactions, which developed anytime during course of treatment and required emergency medical management, reported in postmarketing setting
Studies of addition of progestin for 10 or more days of cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone
In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis; consider discontinuation of treatment if pancreatitis occurs
Although transdermally administered estrogen therapy avoids first-pass hepatic metabolism, estrogens may be poorly metabolized in women with impaired liver function; for women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels; women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of thyroid replacement therapy; these women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range
Estrogens plus progestins may cause some degree of fluid retention; women with conditions which might be influenced by this factor, such as cardiac or renal impairment warrant careful observation when estrogens plus progestins are prescribed
Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur
For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered
Estrogen therapy may cause exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions
Pregnancy & Lactation
Pregnancy Category: X
Lactation: enters breast milk; use with caution
A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
Mechanism of Action
Estradiol: Endogenous estrogen; reduces the release of gonadotropin-releasing hormone from hypothalamus, reduces release of LH and FSH from pituitary gland; increases synthesis of DNA, RNA, and various proteins in target tissues. Estrogen replacement reduces elevated levels of estrogen and progesterone LH and FSH in postmenopausal women.
Norethindrone acetate: Progestin; inhibits secretion of gonadotropins from pituitary gland; prevents follicular maturation and ovulation, stimulates growth of mamary tissues
Peak Plasma Time: Estradiol: 5-8 hr (PO); norethindrone: 1-2 hr (PO)
Protein Bound: Estradiol: 98%, norethindrone: 90-97%
Bioavailability: Estradiol (50%); norethindrone (100%)
- Estradiol: liver, undergoes extensive first-pass metabolism
- Norethindrone: Liver
- Estradiol: 12-14 hr (PO), 2-3 hr (patch)
- Norethindrone: 8-11 hr (PO), 6-8 hr (patch)
- Estradiol: estriol, estrone
- Norethindrone: sulfate, glucuronide (inactive)
- Estradiol: urine as conjugates, most estrogens are also excreted in the bile and undergo enterohepatic recycling
- Norethindrone: Urine 33-81%; Feces 35-43%
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