estradiol/norethindrone acetate (Activella, CombiPatch, Lopreeza, Mimvey)

Dosing and uses of Activella, CombiPatch (estradiol/norethindrone acetate)

• Adult
• Pediatric

 

Adult dosage forms and strengths

estradiol/norethindrone acetate

tablet

• 1mg/0.5mg
• 0.5mg//0.1mg

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

Indications

• 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

 

Pediatric dosage forms and strengths

Not indicated

 

Activella, CombiPatch (estradiol/norethindrone acetate) adverse (side) effects

>10%

Amenorrhea

Breakthrough bleeding

Change in menstrual flow

Spotting

Edema

Anorexia

Weakness

 

Frequency not defined

Change in weight

Depression

Dizziness

Headache

Nervousness

Somnolence

Breast tenderness

Galactorrhea

Abdominal pain

Nausea/vomiting

Cholestatic jaundice

Deep vein thrombosis

Thrombophlebitis

 

Postmarketing reports

Endometrial hyperplasia

Endocervical polyp

Uterine leiomyomata

Fallopian tube cyst

Uterine spasms

Breast cancer

Hypertension

Varicose veins

Jaundice cholestatic

Cholelithiasis

Gall bladder disorder

Transaminases increased

Skin discoloration

Lability affected

Libido disorder

Migraine

Vertigo

Paresthesia

Angioedema

Hypersensitivity

Weight increased

 

Warnings

Black box warnings

Cardiovascular risks

• 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

Dementia risks

• 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

Breast Cancer

• 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

Endometrial cancer

• 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

 

Contraindications

Hypersensitivity, including anaphylaxis or angioedema to estrogen/progestins Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders

Pregnancy

Estrogen-dependent neoplasia

Current/history of: DVT/PE, arterial thromboembolic disease, breast cancer, liver disease/tumours

Undiagnosed abnormal vaginal bleeding

Jaundice with previous oral contraceptive use

Porphyria

History of pruritus gravidarum, pemphigoid gestationis, deterioration of otosclerosis or idiopathic jaundice during pregnancy

Untreated endometrial hyperplasia

 

Cautions

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 and lactation

Pregnancy category: X

Lactation: enters breast milk; use with caution

 

Pregnancy categories

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.

 

Pharmacology of Activella, CombiPatch (estradiol/norethindrone acetate)

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

 

Pharmacokinetics

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%)

Metabolism

• Estradiol: liver, undergoes extensive first-pass metabolism
• Norethindrone: Liver

Half-Life

• Estradiol: 12-14 hr (PO), 2-3 hr (patch)
• Norethindrone: 8-11 hr (PO), 6-8 hr (patch)

Metabolites

• Estradiol: estriol, estrone
• Norethindrone: sulfate, glucuronide (inactive)

Excretion

• Estradiol: urine as conjugates, most estrogens are also excreted in the bile and undergo enterohepatic recycling
• Norethindrone: Urine 33-81%; Feces 35-43%