Estradiol / Norethindrone Acetate

Pronunciation: ES-tra-dye-ole/nor-eth-IN-drone AS-eh-tate
Class: Estrogen and progestin combined

Trade Names:
Activella
- Tablets estradiol 1 mg/norethindrone acetate 0.5 mg/day

Trade Names:
CombiPatch
- Transdermal patch estradiol 0.05 mg/norethindrone acetate 0.14 mg/day
- Transdermal patch estradiol 0.05 mg/norethindrone acetate 0.25 mg/day

Pharmacology

Estrogens are essential in developing and maintaining female reproductive system and secondary sex characteristics. Progestins transform proliferative endometrium into secretory endometrium.

Indications and Usage

Treatment of moderate to severe vasomotor symptoms associated with menopause; treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause; hypoestrogenism caused by hypogonadism, castration, or primary ovarian failure ( CombiPatch only); prevention of postmenopausal osteoporosis ( Activella only).

Contraindications

Known or suspected pregnancy; known or suspected cancer of the breast; known or suspected estrogen-dependent neoplasia; undiagnosed abnormal genital bleeding; active or recent (eg, within past year) arterial thromboembolic disorders (eg, stroke, MI); active deep vein thrombosis, pulmonary embolism, or history of these conditions; liver disease or dysfunction; hypersensitivity to any ingredient in these products.

Dosage and Administration

Activella
Adults

PO 1 tablet daily.

Continuous Combined Regimen
Adults

Transdermal Apply 1 estradiol 0.05 mg/norethindrone acetate 0.14 mg patch twice weekly.

Continuous Sequential Regimen
Adults

Transdermal Apply 1 estradiol 0.05 mg/norethindrone acetate 0.14 mg patch twice weekly during the remaining 14 days of the 28-day cycle. May be applied as a sequential regimen in combination with an estradiol-only transdermal delivery system.

General Advice

  • A dose of estradiol 0.05 mg/norethindrone acetate 0.25 mg may be used if a greater progestin dose is desired.
  • Open pouch, remove one side of protective liner from patch, taking care not to touch adhesive part of patch, and immediately apply patch to clean, smooth (fold-free), dry skin on lower abdomen. Remove the second side of the protective liner and press firmly with palm of hand for approximately 10 sec. Be sure good contact is made, especially at edges. If patch falls off, attempt to reapply to another area of the lower abdomen. If necessary, a new transdermal system may be applied, in which case the original treatment schedule should be continued.
  • Do not apply patch on or near the breasts, skin areas that are oily, damaged, or irritated, or skin areas that have had powder, lotion, or moisturizer applied, or to skin areas where clothing or sitting could dislodge patch.
  • Rotate application sites so that no site is used more than once weekly.

Storage/Stability

Store patches at controlled room temperature (below 77°F) for up to 6 mo. Protect from extreme temperatures. Do not remove from pouch until immediately before application. Store tablets between 59° and 86°F in a dry place protected from light.

Drug Interactions

Inducers of CYP3A4 (eg, carbamazepine, phenobarbital, rifampin, St. John's wort)

Estrogen plasma concentrations may be reduced, decreasing the therapeutic effects and changing the uterine bleeding profile.

Inhibitors of CYP3A4 (eg, clarithromycin, erythromycin, grapefruit juice, itraconazole, ketoconazole, ritonavir)

Estrogen plasma concentrations may be elevated, increasing the risk of adverse reactions.

Laboratory Test Interactions

Increased

Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine; increased T 4 levels (by column or by radioimmunoassay) or T 3 levels by radioimmunoassay; other binding proteins may be elevated in the serum (ie, corticosteroid binding globulin, sex hormone–binding globulin), leading to increases in total circulating corticosteroids and sex steroids; the plasma proteins angiotensinogen/renin substrate, alpha-1 antitrypsin, and ceruloplasmin may be increased.

Decreased

Reduced response to metyrapone test; decreased factor VII, plasminogen activator inhibitor-1, and, to a lesser degree, antithrombin III activity; T 3 resin uptake is decreased, reflecting the elevated TBG; free hormone concentrations may be decreased; LDL, HDL, and total cholesterol concentrations may be decreased; insulin response may decrease without an increase in glucose serum levels.

Adverse Reactions

Cardiovascular

Cerebrovascular accidents, deep and superficial venous thrombosis, increased BP, MI, pulmonary embolism, stroke, thrombophlebitis.

CNS

Headache (25%); asthenia (13%); depression (9%); insomnia (8%); dizziness (7%); emotional lability, nervousness (6%); changes in libido, chorea, exacerbation of epilepsy, fatigue, irritability, migraine, mood disturbances, probable dementia.

Dermatologic

Irritation at application site (23%); rash (6%); acne (5%); chloasma, erythema multiforme, erythema nodosum, hemorrhagic eruption, hirsutism, itching, loss of scalp hair, melasma, seborrhea.

EENT

Intolerance to contact lenses, retinal vascular thrombosis.

GI

Abdominal pain, diarrhea (14%); nausea (12%); dyspepsia (8%); flatulence (7%); gastroenteritis, tooth disorder (6%); constipation (5%); abdominal cramps, appetite change, bloating, increased incidence of gallbladder disease, pancreatitis, vomiting.

Genitourinary

Breast pain (48%); dysmenorrhea (31%); menorrhagia (19%); vaginitis (including vaginal candidiasis) (13%); menstrual disorder (12%); postmenopausal bleeding (11%); leukorrhea (10%); suspicious Pap smear (8%); breast enlargement, ovarian cyst (7%); genital moniliasis, vaginal hemorrhage (6%); uterine fibroid (5%); abnormal withdrawal bleeding or flow, breakthrough bleeding, breast cancer, breast tenderness, changes in amount of cervical secretions, changes in cervical ectropion, changes in vaginal bleeding pattern, cystitis-like syndrome, endometrial cancer, endometrial hyperplasia, fibrocystic breast changes, galactorrhea, increased size of uterine leiomyomata, nipple discharge, ovarian cancer, premenstrual-like syndrome, spotting.

Hepatic

Cholestatic jaundice, enlargement of hepatic hemangiomas.

Metabolic-Nutritional

Increased weight (9%); decreased weight, hypocalcemia, increased triglycerides, reduced carbohydrate tolerance.

Musculoskeletal

Back pain (15%); arthralgia (6%); leg cramps, myalgia.

Respiratory

Rhinitis (22%); upper respiratory tract infection (16%); sinusitis (15%); respiratory disorder (13%); exacerbation of asthma, pharyngitis (10%); bronchitis (5%).

Miscellaneous

Pain (19%); accidental injury (17%); peripheral edema, viral infection (6%); infection (5%); aggravation of porphyria, anaphylactic/anaphylactoid reactions, edema, influenza syndrome.

Precautions

Warnings

Estrogens with or without progestins should not be used for prevention of CV disease or dementia. The Women's Health Initiative study reported increased risks of MI, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women during 5 yr of treatment with oral conjugated estrogens combined with medroxyprogesterone acetate. In addition, increased risk of developing probable dementia in postmenopausal women 65 yr of age and older during 4 yr of treatment with oral conjugated estrogens plus medroxyprogesterone acetate was reported. Although the combination of estradiol/norethindrone acetate was not studied, in the absence of comparable date, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman.


Monitor

Reevaluate patients (eg, 3- to 6-mo intervals) to determine if treatment is still necessary. Ensure that breast, abdominal, and pelvic examination and Pap smear have been completed and documented before starting therapy and are repeated periodically during therapy (at least once a year). Assess BP at beginning of therapy and periodically during treatment.


Pregnancy

Category X .

Lactation

Excreted in breast milk.

Children

Not indicated for use in children.

Hepatic Function

Metabolism may be impaired; use drug with caution.

Special Risk Patients

Because estrogens may cause exacerbation of asthma, diabetes mellitus, epilepsy, hepatic hemangiomas, migraine, porphyria, and systemic lupus erythematosus, use with caution.

Elevated BP

BP may increase.

Endometriosis

May be exacerbated.

Fluid retention

Use with careful observation when conditions that might be affected by this factor are present (eg, cardiac or renal dysfunction).

Gallbladder disease

Risk of gallbladder disease may increase in women receiving postmenopausal estrogens.

Glucose intolerance

A worsening of glucose tolerance has been reported.

Hypercalcemia

Severe hypercalcemia may occur in patients with breast cancer and bone metastases.

Hypertriglyceridemia

In patients with preexisting hypertriglyceridemia, elevations in triglycerides may occur, leading to complications (eg, pancreatitis).

Hypocalcemia

Use with caution in patients with severe hypocalcemia.

Hypothyroidism

Estrogen use may lead to increased TBG levels.

Induction of malignant neoplasia

May increase risk of endometrial or other carcinomas.

Ovarian cancer

Risk of occurrence may be increased.

Visual abnormalities

Sudden partial or complete vision loss, or sudden onset of proptosis, diplopia, or migraine resulting from retinal vascular thrombosis may occur.

Overdosage

Symptoms

Nausea, vomiting, withdrawal bleeding.

Patient Information

  • Advise patient to review patient information leaflet before using for the first time and with each refill.
  • Instruct diabetic patient to monitor blood glucose more frequently when drug is started or dose is changed and to inform health care provider of significant changes in readings.
  • Review nonhormonal modalities that help prevent osteoporosis: 1,500 mg/day of calcium, vitamin D supplementation, exercise.
  • Instruct patient to immediately report the following symptoms to health care provider: abnormal vaginal bleeding; breast lumps; dizziness or fainting; pain in groin or calves; severe abdominal pain; severe depression; sharp chest pain or sudden shortness of breath; sudden severe headache; vision or speech problems; weakness or numbness of arms or legs; yellowing of skin or eyes.
  • Teach patient proper method of breast self-examination.
  • Advise patient that follow-up visits and examinations, including breast exam and Pap smear, will be required at least once a year to monitor therapy and to keep appointments.
  • Patch
  • Teach patient proper method of applying patch. Open pouch, remove one side of protective liner from patch, taking care not to touch adhesive part of patch, and immediately apply patch to clean, smooth (fold-free), dry skin on lower abdomen. Remove the second side of the protective liner and press firmly with palm of hand for approximately 10 sec. Be sure good contact is made, especially at edges.
  • Caution patient not to apply patch on or near the breasts, skin areas that are oily, damaged, or irritated, or skin areas that have had powder, lotion, or moisturizer applied, or to skin areas where clothing or sitting could dislodge patch.
  • Advise patient that if patch falls off to attempt to reapply to another area of the lower abdomen. If that fails, a new patch may be applied, in which case, the original treatment schedule should be continued.
  • Instruct patient to rotate application sites so that no site is used more than once weekly.
  • Advise patient that patch may cause reactions at application site and to inform health care provider if this occurs and is bothersome.
  • Advise patient not to expose patch to direct sunlight for long periods of time (eg, sunbathing).
  • Tell patient that bathing, swimming, or showering should not affect the patch.
  • Advise patient that a new patch is applied every 3 to 4 days and to change the patch on the same days of the week.
  • Advise patient to remove the patch carefully to avoid irritation of the skin. If any adhesive remains on skin, allow area to dry and rub with an oil-based cream or lotion to remove residue.

Copyright © 2009 Wolters Kluwer Health.

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