Estradiol and norethindrone acetate (transdermal patch)

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# Overview
Estradiol and norethindrone acetate (transdermal patch) is an estrogen/progestin combination that is FDA approved for the treatment of moderate to severe vasomotor symptoms due to menopause, moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.   Common adverse reactions include edema, application site irritation, chloasma, hirsutism, loss of scalp hair, persistent erythema of skin, pruritus, weight increased, abdominal pain, bloating symptom, headache, breast tenderness, disorder of menstruation, pain of breast, swelling of breast, vaginal discomfort, withdrawal bleeding, upper respiratory infection, pain.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Initiation of Therapy
- Patients should be started at the lowest dose. estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. The lowest effective dose of estradiol/norethindrone acetate has not been determined in clinical trials.
- Women not currently using continuous estrogen or combination estrogen plus progestin therapy may start therapy with estradiol/norethindrone acetate at any time. However, women currently using continuous estrogen or combination estrogen plus progestin therapy should complete the current cycle of therapy, before initiating estradiol/norethindrone acetate therapy.
- Women often experience withdrawal bleeding at the completion of the cycle. The first day of this bleeding would be an appropriate time to begin estradiol/norethindrone acetate therapy.

### Therapeutic Regimens
- Combination estrogen plus progestin regimens are indicated for women with an intact uterus. Two estradiol/norethindrone acetate (estradiol/NETA) transdermal delivery systems are available: 0.05 mg estradiol with 0.14 mg NETA per day (9 cm2) and 0.05 mg estradiol with 0.25 mg NETA per day (16 cm2). The lowest effective dose should be used. For all regimens, women should be reevaluated at 3- to 6-month intervals to determine if changes in hormone therapy or if continued hormone therapy is appropriate.
- Continuous Combined Regimen
- An Estradiol/Norethindrone Acetate 0.05 mg estradiol/0.14 mg NETA per day (9 cm2) matrix transdermal system is worn continuously on the lower abdomen. Additionally, a dose of 0.05 mg estradiol/0.25 mg NETA (16 cm2 system) is available if a greater progestin dose is desired. A new system should be applied twice weekly during a 28-day cycle. Irregular bleeding may occur particularly in the first six months, but generally decreases with time, and often to an amenorrheic state.
- Continuous Sequential Regimen
- Estradiol/Norethindrone Acetate can be applied as a sequential regimen in combination with an estradiol-only transdermal delivery system.
- In this treatment regimen, a 0.05 mg per day (nominal delivery rate) estradiol transdermal system (Vivelle) is worn for the first 14 days of a 28-day cycle, replacing the system twice weekly according to product directions. For the remaining 14 days of the 28-day cycle, estradiol/norethindrone acetate 0.05 mg estradiol/0.14 mg NETA per day (9 cm2) transdermal system should be applied to the lower abdomen. Additionally, a dose of 0.05 mg estradiol/0.25 mg NETA (16 cm2 system) is available if a greater progestin dose is desired. The estradiol/norethindrone acetate system should be replaced twice weekly during this period in the cycle. Women should be advised that monthly withdrawal bleeding often occurs.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of estradiol/norethindrone acetate in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of estradiol/norethindrone acetate in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Estradiol/Norethindrone Acetate is not indicated in children

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of estradiol/norethindrone acetate in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of estradiol/norethindrone acetate in pediatric patients.

# Contraindications
Estradiol/Norethindrone Acetate is contraindicated in women with any of the following conditions:
- Undiagnosed abnormal genital bleeding.
- Known, suspected, or history of breast cancer.
- Known or suspected estrogen-dependent neoplasia.
- Active DVT, PE, or history of these conditions.
- Active arterial thromboembolic disease (for example, stroke and mi), or a history of these conditions.
- Known anaphylactic reaction or angioedema or hypersensitivity to estradiol/norethindrone acetate.
- Known liver impairment or disease.
- Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders
- Known or suspected pregnancy.

# Warnings
- An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately.
- Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.
- In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years).The increase in risk was demonstrated after the first year and persisted. Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.
- In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.
- Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).
- In the WHI estrogen plus progestin substudy, there was a statistically non significant increased risk of CHD events (defined as non fatal MI, silent MI, or CHD death) reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.
- In the WHI estrogen-alone substudy, no overall effect on CHD events was reported in women receiving estrogen-alone compared to placebo.
- Subgroup analyses of women 50 to 59 years of age suggest a statistically non significant reduction in CHD events (CE -alone compared to placebo) in women less than 10 years since menopause (8 versus 16 per 10,000 women-years).
- In postmenopausal women with documented heart disease (n=2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and estrogen/progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of  CHD events in postmenopausal women with established CHD. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred twenty-one (2,321) women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in the HERS, the HERS II, and overall.
- In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and PE) was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted.Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.
- In the WHI estrogen-alone substudy, the risk of VTE was reported to be increased for women receiving daily CE (0.625 mg)-alone compared to women receiving placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women years). The increase in VTE risk was demonstrated during the first 2 years. (See CLINICAL STUDIES) Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately.
- If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
- Endometrial Cancer
- An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among users of unopposed estrogen is about 2 to 12 times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use with increased risks of 15- to 24-fold for 5 to 10 years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
- Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with un diagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
- Breast Cancer
- The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups.
- The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of CE (0.625)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer (relative risk  0.80).
- Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.
- The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.
- All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
- Ovarian Cancer
- The WHI estrogen plus progestin substudy reported a statistically non significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI 0.77 to 3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association.
- Probable Dementia
- In the WHIMS estrogen plus progestin ancillary substudy of WHI, a population of 4,532 generally healthy postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.
- After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years.
- In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years.
- When data from the 2 populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19 to 2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.
- Gallbladder Disease
- A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
- Hypercalcemia
- 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 the serum calcium level.
- Visual Abnormalities
- Retinal  vascular thrombosis  has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.
- Hereditary Angioedema
- Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

# Precaution

## General
- Addition of a progestin when a Woman has not had a Hysterectomy
- Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of  endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
- There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.
- Elevated Blood Pressure
- In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen.
- Hypertriglyceridemia
- 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.
- Hepatic Impairment and/or Past History of Cholestatic Jaundice
- 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.
- Hypothyroidism
- Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.
- Fluid Retention
- 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.
- Hypocalcemia
- Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.
- Exacerbation of Endometriosis
- A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.
- Exacerbation of Other Conditions
- Estrogen therapy may cause an 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.

# Adverse Reactions

## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

## Postmarketing Experience
- The following additional adverse reactions have been identified during post approval use of estradiol/norethindrone acetate. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

### Genitourinary System
- Endometrial hyperplasia, endocervical polyp, uterine leiomyomata, fallopian tube cyst, uterine spasms.

### Breast
- Breast cancer.

### Cardiovascular
- Hypertension, varicose veins.

### Gastrointestinal
- Jaundice cholestatic, cholelithiasis, gall bladder disorder, transaminases increased.

### Skin
- Skin discoloration.

### Central Nervous System
- Affect lability, libido disorder, migraine, vertigo, paraesthesia.

### Miscellaneous
- Angioedema, hypersensitivity, weight increased.
- Additional post marketing adverse reactions have been reported in patients receiving other forms of hormone therapy.

# Drug Interactions
- In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. Johns wort (hypericum perforatum) preparations, phenobarbital, carbamazepine and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

### Adhesion
- Averaging across 6 clinical trials lasting 3 months to 1 year, of 1,287 patients treated, estradiol/norethindrone acetate transdermal systems completely adhered to the skin nearly 90 percent of the time over the 3- to 4-day wear period. Less than 2 percent of the patients required reapplication or replacement of systems due to lifting or detachment. Two patients (0.2 percent) discontinued therapy during clinical trials due to adhesion failure.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Estradiol/Norethindrone Acetate should not be used during pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Estradiol and norethindrone acetate (transdermal patch) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Estradiol and norethindrone acetate (transdermal patch) during labor and delivery.

### Nursing Mothers
- Estradiol/Norethindrone Acetate should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens and progestins have been identified in the breast milk of women receiving these drugs. Caution should be exercised when estradiol/norethindrone acetate is administered to a nursing woman.

### Pediatric Use
Estradiol/Norethindrone Acetate is not indicated in children. Clinical studies have not been conducted in the pediatric population.

### Geriatic Use
- There have not been sufficient numbers of geriatric women involved in studies utilizing estradiol/norethindrone acetate to determine whether those over 65 years of age differ from younger subjects in their response to estradiol/norethindrone acetate.
- The Womens Health Initiative Studies
- In the WHI estrogen plus progestin substudy (daily CE  plus MPA  versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age.
- In the WHI estrogen-alone substudy (daily CE -alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age.
- In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo.
- Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.

### Gender
There is no FDA guidance on the use of Estradiol and norethindrone acetate (transdermal patch) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Estradiol and norethindrone acetate (transdermal patch) with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Estradiol and norethindrone acetate (transdermal patch) in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Estradiol and norethindrone acetate (transdermal patch) in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Estradiol and norethindrone acetate (transdermal patch) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Estradiol and norethindrone acetate (transdermal patch) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Transdermal patch
- Application of the System
Site Selection
- Estradiol/Norethindrone Acetate should be placed on a smooth (fold-free), clean, dry area of the skin on the lower abdomen. Estradiol/Norethindrone Acetate should not be applied to or near the breasts. The area selected should not be oily (which can impair adherence of the system), damaged, or irritated. The waistline should be avoided, since tight clothing may rub the system off or modify drug delivery. The sites of application must be rotated, with an interval of at least one week allowed between applications to the same site.
Application
- After opening the pouch, remove 1 side of the protective liner, taking care not to touch the adhesive part of the transdermal delivery system with the fingers. Immediately apply the transdermal delivery system to a smooth (fold-free) area of skin on the lower abdomen. Remove the second side of the protective liner and press the system firmly in place with the hand for at least 10 seconds, making sure there is good contact, especially around the edges.
- Care should be taken that the system does not become dislodged during bathing and other activities. If a system should fall off, the same system may be reapplied 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. Only 1 system should be worn at any 1 time during the 3- to 4-day dosing interval.
- Once in place, the transdermal system should not be exposed to the sun for prolonged periods of time.
Removal of the System
- Removal of the system should be done carefully and slowly to avoid irritation of the skin. Should any adhesive remain on the skin after removal of the system, allow the area to dry for 15 minutes. Then gently rub the area with an oil-based cream or lotion to remove the adhesive residue.

### Monitoring
FDA package insert for estradiol/norethindrone acetate contains no information regarding drug monitoring.

# IV Compatibility
There is limited information about the IV compatibility.

# Overdosage
- Overdosage of estrogen or estrogen plus progestin may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of estradiol/norethindrone acetate therapy with institution of appropriate symptomatic care.

# Pharmacology
There is limited information regarding Estradiol and norethindrone acetate (transdermal patch) Pharmacology in the drug label.

## Mechanism of Action
- Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level.
- The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
- Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, 2 estrogen receptors have been identified. These vary in proportion from tissue to tissue.
- Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and follicle stimulating hormone (FSH) through a negative feedback mechanism. estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

## Structure
- Estradiol USP (estradiol) is a white to creamy white, odorless, crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17-diol. The molecular weight of estradiol is 272.39 and the molecular formula is C18H24O2.
- NETA USP is a white to creamy white, odorless, crystalline powder, chemically described as 17-hydroxy-19-nor-17-pregn-4-en-20-yn-3-one acetate. The molecular weight of NETA is 340.47 and the molecular formula is C22H28O3.
- The structural formulas for estradiol and NETA are:

## Pharmacodynamics
There is limited information regarding Estradiol and norethindrone acetate (transdermal patch) Pharmacodynamics in the drug label.

## Pharmacokinetics

### Absorption
- Estradiol: estrogens used in hormone therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. Administration of estradiol/norethindrone acetate every 3 to 4 days in postmenopausal women produces average steady-state estradiol serum concentrations of 45 to 50 pg/mL, which are equivalent to the normal ranges observed at the early follicular phase in premenopausal women. These concentrations are achieved within 12 to 24 hours following estradiol/norethindrone acetate application. Minimal fluctuations in serum estradiol concentrations are observed following estradiol/norethindrone acetate application, indicating consistent hormone delivery over the application interval.
- In 1 study, serum concentrations of estradiol were measured in 40 healthy, postmenopausal women throughout 3 consecutive estradiol/norethindrone acetate applications to the abdomen (each dose was applied for three 3.5-day periods). The corresponding pharmacokinetic parameters are summarized in TABLE 1.
- Norethindrone: progestins used in hormone therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. Norethindrone steady-state concentrations are attained within 24 hours of application of the estradiol/norethindrone acetate transdermal delivery systems. minimal fluctuations in serum norethindrone concentrations are observed following estradiol/norethindrone acetate treatment, indicating consistent hormone delivery over the application interval. Serum concentrations of norethindrone increase linearly with increasing doses of NETA.
- In 1 study, serum concentrations of norethindrone were measured in 40 healthy, postmenopausal women throughout 3 consecutive estradiol/norethindrone acetate applications to the abdomen (each dose was applied for three 3.5-day periods). The corresponding pharmacokinetic parameters are summarized in TABLE 2.

### Distribution
- Estradiol: The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin.
- Norethindrone: In plasma, norethindrone is bound approximately 90 percent to SHBG and albumin.

### Metabolism
- Estradiol: Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
- Norethindrone: NETA is hydrolyzed to the active moiety, norethindrone, in most tissues including skin and blood. Norethindrone is primarily metabolized in the liver.

### Excretion
- Estradiol: Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Estradiol has a short elimination half-life of approximately 2 to 3 hours; therefore, a rapid decline in serum levels is observed after the Estradiol/Norethindrone Acetate estradiol/NETA transdermal system is removed. Within 4 to 8 hours serum estradiol concentrations return to untreated, postmenopausal levels (less than 20 pg/mL).
- Concentration data from Phase II and III studies indicate that the pharmacokinetics of estradiol did not change over time, suggesting no evidence of the accumulation of estradiol following extended patch wear periods (up to 1 year).
- Norethindrone: The elimination half-life of norethindrone is reported to be 6 to 8 hours.Norethindrone serum concentrations diminish rapidly and are less than 50 pg/mL within 48 hours after removal of the estradiol/norethindrone acetate transdermal delivery system.
- Concentration data from Phase II and III studies indicate that the pharmacokinetics of norethindrone did not change over time, suggesting no evidence of the accumulation of norethindrone following extended patch wear periods (up to 1 year).

### Special Populations
- No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
- NETA was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays.

# Clinical Studies

### Effects on Vasomotor Symptoms
- In 2 clinical trials designed to assess the degree of relief of moderate to severe vasomotor symptoms in postmenopausal women (n=332), estradiol/norethindrone acetate was administered for 3 28-day cycles in Continuous Combined or Continuous Sequential treatment regimens versus placebo. In the Continuous Combined regimen, estradiol/norethindrone acetate was applied throughout the 3 cycles, replacing the system twice weekly. In the Continuous Sequential regimen, an estradiol-only transdermal system (Vivelle 0.05 mg) was applied twice weekly during the first 14 days of a 28-day cycle; estradiol/norethindrone acetate was applied for the remaining 14 days of the cycle and replaced twice weekly, as well. The mean number of hot flushes at baseline were 10 to 11 per day and 11 to 12 per day in the Continuous Combined and Continuous Sequential regimen trials, respectively. The mean number and intensity of daily hot flushes (intent-to-treat population) was significantly reduced from baseline to endpoint with either the continuous combined or continuous Sequential administration of estradiol/norethindrone acetate at all doses as compared to placebo (intent-to-treat population). (See TABLES 3 and 4.)

### Effects on the Endometrium
- The use of unopposed estrogen therapy has been associated with an increased risk of endometrial hyperplasia, a possible precursor of endometrial adenocarcinoma. progestins counter the estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.
- Clinical studies indicate that the addition of a progestin to an estrogen regimen at least 12 days per cycle reduces the incidence of endometrial hyperplasia and the potential risk of adenocarcinoma in women with intact uteri. The addition of a progestin to an estrogen regimen has not been shown to interfere with the efficacy of estrogen therapy for its approved indications.
- Estradiol/Norethindrone Acetate was effective in reducing the incidence of estrogen-induced endometrial hyperplasia after 1 year of therapy in 2 Phase II clinical trials. Nine hundred fifty-five (955) postmenopausal women (with intact uteri) were treated with (i) a continuous regimen of Estradiol/Norethindrone Acetate alone (Continuous Combined regimen), (ii) a sequential regimen with an estradiol-only (Vivelle 0.05 mg) transdermal system followed by a Estradiol/Norethindrone Acetate transdermal system (Continuous Sequential regimen), or (iii) continuous regimen with an estradiol-only transdermal system (Vivelle 0.05 mg). The incidence of endometrial hyperplasia (primary endpoint) was significantly less after 1 year of therapy with either estradiol/norethindrone acetate regimen than with the estradiol-only transdermal system. TABLES 5 and 6 summarize these results (intent-to-treat populations).

### Effects on Uterine Bleeding or Spotting
- With the Continuous Combined regimen, of the women treated with estradiol/norethindrone acetate and who completed the 1-year study, the incidence of cumulative amenorrhea (the absence of bleeding or spotting during a 28-day cycle and sustained to the end of the study) increased over time. The incidence of amenorrhea from cycle 10 through 12 was 53 percent and 39 percent for the estradiol/norethindrone acetate 0.05/0.14 mg per day and estradiol/norethindrone acetate 0.05/0.25 mg per day treatment groups, respectively. Women who experienced bleeding usually characterized it as light (intensity of 1.3 on a scale of 1 to 4) with a duration of 4 and 6 days for the estradiol/norethindrone acetate 0.05/0.14 mg per day and estradiol/norethindrone acetate 0.05/0.25 mg per day treatment groups, respectively. (See FIGURE 1)
- Figure 1. Incidence of Cumulative Amenorrhea- in Estradiol/Norethindrone Acetate Continuous Combined Transdermal Therapy by Cycle Over a 1-Year Period (Intent-to-Treat Population)
- Cumulative amenorrhea is defined as the absence of bleeding for the duration of a 28-day cycle and sustained to the end of the study.

### Womens Health Initiative Studies
- The Womens Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in 2 substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) , with invasive breast cancer as the primary adverse outcome. A global index included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms.

### WHI estrogen Plus progestin Substudy
- The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the global index. The absolute excess risk of events included in the global index was 19 per 10,000 women-years.
- For those outcomes included in the WHI global index that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.
- Results of the estrogen plus progestin substudy, which included 16,608 women (average 63 years of age, range 50 to 79 years; 83.9 percent white, 6.8 percent black, 5.4 percent Hispanic, 3.9 percent Other), are presented in TABLE 7. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

# How Supplied
Estradiol/Norethindrone Acetate estradiol/NETA transdermal delivery system is available in:

## Storage

### Storage Conditions
- Prior to dispensing to the patient, store refrigerated 2C to 8C (36F to 46F). After dispensing to the patient, estradiol/norethindrone acetate can be stored at room temperature between 20oC to 25oC (66oF to 77oF) for up to 6 months. For the Pharmacist: When estradiol/norethindrone acetate is dispensed to the patient, place an expiration date on the label. The date should not exceed either six months from the date of sale or the expiration date, whichever comes first.
- Store the systems in the sealed foil pouch.
- Do not store the system in areas where extreme temperatures can occur.
- Keep this and all medicines out of the reach of children.
- Vivelle is a registered trademark of Novartis Pharmaceuticals Corporation.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Physicians are advised to discuss the content of the patient information leaflet with patients for whom they prescribe estradiol/norethindrone acetate.

# Precautions with Alcohol
Alcohol-Estradiol/Norethindrone Acetate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- ESTRADIOL / NORETHINDRONE ACETATE 

# Look-Alike Drug Names
There is limited information about the look-alike drug names.

# Drug Shortage Status

# Price