Menostar® (estradiol transdermal system)

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Menostar® (estradiol transdermal system)

Menostar (estradiol transdermal system) is designed to provide nominal in vivo delivery of 14 mcg of estradiol per day continuously upon application to intact skin. The period of use is 7 days. The transdermal system has a contact surface area of 3.25 cm2 , and contains 1 mg of estradiol USP.

Estradiol USP is a white, crystalline powder, chemically described as estra-1,3,5(10)-triene-3, 17ß-diol. It has an empirical formula of C18H24O2 and molecular weight of 272.38.

The Menostar transdermal system comprises three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are:

  1. A translucent polyethylene film.
  2. An acrylate adhesive matrix containing estradiol USP.
  3. A protective liner of siliconized or fluoropolymer-coated polyester film is attached to the adhesive surface and must be removed before the transdermal system can be used.

The active component of the transdermal system is estradiol. The remaining components of the transdermal system (acrylate copolymer adhesive, fatty acid esters, and polyethylene backing) are pharmacologically inactive.

Indications and usage

Menostar is an estrogen indicated for prevention of Postmenopausal Osteoporosis.

Limitation of Use: When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered.

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, which is 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, two 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.

Dosage and administration

Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be considered to reduce the risk of endometrial cancer. It is recommended that women who have a uterus and are treated with Menostar receive a progestin for 14 days every 6 to 12 months and undergo an endometrial biopsy at yearly intervals or as clinically indicated in order to detect any endometrial stimulation which might require further clinical action. A women without a uterus does not need a progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a progestin.

Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be reevaluated periodically as clinically appropriate to determine if treatment is still necessary.

Prevention of Postmenopausal Osteoporosis: Menostar 14 mcg per day applied to a clean dry area of the lower abdomen once weekly.

Application of the Menostar Transdermal System

Site Selection

  • The adhesive side of Menostar should be placed on a clean, dry area of the lower abdomen or the upper quadrant of the buttock.
  • Menostar should not be applied to or near the breasts.
  • The sites of application must be rotated, with an interval of at least 1-week allowed between applications to a same site.
  • The area selected should not be oily, damaged, or irritated. The waistline should be avoided, since tight clothing may rub the transdermal system off.
  • Application to areas where sitting would dislodge Menostar should also be avoided.

Application

  • Menostar should be applied immediately after opening the pouch and removing the protective liner.
  • Menostar should be pressed firmly in place with the fingers for at least 10 seconds, making sure there is good contact, especially around the edges.
  • If the system lifts, apply pressure to maintain adhesion.
  • In the event that a system should fall off reapply it to a different location. If the system cannot be reapplied, a new system should be applied for the remainder of the 7-day dosing interval.
  • Only one system should be worn at any one time during the 7-day dosing interval.
  • Swimming, bathing, or using a sauna while using Menostar has not been studied, and these activities may decrease the adhesion of the system and the delivery of estradiol.

Removal of the Menostar Transdermal 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 rubbing the area with an oil-based cream or lotion should remove the adhesive residue.
  • Used patches still contain some active hormones. Each patch should be carefully folded in half so that it sticks to itself before throwing it away.

Contraindications

Menostar 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 a history of these conditions
  • Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions
  • Known anaphylactic reaction or angioedema with Menostar
  • Known liver impairment or disease
  • Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders
  • Known or suspected pregnancy

Warnings and precautions

Cardiovascular Disorders: An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin 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

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 unopposed estrogen users 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 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. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

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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 women 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 women 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.

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 estrogenalone 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 estrogens on blood pressure was not seen.

Hypertriglyceridemia: In women with pre-existing 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: 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 may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac or renal impairment, warrant careful observation when estrogen-alone is 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 posthysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

Hereditary Angioedema: Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

Exacerbation of Other Conditions: Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

Laboratory Tests: Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful when the Menostar transdermal system is used for the prevention of postmenopausal osteoporosis.

Adverse reactions

In a prospective, randomized, placebo-controlled, double-blind study, the most common adverse reactions (≥ 10 percent) are upper respiratory tract infections, pain, arthralgia, and leukorrhea.

Drug interactions

Metabolic 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. John’s 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.

Use in specific populations

Pregnancy: Menostar 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 oral contraceptives inadvertently during early pregnancy.

Nursing Mothers: Menostar 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 have been identified in the breast milk of women receiving estrogen therapy. Caution should be exercised when the Menostar transdermal system is administered to a nursing woman.

Pediatric Use: Menostar is not indicated in children. Clinical studies have not been conducted in the pediatric population.

Renal Impairment: In postmenopausal women with end stage renal disease (ESRD) receiving maintenance hemodialysis, total estradiol serum levels are higher than in normal subjects at baseline and following oral doses of estradiol. Therefore, conventional transdermal estradiol doses used in individuals with normal renal function may be excessive for postmenopausal women with ESRD receiving maintenance hemodialysis.

Hepatic Impairment: Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution.

Overdosage

Overdosage of estrogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding in women. Treatment of overdose consists of discontinuation of Menostar therapy with institution of appropriate symptomatic care.

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