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Continuous Delivery for Once-Weekly Application
Menostar (estradiol transdermal system)
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER
Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of "natural" estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses.(See WARNINGS , Malignant neoplasms, Endometrial cancer .)
CARDIOVASCULAR AND OTHER RISKS
Estrogens with and without progestins should not be used for the prevention of cardiovascular disease or dementia. (See WARNINGS , Cardiovascular disorders and Dementia.)
The Women's Health Initiative (WHI) study reported increased risks of stroke and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 6.8 years of treatment with oral conjugated estrogens (CE 0.625 mg) alone per day, relative to placebo. (See CLINICAL STUDIES and WARNINGS , Cardiovascular disorders .)
The WHI-study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5mg) per day, relative to placebo (see CLINICAL STUDIES, and WARNINGS , Cardiovascular disorders and Malignant neoplasms , Breast Cancer .)
The Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI study, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with CE 0.625 mg alone and during 4 years of treatment with CE 0.625 mg combined with MPA 2.5 mg, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES , WARNINGS , Dementia , and PRECAUTIONS , Geriatric Use .)
Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, 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.
Menostar, estradiol transdermal system, is designed to provide nominal in vivo delivery of 14 mcg 17ß-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 cm, and contains 1 mg of estradiol USP.
Estradiol USP (17ß-estradiol) is a white, crystalline powder, chemically described as estra-1,3,5(10)-triene-3, 17ß-diol. It has an empirical formula of CHO and molecular weight of 272.39. The structural formula is:
The Menostar transdermal system comprises three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are
The active component of the transdermal system is 17ß-estradiol. The remaining components of the transdermal system (acrylate copolymer adhesive, fatty acid esters, and polyethylene backing) are pharmacologically inactive.
The Menostar transdermal system provides systemic estrogen therapy by releasing 17ß-estradiol, the major estrogenic hormone secreted by the human ovary.
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 by 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.
The decline of ovarian estrogen production that accompanies menopause or oophorectomy results in the acceleration of bone loss and bone resorption. Bone resorption is increased more than bone formation especially in the early years of menopause where bone loss is the greatest. In some women, these changes will eventually lead to decreased bone mass, osteoporosis and increased risk for fractures, particularly that of the spine, hip, and wrist. Vertebral fractures are the most common type of osteoporotic fracture in postmenopausal women.
Postmenopausal women with low serum estradiol concentrations and high serum concentrations of sex hormone-binding globulin (SHBG) have an increased risk of hip and vertebral fractures. Postmenopausal estrogen therapy decreases bone resorption, helping to reestablish balance between resorption and formation. This effect appears to be effective for as long as treatment is continued.
The bioavailability of estradiol following application of a Menostar transdermal system, relative to that of a transdermal system delivering 25 mcg/day, was investigated in 18 healthy postmenopausal women mean age 66 years (range 60-80 years). The mean serum estradiol concentrations upon administration of the two patches to the lower abdomen are shown in Figure 1. Transdermal administration of Menostar produced geometric mean serum concentration (Cavg) of estradiol of 13.7 pg/mL. No patches failed to adhere during the one week application period of both transdermal systems. Following application of the Menostar transdermal system to the abdomen, it is estimated to provide an average nominal in-vivo daily delivery of 14 mcg estradiol/day.
The Menostar transdermal delivery system continuously releases estradiol which is transported across intact skin leading to sustained circulating levels of estradiol during a 7-day treatment period. The systemic availability of estradiol after transdermal administration is about 20 times higher than that after oral administration. This difference is due to the absence of first pass metabolism when estradiol is given by the transdermal route.
Table 1 provides a summary of estradiol pharmacokinetic parameters determined during evaluation of Menostar using baseline uncorrected serum concentrations.
The estimated estradiol daily delivery rate for Climara 6.5 cm is quoted from the Climara labeling.
|Pharmacokinetic parameters are expressed in geometeric means except for the tmax which represents the median estimate and the Cmin which is expressed as the arithmetic mean.|
|Climara® 6.5 cm2||25||4151||37.2||24.7||42||20.4|
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. In the clinical study with 208 patients on Menostar, SHBG concentration (mean ± SD) remained essentially unchanged over the 2 year period (baseline 45.1 ± 20.1 nmol/L, 24 month visit 46.4 ± 20.9 nmol/L).
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 the 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 proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
Geriatric: The efficacy and safety of Menostar has been studied in women between 60 and 80 years of age, with approximately half over 65 years old.
Pediatric: No pharmacokinetic study for Menostar has been conducted in a pediatric population.
Gender: Menostar is indicated for use in postmenopausal women only.
Race: No studies were done to determine the effect of race on the pharmacokinetics of Menostar.
Patients with Renal Impairment: Total estradiol serum levels are higher in postmenopausal women with end stage renal disease (ESRD) receiving maintenance hemodialysis 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.
Patients with Hepatic Impairment: Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution.
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 preparations (Hypericum perforatum), 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.
In a Menostar pharmacokinetic study with 18 postmenopausal women, no patches failed to adhere during the one week application period.
The efficacy of Menostar in the prevention of postmenopausal osteoporosis was investigated in a 2-year double blind, placebo-controlled, multicenter study in the United States. A total of 417 postmenopausal women, 60 to 80 years old, with an intact uterus were enrolled in the study. All patients received supplemental calcium and vitamin D.
Menostar produced larger increases in bone mass than placebo as reflected by dual-energy x-ray absorptiometric (DEXA) measurements of hip and lumbar spine BMD. The changes in BMD from baseline were statistically significantly (p <0.001) greater during treatment with Menostar than during treatment with placebo for hip and spine after 1 and 2 years.
At lumbar spine Menostar increased BMD by 2.3% after 1 year and 3% after 2 years compared with a 0.5% increase after 1 and 2 years of treatment with placebo. At the hip Menostar increased BMD by 0.9% after one year and 0.84% after two years compared with a mean decrease of 0.22% after 1 year and 0.71% after 2 years of placebo treatment (see Table 2 below).
The BMD data of the study were analyzed according to baseline estradiol levels of the patients. Overall, estimated treatment effects on lumbar spine and total hip BMD after 2 years were approximately twice as large in the subgroup with baseline estradiol levels < 5 pg/mL than in the subgroup with baseline estradiol levels ≥ 5 pg/mL [Table 3].
Menostar therapy also resulted in consistent, statistically significant suppression of bone turnover, as reflected by changes in serum and urine markers of bone formation (osteocalcin and bone-specific alkaline phosphatase) and bone resorption (carboxyterminal telopeptide of type 1 collagen (ICTP) and the urinary deoxypryridoline/creatinine ratio).
|Lumbar spine||Total hip|
|12-month Endpoint||+2.29||+0.51||< 0.001||12-month Endpoint||+0.90||-0.22||< 0.001|
|24-month Endpoint||+2.99||+0.54||< 0.001||24-month Endpoint||+0.84||-0.71||< 0.001|
|Lumbar spine||Total hip|
|Baseline estradiol levels||Menostar||Placebo||Treatment difference||Menostar||Placebo||Treatment difference|
|< 5 pg/mL||n
|(p < 0.001)||(p < 0.001)|
|≥ 5 pg/mL||n
|(p = 0.002)||(p = 0.045)|
The WHI enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral conjugated estrogens (CE 0.625 mg) alone per day or the use of oral conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
The estrogen-alone substudy was stopped early because an increased risk of stroke was observed. Results of the estrogen-alone substudy, which included 10,739 women (average age 63 years, range 50 to 79: 75.3 percent white, 15 percent black, 6.1 percent Hispanic), after an average follow-up of 6.8 years are presented in Table 4.
For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risks per 10,000 women-years in the group treated with CE alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 6 fewer hip fractures. The absolute excess risk of events included in the "global index" was a nonsignificant 2 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS , and PRECAUTIONS.)
The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 5 below:
For those outcomes included in the "global index," the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS , WARNINGS , and PRECAUTIONS .)
CE vs Placebo
at 6.8 Years
|CHD events||0.91 (0.75-1.12)||49||54|
|Non-fatal MI||0.89 (0.7-1.12)||37||41|
|CHD death||0.94 (0.65-1.36)||15||16|
|Invasive breast cancer||0.77 (0.59-1.01)||26||33|
|Pulmonary embolism||1.34 (0.87-2.06)||13||10|
|Colorectal cancer||1.08 (0.75-1.55)||17||16|
|Hip fracture||0.61 (0.41-0.91)||11||17|
|Death due to causes other than the events above||1.08 (0.88-1.32)||53||50|
|Deep vein thrombosis
CE/MPA vs placebo
at 5.2 Years
n = 8102
|CHD events||1.29 (1.02-1.63)||37||30|
|Non-fatal MI||1.32 (1.02-1.72)||30||23|
|CHD death||1.18 (0.7-1.97)||7||7|
|Invasive breast cancer
|Pulmonary embolism||2.13 (1.39-3.25)||16||8|
|Colorectal cancer||0.63 (0.43-0.92)||10||16|
|Endometrial cancer||0.83 (0.47-1.47)||5||6|
|Hip fracture||0.66 (0.45-0.98)||10||15|
|Death due to causes other than the events above||0.92 (0.74-1.14)||37||40|
|Deep vein thrombosis
|Other osteoporotic fractures
The estrogen-alone WHIMS, a substudy of the WHI study, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45 percent were aged 65 to 69 years, 36 percent were 70 to 74 years and 19 percent were 75 years of age and older) to evaluate the effects of conjugated estrogens (CE 0.625 mg) on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen-alone group (37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the estrogen-alone group was 1.49 (95 percent confidence interval (CI), 0.83-2.66) compared to placebo. It is unknown whether these findings apply to postmenopausal women. (See BOXED WARNINGS , WARNINGS , Dementia , and PRECAUTIONS , Geriatric Use.)
The estrogen plus progestin WHIMS substudy of WHI, enrolled 4,532 predominantly postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS , WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.).)
Menostar is indicated for the prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered.
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.
Risk factors for osteoporosis include low bone mineral density, low estrogen levels, family history of osteoporosis, previous fracture, small frame (low BMI), light skin color, smoking, and alcohol intake. Response to therapy can be predicted by pre-treatment serum estradiol (see Table 3), and can be assessed during treatment by measuring biochemical markers of bone formation/resorption, and/or bone mineral density.
Menostar should not be used in women with any of the following conditions:
See BOXED WARNINGS.
Estrogen and estrogen/progestin therapy have been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.
In the WHI estrogen-alone substudy, an increased risk of stroke was observed in women receiving CE compared to placebo (44 versus 32 per 10,000 women-years). (See CLINICAL STUDIES.)
In the CE/MPA substudy of the WHI study, an increased risk of CHD events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 versus 30 per 10,000 women-years). The increase in risk was observed in year one and persisted.
In the same substudy of the WHI study, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 versus 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted.( See CLINICAL STUDIES).
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA (0.625 mg/2.5mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one 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/MPA group and the placebo group in HERS, HERS II, and overall.
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
In the WHI estrogen-alone substudy, an increased risk of deep vein thrombosis was observed in women receiving CE compared to placebo (21 versus 15 per 10,000 women-years). The increase in deep vein thrombosis risk was observed during the first year. (See CLINICAL STUDIES.)
In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. (See CLINICAL STUDIES.)
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.
The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, 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 one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten 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 taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal 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
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