|DRUGS INDEX | MANUFACTURERS INDEX | ANATOMY | GEOGRAPHY | USA STATISTICS | CHINA STATISTICS | RELIGION | JOBS|
Menostar Transdermal System (Berlex)
- Drugs index
Menostar, estradiol transdermal system, is designed to provide nominal in vivo delivery of 14 mcg 17(beta)-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 2 , and contains 1 mg of estradiol USP.
Estradiol USP (17(beta)-estradiol) is a white, crystalline powder, chemically described as estra-1,3,5(10)-triene-3, 17(beta)-diol. It has an empirical formula of C 18 H 24 O 2 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 (1) a translucent polyethylene film, and (2) an acrylate adhesive matrix containing estradiol USP. A protective liner (3) 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 17(beta)-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 17(beta)-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.
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.
The estimated estradiol daily delivery rate for Climara 6.5 cm 2 is quoted from the Climara labeling.
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 gut 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 3.0% 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 0.90% 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 >/= 5.0 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).
Women's Health Initiative Studies
The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated estrogens (CE) per day alone or the use of 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) 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 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 4 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 mortal-ity. (See BOXED WARNINGS , WARNINGS , and PRECAUTIONS .)
Women's Health Initiative Studies
Women's Health Initiative Memory Study The Women's Health Initiative Memory Study (WHIMS), a 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 and WARNINGS , Dementia .)
INDICATIONS AND USAGE
Menostar is indicated for the prevention of postmenopausal osteoporosis. Therapy should be considered only for women at significant risk of osteoporosis. 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.
Estrogen therapy reduces bone resorption and retards or halts postmenopausal bone loss. Studies have shown a risk ratio of about 0.4 for hip and wrist fractures in women whose estrogen therapy was begun within a few years of menopause, compared to women taking calcium and vitamin D alone. Studies also suggest that estrogen reduces the rate of vertebral fractures. Even when started as late as 6 years after menopause, estrogen reduces further loss of bone mass for as long as treatment is continued. When estrogen therapy is discontinued, bone mass declines at a rate comparable to the immediate post-menopausal period.
Data from the Women's Health Initiative study showed that use of estrogen (dose equivalent to 0.625 CE) resulted in about 6 less hip fractures per 10,000 women/years, compared to use of placebo (risk ratio about 0.6).
Menostar should not be used in women with any of the following conditions:
See BOXED WARNINGS .
1. Cardiovascular disorders.
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.
2. Malignant neoplasms
In the Women's Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n=2,229) and 21 women in the placebo group (0.9%, n=2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 - 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY , Clinical Studies and PRECAUTIONS , Geriatric Use .) It is unknown whether these findings apply to estrogen alone therapy.
4. Gallbladder disease
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
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.
6. 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 discontinued.
B. PATIENT INFORMATION
Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Menostar.
C. LABORATORY TESTS
Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g. estradiol, FSH).
D. CARCINOGENESES, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY
Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS , WARNINGS and PRECAUTIONS .)
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.
Menostar should not be used during pregnancy. (See CONTRAINDICATIONS .)
F. NURSING MOTHERS
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Menostar is administered to a nursing woman.
G. Pediatric Use
The safety and efficacy of Menostar in pediatric patients has not been established.
H. Geriatric Use
A total of 417 postmenopausal women 61-79 years old, with an intact uterus, participated in the osteoporosis trial. More than 50% of women receiving study drug, were considered geriatric (65 years or older). Efficacy in older (>/= 65 years) and younger (<65 years) postmenopausal women in the osteoporosis treatment trial was comparable both at 12 and 24 months. Safety in older (>/= 65 years) and younger (<65 years) postmenopausal women in the osteoporosis treatment trial was also comparable throughout the study.
In the Women's Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n=3,729) were 65 to 74 while 18% (n=803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer's disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See WARNINGS , Dementia .)
It is unknown whether these findings apply to estrogen alone therapy.
See BOXED WARNINGS , WARNINGS and PRECAUTIONS .
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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
The following additional adverse reactions have been reported with estrogens:
Overdosage of estrogen may cause nausea, and withdrawal bleeding may occur in females. Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing drug products by young children.
DOSAGE AND ADMINISTRATION
Menostar should only be prescribed to postmenopausal women who are at significant risk of osteoporosis. Non-estrogen medications should be carefully considered. 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.
When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be used, to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
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. (see BOXED WARNINGS and WARNINGS ).
Application of the System
The adhesive side of the Menostar transdermal system should be placed on a clean, dry area of the lower abdomen. 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 particular site. The area selected should not be oily, damaged, or irritated. The waistline should be avoided, since tight clothing may rub and remove the transdermal system. Application to areas where sitting would dislodge the transdermal system should also be avoided. The transdermal system should be applied immediately after opening the pouch and removing the protective liner. The transdermal system should be pressed firmly in place with the fingers for about 10 seconds, making sure there is good contact, especially around the edges. If the transdermal system lifts, apply pressure to maintain adhesion. In the event that a transdermal system should fall off, a new transdermal 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 transdermal system and the delivery of estradiol.
Removal of the 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.
Menostar (estradiol transdermal system), 14 mcg/day -- each 3.25 cm 2 system contains 1 mg of estradiol USP
Do not store above 86°F (30°C). Do not store unpouched. Apply immediately upon removal from the protective pouch.
Menostar® (Men-[omacr ]-star)
(estradiol transdermal system)
Read this before you start taking Menostar and read what you get each time you refill Menostar. There may be new information. This information does not take the place of talking to your health care provider about your medical condition or your treatment.
What is Menostar?
Menostar is a medicine that contains estrogen hormones.
What is Menostar used for?
Menostar is used after menopause to:
Who should not use Menostar?
Do not start using Menostar if you:
Tell your health care provider:
How should I use Menostar
What are the possible side effects of estrogens?
Less common but serious side effects include:
These are some of the warning signs of serious side effects:
Call your health care provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.
Common side effects include:
Other side effects include:
These are not all the possible side effects of Menostar. For more information, ask your health care provider or pharmacist.
What can I do to lower my chances of a serious side effect with Menostar?
General information about safe and effective use of Menostar
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Menostar for conditions for which it was not prescribed. Do not give Menostar to other people, even if they have the same symptoms you have. It may harm them.
Keep Menostar out of the reach of children.
This leaflet provides a summary of the most important information about Menostar. If you would like more information, talk with your health care provider or pharmacist. You can ask for information about Menostar that is written for health professionals. You can get more information by calling the toll free number (1-888-237-5394) or visit www.menostar-us.com.
What are the ingredients in Menostar?
The active ingredient of Menostar is estradiol. Menostar also contains acrylate copolymer adhesive, fatty acid esters, and polyethylene backing. Menostar does not contain latex.
Instructions for Use
How and where do I apply the Menostar patch
© 2004, Berlex, Inc. All rights reserved.
Berlex, Montville NJ 07045
Manufactured by 3m Pharmaceuticals, St. Paul, MN 55144
6006002 (3M # 629300) December 2004