Estradiol Transdermal System

Alora is indicated in:

1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
4. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered 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 1500 mg/day of elemental calcium to remain in neutral calcium balance. 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.

Alora (Estradiol Transdermal System, USP) 0.025 mg/day. Each 9 cm² system contains 0.77 mg of estradiol, USP for nominal delivery of 0.025 mg of estradiol per day when dosed in a twice weekly regimen.

NDC 52544-884-08 Patient Calendar Box of 8 Systems

Alora (Estradiol Transdermal System, USP) 0.05 mg/day. Each 18 cm² system contains 1.5 mg of estradiol, USP for nominal delivery of 0.05 mg of estradiol per day when dosed in a twice weekly regimen.

NDC 52544-471-08 Patient Calendar Box of 8 Systems

Alora (Estradiol Transdermal System, USP) 0.075 mg/day.  Each 27 cm² system contains 2.3 mg of estradiol, USP for nominal delivery of 0.075 mg of estradiol per day when dosed in a twice weekly regimen.

NDC 52544-472-08 Patient Calendar Box of 8 Systems

Alora (Estradiol Transdermal System, USP) 0.1 mg/day. Each 36 cm² system contains 3.1 mg of estradiol, USP for nominal delivery of 0.1 mg of estradiol per day when dosed in a twice weekly regimen.

NDC 52544-473-08 Patient Calendar Box of 8 Systems

Store at 20-25°C (68-77°F). [See USP controlled room temperature.]

Do not store unpouched. Apply immediately upon removal from the protective pouch.

Discard used Alora in household trash in a manner that prevents accidental application or ingestion by children, pets, or others.

Keep out of reach of children.

For all medical inquiries contact: ACTAVIS Medical Communications, Parsippany, NJ 07054, 1-800-272-5525.

Distributed By: Actavis Pharma, Inc., Parsippany, NJ 07054 USA. Revised: Aug 2014

See BOXED WARNINGS.

The use of unopposed estrogens in women who have a uterus is associated with an increased risk of endometrial cancer.

Cardiovascular Disorders

Estrogen and estrogen/progestin therapies 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.

Coronary heart disease and stroke. In the Women's Health Initiative (WHI) study an increased risk of stroke was observed in women receiving CE compared to placebo.

In the CE/MPA substudy of WHI an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs. 30 per 10,000 women-years). The increase in risk was observed in Year 1 and persisted.

In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs. 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted. [see CLINICAL PHARMACOLOGY and 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/2.5 mg 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. Participation in an open label extension of the original HERS trial (HERS II) was agreed to by 2,321 women. 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.

Venous thromboembolism (VTE). In the Women's Health Initiative (WHI) study, an increased risk of deep vein thrombosis was observed in women receiving CE compared to placebo.

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 PHARMACOLOGY and 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.

Malignant Neoplasms.

1. Endometrial cancer. 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 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 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 therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
2. Breast cancer. The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the WHI substudy of CE/MPA [see CLINICAL PHARMACOLOGY and Clinical Studies]. The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration.

The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/ progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about 5 years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy.

In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01 - 1.54), and the overall absolute risk was 41 vs. 33 cases per 10,000 women-years, for CE/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 vs. 25 cases per 10,000 women-years, for CE/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 vs. 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.

The use of 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 self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

Dementia

In the estrogen plus progestin WHIMS, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to CE/MPA or placebo. 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 vs. 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 and Clinical Studies and PRECAUTIONS, Geriatric Use].

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 should be 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 discontinued.

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.

Pharmacodynamics

There are no pharmacodynamic data for Menostar.

Pharmacokinetics

The bioavailability of estradiol following application of a Menostar transdermal system, relative to that of a transdermal system delivering 25 mcg per day, was investigated in 18 healthy postmenopausal women, mean age 66 years (range 60 to 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 13.7pg/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 per 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.

Figure 1: Mean Uncorrected Serum 17ß-Estradiol Concentrations vs. Time Profile Following Application of the Menostar Transdermal System and the Climara® 6.5 cm² Transdermal System

Table 2 provides a summary of estradiol pharmacokinetic parameters determined during evaluation of the Menostar transdermal system using baseline uncorrected serum concentrations.

Summary of Estradiol Pharmacokinetic Parameters (Abdomen Application)

Table 2: Summary of Estradiol Pharmacokinetic Parameters (Abdomen Application)

Pharmacokinetic parameters are expressed in geometric 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 cm² 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 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 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 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.

In a Menostar transdermal system pharmacokinetic study with 18 postmenopausal women, no patches failed to adhere during the one week application period

Clinical Studies

Effects On Bone Mineral Density

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 of age, with an intact uterus were enrolled in the study. All patients received supplemental calcium and vitamin D.

At lumbar spine Menostar increased BMD by 2.3 percent after 1 year and 3 percent after 2 years compared with a 0.5 percent increase after 1 and 2 years of treatment with placebo. At the hip Menostar increased BMD by 0.9 percent after one year and 0.84 percent after two years compared with a mean decrease of 0.22 percent after 1 year and 0.71 percent after 2 years of placebo treatment. The changes in BMD from baseline were statistically significantly (p < 0.001) greater during treatment with Menostar than during treatment with placebo for both the spine and hip after 1 and 2 years (Table 3).

Table 3: Mean Percent BMD Change from Baseline in Lumbar Spine and Total Hip (Full Analysis Set)

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 4).

Table 4: Mean Percent Change in Lumbar Spine and Total Hip BMD at 24 months by Subgroups of Baseline Estradiol Level ( < 5 pg/mL, 5 pg/mL)

Women's Health Initiative Studies

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two 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 CHD (defined as nonfatal MI, silent MI and CHD death), 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 causes. These substudies did not evaluate the effects of CEalone or CE plus MPA on menopausal symptoms.

The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risk and benefits of estrogen-alone in predetermined primary endpoints.

Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79: 75.3 percent white, 15.1 percent black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 7.1 years, are presented in Table 5.

Table 5: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI

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 7 fewer hip fractures.9 The absolute excess risk of events included in the “global index” was a non-significant 5 events per 10,000 women years. There was no difference between the groups in terms of all-cause mortality.

No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years. See Table 5.

Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in the distribution of stroke subtype and severity, including fatal strokes, in women receiving estrogen-alone compared to placebo. Estrogenalone increased the risk of ischemic stroke, and this excess risk was present in all subgroups of women examined.10 See Table 5.

Timing of initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)].

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 reduction per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.5 percent Black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 6. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

Table 6: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years

Timing of initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI 0.44-1.07)].

Women's Health Initiative Memory Study

The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in the study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see WARNINGS AND PRECAUTIONS, and Use in Specific Populations].

The WHIMS estrogen plus progestin ancillary study enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years of age; and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in thestudy included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see WARNINGS AND PRECAUTIONS, and Use in Specific Populations].

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see WARNINGS AND PRECAUTIONS, and Use in Specific Populations]

REFERENCES

8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958.

9. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women's Health Initiative Randomized Trial. J Bone Miner Res. 2006;21:817-828.

10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation. 2006;113:2425-2434.

MENOSTAR
(Men-o-star)
(estradiol) Transdermal System

Read this Patient Information before you start using MENOSTAR and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.

What is the most important information I should know about MENOSTAR (an estrogen hormone)?

• Using estrogen-alone may increase your chance of getting cancer of the uterus (womb). Report any unusual vaginal bleeding right away while you are using MENOSTAR. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
• Do not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function).
• Using estrogen-alone may increase your chances of getting strokes or blood clots.
• Using estrogen-alone may increase your chance of getting dementia, based on a study of women age 65 years of age or older.
• Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or dementia.
• Using estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots.
• Using estrogens with progestins may increase your chance of getting dementia, based on a study of women age 65 years of age or older.
• You and your healthcare provider should talk regularly about whether you still need treatment with MENOSTAR.

What is MENOSTAR?

MENOSTAR is a prescription medicine patch (Transdermal System) that contains estradiol (an estrogen hormone).

What is MENOSTAR used for?

MENOSTAR is used after menopause to:

• Help reduce your chances of getting osteoporosis (thin weak bones) If you use MENOSTAR only to prevent osteoporosis due to menopause, talk with your healthcare provider about whether a different treatment or medicine without estrogens might be better for you.

Who should not use MENOSTAR?

Do not start using MENOSTAR if you:

• have unusual vaginal bleeding
  Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
• currently have or have had certain cancers
  Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use MENOSTAR.
• had a stroke or heart attack
• currently have or have had blood clots
• currently have or have had liver problems
• have been diagnosed with a bleeding disorder
• are allergic to MENOSTAR or any of its ingredients See the list of ingredients in MENOSTAR at the end of this leaflet.
• think you may be pregnant
  MENOSTAR is not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not use MENOSTAR if the test is positive and talk to your healthcare provider.

What should I tell my healthcare provider before I use MENOSTAR?

Before you use MENOSTAR, tell your healthcare provider if you:

• have any unusual vaginal bleeding
  Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
• have any other medical conditions
  Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, angioedema (swelling of face and tongue), or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.
• are going to have surgery or will be on bed rest
  Your healthcare provider will let you know if you need to stop using MENOSTAR.
• are breastfeeding
  The hormone in MENOSTAR can pass into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how MENOSTAR works. MENOSTAR may also affect how your other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I use MENOSTAR?

For detailed instructions, see the step-by-step instructions for using MENOSTAR at the end of this Patient Information.

• Use MENOSTAR exactly as your healthcare provider tells you to use it.
• MENOSTAR is for skin use only.
• Change your MENOSTAR patch 1 time each week or every 7 days.
• Apply your MENOSTAR patch to a clean, dry area on your lower abdomen or buttocks. This area must be clean, dry, and free of powder, oil or lotion for your patch to stick to your skin.
• Apply your MENOSTAR patch to a different area of your abdomen or your buttocks each time.
• Do not use the same application site 2 times in the same week.
• Do not apply MENOSTAR to your breasts.
• If you forget to apply a new MENOSTAR patch, you should apply a new patch as soon as possible.
• You and your healthcare provider should talk regularly (every 3 to 6 months) about the dose you are using and whether you still need treatment with MENOSTAR.

How to Change MENOSTAR.

• When changing MENOSTAR, peel off the used patch slowly from the skin.
• After removal of MENOSTAR, people usually have either no adhesive residue or light adhesive residue. If any adhesive residue remains on your skin after removing the patch, allow the area to dry for 15 minutes. Then, gently rub the area with an oil-based cream or lotion to remove the adhesive from your skin.
• Keep in mind, the new patch must be applied to a different skin area of your abdomen or buttocks. This area must be clean, dry, and free of powder, oil or lotion. The same site should not be used again for at least 1 week after removal of the patch.

What are the possible side effects of MENOSTAR?

Side effects are grouped by how serious they are and how often they happen when you are treated.

Serious, but less common side effects include:

• heart attack
• stroke
• blood clots
• dementia
• breast cancer
• cancer of the lining of the uterus (womb)
• cancer of the ovary
• high blood pressure
• high blood sugar
• gallbladder disease
• liver problems
• changes in your thyroid hormone levels
• enlargement of benign tumors of the uterus (“fibroids”)

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

• new breast lumps
• unusual vaginal bleeding
• changes in vision or speech
• sudden new severe headaches
• severe pains in your chest or legs with or without shortness of breath, weakness and fatigue
• Less serious, but common side effects include:
• headache
• breast tenderness or pain
• irregular vaginal bleeding or spotting
• stomach or abdominal cramps, bloating
• nausea and vomiting
• hair loss
• fluid retention
• vaginal yeast infection
• redness or irritation at the patch placement site

These are not all the possible side effects of MENOSTAR. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or does not go away.

You may report side effects to Bayer Healthcare Pharmaceuticals at 1-888-842-2937 or to FDA at 1-800-FDA-1088.

What can I do to lower my chances of a serious side effect with MENOSTAR?

• Talk with your healthcare provider regularly about whether you should continue using MENOSTAR.
• If you have a uterus, talk with your healthcare provider about whether the addition of a progestin is right for you.
• The addition of a progestin is generally recommended for women with a uterus to reduce the chance of getting cancer of the uterus (womb).
• See your healthcare provider right away if you get vaginal bleeding while using MENOSTAR.
• Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else.
• If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often.
• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances of getting heart disease.

Ask your healthcare provider for ways to lower your chances of getting heart disease.

How should I store and throw away used MENOSTAR?

• Store MENOSTAR at room temperature 68°F to 77°F (20°C to 25°C).
• Do not store MENOSTAR patches outside of their pouches. Apply immediately upon removal from the protective pouch.
• Used patches still contain estrogen. To throw away the patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place this container in the trash. Used patches should not be flushed in the toilet.

Keep MENOSTAR and all medicines out of the reach of children.

General information about the s afe and effective us e of MENOSTAR.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use 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.

This leaflet summarizes the most important information about MENOSTAR. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about MENOSTAR that is written for health professionals.

For more information, go to www.menostar-us.com or call Bayer Healthcare Pharmaceuticals Inc. at 1-888-842-2937.

What are the ingredients in MENOSTAR?

Active ingredient: estradiol

Inactive ingredients: acrylate copolymer adhesive, fatty acid esters, and polythylene backing.

Instructions for Use

MENOSTAR
(Men-o-star) (estradiol transdermal system)

Read this Patient Information before you start using MENOSTAR and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.

You will need the following supplies : See Figure A

Figure A

Step 1: Pick the days you will change your MENOSTAR.

• You will need to change your patch 1 time each week or every 7 days.

Step 2. Remove the MENOSTAR patch from the pouch.

• Remove the patch from its protective pouch by tearing at the notch (do not use scissors). See Figure B
• Do not remove your patch from the protective pouch until you are ready to apply it.

Figure B

Step 3. Remove the adhesive liner. See Figure C

• You will see that MENOSTAR is an oval shaped clear patch that is attached to a thick, hardplastic adhesive liner and covered by a clear, plastic film. See Figure C
• To apply your patch you must first remove the protective, clear plastic film that is attached to the clear thicker plastic backing. See Figure D
• There is a silver foil-sticker attached to the inside of the pouch. Do not remove the silver foil sticker from the pouch. See Figure E

Figure C, D and Figure E

Step 4. Placing the patch on your skin.

• Apply the sticky side of the patch to 1 of the areas of skin shown below. (See Figure F and Figure G)
• Do not touch the sticky side of the patch with your fingers.

Figure F and G

Note:

• Avoid the waistline, since clothing and belts may cause the patch to be rubbed off.
• Do not apply MENOSTAR to your breasts.
• Only apply MENOSTAR to skin that is clean, dry, and free of any powder, oil, or lotion.
• You should not apply the patch to injured, burned, or irritated skin, or areas with skin conditions (such as birth marks, tattoos, or that is very hairy).

Step 5. Press the patch firmly onto your skin.

• Press the patch firmly in place with your fingers for at least 10 seconds.
• Rub the edges of the patch to make sure that it will stick to your skin. (See Figure H)

Figure H

Note:

• Contact with water while you are swimming, using a sauna, bathing, or showering may cause the patch to fall off.
• If your patch falls off reapply it. If you cannot reapply the patch, apply a new patch to another area (See Figure F and Figure G) and continue to follow your original application schedule.
• If you stop using your MENOSTAR patch or forget to apply a new patch as scheduled, you may have spotting, or bleeding, or your symptoms may come back.

Step 6: Throwing away your used patch.

• When it is time to change your patch, remove the old patch before you apply a new patch.
• To throw away the patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place this container in the trash. Used patches should not be flushed in the toilet.

This Patient Information and Instructions for Use have been approved by the U.S Food and Drug Administration.

Estradiol is a form of estrogen, a female sex hormone that regulates many processes in the body.

Estradiol transdermal skin patches are used to treat certain symptoms of menopause such as hot flashes, and vaginal dryness, burning, and irritation. This medication is also used to prevent postmenopausal osteoporosis, or to treat ovarian disorders.

Estradiol transdermal may also be used for purposes not listed in this medication guide.

Estradiol can harm an unborn baby or cause birth defects. Do not use if you are pregnant.

You should not use this medication if you have any of the following conditions: liver disease, a bleeding disorder, unusual vaginal bleeding, a history of breast or uterine cancer, or if you have ever had a heart attack, stroke, or a blood clot.

Estradiol may increase your risk of developing a condition that may lead to uterine cancer. Your doctor may prescribe a progestin while you are using estradiol, to help lower this risk. Report any unusual vaginal bleeding right away.

Long-term use of estradiol may increase your risk of breast cancer, heart attack, stroke, or blood clot. Talk with your doctor about your individual risks before using estradiol transdermal long term.

Have regular physical exams and self-examine your breasts for lumps on a monthly basis while using estradiol transdermal.

Estradiol transdermal should not be used to prevent heart disease, stroke, or dementia, because this medicine may actually increase your risk of developing these conditions.

The following serious adverse reactions are discussed elsewhere in the labeling:

• Cardiovascular Disorders [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
• Malignant Neoplasms [see BOXED WARNING, WARNINGS AND PRECAUTIONS]

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.

Menostar was investigated in a 2-year double blind, placebo-controlled, multicenter study in the United States. A total of 417 postmenopausal women (208 women on Menostar, 209 on placebo) 60 to 80 years old, with an intact uterus were enrolled in the study. At 24 months, 189 women remained in the Menostar group and 186 remained in the placebo group. Adverse events with an incidence of ≥ 5 percent in the Menostar 14 mcg group and greater than those reported in the placebo group are listed in Table 1.

Table 1: Summary of Most Frequently Reported Treatment Emergent Adverse Reactions ( ≥ 5 percent) by Treatment Groups

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of the Climara transdermal system and the Menostar transdermal system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Genitourinary System

Changes in bleeding pattern, pelvic pain

Breast

Breast cancer, breast pain, breast tenderness

Cardiovascular

Changes in blood pressure, palpitations, hot flashes

Gastrointestinal

Vomiting, abdominal pain, abdominal distension, nausea

Skin

Alopecia, hyperhidrosis, night sweats, urticaria, rash

Eyes

Visual disturbances, contact lens intolerance

Central Nervous System

Depression, migraine, paresthesia, dizziness, anxiety, irritability, mood swings, nervousness, insomnia, headache

Miscellaneous

Edema, fatigue, menopausal symptoms, weight increased, application site reaction, anaphylactic reaction

Read the entire FDA prescribing information for Menostar (Estradiol Transdermal System)

You should not use this medication if you are allergic to estradiol, if you are pregnant, or if you have:

• liver disease;
• a bleeding or blood-clotting disorder;
• a history of heart attack, stroke, or blood clot;
• unusual vaginal bleeding that a doctor has not checked; or
• any type of breast, uterine, or hormone-dependent cancer.

To make sure you can safely use estradiol transdermal, tell your doctor about all of your medical conditions, especially:

• heart disease;
• risk factors for coronary artery disease (such as diabetes, smoking, being overweight, having high blood pressure or high cholesterol, having a family history of coronary artery disease, or if you have had a hysterectomy);
• hereditary angioedema (an immune system disorder);
• a history of jaundice caused by pregnancy or birth control pills;
• a thyroid disorder;
• kidney disease;
• asthma;
• epilepsy or other seizure disorder;
• migraines;
• endometriosis or uterine fibroid tumors;
• lupus;
• gallbladder disease; or
• high levels of calcium in your blood.

Estradiol may increase your risk of developing a condition that may lead to uterine cancer. Your doctor may prescribe a progestin to take while you are using estradiol, to help lower this risk. Report any unusual vaginal bleeding right away.

Long-term use of estradiol may increase your risk of breast cancer, heart attack, stroke, or blood clot. Talk with your doctor about your individual risks before using estradiol transdermal long term.

FDA pregnancy category X. This medication can harm an unborn baby or cause birth defects. Do not use estradiol if you are pregnant. Tell your doctor right away if you become pregnant during treatment. Use effective birth control while you are using this medication.

Estradiol can pass into breast milk and may harm a nursing baby. This medication may also slow breast milk production. Do not use if you are breast-feeding a baby.