Pharmacokinetics

Transdermal administration of Estradiol Transdermal System Continuous Delivery (Once-Weekly) produces mean serum concentrations of estradiol comparable to those produced by premenopausal women in the early follicular phase of the ovulatory cycle. The pharmacokinetics of estradiol following application of the Estradiol Transdermal System Continuous Delivery (Once-Weekly) were investigated in 197 healthy postmenopausal women in six studies. In five of the studies Estradiol Transdermal System Continuous Delivery (Once-Weekly) was applied to the abdomen and in a sixth study application to the buttocks and abdomen were compared.

Adhesion

An open-label study of adhesion potentials of placebo transdermal systems that correspond to the 7.75 cm2 and 15.5 cm2 sizes of Estradiol Transdermal System Continuous Delivery (Once-Weekly) was conducted in 112 healthy women of 45 to 75 years of age. Each woman applied both transdermal systems weekly, on the upper outer abdomen, for 3 consecutive weeks. It should be noted that lower abdomen and upper quadrant of the buttock are the approved sites of application for Estradiol Transdermal System Continuous Delivery (Once-Weekly).

The adhesion assessment was done visually on Days 2, 4, 5, 6, 7 of each week of transdermal system wear. A total of 1,654 adhesion observations were conducted for 333 transdermal systems of each size.

Of these observations, approximately 90% showed essentially no lift for both the 7.75 cm2 and 15.5 cm2 transdermal systems. Of the total number of transdermal systems applied, approximately 5% showed complete detachment for each size. Adhesion potentials of the 23.25 cm2 and 31 cm2 sizes of transdermal systems (0.075 mg/day and 0.1 mg/day) have not been studied.

Clinical Studies

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 oral 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 3 below:

Table 3 RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHI*

* adapted from JAMA, 2002; 288:321-333 † nominal confidence intervals unadjusted for multiple looks and multiple comparisons ‡ includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer § a subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes ¶ not included in Global Index
Event	Relative Risk CE/MPA vs. Placebo at 5.2 Years (95% CI †)	Placebo n = 8102	CE/MPA n = 8506
		Absolute Risk per 10,000 Person-years
CHD events      Nonfatal MI      CHD death	1.29 (1.02-1.63) 1.32 (1.02-1.72) 1.18 (0.70-1.97)	30 23 6	37 30 7
Invasive breast cancer‡	1.26 (1.00-1.59)	30	38
Stroke	1.41 (1.07-1.85)	21	29
Pulmonary embolism	2.13 (1.39-3.25)	8	16
Colorectal cancer	0.63 (0.43-0.92)	16	10
Endometrial cancer	0.83 (0.47-1.47)	6	5
Hip fracture	0.66 (0.45-0.98)	15	10
Death due to causes other than the events above	0.92 (0.74-1.14)	40	37
Global Index§	1.15 (1.03-1.28)	151	170
Deep vein thrombosis¶	2.07 (1.49-2.87)	13	26
Vertebral fractures¶	0.66 (0.44-0.98)	15	9
Other osteoporotic fractures¶	0.77 (0.69-0.86)	170	131

For those outcomes included in the “global index,” 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 l0,000 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.)

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 and PRECAUTIONS, Geriatric Use.)

1. Cardiovascular disorders

Estrogen and estrogen/progestin therapy has 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

3. Dementia

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.)

4. Gallbladder disease

A 2-fold to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

5. Hypercalcemia

Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

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 permanently discontinued.

A. General

B. Patient Information

Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Estradiol Transdermal System Continuous Delivery (Once-Weekly).

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. Drug/Laboratory Test Interactions

1.

Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

2.

Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.

3.

Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG)) leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

4.

Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, and in oral formulations increased triglyceride levels.

5.

Impaired glucose tolerance.

6.

Reduced response to metyrapone test.

E. Carcinogenesis, 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.

F. Pregnancy

Estradiol Transdermal System Continuous Delivery (Once-Weekly) should not be used during pregnancy. (See CONTRAINDICATIONS.)

G. 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 Estradiol Transdermal System Continuous Delivery (Once-Weekly) is administered to a nursing woman.

H. Pediatric Use

Estrogen replacement therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established. Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short adult stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration. Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the normal pubertal process and induce gynecomastia. (See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION.)

I. Geriatric Use

There have not been sufficient numbers of geriatric patients involved in clinical studies utilizing Estradiol Transdermal System Continuous Delivery (Once-Weekly) to determine whether those over 65 years of age differ from younger subjects in their response to Estradiol Transdermal System Continuous Delivery (Once-Weekly).

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 2-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 BOXED WARNING and WARNINGS, Dementia.)

Post-marketing Experience

The following adverse reactions have been identified during post approval use of Estradiol Transdermal System Continuous Delivery (Once-Weekly): a few cases in which there were a combination of the symptoms of generalized hives or rash with swelling of the throat or eyelid edema. 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.

The following additional adverse reactions have been reported with estrogen and/or progestin therapy.

Application of the System

The adhesive side of the Estradiol Transdermal System Continuous Delivery (Once-Weekly) should be placed on a clean, dry area of the lower abdomen or the upper quadrant of the buttock. The Estradiol Transdermal System Continuous Delivery (Once-Weekly) should not be applied to or near the breasts. The sites of application must be rotated, with an interval of at least one 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 system. Application to areas where sitting would dislodge the system should also be avoided. The system should be applied immediately after opening the pouch and removing the protective liner. The 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 system lifts, apply pressure to maintain adhesion. In the event that a system should fall off, a new system should be applied for the remainder of the 7 day dosing interval. Only one system should be worn at any one time during the 7 day dosing interval. Swimming, bathing, or using a sauna while using the Estradiol Transdermal System Continuous Delivery (Once-Weekly) has not been studied, and these activities may decrease the adhesion of the system and the delivery of estradiol.

Removal of the System

Removal of the system should be done carefully and slowly to avoid irritation of the skin. Should any adhesive remain on the skin after removal of the system, allow the area to dry for 15 minutes. Then gently 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.

What is Estradiol Transdermal System Continuous Delivery (Once-Weekly)?

Estradiol Transdermal System Continuous Delivery (Once-Weekly) is a medicine that contains estrogen hormones.

What is Estradiol Transdermal System Continuous Delivery (Once-Weekly) used for?

Estradiol Transdermal System Continuous Delivery (Once-Weekly) is used after menopause to:

•

reduce moderate to severe hot flashes. Estrogens are hormones made by a woman’s ovaries. The ovaries normally stop making estrogens when a woman is between 45 to 55 years old. This drop in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause.”

 

When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild, and they will not need estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with Estradiol Transdermal System Continuous Delivery (Once-Weekly).

•

treat moderate to severe dryness, itching, and burning in or around the vagina. You and your healthcare provider should talk regularly about whether you still need treatment with Estradiol Transdermal System Continuous Delivery (Once-Weekly) to control these problems. If you use Estradiol Transdermal System Continuous Delivery (Once-Weekly) only to treat your dryness, itching, and burning in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.

•

treat certain conditions in which a young woman’s ovaries do not produce enough estrogen naturally.

•

help reduce your chances of getting osteoporosis (thin weak bones). Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use Estradiol Transdermal System Continuous Delivery (Once-Weekly) only to prevent osteoporosis from menopause, talk with your healthcare provider about whether a different treatment or medicine without estrogens might be better for you. You and your healthcare provider should talk regularly about whether you should continue with Estradiol Transdermal System Continuous Delivery (Once-Weekly).

 

Weight bearing exercise, like walking or running, and taking calcium and vitamin D supplements may also lower your chances of getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your healthcare provider before starting them.

Who should not use Estradiol Transdermal System Continuous Delivery (Once-Weekly)?

Do not start using Estradiol Transdermal System Continuous Delivery (Once-Weekly) if you:

•

have unusual vaginal bleeding.

•

currently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or had cancer, talk with your healthcare provider about whether you should take Estradiol Transdermal System Continuous Delivery (Once-Weekly).

•

had a stroke or heart attack in the past year.

•

currently have or have had blood clots.

•

currently have or have had liver problems.

•

are allergic to Estradiol Transdermal System Continuous Delivery (Once-Weekly) or any of its ingredients. See section titled “What are the ingredients in Estradiol Transdermal System Continuous Delivery (Once-Weekly)” at the end of this leaflet for a list of ingredients in Estradiol Transdermal System Continuous Delivery (Once-Weekly).

•

think you may be pregnant.

Tell your healthcare provider:

•

if you are breast-feeding. The hormone in Estradiol Transdermal System Continuous Delivery (Once-Weekly) can pass into your milk.

•

about all of your medical problems. Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.

•

about all the medicines you take. This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Estradiol Transdermal System Continuous Delivery (Once-Weekly) works. Estradiol Transdermal System Continuous Delivery (Once-Weekly) may also affect how your other medicines work.

•

if you are going to have surgery or will be on bed rest. You may need to stop taking estrogens.

How should I use Estradiol Transdermal System Continuous Delivery (Once-Weekly)?

Estradiol Transdermal System Continuous Delivery (Once-Weekly) is a patch that you wear on your skin. The estrogen in the Estradiol Transdermal System Continuous Delivery (Once-Weekly) passes through your skin. You must change your Estradiol Transdermal System Continuous Delivery (Once-Weekly) patch every 7 days (once a week). See the end of this leaflet for complete instructions on how to use Estradiol Transdermal System Continuous Delivery (Once-Weekly).

1.

Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you.

2.

Estrogens should be used at the lowest dose possible for your treatment only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 months to 6 months) about the dose you are taking and whether you still need treatment with Estradiol Transdermal System Continuous Delivery (Once-Weekly).

What are the possible side effects of estrogens?

Less common but serious side effects include:

•

Breast cancer

•

Cancer of the uterus

•

Stroke

•

Heart attack

•

Blood clots

•

Dementia

•

Gallbladder disease

•

Ovarian cancer

These are some of the warning signs of serious side effects:

•

Breast lumps

•

Unusual vaginal bleeding

•

Dizziness and faintness

•

Changes in speech

•

Severe headaches

•

Chest pain

•

Shortness of breath

•

Pains in your legs

•

Changes in vision

•

Vomiting

Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.

Common side effects include:

•

Headache

•

Breast pain

•

Irregular vaginal bleeding or spotting

•

Stomach/abdominal cramps, bloating

•

Nausea and vomiting

•

Hair loss

Other side effects include:

•

High blood pressure

•

Liver problems

•

High blood sugar

•

Fluid retention

•

Enlargement of benign tumors of the uterus (“fibroids”)

•

Vaginal yeast infection

These are not all the possible side effects of Estradiol Transdermal System Continuous Delivery (Once-Weekly). For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What can I do to lower my chances of a serious side effect with Estradiol Transdermal System Continuous Delivery (Once-Weekly)?

Talk with your healthcare provider regularly about whether you should continue using Estradiol Transdermal System Continuous Delivery (Once-Weekly).

•

If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you.

•

See your healthcare provider right away if you get vaginal bleeding while using Estradiol Transdermal System Continuous Delivery (Once-Weekly).

•

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

General information about safe and effective use of Estradiol Transdermal System Continuous Delivery (Once-Weekly)

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Estradiol Transdermal System Continuous Delivery (Once-Weekly) for conditions for which it was not prescribed. Do not give Estradiol Transdermal System Continuous Delivery (Once-Weekly) to other people, even if they have the same symptoms you have. It may harm them.

Keep Estradiol Transdermal System Continuous Delivery (Once-Weekly) out of the reach of children.

This leaflet provides a summary of the most important information about Estradiol Transdermal System Continuous Delivery (Once-Weekly). If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Estradiol Transdermal System Continuous Delivery (Once-Weekly) that is written for health professionals. You can get more information by calling the toll free number 1-877-446-3679 (1-877-4-INFO-RX).

What are the ingredients in Estradiol Transdermal System Continuous Delivery (Once-Weekly)?

The active ingredient of Estradiol Transdermal System Continuous Delivery (Once-Weekly) is estradiol. Estradiol Transdermal System Continuous Delivery (Once-Weekly) also contains propylene glycol, povidone, anhydrous colloidal silicon dioxide, pressure sensitive acrylic adhesive, copolymer foam, polyester film, and brown ink (yellow iron oxide pigment, red iron oxide pigment and carbon black pigment).

Instructions for Use

How and Where to Apply the Estradiol Transdermal System Continuous Delivery (Once-Weekly) Patch

Each Estradiol Transdermal System Continuous Delivery (Once-Weekly) patch is individually sealed in a protective pouch. To open the pouch, hold it with the Estradiol Transdermal System Continuous Delivery (Once-Weekly) name facing you. Tear from top to bottom using the right side tear notch. Tear from left to right using the top tear notch. Pull the pouch open. The Estradiol Transdermal System Continuous Delivery (Once-Weekly) patch is the peach colored foam round disk attached to the clear protective release liner.

Apply the sticky side of the Estradiol Transdermal System Continuous Delivery (Once-Weekly) patch to a clean, dry area of the lower stomach below your belly button or the top of the buttocks (see diagram below). Do not apply the Estradiol Transdermal System Continuous Delivery (Once-Weekly) patch to your breasts. The sites of application on the lower stomach and buttocks must be rotated, allowing at least one week between applications to the same site. The site selected should not be oily, damaged, or irritated. Avoid the waistline, since tight clothing may rub and remove the patch. Also, do not put the patch on areas where sitting would rub it off or loosen it. Apply the patch right after opening the pouch and removing the protective liner. Press the patch firmly in place with your fingers for about 10 seconds. Make sure that it sticks all over, especially around the edges.

The Estradiol Transdermal System Continuous Delivery (Once-Weekly) patch should be worn continuously for one week. You may wish to try different sites when putting on a new patch, to find ones that are most comfortable for you and where clothing will not rub on the patch or loosen it.

When to Apply the Estradiol Transdermal System Continuous Delivery (Once-Weekly)?

The Estradiol Transdermal System Continuous Delivery (Once-Weekly) patch should be changed once weekly. Remove the used patch. Carefully fold it in half so that it sticks to itself because used patches still contain active hormones and discard it. Any adhesive that might remain on your skin can be easily rubbed off. Then place the new Estradiol Transdermal System Continuous Delivery (Once-Weekly) patch on a different skin site. (The same skin site should not be used again for at least one week after removal of the patch.)

Contact with water when you are bathing, swimming, or showering may affect the patch. If the patch falls off, the same patch may be reapplied to another area of the lower abdomen. Make sure that there is good contact, especially around the edges. If the patch will not stick completely to your skin, put a new patch on a different area of the lower abdomen. Do not apply two patches at the same time.

Estrogens should be used only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 months to 6 months) about whether you still need treatment with Estradiol Transdermal System Continuous Delivery (Once-Weekly).

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

REVISED AUGUST 2012
PL:ETS:R14