Rx Only

The following prescribing information is based on official labeling in effect November 2000.

Vivelle-Dot™ (estradiol transdermal system) contains estradiol in a multipolymeric adhesive. The system is designed to release 17(beta)-estradiol continuously upon application to intact skin.

Four systems are available to provide nominal in vivo delivery of 0.0375, 0.05, 0.075, or 0.1 mg of estradiol per day via skin of average permeability. Each corresponding system having an active surface area of 3.75, 5.0, 7.5, or 10.0 cm ² contains 0.585, 0.78, 1.17, or 1.56 mg of estradiol USP, respectively. The composition of the systems per unit area is identical.

Estradiol USP (17(beta)-estradiol) is a white, crystalline powder, chemically described as estra-1,3,5 (10)-triene-3,17(beta)-diol.

The structural formula is

The molecular formula of estradiol is C ₁₈ H ₂₄ O ₂ . The molecular weight is 272.39.

The Vivelle-Dot™ system comprises three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a translucent polyolefin film (2) an adhesive formulation containing estradiol, acrylic adhesive, silicone adhesive, oleyl alcohol, povidone and dipropylene glycol, and (3) a polyester release liner which is attached to the adhesive surface and must be removed before the system can be used.

The active component of the system is estradiol. The remaining components of the system are pharmacologically inactive.

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 µg 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.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism and estrogen replacement therapy acts to reduce the elevated levels of these hormones seen in postmenopausal women.

The Vivelle-Dot™ system provides systemic estrogen replacement therapy. Estrogen receptors have been identified in tissues of the reproductive tract, breast, pituitary, hypothalamus, liver, and bone of women. Among numerous effects, estradiol is largely responsible for the development and maintenance of the female reproductive system and secondary sex characteristics. By a direct action, it causes growth and development of the vagina, uterus, and fallopian tubes. With other hormones, such as pituitary hormones and progesterone, it causes enlargement of the breasts through promotion of ductal growth, stromal development, and the accretion of fat. Estrogens contribute to the shaping of the skeleton, to the maintenance of tone and elasticity of urogenital structures, to changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination, to the growth of axillary and pubic hair, and pigmentation of the nipples and genitals.

Estrogens are intricately involved with other hormones, especially progesterone, in the processes of the ovulatory menstrual cycle and pregnancy, and affect the release of pituitary gonadotropins.

Loss of ovarian estradiol secretion after menopause can result in instability of thermoregulation, causing hot flushes associated with sleep disturbance and excessive sweating, and urogenital atrophy, causing dyspareunia and urinary incontinence. Estradiol replacement therapy alleviates many of these symptoms of estradiol deficiency in the menopausal woman.

The skin metabolizes estradiol only to a small extent. In contrast, orally administered estradiol is rapidly metabolized by the liver to estrone and its conjugates, giving rise to higher circulating levels of estrone than estradiol. Therefore, transdermal administration produces therapeutic plasma levels of estradiol with lower circulating levels of estrone and estrone conjugates and requires smaller total doses than does oral therapy.

Absorption

In a multiple-dose study consisting of three consecutive patch applications of the original formulation (Vivelle® system) which was conducted in 17 healthy, postmenopausal women, blood levels of estradiol and estrone were compared following application of these units to sites on the abdomen and buttocks in a crossover fashion. Patches that deliver nominal estradiol doses of approximately 0.0375 mg/day and 0.1 mg/day were applied to abdominal application sites while the 0.1 mg/day doses were also applied to sites on the buttocks. These systems increased estradiol levels above baseline within 4 hours and maintained respective mean levels of 25 and 79 pg/mL above baseline following application to the abdomen; slightly higher mean levels of 88 pg/mL above baseline were observed following application to the buttocks. At the same time, increases in estrone plasma concentrations averaged about 12 and 50 pg/mL, respectively, following application to the abdomen and 61 pg/mL for the buttocks. While plasma concentrations of estradiol and estrone remained slightly above baseline at 12 hours following removal of the patches in this study, results from another study show these levels to return to baseline values within 24 hours following removal of the patches.

The graph illustrates the mean plasma concentrations of estradiol at steady-state during application of these patches at four different dosages.

The corresponding pharmacokinetic parameters are summarized in the table below.

The original formulation that was tested in clinical trials has been revised to reduce the patch sizes and the revised formulation was shown to be bioequivalent to the original formulation.

Distribution

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.

Estradiol and other naturally occurring estrogens are bound mainly to sex hormone binding globulin (SHBG), and to lesser degree to albumin.

Metabolism

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 portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Excretion

Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The half-life values calculated after dosing with the Vivelle-Dot™ systems ranged from 5.9 to 7.7 hours. After removal of the transdermal systems, serum concentrations of estradiol and estrone returned to baseline levels within 24 hours.

Special Populations

The Vivelle-Dot™ systems were investigated in postmenopausal women. No other special populations of volunteers were investigated.

Drug Interactions

No drug interaction studies were conducted with the Vivelle-Dot™ systems since estradiol is well characterized.

The Vivelle-Dot™ (estradiol transdermal system) is indicated in the following:

1. Treatment of moderate-to-severe vasomotor symptoms associated with the menopause. There is no adequate evidence that estrogens are effective for nervous symptoms or depression which might occur during menopause and they should not be used to treat these conditions.
2. Treatment of vulval and vaginal atrophy.
3. Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.

CONTRAINDICATIONS

Patients with known hypersensitivity to any of the components of the therapeutic system should not use the Vivelle-Dot™ system.

Estrogens should not be used in individuals with any of the following conditions:

1. Known or suspected pregnancy (see Boxed Warning ). Estrogen may cause fetal harm when administered to a pregnant woman.
2. Undiagnosed abnormal genital bleeding.
3. Known or suspected cancer of the breast.
4. Known or suspected estrogen-dependent neoplasia.
5. Active thrombophlebitis or thromboembolic disorders, or a documented history of these conditions.

1. Induction of malignant neoplasms.
   Breast Cancer.
   While some epidemiologic studies suggest a very modest increase in breast cancer risk for estrogen alone users versus non-users, other studies have not shown any increased risk. The addition of progestin to estrogen may increase the risk for breast cancer over that noted in non-hormone users more significantly (by about 24-40%), although this is based solely on epidemiologic studies, and definitive conclusions await prospective, controlled clinical trials.
   Women without a uterus who require hormone replacement should receive estrogen-alone therapy, and should not be exposed unnecessarily to progestins. Women with a uterus who are candidates for short-term combination estrogen/progestin therapy (for relief of vasomotor symptoms) are not felt to be at a substantially increased risk for breast cancer. Women with a uterus who are candidates for long-term use of estrogen/progestin therapy should be advised of potential benefits and risks (including the potential for an increased risk of breast cancer). All women should receive yearly breast exams by a health-care provider and perform monthly breast self examinations. In addition, mammography examinations should be scheduled as suggested by providers based on patient age and risk factors. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in nonusers and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the 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 five to 10 years or more. In three studies, persistence of risk was demonstrated for 8 to over 15 years after cessation of estrogen treatment. In one study, a significant decrease in the incidence of endometrial cancer occurred six months after estrogen withdrawal. Concurrent progestin therapy may offset this risk, but the overall health impact in postmenopausal women is not known (see PRECAUTIONS ).
   Estrogen therapy during pregnancy is associated with an increased risk of fetal congenital reproductive tract disorders. In female offspring, there is an increased risk of vaginal adenosis, squamous cell dysplasia of the cervix, and clear cell vaginal cancer later in life; in males, urogenital and possibly testicular abnormalities. Although some of these changes are benign, it is not known whether they are precursors of malignancy.
2. Gallbladder disease. Two studies have reported a 2- to 4-fold increase in the risk of surgically confirmed gallbladder disease in postmenopausal women receiving oral estrogen replacement therapy, similar to the 2-fold increase previously noted in users of oral contraceptives.
3. Cardiovascular disease. 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. These risks cannot necessarily be extrapolated from men to women. However, to avoid the theoretical cardiovascular risk to women caused by high estrogen doses, the dose for estrogen replacement therapy should not exceed the lowest effective dose.
4. Elevated blood pressure. Occasional blood pressure increases during estrogen replacement therapy have been attributed to idiosyncratic reactions to estrogens. More often, blood pressure has remained the same or has dropped.
   Postmenopausal estrogen use does not increase the risk of stroke. Nonetheless, blood pressure should be monitored at regular intervals with estrogen use, especially if high doses are used. Ethinyl estradiol and conjugated estrogens have been shown to increase renin substrate. In contrast to these oral estrogens, transdermally administered estradiol does not affect renin substrate.
5. Hypercalcemia. Administration of estrogen may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If this occurs, the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

PRECAUTIONS

A. General

1. Addition of a progestin. Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration have reported a lower incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Morphologic and biochemical studies of endometria suggest that 10 to 14 days of progestin are needed to provide maximal maturation of the endometrium and to reduce the likelihood of hyperplastic changes.

There are, however, possible risks that may be associated with the use of progestins in estrogen replacement regimens. These include:

1. adverse effects on lipoprotein metabolism (lowering HDL and raising LDL) which could diminish the purported cardioprotective effect of estrogen therapy (see PRECAUTIONS , below);
2. impairment of glucose tolerance; and
3. possible enhancement of mitotic activity in breast epithelial tissue, although few epidemiologic data are available to address this point (see PRECAUTIONS , below).
   The choice of progestin, its dose, and its regimen may be important in minimizing these adverse effects, but these issues will require further study before they are clarified.

2. Cardiovascular risk. The effects of estrogen replacement on the risk of cardiovascular disease have not been adequately studied. However, data from the Heart and Estrogen/Progestin Replacement Study (HERS), a controlled clinical trial of secondary prevention of 2,763 post-menopausal women with documented heart disease, demonstrated no benefit. During an average follow-up of 4.1 years, treatment with oral conjugated estrogen plus medroxyprogesterone acetate did not reduce the overall rate of coronary heart disease (CHD) events in post-menopausal women with established coronary disease. There were more CHD events in the hormone treated group than in the placebo group in year 1, but fewer events in years 3 through 5.

3. Physical examination. A complete medical and family history should be taken prior to the initiation of any estrogen therapy. The pretreatment and periodic physical examinations should include special reference to blood pressure, breasts, abdomen, and pelvic organs and should include a Papanicolaou smear. As a general rule, estrogen should not be prescribed for longer than one year without reexamining the patient.

4. Hypercoagulability Some studies have shown that women taking estrogen replacement therapy have hypercoagulability, primarily related to decreased antithrombin activity. This effect appears dose- and duration-dependent and is less pronounced than that associated with oral contraceptive use. Also, postmenopausal women tend to have increased coagulation parameters at baseline compared to premenopausal women. Epidemiological studies, which employed primary orally administered estrogen products, have suggested that hormone replacement therapy (HRT) may be associated with an increased relative risk of developing venous thromboembolism (VTE), i.e., deep venous thrombosis or pulmonary embolism. Risk/benefit should therefore be carefully weighed in consultation with the patient when prescribing any form of HRT to women with a risk factor for VTE.

5. Familial hyperlipoproteinemia. Estrogen therapy may be associated with massive elevations of plasma triglycerides leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism.

6. Fluid retention. Because estrogens may cause some degree of fluid retention, conditions that might be exacerbated by this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction, require careful observation.

7. Uterine bleeding and mastodynia. Certain patients may develop undesirable manifestations of estrogenic stimulation, such as abnormal uterine bleeding and mastodynia.

8. Impaired liver function. Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution.

B. Information for the Patient.   See text of Patient Package Insert , which appears after the HOW SUPPLIED section.

C. Laboratory Tests.   Estrogen administration should generally be guided by clinical response at the smallest dose, rather than laboratory monitoring, for relief of symptoms for those indications in which symptoms are observable.

D. Drug/Laboratory Test Interactions.   Some of these drug/laboratory test interactions have been observed only with estrogen progestin combinations (oral contraceptives):

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 anti-factor 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) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T ₄ levels (by column or by radioimmunoassay) or T ₃ levels by radioimmunoassay. T ₃ resin uptake is decreased, reflecting the elevated TBG. Free T ₄ and free T ₃ concentrations are unaltered.
3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
4. Increased plasma HDL and HDL-2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
5. Impaired glucose tolerance.
6. Reduced response to metyrapone test.
7. Reduced serum folate concentration.

E. Carcinogenesis, Mutagenesis, and Impairment of Fertility.   Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina, testis, and liver (see CONTRAINDICATIONS and ).

F. Pregnancy Category X.   Estrogens should not be used during pregnancy (see CONTRAINDICATIONS and Boxed Warning ).

G. Nursing Mothers.   As a general principle, the administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk. In addition, estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk.

H. Pediatric Use.   The safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS

See and Boxed Warning regarding the potential adverse effects on the fetus, the induction of malignant neoplasms, gallbladder disease, cardiovascular disease, elevated blood pressure, and hypercalcemia.

The most commonly reported systemic adverse event with the Vivelle-Dot™ systems was mild headache. Topical irritancy evaluations showed that for the majority of the subjects, no erythema was observed at the application sites after removal of the systems. No occurrence of erythema was greater than mild in severity.

The following additional adverse reactions have been reported with estrogen therapy:

1. Genitourinary system. Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding, spotting; increase in size of uterine leiomyomata; vaginal candidiasis; change in amount of cervical secretion.
2. Breasts. Tenderness, enlargement.
3. Gastrointestinal. Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; gallbladder disease.
4. Skin. Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism.
5. Eyes. Steepening of corneal curvature; intolerance to contact lenses.
6. Central Nervous System. Headache, migraine, dizziness; mental depression; chorea.
7. Miscellaneous. Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; changes in libido.

OVERDOSAGE

Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing oral contraceptives by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.

DOSAGE AND ADMINISTRATION

The adhesive side of the Vivelle-Dot™ system should be placed on a clean, dry area of the abdomen. The Vivelle-Dot™ system should not be applied to the breasts. The Vivelle-Dot™ system should be replaced twice weekly. 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 the system off. 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 palm of the hand for about 10 seconds, making sure there is good contact, especially around the edges. In the unlikely event that a system should fall off, the same system may be reapplied. If necessary, a new system may be applied. In either case, the original treatment schedule should be continued.

Initiation of Therapy

For treatment of moderate-to-severe vasomotor symptoms and vulval and vaginal atrophy associated with the menopause, start therapy with Vivelle-Dot™ (estradiol transdermal system) 0.05 mg/day applied to the skin twice weekly. In order to use the lowest dosage necessary for the control of symptoms, decisions to increase dosage should not be made until after the first month of therapy. Some women taking the 0.0375 mg/day dosage may experience a delayed onset of efficacy. Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals.

In women not currently taking oral estrogens or in women switching from another estradiol transdermal therapy, treatment with the Vivelle-Dot™ system may be initiated at once. In women who are currently taking oral estrogens, treatment with the Vivelle-Dot™ system should be initiated 1 week after withdrawal of oral hormone replacement therapy, or sooner if menopausal symptoms reappear in less than 1 week.

Therapeutic Regimen

The Vivelle-Dot™ system may be given continuously in patients who do not have an intact uterus. In those patients with an intact uterus, the Vivelle-Dot™ system may be given on a cyclic schedule (e.g., three weeks on drug followed by one week off drug).

HOW SUPPLIED

Vivelle-Dot™ (estradiol transdermal system), 0.0375 mg/day - each 3.75 cm ² system contains 0.585 mg of estradiol USP for nominal* delivery of 0.0375 mg of estradiol per day.

Patient Calendar Pack of 8 Systems

NDC 0078-0343-42

Carton of 3 Patient Calendar Packs of 8 Systems

NDC 0078-0343-45

Vivelle-Dot™ (estradiol transdermal system), 0.05 mg/day - each 5.0 cm ² system contains 0.78 mg of estradiol USP for nominal* delivery of 0.05 mg of estradiol per day.

Patient Calendar Pack of 8 Systems

NDC 0078-0344-42

Carton of 3 Patient Calendar Packs of 8 Systems

NDC 0078-0344-45

Vivelle-Dot™ (estradiol transdermal system), 0.075 mg/day - each 7.5 cm ² system contains 1.17 mg of estradiol USP for nominal* delivery of 0.075 mg of estradiol per day.

Patient Calendar Pack of 8 Systems

NDC 0078-0345-42

Carton of 3 Patient Calendar Packs of 8 Systems

NDC 0078-0345-45

Vivelle-Dot™ (estradiol transdermal system), 0.1 mg/day - each 10.0 cm ² system contains 1.56 mg of estradiol USP for nominal* delivery of 0.1 mg of estradiol per day.

Patient Calendar Pack of 8 Systems

NDC 0078-0346-42

Carton of 3 Patient Calendar Packs of 8 Systems

NDC 0078-0346-45

Store at controlled room temperature at 25°C (77°F).

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

Rev. SEPTEMBER 2000T2000-56

PRODUCT PHOTO(S):

Information for the Patient

Vivelle-Dot™

(estradiol transdermal system)

Rx Only

INTRODUCTION

Your doctor has prescribed the Vivelle-Dot™ (estradiol transdermal system) for the treatment of your menopausal symptoms. During menopause, production of estrogen hormones by your body decreases well below the amounts normally produced during your fertile years. In many women this decrease in estrogen production causes uncomfortable symptoms, most noticeably hot flushes and sleep disturbance. Estrogens can be given to reduce or eliminate these symptoms.

The Vivelle-Dot™ system that your doctor has prescribed for you releases small amounts of estradiol through the skin in a continuous way. Estradiol is the same hormone that your ovaries produce abundantly before menopause. The dose of estradiol you require will depend upon your individual response. The dose is adjusted by the size of the Vivelle-Dot™ system used; the systems are available in four sizes.

INFORMATION ABOUT VIVELLE-DOT™

(estradiol transdermal system)

How the Vivelle-Dot™ system works

The Vivelle-Dot™ system contains estradiol. When applied to the skin as directed below, the Vivelle-Dot™ system releases estradiol, which flows through the skin into the bloodstream.

Application Instructions for Vivelle-Dot™

(estradiol transdermal system)

1. DETERMINE YOUR SCHEDULE FOR YOUR TWICE-A-WEEK APPLICATION

• Decide upon which two days you will change your patch.
• Your Vivelle-Dot™ individual carton contains a calendar card printed on its inner flap. Mark the two-day schedule you plan to follow on your carton's inner flap.
• BE CONSISTENT.
• If you forget to change your patch on the correct date, apply a new one as soon as you remember.
• No matter what day this happens, stick to the schedule you have marked on the inner flap of your carton (your calendar card).

2. WHERE TO APPLY THE VIVELLE-DOT™ SYSTEM

• Apply patch to lower abdomen, below the waistline. Avoid the waistline, since clothing may cause the patch to rub off.
• DO NOT APPLY PATCH TO BREASTS.
• When changing your patch, based on your twice-a-week schedule, apply your new patch to a different site. Do not apply a new patch to that same area for at least one week.

3. BEFORE YOU APPLY THE VIVELLE-DOT™ SYSTEM

Make sure your skin is:

• Clean (freshly washed), dry and cool.
• Free of any powder, oil, moisturizer or lotion.
• Free of cuts and/or irritations (rashes or other skin problems).

4. HOW TO APPLY THE VIVELLE-DOT™ SYSTEM

• Each patch is individually sealed in a protective pouch.
• Tear open the pouch at the tear notch (do not use scissors).
• Remove the patch.

• Apply the patch immediately after removing from pouch.
• Holding the patch with the rigid protective liner facing you, remove half of the liner, which covers the sticky surface of the patch.

• AVOID TOUCHING THE STICKY SIDE OF THE PATCH WITH YOUR FINGERS.
• Using the other half of the rigid protective liner as a handle, apply the sticky side of the patch to the selected area of the abdomen.

• Press the sticky side of the patch firmly into place.
• Smooth it down.
• While still holding the sticky side down, fold back the other half of the patch.

• Grasp an edge of the remaining protective liner and gently pull it off.
• AVOID TOUCHING THE STICKY SIDE OF THE PATCH WITH YOUR FINGERS.

• Press the entire patch firmly into place with the palm of your hand.
• Continue to apply pressure, with the palm of your hand over the patch, for approximately 10 seconds.

• Make sure that the patch is properlyadhered to your skin.
• Go over the edges with your finger toensure good contact around the patch.

PLEASE NOTE:

• Contact with water while bathing, swimming or showering will not affect the patch.
• In the unlikely event that a patch should fall off, AVOID TOUCHING THE STICKY SIDE WITH YOUR FINGERS . Put the same patch back on a different site, making sure to press the patch firmly into place for at least 10 seconds.
• Continue to follow your original twice-a-week schedule you have marked on the inner flap of your individual carton (your calendar card).
• If necessary, you may apply a new system but continue to follow your original schedule.

5. HOW TO CHANGE AND DISCARD THE VIVELLE-DOT™ SYSTEM

• When changing the patch, peel off the used patch slowly.
• Fold the used patch in half (sticky sides together) and discard appropriately, in the trash.
• PLEASE KEEP OUT OF REACH OF CHILDREN.
• 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 oil or lotion to remove the adhesive from your skin.
• Keep in mind, the new patch must be applied to a different area of your abdomen. This area must be clean, dry and cool; and free of powder, oil and/or lotion.

Benefits of treatment with Vivelle-Dot™

(estradiol transdermal system)

Regular use of the Vivelle-Dot™ system twice weekly offers relief of moderate-to-severe symptoms of menopause. Small quantities of the naturally occurring hormone estradiol are absorbed through the skin from the Vivelle-Dot™ system, ensuring a continuous supply of circulating hormone in the body.

USES OF ESTROGEN

• To reduce moderate or severe menopausal symptoms.
  Estrogens are hormones produced by the ovaries. The decrease in the amount of estrogen that occurs in all women, usually between ages 45 and 55, causes the menopause. Sometimes the ovaries are removed by an operation, causing "surgical menopause." When the amount of estrogen begins to decrease, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest or sudden intense episodes of heat and sweating ("hot flashes"). The use of drugs containing estrogens can help the body adjust to lower estrogen levels.
  Some women have only mild menopausal symptoms, or none at all, and do not need estrogen therapy for these particular symptoms. Other women may need estrogens for a few months while their bodies adjust to lower estrogen levels. For the treatment of menopausal symptoms only, most women need estrogen replacement therapy for no longer than 6 months.
• To treat vulval and vaginal atrophy (itching, burning, dryness in or around the vagina, difficulty or burning on urination) associated with menopause.
• To treat certain conditions in which a young woman's ovaries do not produce enough estrogen naturally.

WHO SHOULD NOT USE ESTROGENS

Estrogens should not be used:

• During pregnancy (see Boxed Warning ).
  If you think you may be pregnant, do not use any form of estrogen-containing drug. Using estrogens while you are pregnant may cause your unborn child to have birth defects. Estrogens do not prevent miscarriage.
• If you have unusual vaginal bleeding which has not been evaluated by your doctor (see Boxed Warning ).
  Unusual vaginal bleeding can be a warning sign of cancer of the uterus, especially if it happens after menopause. Your doctor must find out the cause of the bleeding so that he or she can recommend the proper treatment. Taking estrogens without visiting your doctor can cause you serious harm if your vaginal bleeding is caused by cancer of the uterus.
• If you have had cancer.
  Since estrogens increase the risk of certain types of cancer, you should not use estrogens if you ever had cancer of the breast or uterus.
• If you have any circulation problems.
  Estrogen therapy should be used only after consultation with your doctor and only in recommended doses. Patients with a tendency for abnormal blood clotting should avoid estrogen use (see DANGERS OF ESTROGENS , below).
• When they are ineffective.
  During menopause, some women develop nervous symptoms or depression. Estrogens do not relieve these symptoms. You may have heard that taking estrogens for years after menopause will keep your skin soft and supple and keep you feeling young. There is no evidence for these claims and such long-term estrogen use may have serious risks.
• After childbirth or when breastfeeding a baby.
  Estrogens should not be used to try to stop the breasts from filling with milk after a baby is born. Such treatment may increase the risk of developing blood clots (see DANGERS OF ESTROGEN , below).
  If you are breastfeeding, you should avoid using any drugs because many drugs pass through to the baby in the milk. While nursing a baby, you should take drugs only on the advice of your healthcare provider.

DANGERS OF ESTROGENS

• Cancer of the uterus.
  The risk of developing cancer of the uterus gets higher the longer estrogens are used and when larger doses are taken. One study showed that when estrogens are discontinued, this increased risk of cancer seems to fall off quickly. Three other studies showed that the risk for uterine cancer stayed high for 8 to more than 15 years after stopping estrogen treatment. Because of this risk, IT IS IMPORTANT TO TAKE THE LOWEST DOSE THAT WORKS AND TO TAKE IT ONLY AS LONG AS YOU NEED IT.
  Using progestin therapy together with estrogen therapy may reduce the higher risk of uterine cancer related to estrogen use (see OTHER INFORMATION , below).
  If you have had your uterus removed (total hysterectomy), there is no danger of developing cancer of the uterus.
• Cancer of the breast.
  Studies examining the risk of breast cancer among women using estrogen alone and combined estrogen/progestin therapy have suggested that there may be a mildly increased risk of breast cancer in women taking the combined therapy.
  If you do not have your uterus, there is no need for combined estrogen/progestin therapy since estrogen alone therapy is sufficient and may pose less risk for breast cancer.
  If you do have your uterus, you should discuss the benefits and risks of combined estrogen/progestin therapy with your health care provider. Regular breast exams by a health professional and monthly self-exams are recommended for all women. Mammography may also be recommended depending on your age and risk factors.
• Gallbladder disease.
  Women who use estrogens after menopause are more likely to develop gallbladder disease needing surgery than women who do not use estrogens.
• Abnormal blood clotting.
  Taking estrogens may increase the risk of blood clots. These clots can cause a stroke, heart attack, or pulmonary embolus, any of which may be fatal.

SIDE EFFECTS

In addition to the risks listed above, the following side effects have been reported with estrogen use:

• Headache
• Nausea and vomiting.
• Breast tenderness or enlargement.
• Enlargement of benign tumors ("fibroids") of the uterus.
• Retention of excess fluid. This may make some conditions worsen, such as asthma, epilepsy, migraine, heart disease, or kidney disease.
• A spotty darkening of the skin, particularly on the face. Skin irritation, redness, or rash may occur at the site of application.

REDUCING RISK OF ESTROGEN USE

If you use estrogens, you can reduce your risks by doing these things:

• See your doctor regularly.
  While you are using estrogens, it is important to visit your doctor at least once a year for a check-up. If you develop vaginal bleeding while taking estrogens, you may need further evaluation. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram (breast x-ray), you may need to have more frequent breast examinations.
• Reassess your need for estrogens.
  You and your doctor should reevaluate whether or not you still need estrogens at least every six months.
• Be alert for signs of trouble.
  Report these or any other unusual side effects to your doctor immediately:
  
  • Abnormal bleeding from the vagina.
  • Pains in the calves or chest, sudden shortness of breath, or coughing blood (indicating possible clots in the legs, heart, or lungs).
  • Severe headache, dizziness, faintness, or changes in vision (indicating possible clots in the brain or eye).
  • Breast lumps.
  • Yellowing of the skin or eyes.
  • Pain, swelling, or tenderness in the abdomen.
  • Skin irritation, redness, or rash.

OTHER INFORMATION

If your uterus has not been removed, your doctor may choose to prescribe a progestin, a different hormonal drug to be used in association with estrogen treatment. Progestins lower the risk of developing endometrial hyperplasia, a possible precancerous condition of the uterine lining, which may occur while using estrogen. There are possible additional risks that may be associated with the inclusion of a progestin in estrogen treatment. The possible risks include unfavorable effects on blood fats and sugars, as well as a possible further increase in breast cancer risk that may be associated with long-term estrogen use.

Some research has suggested that estrogen taken without progestins may protect women against developing heart disease. However, this effect of estrogen is not certain.

You are cautioned to discuss very carefully with your doctor or healthcare provider all the possible risks and benefits of long-term estrogen and progestin treatment, as they affect you personally.

Your doctor has prescribed this drug for you and you alone. Do not give the drug to anyone else.

Keep this and all drugs out of the reach of children. In case of overdose, remove the system and call your doctor, hospital, or poison control center immediately.

This leaflet provides a summary of the most important information about estrogens. If you want more information, ask your doctor or pharmacist to show you the professional labeling.

                                                                         T2000-56

Rev. SEPTEMBER 2000                 T2000-56/T2000-57

Manufactured by Noven Pharmaceuticals Inc.

Miami, FL 33186

Distributed by Novartis Pharmaceuticals Corporation

East Hanover, NJ 07936