Prescription Drugs

CLINICAL PHARMACOLOGYEstrogens 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. Pharmacokinetics The pharmacokinetics of transdermally administered estradiol using Esclim (estradiol transdermal) have been evaluated in a total of 138 healthy postmenopausal women in 9 clinical pharmacology and biopharmaceutic studies. Absorption Transdermal administration of estradiol produces therapeutic serum concentrations of estradiol with lower circulating concentrations of estrone and estrone conjugates and requires smaller total doses than does oral therapy. The in vivo estradiol daily delivery rate from Esclim (estradiol transdermal) was estimated using the baseline adjusted average serum concentrations determined from pharmacokinetic studies and an estradiol clearance value of 1600 L/day. The estimated mean in vivo transdermal delivery rates of estradiol are 0.020 mg/day, 0.051 mg/day, and 0.101 mg/day for the 11 cm,2 22 cm2 and 44 cm2 Esclim (estradiol transdermal) systems, respectively. The bioavailability of estradiol from Esclim (estradiol transdermal) was compared with Vivelle™ in a 4-day single application randomized crossover study of Esclim (estradiol transdermal) 0.05 (22 cm2), Esclim (estradiol transdermal) 0.1 (44 cm2) and Vivelle 0.05 in 23 postmenopausal women. The mean maximum serum estradiol concentrations of 62 pg/mL and 124 pg/mL were obtained at a mean Tmax of 27 hours following application of Esclim 0.05 and Esclim 0.1, respectively. In this study, serum estradiol concentration profiles (Figure 1) and pharmacokinetic parameters (Cmax and AUC) obtained with the Esclim (estradiol transdermal) 0.1 system were twice as high as those produced by the Esclim (estradiol transdermal) 0.05 system. Figure 1: Mean Uncorrected Serum Estradiol Concentrations After Application of Esclim (estradiol transdermal) 0.05, Esclim (estradiol transdermal) 0.1 and Vivelle 0.05 for 4 Days In a 3-week multiple application study in 18 postmenopausal women, Esclim (estradiol transdermal) 0.05 (22 cm2) applied to the buttocks increased serum estradiol concentrations within 4 hours and maintained an average serum estradiol concentration of approximately 51 pg/mL above baseline. Trough values of approximately 27 to 35 pg/mL above the baseline were observed at the end of each application interval (3 or 4 days). Nearly identical serum estradiol concentration profiles were seen during each successive week, indicating little or no accumulation of estradiol in the body. In a 3-day, single-application, crossover study in 12 postmenopausal women, estradiol serum concentrations were compared following application of the Esclim (estradiol transdermal) 0.05 system to sites on the buttocks (site used in clinical trials), the femoral triangle, and the upper arm. The profiles of serum estradiol concentrations from these different application sites are shown in Figure 2, and the pharmacokinetic results derived from each site are presented in Table 1. Figure 2:Mean Uncorrected Serum Estradiol Concentrations After Application of Esclim (estradiol transdermal) 0.05 to Different Body Sites for 3 Days Table 1: Mean Uncorrected Estradiol Pharmacokinetic Parameters After Application of Esclim 0.05 Patches to Different Body Sites Parameter Femoral Triangle Upper Arm Buttock Cmax (pg/mL) 80.1 ± 34.9 80.2 ± 44.1 72.6 ± 36.2 Cmin72 (pg/mL) 41.6 ± 18.3 38.7 ± 15.2 34.5 ± 18.8 Cav72 (pg/mL) 49.0 ± 24.6 47.4 ± 24.3 42.8 ± 20.7 Cav96 (pg/mL) 42.8 ± 20.5 40.8 ± 19.7 37.3 ± 17.1 AUC(0-72) (pg•hr/mL) 4106 ± 1826 3825 ± 1897 3477 ± 1530 AUC(0-96) (pg•hr/mL) 4578 ± 1938 4306 ± 1925 3885 ± 1622 Linear pharmacokinetics have been demonstrated for the Esclim transdermal system. Serum estradiol concentrations following a 4-day application of the Esclim (estradiol transdermal) 0.025, 0.05, and 0.1 systems are shown in Figure 3, while the mean values for pharmacokinetic parameters from these applications are summarized in Table 2. Results for the Esclim (estradiol transdermal) 0.025 system are from 1 study, while results for Esclim (estradiol transdermal) 0.05 and 0.1 systems are from a separate study. Cmax occurred at approximately 30 hours. Figure 3: Mean Uncorrected Serum Estradiol Concentrations After Application of Esclim (estradiol transdermal) 0.025, Esclim (estradiol transdermal) 0.05, and Esclim (estradiol transdermal) 0.1 for 4 Days Table 2: Mean ± SD Uncorrected Estradiol Pharmacokinetic Parameters for Esclim Transdermal Systems Applied to the Buttocks (N = 23) Surface Area Estradiol Dose Cmax Cmina Cavg (cm2) (mg/day) (pg/mL) (pg/mL) (pg/mL) 11 0.025 24.5 ± 11b 15.5 ± 6.1b 17.8±6.6b 22 0.05 61.6 ± 33 26.3 ± 14 38.6 ± 21 44 0.1 124 ± 66 51.4 ± 29 74.0 ± 43 aCmin=Serum estradiol concentration at 96 hours following application. bN=17. 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. Since transdermally absorbed estradiol is not subject to first pass liver metabolism, the ratio of serum concentrations of estradiol to either of its major metabolites, estrone or estrone sulfate, is closer to those observed in premenopausal women than when administered by the oral route of administration. The clinical relevance of the estradiol to estrone ratio is presently unknown. In a double-blind, parallel-group, placebo-controlled clinical trial using Esclim, the steady-state serum concentrations of estradiol, estrone, and estrone sulfate were measured between 24 and 72 hours after application of patch at week 13 and are presented in Table 3. Table 3: Mean ±SD Steady State Serum Concentration of Estradiol and Its Metabolites at Week 13 Following the Application of Esclim Steady State Serum Concentration Patch Estradiol (pg/mL) Estrone (pg/mL) Estrone Sulfate (ng/dL) Placebo 19.6 ± 14.0 31a 29.7 ± 11.7 31 42.9 ± 24.0 30 0.025 mg/day 48.2 ± 27.4 22 38.7 ± 21.5 22 152.6 ± 129.7 22 0.05 mg/day 102.8 ± 63.6 24 49.0 ± 28.0 24 236.1 ± 147.1 22 0.1 mg/day 165.3 ± 116.1 28 64.9 ± 31.7 28 373.6 ± 272.0 28 anumber of subjects Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Serum concentrations of estradiol and estrone returned to baseline values within 12 to 24 hours after removal of Esclim (estradiol transdermal) . Special Populations No specific studies have been conducted using Esclim (estradiol transdermal) in any special populations. Drug Interactions No specific drug interaction studies have been conducted using Esclim (estradiol transdermal) . Clinical Trials In a 12-week, double-blind study evaluating the efficacy and safety of Esclim (estradiol transdermal) 0.025, 0.05, and 0.1 versus placebo in symptomatic women (average of 8 or more moderate to severe hot flushes per day), reduction in the frequency of these vasomotor symptoms was demonstrated within 4 weeks. Results from this trial are presented in Table 4 and Figure 4. After 4 weeks of treatment, the mean reduction in the moderate to severe vasomotor symptoms (MSVS) was up to 8.6 MSVS per day in the Esclim (estradiol transdermal) 0.025 group, 9.2 and 10.2 in the Esclim (estradiol transdermal) 0.05, and Esclim (estradiol transdermal) 0.1 groups respectively, compared with 5.3 in the placebo group. After 12 weeks of treatment, this increased to 9.9 in the Esclim (estradiol transdermal) 0.025 group, 10.4 in the Esclim (estradiol transdermal) 0.05 group, and 10.7 in the Esclim (estradiol transdermal) 0.1 group and remained stable at 5.2 in the placebo group. Table 4: Changes From Baseline in Frequency of MSVS Week Placebo (N=54) Esclim 0.025 mg/day (N=48) Esclim 0.05 mg/day (N=47) Esclim 0.1 mg/day (N=47) Week 0 (Baseline) Mean ± SD 11.4 ± 3.7 11.6 ± 5.4 10.9 ± 4.2 11.2 ± 2.8 Week 4 Mean Reduction ± SD(% Reduction) -5.3 ± 4.1 (-48.9%) -8.6 ± 5.7* (-72.6%) -9.2 ± 4.5* (-84.4%) -10.2 ± 2.9* (-92.0%) Week 8 Mean Reduction ± SD(% Reduction) -5.5 ± 4.7 (-51.5%) -9.4 ± 5.7* (-79.8%) -10.3 ± 4.3* (-94.0%) -10.6 ± 2.8* (-95.4%) Week 12 Mean Reduction ± SD(% Reduction) -5.2 ± 5.1 (-50.3%) -9.9 ± 5.8* (-83.4%) -10.4 ± 4.2* (-95.3%) -10.7 ± 2.8* (-95.6%) *Statistically different from placebo in mean reduction (Dunnett’s test) Figure 4: Reduction of MSVS During Double-Blind, Placebo-Controlled Study Maintenance of the relief of VMS over a median period of 2 years was documented in 2 open-label trials.

Esclim™ (estradiol) Transdermal System Continuous delivery for twice-weekly application 1. ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF ENDOMETRIAL CARCINOMA IN POSTMENOPAUSAL WOMEN. Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that "natural" estrogens are more or less hazardous than "synthetic" estrogens at equiestrogenic doses. 2. ESTROGENS SHOULD NOT BE USED DURING PREGNANCY. There is no indication for estrogen therapy during pregnancy or during the immediate postpartum period. Estrogens are ineffective for the prevention or treatment of threatened or habitual abortion. Estrogens are not indicated for the prevention of postpartum breast engorgement. Estrogen therapy during pregnancy is associated with an increased risk of congenital defects in the reproductive organs of the fetus and possibly other birth defects. Studies of women who received diethylstilbestrol (DES) during pregnancy have shown that female offspring have an increased risk of vaginal adenosis, squamous cell dysplasia of the uterine cervix, and clear cell vaginal cancer later in life; male offspring have an increased risk of urogenital abnormalities and possibly testicular cancer later in life. The 1985 DES Task Force concluded that use of DES during pregnancy is associated with a subsequent increased risk of breast cancer in the mothers, although a causal relationship remains unproven, and the observed level of excess risk is similar to that for a number of other breast cancer risk factors. DESCRIPTION The Esclim™ estradiol transdermal system contains estradiol in a polymeric adhesive. The system is designed to release 17Ò²estradiol continuously upon application to intact skin. Five systems are available to provide nominal in vivo delivery of 0.025, 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 11, 16.5, 22, 33, or 44 cm2 contains 5, 7.5, 10, 15, or 20 mg of estradiol USP, respectively. The composition of the systems per unit area is identical. Estradiol USP (17Ò²estradiol) is a white, crystalline powder, chemically described as estra-1, 3, 5 (10)triene3, 17Ò²diol. The structural formula is: The molecular formula of estradiol is C18 H24 O2. The molecular weight is 272.39. Esclim (estradiol transdermal) transdermal systems are composed of a soft, flexible, rectangular foam backing material with rounded corners, covered on 1 side with a self-adhesive polymer matrix which contains estradiol and pharmacologically inactive components. The adhesive surface is covered by a transparent protective release liner as shown in the diagram below. The active component of the system is estradiol. The remaining components of the system (EVA copolymers, ethylcellulose, octyldodecanol, dipropylene glycol, polyester protective release liner) are pharmacologically inactive.

INDICATIONSEsclim (estradiol transdermal system) is indicated in the following: 1. Treatment of moderate to severe vasomotor symptoms associated with menopause. There is no adequate evidence that estrogens are effective for nervous symptoms of depression that 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. DOSAGE AND ADMINISTRATIONThe adhesive side of the Esclim (estradiol transdermal) system should be placed on a clean, dry area of the skin on buttocks, femoral triangle (upper inner thigh), or upper arm, but Esclim (estradiol transdermal) should not be applied to the breasts or other parts of the body. The Esclim (estradiol transdermal) transdermal system should be replaced every 3 to 4 days (twice a week). 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 the treatment of moderate to severe vasomotor symptoms, and vulval and vaginal atrophy associated with menopause, and of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure, treatment is generally initiated with the Esclim (estradiol transdermal) 0.025 transdermal system applied to the skin twice weekly, but the initial selection of the dose should be based on the evaluation of the severity of the patient’s symptomatology and responsiveness to estrogen treatment. Depending upon the clinical response to treatment, the dosage can then be titrated up or down to individual needs. 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 2 or 3 weeks of therapy. 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 Esclim estradiol transdermal system may be initiated at once. In women who are currently taking oral estrogens, treatment with the Esclim estradiol transdermal 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 Esclim (estradiol transdermal) may be given continuously in patients who do not have an intact uterus. In those patients with an intact uterus, Esclim (estradiol transdermal) may be given on a cyclic schedule (e.g., 3 weeks on drug followed by 1 week off drug). HOW SUPPLIEDEsclim™ estradiol transdermal system 0.025 mg/day (Each 11 cm2 system contains 5 mg of estradiol USP) Patient Pack of 8 systems . . . . . . . . . . . . . . . . . . . . . . .NDC 64248-310-01 Esclim™ estradiol transdermal system 0.0375 mg/day (Each 16.5 cm2 system contains 7.5 mg of estradiol USP) Patient Pack of 8 systems . . . . . . . . . . . . . . . . . . . . . . .NDC 64248-320-01 Esclim™ estradiol transdermal system 0.05 mg/day (Each 22 cm2 system contains 10 mg of estradiol USP) Patient Pack of 8 systems . . . . . . . . . . . . . . . . . . . . . . .NDC 64248-330-01 Esclim™ estradiol transdermal system 0.075 mg/day (Each 33 cm2 system contains 15 mg of estradiol USP) Patient Pack of 8 systems . . . . . . . . . . . . . . . . . . . . . . .NDC 64248-340-01 Esclim™ estradiol transdermal system 0.1 mg/day (Each 44 cm2 system contains 20 mg of estradiol USP) Patient Pack of 8 systems . . . . . . . . . . . . . . . . . . . . . . .NDC 64248-350-01 Store at 25°C (77°F); excursion permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature.] Do not store unpouched. Apply immediately upon removal from the protective pouch. Distributed by: WOMEN FIRST HEALTHCARE, INC. San Diego, CA 92130, Manufactured by: Laboratoires Fournier S.A. 21000 Dijon, France, Made In France July 1999, ©WFHC1999 PN0303

PATIENT INFORMATION Esclim™ estradiol transdermal system Information for the Patient INTRODUCTION The Esclim™ (estradiol transdermal) 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 on your individual response. The dose is adjusted by the size of the Esclim (estradiol transdermal) system used; the systems are available in 5 sizes. This leaflet describes when and how to use estrogens, and the risks and benefits of estrogen treatment. Estrogens have important benefits but also some risks. You must decide, with your doctor, whether the risks to you of estrogen use are acceptable because of their benefits. If you use estrogens, check with your doctor to be sure you are using the lowest possible dose that works, and that you don’t use them longer than necessary. How long you need to use estrogens will depend on the reason for use. 1. ESTROGENS INCREASE THE RISK OF CANCER OF THE UTERUS IN WOMEN WHO HAVE HAD THEIR MENOPAUSE ("CHANGE OF LIFE"). If you use any estrogen-containing drug, it is important to visit your doctor regularly and report any unusual vaginal bleeding right away. Vaginal bleeding after menopause may be a warning sign of uterine cancer. Your doctor should evaluate any unusual vaginal bleeding to find out the cause. 2. ESTROGENS SHOULD NOT BE USED DURING PREGNANCY. Estrogens do not prevent miscarriage (spontaneous abortion) and are not needed in the days following childbirth. It you take estrogens during pregnancy, your unborn child has a greater than usual chance of having birth defects. The risk of developing these defects is small, but clearly larger than the risk in children whose mothers did not take estrogens during pregnancy. These birth defects may affect the baby’s urinary system and sex organs. Daughters born to mothers who took DES (an estrogen drug) have a higher than usual chance of developing cancer of the vagina or cervix when they become teenagers or young adults. Sons may have a higher than usual chance of developing cancer of the testicles when they become teenagers or young adults. INFORMATION ABOUT ESCLIM How the Esclim™ (estradiol transdermal) System Works The Esclim system contains 17ß-estradiol. When applied to the skin as directed below, the Esclim system releases 17ß-estradiol continuously through the skin into the bloodstream. How and Where to Apply the Esclim (estradiol transdermal) System Each Esclim (estradiol transdermal) system is individually sealed in a protective pouch. Tear open this pouch at the indentation (do not use scissors) and remove the system. The system is made up of a self-adhesive matrix, which contains the estradiol. The adhesive surface is covered by a transparent protective release liner. The adhesive side will be placed against your skin. This liner must be removed before applying the system. Remove the protective liner and discard it. Try to avoid touching the adhesive. Apply the adhesive side of the Esclim (estradiol transdermal) system to a clean, dry area of the skin on your upper arm, buttocks, or upper inner thigh. Do not apply Esclim (estradiol transdermal) to your breasts or other parts of your body. The sites of application must be rotated, with an interval of at least 1 week allowed between applications to a particular site. The area selected should not be oily, damaged, or irritated. The waistline should be avoided, since tight clothing may rub and remove the system. The system should be applied immediately after opening the pouch and removing the protective foil 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. The Esclim (estradiol transdermal) system should be worn continuously until it is time to replace it with a new system. You may wish to experiment with different locations when applying the system, to find ones that are most comfortable for you and where clothing will not rub on the system. When to Apply the Esclim (estradiol transdermal) System The Esclim (estradiol transdermal) system should be changed every 3 to 4 days, 2 times per week, on the same 2 days of the week. When changing the system, remove the used Esclim (estradiol transdermal) system. After removal, fold the patch in half so that the adhesive sides are together and discard. Any adhesive that might remain on your skin can be easily rubbed off. Then place the new Esclim (estradiol transdermal) system on a different skin site. (The same skin site should not be used again for at least 1 week after removal of the system.) Contact with water when you are bathing, swimming, or showering will not affect the system. In the 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. USES OF ESTROGEN (Not every estrogen drug is approved for every use listed in this section. If you want to know which of these possible uses are approved for the medicine prescribed for you, ask your doctor or pharmacist to show you the professional labeling. You can also look up the specific estrogen product in a book called the "Physicians’ Desk Reference," which is available in many book stores and public libraries. Generic drugs carry virtually the same labeling information as their brand name versions.) - To reduce moderate or severe menopausal symptoms. Estrogens are hormones made by the ovaries of normal women. Between ages 45 and 55, the ovaries normally stop making estrogens. This leads to a drop in body estrogen levels which causes the "change of life" or menopause (the end of monthly menstrual periods). If 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 intense episodes of heat and sweating ("hot flashes" or "hot flushes"). Using estrogen drugs can help the body adjust to lower estrogen levels and reduce these symptoms. Most women have only mild menopausal symptoms or none at all and do not need to use estrogen drugs for these symptoms. Others may need to take estrogens for a few months while their bodies adjust to lower estrogen levels. The majority of women do not need estrogen replacement for longer than 6 months for these symptoms. - 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. - To treat certain types of abnormal vaginal bleeding due to hormonal imbalance when your doctor has found no serious cause of the bleeding. - To treat certain cancers in special situations, in men and women. - To prevent thinning of bones. 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 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 have ever had cancer of the breast or uterus, unless your doctor recommends that the drug may help in the cancer treatment. (For certain patients with breast or prostate cancer, estrogens may help.) - If you have any circulation problems. Estrogen drugs should not be used except in unusually special situations in which your doctor judges that you need estrogen therapy so much that the risks are acceptable. Men and women with abnormal blood clotting conditions should avoid estrogen use (see Dangers of Estrogens, below). - When they do not work. 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 Estrogens, 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 health care provider. DANGERS OF ESTROGENS - Cancer of the uterus. Your risk of developing cancer of the uterus gets higher the longer you use estrogens and the larger doses you use. One study showed that after women stop taking estrogens, this higher cancer risk quickly returns to the usual level of risk (as if you had never used estrogen therapy). Three other studies showed that the cancer risk 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 (but 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. Most studies have not shown a higher risk of breast cancer in women who have ever used estrogens. However, some studies have reported that breast cancer developed more often (up to twice the usual rate) in women who used estrogens for long periods of time (especially more than 10 years), or who used higher doses for shorter time periods. Regular breast examinations by a health professional and monthly self-examination are recommended for all women. - 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 cause changes in your blood clotting system. These changes allow the blood to clot more easily, possibly allowing clots to form in your bloodstream. If blood clots do form in your bloodstream, they can cut off the blood supply to vital organs, causing serious problems. These problems may include a stroke (by cutting off blood to the brain), a heart attack (by cutting off blood to the heart), a pulmonary embolus (by cutting off blood to the lungs), or other problems. Any of these conditions may cause death or serious long-term disability. However, most studies of low dose estrogen usage by women do not show an increased risk of these complications. SIDE EFFECTS In addition to the risks listed above, the following side effects have been reported with estrogen use: - Headaches. - 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 application site. 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 6 months. - Be alert for signs of trouble. If any of these warning signals (or any other unusual symptoms) happen while you are using estrogens, call your doctor immediately: Abnormal bleeding from the vagina (possible uterine cancer). Pains in the calves or chest, sudden shortness of breath, or coughing blood (possible clot in the legs, heart, or lungs). Severe headache or vomiting, dizziness, faintness, changes in vision or speech, weakness or numbness of an arm or leg (possible clot in the brain or eye). Breast lumps (possible breast cancer; ask your doctor or health professional to show you how to examine your breasts monthly). Yellowing of the skin or eyes (possible liver problem). Pain, swelling, or tenderness in the abdomen (possible gallbladder problem). Skin irritation. OTHER INFORMATION 1. Estrogens increase the risk of developing a condition (endometrial hyperplasia) that may lead to cancer of the lining of the uterus. Taking progestins, another hormone drug, with estrogens lowers the risk of developing this condition. Therefore, if your uterus has not been removed, your doctor may prescribe a progestin for you to take together with your estrogen. You should know, however, that taking estrogens with progestins may have additional risks. These include: - Unhealthy effects on blood fats (especially a lowering of HDL blood cholesterol, the "good" blood fat which protects against heart disease). - Unhealthy effects on blood sugar (which might make a diabetic condition worse). - A possible further increase in breast cancer risk which may be associated with long-term estrogen use. Some research has shown that estrogens taken without progestins may protect women against developing heart disease. However, this is not certain. The protection shown may have been caused by the characteristics of the estrogen-treated women, and not by the estrogen treatment itself. In general, treated women were slimmer, more physically active, and were less likely to have diabetes than the untreated women. These characteristics are known to protect against heart disease. You are cautioned to discuss very carefully with your doctor or health care provider all the possible risks and benefits of long-term estrogen and progestin treatment as they affect you personally. 2. Your doctor has prescribed this drug for you and you alone. Do not give the drug to anyone else. 3. Keep this and all drugs out of the reach of children. In case of overdose, call your doctor, hospital, or poison control center immediately. 4. 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. The professional labeling is also published in a book called the "Physicians’ Desk Reference," which is available in book stores and public libraries. Generic drugs carry virtually the same labeling information as their brand name versions. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Do not store unpouched. Apply immediately upon removal from the protective pouch.

OVERDOSESerious 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. CONTRAINDICATIONSPatients with known hypersensitivity to any of the components of the therapeutic system should not use Esclim (estradiol transdermal) . 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 except in appropriately selected patients being treated for metastatic disease. 4. Known or suspected estrogen-dependent neoplasia. 5. Active thrombophlebitis or thromboembolic disorders.

SIDE EFFECTS See WARNINGS 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. Skin irritation: In controlled clinical studies with Esclim (estradiol transdermal) , the most commonly reported adverse events were topical reactions of erythema and/or pruritus at the application site. In general these reactions caused patients little or no discomfort, and led to premature discontinuation of treatment in 0.9% (3/317) of patients in these trials. The rate of application site reactions, based on 8,135 applications of the 0.025, 0.05, and 0.1 Esclim (estradiol transdermal) systems in these trials was 6.1 per 100 applications (4.9, 5.4, 10.7 for the 3 Esclim (estradiol transdermal) doses respectively) compared to 6.2 in the placebo treated patients (2,014 applications). In a placebo-controlled trial of Esclim (estradiol transdermal) 0.025, 0.05, and 0.1 conducted in 196 patients in the US, the adverse events reported by at least 5% of patients in 1 or more of the treatment groups are shown in Table 5. Table 5: Incidence of Adverse Events >5% in a Placebo-Controlled Study of Esclim Data Are Expressed as % of Treatment Group Placebo Esclim Esclim Esclim Adverse Event 0.025 mg/day 0.05 mg/day 0.1 mg/day (N=54) (N=48) (N=47) (N=47) Breast Pain 3.7 25.0 44.7 46.8 Headache 22.2 18.8 8.5 6.4 Infection 7.4 10.4 10.6 8.5 Injury Accident 3.7 10.4 4.3 2.1 Anxiety 0 8.3 2.1 0 Emotional Lability 1.9 8.3 2.1 6.4 Arthralgia 1.9 6.3 2.1 4.3 Flu Syndrome 7.4 6.3 6.4 8.5 Joint Disorder 0 6.3 0 0 Pruritus 1.9 6.3 12.8 0 Rhinitis 1.9 6.3 4.3 4.3 Abdominal Pain 9.3 4.2 10.6 2.1 General Edema 1.9 4.2 6.4 6.4 Monilia Vagina 5.6 4.2 8.5 4.3 Nausea 1.9 4.2 10.6 8.5 Peripheral Edema 0 4.2 2.1 6.4 Sinusitis 7.4 4.2 2.1 4.3 Asthenia 1.9 2.1 10.6 6.4 Back Pain 3.7 2.1 2.1 6.4 Diarrhea 1.9 2.1 8.5 0 Dysmenorrhea 0 2.1 2.1 6.4 Enlarged Abdomen 0 2.1 2.1 6.4 Enlarged Breast 0 2.1 2.1 8.5 Rash 5.6 2.1 4.3 2.1 Anemia 0 0 6.4 4.3 Gastroenteritis 1.9 0 0 6.4 Hyperlipemia 5.6 0 0 2.1 Leukorrhea 0 0 12.8 0 Paresthesia 1.9 0 6.4 0 Urogenital Adverse Events (See Precautions: Addition of a progestin): In the US placebo-controlled study, 72 patients were included who had intact uteri. As expected, after 12-13 weeks of continuous unopposed therapy, findings of endometrial hyperplasia (diagnosed either by endometrial biopsy and/or ultrasonography) were increased with increasing doses of estradiol (placebo: 0/18 patients; Esclim (estradiol transdermal) 0.025: 1/14 (7.1%); Esclim (estradiol transdermal) 0.05: 12/22 (54.5%); Esclim (estradiol transdermal) 0.1: 10/18 (55.6%). In the 86 patients who had not previously undergone a total hysterectomy, vaginal bleeding was also increased with increasing doses of estradiol [placebo: 2/21 patients (9.5%); Esclim (estradiol transdermal) 0.025: 6/19 (31.6%); Esclim (estradiol transdermal) 0.05: 14/25 (56.0%); Esclim (estradiol transdermal) 0.1: 12/21 (57.1%)]. In 2 long-term studies involving a total of 488 patients treated for a mean duration of 618 days and up to 3.5 years, the nature and incidence of adverse events did not change with prolonged duration of treatment. 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. DRUG INTERACTIONSDrug/Laboratory Tests 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), 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. 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 triglyceride levels. 5. Impaired glucose tolerance. 6. Reduced response to metyrapone test. 7. Reduced serum folate concentration.

WARNINGS 1. Induction of Malignant Neoplasms. Some studies have suggested a possible increased incidence of breast cancer in those women taking estrogen therapy at higher doses or for prolonged periods of time. The majority of studies, however, have not shown an association with the usual doses used for estrogen replacement therapy. Women on this therapy should have regular breast examinations and should be instructed in breast self-examination. 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 5 to 10 years or more. In 3 studies, persistence of risk was demonstrated for 8 to over 15 years after cessation of estrogen treatment. In 1 study, a significant decrease in the incidence of endometrial cancer occurred 6 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. PRECAUTIONSGeneral 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 lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Morphological 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 epidemiological 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. A causal relationship between estrogen replacement therapy and reduction of cardiovascular disease in postmenopausal women has not been proven. Furthermore, the effect of added progestins on this putative benefit is not yet known. In recent years, many published studies have suggested that there may be a cause-effect relationship between postmenopausal oral estrogen replacement therapy without added progestins and a decrease in cardiovascular disease in women. Although most of the observational studies which assessed this statistical association have reported a 20% to 50% reduction in coronary heart disease risk and associated mortality in estrogen takers, the following should be considered when interpreting these reports: (1) Because only 1 of these studies was randomized, and it was too small to yield statistically significant results, all relevant studies were subject to selection bias. Thus, the apparently reduced risk of coronary artery disease cannot be attributed with certainty to estrogen replacement therapy. It may instead have been caused by lifestyle and medical characteristics of the women studied with the result that healthier women were selected for estrogen therapy. In general, treated women were of higher socio-economic and educational status, more slender, more physically active, more likely to have undergone surgical menopause, and less likely to have diabetes than the untreated women. Although some studies attempted to control for these selection factors, it is common for properly-designed randomized trials to fail to confirm benefits suggested by less rigorous study designs. Thus ongoing and future large-scale randomized trials may fail to confirm this apparent benefit. (2) Current medical practice often includes the use of concomitant progestin therapy in women with intact uteri (see PRECAUTIONS and WARNINGS). While the effects of added progestins on the risk of ischemic heart disease are not known, all available progestins reverse at least some of the favorable effects of estrogens on HDL and LDL levels. (3) While the effects of added progestins on the risk of breast cancer are also unknown, available epidemiologic evidence suggests that progestins do not reduce, and may enhance, the moderately increased breast cancer incidence that has been reported with prolonged estrogen replacement therapy (see WARNINGS, above). Because relatively long-term use of estrogens by a woman with a uterus has been shown to induce endometrial cancer, physicians often recommend that women who are deemed candidates for hormone replacement should take progestins as well as estrogens. When considering prescribing concomitant estrogens and progestins for hormone replacement therapy, physicians and patients are advised to carefully weigh the potential benefits and risks of the added progestin. Large-scale randomized, placebo-controlled, prospective clinical trials are required to clarify these issues. 3. Physical Examination. A complete medical and family history should be taken prior to the initiation of any estrogen therapy. The pre-treatment 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 1 year without re-examining 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. There is some suggestion that low-dose postmenopausal mestranol may increase the risk of thromboembolism, although the majority of studies (primarily of users of conjugated estrogens) report no such increase. There is insufficient information on hypercoagulability in women who have had previous thromboembolic disease. 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. Information for the Patient See text of Patient Package Insert, which appears after the HOW SUPPLIED section. 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. Carcinogenesis, Mutagenesis, Impairment of Fertility 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 (see CONTRAINDICATIONS and WARNINGS). Pregnancy Category X Estrogens should not be used during pregnancy (see CONTRAINDICATIONS and Boxed Warning). 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.