Prescription Drugs

CLINICAL PHARMACOLOGY Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 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. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. In a study using transdermally administered estradiol, 0.1 mg daily, plasma levels increased by 66 pg/mL, resulting in an average plasma level of 73 pg/mL. There were no significant increases in the concentration of renin substrate or other hepatic proteins (sex hormone-binding globulin, thyroxine-binding globulin, and corticosteroid-binding globulin). Pharmacokinetics 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 Administration of Estraderm produces mean serum concentrations of estradiol comparable to those produced by daily oral administration of estradiol at about 20 times the daily transdermal dose. In single-application studies in 14 postmenopausal women using Estraderm (estradiol transdermal) systems that provided 0.05 and 0.1 mg of exogenous estradiol per day, these systems produced increased blood levels within 4 hours and maintained respective mean serum estradiol concentrations of 32 and 67 pg/mL above baseline over the application period. At the same time, increases in estrone serum concentration averaged only 9 and 27 pg/mL above baseline, respectively. Serum concentrations of estradiol and estrone returned to preapplication levels within 24 hours after removal of the system. The estimated daily urinary output of estradiol conjugates increased 5 to 10 times the baseline values and returned to near baseline within 2 days after removal of the system. By comparison, estradiol (2 mg/day) administered orally to postmenopausal women resulted in increases in mean serum concentration of 59 pg/mL of estradiol and 302 pg/mL of estrone above baseline on the third consecutive day of dosing. Urinary output of estradiol conjugates after oral administration increased to about 100 times the baseline values and did not approach baseline until 7-8 days after the last dose. In a 3-week multiple-application study of 14 postmenopausal women in which Estraderm (estradiol transdermal) 0.05 was applied twice weekly, the mean increments in steady-state serum concentration were 30 pg/mL for estradiol and 12 pg/mL for estrone. Urinary output of estradiol conjugates returned to baseline within 3 days after removal of the last (6th) system, indicating little or no estrogen accumulation in the body. Distribution No specific investigation of the tissue distribution of estradiol absorbed from Estraderm (estradiol transdermal) in humans has been conducted. The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. 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. Transdermal administration produces therapeutic serum levels of estradiol with lower circulating levels of estrone and estrone conjugates and requires smaller total doses than does oral therapy. Because estradiol has a short half-life (~1 hour), transdermal administration of estradiol allows a rapid decline in blood levels after an Estraderm (estradiol transdermal) system is removed, e.g., in a cycling regimen. Special Populations Estraderm (estradiol transdermal) was only investigated in postmenopausal women. Drug Interactions In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects. 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 the use of 0.625 mg conjugated equine estrogens (CE) per day alone and of 0.625 mg conjugated equine 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 1 below. Table 1: RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHIa Eventc Relative Risk CE/MPA vs.Placebo at 5.2Years (95% CI*) Placebo n= 8102 CE/MPA n= 8506 Absolute Risk per 10,000 woman-years CHD events 1.29 (1.02-1.63) 30 37 Non-fatal MI 1.32 (1.02-1.72) 23 30 CHD death 1.18 (0.70-1.97) 6 7 Invasive breast cancerb 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 indexc 1.15 (1.03-1.28) 151 170 Deep vein thrombosisd 2.07 (1.49-2.87) 13 26 Vertebral fracturesd 0.66 (0.44-0.98) 15 9 Other osteoporotic fracturesd 0.77 (0.69-0.86) 170 131 a adapted from JAMA, 2002: 288: 321-333 b includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer c 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. d not included in Global index * nominal confidence intervals unadjusted for multiple looks and multiple comparisons For those outcomes included in the “global index”, absolute excess risks per 10,000 person-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,00 woman-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 woman-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 healthy postmenopausal women 65 years of age and older (47% were aged 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 equine 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 woman-years) and 21 in the placebo group (22 per 10,000 woman-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 WARNINGSand WARNINGS, Dementia.)

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.

CLINICAL PHARMACOLOGY Mechanism Of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Pharmacodynamics There are no pharmacodynamic data for Climara. Pharmacokinetics Absorption Transdermal administration of Climara 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 Climara transdermal system were investigated in 197 healthy postmenopausal women in six studies. In five of the studies, the Climara transdermal system was applied to the abdomen, and in a sixth study, application to the buttocks and abdomen were compared. The Climara transdermal delivery system continuously releases estradiol which is transported across intact skin leading to sustained circulating levels of estradiol during a 7-day treatment period. The systemic availability of estradiol after transdermal administration is about 20 times higher than that after oral administration. This difference is due to the absence of first pass metabolism when estradiol is given by the transdermal route. In a bioavailability study, the Climara 6.5 cm² was studied with the Climara 12.5 cm² as reference. The mean estradiol levels in serum from the two sizes are shown in Figure 1. Figure 1: Mean Serum 17β -Estradiol Concentrations versus Time Profile following Application of a 6.5 cm² Transdermal System and Application of a 12.5 cm² Climara Transdermal System Dose proportionality was demonstrated for the Climara 6.5 cm² transdermal system as compared to the Climara 12.5 cm² transdermal system in a 2-week crossover study with a 1-week washout period between the two-transdermal systems in 24 postmenopausal women. Dose proportionality was also demonstrated for the Climara transdermal system (12.5 cm² and 25 cm²) in a 1-week study conducted in 54 postmenopausal women. The mean steady state levels (Cavg) of the estradiol during the application of Climara 25 cm² and 12.5 cm² on the abdomen were about 80 and 40 pg/mL, respectively. In a 3-week multiple application study in 24 postmenopausal women, the 25 cm² Climara transdermal system produced average peak estradiol concentrations (Cmax) of approximately 100 pg/mL. Trough values at the end of each wear interval (Cmin) were approximately 35 pg/mL. Nearly identical serum curves were seen each week, indicating little or no accumulation of estradiol in the body. Serum estrone peak and trough levels were 60 and 40 pg/mL, respectively. In a single dose, randomized, crossover study conducted to compare the effect of site of application, 38 postmenopausal women wore a single Climara 25 cm² transdermal system for 1 week on the abdomen and buttocks. The estradiol serum concentration profiles are shown in Figure 2. Values of Cmax and Cavg were, respectively, 25 percent and 17 percent higher with the buttock application than with the abdomen application. Figure 2: Observed Mean (± SE) Estradiol Serum Concentrations for a One Week Application of the Climara Transdermal System (25 cm² ) to the Abdomen and Buttocks of 38 Postmenopausal Women Table 2 provides a summary of estradiol pharmacokinetic parameters determined during evaluation of the Climara transdermal system. Table 2: Pharmacokinetic Summary (Mean Estradiol Values) Climara Delivery Rate Surface Area (cm²) Application Site No. of Subjects Dosing Cmax (pg/mL) C min (pg/mL) Cavg (pg/mL) 0.025 6.5 Abdomen 24 Single 32 17 22 0.05 12.5 Abdomen 102 Single 71 29 41 0.1 25 Abdomen 139 Single 147 60 87 0.1 25 Buttock 38 Single 174 71 106 The relative standard deviation of each pharmacokinetic parameter after application to the abdomen averaged 50 percent, which is indicative of the considerable intersubject variability associated with transdermal drug delivery. The relative standard deviation of each pharmacokinetic parameter after application to the buttock was lower than that after application to the abdomen (for example, for Cmax 39 percent versus 62 percent, and for Cavg 35 percent versus 48 percent). 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. Estrogens circulate in the blood largely bound to SHBG and 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 a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Adhesion An open-label study of adhesion potentials of placebo transdermal systems that correspond to the 6.5 cm² and 12.5 cm² sizes of Climara 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 Climara. 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 percent showed essentially no lift for both the 6.5 cm² and 12.5 cm² transdermal systems. Of the total number of transdermal systems applied, approximately 5 percent showed complete detachment for each size. Adhesion potentials of the 18.75 cm² and 25 cm² sizes of transdermal systems (0.075 mg per day and 0.1 mg per day) have not been studied. Clinical Studies Effects On Vasomotor Symptoms A study of 214 women 25 to 74 years of age met the qualification criteria and were randomly assigned to one of the three treatment groups: 72 to the 0.05 mg estradiol patch, 70 to the 0.1 mg estradiol patch, and 72 to placebo. Potential subjects were postmenopausal women in good general health who experienced vasomotor symptoms. Natural menopause patients had not menstruated for at least 12 months and surgical menopause patients had undergone bilateral oophorectomy at least 4 weeks before evaluation for study entry. In order to enter the 11-week treatment phase of the study, potential subjects must have experienced a minimum of five moderate to severe hot flushes per week, or a minimum of 15 hot flushes of any severity per week, for 2 consecutive weeks. Women wore the patches in a cyclical fashion (three weeks on and one week off). During treatment, all subjects used diaries to record the number and severity of hot flushes. Subjects were monitored by clinic visits at the end of weeks 1, 3, 7, and 11 and by telephone at the end of weeks 4, 5, 8, and 9. Adequate data for the analysis of efficacy was available from 191 subjects. The results are presented as the mean ± SD number of flushes in each of the 3 treatment weeks of each 4-week cycle. In the 0.05 mg estradiol group, the mean weekly hot flush rate across all treatment cycles decreased from 46 ± 6.5 at baseline to 20 ± 3 (-67 percent). The 0.1 mg estradiol group had a decline in the mean weekly hot flush rate from 52 ± 4.4 at baseline to 16 ± 2.4 (-72 percent). In the placebo group, the mean weekly hot flush rate declined from 53 ± 4.5 at baseline to 46 ± 6.5 (-18.1 percent). Compared with placebo, the 0.05 mg and 0.1 mg estradiol groups showed a statistically significantly larger mean decrease in hot flushes across all treatment cycles (P<0.05). When the response to treatment was analyzed for each of the three cycles of therapy, similar statistically significant differences were observed between both estradiol treatment groups and the placebo group during all treatment cycles. In a double-blind, placebo-controlled, randomized study of 187 women receiving Climara 0.025 mg per day or placebo continuously for up to three 28-day cycles, the Climara 0.025 mg per day dosage was shown to be statistically better than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to severe vasomotor symptoms. Table 3: Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms Intent to Treat (ITT) Treatment Group Statistics Week 4 Week 8 Week 12 E2 Transdermal System N 82 84 68 Mean -6.45 -7.69 -7.56 SD 4.65 4.76 4.64 Placebo N 83 71 65 Mean -5.11 -5.98 -5.98 SD 7.43 8.63 9.69 p-value <0.002 <0.003 A second active-control trial of 193 randomized subjects was supportive of the placebo-controlled trial. Effects On Bone Mineral Density A two-year clinical trial enrolled a total of 175 healthy, hysterectomized, postmenopausal, non-osteoporotic (that is, lumbar spine bone mineral density >0.9 gm/cm²) women at 10 study centers in the United States. A total of 129 subjects were allocated to receive active treatment with 4 different doses of estradiol patches (6.5, 12.5, 15, 25 cm²) and 46 subjects were allocated to receive placebo patches. Seventy-seven percent of the randomized subjects (100 on active drug and 34 on placebo) contributed data to the analysis of percent change of anterior-posterior (A-P) spine BMD, the primary efficacy variable (see Figure 3). A statistically significant overall treatment effect at each timepoint was noted, implying bone preservation for all active treatment groups at all timepoints, as opposed to bone loss for placebo at all timepoints. Figure 3: Mean Percent Change from Baseline in Lumbar Spine (A-P View) Bone Mineral Density By Treatment and Time Last Observation Carried Forward Percent change in BMD of the total hip (see Figure 4) was also statistically significantly different from placebo for all active treatment groups. This figure is based on 74 percent of the randomized subjects (95 on active drug and 34 on placebo). Figure 4 : Mean Percent Change from Baseline in Total Hip by Treatment and Time Last Observation Carried Forward Women's Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms. WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risk and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79: 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 7.1 years, are presented in Table 4. Table 4: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHIa Event Relative Risk CE vs. Placebo (95% nCIb) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-years CHD eventsc 0.95 (0.78-1.16) 54 57 Non-fatal MIc 0.91 (0.73-1.14) 40 43 CHD deathc 1.01 (0.71-1.43) 16 16 All strokesc 1.33 (1.05-1.68) 45 33 Ischemic strokec 1.55 (1.19-2.01) 38 25 Deep vein thrombosisc,d 1.47 (1.06-2.06) 23 15 Pulmonary embolismc 1.37 (0.9-2.07) 14 10 Invasive breast cancerc 0.80 (0.62-1.04) 28 34 Colorectal cancerc 1.08 (0.75-1.55) 17 16 Hip fracturec 0.65 (0.45-0.94) 12 19 Vertebral fracturesc,d 0.64 (0.44-0.93) 11 18 Lower arm/wrist fracturesc,d 0.58 (0.47-0.72) 35 59 Total fracturesc,d 0.71 (0.64-0.80) 144 197 Death due to causese,f 1.08 (0.88-1.32) 53 50 Overall mortalityc,d 1.04 (0.88-1.22) 79 75 Global Indexg 1.02 (0.92-1.13) 206 201 a) Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b) Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. c) Results are based on centrally adjudicated data for an average follow-up of 7.1 years. d) Not included in “global index”. e) Results are based on an average follow-up of 6.8 years. f) All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g) 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. For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risks per 10,000 women-years in the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures.9 The absolute excess risk of events included in the “global index” was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years. See Table 4. Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in the distribution of stroke subtype and severity, including fatal strokes, in women receiving estrogen-alone compared to placebo. Estrogen-alone increased the risk of ischemic stroke, and this excess risk was present in all subgroups of women examined.10 See Table 4. Timing of initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk-benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)]. WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index”. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reduction per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.5 percent Black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 5 . These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 5 Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years a,b Event Relative Risk CE/MPA vs. placebo (95% nCIc) CE/MPA n = 8,506 Placebo n = 8,102 Absolute Risk per 10,000 Women-years CHD events 1.23 (0.99-1.53) 41 34 Non-fatal MI 1.28 (1.00-1.63) 31 25 CHD death 1.10 (0.70-1.75) 8 8 All strokes 1.31 (1.03-1.68) 33 25 Ischemic stroke 1.44 (1.09-1.90) 26 18 Deep vein thrombosisd 1.95 (1.43-2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive breast cancere 1.24 (1.01-1.54) 41 33 Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancerd 0.81 (0.48-1.36) 6 7 Cervical cancerd 1.44 (0.47-4.42) 2 1 Hip fracture 0.67 (0.47-0.96) 11 16 Vertebral fracturesd 0.65 (0.46-0.92) 11 17 Lower arm/wrist fracturesd 0.71 (0.59-0.85) 44 62 Total fracturesd 0.76 (0.69-0.83) 152 199 Overall mortality 1.00 (0.83-1.19) 52 52 Global Index g 1.13 (1.02-1.25) 184 165 a) Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b) Results are based on centrally adjudicated data. c) Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. d) Not included in “global index”. e) Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. f) All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g) 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. Timing of initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44-1.07)]. Women's Health Initiative Memory Study The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in the study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see WARNINGS AND PRECAUTIONS, and Use In Specific Populations]. The WHIMS estrogen plus progestin ancillary study enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years of age; and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in the study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see WARNINGS AND PRECAUTIONS, and Use In Specific Populations]. When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see WARNINGS AND PRECAUTIONS, and Use In Specific Populations]. REFERENCES 9. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women's Health Initiative Randomized Trial. J Bone Miner Res. 2006;21:817-828. 10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation. 2006;113:2425-2434.

Estraderm® (estradiol) Transdermal System Continuous delivery for twice-weekly application ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER. 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 the use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. (See WARNINGS, Malignant neoplasms, Endometrial cancer.) CARDIOVASCULAR AND OTHER RISKS Estrogens and progestins should not be used for the prevention of cardiovascular disease or dementia. (See WARNINGS, Cardiovascular disorders and Dementia.) The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50-79 years of age) during 5 years of treatment with oral conjugated equine estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo (see CLINICAL PHARMACOLOGY, Clinical Studies). The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated equine estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies). Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. DESCRIPTION Estraderm, estradiol transdermal system, is designed to release estradiol through a rate-limiting membrane continuously upon application to intact skin. Two systems are available to provide nominal in vivo delivery of 0.05 or 0.1 mg of estradiol per day via skin of average permeability (interindividual variation in skin permeability is approximately 20%). Each corresponding system having an active surface area of 10 or 20 cm² contains 4 or 8 mg of estradiol USP and 0.3 or 0.6 mL of alcohol USP, respectively. The composition of the systems per unit area is identical. Estradiol USP is a white, crystalline powder, chemically described as estra-1,3,5 (10)-triene-3,17β-diol. The structural formula is The Estraderm (estradiol transdermal) system comprises four layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a transparent polyester/ethylene vinyl acetate copolymer film, (2) a drug reservoir of estradiol USP and alcohol USP gelled with hydroxypropyl cellulose NF, (3) an ethylene-vinyl acetate copolymer membrane, and (4) an adhesive formulation of light mineral oil NF and polyisobutylene. A protective liner (5) of siliconized polyester film 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. Alcohol is also released from the system during use.

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.

Find Lowest Prices on Climara® (estradiol) Transdermal System WARNING ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed, persistent or recurring abnormal genital bleeding [see WARNINGS AND PRECAUTIONS]. Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see WARNINGS AND PRECAUTIONS, and Clinical Studies]. The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] alone, relative to placebo [see WARNINGS AND PRECAUTIONS, and Clinical Studies]. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see WARNINGS AND PRECAUTIONS, Use In Specific Populations, and Clinical Studies]. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other forms of estrogens. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see WARNINGS AND PRECAUTIONS, and Clinical Studies]. The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see WARNINGS AND PRECAUTIONS, and Clinical Studies]. The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see WARNINGS AND PRECAUTIONS, Use In Specific Populations, and Clinical Studies]. Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see WARNINGS AND PRECAUTIONS, and Clinical Studies]. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. DESCRIPTION Climara (estradiol transdermal system), is designed to release estradiol continuously upon application to intact skin. Six (6.5, 9.375, 12.5, 15, 18.75 and 25 cm²) systems are available to provide nominal in vivo delivery of 0.025, 0.0375, 0.05, 0.06, 0.075 or 0.1 mg respectively of estradiol per day. The period of use is 7 days. Each system has a contact surface area of either 6.5, 9.375, 12.5, 15, 18.75 or 25 cm², and contains 2, 2.85, 3.8, 4.55, 5.7 or 7.6 mg of estradiol USP respectively. The composition of the systems per unit area is identical. Estradiol USP is a white, crystalline powder, chemically described as estra-1,3,5(10)-triene-3, 17β-diol. It has an empirical formula of C18 H24 O2 and molecular weight of 272.38. The structural formula is: The Climara transdermal system comprises three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are: A translucent polyethylene film. An acrylate adhesive matrix containing estradiol USP. A protective liner of siliconized or fluoropolymer-coated polyester film is attached to the adhesive surface and must be removed before the system can be used. The active component of the transdermal system is estradiol. The remaining components of the transdermal system (acrylate copolymer adhesive, fatty acid esters, and polyethylene backing) are pharmacologically inactive.

INDICATIONS Estraderm® (estradiol transdermal system) is indicated in: Treatment of moderate to severe vasomotor symptoms associated with the menopause. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risks of osteoporosis and non-estrogen medications should be carefully considered. The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women. DOSAGE AND ADMINISTRATION The adhesive side of the Estraderm (estradiol transdermal) system should be placed on a clean, dry area of the skin on the trunk of the body (including the buttocks and abdomen). The site selected should be one that is not exposed to sunlight. Estraderm (estradiol transdermal) should not be applied to the breasts. The Estraderm (estradiol transdermal) 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 When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen alone or in combination with a progestin, should be with the lowest effective dose and the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g. 3-month to 6-month intervals) to determine whether treatment is still necessary (See BOXED WARNINGS and WARNINGS). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. Estraderm (estradiol transdermal) is currently available in two dosage forms – 0.05 mg and 0.1 mg. Patients should be started at the lowest dose. The lowest effective dose of Estraderm (estradiol transdermal) has not been determined. For treatment of moderate to severe vasomotor symptoms or moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause, initiate therapy with Estraderm (estradiol transdermal) 0.05 applied to the skin twice weekly. Prophylactic therapy with Estraderm (estradiol transdermal) to prevent postmenopausal bone loss should be initiated with the 0.05 mg/day dosage as soon as possible after menopause. The dosage may be adjusted if necessary. Discontinuation of estrogen therapy may reestablish bone loss at a rate comparable to the immediate postmenopausal period. In women not currently taking oral estrogens, treatment with Estraderm (estradiol transdermal) may be initiated at once. In women who are currently taking oral estrogen, treatment with Estraderm (estradiol transdermal) should be initiated 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week. Therapeutic Regimen Estraderm (estradiol transdermal) therapy may be given continuously in patients who do not have an intact uterus. In those patients with an intact uterus, Estraderm (estradiol transdermal) may be given on a cyclic schedule (e.g., 3 weeks on drug followed by 1 week off drug). HOW SUPPLIED Estraderm estradiol transdermal system 0.05 mg/day – each 10 cm² system contains 4 mg of estradiol USP for nominal* delivery of 0.05 mg of estradiol per day. Patient Calendar Pack of 8 Systems...........................NDC 0083-2310-08 Carton of 6 Patient Calendar Packs of 8 Systems.........NDC 0083-2310-62 Carton of 1 Patient Calendar Pack of 24 Systems.........NDC 0083-2310-24 Estraderm estradiol transdermal system 0.1 mg/day – each 20 cm² system contains 8 mg of estradiol USP for nominal* delivery of 0.1 mg of estradiol per day. Patient Calendar Pack of 8 Systems ...................................................NDC 0083-2320-08 Carton of 6 Patient Calendar Packs of 8 Systems.........NDC 0083-2320-62 Carton of 1 Patient Calendar Pack of 24 Systems.........NDC 0083-2320-24 *See DESCRIPTION. Do not store above 30°C (86°F). Do not store unpouched. Apply immediately upon removal from the protective pouch. REV: JUNE 2004. Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936. FDA revision date: 12/17/2004

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

INDICATIONS Treatment Of Moderate To Severe Vasomotor Symptoms Due To Menopause Treatment Of Moderate To Severe Symptoms Of Vulvar And Vaginal Atrophy Due To Menopause Limitation Of Use When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, topical vaginal products should be considered. Treatment Of Hypoestrogenism Due To Hypogonadism, Castration, Or Primary Ovarian Failure Prevention Of Postmenopausal Osteoporosis Limitation Of Use When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered. DOSAGE AND ADMINISTRATION Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be considered to reduce the risk of endometrial cancer. A woman without a uterus does not need a progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a progestin [see WARNINGS AND PRECAUTIONS]. Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be reevaluated periodically as clinically appropriate to determine if treatment is still necessary. Treatment Of Moderate To Severe Vasomotor Symptoms Due To Menopause Start therapy with 0.025 mg per day applied to the skin once weekly. Therapy should be started at the lowest effective dose and the shortest duration consistent with the treatment goals. Attempts to taper or discontinue the medication should be made at 3 to 6 month intervals. Treatment Of Moderate To Severe Symptoms Of Vulvar And Vaginal Atrophy Due To Menopause Start therapy with 0.025 mg per day applied to the skin once weekly. Therapy should be started at the lowest effective dose and the shortest duration consistent with the treatment goals. Attempts to taper or discontinue the medication should be made at 3 to 6 month intervals. Treatment Of Hypoestrogenism Due To Hypogonadism, Castration, Or Primary Ovarian Failure Start therapy with 0.025 mg per day applied to the skin once weekly. The dose should be adjusted as necessary to control symptoms. Clinical responses (relief of symptoms) at the lowest effective dose should be the guide for establishing administration of the Climara transdermal system, especially in women with an intact uterus. Prevention Of Postmenopausal Osteoporosis Start therapy with 0.025 mg per day applied to the skin once weekly. Application Of The Climara Transdermal System Site Selection The adhesive side of Climara should be placed on a clean, dry area of the lower abdomen or the upper quadrant of the buttock. Climara should not be applied to or near the breasts. The sites of application must be rotated, with an interval of at least 1-week allowed between applications to the same site. The area selected should not be oily, damaged, or irritated. The waistline should be avoided, since tight clothing may rub the transdermal system off. Application to areas where sitting would dislodge Climara should also be avoided. Application Climara should be applied immediately after opening the pouch and removing the protective liner. Climara should be pressed firmly in place with the fingers for at least 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 reapply it to a different location. If the system cannot be reapplied, 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 Climara has not been studied, and these activities may decrease the adhesion of the system and the delivery of estradiol. Removal Of The Climara Transdermal System Removal of Climara should be done carefully and slowly to avoid irritation of the skin. Should any adhesive remain on the skin after removal of the Climara 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. HOW SUPPLIED Dosage Forms And Strengths Climara (estradiol transdermal system), 0.025 mg per day—each 6.5 cm² system contains 2 mg of estradiol Climara (estradiol transdermal system), 0.0375 mg per day—each 9.375 cm² system contains 2.85 mg of estradiol Climara (estradiol transdermal system), 0.05 mg per day—each 12.5 cm² system contains 3.8 mg of estradiol Climara (estradiol transdermal system), 0.060 mg per day—each 15 cm² system contains 4.55 mg of estradiol Climara (estradiol transdermal system), 0.075 mg per day—each 18.75 cm² system contains 5.7 mg of estradiol Climara (estradiol transdermal system), 0.1 mg per day—each 25.0 cm² system contains 7.6 mg of estradiol Climara (estradiol transdermal system), 0.025 mg per day — each 6.5 cm² system contains 2 mg of estradiol USP Individual Carton of 4 systems NDC 50419-454-04 Climara (estradiol transdermal system), 0.0375 mg per day — each 9.375 cm² system contains 2.85 mg of estradiol USP Individual Carton of 4 systems NDC 50419-456-04 Climara (estradiol transdermal system), 0.05 mg per day — each 12.5 cm² system contains 3.8 mg of estradiol USP Individual Carton of 4 systems NDC 50419-451-04 Climara (estradiol transdermal system), 0.06 mg per day — each 15 cm² system contains 4.55 mg of estradiol USP Individual Carton of 4 systems NDC 50419-459-04 Climara (estradiol transdermal system), 0.075 mg per day — each 18.75 cm² system contains 5.7 mg of estradiol USP Individual Carton of 4 systems NDC 50419-453-04 Climara (estradiol transdermal system), 0.1 mg per day — each 25 cm² system contains 7.6 mg of estradiol USP Individual Carton of 4 systems NDC 50419-452-04 Storage And Handling Store at 20°C to 25°C (66°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Do not store above 86°F (30°C). Do not store unpouched. Apply immediately upon removal from the protective pouch. Used transdermal systems still contain active hormone. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet. Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981.Manufactured by : 3M Drug Delivery Systems Northridge, CA 91324. Revised: Nov 2017

PATIENT INFORMATION Estraderm® (estradiol transdermal system) Read this Patient Information before you start using Estraderm®(estradiol transdermal system) and read all the information that you get each time you refill Estraderm (estradiol transdermal) . There may be new information. This information does not take the place of talking to your health care provider about your medical condition or your treatment. What is the most important information I should know about Estraderm (estradiol transdermal) (an estrogen hormone)? Estrogens increase the chances of getting cancer of the uterus. Report any unusual vaginal bleeding right away while you are taking estrogens. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your health care provider should check any unusual vaginal bleeding to find out the cause. Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes. Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may increase your risk of dementia. You and your health care provider should talk regularly about whether you still need treatment with Estraderm. What is Estraderm® (estradiol transdermal) ? Estraderm is a patch that contains the estrogen hormone, estradiol. When applied to the skin as directed below, Estraderm (estradiol transdermal) releases estrogen through the skin into the bloodstream. What is Estraderm (estradiol transdermal) used for? Estraderm (estradiol transdermal) 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 and 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 health care provider should talk regularly about whether you still need treatment with Estraderm (estradiol transdermal) . treat moderate to severe dryness, itching and burning in or around the vagina. You and your health care provider should talk regularly about whether you still need treatment with Estraderm (estradiol transdermal) to control these problems. If you use Estraderm (estradiol transdermal) only to treat your dryness, itching, and burning in or around your vagina, talk with your health care 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 estrogens 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 Estraderm (estradiol transdermal) only to prevent osteoporosis from menopause, talk with your health care provider about whether a different treatment or medicine without estrogens might be better for you. You and your health care provider should talk regularly about whether you should continue with Estraderm (estradiol transdermal) . 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 health care provider before starting them. Who should not use Estraderm (estradiol transdermal) ? Do not start taking Estraderm (estradiol transdermal) 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 health care provider about whether you should take Estraderm (estradiol transdermal) . had a stroke or heart attack in the recent past (for example in the past year). currently have or have had blood clots. currently have or have had liver problems. are allergic to Estraderm (estradiol transdermal) or any of its ingredients. See the end of this leaflet for a list of ingredients in Estraderm (estradiol transdermal) . think you may be, or know that you are, pregnant. Tell your health care provider: if you are breastfeeding. The hormone in Estraderm (estradiol transdermal) can pass into your milk. about all of your medical problems: Your health care provider may need to check you more carefully if you have certain conditions such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Estraderm (estradiol transdermal) works. Estraderm (estradiol transdermal) may also affect how 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 Estraderm (estradiol transdermal) ? Start at the lowest dose and talk to your health care provider about how well that dose is working for you. Estrogens should be used at the lowest dose possible for your treatment, only as long as needed. The lowest effective dose of Estraderm (estradiol transdermal) has not been determined. You and your health care provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with Estraderm (estradiol transdermal) . How and Where to Apply Estraderm (estradiol transdermal) Each Estraderm (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. Bubbles in the system are normal. A stiff protective liner covers the adhesive side of the system — the side that will be placed against your skin. This liner must be removed before applying the system. Slide the protective liner sideways between your thumb and index finger. Then hold the system at one edge. Remove the protective liner and discard it. Try to avoid touching the adhesive. Apply the adhesive side of the system to a clean, dry area of the skin on the trunk of the body (including the buttocks and abdomen). The site selected should be one that is not exposed to sunlight. Some women may find that it is more comfortable to wear Estraderm (estradiol transdermal) on the buttocks. Do not apply Estraderm (estradiol transdermal) to your breasts. The sites of application must be rotated, with an interval of at least 1 week allowed between applications to a particular site. The area selected should not be oily, damaged, or irritated. Avoid the waistline, since tight clothing may rub the system off. Apply the system immediately after opening the pouch and removing the protective liner. Press the system firmly in place with the palm of your hand for about 10 seconds, making sure there is good contact, especially around the edges. The Estraderm (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 a new system, to find ones that are most comfortable for you and where clothing will not rub on the system. When to Apply Estraderm (estradiol transdermal) The Estraderm (estradiol transdermal) system should be replaced twice weekly. Your Estraderm (estradiol transdermal) package contains a calendar checklist on the back to help you remember a schedule. Mark the 2-day schedule you plan to follow. Always change the system on the 2 days of the week you have marked. When changing the system, remove the used Estraderm (estradiol transdermal) and discard it. Any adhesive that might remain on your skin can be easily rubbed off. Then place the new Estraderm (estradiol transdermal) on a different skin site. (The same skin site should not be used again for at least 1 week after removal of the system). Please note: Contact with water when you are bathing, swimming, or showering will not affect the system. In the unlikely event that a system should fall off, put this same system back on and continue to follow your original treatment schedule. If necessary, you may apply a new system but continue to follow your original schedule. 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 health care provider right away if you get any of these warning signs, or any other unusual symptom that concerns you Common side effects include: 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 Other side effects of Estraderm (estradiol transdermal) may be possible. If you have questions, talk to your health care provider or pharmacist. What can I do to lower my chances of a serious side effect with Estraderm (estradiol transdermal) ? Talk with your health care provider regularly about whether you should continue taking Estraderm (estradiol transdermal) . If you have a uterus, talk to your health care provider about whether the addition of a progestin is right for you. See your health care provider right away if you get vaginal bleeding while taking Estraderm (estradiol transdermal) . Have a breast exam and mammogram (breast X-ray) every year unless your health care 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 health care provider for ways to lower your chances for getting heart disease. General information about safe and effective use of Estraderm (estradiol transdermal) Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Estraderm (estradiol transdermal) for conditions for which it was not prescribed. Do not give Estraderm (estradiol transdermal) to other people, even if they have the same symptoms you have. It may harm them. Keep Estraderm (estradiol transdermal) out of the reach of children. This leaflet provides a summary of the most important information about Estraderm (estradiol transdermal) . If you would like more information, talk with your health care provider or pharmacist. You can ask for information about Estraderm (estradiol transdermal) that is written for health professionals. You can get more information by calling the toll free number (888-NOW-NOVA (888-669-6682)) What are the ingredients in Estraderm (estradiol transdermal) ? The Estraderm (estradiol transdermal) system comprises four layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a transparent polyester/ethylene vinyl acetate copolymer film, (2) a drug reservoir of estradiol USP and alcohol USP gelled with hydroxypropyl cellulose NF, (3) an ethylene-vinyl acetate copolymer membrane, and (4) an adhesive formulation of light mineral oil NF and polyisobutylene. A protective liner (5) of siliconized polyester film 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. Alcohol is also released from the system during use.

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.

PATIENT INFORMATION Climara (Kli-mar-uh) (estradiol) Transdermal System Read this Patient Information before you start using Climara and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment. What is the most important information I should know about Climara (an estrogen hormone)? Using estrogen-alone may increase your chance of getting cancer of the uterus (womb). Report any unusual vaginal bleeding right away while you are using Climara. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. Do not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function). Using estrogen-alone may increase your chances of getting strokes or blood clots. Using estrogen-alone may increase your chance of getting dementia, based on a study of women age 65 years of age or older. Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or dementia. Using estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. Using estrogens with progestins may increase your chance of getting dementia, based on a study of women age 65 years of age or older. You and your healthcare provider should talk regularly about whether you still need treatment with Climara. What is Climara? Climara is a prescription medicine patch (Transdermal System) that contains estradiol (an estrogen hormone). What is Climara used for? The Climara 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 and 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 get 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 to use estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with Climara. Treat moderate to severe menopausal changes in and around the vagina You and your healthcare provider should talk regularly about whether you still need treatment with Climara to control these problems. If you use Climara only to treat your menopausal changes 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 women before menopause if their ovaries do not produce enough estrogens naturally Help reduce your chances of getting osteoporosis (thin weak bones) If you use Climara only to prevent osteoporosis due to menopause, talk with your healthcare provider about whether a different treatment or medicine without estrogens might be better for you. You and your healthcare provider should talk regularly about whether you still need treatment with Climara. Who should not use Climara? Do not start using Climara if you: have unusual vaginal bleeding Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. currently have or have had certain cancers Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use Climara. had a stroke or heart attack currently have or have had blood clots currently have or have had liver problems have been diagnosed with a bleeding disorder are allergic to Climara or any of its ingredients See the list of ingredients in Climara at the end of this leaflet. think you may be pregnant Climara is not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not use Climara if the test is positive and talk to your healthcare provider. What should I tell my healthcare provider before I use Climara? Before you use Climara, tell your healthcare provider if you: have any unusual vaginal bleeding Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. have any other medical conditions Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, angioedema (swelling of face and tongue), or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. are going to have surgery or will be on bed rest. Your healthcare provider will let you know if you need to stop using Climara. are breastfeeding The hormone in Climara can pass into your breast milk. Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Climara works. Climara may also affect how your other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine. How should I use Climara? For detailed instructions, see the step-by-step instructions for using Climara at the end of this Patient Information. Use Climara exactly as your healthcare provider tells you to use it. Climara is for skin use only. Change your Climara patch 1 time each week or every 7 days. Apply your Climara patch to a clean, dry area on your lower abdomen or buttocks. This area must be clean, dry, and free of powder, oil or lotion for your patch to stick to your skin. Apply your Climara patch to a different area of your abdomen or your buttocks each time. Do not use the same application site 2 times in the same week. Do not apply Climara to your breasts. If you forget to apply a new Climara patch, you should apply a new patch as soon as possible. You and your healthcare provider should talk regularly (every 3 to 6 months) about the dose you are using and whether you still need treatment with Climara. How to Change Climara When changing Climara, peel off the used patch slowly from the skin. After removal of Climara, people usually have either no adhesive residue or light adhesive residue. If any adhesive residue remains on your skin after removing the patch, allow the area to dry for 15 minutes. Then, gently rub the area with an oil-based cream or lotion to remove the adhesive from your skin. Keep in mind, the new patch must be applied to a different skin area of your abdomen or buttocks. This area must be clean, dry, and free of powder, oil or lotion. The same site should not be used again for at least 1 week after removal of the patch. What are the possible side effects of Climara? Side effects are grouped by how serious they are and how often they happen when you are treated. Serious, but less common side effects include: heart attack stroke blood clots dementia breast cancer cancer of the lining of the uterus (womb) cancer of the ovary high blood pressure high blood sugar gallbladder disease liver problems changes in your thyroid hormone levels enlargement of benign tumors of the uterus (“fibroids”) Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you: new breast lumps unusual vaginal bleeding changes in vision or speech sudden new severe headaches severe pains in your chest or legs with or without shortness of breath, weakness and fatigue Less serious, but common side effects include: headache breast tenderness or pain irregular vaginal bleeding or spotting stomach or abdominal cramps, bloating nausea and vomiting hair loss fluid retention vaginal yeast infection redness or irritation at the patch placement site These are not all the possible side effects of Climara. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or does not go away. Call your doctor for medical advice about side effects. You may report side effects to Bayer Healthcare Pharmaceuticals at 1-888-842-2937 or to FDA at 1-800-FDA-1088. What can I do to lower my chances of a serious side effect with Climara? Talk with your healthcare provider regularly about whether you should continue using Climara. If you have a uterus, talk with your healthcare provider about whether the addition of a progestin is right for you. The addition of a progestin is generally recommended for women with a uterus to reduce the chance of getting cancer of the uterus (womb). See your healthcare provider right away if you get vaginal bleeding while using Climara. Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease. How should I store and throw away used Climara? Store Climara at room temperature 68°F to 77°F (20°C to 25°C). Do not store Climara patches outside of their pouches. Apply immediately upon removal from the protective pouch. Used patches still contain estrogen. To throw away the patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place this container in the trash. Used patches should not be flushed in the toilet. Keep Climara and all medicines out of the reach of children. General information about the safe and effective use of Climara. Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Climara for conditions for which it was not prescribed. Do not give the Climara patch to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about Climara. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Climara that is written for health professionals. For more information, go to www.climara.com or call Bayer HealthCare Pharmaceuticals Inc at 1-888-842-2937. What are the ingredients in Climara? Active ingredient: estradiol Inactive ingredient: acrylate copolymer adhesive, fatty acid esters, and polyethylene backing. Instructions for Use Climara (Kli-mar-uh) (estradiol transdermal system) Read this Patient Information before you start using Climara and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment. You will need the following supplies: See Figure A Figure A Step 1: Pick the days you will change your Climara. You will need to change your patch 1 time each week or every 7 days. Step 2. Remove the Climara patch from the pouch. Remove patch from its protective pouch by tearing at the notch (do not use scissors). See Figure B Do not remove your patch from the protective pouch until you are ready to apply it. Figure B Step 3. Remove the adhesive liner. See Figure C You will see that Climara is an oval shaped clear patch that is attached to a thick, hard-plastic adhesive liner and covered by a clear, plastic film. See Figure C To apply your patch you must first remove the protective, clear plastic film that is attached to the clear thicker plastic backing. See Figure D There is a silver foil-sticker attached to the inside of the pouch. Do not remove the silver foil sticker from the pouch. See Figure E Figure C, D and E Step 4. Placing the patch on your skin. Apply the sticky side of the patch to 1 of the areas of skin shown below. See Figure F and Figure G Avoid touching the sticky side of the patch with your fingers. Figure F and G Note: Avoid the waistline, since clothing and belts may cause the patch to be rubbed off. Do not apply Climara to your breasts. Only apply Climara to skin that is clean, dry, and free of any powder, oil, or lotion. You should not apply the patch to injured, burned, or irritated skin, or areas with skin conditions (such as birth marks, tattoos, or that is very hairy). Step 5. Press the patch firmly onto your skin. Press the patch firmly in place with your fingers for at least 10 seconds Rub the edges of the patch to make sure that it will stick to your skin. (See Figure H) Figure H Note: Contact with water while you are swimming, using a sauna, bathing, or showering may cause the patch to fall off. If your patch falls off reapply it. If you cannot reapply the patch, apply a new patch to another area (See Figures F and G), and continue to follow your original application schedule. If you stop using your Climara patch or forget to apply a new patch as scheduled, you may have spotting, or bleeding, and your symptoms may come back. Step 6: Throwing away your used patch. When it is time to change your patch, remove the old patch before you apply a new patch. To throw away the patch, fold the sticky side of the patch together, place it in a sturdy childproof container, and place this container in the trash. Used patches should not be flushed in the toilet. This Patient Information and Instructions for Use have been approved by the U.S Food and Drug Administration.

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.

SIDE EFFECTS The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see BOXED WARNING, and WARNINGS AND PRECAUTIONS] Malignant Neoplasms [see BOXED WARNING, and WARNINGS AND PRECAUTIONS] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect pooled data from 5 clinical trials of Climara. A total of 614 women were exposed to Climara for 3 months (193 women at 0.025 mg per day, 201 women at 0.05 mg per day, 194 women at 0.1 mg per day) in randomized, double-blind trials of clinical efficacy versus placebo and versus active comparator. All women were postmenopausal, had a serum estradiol level of less than 20 pg/mL, and a minimum of five moderate to severe hot flushes per week or a minimum of 15 hot flushes per week of any severity at baseline. Included in this table are an additional 25 postmenopausal hysterectomized women exposed to Climara 0.025 mg per day for 6 to 24 months (N=16 at 24 months) in a randomized, double-blind, placebo-controlled study of Climara for the prevention of osteoporosis. Table 1: Treatment-Emergent Adverse Reactions Reported at a Frequency of ≥ 5 Percent and More Frequent in Women Receiving Climara Body System Adverse Reactions Climara Placeboc (N=72) 0.025 mg/daya (N=219) 0.05 mg/dayb (N=201) 0.1 mg/dayb (N=194) Body as a Whole 21% 39% 37% 29% Headache 5% 18% 13% 10% Pain 1% 8% 11% 7% Back Pain 4% 8% 9% 6% Edema 0.5% 13% 10% 6% Digestive System 9% 21% 29% 18% Abdominal Pain 0% 11% 16% 8% Nausea 1% 5% 6% 3% Flatulence 1% 3% 7% 1% Musculoskeletal System 7% 9% 11% 4% Arthralgia 1% 5% 5% 3% Nervous System 13% 10% 11% 1% Depression 1% 5% 8% 0% Urogenital System 12% 18% 41% 11% Breast Pain 5% 8% 29% 4% Leukorrhea 1% 6% 7% 1% Respiratory System 15% 26% 29% 14% URTI 6% 17% 17% 8% Pharyngitis 0.5% 3% 7% 3% Sinusitis 4% 4% 5% 3% Rhinitis 2% 4% 6% 1% Skin and Appendages 19% 12% 12% 15% Pruritus 0.5% 6% 3% 6% a) Adverse reactions occurring at rate of ≥ 5 percent in Climara trials of clinical efficacy versus placebo and versus active comparator; and trial of Climara versus placebo for the prevention of osteoporosis b) Adverse reactions occurring at rate of ≥ 5 percent in Climara trials of clinical efficacy versus placebo and versus active comparator c) Adverse reactions occurring in placebo group in Climara trial of clinical efficacy versus placebo Postmarketing Experience The following adverse reactions have been identified during post-approval use of the Climara transdermal system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Genitourinary System Changes in bleeding pattern, pelvic pain Breast Breast cancer, breast pain, breast tenderness Cardiovascular Changes in blood pressure, palpitations, hot flashes Gastrointestinal Vomiting, abdominal pain, abdominal distension, nausea Skin Alopecia, hyperhidrosis, night sweats, urticaria, rash Eyes Visual disturbances, contact lens intolerance, Central Nervous System Depression, migraine, paresthesia, dizziness, anxiety, irritability, mood swings, nervousness, insomnia, headache Miscellaneous Fatigue, menopausal symptoms, weight increase, application site reaction, anaphylactic reactions DRUG INTERACTIONS Metabolic Interactions In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's wort (hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

WARNINGS See BOXED WARNINGS. The use of unopposed estrogens in women who have a uterus is associated with an increased risk of endometrial cancer. Cardiovascular disorders Estrogen and estrogen/progestin therapy have been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately. Risk factors for arterial vascular disease (e.g. hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. Coronary heart disease and stroke In the Women's Health Initiative study (WHI), an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. In the CE/MPA substudy of WHI an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 women years). The increase in risk was observed in year one and persisted. In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 woman-years). The increase in risk was observed after the first year and persisted. In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA-0.625 mg/ 2.5 mg per day demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and in the placebo group in HERS, HERS II, and overall. Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. Venous thromboembolism (VTE) In the Women's Health Initiative study (WHI), an increase in VTE has been observed in women receiving CE compared to placebo. In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 woman-years in the CE/MPA group compared to 16 per 10,000 woman-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Malignant Neoplasms Endometrial cancer The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with 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 ten years or more, and this risk has been shown to persist for at least 8 to15 years after estrogen therapy is discontinued. Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Breast cancer The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women's Health Initiative (WHI) substudy of CE/MPA (see CLINICAL PHARMACOLOGY, Clinical Studies). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration. The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy. In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs 33 cases per 10,000 woman-years, for CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs 25 cases per 10,000 woman-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs 36 cases per 10,000 woman-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups. The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a health care provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. 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 woman-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 woman-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.) Gallbladder Disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. Hypercalcemia 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. 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. PRECAUTIONS General Addition of a progestin when a woman has not had a hysterectomy. Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer. Elevated blood pressure. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use. Hypertriglyceridemia. In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. Impaired liver function and past history of cholestatic jaundice. Although transdermally administered estrogen therapy avoids first-pass hepatic metabolism, estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. Hypothyroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. Fluid retention. Because estrogens may cause some degree of fluid retention, conditions which might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. Hypocalcemia. Estrogens should be used with caution in individuals with severe hypocalcemia. Ovarian cancer. The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations. Exacerbation of endometriosis. Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. Exacerbation of other conditions. Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. Patient Information. Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Estraderm (estradiol transdermal) . Laboratory Tests Estrogen administration should be initiated at the lowest dose for the approved indication and then guided by clinical response, rather than by serum hormone levels (e.g., estradiol, FSH). Carcinogenesis, Mutagenesis, 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. Pregnancy Estrogens should not be used during pregnancy. (See CONTRAINDICATIONS.) 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 Estraderm (estradiol transdermal) is administered to a nursing woman. Pediatric Use Estrogen 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. (See INDICATIONS and DOSAGE AND ADMINISTRATION.) Geriatric Use Clinical studies of Estraderm (estradiol transdermal) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautions, usually starting at the low end of the range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. In the Women's Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer's disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See WARNINGS, Dementia.)

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.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Cardiovascular Disorders An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. Stroke In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies]. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).1 In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women years) [see Clinical Studies]. The increase in risk was demonstrated after the first year and persisted.1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. Coronary Heart Disease In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo2 [see Clinical Studies]. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).1 In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies]. In postmenopausal women with documented heart disease (n = 2,763), average 66.7 years of age, in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. A total of 2,321 women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall. Venous Thromboembolism In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years3 [see Clinical Studies]. Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately. In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted4 [see Clinical Studies]. Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Malignant Neoplasms Endometrial Cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15-to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Breast Cancer The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80]5 [see Clinical Studies]. The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years for CE plus MPA compared with placebo [see Clinical Studies]. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups6 [see Clinical Studies]. Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. Ovarian Cancer The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7 A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years]vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27 to 1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown. Probable Dementia In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8 [see Use In Specific Populations, and Clinical Studies]. In the WHIMS estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8 [see Use In Specific Populations, and Clinical Studies]. When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see Use In Specific Populations, and Clinical Studies]. Gallbladder Disease A 2-to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. Hypercalcemia Estrogen administration may lead to severe hypercalcemia in women 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. Visual Abnormalities Retinal vascular thrombosis has been reported in women 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. Addition Of A Progestin When A Woman Has Not Had A Hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. Elevated Blood Pressure In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs. Hepatic Impairment And/Or Past History Of Cholestatic Jaundice Estrogens may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued. Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. Fluid Retention Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac or renal impairment, warrant careful observation when estrogen-alone is prescribed. Hypocalcemia Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. Exacerbation Of Endometriosis A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. Hereditary Angioedema Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Exacerbation Of Other Conditions Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. Laboratory Tests Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy. Drug-Laboratory Test Interactions 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. Increased TBG levels 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. Women on thyroid replacement therapy may require higher doses of thyroid hormone. Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-l-antitrypsin, ceruloplasmin). Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, and increased triglyceride levels. Impaired glucose tolerance. Patient Counseling Information See FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use) Vaginal Bleeding Inform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare provider as soon as possible [see WARNINGS AND PRECAUTIONS]. Possible Serious Adverse Reactions With Estrogen-Alone Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy including cardiovascular disorders, malignant neoplasms, and probable dementia [see WARNINGS AND PRECAUTIONS]. Possible Less Serious But Common Adverse Reactions With Estrogen-Alone Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting. Nonclinical Toxicology 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. Use In Specific Populations Pregnancy Climara should not be used during pregnancy [see CONTRAINDICATIONS]. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as oral contraceptives inadvertently during early pregnancy. Nursing Mothers Climara should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the breast milk of women receiving estrogen therapy. Caution should be exercised when the Climara transdermal system is administered to a nursing woman. Pediatric Use Climara is not indicated in children. Clinical studies have not been conducted in the pediatric population. Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Climara to determine whether those over 65 years of age differ from younger subjects in their response to Climara. The Women’s Health Initiative Studies In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies]. In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies]. The Women’s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see WARNINGS AND PRECAUTIONS, and Clinical Studies]. Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see WARNINGS AND PRECAUTIONS, and Clinical Studies]. Renal Impairment In postmenopausal women with end stage renal disease (ESRD) receiving maintenance hemodialysis, total estradiol serum levels are higher than in normal subjects at baseline and following oral doses of estradiol. Therefore, conventional transdermal estradiol doses used in individuals with normal renal function may be excessive for postmenopausal women with ESRD receiving maintenance hemodialysis. Hepatic Impairment Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution. REFERENCES 1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477. 2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357-365. 3. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780. 4. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580. 5. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA. 2006;295:1647-1657. 6. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253. 7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748. 8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958.