PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption Transdermal administration of Climara Pro produces mean maximum estradiol concentrations in serum in about to 2.5 days. Estradiol concentrations equivalent to the normal ranges observed at the early follicular phase in premenopausal women are achieved within 12-24 hours after the first application. In one study, steady state estradiol concentrations in serum were measured during week in 44 healthy, postmenopausal women during four consecutive Climara Pro applications of two formulations (0.045 mg estradiol/0.03 mg levonorgestrel and 0.045 mg estradiol/0.015 mg levonorgestrel) to the abdomen (each dose was applied for four 7-day periods). Both formulations were bioequivalent in terms of estradiol and estrone Cmax and AUC parameters. summary of Climara Pro single and multiple applications estradiol, estrone and levonorgestrel pharmacokinetic parameters is shown in Table 2.Table 2: Summary of Mean Pharmacokinetic ParametersSummary of Mean (+- SD) Pharmacokinetic Parameters Following Single Application of Climara Pro in 24 Healthy Postmenopausal WomenParameterUnitsEstradiolEstroneLevonorgestrelSingle applicationWeek DataCave Pg/mL37.7 +- 10.441 +- 15136 +- 52.7Cmax Pg/mL54.3 +- 18.943.9 +- 14.9138 +- 51.8Tmax Hours428490Cmin Pg/mL27.2 +- 7.6632.6 +- 14.3110 +- 41.7AUCPg.h/mL6340 +- 17406890 +- 252022900 +- 8860Summary of Mean (+- SD) Pharmacokinetic Parameters (Week 4) Following Four Consecutive Weekly Applications of Climara Pro in 44 Healthy Postmenopausal WomenMultiple applicationWeek DataCave Pg/mL35.7 +- 11.445.5 +- 62.6166 +- 97.8Cmax Pg/mL50.7 +- 28.681.6 +- 252194 +- 111Tmax Hours364848Cmin Pg/mL33.8 +- 28.772.5 +- 253153 +- 69.6AUCPg.h/mL6002 +- 19197642 +- 1051827948 +- 16426All mean parameters are arithmetic means except Tmax which is expressed as the median. At steady state, Climara Pro maintains during the application period an average serum estradiol concentration of 35.7 pg/mL as depicted in Figure 1.Figure 1: Mean Estradiol Concentration Profile (Week 4) Following Four Consecutive Weekly Applications of Climara ProFollowing the application of the Climara Pro transdermal system, levonorgestrel concentrations are maximum in about 2.5 days. At steady state, Climara Pro maintains during the application period an average serum levonorgestrel concentration of 166 pg/mL as depicted in Figure 2. The mean levonorgestrel pharmacokinetic parameters of Climara Pro are summarized in Table 2.Figure 2: Mean Levonorgestrel Concentration Profile (Week 4) Following Four Consecutive Weekly Applications of Climara Pro. figure 1. Figure 2. Adhesion. study of the adhesion potential of Climara Pro was conducted in 104 healthy women of 45-75 years of age. Each woman applied placebo patch, containing only the Climara Pro adhesive without active ingredient, to the upper outer abdominal areas weekly for three weeks. The adhesion assessment was done visually on Days 2, 4, 5, and of each of the three weeks using four-point scale. The mean scores ranked in the highest category possible on the to scale demonstrating clinically acceptable adhesion performance. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Following patch removal, serum estradiol concentrations decline with mean (+- SD) terminal half-life of 3+- 0.67 hours. Levonorgestrel and its metabolites are primarily excreted in the urine. Mean (+- SD) terminal half-life for levonorgestrel was determined to be 28 +- 6.4 hours. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in 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 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, significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as circulating reservoir for the formation of more active estrogens.The most important metabolic pathway for levonorgestrel occurs in the reduction of the 4- and the 3-oxo-group as well as hydroxylations at positions 2, 1, and 16, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3, 5-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as the 17-sulfate. In-vitro studies on the biotransformation of levonorgestrel in human skin did not indicate any significant metabolism of levonorgestrel during skin penetration. 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.Levonorgestrel in serum is bound to both SHBG and albumin. Following four consecutive weekly applications of Climara Pro mean (+- SD) SHBG concentrations declined from predose value of 47.5 (25.8) to 41.2 (22.4) nmol/L at week 4.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed elsewhere in the labeling:oCardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)]oMalignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)]. oCardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)]. oMalignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)]. oThe most common adverse reactions (>=5 percent) with Climara Pro are: application site reaction, vaginal bleeding, breast pain, upper respiratory infection, back pain, depression, pain, headache and flu syndrome. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact 1-888-84-BAYER (1-888-842-2937) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. oThe most common adverse reactions (>=5 percent) with Climara Pro are: application site reaction, vaginal bleeding, breast pain, upper respiratory infection, back pain, depression, pain, headache and flu syndrome. (6.1) 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 is from one-year, prospective, multicenter, double blind, double dummy, randomized, controlled trial investigating the effect of three different dosage combinations of E2/LNG versus E2 alone on the development of endometrial hyperplasia. All women were postmenopausal, had serum estradiol level of less than 20 pg/mL, and the sample included both symptomatic and asymptomatic women. The data below includes all adverse reactions reported at frequency of >3% in the E2/LNG 0.045 0.015 group (the approved dosage for Climara Pro, N=212) and the E2 alone group (N=204).Table 1: All Treatment Emergent Reactions Regardless of Relationship Reported at Frequency of >3% with Climara Pro in the 1-year Endometrial Hyperplasia StudyBody System Adverse ReactionClimara Pro0.045 0.015E2 NN total number of subjects in treatment group; = number of subjects with event. 212N 204Body as Whole Abdominal pain (4.2)11 (5.4) Accidental injury (3.3)6 (2.9) Back pain 13 (6.1)12 (5.9) Flu syndrome 10 (4.7)13 (6.4) Infection (3.3)10 (4.9) Pain 11 (5.2)13 (6.4)Cardiovascular System Hypertension (3.3)9 (4.4)Digestive System Flatulence (3.8)11 (5.4)Metabolic and Nutritional Edema (3.8)5 (2.5) Weight gain (2.8)10 (4.9)Musculoskeletal System Arthralgia (4.2)10 (4.9)Nervous System Depression 12 (5.7)7 (3.4) Headache 11 (5.2)14 (6.9)Respiratory System Bronchitis (4.2)7 (3.4) Sinusitis (3.8)12 (5.9) Upper respiratory infection 28 (13.2)26 (12.7)Skin and Appendages Application site reaction 86 (40.6)69 (33.8) Breast pain 40 (18.9)20 (9.8) Rash (2.4)10 (4.9)Urogenital System Urinary Tract Infection7 (3.3)8 (3.9) Vaginal Bleeding 78 (36.8)44 (21.6) Vaginitis (1.9)6 (2.9)Irritation potential of Climara Pro was assessed in 3-week irritation study. The study compared the irritation of Climara Pro placebo patch (22 cm2) to placebo (25 cm2). Visual assessments of irritation were made on Day of each wear period, approximately 30 minutes after patch removal using 7-point scale (0 no evidence of irritation; = minimal erythema, barely perceptible; = definite erythema, readily visible, or minimal edema, or minimal papular response; 3-7 erythema and papules, edema, vesicles, strong extensive reaction). The mean irritation scores were 0.13 (week 1), 0.12 (week 2), and 0.06 (week 3) for the Climara Pro placebo. The mean scores for the placebo group were 0.2 (week 1), 0.26 (week 2), 0.12 (week 3). There were no irritation scores greater than at any timepoint in any woman. In controlled clinical trials, withdrawals due to application site reactions occurred in (2.1 percent) of women in the 12-week symptom study and in 71 (8.5 percent) of subjects in the 1-year endometrial protection study. Adverse Reaction. Abdominal pain Accidental injury Back pain Flu syndrome Infection Pain Hypertension Flatulence Edema Weight gain Arthralgia Depression Headache Bronchitis Sinusitis Upper respiratory infection Application site reaction Breast pain Rash Urinary Tract Infection. Vaginal Bleeding Vaginitis 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of Climara Pro. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Genitourinary System. Changes in bleeding patterns. Gastrointestinal Abdominal distension, abdominal pain, nausea Skin. Alopecia, night sweats, pruritus, Rash, hot flush Central Nervous System. Dizziness, headache, insomnia. Miscellaneous. Application site reaction, weight increased, anaphylactic reaction Combined two or more similar ARs.

BOXED WARNING SECTION.

WARNING: CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, and ENDOMETRIAL CANCER Estrogen Plus Progestin TherapyCardiovascular Disorders and Probable DementiaThe Womens Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (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 conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.5)]. The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 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 (5.3 ), Use in Specific Populations (8.5), and Clinical Studies (14.6)]. Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 14.6)]. Breast CancerThe WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.5)].Only daily oral 0.625 mg CE and MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.Estrogen-Alone TherapyEndometrial CancerThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens. Adding progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be precursor to endometrial cancer. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2)].Cardiovascular Disorders and Probable DementiaThe WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.5)]. The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and 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 (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.6)].Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 14.6)]. Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.. WARNING: CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, and ENDOMETRIAL CANCER See full prescribing information for complete boxed warning.Estrogen Plus Progestin TherapyoThe Womens Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI) (5.1)oThe WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer (5.2)oThe WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3)oDo not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia (5.1, 5.3)Estrogen-Alone TherapyoThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens (5.2) oThe WHI estrogen-alone substudy reported increased risks of stroke and DVT (5.1) oThe WHIMS estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3)oDo not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia (5.1, 5.3). oThe Womens Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI) (5.1). oThe WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer (5.2). oThe WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3). oDo not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia (5.1, 5.3). oThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens (5.2) oThe WHI estrogen-alone substudy reported increased risks of stroke and DVT (5.1) oThe WHIMS estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3). oDo not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia (5.1, 5.3).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 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 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 negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Levonorgestrel inhibits gonadotropin production resulting in retardation of follicular growth and inhibition of ovulation. Studies to assess the potency of progestins using estrogen-primed postmenopausal endometrial biochemistry and morphologic features have shown that levonorgestrel counteracts the proliferative effects of estrogens on the endometrium.. 12.2 Pharmacodynamics. Generally, serum estrogen concentration does not predict an individual womans therapeutic response to Climara nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.. 12.3 Pharmacokinetics. Absorption Transdermal administration of Climara Pro produces mean maximum estradiol concentrations in serum in about to 2.5 days. Estradiol concentrations equivalent to the normal ranges observed at the early follicular phase in premenopausal women are achieved within 12-24 hours after the first application. In one study, steady state estradiol concentrations in serum were measured during week in 44 healthy, postmenopausal women during four consecutive Climara Pro applications of two formulations (0.045 mg estradiol/0.03 mg levonorgestrel and 0.045 mg estradiol/0.015 mg levonorgestrel) to the abdomen (each dose was applied for four 7-day periods). Both formulations were bioequivalent in terms of estradiol and estrone Cmax and AUC parameters. summary of Climara Pro single and multiple applications estradiol, estrone and levonorgestrel pharmacokinetic parameters is shown in Table 2.Table 2: Summary of Mean Pharmacokinetic ParametersSummary of Mean (+- SD) Pharmacokinetic Parameters Following Single Application of Climara Pro in 24 Healthy Postmenopausal WomenParameterUnitsEstradiolEstroneLevonorgestrelSingle applicationWeek DataCave Pg/mL37.7 +- 10.441 +- 15136 +- 52.7Cmax Pg/mL54.3 +- 18.943.9 +- 14.9138 +- 51.8Tmax Hours428490Cmin Pg/mL27.2 +- 7.6632.6 +- 14.3110 +- 41.7AUCPg.h/mL6340 +- 17406890 +- 252022900 +- 8860Summary of Mean (+- SD) Pharmacokinetic Parameters (Week 4) Following Four Consecutive Weekly Applications of Climara Pro in 44 Healthy Postmenopausal WomenMultiple applicationWeek DataCave Pg/mL35.7 +- 11.445.5 +- 62.6166 +- 97.8Cmax Pg/mL50.7 +- 28.681.6 +- 252194 +- 111Tmax Hours364848Cmin Pg/mL33.8 +- 28.772.5 +- 253153 +- 69.6AUCPg.h/mL6002 +- 19197642 +- 1051827948 +- 16426All mean parameters are arithmetic means except Tmax which is expressed as the median. At steady state, Climara Pro maintains during the application period an average serum estradiol concentration of 35.7 pg/mL as depicted in Figure 1.Figure 1: Mean Estradiol Concentration Profile (Week 4) Following Four Consecutive Weekly Applications of Climara ProFollowing the application of the Climara Pro transdermal system, levonorgestrel concentrations are maximum in about 2.5 days. At steady state, Climara Pro maintains during the application period an average serum levonorgestrel concentration of 166 pg/mL as depicted in Figure 2. The mean levonorgestrel pharmacokinetic parameters of Climara Pro are summarized in Table 2.Figure 2: Mean Levonorgestrel Concentration Profile (Week 4) Following Four Consecutive Weekly Applications of Climara Pro. figure 1. Figure 2. Adhesion. study of the adhesion potential of Climara Pro was conducted in 104 healthy women of 45-75 years of age. Each woman applied placebo patch, containing only the Climara Pro adhesive without active ingredient, to the upper outer abdominal areas weekly for three weeks. The adhesion assessment was done visually on Days 2, 4, 5, and of each of the three weeks using four-point scale. The mean scores ranked in the highest category possible on the to scale demonstrating clinically acceptable adhesion performance. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Following patch removal, serum estradiol concentrations decline with mean (+- SD) terminal half-life of 3+- 0.67 hours. Levonorgestrel and its metabolites are primarily excreted in the urine. Mean (+- SD) terminal half-life for levonorgestrel was determined to be 28 +- 6.4 hours. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in 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 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, significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as circulating reservoir for the formation of more active estrogens.The most important metabolic pathway for levonorgestrel occurs in the reduction of the 4- and the 3-oxo-group as well as hydroxylations at positions 2, 1, and 16, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3, 5-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as the 17-sulfate. In-vitro studies on the biotransformation of levonorgestrel in human skin did not indicate any significant metabolism of levonorgestrel during skin penetration. 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.Levonorgestrel in serum is bound to both SHBG and albumin. Following four consecutive weekly applications of Climara Pro mean (+- SD) SHBG concentrations declined from predose value of 47.5 (25.8) to 41.2 (22.4) nmol/L at week 4.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Effects on Vasomotor Symptoms in Postmenopausal Women The efficacy of 0.045 mg estradiol/0.03 mg levonorgestrel administered weekly versus placebo in the relief of moderate to severe vasomotor symptoms in postmenopausal women was studied in one 12-week clinical trial (n=183, average age 52.1 +- 4.93, 82 percent Caucasian). The 0.045 mg estradiol/0.03 mg levonorgestrel dosage strength was shown to be statistically better than placebo at weeks and 12 for relief of both the number and severity of moderate to severe hot flushes. See Tables and 4. Climara Pro and the 0.045 mg estradiol/0.03 mg levonorgestrel dosage strength are bioequivalent in terms of estradiol delivery [See Clinical Pharmacology (12.3)]. Table 3: Summary of Mean Daily Number of Moderate to Severe Hot Flushes-ITTIntent-to-Treat population BaselineA participating woman was included at baseline only if she had post-baseline mean score. The post-baseline mean score required days in one week.Week 4Week 8Week 12Placebonn Number of participating women in treatment group in cycle; number of women varied from cycle to cycle due to missing data. 88827369Mean (SD)SD standard deviation 10.8(5.803)6.13(4.311)5.35(4.095)5.59(4.93)Mean Changefrom baseline (SD)NA-4.23(4.374)-4.8(4.448)-4.55(5.407)0.045/.03n 92888073Mean (SD) 10.13(3.945)2.69(4.455)1.22(2.804)1.06(3.187)Mean Changefrom baseline (SD) NA-7.4(4.715)-8.68(4.146)-8.82(4.336)p-Value p-value for comparison to placebo, adjusted by the method of Bonferroni NA<0.001p <0.025 NA<0.001 Table 4: Summary of Mean Severity of Moderate to Severe Hot Flushes-ITTITT= Intent-to-Treat population BaselineA participating woman was included at baseline only if she had at least post-baseline value. Week 4(day 7)Week 8(day 7)Week 12(day 7)Placebon 89766857Mean (SD)d2.42(0.282)1.99(0.875)1.93(0.955)1.8(1.034)Mean Changefrom baseline(SD)SD= standard deviation Severity scores are: = Mild, = Moderate, = Severe. Mean severity of hot flushes by day is [(2X number of moderate hot flushes) (3X number of severe hot flushes)] total number of moderate to severe hot flushes on that day. If no moderate to severe hot flush was indicated, the mean severity was 0. NA-0.4(0.865)-0.48(0.922)-0.57(1.044)0.045/.03 92837255Mean (SD) 2.48(0.295)1.1(1.191)0.82(1.226)0.44(0.96)Mean Changefrom baseline(SD) NA-1.4(1.164)-1.67(1.245)-2.06(1.005)p-value p-value for comparison to placebo, adjusted by the method of Bonferroni NA<0.001 <0.025 NA<0.001 14.2 Effects on the Endometrium in Postmenopausal Women In 1-year clinical trial of 412 postmenopausal women (with intact uteri) treated with continuous regimen of Climara Pro or with an continuous estradiol-only transdermal system, results of evaluable endometrial biopsies show that no hyperplasia was seen with Climara Pro. Table below summarizes these results (Intent-to-Treat populations).Table 5: Incidence of Endometrial Hyperplasia during Continuous Combined Treatment with Climara Pro, ITTITT Intent-to-Treat population Climara ProE2 0.045 mg LNG 0.015 mgEstradiolE2 0.045 mgnn number of intent-to-treat in women. 210na 202No. of Patients with Biopsies at >6 monthsDefined as at least 180 days of treatment. 124139No. of Patients with Biopsies at yearDefined as >= 323 days of treatment. 102110No. (%) of Patients with HyperplasiaIncludes hyperplasia occurring at any time after initiation of treatment as proportion of patients with biopsies at year. (0%)p 0.0167 p-value for comparison to unopposed estradiol dose using the Fisher Exact test. P-values were adjusted by the method of Bonferroni. 19 (17.3%)95% Confidence Interval0-3.55%9.75-24.79%. 14.3 Effects on Uterine Bleeding or Spotting in Postmenopausal Women. The effects of Climara Pro on uterine bleeding or spotting, as recorded using an interactive voice response system, were evaluated in one 12-month clinical trial. Results are shown in Figure 3.Figure 3: Cumulative Proportion of Subjects at Each Cycle with No Bleeding/Spotting Through the End of Cycle 13 Last Observation Carried ForwardoPercent based upon the number of participating women with dataoLast non-missing cycle carried forward through cycle 13oBleeding associated with endometrial biopsies not included oPercent based upon the number of participating women with data. oLast non-missing cycle carried forward through cycle 13. oBleeding associated with endometrial biopsies not included fig 3. 14.4 Effects on Bone Mineral Density in Postmenopausal Women. The effects on bone mineral density (BMD) were studied in randomized, double-blind, placebo-controlled clinical trial of transdermal systems (patches) containing only estradiol (E2). Participants were postmenopausal women with hysterectomies, 40-83 years of age (mean=51.4 years), and 77.3 percent Caucasian. Women received calcium supplements if they appeared deficient on questionnaire. Vitamin supplements were not given. total of 154 women were randomized in 2:2:3 ratio to weekly application of 22 cm2 patches containing 2.2 mg E2, 4.4 mg E2, or placebo, for 728 days of continuous treatment (26 28-day cycles). Only the results for the estradiol dose in Climara Pro (4.4 mg E2) and for placebo are presented. Statistically significant increases in the primary efficacy variable, BMD of the lumbar spine (A-P view, L2-L4), were seen for 4.4 mg E2 compared to placebo (see Table and Figure 4). BMD was also measured at the hip (total, non-dominant side) and radius (midshaft, non-dominant side) with statistically significant treatment effects only observed for the hip (see Table 6). Table 6: Mean Bone Mineral Density (Standard Deviation)Intent-to-treat population with on-treatment efficacy data 4.4 mg E2 E2=estradiol; LOCF= Last Observation Carried ForwardPlacebo Total Lumbar Spine Baseline (g/cm2) n=361.1 (0.2)n=461.1 (0.2) Change from baseline LOCF +1.7% (4.4)-2.9% (3.8)P-value compared to placebo <0.0001Total Hip Baseline (g/cm2) n=360.97 (0.1)n=480.94 (0.1) Change from baseline LOCF +1.3% (4.2)-0.9% (5.2)P-value compared to placebo 0.05 Figure 4: Percent Change From Baseline in Bone Mineral Density (g/cm2) of Lumbar Spine (A-P View, L2-L4) by Treatment Group and Cycle (Mean +- SE) Data in the figure is for 21 patients on 4.4 mg E2 and 27 placebo patients who completed the study; approximately 44 percent of randomized patients. fig 4. 14.5 Womens 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. 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 cause. These substudies did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms. 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 more CHD events, more strokes, 10 more PEs, and more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were fewer colorectal cancers and 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, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 7. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.Table 7: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 YearsAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. Results are based on centrally adjudicated data. EventRelative RiskCE/MPA vs. Placebo (95% nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons)CE/MPA = 8,506 Placebo = 8,102 Absolute Risk per 10,000 Women-YearsCHD events Non-fatal MI CHD death 1.23 (0.99-1.53) 1.28 (1.00-1.63) 1.10 (0.70-1.75) 4134312588All strokes1.31 (1.03-1.68)3325Ischemic stroke1.44 (1.09-1.90)2618Deep vein thrombosisNot included in global index. 1.95 (1.43-2.67)2613Pulmonary embolism2.13 (1.45-3.11)188Invasive breast cancerIncludes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. 1.24 (1.01-1.54)4133Colorectal cancer0.61 (0.42-0.87)1016Endometrial cancer 0.81 (0.48-1.36)67Cervical cancer 1.44 (0.47-4.42)21Hip fracture 0.67 (0.47-0.96)1116Vertebral fractures 0.65 (0.46-0.92)1117Lower arm/wrist fractures 0.71 (0.59-0.85)4462Total fractures 0.76 (0.69-0.83)152199Overall MortalityAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.00 (0.83-1.19)5252Global IndexA subset of the events was combined in global index, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. 1.13 (1.02-1.25)184165Timing of the 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, non-significant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44-1.07)]. 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 risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average age of 63 years, 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 8.Table 8: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI EventRelative RiskCE vs. Placebo(95% nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons.)CEn 5,310Placebon 5,429Absolute Risk per 10,000 Women-YearsCHD eventsResults are based on centrally adjudicated data for an average follow-up of 7.1 years. 0.95 (0.78-1.16)5457 Non-fatal MI0.91 (0.73-1.14)4043 CHD death1.01 (0.71-1.43)1616All strokes 1.33 (1.05-1.68)4533Ischemic stroke1.55 (1.19-2.01)3825Deep vein thrombosis Not included in global index. 1.47 (1.06-2.06)2315Pulmonary embolism 1.37 (0.90-2.07)1410Invasive breast cancer 0.80 (0.62-1.04)2834Colorectal cancer 1.08 (0.75-1.55)1716Hip fracture 0.65 (0.45-0.94)1219Vertebral fractures 0.64 (0.44-0.93)1118Lower arm/wrist fractures 0.58 (0.47-0.72)3559Total fractures 0.71 (0.64-0.80)144197Death due to other causesResults are based on an average follow-up of 6.8 years. All deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease. 1.08 (0.88-1.32)5350Overall Mortality 1.04 (0.88-1.22)7975Global IndexA subset of the events was combined in global index, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. 1.02 (0.92-1.13)206201For those outcomes included in the WHI global index that reached statistical significance, the absolute excess risk 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 fewer hip fractures.9 The absolute excess risk of events included in the global index was non-significant 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.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 distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.10 Timing of the 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, non-significant trend toward reduced risk for CHD [HR 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)]. Non-fatal MI. CHD death. 14.6 Womens Health Initiative Memory Study The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 to 79 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 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 was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimers disease (AD), vascular dementia (VaD) and mixed type (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 (5.3), and Use in Specific Populations (8.5)]. The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 years of age and older (45 percent were age 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 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 this study included Alzheimers disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo groups 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 (5.3), and Use in Specific Populations (8.5)].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 (5.3), and Use in Specific Populations (8.5)].

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Use estrogen-alone, or in combination with progestogen, at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual women. Reevaluate postmenopausal women periodically as clinically appropriate to determine if treatment is still necessary. One Climara Pro transdermal system is available for use.. oApply Climara Pro 0.045 mg per day/0.015 mg per day once-weekly to the lower abdomen (2.3). oApply Climara Pro 0.045 mg per day/0.015 mg per day once-weekly to the lower abdomen (2.3). 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause. Start therapy with Climara Pro 0.045 mg per day/0.015 mg per day applied to the skin once weekly. Start therapy at the lowest effective dose and the shortest duration consistent with the treatment goals. Attempts to discontinue Climara Pro should be made at to month intervals.. 2.2 Prevention of Postmenopausal Osteoporosis. Apply Climara Pro 0.045 mg per day/0.015 mg per day applied to the skin once weekly.. 2.3 Application of the Climara Pro Transdermal System Initiation of Therapy Women not currently using continuous estrogen-alone therapy or estrogen plus progestogen therapy may start therapy with Climara Pro at any time. However, women currently using continuous estrogen-alone therapy or estrogen plus progestogen therapy should complete the current cycle of therapy before initiating Climara Pro therapy. Women often experience withdrawal bleeding at the completion of the cycle. The first day of this bleeding would be an appropriate time to begin Climara Pro therapy.. Site Selection. oPlace the adhesive side of Climara Pro on smooth (fold free), clean, dry area of the skin on the lower abdomen or the upper quadrant of the buttock. oDo not apply Climara Pro to or near the breasts. oSelect an area selected that is not oily (which can impair adherence of the system), damaged, or irritated. oAvoid the waistline; tight clothing may rub Climara Pro off or modify drug delivery.oAvoid application to areas where sitting would dislodge Climara Pro.oRotate the sites of application, with an interval of at least 1-week allowed between applications to the same site. oPlace the adhesive side of Climara Pro on smooth (fold free), clean, dry area of the skin on the lower abdomen or the upper quadrant of the buttock. oDo not apply Climara Pro to or near the breasts. oSelect an area selected that is not oily (which can impair adherence of the system), damaged, or irritated. oAvoid the waistline; tight clothing may rub Climara Pro off or modify drug delivery.. oAvoid application to areas where sitting would dislodge Climara Pro.. oRotate the sites of application, with an interval of at least 1-week allowed between applications to the same site. Application oApply Climara Pro immediately after opening the pouch and removing the protective lining. oPress Climara Pro firmly in place with the fingers for at least 10 seconds, making sure there is good contact, especially around the edges.oIf the system lifts, apply pressure to maintain adhesion. oIn the event that system should fall off, reapply the same system to another area of the lower abdomen. If the system cannot be reapplied, new system may be applied, in which case, the original treatment schedule should be continued. oOnly one system should be worn at any one time during 7-day dosing interval. oDo not expose the applied transdermal system to the sun for prolonged periods of time. oSwimming, bathing, or using sauna while using Climara Pro has not been studied, and these activities may decrease the adhesion of the system and the delivery of the estrogen and progestin.. oApply Climara Pro immediately after opening the pouch and removing the protective lining. oPress Climara Pro firmly in place with the fingers for at least 10 seconds, making sure there is good contact, especially around the edges.. oIf the system lifts, apply pressure to maintain adhesion. oIn the event that system should fall off, reapply the same system to another area of the lower abdomen. If the system cannot be reapplied, new system may be applied, in which case, the original treatment schedule should be continued. oOnly one system should be worn at any one time during 7-day dosing interval. oDo not expose the applied transdermal system to the sun for prolonged periods of time. oSwimming, bathing, or using sauna while using Climara Pro has not been studied, and these activities may decrease the adhesion of the system and the delivery of the estrogen and progestin.. 2.4 Removal of the Climara Pro Transdermal System oRemove Climara Pro carefully and slowly to avoid irritation of the skin. oIf any adhesive remain on the skin after removal of Climara Pro, allow the area to dry for 15 minutes and then gently rub the area with an oil-based cream or lotion should remove the adhesive residue. oUsed patches still contain some active hormones. Carefully fold each patch in half so that it sticks to itself before throwing it away.. oRemove Climara Pro carefully and slowly to avoid irritation of the skin. oIf any adhesive remain on the skin after removal of Climara Pro, allow the area to dry for 15 minutes and then gently rub the area with an oil-based cream or lotion should remove the adhesive residue. oUsed patches still contain some active hormones. Carefully fold each patch in half so that it sticks to itself before throwing it away.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Package Insert. Patient InformationClimara Pro (Kli-mar-uh pro)(estradiol/levonorgestrel transdermal system)Read this Patient Information before you start using Climara Pro and each time you get 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 should know about Climara Pro (a combination of estrogen and progestogen)oDo not use estrogens with or without progestogens to prevent heart disease, heart attacks, strokes, or dementia (declines of brain function).oUsing estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. oUsing estrogens with progestogens may increase your chance of getting dementia, based on study of women 65 years of age and older.oUsing estrogen-alone may increase your chance of getting cancer of the uterus (womb).oDo not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia.oUsing estrogen-alone may increase your chances of getting strokes or blood clots.oUsing estrogen-alone may increase your chance of getting dementia, based on study of women 65 years of age and older.oOnly one estrogen with progestogen product and dose have been shown to increase your chances of getting heart attacks, strokes, breast cancer, blood clots, and dementia. Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. Because other products and doses have not been studied in the same way, it is not known how the use of Climara Pro will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with Climara Pro.What is Climara ProClimara Pro is prescription medicine patch (transdermal system) that contains two kinds of hormones, an estrogen and progestogen. What is Climara Pro used for Climara Pro is used after menopause to:oReduce moderate to severe hot flashes Estrogens are hormones made by womans ovaries. The ovaries normally stop making estrogens when 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 intense 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. oHelp reduce your chances of getting osteoporosis (thin weak bones) Osteoporosis from menopause is thinning of the bones that makes them weaker and easier to break. If you use Climara Pro to prevent osteoporosis from menopause, talk with your healthcare provider about whether 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 Pro. Who should not use Climara ProDo not use Climara Pro if you have had your uterus (womb) removed (hysterectomy). Climara Pro contains progestogen to decrease the chance of getting cancer of the uterus. If you do not have uterus, you do not need progestogen and you should not use Climara Pro. Do not start using Climara Pro if you:ohave any unusual vaginal bleeding Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.ohave been diagnosed with bleeding disorderocurrently have or have had certain cancers Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use Climara Pro.ohad stroke or heart attack ocurrently have or have had blood clotsocurrently have or have had liver problemsoare allergic to Climara Pro or any of the ingredients in it. See the list of ingredients in Climara Pro at the end of this leaflet. Before you use Climara Pro, tell your healthcare provider about all of your medical conditions, including if you:ohave any unusual vaginal bleeding Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.ohave any other medical conditions that may become worse while you are using Climara 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.oare going to have surgery or will be on bed rest Your healthcare provider will let you know if you need to stop using Climara Pro. oare pregnant or think you may be pregnant. Climara is not for pregnant women.oare breastfeeding The hormones in Climara Pro can pass into your breast milk.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how Climara Pro works. Climara Pro may also affect how your other medicines work. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine. How should use Climara ProFor detailed instructions, see the step-by-step instructions for using Climara Pro at the end of this Patient Information.oUse Climara Pro exactly as your healthcare provider tells you to use it.oClimara Pro is for skin use only.oChange your Climara Pro patch time each week or every days. oApply your Climara Pro patch to 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.oApply your Climara Pro patch to different area of your abdomen or your buttocks each time. Do not use the same application site times in the same week.oDo not apply Climara Pro to your breasts.oIf you forget to apply new Climara Pro, apply new patch as soon as possible.oYou and your healthcare provider should talk regularly (every to months) about the dose you are using and whether you still need treatment with Climara Pro.How do change Climara ProoWhen changing Climara Pro, peel off the used patch slowly from the skin.oAfter removal of Climara Pro, 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. oApply the new patch to different skin area of your lower abdomen or buttocks. This area must be clean, dry, and free of powder, oil or lotion. Do not use the same site again for at least week after removal of the patch.What are the possible side effects of Climara ProSide effects are grouped by how serious they are and how often they happen when you are treated.Serious, but less common side effects include:oheart attackostroke oblood clotsobreast cancerocancer of the lining of the uterus (womb)ocancer of the ovaryodementiaohigh or low blood calciumogallbladder disease ovisual abnormalitiesohigh blood pressure ocancer changes of endometriosisohigh levels of fat (triglyceride) in your bloodoliver problemsochanges in your thyroid hormone levelsofluid retentionoenlargement of benign tumors of the uterus (fibroids)oworsening of swelling of face and tongue (angioedema) in women with history of angioedemaCall your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:onew breast lumpsounusual vaginal bleedingochanges in vision or speechosudden new severe headachesosevere pains in your chest or legs with or without shortness of breath, weakness and fatigue Common side effects of Climara Pro include:These are not all the possible side effects of Climara Pro. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or do not go away. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Bayer Healthcare Pharmaceuticals at 1-888-842-2937. What can do to lower my chances of serious side effect with Climara ProoTalk with your healthcare provider regularly about whether you should continue using Climara Pro.oIf you have uterus, talk with your healthcare provider about whether Climara Pro is right for you. In general, the addition of progestogen is generally recommended for woman with uterus to reduce the chance of getting cancer of the uterus (womb).oSee your healthcare provider right away if you get vaginal bleeding while using Climara Pro.oHave 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.oIf 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 store and throw away used Climara ProoStore at room temperature between 68F to 77F (20C to 25C).oDo not store Climara Pro patches outside of their pouches. Apply immediately after removal from the protective pouch.oUsed patches still contain estrogen. To throw away the patch, fold the sticky side of the patch together, place it in sturdy child-proof container, and place this container in the trash. Used patches should not be flushed in the toilet.KEEP CLIMARA PRO and all medicines out of the reach of children.General information about the safe and effective use of Climara Pro.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use Climara Pro for conditions for which it was not prescribed. Do not give Climara Pro to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about Climara Pro that is written for health professionals. For more information, go to www.climara-us.com or call Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937. What are the ingredients in Climara ProActive ingredient: estradiol and levonorgestrelInactive ingredient: acrylate copolymer adhesive, and polyvinylpyrrolidone/vinyl acetate copolymer. Instructions for UseClimara Pro (Kli-mar-uh pro)(estradiol transdermal system)Read this Patient Information before you start using Climara Pro and each time you get 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 AFigure AStep 1: Pick the days you will change your Climara Pro.oYou will need to change your patch time each week or every days. Step 2. Remove the Climara Pro patch from the pouch.oRemove patch from its protective pouch by tearing at the notch (do not use scissors). See Figure BoDo not remove your patch from the protective pouch until you are ready to apply it. Figure BStep 3. Remove the adhesive liner. See Figure CoYou will see that Climara Pro is an oval shaped clear patch that is attached to thick, hard-plastic adhesive liner and covered by clear, plastic film. See Figure CoTo apply your patch you must first remove the protective, clear plastic film that is attached to the clear thicker plastic backing. See Figure DoThere is silver foil-sticker attached to the inside of the pouch. Do not remove the silver foil sticker from the pouch. See Figure EFigure CFigure DFigure EStep 4. Placing the patch on your skin.oApply the sticky side of the patch to one of the areas of skin shown below. See Figure and Figure GoDo not touch the sticky side of the patch with your fingers.Figure FFigure GNote:oAvoid the waistline, since clothing and belts may cause the patch to be rubbed off.oDo not apply Climara Pro to your breasts.oOnly apply Climara Pro to skin that is clean, dry, and free of any powder, oil, or lotion.oYou 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.oPress the patch firmly in place with your fingers for at least 10 secondsoRub the edges of the patch to make sure that it will stick to your skin. (See Figure H)Figure HNote:oContact with water while you are swimming, using sauna, bathing, or showering may cause the patch to fall off.oIf your patch falls off reapply it. If you cannot reapply the patch, apply new patch to another area (See Figures and G) and continue to follow your original application schedule.oIf you stop using your Climara Pro or forget to apply new patch as scheduled, you may have spotting, or bleeding, and your symptoms may come back.Step 6: Throwing away your used patch.oWhen it is time to change your patch, remove the old patch before you apply new patch.oTo throw away the patch, fold the sticky side of the patch together, place it in sturdy child-proof container, and place this container in the trash. Do not flush used patches in the toilet.This Patient Information and Instructions for Use have been approved by the U.S Food and Drug Administration.(C) 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.11/2021Manufactured for:Bayer HealthCare Pharmaceuticals Inc.Whippany, NJ 07981. oDo not use estrogens with or without progestogens to prevent heart disease, heart attacks, strokes, or dementia (declines of brain function).. oUsing estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. oUsing estrogens with progestogens may increase your chance of getting dementia, based on study of women 65 years of age and older.. oUsing estrogen-alone may increase your chance of getting cancer of the uterus (womb).. oDo not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia.. oUsing estrogen-alone may increase your chances of getting strokes or blood clots.. oUsing estrogen-alone may increase your chance of getting dementia, based on study of women 65 years of age and older.. oOnly one estrogen with progestogen product and dose have been shown to increase your chances of getting heart attacks, strokes, breast cancer, blood clots, and dementia. Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. Because other products and doses have not been studied in the same way, it is not known how the use of Climara Pro will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with Climara Pro.. oReduce moderate to severe hot flashes Estrogens are hormones made by womans ovaries. The ovaries normally stop making estrogens when 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 intense 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. oHelp reduce your chances of getting osteoporosis (thin weak bones). Osteoporosis from menopause is thinning of the bones that makes them weaker and easier to break. If you use Climara Pro to prevent osteoporosis from menopause, talk with your healthcare provider about whether 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 Pro. Climara Pro contains progestogen to decrease the chance of getting cancer of the uterus. If you do not have uterus, you do not need progestogen and you should not use Climara Pro. ohave any unusual vaginal bleeding. Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.. ohave been diagnosed with bleeding disorder. ocurrently have or have had certain cancers Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use Climara Pro.. ohad stroke or heart attack ocurrently have or have had blood clots. ocurrently have or have had liver problems. oare allergic to Climara Pro or any of the ingredients in it.. See the list of ingredients in Climara Pro at the end of this leaflet. ohave any unusual vaginal bleeding. Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.. ohave any other medical conditions that may become worse while you are using Climara. 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.. oare going to have surgery or will be on bed rest. Your healthcare provider will let you know if you need to stop using Climara Pro. oare pregnant or think you may be pregnant. Climara is not for pregnant women.. oare breastfeeding The hormones in Climara Pro can pass into your breast milk.. oUse Climara Pro exactly as your healthcare provider tells you to use it.. oClimara Pro is for skin use only.. oChange your Climara Pro patch time each week or every days. oApply your Climara Pro patch to 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.. oApply your Climara Pro patch to different area of your abdomen or your buttocks each time. Do not use the same application site times in the same week.. oDo not apply Climara Pro to your breasts.. oIf you forget to apply new Climara Pro, apply new patch as soon as possible.. oYou and your healthcare provider should talk regularly (every to months) about the dose you are using and whether you still need treatment with Climara Pro.. oWhen changing Climara Pro, peel off the used patch slowly from the skin.. oAfter removal of Climara Pro, 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. oApply the new patch to different skin area of your lower abdomen or buttocks. This area must be clean, dry, and free of powder, oil or lotion. Do not use the same site again for at least week after removal of the patch.. oheart attack. ostroke oblood clots. obreast cancer. ocancer of the lining of the uterus (womb). ocancer of the ovary. odementia. ohigh or low blood calcium. ogallbladder disease ovisual abnormalities. ohigh blood pressure ocancer changes of endometriosis. ohigh levels of fat (triglyceride) in your blood. oliver problems. ochanges in your thyroid hormone levels. ofluid retention. oenlargement of benign tumors of the uterus (fibroids). oworsening of swelling of face and tongue (angioedema) in women with history of angioedema. onew breast lumps. ounusual vaginal bleeding. ochanges in vision or speech. osudden new severe headaches. osevere pains in your chest or legs with or without shortness of breath, weakness and fatigue oTalk with your healthcare provider regularly about whether you should continue using Climara Pro.. oIf you have uterus, talk with your healthcare provider about whether Climara Pro is right for you. In general, the addition of progestogen is generally recommended for woman with uterus to reduce the chance of getting cancer of the uterus (womb).. oSee your healthcare provider right away if you get vaginal bleeding while using Climara Pro.. oHave 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.. oIf 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.. oStore at room temperature between 68F to 77F (20C to 25C).. oDo not store Climara Pro patches outside of their pouches. Apply immediately after removal from the protective pouch.. oUsed patches still contain estrogen. To throw away the patch, fold the sticky side of the patch together, place it in sturdy child-proof container, and place this container in the trash. Used patches should not be flushed in the toilet.. oYou will need to change your patch time each week or every days. oRemove patch from its protective pouch by tearing at the notch (do not use scissors). See Figure B. oDo not remove your patch from the protective pouch until you are ready to apply it. oYou will see that Climara Pro is an oval shaped clear patch that is attached to thick, hard-plastic adhesive liner and covered by clear, plastic film. See Figure C. oTo apply your patch you must first remove the protective, clear plastic film that is attached to the clear thicker plastic backing. See Figure D. oThere is silver foil-sticker attached to the inside of the pouch. Do not remove the silver foil sticker from the pouch. See Figure E. oApply the sticky side of the patch to one of the areas of skin shown below. See Figure and Figure G. oDo not touch the sticky side of the patch with your fingers.. oAvoid the waistline, since clothing and belts may cause the patch to be rubbed off.. oDo not apply Climara Pro to your breasts.. oOnly apply Climara Pro to skin that is clean, dry, and free of any powder, oil, or lotion.. oYou 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).. oPress the patch firmly in place with your fingers for at least 10 seconds. oRub the edges of the patch to make sure that it will stick to your skin. (See Figure H). oContact with water while you are swimming, using sauna, bathing, or showering may cause the patch to fall off.. oIf your patch falls off reapply it. If you cannot reapply the patch, apply new patch to another area (See Figures and G) and continue to follow your original application schedule.. oIf you stop using your Climara Pro or forget to apply new patch as scheduled, you may have spotting, or bleeding, and your symptoms may come back.. oWhen it is time to change your patch, remove the old patch before you apply new patch.. oTo throw away the patch, fold the sticky side of the patch together, place it in sturdy child-proof container, and place this container in the trash. Do not flush used patches in the toilet.. Fig A. Tear pouch. Fig C. fig d. Fig E. Fig F. Fig G. Fig H.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oEstrogens increase the risk of gallbladder disease (5.4)oDiscontinue estrogens if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.5, 5.6, 5.9, 5.10)oMonitor thyroid function in women on thyroid hormone replacement therapy (5.11, 5.18) oEstrogens increase the risk of gallbladder disease (5.4). oDiscontinue estrogens if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.5, 5.6, 5.9, 5.10). oMonitor thyroid function in women on thyroid hormone replacement therapy (5.11, 5.18) 5.1 Cardiovascular Disorders. Increased risks of PE, DVT, stroke and MI are reported with estrogen plus progestin therapy. Increased risks of stroke and DVT are reported with estrogen-alone therapy. Immediately discontinue estrogen with or without progestogen therapy if any of these occur or are suspected. Manage appropriately any 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).. Stroke. The WHI estrogen plus progestin substudy reported statistically significant increased risk of stroke 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 strokes per 10,000 women-years, respectively) [see Clinical Studies (14.5)]. The increase in risk was demonstrated after the first year and persisted.1 Immediately discontinue estrogen plus progestogen therapy if stroke occurs or is suspected.The WHI estrogen-alone substudy, reported statistically significant increased risk of stroke 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 strokes per 10,000 women-years, respectively). The increase in risk was demonstrated in year and persisted [see Clinical Studies (14.5)]. Immediately discontinue estrogen-alone therapy if stroke occurs or is suspected.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 Coronary Heart Disease. The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) of coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) 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 trend toward decreasing relative risk was reported in years through [see Clinical Studies (14.5)].The WHI estrogen-alone substudy reported no overall effect on CHD events in women receiving estrogen-alone compared to placebo2 [see Clinical Studies (14.5].Subgroup analyses of women 50 to 59 years of age, who were less than 10 years since menopause, suggest reduction (not statistically significant) of CHD events in those women receiving CE (0.625 mg)-alone compared to placebo (8 versus 16 per 10,000 women-years).1 In postmenopausal women with documented heart disease (n 2,763), average 66.7 years of age, in 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 CHD. 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. Two thousand three hundred twenty-one (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 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 The WHI estrogen plus progestin substudy reported statistically significant 2-fold greater rate of VTE (DVT and PE) 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 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted3 [see Clinical Studies (14.5)]. Immediately discontinue estrogen plus progestogen therapy if VTE occurs or is suspected.In the WHI estrogen-alone substudy, the risk of VTE 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 years4 [see Clinical Studies (14.5)]. Immediately discontinue estrogen-alone therapy if VTE occurs or is suspected.If feasible, discontinue estrogens at least to weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 5.2 Malignant Neoplasms. Breast Cancer. After mean follow-up of 5.6 years, the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg) reported an increased risk of invasive breast cancer in women who took daily CE plus MPA compared to placebo. 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. 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 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 groups5 [see Clinical Studies (14.5)]. The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. 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] [see Clinical Studies (14.5)].Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer with estrogen plus progestin therapy, and smaller increase in the risk for breast cancer with estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 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. 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 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.. Endometrial Cancer. An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in woman with uterus. The reported endometrial cancer risk among unopposed estrogen users is about 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 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for to 10 years or more. This risk has been shown to persist for at least to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women using estrogen-alone or estrogen plus progestogen therapy is important. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding with unknown etiology. There is no evidence that the use of natural estrogens results in different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding progestogen to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be precursor to endometrial cancer. Ovarian Cancer. The CE plus 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 plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24), but it was not statistically significant. The absolute risk for CE plus MPA versus placebo was versus cases per 10,000 women-years.7 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 years [median of years] vs. greater than years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 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.. 5.3 Probable Dementia. In the WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI, 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 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 (8.5), and Clinical Studies (14.6)].In the WHIMS estrogen-alone ancillary study of WHI, 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 (8.5), and Clinical Studies (14.6)].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 (8.5), and Clinical Studies (14.6)].. 5.4 Gallbladder Disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. 5.5 Hypercalcemia Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including Climara Pro if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level. 5.6 Visual Abnormalities Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue Climara Pro pending examination if there is sudden partial or complete loss of vision, or sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens, including Climara Pro, if examination reveals papilledema or retinal vascular lesions.. 5.7 Addition of Progestogen When Woman Has Not Had Hysterectomy Studies of the addition of progestogen for 10 or more days of cycle of estrogen administration, or daily with estrogen in continuous regimen, have reported lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestogens with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. 5.8 Elevated Blood Pressure. In small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In large, randomized, placebo-controlled clinical trial, generalized effect of estrogens on blood pressure was not seen. 5.9 Exacerbation of Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Discontinue Climara Pro if pancreatitis occurs.. 5.10 Hepatic Impairment and/or Past History of Cholestatic Jaundice Estrogens may be poorly metabolized in women with hepatic impairment. Exercise caution in any woman with history of cholestatic jaundice associated with past estrogen use or with pregnancy. In the case of recurrence of cholestatic jaundice, discontinue Climara Pro. 5.11 Exacerbation of 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. Monitor thyroid function in these women during treatment with Climara Pro to maintain their free thyroid hormone levels in an acceptable range. 5.12 Fluid Retention Estrogens plus progestogens may cause some degree of fluid retention. Monitor any woman with condition(s) that might predispose her to fluid retention, such as cardiac or renal impairment. Discontinue estrogens plus progestogens therapy, including Climara Pro, with evidence of medically concerning fluid retention.. 5.13 Hypocalcemia Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy, including Climara Pro, outweigh the risks in such women.. 5.14 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.. 5.15 Hereditary Angioedema. Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy, including Climara Pro, outweigh the risks in such women.. 5.16 Exacerbation of Other Conditions Estrogen therapy, including Climara Pro, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas. Consider whether the benefits of estrogen therapy outweigh the risks in women with these conditions.. 5.17 Laboratory Tests Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of postmenopausal women with soderate to severe vasomotor symptoms.. 5.18 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 in oral formulations increased triglycerides levels. Impaired glucose tolerance.