Climara Pro

1 INDICATIONS AND USAGE Climara Pro is indicated for: Climara Pro is an estrogen plus progestin indicated in a woman with a uterus for: Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause ( 1.1 ) Prevention of Postmenopausal Osteoporosis ( 1.2 ) Limitations of Use: When prescribing solely for the prevention of postmenopausal osteoporosis, first consider the use of non-estrogen medications. Consider estrogen therapy only for women at significant risk of osteoporosis. 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause 1.2 Prevention of Postmenopausal Osteoporosis Limitation of Use When prescribing solely for the prevention of postmenopausal osteoporosis, first consider the use of non-estrogen medications. Consider estrogen therapy only for women at significant risk of osteoporosis.

2 DOSAGE AND ADMINISTRATION Use estrogen-alone, or in combination with a 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. Apply 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 3 to 6 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 Place the adhesive side of Climara Pro on a smooth (fold free), clean, dry area of the skin on the lower abdomen or the upper quadrant of the buttock. Do not apply Climara Pro to or near the breasts. Select an area selected that is not oily (which can impair adherence of the system), damaged, or irritated. Avoid the waistline; tight clothing may rub Climara Pro off or modify drug delivery. Avoid application to areas where sitting would dislodge Climara Pro. Rotate the sites of application, with an interval of at least 1-week allowed between applications to the same site. Application Apply Climara Pro immediately after opening the pouch and removing the protective lining. Press Climara Pro 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 the same system to another area of the lower abdomen. If the system cannot be reapplied, a new system may be applied, in which case, the original treatment schedule should be continued. Only one system should be worn at any one time during 7-day dosing interval. Do not expose the applied transdermal system to the sun for prolonged periods of time. Swimming, bathing, or using a 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 Remove Climara Pro carefully and slowly to avoid irritation of the skin. If 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. Used patches still contain some active hormones. Carefully fold each patch in half so that it sticks to itself before throwing it away.

5 WARNINGS AND PRECAUTIONS Estrogens increase the risk of gallbladder disease ( 5.4 ) Discontinue estrogens if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs ( 5.5 , 5.6 , 5.9 , 5.10 ) Monitor 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 a 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 a stroke occurs or is suspected. The WHI estrogen-alone substudy, reported a 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 1 and persisted [see Clinical Studies (14.5) ] . Immediately discontinue estrogen-alone therapy if a 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 a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies (14.5) ] . The WHI estrogen-alone substudy reported no overall effect on CHD events in women receiving estrogen-alone compared to placebo 2 [see Clinical Studies (14.5 ] . Subgroup analyses of women 50 to 59 years of age, who were less than 10 years since menopause, suggest a 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 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 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 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…

4 CONTRAINDICATIONS Climara Pro is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.2) ] Breast cancer or history of breast cancer [see Warnings and Precautions (5.2) ] Estrogen-dependent neoplasia [see Warnings and Precautions (5.2) ] Active DVT, PE or a history of these conditions [see Warnings and Precautions (5.1) ] Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions [ see Warnings and Precautions (5.1) ] Known anaphylactic reaction, or angioedema, or hypersensitivity to Climara Pro Hepatic impairment or disease Protein C, protein S, or antithrombin deficiency, or other thrombophilic disorders Undiagnosed abnormal genital bleeding ( 4 , 5.2 ) Breast cancer or a history of breast cancer ( 4 , 5.2 ) Estrogen-dependent neoplasia ( 4 , 5.2 ) Active DVT, PE or a history of these conditions ( 4 , 5.1 ) Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions ( 4 , 5.1 ) Known anaphylactic reaction or angioedema or hypersensitivity to Climara Pro ( 4 ) Hepatic impairment or disease ( 4 , 5.10 ) Protein C, protein S, or antithrombin deficiency, or other thrombophilic disorders ( 4 )

7 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 (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 adverse reactions. Hydroxylation of levonorgestrel is a conversion step, which is mediated by cytochrome P450 enzymes. Based on in-vitro and in vivo studies, it can be assumed that CYP3A, CYP2E and CYP2C are involved in the metabolism of levonorgestrel. Likewise, inducers or inhibitors of these enzymes may either, respectively, decrease the therapeutic effects or result in adverse reactions. Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. ( 7 ) Hydroxylation of levonorgestrel may interact with inhibitors of CYP3A, CYP2E and CYP2C and decrease the therapeutic effects. ( 7 )

8.1 Pregnancy Risk Summary Climara Pro is not indicated for use in pregnancy. There are no data with the use of Climara Pro in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [ see Boxed Warning , Warnings and Precautions (5.1) ] Malignant Neoplasms [see Boxed Warning , Warnings and Precautions (5.2) ] The 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 Bayer HealthCare Pharmaceuticals Inc. at 1-888-84-BAYER (1-888-842-2937) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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 is from a one-year, prospective, multicenter, double blind, double dummy, randomized, controlled trial investigating the effect of three different dosage combinations of E 2 /LNG versus E 2 alone on the development of endometrial hyperplasia. All women were postmenopausal, had a 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 a frequency of >3% in the E 2 /LNG 0.045 / 0.015 group (the approved dosage for Climara Pro, N=212) and the E 2 alone group (N=204). Table 1: All Treatment Emergent Reactions Regardless of Relationship Reported at a Frequency of >3% with Climara Pro in the 1-year Endometrial Hyperplasia Study Body System Adverse Reaction Climara Pro 0.045 / 0.015 E 2 N N = total number of subjects in a treatment group; n = number of subjects with event. = 212 N = 204 Body as a Whole Abdominal pain 9 (4.2) 11 (5.4) Accidental injury 7 (3.3) 6 (2.9) Back pain 13 (6.1) 12 (5.9) Flu syndrome 10 (4.7) 13 (6.4) Infection 7 (3.3) 10 (4.9) Pain 11 (5.2) 13 (6.4) Cardiovascular System Hypertension 7 (3.3) 9 (4.4) Digestive System Flatulence 8 (3.8) 11 (5.4) Metabolic and Nutritional Edema 8 (3.8) 5 (2.5) Weight gain 6 (2.8) 10 (4.9) Musculoskeletal System Arthralgia 9 (4.2) 10 (4.9) Nervous System Depression 12 (5.7) 7 (3.4) Headache 11 (5.2) 14 (6.9) Respiratory System Bronchitis 9 (4.2) 7 (3.4) Sinusitis 8 (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 5 (2.4) 10 (4.9) Urogenital System Urinary Tract Infection 7 (3.3) 8 (3.9) Vaginal Bleeding 78 (36.8) 44 (21.6) Vaginitis 4 (1.9) 6 (2.9) Irritation potential of Climara Pro was assessed in a 3-week irritation study. The study compared the irritation of a Climara Pro placebo patch (22 cm 2 ) to a placebo (25 cm 2 ). Visual assessments of irritation were made on Day 7 of each wear period, approximately 30 minutes after patch removal using a 7-point scale (0 = no evidence of irritation; 1 = minimal erythema, barely perceptible; 2 = 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. 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 2 at any timepoint in any woman. In controlled clinical trials, withdrawals due to application site reactions occurred in 6 (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. 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 a population of uncertain size, it is not always possible to reliab…