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IMPORTANT SAFETY INFORMATION

WARNING: CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, AND ENDOMETRIAL CANCER

Estrogen Plus Progestin Therapy

Cardiovascular Disorders and Probable Dementia

WARNING: CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, AND ENDOMETRIAL CANCER

Estrogen Plus Progestin Therapy

Cardiovascular Disorders and Probable Dementia

The Women's 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.

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 or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.

Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia.

Breast Cancer

The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.

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 Therapy

Endometrial Cancer

There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a 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.

Cardiovascular Disorders and Probable Dementia

The 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.

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.

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.

Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia.

Breast Cancer

The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.

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 Therapy

Endometrial Cancer

Cardiovascular Disorders and Probable Dementia

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.

CONTRAINDICATIONS

Climara Pro is contraindicated in women with any of the following conditions: undiagnosed abnormal genital bleeding, Breast cancer or history of breast cancer, estrogen-dependent neoplasia, active deep vein thrombosis, pulmonary emboli or a history of these conditions, active arterial thromboembolic disease (e.g., stroke or myocardial infarction), or a history of these conditions, 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.

WARNINGS AND PRECAUTIONS

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). If feasible, discontinue Climara Pro at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Malignant Neoplasia: A mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA compared to placebo. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammography results. The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The greatest risk appears to be associated with prolonged use and may persist for at least 8 to 15 years after discontinuation. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen-alone or estrogen plus progestogen therapy is important. 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. Estrogens with or without progestin may increase the risk of ovarian cancer.

Probable Dementia: Climara Pro should not be used for the prevention of dementia (see Boxed Warning).

Gallbladder Disease: An increased risk of gallbladder disease which may require surgery has been reported in postmenopausal women receiving estrogens.

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 levels.

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 a sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens, including Climara Pro, if examination reveals papilledema or retinal vascular lesions.

Addition of a Progestogen When a Woman Has Not Had a Hysterectomy

Studies of the addition of a progestogen for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

Elevated Blood Pressure: In a small number of case reports, increases in blood pressure have been attributed to idiosyncratic reactions to estrogens.

Exacerbation of Hypertriglyceridemia: Increased plasma triglycerides leading to pancreatitis may occur with estrogens in women with preexisting hypertriglyceridemia. Discontinue Climara Pro if pancreatitis occurs.

Liver Disease: Estrogens may be poorly metabolized in women with hepatic impairment. Discontinue Climara Pro if cholestatic jaundice occurs.

Exacerbation of Hypothyroidism: Increased thyroid-binding globulin levels may occur. Monitor thyroid function in women on thyroid replacement therapy during treatment with Climara Pro.

Fluid retention: Estrogens plus progestogens may cause fluid retention; monitoring may be warranted. Discontinue estrogen plus progestogen therapy including Climara Pro, with evidence of medically concerning fluid retention.

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.

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.

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.

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.

ADVERSE REACTIONS

The most common adverse reactions (≥5%) with Climara Pro, are: application site reaction, vaginal bleeding, breast pain, upper respiratory infection, back pain, depression, pain, headache, and flu syndrome.

INDICATIONS FOR CLIMARA PRO

In women with an intact uterus, Climara Pro® (estradiol/levonorgestrel transdermal system) is indicated for treatment of moderate to severe vasomotor symptoms due to menopause. Climara Pro is also indicated for the prevention of postmenopausal osteoporosis. 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.

For important risk and use information about Climara Pro, including Boxed Warning, please see the accompanying Full Prescribing Information.

You are encouraged to report adverse side effects or quality complaints for Bayer’s prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088

BAYER, the Bayer Cross, and Climara Pro are registered trademarks of Bayer.