Estradiol and Levonorgestrel

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. Prevention of Postmenopausal Osteoporosis. 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.

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

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

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 DVT, PE or a history of these conditions Active arterial thromboembolic disease (for example, stroke or MI), 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 Undiagnosed abnormal genital bleeding. Breast cancer or a history of breast cancer. Estrogen-dependent neoplasia. Active DVT, PE or a history of these conditions.

Boxed 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. Estrogens increase the risk of gallbladder disease. Discontinue estrogens if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs. Monitor thyroid function in women on thyroid hormone replacement therapy

The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders Malignant Neoplasms 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.

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.

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). Do not store unpouched.