84 HR estradiol 0.00156 MG/HR Transdermal System [Vivelle]

INDICATIONS AND USAGE Estradiol transdermal system, USP (twice-weekly) is indicated for: Estradiol transdermal system, USP (twice-weekly) is an estrogen indicated for: Treatment of moderate to severe vasomotor symptoms due to menopause ( 1.1 ) Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause ( 1.2 ) Limitations of Use When prescribing solely for the treatment of moderate to severe vaginal atrophy, first consider the use of topical vaginal products. Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure ( 1.3 ) Prevention of postmenopausal osteoporosis ( 1.4 ) 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 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy Due to Menopause Limitations of Use : When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy, first consider the use of topical vaginal products. 1.3 Treatment of Hypoestrogenism Due to Hypogonadism, Castration, or Primary Ovarian Failure 1.4 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.

DOSAGE AND ADMINISTRATION Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, consider addition of a progestogen to reduce the risk of endometrial cancer. Generally, a woman without a uterus does not need to use a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women who have a history of endometriosis may need a progestogen [see Warnings and Precautions ( 5.2 , 5.14 )] . Use estrogen-alone or in combination with a progestogen at the lowest effective dose and the shortest duration consistent with treatment goals and risks for the individual woman. Reevaluate postmenopausal women periodically as clinically appropriate to determine whether treatment is still necessary. Start therapy with estradiol transdermal system (twice-weekly) 0.0375 mg/day applied to the skin twice weekly for the treatment of moderate to severe vasomotor symptoms due to menopause or moderate to severe symptoms of vulvar and vaginal atrophy symptoms due to menopause. Dosage adjustment should be guided by the clinical response ( 2.1 , 2.2 , 2.3 ) Start therapy with estradiol transdermal system (twice-weekly) 0.025 mg/day for the prevention of postmenopausal osteoporosis ( 2.4 ) Place estradiol transdermal system (twice-weekly) on a clean, dry area of the lower abdomen or buttocks. Do not apply estradiol transdermal system (twice-weekly) to the breasts ( 2.5 ) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Start therapy with estradiol transdermal system (twice-weekly) 0.0375 mg per day applied to the skin twice weekly. Make dosage adjustments based on the clinical response. Initiate estradiol transdermal system (twice-weekly) at once in a woman not currently taking oral estrogens or in a woman switching from another estradiol transdermal therapy. In women who are currently taking oral estrogens, initiate treatment with estradiol transdermal system (twice-weekly) 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week. Attempts to taper or discontinue estradiol transdermal system (twice-weekly) at 3 to 6 month intervals. Give estradiol transdermal system (twice-weekly) continuously in a woman who does not have an intact uterus. In a woman with an intact uterus, give estradiol transdermal system (twice-weekly) on a cyclic schedule [for example, 3 weeks on estradiol transdermal system (twice-weekly) followed by 1 week off estradiol transdermal system (twice-weekly)]. 2.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Start therapy with estradiol transdermal system (twice-weekly) 0.0375 mg per day applied to the skin twice weekly. Dosage adjustment should be guided by the clinical response. Attempts to taper or discontinue estradiol transdermal system (twice-weekly) at 3 to 6 month intervals. In women not currently taking oral estrogens or in women switching from another estradiol transdermal therapy, treatment with estradiol transdermal system (twice-weekly) may be initiated at once. In women who are currently taking oral estrogens, initiate treatment with estradiol transdermal system (twice-weekly) 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week. Give estradiol transdermal system (twice-weekly) continuously in a woman who does not have an intact uterus. In a woman with an intact uterus, give estradiol transdermal system (twice-weekly) on a cyclic schedule [for example, 3 weeks on estradiol transdermal system (twice-weekly) followed by 1 week off estradiol transdermal system (twice-weekly)]. 2.3 Hypoestrogenism Due to Hypogonadism, Castration, or Primary Ovarian Failure 2.4 Prevention of Postmenopausal Osteoporosis Start therapy with estradiol transdermal system (twice-weekly) 0.025 mg per day applied to the skin twice weekly. In women not currently taking oral estrogens or in women switching from another estradiol transdermal therapy, treatment with estradiol transdermal system (twice-weekly) may be initiated at once. In women who are currently taking oral estrogens, initiate treatment with estradiol transdermal system (twice-weekly) 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week. Estradiol transdermal system (twice-weekly) may be given continuously in a woman who does not have an intact uterus. In a woman with an intact uterus, estradiol transdermal system (twice-weekly) may be given on a cyclic schedule [for example, 3 weeks on estradiol transdermal system (twice-weekly) followed by 1 week off estradiol transdermal system (twice-weekly)]. 2.5 Application Instructions Place the adhesive side of estradiol transdermal system (twice-weekly) on a clean, dry area of the trunk of the body (including the abdomen or buttocks). Do not apply estradiol transdermal system (twice-weekly) to the breasts. Replace estradiol transdermal system (twice-weekly) twice weekly. Rotate the sites of application, with an interval of at least 1 week allowed between applications to a particular site. Select an area that is not oily, damaged, or irritated. Avoid the waistline, since tight clothing may rub the system off. Apply the system immediately after opening the pouch and removing the protective liner. Press the system firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact, especially around the edges. In the event that a system falls off, reapply the same system or apply a new system to another location. In either case, continue the original treatment schedule. If a woman has forgotten to apply estradiol transdermal system (twice-weekly), have her apply a new system as soon as possible. Apply the new system on the original treatment schedule. The interruption of treatment in women taking estradiol transdermal system (twice-weekly) might increase the likelihood of breakthrough bleeding, spotting and recurrence of symptoms.

WARNINGS See BOXED WARNINGS . Systemic absorption may occur with the use of Estradiol Vaginal Cream, 0.01%. The warnings, precautions, and adverse reactions associated with oral estrogen treatment should be taken into account. 1. Cardiovascular Disorders An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. a. Stroke In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted [see CLINICAL STUDIES ]. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years) 3 . In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) [see CLINICAL STUDIES ]. The increase in risk was demonstrated after the first year and persisted 3 . Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. b. Coronary Heart Disease In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI and CHD death) was reported in women receiving estrogen-alone compared to placebo 4 [see CLINICAL STUDIES ]. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years) 3 . In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years) 3 . An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see CLINICAL STUDIES ]. In postmenopausal women with documented heart disease (n = 2,763), average age 66.7 years of age, in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand, three hundred and 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 HERS, HERS II, and overall. c. Venous Thromboembolism In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily CE (0.625 mg)-alone compared to women receiving placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years 5 [see CLINICAL STUDIES ]. Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately. In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was observed during the first year and persisted 6 [see CLINICAL STUDIES ]. Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2. Malignant Neoplasms a. Endometrial Cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, 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 one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. b. Breast Cancer The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80) 7 [see CLINICAL STUDIES ]. The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and th

CONTRAINDICATIONS Estradiol transdermal system (twice-weekly) is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding [see Warnings and Precautions ( 5.2 )] . Breast cancer or a 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 and MI), or a history of these conditions [see Warnings and Precautions ( 5.1 )] . Known anaphylactic reaction, or angioedema, or hypersensitivity to estradiol transdermal system (twice-weekly) Hepatic impairment or disease Protein C, protein S, or antithrombin deficiency, or other known 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 with estradiol transdermal system (twice-weekly) ( 4 , 5.15 ) Hepatic impairment or disease ( 4 , 5.10 ) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 )

CLINICAL PHARMACOLOGY Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Pharmacokinetics Absorption Estrogen drug products are absorbed through the skin, mucous membranes, and the gastrointestinal tract after release from the drug formulation. 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 sex hormone binding globulin (SHBG) and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Special Populations No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment. Drug Interactions In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects. CLINICAL STUDIES Women’s Health Initiative Studies The 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 coronary heart disease (CHD) (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE or CE plus MPA on menopausal symptoms. WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 7.1 years are presented in Table 1. TABLE 1 - Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI a Event Relative Risk CE vs. Placebo (95% nCI b ) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-Years CHD events c 0.95 (0.78-1.16) 54 57 Non-fatal MI c 0.91 (0.73-1.14) 40 43 CHD death c 1.01 (0.71-1.43) 16 16 All Stroke c 1.33 (1.15-1.68) 45 33 Ischemic stroke c 1.55 (1.19-2.01) 38 25 Deep vein thrombosis c,d 1.47 (1.06-2.06) 23 15 Pulmonary embolism c 1.37 (0.90-2.07) 14 10 Invasive breast cancer c 0.80 (0.62-1.04) 28 34 Colorectal cancer c 1.08 (0.75-1.55) 17 16 Hip fracture c 0.65 (0.45-0.94) 12 19 Vertebral fractures c,d 0.64 (0.44-0.93) 11 18 Lower arm/wrist fractures c,d 0.58 (0.47-0.72) 35 59 Total fractures c,d 0.71 (0.64-0.80) 144 197 Death due to other causes e,f 1.08 (0.88-1.32) 53 50 Overall mortality c,d 1.04 (0.88-1.22) 79 75 Global index g 1.02 (0.92-1.13) 206 201 a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. c Results are based on centrally adjudicated data for an average follow-up of 7.1 years. d Not included in “global index”. e Results are based on an average follow-up of 6.8 years. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g A subset of the events was combined in a “global index” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess 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 7 fewer hip fractures 1 . The absolute excess risk of events included in the "global index" was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years. Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant differences in distribution of stroke subtypes 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 2 . 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 a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63