Conjugated estrogens: uses, appearance and warnings

Conjugated estrogens tablets is a mixture of estrogens indicated for: •Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause. ( 1.1 ) •Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause ( 1.2 ) •Treatment of Hypoestrogenism due to Hypogonadism, Castration or Primary Ovarian Failure ( 1.3 ) •Treatment of Breast Cancer (for Palliation Only) in Appropriately Selected Women and Men with Metastatic Disease ( 1.4 ) •Treatment of Advanced Androgen-Dependent Carcinoma of the Prostate (for Palliation Only) ( 1.5 ) •Prevention of Postmenopausal Osteoporosis ( 1.6 ) 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 due to menopause, topical vaginal products should be considered. 1.3 Treatment of Hypoestrogenism due to Hypogonadism, Castration or Primary Ovarian Failure 1.4 Treatment of Breast Cancer (for Palliation Only) in Appropriately Selected Women and Men with Metastatic Disease 1.5 Treatment of Advanced Androgen-Dependent Carcinoma of the Prostate (for Palliation Only) 1.6 Prevention of Postmenopausal Osteoporosis Limitations of Use When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered.

Tablets: 0.9 mg, and 1.25 mg ( 3 ) image description

16.1 How Supplied Conjugated estrogens tablets, USP Each white oval biconvex coated tablet contains 0.9 mg, in bottles of 100 (NDC 50742-390-01) and 1,000 (NDC 50742-390-10). Each yellow oval biconvex coated tablet contains 1.25 mg, in bottles of 100 (NDC 50742-391-01) and 1,000 (NDC 50742-391-10). 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a well-closed container, as defined in the USP.

Conjugated estrogens tablets therapy is contraindicated in individuals with any of the following conditions: • Undiagnosed abnormal genital bleeding [see Warnings and Precautions ( 5.2 )] • Breast cancer or a history of breast cancer except in appropriately selected patients being treated for metastatic disease [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 with conjugated estrogens tablets [see Warnings and Precautions ( 5.7 , 5.15 )] • Hepatic impairment or disease [see Warnings and Precautions ( 5.11 )] • Protein C, protein S or antithrombin deficiency, or other known thrombophilic disorders. •Undiagnosed abnormal genital bleeding ( 4 ) •Breast cancer or history of breast cancer except in appropriately selected patients being treated for metastatic diseases( 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 with conjugated estrogens tablets ( 5.7 , 5.15 ) •Hepatic impairment or disease ( 4 , 5.11 ) •Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 )

•Estrogens increase the risk of gallbladder disease ( 5.4 ) •Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs ( 5.5 , 5.6 , 5.10, 5.11 ) •Monitor thyroid function in patients on thyroid replacement therapy ( 5.12 , 5.19 ) 5.1 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 events occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. 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 1 and persisted [see Clinical Studies (14.5) ] . 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). 1 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 (14.5) ] . The increase in risk was demonstrated after the first year and persisted. 1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. Coronary Heart Disease In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo 2 [see Clinical Studies (14.5)] . 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). 1 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). 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) ] . 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 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 (0.625 mg) plus MPA (2.5 mg) group and the placebo group in HERS, HERS II, and overall. Venous Thromboembolism (VTE) 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 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 3 [see Clinical Studies (14.5) ] . 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 demonstrated during the first year and persisted 4 [see Clinical Studies (14.5) ] . 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. 5.2 Malignant Neoplasms 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 1 year. …

The following serious adverse reactions are discussed elsewhere in labeling: •Cardiovascular Disorders [see Boxed Warning , Warnings and Precautions (5.1) ] •Malignant Neoplasms [see Boxed Warning , Warnings and Precautions (5.2) ] Most common adverse reactions (≥ 5 %) are: abdominal pain, asthenia, pain, back pain, headache, flatulence, nausea, depression, insomnia, breast pain, endometrial hyperplasia, leucorrhea, vaginal hemorrhage, and vaginitis. …

Data from a single-dose drug-drug interaction study involving CE and MPA indicate that the pharmacokinetic disposition of both drugs is not altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been conducted with CE. Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism ( 7.1 ) 7.1 Metabolic 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. …