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Indications
Estradiol vaginal cream 0.01% is indicated in the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause.
Contraindications
Estradiol vaginal cream 0.01% should not be used in women with any of the following conditions: 1. Undiagnosed abnormal genital bleeding. 2. Known, suspected, or history of cancer of the breast. 3. Known or suspected estrogen-dependent neoplasia. 4. Active DVT, PE or history of these conditions. 5. Active arterial thromboembolic disease (for example, stroke, MI) or a history of these conditions. 6. Known anaphylactic reaction or angioedema to estradiol vaginal cream 0.01%. 7.
Known liver dysfunction or disease. 8. Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. 9. Known or suspected pregnancy.
Warnings and precautions
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
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Interactions
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.
Adverse reactions
See BOXED WARNINGS , WARNINGS and PRECAUTIONS . 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. The following adverse reactions have been reported with estrogen and/or progestin therapy. 1. Genitourinary System Abnormal uterine bleeding or spotting; dysmenorrhea or pelvic pain, increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in cervical secretion; cystitis-like syndrome; application site reactions of vulvovaginal discomfort including burning and irritation; genital pruritus; ovarian cancer; endometrial hyperplasia; endometrial cancer. 2.
Breasts Tenderness, enlargement, pain, nipple discharge, fibrocystic breast changes; breast cancer. 3. Cardiovascular Deep and superficial venous thrombosis; pulmonary embolism; myocardial infarction; stroke; increase in blood pressure. 4. Gastrointestinal Nausea, vomiting; abdominal cramps, bloating; increased incidence of gallbladder disease. 5. Skin Chloasma that may persist when drug is discontinued; loss of scalp hair; hirsutism; rash. 6.
Eyes Retinal vascular thrombosis, intolerance to contact lenses. 7. Central Nervous System Headache; migraine; dizziness; mental depression; nervousness; mood disturbances; irritability; dementia. 8. Miscellaneous Increase or decrease in weight; glucose intolerance; edema; arthralgias; leg cramps; changes in libido; urticaria; exacerbation of asthma; increased triglycerides; hypersensitivity.
Composition
Active ingredients
ESTRADIOL 0.01%
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
