Estradiol Vaginal Cream 0.01% is indicated in the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause.
đHow to take it
Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Estradiol Vaginal Cream 0.01% therapy together with institution of appropriate symptomatic care.
âšī¸Common side effects
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.
â ī¸Serious risks
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 progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
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Each gram of estradiol vaginal cream, USP, 0.01% contains 0.1 mg estradiol (as estradiol hemihydrate) in a nonliquefying base containing propylene glycol, methylparaben, sodium lauryl sulfate, mono- and di-glycerides, stearyl alcohol, ceresin wax, tert-butylhydroquinone, disodium EDTA, hypromellose, and purified water. Estradiol hemihydrate is chemically described as estra-1,3,5(10)-triene-3,17 -diol hemihydrate. It has an empirical formula of C18H24O2 . H2O and molecular weight of 272.37. The structural formula is:
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.
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.
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 WHIa Event Relative Risk CE vs. Placebo (95 % n CI b ) CEn = 5,310 Placebon = 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 fractures1. 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 examined2. 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 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)]. W HI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was also stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the global index. The absolute excess risk of events included in the global index was 19 per 10,000 women-years. For those outcomes included in the WHI global index that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 2. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. TABLE 2 -Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years a,b Event Relative Risk CE/MPA v s. P lacebo (95 % n CI c ) CE/MPA n = 8,506 Placebon = 8,102 Absolute Risk per 10,000 Women-Years CHD events 1.23 (0.99-1.53) 41 34 Non-fatal MI 1.28 (1.00-1.63) 31 25 CHD death 1.10 (0.70-1.75) 8 8 All strokes 1.31 (1.03-1.68) 33 25 Ischemic stroke 1.44 (1.09-1.90) 26 18 Deep vein thrombosis d 1.95 (1.43-2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive breast cancer e 1.24 (1.01-1.54) 41 33 Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancer d 0.81 (0.48-1.36) 6 7 Cervical cancer d 1.44 (0.47-4.42) 2 1 Hip fracture 0.67 (0.47-0.96) 11 16 Vertebral fractures d 0.65 (0.46-0.92) 11 17 Lower arm/wrist fractures d 0.71 (0.59-0.85) 44 62 Total fractures d 0.76 (0.69-0.83) 152 199 Overall mortality f 1.00 (0.83-1.19) 52 52 Global index g 1.13 (1.02-1.25) 184 165 a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Results are based on centrally adjudicated data. c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. d Not included in global index . e Includes metastatic and non-metastatic breast cancer, with the exception of in situ cancer. 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, colorectal cancer, hip fracture, or death due to other causes. Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44-1.07)]. Women s Health Initiative Memory Study The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer s disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see BOXED WARNINGS , WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use ]. The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years; 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use ]. When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use ].
Estradiol Vaginal Cream 0.01% is indicated in the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause.
Estradiol Vaginal Cream 0.01% should not be used in women with any of the following conditions: Undiagnosed abnormal genital bleeding. Known, suspected, or history of cancer of the breast. Known or suspected estrogen-dependent neoplasia. Active DVT, PE or history of these conditions. Active arterial thromboembolic disease (for example, stroke, MI) or a history of these conditions. Known anaphylactic reaction or angioedema to Estradiol Vaginal Cream 0.01%. Known liver dysfunction or disease. Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. Known or suspected pregnancy.
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.
Increase or decrease in weight; glucose intolerance; edema; arthralgias; leg cramps; changes in libido; urticaria; exacerbation of asthma; increased triglycerides; hypersensitivity.
In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years10 [see CLINICAL STUDIES and PRECAUTIONS, Geriatric Use ]. In the WHIMS estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years 10 [see CLINICAL STUDIES and PRECAUTIONS, Geriatric Use ]. When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 10 [see PRECAUTIONS, Geriatric Use ].
1. Addition of a P rogestin W hen a W oman H as N ot H ad a H ysterectomy Studies of the addition of a progestin 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. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer. 2. Elevated B lood P ressure In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. 3. Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. Consider discontinuation of treatment if pancreatitis occurs. 4. Hepatic Impair ment and /or P ast H istory of C holestatic J aundice Estrogens may be poorly metabolized in patients with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. 5. Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. 6. Fluid R etention Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogen-alone is prescribed. 7. Hypocalcemia Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. 8. Exacerbation of E ndometriosis A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. 9 . Exacerbation of O ther C onditions Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.
Physicians are advised to discuss the PATIENT INFORMATION leaflet with women for whom they prescribe Estradiol Vaginal Cream 0.01%.
Serum FSH and estradiol levels have not been shown to be useful in the management of moderate to severe symptoms of vulvar and vaginal atrophy.
Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer (see BOXED WARNINGS , WARNINGS and PRECAUTIONS ). Long term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
Estradiol Vaginal Cream 0.01% should not be used during pregnancy [see CONTRAINDICATIONS ]. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.
Estradiol Vaginal Cream 0.01% should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the milk of women receiving estrogen therapy. Caution should be exercised when Estradiol Vaginal Cream 0.01% is administered to a nursing woman.
Estradiol Vaginal Cream 0.01% is not indicated in children. Clinical studies have not been conducted in the pediatric population.
There have not been sufficient numbers of geriatric patients involved in studies utilizing Estradiol Vaginal Cream 0.01% to determine whether those over 65 years of age differ from younger subjects in their response to Estradiol Vaginal Cream 0.01%. The Women s Health Initiative Study In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see CLINICAL STUDIES and WARNINGS ]. In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see CLINICAL STUDIES and WARNINGS ]. The Women s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see CLINICAL STUDIES and WARNINGS ]. Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women10 [see CLINICAL STUDIES and WARNINGS ].
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.
Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Estradiol Vaginal Cream 0.01% therapy together with institution of appropriate symptomatic care.
Use of Estradiol Vaginal Cream 0.01% alone or in combination with a progestin, should be limited to the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should reevaluate periodically as clinically appropriate to determine if treatment is still necessary. For treatment of vulvar and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible. For women who have a uterus, adequate diagnostic measures, including directed and random endometrial sampling when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal genital bleeding. Usual Dosage: The usual dosage range is 2 to 4 g (marked on the applicator) daily for one or two weeks, then gradually reduced to one half initial dosage for a similar period. A maintenance dosage of 1 g, one to three times a week, may be used after restoration of the vaginal mucosa has been achieved. NOTE: The number of doses per tube will vary with dosage requirements and patient handling.
Estradiol Vaginal Cream, USP 0.01%. NDC 47781-104-44: Tube containing 1 oz (42.5 grams) with a calibrated plastic applicator for delivery of 1 gram, 2 grams, 3 grams, or 4 grams. Store at 25 C (77 F); excursions permitted to 15 to 30 C (59 to 86 F) [See USP Controlled Room Temperature]. Protect from temperatures in excess of 40 C (104 F). Keep Estradiol Vaginal Cream 0.01% out of the reach of children.
1. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women s Health Initiative Randomized Trial. J Bone Miner Res. 2006;21:817-828. 2. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women s Health Initiative. Circulation. 2006;113:2425-2434. 3. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477. 4. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357-365. 5. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780. 6. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580. 7. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA. 2006;295:1647-1657. 8. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253. 9. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748. 10. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:29472958. Product of Germany Distributed by:Alvogen, Inc.Morristown, NJ 07960 USA Revised: June 2023 PI104-03
PATIENT INFORMATION Estradiol (es tra dye ol) Vaginal Cream, USP 0.01% Read this Patient Information before you start using Estradiol Vaginal Cream 0.01% and each time you refill. There may be new information. This information does not take the place of talking with your healthcare provider about your menopausal symptoms or your treatment. What is the most important information I should know about Estradiol Vaginal Cream 0.01% (an estrogen hormone)? Using estrogen-alone may increase your chance of getting cancer of the uterus (womb). Report any unusual vaginal bleeding right away while you are using Estradiol Vaginal Cream 0.01%. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Have your healthcare provider check any unusual vaginal bleeding to find out the cause. Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia (decline in brain function). Using estrogen-alone may increase your chances of getting strokes or blood clots. Using estrogen-alone may increase your chance of getting dementia, based on a study of women - 65 years of age or older. Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or dementia. Using estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. Using estrogens with progestins may increase your chance of getting dementia, based on a study of women 65 years of age or older. Talk regularly with your healthcare provider about whether you still need treatment with Estradiol Vaginal Cream 0.01%. What is Estradiol Vaginal Cream 0.01%? Estradiol Vaginal Cream 0.01% is a prescription medicine that contains estradiol (an estrogen hormone). What is Estradiol Vaginal Cream 0.01% used for? Estradiol Vaginal Cream 0.01% is used after menopause to: Treat moderate to severe menopausal changes in and around the vagina. Talk regularly with your healthcare provider about whether you still need treatment with Estradiol Vaginal Cream 0.01%. Who should not use Estradiol Vaginal Cream 0.01%? Do not start using Estradiol Vaginal Cream 0.01% if you: have unusual vaginal bleeding. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Have your healthcare provider check any unusual bleeding to find out the cause. currently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use Estradiol Vaginal Cream 0.01%. currently have or have had blood clots. had a stroke or heart attack. are allergic to Estradiol Vaginal Cream 0.01% or any of its ingredients. See the list of ingredients in Estradiol Vaginal Cream 0.01% at the end of this leaflet. currently have or have had liver problems. have been diagnosed with a bleeding disorder. think you may be pregnant. Before you use Estradiol Vaginal Cream 0.01%, tell your healthcare provider about all of your medical conditions, including if you: have unusual vaginal bleeding. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. have any other medical conditions. Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), diabetes, epilepsy (seizures), migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. are going to have surgery or will be on bed rest. Your healthcare provider will let you know if you need to stop using Estradiol Vaginal Cream 0.01%. are breastfeeding. The hormone in Estradiol Vaginal Cream 0.01% can pass into your breast milk. Tell your healthcare provider about the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how Estradiol Vaginal Cream 0.01% works. Estradiol Vaginal Cream 0.01% may also affect how your other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I use Estradiol Vaginal Cream 0.01%? Estradiol Vaginal Cream 0.01% is a cream that you place in your vagina with the applicator provided with the cream. Take the dose recommended by your healthcare provider and talk to them about how well that dose is working for you. Use estrogens at the lowest dose possible for your treatment only as long as needed. Talk regularly (for example, every 3 to 6 months) with your healthcare provider about the dose you are using and whether you still need treatment with Estradiol Vaginal Cream 0.01%. Figure A Step 1. Wash and dry your hands well. Step 2. Remove the cap from the Estradiol Vaginal Cream 0.01% tube. (There is no seal on tube). Step 3. Hold the applicator as shown. Do not separate the plunger from applicator (Figure B). Figure B Step 4. Screw threaded end of applicator onto the open nozzle of the Estradiol Vaginal Cream 0.01% tube until secure. Do not attach the plunger end of the applicator onto the open Estradiol Vaginal Cream 0.01% tube (see Figure C). Figure C Step 5. Position upright to view the calibrated gram amounts. Step 6. Gently squeeze tube from the bottom to push the prescribed amount of Estradiol Vaginal Cream 0.01% into the applicator. As Estradiol Vaginal Cream 0.01% is squeezed out, the plunger will rise to indicate the amount of grams (see Figure D). Figure D *This Figure shows a 2 g dose for illustrative purposes only. Your prescribed dosage may vary. Step 7. Unscrew applicator from tube. Step 8. Replace cap on tube. Step 9. Lie on your back with knees bent. To deliver the medicine, gently insert applicator deeply into your vagina and press the plunger downward to its original position (see Figure E). Figure E Step 10. Remove the applicator from your vagina. Step 11. To cleanse applicator: Pull plunger to remove it from barrel. Wash with mild soap and warm water (Do not boil or use hot water) (see Figure F). Figure F What are the possible side effects of Estradiol Vaginal Cream 0.01%? Side effects are grouped by how serious they are and how often they happen when you are treated. Serious, but less common side effects include: stroke blood clots breast cancer dementia high or low blood calcium severe allergic reaction high blood pressure liver problems fluid retention- this can make medical conditions worse in people with heart or kidney disease worsening of endometriosis changes in certain laboratory test results heart disease (such as heart attack) cancer of the lining of the uterus (womb) cancer of the ovary gallbladder disease changes in vision worsening of angioedema (swelling of face and tongue) high triglyceride (fat) levels in your blood low thyroid levels in your blood worsening of other medical conditions high blood sugar enlargement of benign tumors of the uterus ( fibroids ) Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you: new breast lumps unusual vaginal bleeding changes in vision or speech sudden new severe headaches severe pains in your chest or legs with or without shortness of breath, weakness and fatigue swollen lips, tongue or face Less serious, but common side effects include: headache breast pain irregular vaginal bleeding or spotting stomach or abdominal cramps, bloating nausea and vomiting hair loss fluid retention vaginal yeast infection reactions from inserting Estradiol Vaginal Cream 0.01%, such as vaginal burning, irritation, and itching These are not all the possible side effects of Estradiol Vaginal Cream 0.01%. For more information, ask your healthcare provider or pharmacist for advice about side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Estradiol Vaginal Cream 0.01%? Store Estradiol Vaginal Cream 0.01% at 77 F (25 C); excursions permitted to 59 to 86 F (15 to 30 C) [See USP Controlled Room Temperature] Protect from temperatures above 104 F (40 C) Keep Estradiol Vaginal Cream 0.01% and all medicines out of the reach of children What can I do to lower my chances of a serious side effect with Estradiol Vaginal Cream 0.01%? Talk with your healthcare provider regularly about whether you should continue using Estradiol Vaginal Cream 0.01%. If you have a uterus, talk with your healthcare provider about whether the addition of a progestin is right for you. In general, the addition of a progestin is generally recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus. See your healthcare provider right away if you get vaginal bleeding while using Estradiol Vaginal Cream 0.01%. Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease. General information about safe and effective use of Estradiol Vaginal Cream 0.01% Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use Estradiol Vaginal Cream 0.01% for conditions for which it was not prescribed. Do not give Estradiol Vaginal Cream 0.01% to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Estradiol Vaginal Cream 0.01% that is written for health professionals. What are the ingredients in Estradiol Vaginal Cream 0.01%? Active Ingredient: estradiol Inactive Ingredients: propylene glycol, methylparaben, sodium lauryl sulfate, mono- and di-glycerides, stearyl alcohol, ceresin wax, tert-butylhydroquinone, disodium EDTA, hypromellose, and purified water. Product of Germany Distributed by: Alvogen, Inc. Morristown, NJ 07960 USA Revised: June 2023 PL104-02
NDC 47781-104-44Estradiol Vaginal Cream, USP0.01% Rx Only NET WT 1 OZ (42.5 Grams) TUBE Each gram contains 0.1 mg estradiol in a nonliquefying base
