PRECAUTIONS SECTION.

PRECAUTIONS. A. General. 1. Addition of Progestin When Woman Has Not Had HysterectomyStudies of the addition of progestin for 10 or more days of cycle of estrogen administration,or daily with estrogen in continuous regimen, have reported lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be 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 possible increased risk of breast cancer. 2. Elevated Blood PressureIn small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In large, randomized, placebo-controlled clinical trial, generalized effect of estrogens on blood pressure was not seen. 3. HypertriglyceridemiaIn 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 Impairment and/or Past History of Cholestatic JaundiceEstrogens may be poorly metabolized in patients with impaired liver function. For women with 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. HypothyroidismEstrogen 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 RetentionEstrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogen- alone is prescribed. 7. HypocalcemiaEstrogen therapy should be used with caution in women with hypoparathyroidism as estrogen- induced hypocalcemia may occur. 8. Exacerbation of EndometriosisA 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 Other Conditions 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.. B. Patient Information Physicians are advised to discuss the PATIENT INFORMATION leaflet with women for whom they prescribe estradiol vaginal cream, USP, 0.01%.. C. Laboratory Tests. 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.. D. Drug-Laboratory Test Interactions. 1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone levels, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher dose of thyroid hormone.3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).4. Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels.5. Impaired glucose tolerance.. E. Carcinogenesis,Mutagenesis, and Impairment of Fertility Long-term continuous administration of estrogen, with and without progestin, in women with and without 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.. F. Pregnancy. Estradiol vaginal cream, USP, 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.. G. NursingMothers. Estradiol vaginal cream, USP, 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, USP, 0.01% is administered to nursing woman.. H. Pediatric Use. Estradiol vaginal cream, USP, 0.01% is not indicated in children. Clinical studies have not been conducted in the pediatric population.. I. Geriatric Use. There have not been sufficient numbers of geriatric patients involved in studies utilizing estradiol vaginal cream, USP, 0.01% to determine whether those over 65 years of age differ from younger subjects in their response to estradiol vaginal cream, USP, 0.01%.The Womens Health Initiative StudyIn the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was 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 higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see CLINICAL STUDIES and WARNINGS]. The Womens Health Initiative Memory StudyIn 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 women 10 [see CLINICAL STUDIES and WARNINGS].

BOXED WARNING SECTION.

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER and PROBABLE DEMENTIA. Estrogen-Alone Therapy Endometrial CancerThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens. Adding progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be precursor to endometrial cancer. 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 [see WARNINGS, Malignant Neoplasms, Endometrial Cancer]. Cardiovascular Disorders and Probable DementiaEstrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders, and Probable Dementia]. The Womens Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone,relative to placebo [see CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders]. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg) -alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see CLINICAL STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use]. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens.Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable DementiaEstrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders, and Probable Dementia]. The WHI estrogen plus progestin substudy reported increased risks of 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 CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders]. The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see CLINICAL STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use]. Breast CancerThe WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see CLINICAL STUDIES and WARNINGS, Malignant Neoplasms, Breast Cancer]. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins.Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

CLINICAL PHARMACOLOGY SECTION.

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 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 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 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, significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as 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. Johns Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in 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 SECTION.

CLINICAL STUDIES. Womens Health Initiative StudiesThe 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. 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 SubstudyThe 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 -Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHIa 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 fewer hip fractures1. The absolute excess risk of events included in the global index was non-significant 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 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)]. WHI Estrogen Plus Progestin SubstudyThe 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 more CHD events, more strokes, 10 more PEs, and more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were fewer colorectal cancers and 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 -Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years a,b 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, non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44-1.07)].Womens Health Initiative Memory StudyThe 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 Alzheimers 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 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].. table 1. Table 2.

GENERAL PRECAUTIONS SECTION.

A. General. 1. Addition of Progestin When Woman Has Not Had HysterectomyStudies of the addition of progestin for 10 or more days of cycle of estrogen administration,or daily with estrogen in continuous regimen, have reported lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be 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 possible increased risk of breast cancer. 2. Elevated Blood PressureIn small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In large, randomized, placebo-controlled clinical trial, generalized effect of estrogens on blood pressure was not seen. 3. HypertriglyceridemiaIn 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 Impairment and/or Past History of Cholestatic JaundiceEstrogens may be poorly metabolized in patients with impaired liver function. For women with 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. HypothyroidismEstrogen 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 RetentionEstrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogen- alone is prescribed. 7. HypocalcemiaEstrogen therapy should be used with caution in women with hypoparathyroidism as estrogen- induced hypocalcemia may occur. 8. Exacerbation of EndometriosisA 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 Other Conditions 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.

SPL PATIENT PACKAGE INSERT SECTION.

INFORMATION FOR THE PATIENT. Rx onlyEstradiol Vaginal Cream, USP, 0.01% INFORMATION FOR THE PATIENTRead this PATIENT INFORMATION before you start using estradiol vaginal cream, USP, 0.01% and read what you get each time you refill your estradiol vaginal cream, USP, 0.01% prescription. 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 should know about ESTRADIOL VAGINAL CREAM, 0.01% (an estrogen hormone)o 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 warning sign of cancer of the uterus (womb). Your healthcare provider should 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)o Using estrogen-alone may increase your chances of getting strokes or blood clotso Using estrogen-alone may increase your chance of getting dementia, based on study of women age 65 years of age or oldero Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or dementiao Using estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clotso Using estrogens with progestins may increase your chance of getting dementia, based on study of women age 65 years of age or oldero You and your healthcare provider should talk regularly 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 medicine that contains an estrogen hormone.What is Estradiol Vaginal Cream, 0.01% used for Estradiol Vaginal Cream, 0.01% is used after menopause to:o re at moderate to severe menopausal changes in and around the vagina You and your healthcare provider should talk regularly about whether you still need treatment with estradiol vaginal cream, 0.01% to control these problems.Who should not use Estradiol Vaginal Cream, 0.01%Do not start using estradiol vaginal cream, 0.01% if you:o Have unusual vaginal bleeding 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%.o Had stroke or heart attack Currently have or have had blood clots Currently have or have had liver problems Have been diagnosed with bleeding disorder 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.o Th ink you may be pregnant Tell your healthcare provider:o If you have unusual vaginal bleeding Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.o About all of your medical problems Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.o About all the medicines you take This includes prescription and nonprescription 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. If you are going to have surgery or will be on bed rest. You may need to stop using estradiol vaginal cream, 0.01%. If you are breastfeeding The estrogen hormone in estradiol vaginal cream, 0.01% can pass into your breast milk.How should use Estradiol Vaginal Cream, 0.01%Estradiol vaginal cream, 0.01% is cream that you place in your vagina with the applicator provided with the cream.o Take the dose recommended by your healthcare provider and talk to him or her about how well that dose is working for youo Estrogens should be used at the lowest dose possible for your treatment only as long as needed. You and your healthcare provider should talk regularly (for example, every to months) about the dose you are using and whether you still need treatment with estradiol vaginal cream, 0.01%o Step 1. Remove the cap from the tube. (There is no seal on tube)o Step 2. Do not separate plunger from applicator.o Step 3. Screw threaded end of applicator onto the open tube until secure.o Step 4. Position upright in order to view the calibrated gram amounts.o Step 5. Gently squeeze tube from the bottom to expel the prescribed amount of estradiol vaginal cream, 0.01% into the applicator. As cream is squeezed out, plunger will rise to indicate amount of grams.o Step 6. Unscrew applicator from tube.o Step 7. Replace cap on tube.o Step 8. Lie on back with knees drawn up. To deliver medication, gently insert applicator deeply into vagina and press plunger downward to its original position.o Step 9. To cleanse applicator: Pull plunger to remove it from barrel. Wash with mild soap and warm water (DO NOT BOIL OR USE HOT WATER)What are the possible side effects of Estradiol Vaginal Cream, 0.01%Although estradiol vaginal cream, 0.01% is only used in and around the vagina, the risks associated with oral estrogens should be taken into account.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:o Heart attacko Strokeo Blood clotso Dementiao Breast cancero Cancer of the lining of the uterus (womb)o Cancer of the ovaryo High blood pressureo High blood sugaro Gallbladder diseaseo Liver problemso Enlargement of benign tumors of the uterus (fibroids)o Severe allergic reactionCall your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:o New breast lumpso Unusual vaginal bleedingo Changes in vision or speecho Sudden new severe headacheso Severe pains in your chest or legs with or without shortness of breath, weakness and fatigueo Swollen lips, tongue or faceLess serious, but common side effects include:o Headacheo Breast paino Irregular vaginal bleeding or spottingo Stomach or abdominal cramps, bloatingo Nausea and vomitingo Hair losso Fluid retentiono Vaginal yeast infectiono Reactions from inserting estradiol vaginal cream, 0.01%, such as vaginal burning, irritation, and itchingThese 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. You may report side effects to FDA at 1-800-FDA-1088. What can do to lower my chances of serious side effect with Estradiol Vaginal Cream, 0.01%o Talk with your healthcare provider regularly about whether you should continue using estradiol vaginal cream, 0.01%.o If you have uterus, talk with your healthcare provider about whether the addition of progestin is right for you. The addition of progestin is generally recommended for woman with uterus to reduce the chance of getting cancer of the uterus.o See your healthcare provider right away if you get vaginal bleeding while using estradiol vaginal cream, 0.01%.o Have 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.o 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 Cream, 0.01%Medicines are sometimes prescribed for conditions that are not mentioned 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.Keep estradiol vaginal cream, 0.01% out of the reach of children.This leaflet provides summary of the most important information about estradiol vaginal cream, 0.01%. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about estradiol vaginal cream, 0.01% that is written for health professionals. You can get more information by calling the toll free number 1-866-832-8537.What are the ingredients in Estradiol Vaginal Cream, 0.01%Each gram of estradiol vaginal cream, 0.01% contains 0.1 mg estradiol in nonliquefying base containing purified water, propylene glycol, stearyl alcohol, white ceresin wax, mono- and di- glycerides, hypromellose 2208 (4000 cps), sodium lauryl sulfate, methylparaben, edetate di- sodium and tertiary-butylhydroquinone.

SPL UNCLASSIFIED SECTION.

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, 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 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, 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 persisted3. Should 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 placebo4 [see CLINICAL STUDIES].Subgroup analyses of women 50 to 59 years of age suggest 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 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 trend toward decreasing relative risk was reported in years through [see CLINICAL STUDIES].In postmenopausal women with documented heart disease (n 2,763), average age 66.7 years of age, in 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 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 years5 [see CLINICAL STUDIES]. Should VTE occur or be suspected, estrogen- alone therapy should be discontinued immediately.In the WHI estrogen plus progestin substudy, 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 per 10,000 women-years) were also demonstrated. The increase in VTE risk was observed during the first year and persisted [see CLINICAL STUDIES]. Should VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.If feasible, estrogens should be discontinued at least to weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

WARNINGS SECTION.

WARNINGS. See BOXED WARNINGS. Systemic absorption may occur with the use of estradiol vaginal cream, USP, 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, 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 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, 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 persisted3. Should 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 placebo4 [see CLINICAL STUDIES].Subgroup analyses of women 50 to 59 years of age suggest 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 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 trend toward decreasing relative risk was reported in years through [see CLINICAL STUDIES].In postmenopausal women with documented heart disease (n 2,763), average age 66.7 years of age, in 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 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 years5 [see CLINICAL STUDIES]. Should VTE occur or be suspected, estrogen- alone therapy should be discontinued immediately.In the WHI estrogen plus progestin substudy, 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 per 10,000 women-years) were also demonstrated. The increase in VTE risk was observed during the first year and persisted [see CLINICAL STUDIES]. Should VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.If feasible, estrogens should be discontinued at least to 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 woman with 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 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 different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be 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) [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 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 the absolute risk was 40 versus 36 cases per 10,000 women- years, for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups [see CLINICAL STUDIES].Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and smaller increased risk for estrogen- alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline in about years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.The use of estrogen-alone and estrogen plus progestin therapy has been reported to result in an increase in abnormal mammograms requiring further evaluation.All women should receive yearly breast examinations by healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.. c. OvarianCancer. The WHI estrogen plus progestin substudy reported statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24). The absolute risk for CE plus MPA was versus cases per 10,000 women-years 9. meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than years [median of years] vs. greater than years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within years before cancer diagnosis) was 1.37 (95% CI 1.27-1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.. 3. Probable Dementia. In the WHIMS estrogen-alone ancillary study of WHI, 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-years 10 [see CLINICAL STUDIES and PRECAUTIONS, Geriatric Use].In the WHIMS estrogen plus progestin ancillary study, 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 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].. 4.Gallbladder Disease. 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.. 5. Hypercalcemia. Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.. 6. Visual Abnormalities. Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.. 7.Anaphylactic Reaction and Angioedema. Cases of anaphylaxis, which develop within minutes to hours after taking orally-administered estrogen and require emergency medical management, have been reported in the postmarketing setting. Skin (hives, pruritis, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) involvement has been noted.Angioedema involving the tongue, larynx, face, hands and feet requiring medical intervention has occurred postmarketing in patients taking orally-administered estrogen. If angioedema involves the tongue, glottis, or larynx, airway obstruction may occur. Patients who develop an anaphylactic reaction with or without angioedema after treatment with oral estrogen should not receive oral estrogen again.. 8.HereditaryAngioedema. Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.