EstroGel 1.25 g is the single approved dose for the treatment of moderate to severe vasomotor symptoms and/or moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause. The lowest effective dose of EstroGel for these indications has not been determined. When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. When estrogen is prescribed for a postmenopausal woman with an intact uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be limited to the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (eg, 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS). For women who have an intact uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
EstroGel (estradiol gel) contains 0.06% estradiol in an absorptive hydroalcoholic gel base formulated to provide a controlled release of the active ingredient. The gel is applied over a large area (750 cm) of the skin in a thin layer. The recommended area of application is the arm, from wrist to shoulder. An EstroGel unit dose of 1.25 g contains 0.75 mg of estradiol. Estradiol is a white crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17��-diol. It has an empirical formula of CHOand molecular weight of 272.39. The structural formula is: The active component of the transdermal gel is estradiol. The remaining components of the gel (purified water, alcohol, triethanolamine and carbomer 934P) are pharmacologically inactive.
EstroGel provides systemic estrogen replacement therapy by releasing estradiol, the major estrogenic hormone secreted by the human ovary. 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 andthe 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, 2 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 elevated levels of these hormones seen in postmenopausal women.<br/>Pharmacokinetics: A. Absorption Estradiol is transported across intact skin and into the systemic circulation by a passive diffusion process. The rate of diffusion across the stratum corneum is the rate-limiting factor. When EstroGel is applied to the skin, it dries in 2 to 5 minutes. EstroGel 1.25 g was administered to 24 postmenopausal women once daily on the posterior surface of 1 arm from wrist to shoulder for 14 consecutive days. Mean maximal serum concentrations of estradiol and estrone on day 14 were 46.4 pg/mL and 64.2 pg/mL, respectively. The time-averaged serum estradiol and estrone concentrations over the 24-hour dose interval after administration of 1.25 g EstroGel on day 14 are 28.3 pg/mL and 48.6 pg/mL, respectively. Mean concentration-time profiles for unadjusted estradiol and estrone on day 14 are shown in Figure 1. The serum concentrations of estradiol following 2.5-g EstroGel applications (1.25 g on each arm from wrist to shoulder) appeared to reach steady state after the third daily application. B. 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 blood largely bound to sex hormone-binding globulin (SHBG) and albumin. C. 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, 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. Although the clinical significance has not been determined, estradiol from EstroGel does not go through first-pass liver metabolism. D. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The apparent terminal exponential half-life for estradiol was about 36 hours following administration of 1.25 g EstroGel. E. Special populations EstroGel has been studied only in postmenopausal women. No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment. F. Drug interactions No clinical drug-drug interaction studies have been conducted with EstroGel. 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 resultingin 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 estrogen and may result in side effects. G. Potential for estradiol transfer and effects of washing The effect of estradiol transfer was evaluated in 24 healthy postmenopausal women who topically applied 1.25 g of EstroGel once daily on the posterior surface of 1 arm from the wrist to shoulder for a period of 14 consecutive days. On each day, 1 hour after gel application, a cohort of 24 non-dosed healthy postmenopausal females directly contacted the dosed cohort at the site of gel application for 15 minutes. No change in endogenous mean serum concentrations of estradiol was observed in the non-dosed cohort after direct skin-to-skin contact with subjects administered EstroGel. The effect of application site washing on the serum concentrations of estradiol was determined in 24 healthy postmenopausal females who applied 1.25 g of EstroGel once daily for 14 consecutive days. Site washing 1 hour after the application resulted in a 22% mean decrease in average 24-hour serum concentrations of estradiol.<br/>CLINICAL STUDIES: Effects on vasomotor symptoms In a placebo-controlled study, 145 postmenopausal women between 29 and 67 years of age (81.4% were White) were randomly assigned to receive 1.25 g of EstroGel (containing 0.75 mg of estradiol) or placebo gel for 12 weeks. Efficacy was assessed at 4 and 12 weeks of treatment. A statistically significant reduction in the frequency and severity of moderate to severe hot flushes was shown at weeks 4 and 12. (See Table 1.) Effects on vulvar and vaginal atrophy Results of the vaginal wall cytology showed a significant (P=0.001) increase from baseline in the percent of superficial epithelial cells at week 12 for 1.25 g EstroGel. In contrast, no significant change from baseline was observed in the placebo group. Transdermal effects In 2 controlled clinical trials, application site reactions were reported by 0.6% of patients who received 1.25 g of EstroGel. Other skin reactions, such as pruritus and rash, were also noted. (See Table 4.) Women's Health Initiative studies The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated estrogens (CE) per day alone or the use of 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction (MI), silent MI, and CHD death), with invasive breast cancer as the primary adverse outcome studied. A���global index���included the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms. The estrogen-alone substudy was stopped early because an increased risk of stroke was observed. Results of the estrogen-alone substudy, which included 10,739 women (average age of 63 years, range 50-79; 75.3 percent White, 15 percent Black, 6.1 percent Hispanic, 3.5% Other), after an average follow-up of 6.8 years are presented in Table 2. 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 6 fewer hip fractures. The absolute excess risk of events included in the "global index" was a nonsignificant 2 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.) Final adjudicated results for CHD events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) in women receiving CE alone compared with placebo (see Table 2). The CE/MPA substudy was also stopped early. According to the predefined stopping rule, after an average follow-up of 5.2 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 (RR 1.15, 95% nCI, 1.03-1.28). For those outcomes included in the "global index," that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 person-years in the group treated with CE/MPA were 6 more CHD events, 7 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 7 fewer colorectal cancers and 5 fewer hip fractures. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.) Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50-79; 83.9% White, 6.8% Black, 5.4% Hispanic, 3.9% Other), are presented in Table 3 below. Women's Health Initiative Memory Study The estrogen-alone Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI, enrolled 2947 predominantly healthy postmenopausal women aged 65 years and older (45% aged 65-69 years, 36% aged 70-74 years, and 19% aged 75 years and older) to evaluate the effects of conjugated estrogens (CE 0.625 mg) daily on the incidence of probable dementia (primary outcome) compared with placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group (37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the estrogen-alone group was 1.49 (95% confidence interval [CI], 0.83-2.66) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.) The estrogen plus progestin WHIMS substudy enrolled 4532 predominantly healthy postmenopausal women aged 65 years and older (47% aged 65-69 years, 35% aged 70-74 years, and 18% aged 75 years and older) to evaluate the effects of CE 0.625 mg plus MPA 2.5 mg daily on the incidence of probable dementia (primary outcome) compared with placebo. After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21-3.48) compared to placebo. When data from the 2 populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (93% 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 BOXED WARNINGS, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)
Estrogens should not be used in individuals with any of the following conditions: 1. Undiagnosed abnormal genital bleeding 2. Known, suspected, or history of breast cancer 3. Known or suspected estrogen-dependent neoplasia 4. Active deep vein thrombosis, pulmonary embolism, or history of these conditions 5. Active or recent (eg, within the past year) arterial thromboembolic disease (eg, stroke, myocardial infarction) 6. Liver dysfunction or disease 7. Known hypersensitivity to ingredients in EstroGel 8. Known or suspected pregnancy. There is no indication for EstroGel in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. (See PRECAUTIONS.)
EstroGel is a clear, colorless, hydroalcoholic 0.06% estradiol gel supplied in a non-aerosol, metered-dose pump. The pump consists of an LDPE inner liner encased in rigid plastic with a resealable polypropylene cap. Three pump sizes are available, a 93-gram, a 50-gram, and a 25-gram. Each individually packaged pump contains 93 grams of gel and is capable of delivering 64 metered 1.25-g doses. Each individually packaged 50-gram pump contains 50 grams of gel and is capable of delivering 32 metered 1.25-g doses. Each individually packaged 25-gram pump contains 25 gramsof gel and is capable of delivering 14 metered 1.25-g doses. NDC: 0051-1028-58������������������������...(93-gram pump) NDC: 17139-617-40������������������������...(50-gram pump) NDC: 17139-617-20������������������������...(25-gram sample pump) NDC: 0051-1028-20������������������������...(25-gram sample pump) Keep out of reach of children. Store at 20��to 25��C (68��to 77��F); excursions permitted to 15��to 30��C (59��to 86��F) [See USP Controlled Room Temperature]. Manufactured for: Ascend Therapeutics, Inc.Herndon, VA 20170By Laboratoires Besins InternationalMontrouge, France 5000718E01306 ARev2 01/2007 Utilizes EHGTechnology ��2007 Ascend Therapeutics, Inc.
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER: Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of "natural" estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. (See WARNINGS, Malignant neoplasms, Endometrial cancer.) CARDIOVASCULAR AND OTHER RISKS Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. (See CLINICAL STUDIES, and WARNINGS, Cardiovascular disorders and Dementia.) The estrogen-alone substudy of the Women's Health Initiative (WHI) reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (aged 50-79 years) during 6.8 and 7.1 years, respectively, of treatment with oral conjugated estrogens (CE 0.625 mg) per day, relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders.) The estrogen-plus-progestin substudy of the WHI reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (aged 50-79 years) during 5.6 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) per day relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Malignant neoplasms, Breast cancer.) The Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI study, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with CE 0.625 mg alone and during 4 years of treatment with 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, Dementia, and PRECAUTIONS, Geriatric Use.) Other doses of conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins, were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, 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.
A. General:<br/>B. Patient Information: Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe EstroGel.<br/>C. Laboratory Tests: Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (eg, estradiol, FSH).<br/>D. Drug and Laboratory Test Interactions:<br/>E. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term continuous administration of estrogen, with and without progestin, in women, with and without an intact 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.<br/>F. Pregnancy: EstroGel should not be used during pregnancy. (See CONTRAINDICATIONS.)<br/>G. Nursing Mothers: Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogen have been identified in the milk of mothers receiving this drug. Caution should be exercised when EstroGel is administered to a nursing woman.<br/>H. Pediatric Use: EstroGel is not indicated for use in children.<br/>I. Geriatric Use: There have not been sufficient numbers of geriatric patients involved in studies utilizing EstroGel to determine whether those over 65 years differ from younger subjects in their response to EstroGel. Of the total number of subjects in the estrogen-alone substudy of the WHI study, 46% (n=4943) were aged 65 years and older, while 7.1% (n=767) were aged 75 years and older. There was a higher relative risk (CE vs placebo) of stroke in women aged less than 75 years compared to women aged 75 years and older. In the estrogen-alone substudy of the WHIMS, a population of 2947 hysterectomized women aged 65 to 79 years was randomized to estrogen alone (CE 0.625 mg daily) or placebo. After an average follow-up of 5.2 years, the relative risk (CE vs placebo) of probable dementia was 1.49 (95% CI, 0.83-2.66). The absolute risk of developing probable dementia with estrogen-alone was 37 vs 25 cases per 10,000 women-years. Of the total number of subjects in the estrogen plus progestin substudy of the WHI study, 44% (n=7320) were aged 65 years and older, while 6.6% (n=1095) were aged 75 years and older. There was a higher relative risk (CE/MPA vs placebo) of non-fatal stroke and invasive breast cancer in women aged 75 and older compared to women aged less than 75 years. In women aged greater than 75 years, the increased risk of non-fatal stroke and invasive breast cancer observed on the estrogen-plus-progestin combination group compared to the placebo group was 75 vs 24 per 10,000 women-years and 52 vs 12 per 10,000 women-years, respectively. In the estrogen-plus-progestin substudy of WHIMS, a population of 4532 postmenopausal women aged 65 to 79 years was randomized to conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) or placebo. In the estrogen-plus-progestin group, after an average follow-up of 4 years, the relative risk (CE/MPA vs placebo) of probable dementia was 2.05 (95% CI, 1.21-3.48). Seventy-nine percent of the cases of probable dementia occurred in women that were older than 70 years for the CE-alone group, and 82% of the cases of probable dementia occurred in women who were older than 70 years in the CE/MPA group. The most common classification of probable dementia in both the treatment groups and placebo groups was Alzheimer's disease. Pooling the events in women receiving CE or CE/MPA in comparison to those in women on placebo, the reported overall relative risk of probable dementia was 1.76 (95% CI, 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)
Serious adverse events have not been reported following acute ingestion of large doses of estrogen-containing products by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.
See BOXED WARNINGS.
EstroGel is indicated in the 1. Treatment of moderate to severe vasomotor symptoms associated with menopause. 2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.