Prescription Drugs

CLINICAL PHARMACOLOGY EstroGel provides systemic estrogen therapy by releasing estradiol, the major estrogenic hormone secreted by the human ovary. Mechanism Of Action 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 in the 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 FSH through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Pharmacodynamics There are no pharmacodynamic data for EstroGel. Pharmacokinetics 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 (containing 0.75 mg of estradiol) 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. FIGURE 1: Mean Serum Concentration - time Profiles for Unadjusted Estradiol and Estrone After Multiple- dose Application of 1.25g ExtroGel 0.06% for 14 Days 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. 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 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 a 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 intestine 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. 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. Use in Specific Populations No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment. Effect of Application Site Washing The effect of application site washing on the serum concentrations of estradiol was determined in 24 healthy postmenopausal women who applied 1.25 g of EstroGel once daily for 14 consecutive days. Site washing 1 hour after the application resulted in a 22 percent mean decrease in average 24-hour serum concentrations of estradiol. Potential for Estradiol Transfer 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 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. Effect of Moisturizer Lotion/Sunscreen on Estradiol Absorption The effect of sunscreen and moisturizer lotion on estradiol absorption from 0.06% estradiol topical gel was evaluated in a randomized, open-label, three-period crossover study in 42 healthy postmenopausal women. The study results showed that repeated daily application of sunscreen for 7 days at 1 hour after the administration of 0.06% estradiol topical gel decreased the mean AUC0-24h and Cmax of estradiol by 16%. Repeated daily application of moisturizer lotion for 7 days at 1 hour after the administration of 0.06% estradiol topical gel increased the mean AUC0-24h and Cmax of estradiol by 38% and 73%, respectively. The effect of daily application of sunscreen/moisturizer lotion on estradiol absorption, when sunscreen/moisturizer lotion is applied before administration of 0.06% estradiol topical gel, was not studied. Clinical Studies Effects On Vasomotor Symptoms In a placebo-controlled study, 145 postmenopausal women between 29 and 67 years of age (81.4 percent 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 2) TABLE 2 : Mean Change from Baseline in the Number and Severity of Hot Flushes per Day, ITT Population, LOCF Number of Hot Flushes/Day (Moderate to Severe) Severity Score/Day (Mild, Moderate, Severe) Placebo n=73 EstroGel 0.06% 1.25 g n=72 Placebo n=73 EstroGel 0.06% 1.25 g n=72 Baseline Mean (SD) 11.01 (5.66) 10.33 (3.07) 2.30 (0.24) 2.36 (0.29) Week 4* Mean (SD) 5.95 (5.17) 4.43 (4.13) 2.00 (0.63) 1.73 (0.73) Mean change from baseline (SD) -5.06 (4.91) -5.91 (3.68) -0.31 (0.62) -0.63 (0.71) Diff. vs placebo 0.85 0.32 P value† 0.019‡ 0.005‡ Week 12* Mean (SD) 5.17 (6.52) 2.79 (3.70) 1.76 (0.84) 1.33 (0.97) Mean change from baseline (SD) -5.84 (4.52) -7.55 (3.52) -0.54 (0.84) -1.03 (0.94) Diff. vs placebo 1.71 0.49 P value† 0.043‡ < 0.001‡ * Primary timepoint. † P values from Elteren's nonparametric test. ‡ Statistically significantly different from placebo. 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. 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 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 causes. These substudies did not evaluate the effects of CE-alone 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 50-79; 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 3. TABLE 3 : Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHIa Event Relative Risk CE vs. Placebo (95% nCIb) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-Years CHD eventsc 0.95 (0.78-1.16) 54 57 Non-fatal MIc 0.91 (0.73-1.14) 40 43 CHD deathc 1.01 (0.71-1.43) 16 16 All strokesc 1.33 (1.05-1.68) 45 33 Ischemic strokec 1.55 (1.19-2.01) 38 25 Deep vein thrombosisc,d 1.47 (1.06-2.06) 23 15 Pulmonary embolismc 1.37 (0.90-2.07) 14 10 Invasive breast cancerc 0.80 (0.62-1.04) 28 34 Colorectal cancerc 1.08 (0.75-1.55) 17 16 Hip fracturec 0.65 (0.45-0.94) 12 19 Vertebral fracturesc,d 0.64 (0.44-0.93) 11 18 Lower arm/wrist fracturesc,d 0.58 (0.47-0.72) 35 59 Total fracturesc,d 0.71 (0.64-0.80) 144 197 Death due to other causese,f 1.08 (0.88-1.32) 53 50 Overall mortalityc,d 1.04 (0.88-1.22) 79 75 Global indexg 1.02 (0.92-1.13) 206 201 aAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. bNominal confidence intervals unadjusted for multiple looks and multiple comparisons. cResults are based on centrally adjudicated data for an average follow-up of 7.1 years. dNot included in “global index”. eResults are based on an average follow-up of 6.8 years. fAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. gA 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 fractures.9 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 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. See Table 3. Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in the distribution of stroke subtype or severity, including fatal strokes, in women receiving estrogen-alone compared to placebo. Estrogen-alone therapy increased the risk of ischemic stroke, and this excess risk was present in all subgroups of women examined.10 See Table 3. Timing of 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)]. WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive 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 reduction 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 50-79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 4. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. TABLE 4 : Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Yearsa,b Event Relative Risk CE/MPA vs. Placebo (95% nCIc) CE/MPA n = 8,506 Placebo n = 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 thrombosisd 1.95 (1.43-2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive breast cancere 1.24 (1.01-1.54) 41 33 Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancerd 0.81 (0.48-1.36) 6 7 Cervical cancerd 1.44 (0.47-4.42) 2 1 Hip fracture 0.67 (0.47-0.96) 11 16 Vertebral fracturesd 0.65 (0.46-0.92) 11 17 Lower arm/wrist fracturesd 0.71 (0.59-0.85) 44 62 Total fractures 0.76 (0.69-0.83) 152 199 Overall mortalityf 1.00 (0.83-1.19) 52 52 Global Indexg 1.13 (1.02-1.25) 184 165 aAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. bResults are based on centrally adjudicated data. cNominal confidence intervals unadjusted for multiple looks and multiple comparisons. dNot included in “global index”. eIncludes metastatic and non-metastatic breast cancer, with the exception of in-situ breast cancer. fAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. gA 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. Timing of 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, 0.44­1.07)]. Women's Health Initiative Memory Study The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 years of age and older (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 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 the study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed type (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 AND PRECAUTIONS, and Use In Specific Populations]. The WHIMS estrogen plus progestin ancillary study 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 of age, and 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 cases per 10,000 women-years. Probable dementia as defined in the study included AD, VaD and mixed type (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 AND PRECAUTIONS, and Use in Specific Populations]. 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 AND PRECAUTIONS, and Use In Specific Populations]. REFERENCES 8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958. 9. 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. 10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation. 2006;113:2425-2434.

CLINICAL PHARMACOLOGY Mechanism Of Action 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 in the 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 FSH through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Pharmacodynamics Currently, there are no pharmacodynamic data known for ELESTRIN. Pharmacokinetics Absorption Steady-state serum concentrations of estradiol are achieved in approximately 3 days following daily application of ELESTRIN to the upper arm. Pharmacokinetic parameters for estradiol on Day 14 following daily application of 0.87 g or 1.7 g of ELESTRIN are summarized in Table 2. Dose dependent PK parameters for ELESTRIN 0.87 g and 1.7 g indicated the dose and serum estradiol (E2) concentrations to be linearly related but not dose-proportional (i.e., doubling in dose led to a 2.5-to 3.0-fold increase in PK parameters). The nominal mean delivery rates of estradiol using the baseline-adjusted average serum concentrations from pharmacokinetic studies using 0.87 g per day and 1.7 g per day are 0.0125 mg per day and 0.0375 mg per day, respectively. TABLE 2 :Summary of Unadjusted PK Parameters for Estradiol after 14 Days of Dosing Pharmacokinetic Parameter 0.87 g ELESTRIN (0.52 mg/d Estradiol) Mean 1.7 g ELESTRIN (1.04 mg/d Estradiol) Mean AUC0-24 (pg'hr/mL) 335.2 940.2 Cmax (pg/mL) 21.6 66.7 Cave (pg/mL) 15.4 39.2 Cmin (pg/mL) 9.4 21.1 Tmax (h)a 18 (1 – 20) 4 (1 – 20) Fluctuation Index 0.8 1.16 E2:E1b ratio 0.53 0.98 aTmax shown as median (range) bE2:E1 (estradiol:estrone) ratio Mean concentrations of estradiol over a 24-hour period on Day 14 are shown in Figure 1. Figure 1 :Mean Serum Estradiol Concentrations (Unadjusted) After Multiple Doses. Error bars represent standard deviations. Based on the Cave values at steady state, the E2:E1 ratio was 0.53 for the 0.87 g and 0.98 for the 1.7 g doses. The significance of this finding is that the 1.7 g dose produced an E2:E1 ratio of a premenopausal woman. The 1.7 g dose of ELESTRIN reached the goal of restoring the E2:E1 ratio (~1.0) to that observed in premenopausal women in the early follicular phase of the menstrual cycle. Application of sunscreen 10 minutes before application of ELESTRIN increased the exposure to estradiol by approximately 55 percent. No significant change in estradiol exposure was observed when sunscreen was applied 25 minutes after application of ELESTRIN. In the same study, prolonged (7 days) concomitant application of sunscreen to the site of ELESTRIN application increased exposure to estradiol by about 2-fold, regardless of whether it was applied before or after application of ELESTRIN. 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 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 a 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 intestine 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. Use in Specific Populations No pharmacokinetic studies were conducted in specific populations, including women with renal or hepatic impairment. Potential for Estradiol Transfer The potential for estradiol transfer between treated postmenopausal female subjects and their untreated male partners was evaluated. Two and 8 hours after women applied 2.6 g ELESTRIN to one arm (12 women per time point), they engaged in direct arm-to-arm contact with a male partner for 5 minutes. No significant changes in estradiol pharmacokinetic parameters were observed in the male partners after contact. Less than 10 percent of the estradiol dose was measured on the skin at 2 and 8 hours after application. After washing the application site with soap and water at 8 hours after application, about 1 percent of the dose of estradiol was measurable. Clinical Studies Effects On Vasomotor Symptoms A randomized, double-blind, placebo-controlled clinical trial evaluated the efficacy of 12-week treatment with three different daily doses of ELESTRIN for the treatment of vasomotor symptoms in 484 postmenopausal women between 28 and 74 years of age (mean 54 years; 83-88 percent Caucasian per group) who had at least 60 moderate-to-severe hot flushes per week at baseline. At baseline, mean hot flushes is 13 per day, mean serum estradiol is 11.2-13.2 pg/mL, and prior hormone/estrogen therapy is 75.7-84.5 percent. Subjects applied placebo, ELESTRIN 1.7 g (1.04 mg estradiol), or 2.6 g (1.56 mg estradiol) once daily to the upper arm. The study was amended to identify the lowest effective dose of ELESTRIN and limit the number of subjects exposed to the 2.6 g dose. After the study amendment, ELESTRIN 0.87 g (0.52 mg estradiol) was added and the 2.6 g was discontinued from further enrollment. Reduction in both the frequency and severity of moderate to severe hot flushes was statistically significant for the ELESTRIN 1.7 g per day dose compared to placebo at week 4. Statistically significant reductions in both the frequency and severity of moderate to severe hot flushes when compared to placebo were delayed for the ELESTRIN 0.87 g per day dose to week 5. Both the 0.87 g per day and 1.7 g per day doses were statistically significant compared to placebo at week 12. Statistically significant reductions in the frequency and severity of daily moderate-to-severe hot flush rate compared to placebo were noted beginning at week 3 for the 1.7 g per day ELESTRIN treatment (data on file). The reductions in frequency and severity are shown in Table 3. TABLE 3 :Mean Change From Baselinea in the Number and Severity of Hot Flushes after ELESTRIN Treatment Evaluation Placebo (N=137) ELESTRIN 0.87 g/day (N=136) ELESTRIN 1.7 g/day (N=142) Number of Daily Hot Flushes Baseline (Mean ± SD)b 13.5 ± 4.5 13.3 ± 4.6 13.1 ± 6.5 Mean Change: Week 4 -5.1 -6.5# -8.0*** Week 5 -5.1 -7.5* -8.8*** Week 12 -5.4 -8.5*** -10.0*** Daily Hot Flush Severityc Baseline (Mean ± SD)b 2.4 ± 0.3 2.4 ± 0.3 2.4 ± 0.3 Mean Change: Week 4 -0.2 -0.5# -0.7*** Week 5 -0.2 -0.5* -0.8*** Week 12 -0.3 -0.8*** -1.2*** aDifferences from baseline based on LS means derived from the ANCOVA model with factors for baseline, treatment, site, and treatment-by-baseline interaction. bUnadjusted means and standard deviations, based on the first 14 days of the Screening Period. c Severity score: 1=mild, 2=moderate, 3=severe. SD: standard deviation #P=ns, *P < 0.01, **P < 0.001, ***P < 0.0001 for treatment comparison with placebo (Dunnett's test). 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 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-alone 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 risk and benefits of estrogen-alone in predetermined 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 4. TABLE 4 : Relative and Absolute Risk Seen in the Estrogen-Alone substudy of WHIa Event Relative Risk CE vs. Placebo (95% nCIb) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-Years CHD eventsc 0.95 (0.78-1.16) 54 57 Non-fatal MI c 0.91 (0.73-1.14) 40 43 CHD deathc 1.01 (0.71-1.43) 16 16 All Strokec 1.33 (1.15-1.68) 45 33 Ischemic strokec 1.55 (1.19-2.01) 38 25 Deep vein thrombosisc,d 1.47 (1.06-2.06) 23 15 Pulmonary embolismc 1.37 (0.90-2.07) 14 10 Invasive breast cancerc 0.80 (0.62-1.04) 28 34 Colorectal cancerc 1.08 (0.75-1.55) 17 16 Hip fracturec 0.65 (0.45-0.94) 12 19 Vertebral fracturesc,d 0.64 (0.44-0.93) 11 18 Lower arm/wrist fracturesc,d 0.58 (0.47-0.72) 35 59 Total fracturesc,d 0.71 (0.64-0.80) 144 197 Death due to other causese,f 1.08 (0.88-1.32) 53 50 Overall mortalityc,d 1.04 (0.88-1.22) 79 75 Global indexg 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 risks per 10,000 women-years in the group treated with CE-alone were 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures.9 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 difference in the distribution of stroke subtype and severity, including fatal strokes, in women receiving estrogen-alone compared to placebo. Estrogen-alone therapy increased the risk of ischemic stroke, and this excess risk was present in all subgroups of women examined.10 Timing of 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)]. WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive 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 reduction 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 5. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. TABLE 5 :Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Yearsa,b Event Relative Risk CE/MPA vs. Placebo (95% nCIc) CE/MPA n = 8,506 Placebo n = 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 Stroke 1.31 (1.03-1.68) 33 25 Ischemic stroke 1.44 (1.09-1.90) 26 18 Deep vein thrombosisd 1.95 (1.43-2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive breast cancere 1.24 (1.01-1.54) 41 33 Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancerd 0.81 (0.48-1.36) 6 7 Cervical cancerd 1.44 (0.47-4.42) 2 1 Hip fracture 0.67 (0.47-0.96) 11 16 Vertebral fracturesd 0.65 (0.46-0.92) 11 17 Lower arm/wrist fracturesd 0.71 (0.59-0.85) 44 62 Total fractures 0.76 (0.69-0.83) 152 199 Overall mortalityf 1.00 (0.83-1.19) 52 52 Global Indexg 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 breast 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, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. Timing of 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 (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 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 the study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed type (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 AND PRECAUTIONS, and Use In Specific Populations]. The WHIMS estrogen plus progestin ancillary study 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 of age, and 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 cases per 10,000 women-years. Probable dementia as defined in the 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 AND PRECAUTIONS, and Use In Specific Populations]. 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 AND PRECAUTIONS, and Use in Specific Populations]. REFERENCES 9. 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. 10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation. 2006;113:2425-2434.

CLINICAL PHARMACOLOGY Divigel® provides estrogen therapy by delivering estradiol, the major estrogenic hormone secreted by the human ovary, to the systemic circulation following topical application. 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. Pharmacokinetics Absorption Estradiol diffuses across intact skin and into the systemic circulation by a passive absorption process, with diffusion across the stratum corneum being the rate-limiting factor. In a 14-day, Phase 1, multiple-dose study, Divigel® demonstrated linear and approximately dose-proportional estradiol pharmacokinetics at steady state for both AUC0-24 and Cmax following once daily dosing to the skin of either the right or left upper thigh (Table 1). Table 1: Mean (%CV) Pharmacokinetic Parameters for Estradiol (uncorrected for baseline) on Day 14 Following Multiple Daily Doses of Divigel® 0.1% Parameter (units) Divigel® 0.25 g Divigel® 0.5 g Divigel® 1.0 g AUC0-24 (pg•h/mL) 236 (94) 504 (149) 732 (81) Cmax (pg/mL) 14.7 (84) 28.4 (139) 51.5 (86) Cavg (pg/mL) 9.8 (92) 21 (148) 30.5 (81) tmax* (h) 16 (0, 72) 10 (0, 72) 8 (0, 48) E2:E1 ratio 0.42 0.65 0.65 *Median (Min, Max). Steady-state serum concentration of estradiol are achieved by day 12 following daily application of Divigel® to the skin of the upper thigh. The mean (SD) serum estradiol levels following once daily dosing at day 14 are shown in Figure 1. Figure 1: Mean (SD) Serum Estradiol Concentrations (Values Uncorrected for Baseline) on Day 14 Following Multiple Daily Doses of Divigel 0.1% The effect of sunscreens and other topical lotions on the systemic exposure of Divigel® has not been evaluated. Studies conducted using topical estrogen gel approved products have shown that sunscreens have the potential for changing the systemic exposure of topically applied estrogen gels. 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 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 intestine 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. Estradiol from Divigel® avoids first pass metabolism and provides estradiol/estrone ratios at steady state in the range of 0.42 to 0.65. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The apparent terminal half-life for estradiol was about 10 hours following administration of Divigel®. Special Populations Divigel® has been studied only in postmenopausal women. 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 result in side effects. Potential for Estradiol Transfer and Effects of Washing As with most topical products, there is a potential for estradiol transfer following physical contact with Divigel® application sites. The effect of estradiol transfer was evaluated in healthy postmenopausal women who topically applied 1.0 g of Divigel® (single dose) on one thigh. One and 8 hours after gel application, they engaged in direct thigh- to- arm contact with a partner for 15 minutes. While some elevation of estradiol levels over baseline was seen in the male subjects, the degree of transferability in this study was inconclusive. The effect of application site washing on skin surface levels and serum concentrations of estradiol was determined in 16 healthy postmenopausal women after application of 1.0 g of Divigel® to a 200 cm² area on the thigh. Washing the application site with soap and water 1 hour after application removed all detectable amounts of estradiol from the surface of the skin, and resulted in a 30-38% decrease in the mean total 24-hour exposure to estradiol. Clinical Studies Effects on Vasomotor Symptoms A randomized, double-blind, placebo-controlled trial evaluated the efficacy of 12-week treatment with three different daily doses of Divigel® for vasomotor symptoms in 495 postmenopausal women (86.5% White; 10.1% Black) between 34 and 89 years of age (mean age 54.6) who had at least 50 moderate to severe hot flushes per week at baseline (2 week period prior to treatment). Subjects applied placebo, Divigel® 0.25 g (0.25 mg estradiol), Divigel® 0.5 g (0.5 mg estradiol) or Divigel® 1.0 g (1.0 mg estradiol) once daily to the thigh. Reductions in both the median daily frequency and the median daily severity of moderate to severe hot flushes were statistically significant for the 0.5 g/day and the 1.0 g/day Divigel® doses when compared to placebo at week 4. Statistically significant reductions in both the median daily frequency and the median daily severity of moderate to severe hot flushes for the Divigel® 0.25 g/day dose when compared to placebo were delayed to week 7. There were statistically significant reductions in median daily frequency and severity of hot flushes for all three Divigel® doses (0.25 g/day, 0.5 g/day and 1.0 g/day) compared to placebo at week 12. See Table 2 for results. Table 2: Summary of Change From Baseline in the Median Daily Frequency and Severity of Hot Flushes during Divigel® Treatment (ITT Population) Evaluation Divigel® Placebo N=124 0.25 g/day N=121 0.5 g/day N=119 1.0 g/day N=124 Frequency of Daily Hot Flushes Baseline Median 9.72 9.24 9.64 9.32 Median Change: Week 4 -5.00 -5.73 -7.20 -3.63 p-value† 0.132 0.011 <0.001 Median Change: Week 7 -6.62 -7.14 -7.71 -4.37 p-value† <0.001 <0.001 <0.001 Median Change: Week 12 -6.88 -7.29 -8.35 -4.48 p-value† <0.001 <0.001 <0.001 Severity of Daily Hot Flushes Baseline Median 2.52 2.51 2.52 2.54 Median Change: Week 4 -0.07 -0.18 -0.47 -0.04 p-value† 0.283 <0.001 <0.001 Median Change: Week 7 -0.24 -0.46 -1.06 -0.06 p-value† <0.001

Find Lowest Prices on EstroGel® 0.06%  (estradiol) Gel WARNING ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA 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. 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 AND PRECAUTIONS]. Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see WARNINGS AND PRECAUTIONS, and Clinical Studies]. The Women's 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 WARNINGS AND PRECAUTIONS, and Clinical Studies]. 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 WARNINGS AND PRECAUTIONS, Use in Specific Populations, and Clinical Studies]. 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 Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see WARNINGS AND PRECAUTIONS, and Clinical Studies]. 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 WARNINGS AND PRECAUTIONS, and Clinical Studies]. The WHIMS estrogen plus progestin ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 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 WARNINGS AND PRECAUTIONS, Use in Specific Populations, and Clinical Studies]. Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see WARNINGS AND PRECAUTIONS, and Clinical Studies]. 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. DESCRIPTION EstroGel (estradiol gel) contains 0.06 percent estradiol in an absorptive hydroalcoholic gel base. It is a clear, colorless gel, which is odorless when dry. One pump depression of EstroGel delivers 1.25 g of gel containing 0.75 mg estradiol. Estradiol is a white crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17β-diol. It has an empirical formula of C18H24O2 and 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.

Find Lowest Prices on Elestrin™ (estradiol) Gel WARNING ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER and PROBABLE DEMENTIA 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. 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 AND PRECAUTIONS]. Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see WARNINGS AND PRECAUTIONS and Clinical Studies]. The Women's 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 WARNINGS AND PRECAUTIONS, and Clinical Studies]. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the 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 WARNINGS AND PRECAUTIONS, Use in Specific Populations, and Clinical Studies]. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other 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 Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see WARNINGS AND PRECAUTIONS, and Clinical Studies. 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 WARNINGS AND PRECAUTIONS, and Clinical Studies]. 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 4 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 WARNINGS AND PRECAUTIONS, Use in Specific Populations, and Clinical Studies]. Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see WARNINGS AND PRECAUTIONS, and Clinical Studies]. 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 women. DESCRIPTION ELESTRIN (estradiol gel) contains 0.06% of estradiol, an estrogen, in a colorless, non-staining hydroalcoholic gel base. One pump actuation delivers ELESTRIN in a unit dose of 0.52 mg of estradiol in 0.87 g of gel. Estradiol is a white crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17-diol, (17β)-. It has a molecular formula of C18H24O2•½H2O and molecular weight of 281.4. The structural formula is: The active component of ELESTRIN is estradiol. The remaining components of the gel (ethanol, propylene glycol, diethylene glycol monoethyl ether, carbomer 940, triethanolamine, edetate disodium, and purified water) are pharmacologically inactive.

Find Lowest Prices on Divigel® (estradiol gel) 0.1% 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 or dementia. (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 in postmenopausal women (50 to 79 years of age) during 6.8 years and 7.1 years, respectively, of treatment with oral conjugated estrogens (CE 0.625 mg) alone per day, relative to placebo. (See Clinical Studies and WARNINGS, Cardiovascular disorders.) The estrogen-plus-progestin substudy of the WHI reported increased risk of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) 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, reported an 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, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.) Other doses of oral 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. DESCRIPTION Divigel® (estradiol gel) 0.1% is a clear, colorless gel, which is odorless when dry. It is designed to deliver sustained circulating concentrations of estradiol when applied once daily to the skin. The gel is applied to a small area (200 cm²) of the thigh in a thin, quick-drying layer. Divigel® is available in three doses of 0.25, 0.5, and 1.0 g for topical application (corresponding to 0.25, 0.5, and 1.0 mg estradiol, respectively). The active component of the topical gel is estradiol. Estradiol is a white crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17β-diol. It has an empirical formula of C18H24O2 and molecular weight of 272.39. The structural formula is: The remaining components of the gel (carbomer, ethanol, propylene glycol, purified water, and triethanolamine) are pharmacologically inactive.

INDICATIONS Treatment Of moderate To Severe Vasomotor Symptoms Due To Menopause Treatment Of Moderate To Severe Symptoms Of Vulvar And Vaginal Aatrophy Due To Menopause Limitation of Use When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, topical vaginal products should be considered. DOSAGE AND ADMINISTRATION Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be considered to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a progestin [see WARNINGS AND PRECAUTIONS]. Use of estrogen-alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be reevaluated periodically as clinically appropriate to determine if treatment is still necessary. Treatment Of Moderate To Severe Vasomotor Symptoms Due To Menopause. EstroGel 0.06% 1.25 g per day is the single approved dose for the treatment of moderate to severe vasomotor symptoms due to menopause. The lowest effective dose of EstroGel 0.06% for this indication has not been determined. Before using the canister for the first time, it must be primed. Remove the large canister cover, and fully depress the pump 3 times. Discard the unused gel by thoroughly rinsing down the sink or placing it in the household trash. After priming, the pump is ready to use. The recommended area of application is the arm. Apply a thin layer over the entire arm on the inside and outside from wrist to shoulder. Treatment Of Moderate To Severe Symptoms Of Vulvar And Vaginal Atrophy Due To Menopause. EstroGel 0.06% 1.25 g per day is the single approved dose for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. The lowest effective dose of EstroGel 0.06% for this indication 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. Before using the canister for the first time, it must be primed. Remove the large canister cover, and fully depress the pump 3 times. Discard the unused gel by thoroughly rinsing down the sink or placing it in the household trash. After priming, the pump is ready to use. The recommended area of application is the arm. Apply a thin layer over the entire arm on the inside and outside from wrist to shoulder. HOW SUPPLIED Dosage Forms And Strengths EstroGel 0.06% is an estradiol transdermal gel. One pump depression delivers 1.25 g of gel that contains 0.75 mg estradiol. EstroGel is a clear, colorless, hydroalcoholic 0.06 percent 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. Two pump sizes are available, a 50-gram (1.75 oz), and a 25-gram (0.88 oz). 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 grams of gel and is capable of delivering 14 metered 1.25-g doses. One pump depression (1.25 g EstroGel) contains 0.75 mg estradiol. NDC: 17139-617-40............................. (50-gram pump) NDC: 17139-617-20............................. (25-gram sample pump) Storage And Handling 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® US, LLC, Herndon, VA 20170, By DPT Laboratories, San Antonio, TX 78215. Revised: 3/2014

INDICATIONS Treatment Of Moderate To Severe Vasomotor Symptoms Due To Menopause DOSAGE AND ADMINISTRATION Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be considered to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a progestin [see WARNINGS AND PRECAUTIONS]. Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. The gel is applied onto the skin in a thin layer. The recommended area of application is the upper arm to shoulder (approximately 320 cm²). Treatment Of Moderate To Severe Vasomotor Symptoms Due To Menopause ELESTRIN is applied once daily to the upper arm for the treatment of moderate to severe vasomotor symptoms due to menopause using a metered-dose pump which delivers 0.87 gram of estradiol gel (0.52 mg estradiol) per actuation (1 pump). Patients should be started with the lowest effective dose of ELESTRIN, which is one pump per day (0.87 g per day, which contains 0.52 mg of estradiol). Subsequent dosage adjustment may be made based upon the individual patient response. This dose should be periodically reassessed by the healthcare provider. HOW SUPPLIED Dosage Forms And Strengths Elestrin (estradiol gel) 0.06% is available in a metered dose pump which delivers 0.52 mg of estradiol in 0.87 g of gel per pump actuation Elestrin® (estradiol gel) 0.06% is a colorless, non-staining hydroalcoholic gel supplied in a non-aerosol, metered-dose pump container constructed of polypropylene. The drug product is contained within a collapsible inner liner/bag consisting of an inner and outer layer of low density polyethylene with a resealable polypropylene cap. Each pump container holds 35 g of gel and is capable of delivering 26 g of gel as 30 metered doses. Each metered dose delivers 0.87 g of gel which contains 0.52 mg of estradiol. NDC 18860-480-01….. 35 g of pump container. This pump container is packaged individually or as two pump containers together in Cartons (18860-480-30 and 18860-480-60). NDC 18860-480-30.....Carton containing one ELESTRIN 35 g pump container. NDC 18860-480-60.....Carton containing two ELESTRIN 35 g pump containers. Storage And Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. Distributed by: Meda Pharmaceuticals Commercial Corp., 1818 Market Street, Suite 2350, Philadelphia, PA 19103. Manufactured by: DPT Laboratories, Ltd. 318 McCullough San Antonio, TX 78215. Revised: Feb 2014

INDICATIONS Divigel® (estradiol gel) 0.1% is indicated in the treatment of moderate to severe vasomotor symptoms associated with menopause. DOSAGE AND ADMINISTRATION When estrogen is prescribed for a postmenopausal woman with a 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 with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS). For women who have a 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. Divigel® (estradiol gel) 0.1%, at doses of 0.25, 0.5, and 1.0 g/day, is indicated for topical use in the treatment of moderate to severe vasomotor symptoms associated with menopause. Each gram of Divigel® contains 1 mg of estradiol. Patients should be treated with the lowest effective dose of Divigel®. Generally, women should be started at 0.25 gram Divigel® daily. Subsequent dosage adjustments may be made based upon the individual patient response. This dose should be periodically reassessed by the healthcare provider. Divigel® should be applied once daily on the skin of either the right or left upper thigh. The application surface area should be about 5 by 7 inches (approximately the size of two palm prints). The entire contents of a unit dose packet should be applied each day. To avoid potential skin irritation, Divigel® should be applied to the right or left upper thigh on alternating days. Divigel® should not be applied on the face, breasts, or irritated skin or in or around the vagina. After application, the gel should be allowed to dry before dressing. The application site should not be washed within 1 hour after applying Divigel®. Contact of the gel with eyes should be avoided. Hands should be washed after application. HOW SUPPLIED Divigel® (estradiol gel) 0.1% is a clear, colorless, smooth, opalescent gel supplied in single-dose foil packets of 0.25, 0.5, and 1.0 g, corresponding to 0.25, 0.5, and 1.0 mg estradiol, respectively. NDC 0245-0880-30, carton of 30 packets, 0.25 mg estradiol per single-dose foil packet NDC 0245-0881-30, carton of 30 packets, 0.5 mg estradiol per single-dose foil packet NDC 0245-0882-30, carton of 30 packets, 1.0 mg estradiol per single-dose foil packet Keep out of the 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 by: Orion Corporation Orion Pharma, Tengströminkatu 8, FI-20360 Turku, Finland. Distributed by: Upsher-Smith Laboratories, Inc., Minneapolis, MN 55447, 1-800-654-2299, Product of Finland. Revised June 2007

PATIENT INFORMATION EstroGel® 0.06%  (es' tre jel) (estradiol) Gel Read this Patient Information before you start using EstroGel, and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment. What is the most important information I should know about EstroGel (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 EstroGel. 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. 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 and 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 attack, 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. You and your healthcare provider should talk regularly about whether you still need treatment with EstroGel. What is EstroGel? EstroGel is a prescription medicine gel that contains estradiol (an estrogen hormone). What is EstroGel used for? EstroGel is used after menopause to: Reduce moderate to severe hot flashes Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause.” When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild, and they will not need to use estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with EstroGel. Treat 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 EstroGel to control these problems. If you use EstroGel only to treat your menopausal changes in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you. Who should not use EstroGel? Do not start using EstroGel 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. currently have or have had certain cancers Estrogens may increase the chance of getting certain types of cancer, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use EstroGel. had a stroke or heart attack currently have or have had blood clots currently have or have had liver problems have been diagnosed with a bleeding disorder are allergic to EstroGel or any of its ingredients See the list of ingredients in EstroGel at the end of this leaflet. think you may be pregnant EstroGel is not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not use EstroGel if the test is positive and talk to your healthcare provider. What should I tell my healthcare provider before I use EstroGel? Before you use EstroGel, tell your healthcare provider if you: have any 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), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, angioedema (swelling of face and tongue), or problems with your heart, liver, thyroid, kidneys, or 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 EstroGel. are breastfeeding The hormone in EstroGel can pass into your breast milk. Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how EstroGel works. EstroGel 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 EstroGel? For detailed instructions, see the step-by-step instructions for using EstroGel at the end of this Patient Information. Use EstroGel exactly as your healthcare provider tells you to use it. EstroGel is for skin use only. EstroGel contains alcohol, which is flammable. Avoid fire, flame or smoking until EstroGel has dried. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are using and whether you still need treatment with EstroGel. What are the possible side effects of EstroGel? 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: heart attack stroke blood clots dementia breast cancer cancer of the lining of the uterus (womb) cancer of the ovary high blood pressure high blood glucose gallbladder disease liver problems changes in your thyroid hormone levels enlargement of benign tumors (“fibroids”) Call your healthcare provider right away if you get any of the following warnings 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 Less serious, but common side effects include: headache breast pain stomach or abdominal cramps, bloating nausea and vomiting hair loss fluid retention vaginal yeast infection These are not all of the possible side effects of EstroGel. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or does not go away. You may report side effects to ASCEND Therapeutics US, LLC at 1-887-204-1013 or to FDA at 1-800-FDA-1088. What can I do to lower my chances of a serious side effect with EstroGel? Talk with your healthcare provider regularly about whether you should continue using EstroGel. If you have a uterus, talk with your healthcare provider about whether the addition of a progestin is right for you. The addition of a progestin is generally recommended for women with a uterus to reduce the chance of getting cancer of the uterus (womb). See your healthcare provider right away if you get vaginal bleeding while using EstroGel. 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 (breast x-ray), 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 of getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease. How should I store EstroGel? Store EstroGel at room temperature between 68°F to 77°F (20°C to 25°C). Keep EstroGel and all medicines out of the reach of children. General information about the safe and effective use of EstroGel Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use EstroGel for conditions for which it was not prescribed. Do not give EstroGel to other people, even if they have the same symptoms you have. It may harm them. This patient leaflet summarizes the most important information about EstroGel. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about EstroGel that is written for health professionals. For more information, go to www.estrogel.com, or call ASCEND Therapeutics, US, LLC at 1-877-204-1013. What are the ingredients in EstroGel? Active ingredient: estradiol Inactive ingredients: purified water, alcohol, triethanolamine, and carbomer 934P. Instructions for Use EstroGel® 0.06% (es' tre jel) (estradiol gel) Read this Instructions for Use before you start using EstroGel and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment. You will need the following supplies to use EstroGel: See Figure A. Figure A EstroGel is supplied in a metered-dose pump that delivers a measured amount of estradiol to your skin each time you press the pump. EstroGel is available in 2 sizes: a 50-gram canister a 25-gram canister Your healthcare provider will prescribe the size canister that is right for you. The instructions below are the same for both canister sizes. Step 1. Priming the EstroGel pump Before using the EstroGel pump for the first time, the pump must be primed. The EstroGel canister contains enough medicine to allow you to prime the pump before you use it for the first time. Remove the large cap from the canister and the small cap from the tip of the pump. See Figure B. Figure B Slowly push the pump all the way down 3 times. Do not use any EstroGel that came out while priming. Wash it down the sink to avoid accidental exposure to others. After priming, the EstroGel pump is ready to use. One complete press of the pump will give the same amount of EstroGel each time. Step 2. Applying EstroGel to your skin Do not allow other people to apply EstroGel to your skin for you. Apply EstroGel to clean, dry, unbroken skin. Apply EstroGel after your bath or shower. If you go swimming, try to leave as much time as possible between using your EstroGel and going swimming. Remove the small cover on the tip of the pump if you have not done so already. See Figure C. Figure C To use Estrogel, press the EstroGel pump firmly and fully 1 time into the palm of your hand. See Figure D. Figure D Using your hand, apply EstroGel to the skin of your other arm. See Figure E. Spread the gel as thinly as possible over the entire area on the inside and outside of your arm from your wrist to your shoulder. See Figure F. Figure E Figure F Do not apply EstroGel directly to your breasts or in and around your vagina. Do not massage or rub in EstroGel. Allow the gel to dry for 5 minutes before you get dressed. Step 3. After you use EstroGel Place the small cap back on the tip of the pump. Place the large cap over the top of the canister. Wash your hands right away with soap and water after applying EstroGel. This will lower the chance that the medicine will spread from your hands to other people. Do not allow others to make contact with the area of skin where you applied the gel for at least 1 hour after application. EstroGel is flammable until dry. Let EstroGel dry before smoking or going near an open flame. Step 4. Throwing away used EstroGel canisters The EstroGel 50-gram canister contains enough medicine to allow for priming your canister with 3 full pump depressions and delivery of 32 daily doses. After you have first primed your canister and used 32 doses, you will need to throw away the canister. Do not use the canister for more than 32 doses even though the canister may not be completely empty. You may not get the correct dose. The EstroGel 25-gram canister contains enough medicine to allow for priming your canister with 3 full pump depressions and delivery of 14 daily doses. After you have first primed your canister and used 14 doses, you will need to throw away the canister. Do not use the canister for more than 14 doses even though the canister may not be completely empty. You may not get the correct dose. This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

PATIENT INFORMATION ELESTRIN™ (estradiol) Gel Read this PATIENT INFORMATION before you start using ELESTRIN and read what you get each time you refill your ELESTRIN prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment. What is the most important information I should know about ELESTRIN (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 ELESTRIN. 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. 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 age 65 years 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 age 65 years or older You and your healthcare provider should talk regularly about whether you still need treatment with ELESTRIN What is ELESTRIN? ELESTRIN is a medicine in a colorless gel that contains an estrogen hormone (estradiol) which is absorbed through the skin into the bloodstream. What is ELESTRIN used for? ELESTRIN is used after menopause to: Reduce moderate to severe hot flashes Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 to 55 years old. This drop in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause.” When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild, and they will not need estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with ELESTRIN. Who should not use ELESTRIN? Do not start using ELESTRIN if you: Have unusual vaginal bleeding Currently have or have had certain cancers Estrogens may increase the chance 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 ELESTRIN. Had a stroke or heart attack Currently have or have had blood clots Currently have or have had liver problems Have been diagnosed with a bleeding disorder Are allergic to ELESTRIN or any of its ingredients See the list of ingredients in ELESTRIN at the end of this leaflet Think you may be pregnant Tell your healthcare provider: If you have any 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. 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, or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. About all the medicines you take This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how ELESTRIN works. ELESTRIN 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 ELESTRIN. If you are breastfeeding The hormone in ELESTRIN can pass into your breast milk. How should I use ELESTRIN? Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you. ELESTRIN should be used at the lowest dose possible for your treatment and only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with ELESTRIN. ELESTRIN comes in a metered-dose pump. One dose of ELESTRIN is released each time the pump is depressed (pressed down). Use ELESTRIN exactly how your healthcare provider tells you. The ELESTRIN pump contains enough of the medicine to let you prime the pump (get the pump ready) before you use it the first time. To prime the pump, push the head of the pump down slowly , then remove your finger from the pump head and allow it to spring back automatically (by itself). Repeat this until the gel comes out. Throw away this first amount of gel as it will not be a full dose. Once the pump head has come all the way back up, the pump is now primed and ready to use. With each dose, remember to push the pump head down slowly and allow it to spring back automatically let the pump head come all the way back up before you push it down again. If using more than 1 dose, wait 5 seconds before pumping the next dose. This will make sure that the pump works correctly and gives your full dose of ELESTRIN. Use the pump a total of 30 times (30 pushes) as your healthcare provider tells you. After you have initially primed the pump and have used a total of 30 doses of ELESTRIN, you will need to throw the pump away and use a new one. The correct amount of medicine in each dose cannot be assured after 30 doses have been used, even though the pump container is not completely empty. Important things to remember when using ELESTRIN Wash your hands with soap and water after applying the gel to reduce the chance that the medicine will be spread from your hands to other people. Allow the gel to dry for five minutes or more before dressing. Try to keep the area dry for as long as possible. Do not allow others to come in contact with the area of skin where you applied the gel for at least two hours after you apply ELESTRIN. Always move the spout into locked position and place the cap over the top of the pump after each use. Never apply ELESTRIN to the breast. Never apply ELESTRIN in or around the vagina. Do not allow others to apply the gel for you. Do not apply sunscreen to the area where the gel was applied for at least 25 minutes. Do not apply sunscreen to the area where the gel was applied for 7 or more consecutive days. Avoid fire, flame or smoking until the gel has dried. ELESTRIN contains alcohol. Alcohol based gels are flammable. It is important that you read and follow the detailed “Patient Instructions for Use” at the end of this leaflet on how to use the ELESTRIN pump and apply the dose. What should I do if someone else is exposed to ELESTRIN? If someone else is exposed to ELESTRIN by direct contact with the gel, that person should wash the area of contact with soap and water as soon as possible. The longer the gel is in contact with the skin before washing, the greater is the chance that the other person will absorb some of the estrogen hormone. This is especially important for men and children. What should I do if I get ELESTRIN in my eyes? If you get ELESTRIN in your eyes, rinse your eyes right away with warm clean water to flush out any ELESTRIN. Seek medical attention if needed. What should I do if I miss a dose? If you miss a dose, do not double the dose on the next day to catch up. If your next dose is less than 12 hours away, it is best just to wait and apply your normal dose the next day. If it is more than 12 hours until the next dose, apply the dose you missed and resume your normal dosing the next day. What are the possible side effects of ELESTRIN? 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: Heart attack Stroke Blood clots Dementia Breast cancer Cancer of the lining of the uterus (womb) Cancer of the ovary High blood pressure High blood sugar Gallbladder disease Liver problems 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 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 These are not all the possible side effects of ELESTRIN. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report side effects to Meda Pharmaceuticals at 1-800-890-3098 or to FDA at 1-800-FDA-1088. What can I do to lower my chances of a serious side effect with ELESTRIN? Talk with your healthcare provider regularly about whether you should continue using ELESTRIN If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you 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 ELESTRIN. 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 a higher chance for getting heart disease Ask your healthcare provider for ways to lower your chances of getting heart disease. General information about safe and effective use of ELESTRIN Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use ELESTRIN for conditions for which it was not prescribed. Do not give ELESTRIN to other people, even if they have the same symptoms you have. It may harm them. Keep ELESTRIN out of the reach of children This leaflet provides a summary of the most important information about ELESTRIN. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about ELESTRIN that is written for health professionals. You can get more information by calling 1-800-890-3098 (toll free). Patient Instructions for Use. 1. Remove the cap. 2. Activate the pump. Unlock the pump by turning the spout on top of the bottle a quarter turn to the left or the right. 3. Prime the pump (get the pump ready) before using the pump for the first time. Push the head of the pump down slowly and allow it to spring back automatically. Repeat this until gel comes out. Throw away the first amount of gel as it will not be a full dose. Once the pump head has come all the way back up, the pump is now primed and ready to use. Throw away the unused gel by placing it in the trash to avoid another person or pet from accidental contact with the gel or, eating or drinking it. After priming, the pump is ready to use. One complete pump depression will dispense the same amount of ELESTRIN each time. After each daily dose, return the spout to the locked position and replace the cap before you put it away. 4. Apply ELESTRIN. Dry skin completely before applying ELESTRIN You should apply your daily dose of gel to clean, dry, unbroken skin. If you take a bath or shower or use a sauna, apply ELESTRIN after your bath, shower, or sauna. If you go swimming, try to leave as much time as possible, at least 2 hours, between applying your ELESTRIN dose and going into the water. Apply ELESTRIN at the same time each day. Figure 1 To apply the dose, hold the pump with the tip facing the application area of the arm. For each pump depression needed, press the pump firmly and fully with a continuous motion without hesitation. Figure 2 Gently spread the gel using only 2 fingers. Spread and gently rub in the gel over the entire area of your upper arm and shoulder area, as illustrated. 5. Wash your hands with soap and water. ELESTRIN should not be used after the date printed on the container (expiration date). What are the ingredients in ELESTRIN? Active ingredient: estradiol. Inactive ingredients: purified water, ethanol, propylene glycol, diethylene glycol monoethyl ether, carbomer 940, triethanolamine, and edetate disodium.

PATIENT INFORMATION Divigel® (estradiol gel) 0.1% Read this PATIENT INFORMATION leaflet before you start using Divigel® and read what you get each time you refill your Divigel® prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT Divigel® (AN ESTROGEN HORMONE)? Estrogens increase the chance of getting cancer of the uterus. Report any unusual vaginal bleeding right away while you are taking estrogens. 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. Do not use estrogens, with or without progestins, to prevent heart disease, heart attacks, or strokes. Using estrogens, with or without progestins, may increase your chance of getting heart attacks, strokes, breast cancer, and blood clots. Do not use estrogens, with or without progestins, to prevent dementia. Using estrogens, with or without progestins, may increase your risk of dementia. You and your healthcare provider should talk regularly about whether you still need treatment with Divigel®. What is Divigel®? Divigel® is a medicine that contains an estrogen hormone (estradiol). Divigel® is a clear, colorless, smooth gel that is odorless when dry. What is Divigel® used for? Divigel® is used after menopause to: Reduce moderate to severe hot flashes Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 to 55 years old. This drop in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause.” When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild, and they will not need estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with Divigel®. Who should not use Divigel®? Do not start using Divigel® if you: 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 Divigel®. Had a stroke or heart attack in the past year Currently have or have had blood clots Currently have or have had liver problems Are allergic to Divigel® or any of its ingredients See the next section of this leaflet for a list of ingredients in Divigel®. Think you may be pregnant Tell your healthcare provider: If you are breastfeeding The hormone in Divigel® can pass into your milk. 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); migraine; endometriosis; lupus; problems with your heart, liver, thyroid, or kidneys; or have high calcium levels in your blood. About all the medicines you take This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Divigel® works. Divigel® may also affect how your other medicines work. If you are going to have surgery or will be on bedrest You may need to stop using Divigel®. What are the ingredients in Divigel®? The active ingredient in Divigel® is estradiol. The inactive ingredients are carbomer, ethanol, propylene glycol, purified water, and triethanolamine. How should I use Divigel®? Divigel® should be used once daily. Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you Divigel® should be used at the lowest dose possible for your treatment and only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with Divigel®. Important things to remember when using Divigel® Wash your hands with soap and water after applying the gel to reduce the chance that the medicine will be spread from your hands to other people. Allow the gel to dry before dressing. Try to keep the area dry for as long as possible. Do not allow others to come in contact with the area of skin where you applied the gel for at least one hour after you apply Divigel®. You should not allow others to apply the gel for you. However, if this is necessary, the individual should wear a disposable plastic glove to avoid direct contact with Divigel® Do not apply Divigel® to your face, breast, or irritated skin Never apply Divigel® in or around the vagina Divigel® contains alcohol. Alcohol based gels are flammable. Avoid fire, flame or smoking until the gel has dried. What should I do if I miss a dose? If you miss a dose, do not double the dose on the next day to catch up. If your next dose is less than 12 hours away, it is best just to wait and apply your normal dose the next day. If it is more than 12 hours until the next dose, apply the dose you missed and resume your normal dosing the next day. Do not apply Divigel® more than once each day. If you accidentally spill some of the contents of a Divigel® packet, do not open a new packet. Wait and apply your normal dose the next day. What should I do if someone else is exposed to Divigel®? Once you have applied Divigel®, it has dried, and you have washed your hands, there is little risk of transfer to another person. If someone else is exposed to Divigel® by direct contact with the wet gel, that person should wash the area of contact with soap and water as soon as possible. This is especially important for men and children. The longer the gel is in contact with the skin before washing, the chance is greater that the other person will absorb some of the estrogen hormone. What should I do if I get Divigel® in my eyes? If you get Divigel® in your eyes, flush your eyes right away with lukewarm tap water. If you have concerns, contact your healthcare provider. What are the possible side effects of estrogens? Less common but serious side effects include: Breast cancer Cancer of the uterus Stroke Heart attack Blood clots Dementia Gallbladder disease Ovarian cancer Some of the warning signs of serious side effects include: Breast lumps Unusual vaginal bleeding Dizziness and faintness Changes in speech Severe headaches Chest pain Shortness of breath Pains in your legs Changes in vision Vomiting Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you. Common side effects include: Headache Breast pain Irregular vaginal bleeding or spotting Stomach/abdominal cramps, bloating Nausea and vomiting Hair loss Other side effects include: High blood pressure Liver problems High blood sugar Fluid retention Enlargement of benign tumors of the uterus (“fibroids”) Vaginal yeast infection These are not all the possible side effects of Divigel®. For more information, ask your healthcare provider or pharmacist. What can I do to lower my chances of a serious side effect with Divigel®? Talk with your healthcare provider regularly about whether you should continue taking Divigel®. If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you. In general, the addition of a progestin is recommended for women 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 taking Divigel®. Have a breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you otherwise. 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 of getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease. Have an annual gynecological exam. General information about safe and effective use of Divigel® Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Divigel® for conditions for which it was not prescribed. Do not give Divigel® to other people, even if they have the same symptoms you have. It may harm them. Keep Divigel® out of the reach of children. This leaflet provides a summary of the most important information about Divigel®. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Divigel® that is written for health professionals. You can get more information by calling the toll free number 1-800-654-2299. How should Divigel® be applied? Divigel® should be applied once a day, around the same time each day. Apply Divigel® to clean, dry, and unbroken (without cuts or scrapes) skin. If you take a bath or shower, be sure to apply your Divigel® after your skin is dry. The application site should be completely dry before dressing or swimming. Apply Divigel® to either your left or right upper thigh. Change between your left and right upper thigh each day to help prevent skin irritation. To Apply: 1. Wash and dry your hands thoroughly. 2. Sit in a comfortable position. 3. Cut or tear the Divigel® packet as shown in Diagram 1. Diagram 1 4. Using your thumb and index finger, squeeze the entire contents of the packet onto the skin of the upper thigh as shown in Diagram 2. Diagram 2 5. Gently spread the gel in a thin layer on your upper thigh over an area of about 5 by 7 inches, or two palm prints as shown in Diagram 3. It is not necessary to massage or rub in Divigel®. Diagram 3 6. Allow the gel to dry completely before dressing. 7. Dispose of the empty Divigel® packet in the trash. 8. Wash your hands with soap and water immediately after applying Divigel® to remove any remaining gel and reduce the chance of transferring Divigel® to other people. HOW IS Divigel® SUPPLIED? Divigel® is supplied in individual foil packets, each one containing a single day's dose. Store Divigel® packets 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.]

SIDE EFFECTS The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see BOXED WARNING, and WARNINGS AND PRECAUTIONS] Malignant Neoplasms [see BOXED WARNING, and WARNINGS AND PRECAUTIONS] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. EstroGel was studied in 2 well-controlled, 12-week clinical trials. Incidence of adverse drug reactions ≥ 5 percent for 1.25 g EstroGel 0.06% and placebo is given in Table 1. TABLE 1 : Incidence of Adverse Drug Reactions ≥ 5 Percent Occurrence in the EstroGel Treatment Group for the Intent-to-Treat Safety Population in 2 Well-controlled Clinical Studies (Expressed as Percent of Treatment Group) Body System/ Adverse Drug Reactions EstroGel 0.06% 1.25 g /day (n=168) Placebo (n=73) BODY AS A WHOLE Headache 9.5 2.7 DIGESTIVE SYSTEM Flatulence 5.4 4.1 UROGENITAL SYSTEM Breast pain 10.7 8.2 In 2 controlled clinical trials, application site reactions were reported by 0.6 percent of patients who received 1.25 g of EstroGel. Other skin reactions, such as pruritus and rash, were also noted. Postmarketing Experience The following adverse reactions have been identified during post-approval use of EstroGel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Genitourinary System Endometrial cancer Breast Pain; tenderness; breast cancer Cardiovascular Deep vein thrombosis; myocardial ischemia; phlebitis Gastrointestinal Nausea; abdominal distension; diarrhea; stomach discomfort Skin Alopecia; rash; pruritus; application site: dryness, pain, discoloration, reaction, rash Eyes Retinal vein occlusion Central Nervous System Headache; dizziness; insomnia; hypoesthesia; meningioma; aphasia; bradyphrenia; paresthesia Miscellaneous Drug ineffective; hot flush; arthralgia; night sweats; drug effect decreased; pain in extremity; fatigue; weight increased; pain; hypersensitivity; dyspnea; malignant mesenchymoma; angioedema; hepatitis acute; face edema; accidental exposure; myoclonus; gait disturbance; flushing DRUG INTERACTIONS No drug-drug interaction studies have been conducted for EstroGel. Metabolic Interactions In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John's wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. 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.

SIDE EFFECTS The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see BOXED WARNING, and WARNINGS AND PRECAUTIONS] Malignant Neoplasms [see BOXED WARNING, and WARNINGS AND PRECAUTIONS] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. ELESTRIN was studied in a placebo-controlled trial that included a total of 484 postmenopausal women. The adverse reactions that occurred at a rate greater than 5 percent in any of the treatment groups are summarized in Table 1. TABLE 1 :Incidence of Treatment-Emergent Adverse Reactions Occurring in ≥ 5 Percent of Subjects Body System / Signs and Symptoms Number (%) of Subjects Placebo (n = 137) ELESTRIN 0.87 g/day (n = 136) ELESTRIN 1.7 g/day (n = 142) Reproductive system & breast disorders Breast tenderness 5 (3.6) 9 (6.6) 11 (7.7) Metrorrhagia 3 (2.2) 6 (4.4) 13 (9.2) Respiratory, thoracic & mediastinal disorders Nasopharyngitis 10 (7.3) 14 (10.3) 12 (8.5) Upper respiratory tract infection 5 (3.6) 8 (5.9) 5 (3.5) Postmarketing Experience The following adverse reactions have been identified during post-approval use of ELESTRIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Genitourinary System Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea; increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer. Breasts Tenderness; enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer. Cardiovascular Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure. Gastrointestinal Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas. Skin Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash. Eyes Retinal vascular thrombosis, intolerance to contact lenses. Central Nervous System Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia. Miscellaneous Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgias; leg cramps; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides. Additional postmarketing adverse reactions have been reported in women receiving other forms of hormone therapy. DRUG INTERACTIONS No drug-drug interaction studies have been conducted for ELESTRIN. Metabolic Interactions In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John's wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice, may increase plasma concentrations of estrogens and result in side effects.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS 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 (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. Stroke In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies]. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately. Subgroup analysis of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).1 In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) [see Clinical Studies]. The increase in risk was demonstrated after the first year and persisted.1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. Coronary Heart Disease In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo2 [see Clinical Studies]. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).1 In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies]. In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established 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 twenty-one (2,321) women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall. 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 placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years3 [see Clinical Studies]. Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately. In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted4 [see Clinical Studies]. Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. If feasible, estrogens should be discontinued at least 4 to 6 weeks before any surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Malignant Neoplasms Endometrial Cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears to be associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. 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-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.8])5 [see Clinical Studies]. The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo [see Clinical Studies]. 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 a 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 groups6 [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 a 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 over about 5 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 has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a 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. Ovarian Cancer The WHI estrogen plus progestin substudy reported a statistically non-significant increase in the 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 versus placebo was 4 versus 3 cases per 10,000 women-years.7 In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies, and some report no association. Probable Dementia 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-years8 [see Use In Specific Populations, and Clinical Studies]. In the WHIMS estrogen plus progestin ancillary study of WHI, 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-years8 [see Use in Specific Populations, and Clinical Studies]. 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 [see Use In Specific Populations, and Clinical Studies]. Gallbladder Disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. 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. 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 a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued. Addition Of A Progestin When A Woman Has Not Had A Hysterectomy 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 an increased risk of breast cancer. Elevated Blood Pressure 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. Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs. Hepatic Impairment And/Or Past History Of Cholestatic Jaundice Estrogens may be poorly metabolized in women 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. 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 an acceptable range. Fluid Retention 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. Hypocalcemia Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. Exacerbation Of Endometriosis A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. Hereditary Angioedema Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Exacerbation Of Other Conditions Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. Alcohol-based Products Are Flammable. Avoid fire, flame, or smoking until the gel has dried. Moisturizer Lotion Application Use of moisturizing lotion one hour after application of EstroGel 0.06% significantly increased estradiol absorption [see CLINICAL PHARMACOLOGY]. Laboratory Tests Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy. Drug-Laboratory Test Interactions 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. Increased thyroid-binding globulin (TBG) levels 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 T3 concentrations are unaltered. Women on thyroid-replacement therapy may require higher doses of thyroid hormone. Other binding proteins may be elevated in serum (for example, 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). Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglyceride levels. Impaired glucose tolerance. Patient Counseling Information See FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use) Vaginal Bleeding Inform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare provider as soon as possible [see WARNINGS AND PRECAUTIONS]. Possible Serious Adverse Reactions With Estrogen-Alone Therapy Inform postmenopausal women of the possible serious adverse reactions of estrogen-alone therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see WARNINGS AND PRECAUTIONS.] Possible Less Serious But Common Adverse Reactions With Estrogen-Alone Therapy Inform postmenopausal women of possible less serious adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility 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. Use In Specific Populations Pregnancy EstroGel 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. Nursing Mothers EstroGel 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 estrogen have been identified in the milk of women receiving estrogen therapy. Caution should be exercised when EstroGel is administered to a nursing woman. Pediatric Use EstroGel is not indicated in children. Clinical studies have not been conducted in the pediatric population. Geriatric Use There have not been sufficient numbers of geriatric women involved in studies utilizing EstroGel to determine whether those over 65 years of age differ from younger subjects in their response to EstroGel. The Women's Health Initiative Studies 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]. 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]. 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 WARNINGS AND PRECAUTIONS, and Clinical Studies]. Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8[see WARNINGS AND PRECAUTIONS, and Clinical Studies]. Renal Impairment The effect of renal impairment on the pharmacokinetics of EstroGel has not been studied. Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of EstroGel has not been studied. REFERENCES 1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297:14651477. 2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357-365. 3. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780. 4. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580. 5. 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. 6. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253. 7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS 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 (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. Stroke In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies]. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).1 In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) [see Clinical Studies]. The increase in risk was demonstrated after the first year and persisted.1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. Coronary Heart Disease In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI and CHD death) was reported in women receiving estrogen-alone compared to placebo2 [see Clinical Studies]. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).1 In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years)1. An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies]. In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS] treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand, three hundred and twenty one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall. 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 placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years3 [see Clinical Studies]. Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately. In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted4 [see Clinical Studies]. Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Malignant Neoplasms Endometrial Cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with an increased risk of 15-to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. In a 12-week clinical trial, one case of complex hyperplasia with atypia was reported in the ELESTRIN 1.7 g per day dose. 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 of follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80]5 [see Clinical Studies]. The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and 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 a 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.6 [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 a 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 5 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 has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. Ovarian Cancer The WHI estrogen plus progestin substudy reported a 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 percentCI, 0.77-3.24]. The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7 In some epidemiological studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies, and some report no association. Probable Dementia 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-years8 [see Use In Specific Populations, and Clinical Studies]. 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% 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 womenyears8 [see Use In Specific Populations, and Clinical Studies]. 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% 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 women8 [see Use in Specific Populations, and Clinical Studies]. Gallbladder Disease A 2-to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. Hypercalcemia Estrogen administration may lead to severe hypercalcemia in women 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. Visual Abnormalities Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued. Addition Of A Progestin When A Woman Has Not Had A Hysterectomy 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 an increased risk of breast cancer. Elevated Blood Pressure 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. Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs. Hepatic Impairment And/Or Past History Of Cholestatic Jaundice Estrogens may be poorly metabolized in women 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. 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 to maintain their free thyroid hormone levels in an acceptable range. Fluid Retention 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 estrogens-alone is prescribed. Hypocalcemia Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. Exacerbation Of Endometriosis A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. Hereditary Angioedema Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema Exacerbation Of Other Conditions Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. Photosensitivity Or Photoallergy Increased sensitivity to direct exposure to the sun on areas of ELESTRIN application has not been evaluated. Sunscreen Application Estradiol absorption was increased when sunscreen was applied 10 minutes before ELESTRIN application. Sunscreen should not be applied to the same site until at least 25 minutes after the application of ELESTRIN. Concomitant application of sunscreen and ELESTRIN to the same application site for 7 or more days may increase estradiol absorption. Avoid applying sunscreen to the area of ELESTRIN application for an extended period of 7 or more days [see CLINICAL PHARMACOLOGY, Pharmacokinetics]. Miscellaneous Alcohol based gels potentially are flammable. Avoid fire, flame, or smoking until the gel has dried. Laboratory Tests Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms. Drug-Laboratory Test Interactions 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. Increased thyroid binding globulin (TBG) levels 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 doses of thyroid hormone. Other binding proteins may be elevated in serum, for example, 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). Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels. Impaired glucose tolerance. REFERENCES 1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477. 2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357-365. 3. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780. 4. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580. 5. 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. 6. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253. 7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748. 8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958. Patient Counseling Information See FDA-Approved Patient Labeling. Vaginal Bleeding Inform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare provider as soon as possible [see WARNINGS AND PRECAUTIONS]. Possible Serious Adverse Reactions With Estrogen-Alone Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see WARNINGS AND PRECAUTIONS]. Possible Less Serious But Common Adverse Reactions With Estrogen-Alone Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility 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. Use In Specific Populations Pregnancy ELESTRIN 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. Nursing Mothers ELESTRIN 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 breast milk of women receiving estrogen therapy. Caution should be exercised when ELESTRIN is administered to a nursing woman. Pediatric Use ELESTRIN is not indicated in children. Clinical studies have not been conducted in the pediatric population. Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing ELESTRIN to determine whether those over 65 years of age differ from younger subjects in their response to ELESTRIN. 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]. 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]. 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 WARNINGS AND PRECAUTIONS, and Clinical Studies]. Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see WARNINGS AND PRECAUTIONS, and Clinical Studies]. Renal Impairment The effect of renal impairment on the pharmacokinetics of ELESTRIN has not been studied. Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of ELESTRIN has not been studied.

WARNINGS See BOXED WARNINGS. Cardiovascular Disorders Estrogen-alone therapy has been associated with an increased risk of stroke and deep vein thrombosis (DVT). Estrogen-plus progestin therapy has been associated with an increased risk of myocardial infarction as well as stroke, venous thrombosis and pulmonary embolism. Should any of these occur or be suspected, estrogens should be discontinued immediately. Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. Stroke In the estrogen-alone substudy of the Women's Health Initiative (WHI), a statistically significant increased risk of stroke was observed in women receiving CE 0.625 mg daily compared to placebo (44 versus 32 per 10,000 women-years). The increase in risk was observed in year 1 and persisted. (See Clinical Studies.) In the estrogen-plus-progestin substudy of the WHI study, a statistically significant increased risk of stroke was reported in women receiving CE/MPA 0.625 mg/2.5 mg daily compared to women receiving placebo (31 versus 24 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Coronary heart disease In the estrogen-alone substudy of WHI, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or death, due to CHD) was reported in women receiving estrogen-alone compared to placebo. (See Clinical Studies.) In the estrogen-plus-progestin substudy of WHI, no statistically significant increase of CHD events was reported in women receiving CE/MPA compared to women receiving placebo (39 vs. 33 per 10,000 women-years). An increase in relative risk was demonstrated in year one and a trend toward decreasing relative risk was reported in years 2 through 5. In postmenopausal women with documented heart disease (n=2,763, average age 66.7 years), a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study (HERS)) treatment with CE/MPA (0.625 mg/2.5 mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/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/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Participation in an open label extension of the original HERS trial (HERS II) was agreed to by 2,321 women. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall. Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of non-fatal myocardial infarction, pulmonary embolism, and thrombophlebitis. Venous Thromboembolism In the estrogen-alone substudy of WHI the risk of VTE (DVT and pulmonary embolism [PE]), was reported to be increased for women taking conjugated estrogens compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 vs. 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first two years. (See Clinical Studies.) In the estrogen-plus-progestin substudy of WHI, a statistically significant two-fold greater rate of VTE, was reported in women receiving CE/MPA compared to women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. (See Clinical Studies.) If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Malignant Neoplasms Endometrial Cancer The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risk of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women taking estrogen/progestin combinations 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 of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Breast Cancer In some studies, the use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women's Health Initiative (WHI) (see Clinical Studies). The results from observational studies are generally consistent with those of the WHI clinical trial. Observational studies have also reported an increased risk of breast cancer for estrogen-plusprogestin combination therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. For both findings, the excess risk increased with duration of use, and appeared to return to baseline over about five years after stopping treatment (only the observational studies have substantial data on risk after stopping). In these studies, the risk of breast cancer was greater, and became apparent earlier, with estrogen-plus-progestin combination therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogens or among different estrogen-plus-progestin combinations, doses, or routes of administration. In the estrogen-alone substudy of WHI, after an average of 7.1 years of follow-up, CE (0.625 mg daily) was not associated with an increased risk of invasive breast cancer (RR 0.80, 95 % nCI 0.62-1.04). In the estrogen-plus-progestin substudy, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer. In this substudy, prior use of estrogenalone or estrogen/progestin combination hormone therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24 (95% nCI, 1.01-1.54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen-plus-progestin compared with placebo, respectively. 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 estrogen-plus-progestin 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 estrogen-plus-progestin compared with placebo. In the WHI trial, invasive breast cancers were larger and diagnosed at a more advanced stage in the estrogen-plusprogestin 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. The use of estrogen-alone and estrogen-plus-progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a 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. Dementia In the estrogen-alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women aged 65 to 79 years was randomized to CE (0.625 mg daily) or placebo. In the estrogen-plus-progestin WHIMS, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to CE/MPA (0.625 mg/2.5 mg daily) or placebo. In the estrogen-alone substudy, 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% 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. In the estrogen-plus-progestin substudy, after an average follow-up of 4 years, 40 women in the estrogen-plus-progestin group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen-plus-progestin versus placebo was 2.05 (95% CI, 1.21-3.48). The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years. 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% 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 PRECAUTIONS, and Geriatric Use.) Gallbladder Disease A two- to four-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. 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. 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 a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued. PRECAUTIONS General Addition of a progestin when a woman has not had a hysterectomy 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, adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL), and impairment of glucose tolerance. Elevated blood pressure 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. Blood pressure should be monitored at regular intervals with estrogen use. Hypertriglyceridemia In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. Impaired liver function and past history of cholestatic jaundice Estrogens may be poorly metabolized in patients with impaired liver function. For patients 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. Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients 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. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored to maintain their free thyroid hormone levels in an acceptable range. Fluid retention Estrogens may cause some degree of fluid retention. Because of this, patients who have conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. Hypocalcemia Estrogens should be used with caution in individuals with severe hypocalcemia. Ovarian cancer The estrogen-plus-progestin substudy of the WHI reported that after an average follow-up of 5.6 years, the relative risk for ovarian cancer for estrogen-plus-progestin versus placebo was 1.58 (95% nCI, 0.77-3.24), but was not statistically significant. The absolute risk for estrogen-plus-progestin versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen only products in particular for 10 or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations. Exacerbation of endometriosis Endometriosis may be exacerbated with administration of estrogens. Malignant transformation of residual endometrial implants have been reported in women treated posthysterectomy with estrogen-alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. Exacerbation of other conditions Estrogens 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. Photosensitivity/Photoallergy The effects of direct sun exposure to Divigel® application sites have not been evaluated in clinical trials. Nonclinical studies in guinea pigs showed no phototoxicity or photosensitivity. In addition, Divigel® has been shown to absorb light primarily at wavelengths below 290 nm. Therefore, Divigel® is not considered to have photosensitizing potential. Sunscreen application Studies conducted using other approved topical estrogen gel products have shown that sunscreens have the potential for changing the systemic exposure of topically applied estrogen gels. The effect of concomitant application of sunscreen and Divigel® to the same application site has not been clinically evaluated. Miscellaneous Alcohol based gels are flammable. Avoid fire, flame, or smoking until the gel has dried. Occlusion of the area where the topical drug product is applied with clothing or other barriers is not recommended until the gel is completely dried. Potential for Estradiol Transfer and Effects of Washing There is a potential for drug transfer from one individual to the other following physical contact of Divigel® application sites. In a study to evaluate transferability to males from their female contacts, there was some elevation of estradiol levels over baseline in the male subjects, however, the degree of transferability in this study was inconclusive. Patients are advised to avoid skin contact with other subjects until the gel is completely dried. The site of application should be covered (clothed) after drying. Washing the application site with soap and water 1 hour after application resulted in a 30 to 38% decrease in the mean total 24-hour exposure to estradiol. Therefore, patients should refrain from washing the application site for at least one hour after application. Information for Patients Physicians and pharmacists are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe or dispense Divigel®. Laboratory Tests Estrogen administration should be initiated at the lowest dose approved for the treatment of moderate-to-severe vasomotor symptoms associated with menopause and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH). Carcinogenesis, Mutagenesis, Impairment of Fertility 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. Pregnancy Estrogen products, including Divigel®, should not be used in pregnancy. (See CONTRAINDICATIONS.) Nursing Mothers Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving estrogen therapy. Caution should be exercised when estrogen products, including Divigel®, are administered to a nursing woman. Pediatric Use Safety and efficacy of Divigel® in pediatric patients has not been established. Geriatric Use There have not been sufficient numbers of geriatric patients involved in studies utilizing Divigel® to determine whether those over 65 years of age differ from younger subjects in their response to Divigel®. Of the total number of subjects in the estrogen-alone substudy of the Women's Health Initiative (WHI), 46% (n=4,943) were 65 years and older, while 7.1% (n=767) were 75 years and older. There was a higher relative risk (CE versus placebo) of stroke in women less than 75 years of age compared to women 75 years and older. In the estrogen-alone substudy of the Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women, aged 65 to 79 years, was randomized to CE (0.625 mg per day) or placebo. After an average follow-up of 5.2 years, the relative risk (CE versus 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 with placebo. Of the total number of subjects in the estrogen-plus-progestin substudy of the WHI, 44% (n=7,320) were 65 years and older, while 6.6% (n=1,095) were 75 years and older. There was a higher relative risk (CE/MPA versus placebo) of stroke and invasive breast cancer in women 75 and older compared to women less than 75 years of age. In women greater than 75, the increased risk of non-fatal stroke and invasive breast cancer observed in the estrogenplus- 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 4,532 postmenopausal women, aged 65 to 79 years, was randomized to CE/MPA (CE 0.625 mg/2.5 mg daily) or placebo. In the estrogen-plus-progestin group, after an average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of probable dementia was 2.05 (95% CI, 1.21-3.48). The absolute risk of developing probable dementia with CE/MPA was 45 vs. 22 cases per 10,000 women-years with placebo. Seventy-nine percent of the cases of probable dementia occurred in women that were older than 70 for the CE group, and 82 percent of the cases of probable dementia occurred in women who were older than 70 in the CE/MPA group. The most common classification of probable dementia in both the treatment groups and placebo groups was Alzheimer's disease. When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall 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.)