Generally, start therapy with the IMVEXXY 4 mcg dosage strength administered intravaginally; insert with the smaller end up for a depth of about two inches into the vaginal canal. Administer 1 insert daily at approximately the same time for 2 weeks, followed by 1 insert twice weekly, every three to four days (for example, Monday and Thursday). Make dosage adjustment based on the clinical response.

IMVEXXY are small, light pink, tear-shaped, vaginal inserts for manual placement into the vagina. IMVEXXY inserts contain 4 mcg or 10 mcg of estradiol. Each insert is imprinted in white ink on one side with "04" or "10" corresponding to the insert's dosage strength.

{ "type": "p", "children": [], "text": "IMVEXXY are small, light pink, tear-shaped, vaginal inserts for manual placement into the vagina. IMVEXXY inserts contain 4 mcg or 10 mcg of estradiol. Each insert is imprinted in white ink on one side with \"04\" or \"10\" corresponding to the insert's dosage strength." }

IMVEXXY is contraindicated in women with any of the following conditions:

{ "type": "p", "children": [], "text": "IMVEXXY is contraindicated in women with any of the following conditions:" }

{ "type": "ul", "children": [ "Undiagnosed abnormal genital bleeding [see Warning and Precautions (5.3)].\n", "Breast cancer or a history of breast cancer [see Warnings and Precautions (5.3)].\n", "Estrogen-dependent neoplasia [see Warnings and Precautions (5.3)].\n", "Active DVT, PE, or history of these conditions [see Warnings and Precautions (5.2)].\n", "Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions [see Warnings and Precautions (5.2)].\n", "Known anaphylactic reaction, angioedema, or hypersensitivity to IMVEXXY.", "Hepatic impairment or disease.", "Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders." ], "text": "" }

IMVEXXY is intended only for vaginal administration. Systemic absorption may occur with the use of IMVEXXY [see Pharmacokinetics (12.3)]. The warnings, precautions, and adverse reactions associated with the use of systemic estrogen-alone therapy should be taken into account.

Increased risks of stroke and DVT are reported with estrogen-alone therapy. Increased risks of PE, DVT, stroke, and MI are reported with estrogen plus progestin therapy. Immediately discontinue estrogen with or without progestogen therapy if any of these occur or are suspected. Manage appropriately any 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).

Stroke

The WHI estrogen-alone substudy reported a statistically significant increased risk of stroke 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, respectively). The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies (14.2)]. Immediately discontinue estrogen-alone therapy if a stroke occurs or is suspected.

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

The WHI estrogen plus progestin substudy reported a statistically significant increased risk of stroke 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, respectively) [see Clinical Studies (14.2)]. The increase in risk was demonstrated after the first year and persisted.1 Immediately discontinue estrogen with or without progestogen therapy if a stroke occurs or is suspected.

Coronary Heart Disease

The WHI estrogen-alone substudy reported no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in women receiving estrogen-alone compared to placebo2 [see Clinical Studies (14.2)].

Subgroup analysis of women 50 to 59 years of age, who were less than 10 years since menopause, suggests a reduction (not statistically significant) of CHD events in those women receiving daily CE (0.625 mg)-alone compared to placebo (8 versus 16 per 10,000 women-years).1

The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) of CHD events 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 (14.2)].

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 CHD. 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 the original 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 (14.2)]. Immediately discontinue estrogen-alone therapy if a VTE occurs or is suspected.

The WHI estrogen plus progestin substudy reported a statistically significant 2-fold greater rate of VTE 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 (14.2)]. Immediately discontinue estrogen plus progestogen therapy if a VTE occurs or is suspected.

If feasible, discontinue estrogens at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

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-fold 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, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women using estrogen-alone or estrogen plus progestogen therapy is important. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, 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 progestogen 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 WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. 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) 0.80]5 [see Clinical Studies (14.2)].

After a mean follow-up of 5.6 years, the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg) reported an increased risk of invasive breast cancer in women who took daily CE plus MPA compared to placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26% 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 [see Clinical Studies (14.2)].

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. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to > 10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy. 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. These studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.

The use of estrogen-alone and estrogen plus progestin therapy has been reported to result in an increase in abnormal mammograms requiring further evaluation.

All women should receive yearly breast examinations by 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 CE plus MPA substudy of WHI reported that estrogen plus progestin increased 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% confidence interval [CI], 0.77 to 3.24), but it was not statistically significant. The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7

A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% CI 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI, 1.27 to 1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.

In the WHI Memory Study (WHIMS) estrogen-alone ancillary study, 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% CI, 0.83 to 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 (8.5), and Clinical Studies (14.3)].

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 to 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 (8.5), and Clinical Studies (14.3)].

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 to 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 (8.5), and Clinical Studies (14.3)].

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including IMVEXXY, if hypercalcemia occurs and take appropriate measures to reduce the serum calcium level.

Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue IMVEXXY pending examination if there is a sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens, including IMVEXXY, if examination reveals papilledema or retinal vascular lesions.

Studies of the addition of a progestogen 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 progestogens with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.

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.

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Discontinue IMVEXXY if pancreatitis occurs.

Estrogens may be poorly metabolized in women with hepatic impairment. Exercise caution in any woman with a history of cholestatic jaundice associated with past estrogen use or with pregnancy. In the case of recurrence of cholestatic jaundice, discontinue IMVEXXY.

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. Monitor thyroid function in these women during treatment with IMVEXXY to maintain their free thyroid hormone levels in an acceptable range.

Estrogens may cause some degree of fluid retention. Monitor any woman with a condition(s) that might predispose her to fluid retention, such as cardiac or renal impairment. Discontinue estrogen-alone therapy, including IMVEXXY, with evidence of medically concerning fluid retention.

Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy, including IMVEXXY, outweigh the risks in such women.

A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. Consider the addition of progestogen therapy for women known to have residual endometriosis post-hysterectomy.

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy, including IMVEXXY, outweigh the risks in such women.

Estrogen therapy, including IMVEXXY, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas. Consider whether the benefits of estrogen therapy outweigh the risks in women with these conditions.

Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of postmenopausal women with moderate to severe symptoms of vulvar and vaginal atrophy due to menopause.

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.

The safety of IMVEXXY 4 mcg and 10 mcg was assessed in a single, double-blind, parallel-group, placebo-controlled trial (N = 382). The duration of treatment in this trial was 12 weeks (dosing occurred every day for 14 days and then twice weekly thereafter for maintenance).

Adverse reactions with an incidence of ≥ 3% in any IMVEXXY group and numerically greater than those reported in the placebo group are listed in Table 1.

<div class="scrollingtable"><table width="65%"> <caption> <span>Table 1: Treatment-Emergent Adverse Reactions Reported at a Frequency of ≥ 3% and Numerically More Common in Women Receiving IMVEXXY</span> </caption> <col align="center" valign="top" width="40%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" valign="middle">Preferred Term</th><th align="center" class="Rrule">IMVEXXY<br/>4 mcg<br/>(N=191)</th><th align="center" class="Rrule">IMVEXXY<br/>10 mcg<br/>(N=191)</th><th align="center" class="Rrule" valign="middle">Placebo<br/>(N=192)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">Nervous system disorders, n (%)</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">Headache</td><td align="center" class="Rrule">7 (3.7)</td><td align="center" class="Rrule">5 (2.6)</td><td align="center" class="Rrule">6 (3.1)</td> </tr> </tbody> </table></div>

The following adverse reactions have been identified during post-approval use of IMVEXXY 4 and 10 mcg. 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

Vaginal discharge.

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 may result in side effects.

{ "type": "p", "children": [], "text": "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 may result in side effects." }

Risk Summary

IMVEXXY is not indicated for use in pregnancy. There are no data with the use of IMVEXXY in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Risk Summary

Estrogens are present in human milk and can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breastfeeding is well-established. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for IMVEXXY and any potential adverse effects on the breastfed child from IMVEXXY or from the underlying maternal condition.

IMVEXXY is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.

There have not been sufficient numbers of geriatric women involved in clinical studies utilizing IMVEXXY to determine whether those over 65 years of age differ from younger subjects in their response to IMVEXXY.

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 (14.2)].

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 (14.2)].

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 (5.4), and Clinical Studies (14.3)].

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 (5.4), and Clinical Studies (14.3)].

Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of IMVEXXY therapy with institution of appropriate symptomatic care.

{ "type": "p", "children": [], "text": "Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of IMVEXXY therapy with institution of appropriate symptomatic care." }

IMVEXXY (estradiol vaginal inserts) are small, light pink, tear-shaped, vaginal inserts for manual placement into the vagina. Inserts contain 4 mcg or 10 mcg of estradiol, an estrogen. Each insert is imprinted in white ink on one side with "04" or "10" corresponding to the insert's dosage strength. IMVEXXY vaginal inserts are used intravaginally. When the insert comes in contact with the vaginal mucosa, estradiol is released into the vagina.

{ "type": "p", "children": [], "text": "IMVEXXY (estradiol vaginal inserts) are small, light pink, tear-shaped, vaginal inserts for manual placement into the vagina. Inserts contain 4 mcg or 10 mcg of estradiol, an estrogen. Each insert is imprinted in white ink on one side with \"04\" or \"10\" corresponding to the insert's dosage strength. IMVEXXY vaginal inserts are used intravaginally. When the insert comes in contact with the vaginal mucosa, estradiol is released into the vagina." }

Estradiol is chemically described as estra-1,3,5 (10)-triene-3,17β-diol. The chemical formula is C18H24O2 with a molecular weight of 272.38.

{ "type": "p", "children": [], "text": "Estradiol is chemically described as estra-1,3,5 (10)-triene-3,17β-diol. The chemical formula is C18H24O2 with a molecular weight of 272.38." }

The structural formula is:

{ "type": "p", "children": [], "text": "The structural formula is:" }

IMVEXXY (estradiol vaginal inserts) contain the following inactive ingredients: ammonium hydroxide, ethanol, ethyl acetate, ethylene glycol palmitostearate, FD&C Red #40, gelatin, glycerin, isopropyl alcohol, lecithin, medium chain triglycerides, polyethylene glycol, polyethylene glycol stearates, polyvinyl acetate phthalate, propylene glycol, purified water, sorbitol-sorbitan solution, and titanium dioxide. FDA approved acceptance criteria for assay, organic impurities, and dissolution tolerances differ from the USP test.

{ "type": "p", "children": [], "text": "IMVEXXY (estradiol vaginal inserts) contain the following inactive ingredients: ammonium hydroxide, ethanol, ethyl acetate, ethylene glycol palmitostearate, FD&C Red #40, gelatin, glycerin, isopropyl alcohol, lecithin, medium chain triglycerides, polyethylene glycol, polyethylene glycol stearates, polyvinyl acetate phthalate, propylene glycol, purified water, sorbitol-sorbitan solution, and titanium dioxide. FDA approved acceptance criteria for assay, organic impurities, and dissolution tolerances differ from the USP test." }

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.

Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to IMVEXXY nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

Absorption

Estrogen drug products are well absorbed through the skin, mucous membranes, and the gastrointestinal tract. The vaginal delivery of estrogens circumvents first-pass metabolism.

In a multicenter, double-blind placebo-controlled study of 574 postmenopausal women randomized to placebo, or 4 and 10 mcg of IMVEXXY, a subset of 54 women participated in a pharmacokinetics substudy. Women received 1 vaginal insert daily for the first 2 weeks, followed by 1 insert twice weekly for the following 10 weeks.

Mean (±SD) serum estradiol and estrone following 14 days of once daily administration of IMVEXXY are shown in Figure 1. Administration of the 4 mcg and 10 mcg IMVEXXY vaginal inserts and placebo once daily for 14 days resulted in a mean estradiol Cavg (0-24) of 3.6, 4.6, and 4.3 pg/mL, respectively, Table 2.

Figure 1: Mean (±SD) Serum Concentration of Estradiol and Estrone on Day 14 Following Daily Administration of IMVEXXY 4 mcg, IMVEXXY 10 mcg, and Placebo

<div class="scrollingtable"><table width="70%"> <caption> <span>Table 2: Arithmetic Mean (SD) of Estradiol and Estrone Pharmacokinetic Parameters Following 14 Daily Doses – Unadjusted for Baseline</span> </caption> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <thead> <tr class="Botrule First"> <th align="center" class="Lrule Rrule"></th><th align="center" class="Rrule" colspan="2">Estradiol</th><th align="center" class="Rrule" colspan="2">Estrone</th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule"></th><th align="center" class="Rrule">C<span class="Sub">max</span> <br/>(pg/mL)</th><th align="center" class="Rrule">C<span class="Sub">avg (0—24)</span> <br/>(pg/mL)</th><th align="center" class="Rrule">C<span class="Sub">max</span> <br/>(pg/mL)</th><th align="center" class="Rrule">C<span class="Sub">avg (0—24)</span> <br/>(pg/mL)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">4 mcg</td><td align="center" class="Rrule">4.8 (2.3)</td><td align="center" class="Rrule">3.6 (1.8)</td><td align="center" class="Rrule">16.0 (5.5)</td><td align="center" class="Rrule">13.6 (4.8)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">10 mcg</td><td align="center" class="Rrule">7.3 (2.4)</td><td align="center" class="Rrule">4.6 (2.3)</td><td align="center" class="Rrule">23.9 (13.5)</td><td align="center" class="Rrule">19.3 (10.2)</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">Placebo</td><td align="center" class="Rrule">5.5 (3.4)</td><td align="center" class="Rrule">4.3 (2.8)</td><td align="center" class="Rrule">22.8 (10.9)</td><td align="center" class="Rrule">17.8 (7.5)</td> </tr> </tbody> </table></div>

At Day 84, estradiol concentrations compared to Baseline concentrations were: 4.3 vs 3.9 pg/mL for 4 mcg; 4.8 vs 5.0 pg/mL for 10 mcg; and 4.4 vs 4.5 pg/mL for placebo.

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 SHBG and albumin.

Metabolism

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant portion 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.

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.

The effectiveness and safety of IMVEXXY on moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy due to menopause were examined in one placebo-controlled clinical trial.

This 12-week, randomized, double-blind, placebo-controlled, parallel-group trial enrolled 574 generally healthy postmenopausal women between 40 to 75 years of age (mean 59 years of age) who at baseline assessment had ≤ 5% superficial cells on a vaginal smear, a vaginal pH > 5.0, and also identified, at baseline, moderate to severe dyspareunia as the most bothersome symptom to her. Greater than 90% of women also reported moderate to severe vaginal dryness at baseline. Treatment groups included 4 mcg IMVEXXY (N = 191), 10 mcg IMVEXXY (N = 191), and placebo (N = 192). All women were assessed for improvement in the mean change from Baseline to Week 12 for the co-primary efficacy variables of: most bothersome moderate to severe symptom of dyspareunia, percentage of vaginal superficial and percentage of vaginal parabasal cells on a vaginal smear, and vaginal pH.

IMVEXXY 4 mcg and 10 mcg inserts were statistically superior to placebo in reducing the severity of moderate to severe dyspareunia at Week 12 (see Table 3). A statistically significant increase in the percentage of superficial cells and a corresponding statistically significant decrease in the percentage of parabasal cells on a vaginal smear was also demonstrated for IMVEXXY 4 and 10 mcg inserts (p < 0.0001). The mean reduction in vaginal pH between Baseline and Week 12 was also statistically significant for IMVEXXY 4 and 10 mcg inserts (p < 0.0001).

<div class="scrollingtable"><table width="70%"> <caption> <span>Table 3: Efficacy of Dyspareunia Associated with Postmenopausal Vulvar and Vaginal Atrophy (Least Square Mean Change from Baseline to Week 12 in Severity of Woman's Self-Identified Most Bothersome Moderate to Severe Symptom of Vulvar and Vaginal Atrophy)</span> </caption> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" valign="middle">Most Bothersome Moderate to Severe Symptom at Baseline</th><th align="center" class="Rrule" valign="middle">IMVEXXY<br/>4 mcg<br/>(N = 151)</th><th align="center" class="Rrule" valign="middle">IMVEXXY<br/>10 mcg<br/>(N = 154)</th><th align="center" class="Rrule" valign="middle">Placebo<br/>(N = 163)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="4" valign="top">The modified intent-to-treat population (MITT) included only women in the ITT population who at baseline met the inclusion criteria of ≤ 5% superficial cells on a vaginal smear, a vaginal pH &gt; 5.0, and who identified moderate or severe dyspareunia as her most bothersome vaginal symptom. Definitions: SD – standard deviation; SE – standard error; LS – least square</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule"><span class="Bold Italics">Dyspareunia</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr> <td align="center" class="Lrule Rrule">Baseline Mean (SD)</td><td align="center" class="Rrule" valign="middle">2.7 (0.48)</td><td align="center" class="Rrule" valign="middle">2.6 (0.48)</td><td align="center" class="Rrule" valign="middle">2.7 (0.46)</td> </tr> <tr> <td align="center" class="Lrule Rrule">LS Mean Change from Baseline (SE)</td><td align="center" class="Rrule" valign="middle">-1.52 (0.071)</td><td align="center" class="Rrule" valign="middle">-1.69 (0.071)</td><td align="center" class="Rrule" valign="middle">-1.28 (0.070)</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">p-value vs. placebo</td><td align="center" class="Rrule" valign="middle">0.0149</td><td align="center" class="Rrule" valign="middle">&lt;0.0001</td><td align="center" class="Rrule" valign="middle">-----</td> </tr> </tbody> </table></div>

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 to 79; 75.3% White, 15.1% Black, 6.1% Hispanic, 3.6% Other) after an average follow-up of 7.1 years, are presented in Table 4.

<div class="scrollingtable"><table width="70%"> <caption> <span>Table 4: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></span> </caption> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="30%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="Botrule First"> <th align="center" class="Lrule Rrule" valign="middle">Event</th><th align="center" class="Rrule" valign="middle">Relative Risk CE vs Placebo<br/>(95% nCI<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a>)</th><th align="center" class="Rrule" valign="middle">CE<br/>N = 5,310</th><th align="center" class="Rrule" valign="middle">Placebo<br/> N = 5,429</th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule"></th><th align="center" class="Rrule"></th><th align="center" class="Rrule" colspan="2">Absolute Risk per 10,000 Women-Years</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">‡</a> </dt> <dd>Results are based on centrally adjudicated data for an average follow-up of 7.1 years.</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">§</a> </dt> <dd>Not included in "global index."</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">¶</a> </dt> <dd>Results are based on an average follow-up of 6.8 years.</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">#</a> </dt> <dd>All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">Þ</a> </dt> <dd>A subset of the events was combined in a "global index," defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">CHD events<a class="Sup" href="#footnote-3" name="footnote-reference-3">‡</a> <br/>Non-fatal MI<a class="Sup" href="#footnote-3">‡</a> <br/>CHD death<a class="Sup" href="#footnote-3">‡</a></td><td align="center" class="Rrule" valign="middle">0.95 (0.78-1.16)<br/>0.91 (0.73-1.14)<br/>1.01 (0.71-1.43)</td><td align="center" class="Rrule" valign="middle">54<br/>40<br/>16</td><td align="center" class="Rrule" valign="middle">57<br/>43<br/>16</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">All Strokes<a class="Sup" href="#footnote-3">‡</a> <br/>Ischemic stroke<a class="Sup" href="#footnote-3">‡</a></td><td align="center" class="Rrule" valign="middle">1.33 (1.05-1.68)<br/>1.55(1.19-2.01)</td><td align="center" class="Rrule" valign="middle">45<br/>38</td><td align="center" class="Rrule" valign="middle">33<br/>25</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Deep vein thrombosis<a class="Sup" href="#footnote-3">‡</a><span class="Sup">,</span><a class="Sup" href="#footnote-4" name="footnote-reference-4">§</a></td><td align="center" class="Rrule" valign="middle">1.47 (1.06-2.06)</td><td align="center" class="Rrule" valign="middle">23</td><td align="center" class="Rrule" valign="middle">15</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Pulmonary embolism<a class="Sup" href="#footnote-3">‡</a></td><td align="center" class="Rrule" valign="middle">1.37 (0.90-2.07)</td><td align="center" class="Rrule" valign="middle">14</td><td align="center" class="Rrule" valign="middle">10</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Invasive breast cancer<a class="Sup" href="#footnote-3">‡</a></td><td align="center" class="Rrule" valign="middle">0.80 (0.62-1.04)</td><td align="center" class="Rrule" valign="middle">28</td><td align="center" class="Rrule" valign="middle">34</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Colorectal cancer<a class="Sup" href="#footnote-3">‡</a></td><td align="center" class="Rrule" valign="middle">1.08 (0.75-1.55)</td><td align="center" class="Rrule" valign="middle">17</td><td align="center" class="Rrule" valign="middle">16</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Hip fracture<a class="Sup" href="#footnote-3">‡</a></td><td align="center" class="Rrule" valign="middle">0.65 (0.45-0.94)</td><td align="center" class="Rrule" valign="middle">12</td><td align="center" class="Rrule" valign="middle">19</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Vertebral fractures<a class="Sup" href="#footnote-3">‡</a><span class="Sup">,</span><a class="Sup" href="#footnote-4">§</a></td><td align="center" class="Rrule" valign="middle">0.64 (0.44-0.93)</td><td align="center" class="Rrule" valign="middle">11</td><td align="center" class="Rrule" valign="middle">18</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Lower arm/wrist fracture<a class="Sup" href="#footnote-3">‡</a><span class="Sup">,</span><a class="Sup" href="#footnote-4">§</a></td><td align="center" class="Rrule" valign="middle">0.58 (0.47-0.72)</td><td align="center" class="Rrule" valign="middle">35</td><td align="center" class="Rrule" valign="middle">59</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Total fractures<a class="Sup" href="#footnote-3">‡</a><span class="Sup">,</span><a class="Sup" href="#footnote-4">§</a></td><td align="center" class="Rrule" valign="middle">0.71 (0.64-0.80)</td><td align="center" class="Rrule" valign="middle">144</td><td align="center" class="Rrule" valign="middle">197</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Death due to other causes<a class="Sup" href="#footnote-5" name="footnote-reference-5">¶</a><span class="Sup">,</span><a class="Sup" href="#footnote-6" name="footnote-reference-6">#</a></td><td align="center" class="Rrule" valign="middle">1.08 (0.88-1.32)</td><td align="center" class="Rrule" valign="middle">53</td><td align="center" class="Rrule" valign="middle">50</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Overall mortality<a class="Sup" href="#footnote-3">‡</a><span class="Sup">,</span><a class="Sup" href="#footnote-4">§</a></td><td align="center" class="Rrule" valign="middle">1.04 (0.88-1.22)</td><td align="center" class="Rrule" valign="middle">79</td><td align="center" class="Rrule" valign="middle">75</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">Global Index<a class="Sup" href="#footnote-7" name="footnote-reference-7">Þ</a></td><td align="center" class="Rrule" valign="middle">1.02 (0.92-1.13)</td><td align="center" class="Rrule" valign="middle">206</td><td align="center" class="Rrule" valign="middle">201</td> </tr> </tbody> </table></div>

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 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 distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.10

Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50-59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95% CI, 0.36 to 1.09)] and overall mortality [HR 0.71 (95% CI, 0.46 to 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 reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9% White, 6.8% Black, 5.4% Hispanic, 3.9% Other) are presented in Table 5. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

<div class="scrollingtable"><table width="70%"> <caption> <span>Table 5: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years<a class="Sup" href="#footnote-8" name="footnote-reference-8">*</a><span class="Sup">.</span><a class="Sup" href="#footnote-9" name="footnote-reference-9">†</a></span> </caption> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="30%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="Botrule First"> <th align="center" class="Lrule Rrule" valign="middle">Event</th><th align="center" class="Rrule" valign="middle">Relative Risk CE/MPA vs Placebo (95% nCI<a class="Sup" href="#footnote-10" name="footnote-reference-10">‡</a>)</th><th align="center" class="Rrule" valign="middle">CE/MPA<br/>N = 8.506</th><th align="center" class="Rrule" valign="middle">Placebo<br/> N = 8,102</th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule"></th><th align="center" class="Rrule"></th><th align="center" class="Rrule" colspan="2">Absolute Risk per 10,000 Women-Years</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-8" name="footnote-8">*</a> </dt> <dd>Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">†</a> </dt> <dd>Results are based on centrally adjudicated data. </dd> <dt> <a href="#footnote-reference-10" name="footnote-10">‡</a> </dt> <dd>Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">§</a> </dt> <dd>Not included in "global index."</dd> <dt> <a href="#footnote-reference-12" name="footnote-12">¶</a> </dt> <dd>Includes metastatic and non-metastatic breast cancer with the exception of in situ cancer.</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">#</a> </dt> <dd>All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.</dd> <dt> <a href="#footnote-reference-14" name="footnote-14">Þ</a> </dt> <dd>A subset of the events was combined in a "global index," defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, PE, colorectal cancer, hip fracture, or death due to other causes.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">CHD events<br/>Non-fatal MI<br/>CHD death</td><td align="center" class="Rrule">1.23 (0.99-1.53)<br/>1.28 (1.00-1.63)<br/>1.10 (0.70-1.75)</td><td align="center" class="Rrule">41<br/>31<br/>8</td><td align="center" class="Rrule">34<br/>25<br/>8</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">All Strokes<br/>Ischemic stroke</td><td align="center" class="Rrule">1.31 (1.03-1.68)<br/>1.44 (1.09-1.90)</td><td align="center" class="Rrule">33<br/>26</td><td align="center" class="Rrule">25<br/>18</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Deep vein thrombosis<a class="Sup" href="#footnote-11" name="footnote-reference-11">§</a></td><td align="center" class="Rrule">1.95 (1.43-2.67)</td><td align="center" class="Rrule">26</td><td align="center" class="Rrule">13</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Pulmonary embolism</td><td align="center" class="Rrule">2.13 (1.45-3.11)</td><td align="center" class="Rrule">18</td><td align="center" class="Rrule">8</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Invasive breast cancer<a class="Sup" href="#footnote-12" name="footnote-reference-12">¶</a></td><td align="center" class="Rrule">1.24 (1.01-1.54)</td><td align="center" class="Rrule">41</td><td align="center" class="Rrule">33</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Colorectal cancer</td><td align="center" class="Rrule">0.61 (0.42-0.87)</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">16</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Endometrial cancer<a class="Sup" href="#footnote-11">§</a></td><td align="center" class="Rrule">0.81 (0.48-1.36)</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">7</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Cervical cancer<a class="Sup" href="#footnote-11">§</a></td><td align="center" class="Rrule">1.44 (0.47-4.42)</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Hip fracture</td><td align="center" class="Rrule">0.67 (0.47-0.96)</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">16</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Vertebral fractures<a class="Sup" href="#footnote-11">§</a></td><td align="center" class="Rrule">0.65 (0.46-0.92)</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">17</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Lower arm/wrist fracture<a class="Sup" href="#footnote-11">§</a></td><td align="center" class="Rrule">0.71 (0.59-0.85)</td><td align="center" class="Rrule">44</td><td align="center" class="Rrule">62</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Total fractures<a class="Sup" href="#footnote-11">§</a></td><td align="center" class="Rrule">0.76 (0.69-0.83)</td><td align="center" class="Rrule">152</td><td align="center" class="Rrule">199</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Overall mortality<a class="Sup" href="#footnote-10">‡</a><span class="Sup">,</span><a class="Sup" href="#footnote-13" name="footnote-reference-13">#</a></td><td align="center" class="Rrule">1.00 (0.83-1.19)</td><td align="center" class="Rrule">52</td><td align="center" class="Rrule">52</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">Global Index<a class="Sup" href="#footnote-14" name="footnote-reference-14">Þ</a></td><td align="center" class="Rrule">1.13 (1.02-1.25)</td><td align="center" class="Rrule">184</td><td align="center" class="Rrule">165</td> </tr> </tbody> </table></div>

Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50-59 years of age, a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95% CI, 0.44 to 1.07)].

The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominately healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45% were 65 to 69 years of age; 36% were 70 to 74 years of age; 19% 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% CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.4), and Use in Specific Populations (8.5)].

The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were 65 to 69 years of age; 35% were 70 to 74 years; 18% 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% CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.4), and Use in Specific Populations (8.5)].

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 to 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 (5.4), and Use in Specific Populations (8.5)].

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IMVEXXY (estradiol vaginal inserts) are small, light pink, tear-shaped inserts for manual placement into the vagina. Inserts contain 4 mcg or 10 mcg of estradiol. Each insert is imprinted in white ink on one side with "04" or "10" corresponding to the insert's dosage strengths.

IMVEXXY (estradiol vaginal inserts), 4 mcg and 10 mcg, are provided in opaque pushthrough blisters and are packaged in cartons containing either 18 inserts for the starter pack or 8 inserts for the maintenance pack.

<div class="scrollingtable"><table class="Noautorules" width="60%"> <col align="left" valign="top" width="34%"/> <col align="left" valign="top" width="33%"/> <col align="left" valign="top" width="33%"/> <tbody class="Headless"> <tr> <td align="left">IMVEXXY 4 mcg</td><td align="left">8 inserts</td><td align="left">NDC 68308-747-08</td> </tr> <tr> <td align="left">IMVEXXY 4 mcg</td><td align="left">18 inserts</td><td align="left">NDC 68308-747-18</td> </tr> <tr> <td align="left">IMVEXXY 10 mcg</td><td align="left">8 inserts</td><td align="left">NDC 68308-748-08</td> </tr> <tr> <td align="left">IMVEXXY 10 mcg</td><td align="left">18 inserts</td><td align="left">NDC 68308-748-18</td> </tr> </tbody> </table></div>

Keep out of reach of children. Packages are not child-resistant.

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.]

Vaginal Bleeding

Inform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.3)].

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 (5.2, 5.3, 5.4)].

Possible 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.

<div class="scrollingtable"><table width="100%"> <col align="left" valign="middle" width="3%"/> <col align="left" valign="middle" width="47%"/> <col align="left" valign="middle" width="50%"/> <tfoot> <tr class="First Last"> <td align="left" valign="middle"></td><td align="left" valign="middle"></td><td align="left" valign="middle"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule" colspan="3" valign="top">PATIENT INFORMATION<br/>IMVEXXY (ĭm vex' ee)<br/>(estradiol vaginal inserts)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top">Read this Patient Information before you start using IMVEXXY 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.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <a name="p01"></a><span class="Bold">What is the most important information I should know about IMVEXXY (an estrogen hormone)?</span> </p> <ul class="Disc"> <li>Using estrogen-alone may increase your chance of getting cancer of the uterus (womb).</li> <li>Report any unusual vaginal bleeding right away while you are using IMVEXXY. 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.</li> <li>Do not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline of brain function).</li> <li>Using estrogen-alone may increase your chances of getting strokes or blood clots.</li> <li>Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age and older.</li> <li>Do not use estrogens with progestogens to prevent heart disease, heart attacks, strokes or dementia.</li> <li>Using estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots.</li> <li>Using estrogens with progestogens may increase your chance of getting dementia, based on a study of women 65 years of age and older.</li> <li>Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. Only one estrogen with progestogen product and dose have been shown to increase your chances of getting heart attacks, strokes, breast cancer, blood clots, and dementia. Because other products and doses have not been studied in the same way, it is not known how the use of IMVEXXY will affect your chances of having these conditions.</li> <li>You and your healthcare provider should talk regularly about whether you still need treatment with IMVEXXY.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"><span class="Bold">What is IMVEXXY?</span> <br/>IMVEXXY is a prescription medicine that contains an estrogen hormone in a vaginal insert.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"><span class="Bold">What is IMVEXXY used for?</span> <br/>IMVEXXY is used after menopause to treat moderate to severe painful intercourse, a symptom of changes in and around your vagina, due to menopause.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"><span class="Bold">Who should not use IMVEXXY?</span> <br/>Do not start using IMVEXXY if you:<br/> <ul class="Disc"> <li> <span class="Bold">have unusual vaginal bleeding.</span> <br/>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.</li> <li> <span class="Bold">have been diagnosed with a bleeding disorder.</span> </li> <li> <span class="Bold">currently have or have had certain cancers.</span> <br/>Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use IMVEXXY.</li> <li> <span class="Bold">currently have or have had blood clots.</span> </li> <li> <span class="Bold">had a stroke or heart attack.</span> </li> <li> <span class="Bold">currently have or have had liver problems.</span> </li> <li> <span class="Bold">are allergic to IMVEXXY or any of its ingredients.</span> See the list of ingredients in IMVEXXY at the end of this leaflet.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Before you use IMVEXXY, tell your healthcare provider about all of your medical conditions, including if you:</span> <br/> <ul class="Disc"> <li> <span class="Bold">have any unusual vaginal bleeding.</span> Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding or spotting to find out the cause.</li> <li> <span class="Bold">have any other medical conditions that may become worse while you are using IMVEXXY.</span> Your healthcare provider may need to check you more carefully if you have certain medical conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, angioedema (swelling of face and tongue), problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.</li> <li> <span class="Bold">are going to have surgery or will be on bed rest.</span> You may need to stop using IMVEXXY.</li> <li> <span class="Bold">are pregnant or think you may be pregnant.</span> Imvexxy is not for pregnant women.</li> <li> <span class="Bold">are breast feeding.</span> The hormone in IMVEXXY can pass into your breast milk.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how IMVEXXY works.</p> <p>IMVEXXY may also affect how other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.</p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"><span class="Bold">How should I use IMVEXXY?</span> <br/> <span class="Bold">For detailed instructions, see the step-by-step instructions for using IMVEXXY at the end of this Patient Information.</span> <br/> <ul class="Disc"> <li>Use IMVEXXY exactly as your healthcare provider tells you to use it.</li> <li>IMVEXXY is a vaginal insert that you place in your vagina.</li> <li>IMVEXXY is only for use in the vagina. <span class="Bold">Do not</span> take IMVEXXY by mouth (orally).</li> <li>Estrogens should be used at the lowest dose possible for your treatment and for only as long as needed.</li> <li>Put 1 IMVEXXY insert inside your vagina, 1 time a day at about the same time for the first two weeks.</li> <li>Then put 1 IMVEXXY insert into your vagina two times a week, every three to four days (for example, Monday and Thursday), for as long as you use IMVEXXY.</li> <li>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 IMVEXXY.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">What are the possible side effects of IMVEXXY?</span> <br/> <span class="Bold">Side effects are grouped by how serious they are and how often they happen when you are treated.</span> <br/> <span class="Bold">Serious, but less common side effects could include:</span></td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" valign="top"> <ul class="Circle"> <li>heart attack</li> <li>breast cancer</li> <li>dementia</li> <li>gallbladder disease</li> <li>high levels of fat (triglyceride) in your blood</li> <li>enlargement of benign tumors of the uterus ("fibroids")</li> <li>stroke</li> <li>cancer of the lining of the uterus (womb)</li> </ul> </td><td align="left" class="Rrule" valign="top"> <ul class="Circle"> <li>high or low blood calcium</li> <li>visual abnormalities</li> <li>liver problems</li> <li>worsening of swelling of face and tongue (angioedema) in women with a history of angioedema </li> <li>blood clots</li> <li>cancer of the ovary</li> <li>high blood pressure</li> <li>changes in your thyroid hormone levels</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:</span> <ul class="Disc"> <li>new breast lumps</li> <li>unusual vaginal bleeding</li> <li>changes in vision or speech</li> <li>sudden, new, severe headaches</li> <li>severe pains in your chest or legs with or without shortness of breath, weakness, and fatigue</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Common side effects of IMVEXXY include:</span> <ul class="Disc"> <li>headache</li> <li>breast tenderness or pain</li> <li>nausea and vomiting</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top">These are not all of the possible side effects of IMVEXXY. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or that do not go away.<br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Mayne Pharma at 1- 844-825-8500.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"><span class="Bold">What can I do to lower my chances of a serious side effect with IMVEXXY?</span> <br/> <ul class="Disc"> <li>Talk with your healthcare provider regularly about whether you should continue using IMVEXXY.</li> <li>If you have a uterus (womb), talk with your healthcare provider about whether the addition of a progestogen is right for you. In general, the addition of a progestogen is recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus.</li> <li>See your healthcare provider right away if you get vaginal bleeding while using <span class="Sup">®</span> IMVEXXY.</li> <li>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 had breast lumps or an abnormal mammogram, you may need to have breast exams more often.</li> <li>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 of getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"><span class="Bold">General information about the safe and effective use of IMVEXXY.</span> <br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use IMVEXXY for a condition for which it was not prescribed. Do not give IMVEXXY to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about IMVEXXY that is written for health professionals</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"><span class="Bold">What are the ingredients in IMVEXXY?</span> <br/> <span class="Bold">Active ingredient:</span> IMVEXXY (estradiol vaginal inserts) are small, light pink, tear-shaped inserts that contain estradiol.<br/> <span class="Bold">Inactive ingredients:</span> Each insert also contains ammonium hydroxide, ethanol, ethyl acetate, ethylene glycol palmitostearate, FD&amp;C Red #40, gelatin, glycerin, isopropyl alcohol, lecithin, medium chain triglycerides, polyethylene glycol, polyethylene glycol stearates, polyvinyl acetate phthalate, propylene glycol, purified water, sorbitol-sorbitan solution, and titanium dioxide. IMVEXXY is supplied in blister cartons of 18 or 8 vaginal inserts.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"middle\" width=\"3%\"/>\n<col align=\"left\" valign=\"middle\" width=\"47%\"/>\n<col align=\"left\" valign=\"middle\" width=\"50%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" valign=\"middle\"></td><td align=\"left\" valign=\"middle\"></td><td align=\"left\" valign=\"middle\"></td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Lrule Rrule Toprule\" colspan=\"3\" valign=\"top\">PATIENT INFORMATION<br/>IMVEXXY (ĭm vex' ee)<br/>(estradiol vaginal inserts)</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">Read this Patient Information before you start using IMVEXXY 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.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<a name=\"p01\"></a><span class=\"Bold\">What is the most important information I should know about IMVEXXY (an estrogen hormone)?</span>\n</p>\n<ul class=\"Disc\">\n<li>Using estrogen-alone may increase your chance of getting cancer of the uterus (womb).</li>\n<li>Report any unusual vaginal bleeding right away while you are using IMVEXXY. 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.</li>\n<li>Do not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline of brain function).</li>\n<li>Using estrogen-alone may increase your chances of getting strokes or blood clots.</li>\n<li>Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age and older.</li>\n<li>Do not use estrogens with progestogens to prevent heart disease, heart attacks, strokes or dementia.</li>\n<li>Using estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots.</li>\n<li>Using estrogens with progestogens may increase your chance of getting dementia, based on a study of women 65 years of age and older.</li>\n<li>Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. Only one estrogen with progestogen product and dose have been shown to increase your chances of getting heart attacks, strokes, breast cancer, blood clots, and dementia. Because other products and doses have not been studied in the same way, it is not known how the use of IMVEXXY will affect your chances of having these conditions.</li>\n<li>You and your healthcare provider should talk regularly about whether you still need treatment with IMVEXXY.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\"><span class=\"Bold\">What is IMVEXXY?</span>\n<br/>IMVEXXY is a prescription medicine that contains an estrogen hormone in a vaginal insert.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\"><span class=\"Bold\">What is IMVEXXY used for?</span>\n<br/>IMVEXXY is used after menopause to treat moderate to severe painful intercourse, a symptom of changes in and around your vagina, due to menopause.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\"><span class=\"Bold\">Who should not use IMVEXXY?</span>\n<br/>Do not start using IMVEXXY if you:<br/>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">have unusual vaginal bleeding.</span>\n<br/>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.</li>\n<li>\n<span class=\"Bold\">have been diagnosed with a bleeding disorder.</span>\n</li>\n<li>\n<span class=\"Bold\">currently have or have had certain cancers.</span>\n<br/>Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use IMVEXXY.</li>\n<li>\n<span class=\"Bold\">currently have or have had blood clots.</span>\n</li>\n<li>\n<span class=\"Bold\">had a stroke or heart attack.</span>\n</li>\n<li>\n<span class=\"Bold\">currently have or have had liver problems.</span>\n</li>\n<li>\n<span class=\"Bold\">are allergic to IMVEXXY or any of its ingredients.</span> See the list of ingredients in IMVEXXY at the end of this leaflet.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\"><span class=\"Bold\">Before you use IMVEXXY, tell your healthcare provider about all of your medical conditions, including if you:</span>\n<br/>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">have any unusual vaginal bleeding.</span> Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding or spotting to find out the cause.</li>\n<li>\n<span class=\"Bold\">have any other medical conditions that may become worse while you are using IMVEXXY.</span> Your healthcare provider may need to check you more carefully if you have certain medical conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, angioedema (swelling of face and tongue), problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.</li>\n<li>\n<span class=\"Bold\">are going to have surgery or will be on bed rest.</span> You may need to stop using IMVEXXY.</li>\n<li>\n<span class=\"Bold\">are pregnant or think you may be pregnant.</span> Imvexxy is not for pregnant women.</li>\n<li>\n<span class=\"Bold\">are breast feeding.</span> The hormone in IMVEXXY can pass into your breast milk.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how IMVEXXY works.</p>\n<p>IMVEXXY may also affect how other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\"><span class=\"Bold\">How should I use IMVEXXY?</span>\n<br/>\n<span class=\"Bold\">For detailed instructions, see the step-by-step instructions for using IMVEXXY at the end of this Patient Information.</span>\n<br/>\n<ul class=\"Disc\">\n<li>Use IMVEXXY exactly as your healthcare provider tells you to use it.</li>\n<li>IMVEXXY is a vaginal insert that you place in your vagina.</li>\n<li>IMVEXXY is only for use in the vagina. <span class=\"Bold\">Do not</span> take IMVEXXY by mouth (orally).</li>\n<li>Estrogens should be used at the lowest dose possible for your treatment and for only as long as needed.</li>\n<li>Put 1 IMVEXXY insert inside your vagina, 1 time a day at about the same time for the first two weeks.</li>\n<li>Then put 1 IMVEXXY insert into your vagina two times a week, every three to four days (for example, Monday and Thursday), for as long as you use IMVEXXY.</li>\n<li>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 IMVEXXY.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\"><span class=\"Bold\">What are the possible side effects of IMVEXXY?</span>\n<br/>\n<span class=\"Bold\">Side effects are grouped by how serious they are and how often they happen when you are treated.</span>\n<br/>\n<span class=\"Bold\">Serious, but less common side effects could include:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" valign=\"top\">\n<ul class=\"Circle\">\n<li>heart attack</li>\n<li>breast cancer</li>\n<li>dementia</li>\n<li>gallbladder disease</li>\n<li>high levels of fat (triglyceride) in your blood</li>\n<li>enlargement of benign tumors of the uterus (\"fibroids\")</li>\n<li>stroke</li>\n<li>cancer of the lining of the uterus (womb)</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>high or low blood calcium</li>\n<li>visual abnormalities</li>\n<li>liver problems</li>\n<li>worsening of swelling of face and tongue (angioedema) in women with a history of angioedema </li>\n<li>blood clots</li>\n<li>cancer of the ovary</li>\n<li>high blood pressure</li>\n<li>changes in your thyroid hormone levels</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\"><span class=\"Bold\">Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:</span>\n<ul class=\"Disc\">\n<li>new breast lumps</li>\n<li>unusual vaginal bleeding</li>\n<li>changes in vision or speech</li>\n<li>sudden, new, severe headaches</li>\n<li>severe pains in your chest or legs with or without shortness of breath, weakness, and fatigue</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\"><span class=\"Bold\">Common side effects of IMVEXXY include:</span>\n<ul class=\"Disc\">\n<li>headache</li>\n<li>breast tenderness or pain</li>\n<li>nausea and vomiting</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">These are not all of the possible side effects of IMVEXXY. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or that do not go away.<br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Mayne Pharma at 1- 844-825-8500.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\"><span class=\"Bold\">What can I do to lower my chances of a serious side effect with IMVEXXY?</span>\n<br/>\n<ul class=\"Disc\">\n<li>Talk with your healthcare provider regularly about whether you should continue using IMVEXXY.</li>\n<li>If you have a uterus (womb), talk with your healthcare provider about whether the addition of a progestogen is right for you. In general, the addition of a progestogen is recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus.</li>\n<li>See your healthcare provider right away if you get vaginal bleeding while using <span class=\"Sup\">®</span> IMVEXXY.</li>\n<li>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 had breast lumps or an abnormal mammogram, you may need to have breast exams more often.</li>\n<li>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 of getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\"><span class=\"Bold\">General information about the safe and effective use of IMVEXXY.</span>\n<br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use IMVEXXY for a condition for which it was not prescribed. Do not give IMVEXXY to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about IMVEXXY that is written for health professionals</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\"><span class=\"Bold\">What are the ingredients in IMVEXXY?</span>\n<br/>\n<span class=\"Bold\">Active ingredient:</span> IMVEXXY (estradiol vaginal inserts) are small, light pink, tear-shaped inserts that contain estradiol.<br/>\n<span class=\"Bold\">Inactive ingredients:</span> Each insert also contains ammonium hydroxide, ethanol, ethyl acetate, ethylene glycol palmitostearate, FD&amp;C Red #40, gelatin, glycerin, isopropyl alcohol, lecithin, medium chain triglycerides, polyethylene glycol, polyethylene glycol stearates, polyvinyl acetate phthalate, propylene glycol, purified water, sorbitol-sorbitan solution, and titanium dioxide. IMVEXXY is supplied in blister cartons of 18 or 8 vaginal inserts.</td>\n</tr>\n</tbody>\n</table></div>" }

Read this Instructions for Use before you start using IMVEXXY 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.

{ "type": "p", "children": [], "text": "Read this Instructions for Use before you start using IMVEXXY 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." }

How should I use IMVEXXY?

{ "type": "p", "children": [], "text": "\nHow should I use IMVEXXY?\n" }

{ "type": "ul", "children": [ "IMVEXXY is an insert only for use in the vagina. Do not take by mouth.", "Put 1 IMVEXXY insert inside your vagina, 1 time a day at about the same time for the first two weeks, then put 1 IMVEXXY insert into your vagina two times a week, every three to four days (for example, Monday and Thursday), for as long as you use IMVEXXY.", "Write down the days you will put in your IMVEXXY insert.", "Wash and dry your hands before handling the IMVEXXY insert." ], "text": "" }

Step 1: Push 1 IMVEXXY insert through the foil of the blister package.

{ "type": "p", "children": [], "text": "\nStep 1: Push 1 IMVEXXY insert through the foil of the blister package." }

Figure A

{ "type": "p", "children": [], "text": "\nFigure A\n" }

Step 2: Hold the IMVEXXY insert with the larger end between your fingers.

{ "type": "p", "children": [], "text": "\nStep 2: Hold the IMVEXXY insert with the larger end between your fingers." }

Figure B

{ "type": "p", "children": [], "text": "\nFigure B\n" }

Step 3: Select the best position for vaginal insertion that is most comfortable for you to put in the IMVEXXY insert. See Figure C for suggested insertion in the lying down position or Figure D for suggested insertion in the standing position. With the smaller end up, put the insert about two inches into your vagina using your finger.

{ "type": "p", "children": [], "text": "\nStep 3: Select the best position for vaginal insertion that is most comfortable for you to put in the IMVEXXY insert. See Figure C for suggested insertion in the lying down position or Figure D for suggested insertion in the standing position. With the smaller end up, put the insert about two inches into your vagina using your finger." }

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" valign="middle" width="10%"/> <col align="left" valign="middle" width="9%"/> <col align="left" valign="middle" width="10%"/> <col align="left" valign="middle" width="71%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" valign="top"> <p class="First"> <a name="figC"></a><span class="Bold">      Figure C</span> </p> </td><td align="center" valign="top"><span class="Bold">or</span></td><td align="center" valign="top"> <p class="First"> <a name="figD"></a><span class="Bold">Figure D</span> </p> </td><td align="center" valign="top"></td> </tr> <tr class="Last"> <td align="center" valign="top"> <p class="First"> <img alt="Figure C" src="/dailymed/image.cfm?name=imvexxy-05.jpg&amp;setid=6ce645c0-a550-4ae9-8dbd-3853ee8b7d26"/></p> </td><td align="left" valign="top"></td><td align="center" valign="top"><img alt="Figure D" src="/dailymed/image.cfm?name=imvexxy-06.jpg&amp;setid=6ce645c0-a550-4ae9-8dbd-3853ee8b7d26"/></td><td align="center" valign="top"></td> </tr> </tbody> </table></div>

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If you have any questions, please ask your healthcare provider or pharmacist.

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How should I store IMVEXXY?

{ "type": "p", "children": [], "text": "\nHow should I store IMVEXXY?\n" }

{ "type": "ul", "children": [ "Store IMVEXXY at room temperature between 68°F to 77°F (20°C to 25°C).", "IMVEXXY packaging is not child-resistant." ], "text": "" }

Keep IMVEXXY and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep IMVEXXY and all medicines out of the reach of children.\n" }

For information, call Mayne Pharma at 1-844-825-8500

{ "type": "p", "children": [], "text": "For information, call Mayne Pharma at 1-844-825-8500" }

Distributed by: Mayne Pharma Raleigh, NC 27609

{ "type": "p", "children": [], "text": "Distributed by: Mayne Pharma Raleigh, NC 27609" }

IMVEXXY is a registered trademark of TherapeuticsMD, Inc. used under license.

{ "type": "p", "children": [], "text": "IMVEXXY is a registered trademark of TherapeuticsMD, Inc. used under license." }

The Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "The Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration." }

Revised: 11/2023

{ "type": "p", "children": [], "text": "Revised: 11/2023" }

NDC 68308-747-08

{ "type": "p", "children": [], "text": "NDC 68308-747-08" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Imvexxy®

{ "type": "p", "children": [], "text": "Imvexxy®\n" }

4 mcg (estradiol vaginal inserts)

{ "type": "p", "children": [], "text": "4 mcg (estradiol vaginal inserts)" }

FOR VAGINAL USE ONLY

{ "type": "p", "children": [], "text": "FOR VAGINAL USE ONLY" }

8 vaginal inserts

{ "type": "p", "children": [], "text": "8 vaginal inserts" }

mayne pharma

{ "type": "p", "children": [], "text": "mayne pharma" }

NDC 68308-748-08

{ "type": "p", "children": [], "text": "NDC 68308-748-08" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Imvexxy®

{ "type": "p", "children": [], "text": "Imvexxy®\n" }

10 mcg (estradiol vaginal inserts)

{ "type": "p", "children": [], "text": "10 mcg (estradiol vaginal inserts)" }

FOR VAGINAL USE ONLY

{ "type": "p", "children": [], "text": "FOR VAGINAL USE ONLY" }

8 vaginal inserts

{ "type": "p", "children": [], "text": "8 vaginal inserts" }

mayne pharma

{ "type": "p", "children": [], "text": "mayne pharma" }

Start therapy with the 0.25 grams applied once daily on the skin of either the right or left upper thigh. Adjust the dose up to a maximum of 1.25 grams, as needed.

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, apply estradiol gel 0.1% to the right or left upper thigh on alternating days. Do not apply Estradiol gel 0.1% on the face, breasts, or irritated skin or in or around the vagina. Allow gel to dry after application before dressing. Do not wash the application site within 1 hour after applying estradiol gel 0.1%. Avoid contact of the gel with eyes. Wash hands after application.

Estradiol gel 0.1% is available in five doses of 0.25, 0.5, 0.75, 1.0, and 1.25 grams for transdermal application (corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively). Estradiol gel 0.1% is a clear, colorless gel, which is odorless when dry.

{ "type": "p", "children": [], "text": "Estradiol gel 0.1% is available in five doses of 0.25, 0.5, 0.75, 1.0, and 1.25 grams for transdermal application (corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively). Estradiol gel 0.1% is a clear, colorless gel, which is odorless when dry." }

Estradiol gel 0.1% is contraindicated in women with any of the following conditions:

{ "type": "p", "children": [], "text": "Estradiol gel 0.1% is contraindicated in women with any of the following conditions:" }

{ "type": "ul", "children": [ "Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.2)]\n", "Breast cancer or history of breast cancer [see Warnings and Precautions (5.2)]\n", "Estrogen-dependent neoplasia [see Warnings and Precautions (5.2)]\n", "Active DVT, PE, or history of these conditions [see Warnings and Precautions (5.1)]\n", "Active arterial thromboembolic disease (e.g., stroke and MI), or a history of these conditions [see Warnings and Precautions (5.1)]\n", "Known anaphylactic reaction, angioedema, or hypersensitivity to estradiol gel 0.1%", "Hepatic impairment or disease", "Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders" ], "text": "" }

Increased risks of stroke and DVT are reported with estrogen-alone therapy. Increased risk of PE, DVT, stroke and MI are reported with estrogen plus progestin therapy.

Immediately discontinue estrogen with or without progestogen therapy if any of these occur or are suspected.

Manage appropriately any risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus).

Stroke

The WHI estrogen-alone substudy reported a statistically significant increased risk of stroke 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 strokes per 10,000 women-years, respectively). The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies (14.2)]. Immediately discontinue estrogen-alone therapy if a stroke occurs or is suspected.

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

The WHI estrogen plus progestin substudy reported a statistically significant increased risk of stroke 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, respectively) [see Clinical Studies (14.2)]. The increase in risk was demonstrated after the first year and persisted.1 Immediately discontinue estrogen plus progestogen therapy if a stroke occurs or is suspected.

Coronary Heart Disease

The WHI estrogen-alone substudy reported no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in women receiving estrogen-alone compared to placebo2[see Clinical Studies (14.2)].

Subgroup analyses of women 50 to 59 years of age, who were less than 10 years since menopause, suggest a reduction (not statistically significant) of CHD events in those women receiving daily CE (0.625 mg)-alone compared to placebo (8 versus 16 per 10,000 women-years).1

The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) of CHD events in those 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 (14.2)].

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 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 (0.625 mg) plus MPA (2.5 mg) 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 (14.2)]. Immediately discontinue estrogen-alone therapy if a VTE occurs or is suspected.

The WHI estrogen plus progestin substudy reported a statistically significant 2-fold greater rate of VTE 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 (14.2)]. Immediately discontinue estrogen plus progestogen therapy if a VTE occurs or is suspected.

If feasible, discontinue estrogens at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

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-fold 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 and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women using estrogen-alone or estrogen plus progestogen therapy is important. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding with unknown etiology. 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 progestogen to postmenopausal 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 WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. 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) 0.80] compared to placebo5 [see Clinical Studies (14.2)].

After a mean follow-up of 5.6 years, the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg) reported an increased risk of invasive breast cancer in women who took daily CE plus MPA compared to placebo. 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 groups6[see Clinical Studies (14.2)].

Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer with estrogen plus progestin therapy, and a smaller increase in the risk for breast cancer with estrogen-alone therapy, after several years of use. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy. 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.

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.

Have all women receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, base the scheduling of mammography examinations on patient age, risk factors, and prior mammogram results.

Ovarian Cancer

The CE plus MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77–3.24), but was not statistically significant. The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7

A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer.  The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies.  The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis).  The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27-1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products.  The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.

In the WHI Memory Study (WHIMS) estrogen-alone ancillary study, 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 (8.5), and Clinical Studies (14.3)].

In the WHIMS estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.

After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21–3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8[see Use in Specific Populations (8.5), and Clinical Studies (14.3)].

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 women8[see Use in Specific Populations (8.5), and Clinical Studies (14.3)].

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including estradiol gel 0.1%, if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level.

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue estradiol gel 0.1% pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens, including estradiol gel 0.1%, if examination reveals papilledema or retinal vascular lesions.

Studies of the addition of a progestogen 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 progestogens with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.

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.

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Discontinue estradiol gel 0.1% if pancreatitis occurs.

Estrogens may be poorly metabolized in women with hepatic impairment. Exercise caution in any woman with a history of cholestatic jaundice associated with past estrogen use or with pregnancy. In the case of recurrence of cholestatic jaundice, discontinue estradiol gel 0.1%.

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. Monitor thyroid function in these women during treatment with estradiol gel 0.1% to maintain their free thyroid hormone levels in an acceptable range.

Estrogens may cause some degree of fluid retention. Monitor any woman with a condition(s) that might predispose her to fluid retention, such as a cardiac or renal impairment. Discontinue estrogen-alone therapy, including estradiol gel 0.1%, with evidence of medically concerning fluid retention.

Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy outweigh the risks in such women.

A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. Consider the addition of a progestogen therapy for a woman known to have residual endometriosis post-hysterectomy.

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy, including estradiol gel 0.1%, outweigh the risks in such women.

Estrogen therapy, including estradiol gel 0.1%, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas. Consider whether the benefits of estrogen therapy outweigh the risks in women with such conditions.

The effects of direct sun exposure to estradiol gel 0.1% application sites have not been evaluated in clinical trials.

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 sunscreens and other topical lotions on the systemic exposure of estradiol gel 0.1% has not been evaluated in clinical trials.

Alcohol based gels are flammable. Avoid fire, flame, or smoking until estradiol gel 0.1% has dried.

Occlusion of the area where the topical drug product is applied with clothing or other barriers is not recommended until estradiol gel 0.1% has completely dried.

There is a potential for drug transfer from one individual to the other following physical contact of estradiol gel 0.1% 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. Women are advised to avoid skin contact with other persons 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 percent decrease in the mean total 24-hour exposure to estradiol. Therefore, women should refrain from washing the application site for at least one hour after application.

Serum follicle stimulating hormone (FSH) and estradiol levels are not useful in the management of moderate to severe vasomotor symptoms.

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.

Estradiol gel 0.1% was studied at doses of 0.25, 0.5 and 1.0 gram per day in a 12-week, double-blind, placebo-controlled study that included a total of 495 postmenopausal women (86.5 percent Caucasian). The adverse reactions that occurred at a rate greater than 5 percent and greater than placebo in any of the treatment groups are summarized in Table 1.

<div class="scrollingtable"><table> <caption> <span>Table 1: Number (%) of Subjects with Common Adverse Reactions* in a 12-Week Placebo-Controlled Study of Estradiol Gel 0.1%</span> </caption> <col/> <col/> <col/> <col/> <col/> <thead> <tr class="First"> <th></th><th colspan="3"><span class="Bold">Estradiol Gel 0.1%</span></th><th><span class="Bold">Placebo</span></th> </tr> <tr class="Last"> <th><span class="Bold">SYSTEM ORGAN CLASS <br/> Preferred Term</span></th><th><span class="Bold">0.25 grams/day <br/>N=122 <br/>n (%)</span></th><th><span class="Bold">0.5 grams/day <br/>N=123 <br/>n (%)</span></th><th><span class="Bold">1.0 gram/day <br/>N=125 <br/>n (%)</span></th><th><span class="Bold">N=125 <br/>n (%)</span></th> </tr> </thead> <tfoot> <tr class="First Last"> <td colspan="5">*Adverse reactions reported by &gt;5 percent of patients in any treatment group.</td> </tr> </tfoot> <tbody> <tr class="First"> <td><span class="Bold">INFECTIONS &amp; INFESTATIONS</span></td><td></td><td></td><td></td><td></td> </tr> <tr> <td> Nasopharyngitis</td><td>7 (5.7)</td><td>5 (4.1)</td><td>6 (4.8)</td><td>5 (4.0)</td> </tr> <tr> <td> Upper Respiratory Tract Infection</td><td>7 (5.7)</td><td>3 (2.4)</td><td>2 (1.6)</td><td>2 (1.6)</td> </tr> <tr> <td> Vaginal mycosis</td><td>1 (0.8)</td><td>3 (2.4)</td><td>8 (6.4)</td><td>4 (3.2)</td> </tr> <tr> <td><span class="Bold">REPRODUCTIVE SYSTEM &amp; BREAST DISORDERS</span></td><td></td><td></td><td></td><td></td> </tr> <tr> <td> Breast Tenderness</td><td>3 (2.5)</td><td>7 (5.7)</td><td>11 (8.8)</td><td>2 (1.6)</td> </tr> <tr class="Last"> <td> Metrorrhagia</td><td>5 (4.1)</td><td>7 (5.7)</td><td>12 (9.6)</td><td>2 (1.6)</td> </tr> </tbody> </table></div>

In a 12-week placebo-controlled study of estradiol gel 0.1%, application site reactions were seen in <1 percent of participating women.

The following adverse reactions have been identified during post-approval use of estradiol gel 0.1%. 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 Amenorrhea, dysmenorrhea, ovarian cyst, vaginal discharge

Breasts Gynecomastia

Cardiovascular Palpitations, ventricular extrasystoles

Gastrointestinal Flatulence

Skin Rash pruritic, urticaria

Eyes Retinal vein occlusion

Central Nervous System Tremor

Miscellaneous Arthralgia, application site rash, asthenia, chest discomfort, fatigue, feeling abnormal, heart rate increased, insomnia, malaise, muscle spasms, pain in extremity, weight increased

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 adverse reactions.

{ "type": "p", "children": [], "text": "\nIn 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 adverse reactions. \n\n" }

Risk Summary Estradiol gel 0.1% is not indicated for use in pregnant women. There are no data with the use of estradiol gel 0.1% in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Risk Summary Estrogens are present in human milk and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well established.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for estradiol gel 0.1% and any potential adverse effects on the breastfed child from estradiol gel 0.1% or from the underlying maternal condition.

Estradiol gel 0.1% is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.

There have not been sufficient numbers of geriatric women involved in studies utilizing estradiol gel 0.1% to determine whether those over 65 years of age differ from younger subjects in their response to estradiol gel 0.1%.

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 Warnings and Precautions (5.1) and Clinical Studies (14.2)].

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 Warnings and Precautions (5.1, 5.2), and Clinical Studies (14.2)].

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 (5.3), and Clinical Studies  (14.3)].

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  (5.3), and Clinical Studies (14.3)] .

Overdosage of estrogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding in women. Treatment of overdose consists of discontinuation of estradiol gel 0.1% therapy with institution of appropriate symptomatic care.

{ "type": "p", "children": [], "text": "Overdosage of estrogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding in women. Treatment of overdose consists of discontinuation of estradiol gel 0.1% therapy with institution of appropriate symptomatic care." }

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 layer. Estradiol gel 0.1% is available in five doses of 0.25, 0.5, 0.75, 1.0, and 1.25 grams for topical application (corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively).

{ "type": "p", "children": [], "text": "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 layer. Estradiol gel 0.1% is available in five doses of 0.25, 0.5, 0.75, 1.0, and 1.25 grams for topical application (corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively)." }

The active component of the topical gel is estradiol, an estrogen.

{ "type": "p", "children": [], "text": "The active component of the topical gel is estradiol, an estrogen." }

Estradiol is a white crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17ß-diol. It has an empirical formula of C18H24O2 and molecular weight of 272.39. The structural formula is:

{ "type": "p", "children": [], "text": "Estradiol is a white crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17ß-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.

{ "type": "p", "children": [], "text": "The remaining components of the gel (carbomer, ethanol, propylene glycol, purified water, and triethanolamine) are pharmacologically inactive." }

Estradiol gel 0.1% contains: 58.6% alcohol.

{ "type": "p", "children": [], "text": "Estradiol gel 0.1% contains: 58.6% alcohol." }

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, which is 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.

Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to estradiol gel 0.1% nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

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, estradiol gel 0.1% 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 2).

Table 2: Mean (%CV) Pharmacokinetic Parameters for Estradiol (uncorrected for baseline) on Day 14 Following Multiple Daily Doses of Estradiol Gel 0.1%

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="justify" valign="top"><span class="Bold">Parameter (units)</span></td><td align="center" valign="top"><span class="Bold">Estradiol Gel 0.25 grams</span></td><td align="center" valign="top"><span class="Bold">Estradiol Gel 0.5 grams</span></td><td align="center" valign="top"><span class="Bold">Estradiol Gel 1.0 gram</span></td> </tr> <tr> <td align="justify" valign="top">AUC<span class="Sub">0-24</span> (pg•h/mL)</td><td align="center" valign="top">236 (94)</td><td align="center" valign="top">504 (149)</td><td align="center" valign="top">732 (81)</td> </tr> <tr> <td align="justify" valign="top">C<span class="Sub">max</span> (pg/mL)</td><td align="center" valign="top">14.7 (84)</td><td align="center" valign="top">28.4 (139)</td><td align="center" valign="top">51.5 (86)</td> </tr> <tr> <td align="justify" valign="top">C<span class="Sub">avg</span> (pg/mL)</td><td align="center" valign="top">9.8 (92)</td><td align="center" valign="top">21 (148)</td><td align="center" valign="top">30.5 (81)</td> </tr> <tr> <td align="justify" valign="top">t<span class="Sub">max</span> * (h)</td><td align="center" valign="top">16 (0,72)</td><td align="center" valign="top">10 (0,72)</td><td align="center" valign="top">8 (0,48)</td> </tr> <tr class="Last"> <td align="justify" valign="top">E2:E1 ratio</td><td align="center" valign="top">0.42</td><td align="center" valign="top">0.65</td><td align="center" valign="top">0.65</td> </tr> </tbody> </table></div>

*Median (Min, Max).

Steady-state serum concentration of estradiol are achieved by day 12 following daily application of estradiol gel 0.1% 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 Estradiol Gel 0.1%

The effect of sunscreens and other topical lotions on the systemic exposure of estradiol gel 0.1% 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 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 estradiol gel 0.1% does not undergo first pass metabolism and provides estradiol to 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 estradiol gel 0.1%.

Potential for Estradiol Transfer

The effect of estradiol transfer was evaluated in healthy postmenopausal women who topically applied 1.0 gram of estradiol gel 0.1% (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.

Effects of Washing

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 gram of estradiol gel 0.1% 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 to 38 percent decrease in the mean total 24-hour exposure to estradiol.

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.

A randomized, double-blind, placebo-controlled trial evaluated the efficacy of 12-week treatment with three different daily doses of estradiol gel 0.1% for vasomotor symptoms in 495 postmenopausal women (86.5 percent White; 10.1 percent 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). Women applied placebo, estradiol gel 0.1% 0.25 grams (0.25 mg estradiol), estradiol gel 0.1% 0.5 grams (0.5 mg estradiol) or estradiol gel 0.1% 1.0 gram (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 grams per day and the 1.0 gram per day estradiol gel 0.1% 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 estradiol gel 0.1% 0.25 grams per 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 estradiol gel 0.1% doses (0.25 grams per day, 0.5 grams per day and 1.0 gram per day) compared to placebo at week 12. See Table 3 for results.

Table 3: Summary of Change From Baseline in the Median Daily Frequency and Severity of Hot Flushes during Estradiol Gel 0.1% Treatment (ITT Population)

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" colspan="4" valign="top"><span class="Bold">Estradiol Gel 0.1%</span></td><td align="center" valign="top"><span class="Bold">Placebo</span></td> </tr> <tr> <td align="justify" valign="top"><span class="Bold">Evaluation</span></td><td align="center" valign="top"> <p class="First">0.25 grams/day</p> <p>N=121</p> </td><td align="center" valign="top"> <p class="First">0.5 grams/day</p> <p>N=119</p> </td><td align="center" valign="top"> <p class="First">1.0 gram/day</p> <p>N=124</p> </td><td align="center" valign="top">N=124</td> </tr> <tr> <td align="center" colspan="5" valign="top"><span class="Bold">Frequency of Daily Hot Flushes</span></td> </tr> <tr> <td align="justify" valign="top">Baseline Median</td><td align="center" valign="top">9.72</td><td align="center" valign="top">9.24</td><td align="center" valign="top">9.64</td><td align="center" valign="top">9.32</td> </tr> <tr> <td align="justify" valign="top"> <p class="First">Median Change: Week 4</p> <p>                             p-value<span class="Sup">†</span> </p> </td><td align="center" valign="top"> <p class="First">-5.00</p> <p>0.132</p> </td><td align="center" valign="top"> <p class="First">-5.73</p> <p>0.011</p> </td><td align="center" valign="top"> <p class="First">-7.20</p> <p>&lt;0.001</p> </td><td align="center" valign="top">-3.63</td> </tr> <tr> <td align="justify" valign="top"> <p class="First">Median Change: Week 7</p> <p>                            p-value<span class="Sup">†</span> </p> </td><td align="center" valign="top"> <p class="First">-6.62</p> <p>&lt;0.001</p> </td><td align="center" valign="top"> <p class="First">-7.14</p> <p>&lt;0.001</p> </td><td align="center" valign="top"> <p class="First">-7.71</p> <p>&lt;0.001</p> </td><td align="center" valign="top">-4.37</td> </tr> <tr> <td align="justify" valign="top"> <p class="First">Median Change: Week 12</p> <p>                            p-value<span class="Sup">†</span> </p> </td><td align="center" valign="top"> <p class="First">-6.88</p> <p>&lt;0.001</p> </td><td align="center" valign="top"> <p class="First">-7.29</p> <p>&lt;0.001</p> </td><td align="center" valign="top"> <p class="First">-8.35</p> <p>&lt;0.001</p> </td><td align="center" valign="top">-4.48</td> </tr> <tr> <td align="center" colspan="5" valign="top"><span class="Bold">Severity of Daily Hot Flushes</span></td> </tr> <tr> <td align="justify" valign="top">Baseline Median</td><td align="center" valign="top">2.52</td><td align="center" valign="top">2.51</td><td align="center" valign="top">2.52</td><td align="center" valign="top">2.54</td> </tr> <tr> <td align="justify" valign="top"> <p class="First">Median Change: Week 4</p> <p>                            p-value<span class="Sup">†</span> </p> </td><td align="center" valign="top"> <p class="First">-0.07</p> <p>0.283</p> </td><td align="center" valign="top"> <p class="First">-0.18</p> <p>&lt;0.001</p> </td><td align="center" valign="top"> <p class="First">-0.47</p> <p>&lt;0.001</p> </td><td align="center" valign="top">-0.04</td> </tr> <tr> <td align="justify" valign="top"> <p class="First">Median Change: Week 7</p> <p>                            p-value<span class="Sup">†</span> </p> </td><td align="center" valign="top"> <p class="First">-0.24</p> <p>&lt;0.001</p> </td><td align="center" valign="top"> <p class="First">-0.46</p> <p>&lt;0.001</p> </td><td align="center" valign="top"> <p class="First">-1.06</p> <p>&lt;0.001</p> </td><td align="center" valign="top">-0.06</td> </tr> <tr class="Last"> <td align="justify" valign="top"> <p class="First">Median Change: Week 12</p> <p>                            p-value<span class="Sup">†</span> </p> </td><td align="center" valign="top"> <p class="First">-0.33</p> <p>0.021</p> </td><td align="center" valign="top"> <p class="First">-0.56</p> <p>0.002</p> </td><td align="center" valign="top"> <p class="First">-1.69</p> <p>&lt;0.001</p> </td><td align="center" valign="top">-0.13</td> </tr> </tbody> </table></div>

†p-values from the van Elteren’s test stratified by pooled center; comparison in median change was significant if p<0.05.

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 risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 7.1 years are presented in Table 4.

Table 4: Relative And Absolute Risk Seen In the Estrogen-Alone Substudy Of WHIa

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" rowspan="2" valign="middle"><span class="Bold">Event</span></td><td align="center" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Relative Risk CE vs. Placebo</span> </p> <p> <span class="Bold">(95% nCI<span class="Sup">b</span>)</span> </p> </td><td align="center" valign="middle"><span class="Bold">CE n = 5,310</span></td><td align="center" valign="middle"><span class="Bold">Placebo n = 5,429</span></td> </tr> <tr> <td align="center" colspan="2" valign="middle"><span class="Bold">Absolute Risk per 10,000 Women-Years</span></td> </tr> <tr> <td align="justify" valign="middle">CHD events<span class="Sup">c</span></td><td align="center" valign="middle">0.95 (0.78 – 1.16)</td><td align="center" valign="middle">54</td><td align="center" valign="middle">57</td> </tr> <tr> <td align="justify" valign="middle"><span class="Italics">Nonfatal MI</span><span class="Sup">c</span></td><td align="center" valign="middle"><span class="Italics">0.91 (0.73 – 1.14)</span></td><td align="center" valign="middle"><span class="Italics">40</span></td><td align="center" valign="middle"><span class="Italics">43</span></td> </tr> <tr> <td align="justify" valign="middle"><span class="Italics">CHD death</span><span class="Sup">c</span></td><td align="center" valign="middle"><span class="Italics">1.01 (0.71 – 1.43)</span></td><td align="center" valign="middle"><span class="Italics">16</span></td><td align="center" valign="middle"><span class="Italics">16</span></td> </tr> <tr> <td align="justify" valign="middle">All strokes<span class="Sup">c</span></td><td align="center" valign="middle">1.33 (1.05 – 1.68)</td><td align="center" valign="middle">45</td><td align="center" valign="middle">33</td> </tr> <tr> <td align="justify" valign="middle"><span class="Italics">Ischemic stroke</span><span class="Sup">c</span></td><td align="center" valign="middle"><span class="Italics">1.55 (1.19 – 2.01)</span></td><td align="center" valign="middle"><span class="Italics">38</span></td><td align="center" valign="middle"><span class="Italics">25</span></td> </tr> <tr> <td align="justify" valign="middle">Deep vein thrombosis<span class="Sup">c,d</span></td><td align="center" valign="middle">1.47 (1.06 – 2.06)</td><td align="center" valign="middle">23</td><td align="center" valign="middle">15</td> </tr> <tr> <td align="justify" valign="middle">Pulmonary embolism<span class="Sup">c</span></td><td align="center" valign="middle">1.37 (0.90 – 2.07)</td><td align="center" valign="middle">14</td><td align="center" valign="middle">10</td> </tr> <tr> <td align="justify" valign="middle">Invasive breast cancer<span class="Sup">c</span></td><td align="center" valign="middle">0.80 (0.62 – 1.04)</td><td align="center" valign="middle">28</td><td align="center" valign="middle">34</td> </tr> <tr> <td align="justify" valign="middle">Colorectal cancer<span class="Sup">g</span></td><td align="center" valign="middle">1.08 (0.75 – 1.55)</td><td align="center" valign="middle">17</td><td align="center" valign="middle">16</td> </tr> <tr> <td align="justify" valign="middle">Hip fracture<span class="Sup">c</span></td><td align="center" valign="middle">0.65 (0.45 – 0.94)</td><td align="center" valign="middle">12</td><td align="center" valign="middle">19</td> </tr> <tr> <td align="justify" valign="middle">Vertebral fractures<span class="Sup">c,d</span></td><td align="center" valign="middle">0.64 (0.44 – 0.93)</td><td align="center" valign="middle">11</td><td align="center" valign="middle">18</td> </tr> <tr> <td align="justify" valign="middle">Lower arm/wrist fractures<span class="Sup">c,d</span></td><td align="center" valign="middle">0.58 (0.47 – 0.72)</td><td align="center" valign="middle">35</td><td align="center" valign="middle">59</td> </tr> <tr> <td align="justify" valign="middle">Total fractures<span class="Sup">c,d</span></td><td align="center" valign="middle">0.71 (0.64 – 0.80)</td><td align="center" valign="middle">144</td><td align="center" valign="middle">197</td> </tr> <tr> <td align="justify" valign="middle">Death due to other causes<span class="Sup">g,f</span></td><td align="center" valign="middle">1.08 (0.88 – 1.32)</td><td align="center" valign="middle">53</td><td align="center" valign="middle">50</td> </tr> <tr> <td align="justify" valign="middle">Overall mortality<span class="Sup">c,d</span></td><td align="center" valign="middle">1.04 (0.88 – 1.22)</td><td align="center" valign="middle">79</td><td align="center" valign="middle">75</td> </tr> <tr class="Last"> <td align="justify" valign="middle">Global index<span class="Sup">g</span></td><td align="center" valign="middle">1.02 (0.91 – 1.13)</td><td align="center" valign="middle">206</td><td align="center" valign="middle">201</td> </tr> </tbody> </table></div>

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, 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 nonsignificant 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. See Table 4.

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 distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.10

Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36–1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46–1.11)].

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 breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years.

For those outcomes included in the WHI "global index" that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 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

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" rowspan="2" valign="middle"><span class="Bold">Event<span class="Sup">c</span></span></td><td align="center" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Relative Risk CE/MPA vs. Placebo</span> </p> <p> <span class="Bold">(95% nCI<span class="Sup">c</span>)</span> </p> </td><td align="center" valign="middle"><span class="Bold">CE/MPA n = 8,506</span></td><td align="center" valign="middle"><span class="Bold">Placebo n = 8,102</span></td> </tr> <tr> <td align="center" colspan="2" valign="middle"><span class="Bold">Absolute Risk per 10,000 Women-Years</span></td> </tr> <tr> <td align="justify" valign="middle"> <p class="First">CHD events</p> <p> <span class="Italics">Non-fatal MI</span> </p> <p> <span class="Italics">CHD death</span> </p> </td><td align="center" valign="middle"> <p class="First">1.23 (0.99 – 1.53)</p> <p> <span class="Italics">1.28 (1.00 – 1.63)</span> </p> <p> <span class="Italics">1.10 (0.70 – 1.75)</span> </p> </td><td align="center" valign="middle"> <p class="First">41</p> <p> <span class="Italics">31</span> </p> <p> <span class="Italics">8</span> </p> </td><td align="center" valign="middle"> <p class="First">34</p> <p> <span class="Italics">25</span> </p> <p> <span class="Italics">8</span> </p> </td> </tr> <tr> <td align="justify" valign="middle">All strokes</td><td align="center" valign="middle">1.31 (1.03 – 1.68)</td><td align="center" valign="middle">33</td><td align="center" valign="middle">25</td> </tr> <tr> <td align="justify" valign="middle"><span class="Italics">Ischemic stroke</span></td><td align="center" valign="middle"><span class="Italics">1.44 (1.09 – 1.90)</span></td><td align="center" valign="middle"><span class="Italics">26</span></td><td align="center" valign="middle"><span class="Italics">18</span></td> </tr> <tr> <td align="justify" valign="middle">Deep vein thrombosis<span class="Sup">d</span></td><td align="center" valign="middle">1.95 (1.43 – 2.67)</td><td align="center" valign="middle">26</td><td align="center" valign="middle">13</td> </tr> <tr> <td align="justify" valign="middle">Pulmonary embolism</td><td align="center" valign="middle">2.13 (1.45 – 3.11)</td><td align="center" valign="middle">18</td><td align="center" valign="middle">8</td> </tr> <tr> <td align="justify" valign="middle">Invasive breast cancer<span class="Sup">g</span></td><td align="center" valign="middle">1.24 (1.01 – 1.54)</td><td align="center" valign="middle">41</td><td align="center" valign="middle">33</td> </tr> <tr> <td align="justify" valign="middle">Colorectal cancer</td><td align="center" valign="middle">0.61 (0.42 – 0.87)</td><td align="center" valign="middle">10</td><td align="center" valign="middle">16</td> </tr> <tr> <td align="justify" valign="middle">Endometrial cancer<span class="Sup">d</span></td><td align="center" valign="middle">0.81 (0.48 – 1.36)</td><td align="center" valign="middle">6</td><td align="center" valign="middle">7</td> </tr> <tr> <td align="justify" valign="middle">Cervical cancer<span class="Sup">d</span></td><td align="center" valign="middle">1.44 (0.47 – 4.42)</td><td align="center" valign="middle">2</td><td align="center" valign="middle">1</td> </tr> <tr> <td align="justify" valign="middle">Hip fracture</td><td align="center" valign="middle">0.67 (0.47 – 0.96)</td><td align="center" valign="middle">11</td><td align="center" valign="middle">16</td> </tr> <tr> <td align="justify" valign="middle">Vertebral fractures<span class="Sup">d</span></td><td align="center" valign="middle">0.65 (0.46 – 0.92)</td><td align="center" valign="middle">11</td><td align="center" valign="middle">17</td> </tr> <tr> <td align="justify" valign="middle">Lower arm/wrist fractures<span class="Sup">d</span></td><td align="center" valign="middle">0.71 (0.59 – 0.85)</td><td align="center" valign="middle">44</td><td align="center" valign="middle">62</td> </tr> <tr> <td align="justify" valign="middle">Total fractures<span class="Sup">d</span></td><td align="center" valign="middle">0.76 (0.69 – 0.83)</td><td align="center" valign="middle">152</td><td align="center" valign="middle">199</td> </tr> <tr> <td align="justify" valign="middle">Overall mortality<span class="Sup">f</span></td><td align="center" valign="middle">1.00 (0.83 – 1.19)</td><td align="center" valign="middle">52</td><td align="center" valign="middle">52</td> </tr> <tr class="Last"> <td align="justify" valign="middle">Global Index<span class="Sup">g</span></td><td align="center" valign="middle">1.13 (1.02 – 1.25)</td><td align="center" valign="middle">184</td><td align="center" valign="middle">165</td> </tr> </tbody> </table></div>

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, colorectal cancer, hip fracture, or death due to other causes.

Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified for 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)].

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 year 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 this study included Alzheimer 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 (5.3), and Use in Specific Populations  (8.5)].

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 per 10,000 women-years. Probable dementia as defined in this 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 (5.3), and Use in Specific Populations (8.5)].

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 (5.3), and Use in Specific Populations (8.5)].

{ "type": "", "children": [], "text": "" }

Estradiol gel 0.1% is a clear, colorless, smooth, opalescent gel supplied in single-dose foil packets of 0.25, 0.5, 0.75, 1.0, and 1.25 grams, corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively.

NDC 70700-143-35, carton of 30 packets, 0.25 mg estradiol per single-dose foil packet

NDC 70700-144-35, carton of 30 packets, 0.5 mg estradiol per single-dose foil packet

NDC 70700-194-35, carton of 30 packets, 0.75 mg estradiol per single-dose foil packet

NDC 70700-145-35, carton of 30 packets, 1.0 mg estradiol per single-dose foil packet

NDC 70700-195-35, carton of 30 packets, 1.25 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.]

Advise women to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

{ "type": "p", "children": [], "text": "Advise women to read the FDA-approved patient labeling (Patient Information and Instructions for Use).\n" }

Vaginal Bleeding

{ "type": "p", "children": [], "text": "\nVaginal Bleeding\n" }

Inform postmenopausal women to report any vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Inform postmenopausal women to report any vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.2)].\n" }

Unintentional Secondary Exposure to Estradiol Gel 0.1%

{ "type": "p", "children": [], "text": "\nUnintentional Secondary Exposure to Estradiol Gel 0.1%\n" }

Inform women about the possibility of secondary exposure to Divigel:

{ "type": "p", "children": [], "text": "Inform women about the possibility of secondary exposure to Divigel:" }

{ "type": "ul", "children": [ "\nApply estradiol gel 0.1% as directed and keep children from contacting exposed application site(s). If direct contact with the application site occurs, wash the contact area thoroughly with soap and water.\n", "\nLook for signs of unexpected sexual development, such as breast mass or increased breast size in prepubertal children.\n", "\nIf signs of unintentional secondary exposure are noticed:\n", "\nHave the child(ren) evaluated by a healthcare provider.\n" ], "text": "" }

{ "type": "ul", "children": [ "\nHave women contact their healthcare provider to discuss the appropriate use and handling of estradiol gel 0.1% when around children.\n", "\nPets may also be unintentionally exposed to estradiol gel 0.1% if above precautions are not followed.\n" ], "text": "" }

Possible Serious Adverse Reactions with Estrogen-Alone Therapy

{ "type": "p", "children": [], "text": "\nPossible Serious Adverse Reactions with Estrogen-Alone Therapy\n" }

Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions  (5.1, 5.2, 5.3)].

{ "type": "p", "children": [], "text": "Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions  (5.1, 5.2, 5.3)].\n" }

Possible Less Serious but Common Adverse Reactions with Estrogen-Alone Therapy

{ "type": "p", "children": [], "text": "\nPossible Less Serious but Common Adverse Reactions with Estrogen-Alone Therapy\n" }

Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headaches, breast pain and tenderness, nausea and vomiting.

{ "type": "p", "children": [], "text": "Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headaches, breast pain and tenderness, nausea and vomiting." }

Estradiol gel 0.1%

{ "type": "p", "children": [], "text": "\nEstradiol gel 0.1%\n" }

Read this Patient Information leaflet before you start using estradiol gel 0.1% 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.

{ "type": "p", "children": [], "text": "Read this Patient Information leaflet before you start using estradiol gel 0.1% 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." }

<div class="scrollingtable"><table> <col/> <tbody class="Headless"> <tr class="First"> <td><span class="Bold">WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT ESTRADIOL GEL 0.1% (AN ESTROGEN HORMONE)?</span></td> </tr> <tr class="Last"> <td> <ul> <li> <p class="First">Using estrogen-alone increases your chance of getting cancer of the uterus (womb).</p> </li> <li> <p class="First">Report any unusual vaginal bleeding right away while you are using estradiol gel 0.1%. 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.</p> </li> <li>Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia (decline of brain function)</li> <li>Using estrogen-alone may increase your chances of getting strokes or blood clots</li> <li>Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age and older</li> <li>Do not use estrogens with progestogens to prevent heart disease, heart attacks, strokes or dementia</li> <li>Using estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots</li> <li>Using estrogens with progestogens may increase your chance of getting dementia, based on a study of women 65 years of age or older</li> <li> <p class="First">Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. Only one estrogen with progestogen product and dose have been shown to increase your chances of getting heart attacks, strokes, breast cancer, blood clots, and dementia. Because other products and doses have not been studied in the same way, it is not known how the use of estradiol gel, 0.1% will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol gel 0.1%.</p> </li> </ul> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td><span class=\"Bold\">WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT ESTRADIOL GEL 0.1% (AN ESTROGEN HORMONE)?</span></td>\n</tr>\n<tr class=\"Last\">\n<td>\n<ul>\n<li>\n<p class=\"First\">Using estrogen-alone increases your chance of getting cancer of the uterus (womb).</p>\n</li>\n<li>\n<p class=\"First\">Report any unusual vaginal bleeding right away while you are using estradiol gel 0.1%. 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.</p>\n</li>\n<li>Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia (decline of brain function)</li>\n<li>Using estrogen-alone may increase your chances of getting strokes or blood clots</li>\n<li>Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age and older</li>\n<li>Do not use estrogens with progestogens to prevent heart disease, heart attacks, strokes or dementia</li>\n<li>Using estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots</li>\n<li>Using estrogens with progestogens may increase your chance of getting dementia, based on a study of women 65 years of age or older</li>\n<li>\n<p class=\"First\">Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. Only one estrogen with progestogen product and dose have been shown to increase your chances of getting heart attacks, strokes, breast cancer, blood clots, and dementia. Because other products and doses have not been studied in the same way, it is not known how the use of estradiol gel, 0.1% will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol gel 0.1%.</p>\n</li>\n</ul>\n</td>\n</tr>\n</tbody>\n</table></div>" }

What is estradiol gel 0.1%?

{ "type": "p", "children": [], "text": "\nWhat is estradiol gel 0.1%?\n" }

Estradiol gel 0.1% is a prescription medicine that contains estradiol (an estrogen hormone). Estradiol gel 0.1% is a clear, colorless, smooth gel that is odorless when dry. When applied to the skin, estradiol is absorbed through the skin into the bloodstream.

{ "type": "p", "children": [], "text": "Estradiol gel 0.1% is a prescription medicine that contains estradiol (an estrogen hormone). Estradiol gel 0.1% is a clear, colorless, smooth gel that is odorless when dry. When applied to the skin, estradiol is absorbed through the skin into the bloodstream." }

What is estradiol gel 0.1% used for?

{ "type": "p", "children": [], "text": "\nWhat is estradiol gel 0.1% used for?\n" }

Estradiol gel 0.1% is used after menopause to:

{ "type": "p", "children": [], "text": "Estradiol gel 0.1% is used after menopause to:" }

{ "type": "ul", "children": [ " Reduce moderate to severe hot flashes " ], "text": "" }

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."

{ "type": "p", "children": [], "text": "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 intense 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.

{ "type": "p", "children": [], "text": "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 intense 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." }

Who should not use estradiol gel 0.1%?

{ "type": "p", "children": [], "text": "\nWho should not use estradiol gel 0.1%?\n" }

Do not start using estradiol gel 0.1% if you:

{ "type": "p", "children": [], "text": "\nDo not start using estradiol gel 0.1% if you:\n" }

{ "type": "ul", "children": [ "\n\nhave any unusual vaginal bleeding\n 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.\n", "\n\nhave been diagnosed with a bleeding disorder\n\n", "\n\ncurrently have or have had certain cancers\nEstrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use estradiol gel 0.1%.\n", "\nhad a stroke or heart attack\n", "\ncurrently have or have had blood clots\n", "\ncurrently have or have had liver problems\n", "\nare allergic to estradiol gel 0.1% or any of its ingredients\nSee the list of ingredients in estradiol gel 0.1% at the end of this leaflet." ], "text": "" }

Before you use estradiol gel 0.1%, tell your healthcare provider about all of your medical conditions, including if you:

{ "type": "p", "children": [], "text": "\nBefore you use estradiol gel 0.1%, tell your healthcare provider about all of your medical conditions, including if you:\n" }

{ "type": "ul", "children": [ "\nhave any unusual vaginal bleeding\nVaginal 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.", "\n\nhave any other medical conditions that may become worse while you are using estradiol gel 0.1%\nYour healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraines, endometriosis, lupus, angioedema (swelling of face and tongue), problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.\n", "\n\nare going to have surgery or will be on bedrest\nYour healthcare provider will let you know if you need to stop using estradiol gel 0.1%.\n", "\n\nare pregnant or think you may be pregnant\nEstradiol gel 0.1% is not for pregnant women.\n", "\nare breastfeeding\nThe hormone in estradiol gel 0.1% can pass into your breast milk." ], "text": "" }

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how estradiol gel 0.1% works. Estradiol gel 0.1% 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 new medicine.

{ "type": "p", "children": [], "text": "\nTell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how estradiol gel 0.1% works. Estradiol gel 0.1% 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 new medicine." }

How should I use estradiol gel 0.1%?

{ "type": "p", "children": [], "text": "\nHow should I use estradiol gel 0.1%?\n" }

{ "type": "ul", "children": [ "Take the dose recommended by your healthcare provider and talk to him or her about how well that dose is working for you.", "Estrogens should be used at the lowest dose possible for your treatment and only as long as needed." ], "text": "" }

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 estradiol gel 0.1%.

{ "type": "p", "children": [], "text": "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 estradiol gel 0.1%." }

How should estradiol gel 0.1% be applied?

{ "type": "p", "children": [], "text": "\nHow should estradiol gel 0.1% be applied?\n" }

{ "type": "ul", "children": [ "\nEstradiol gel 0.1% should be applied 1-time a day, around the same time each day.\n", "Apply estradiol gel 0.1% to clean, dry, and unbroken (without cuts or scrapes) skin. If you take a bath or shower, be sure to apply your estradiol gel 0.1% after your skin is dry. The application site should be completely dry before dressing or swimming.", "Apply estradiol gel 0.1% to either your left or right upper thigh. Change between your left and right upper thigh each day to help prevent skin irritation." ], "text": "" }

TO APPLY:

{ "type": "p", "children": [], "text": "\nTO APPLY:\n" }

Step 1: Wash and dry your hands thoroughly.

{ "type": "p", "children": [], "text": "\nStep 1: Wash and dry your hands thoroughly. " }

Step 2: Sit in a comfortable position.

{ "type": "p", "children": [], "text": "\nStep 2: Sit in a comfortable position. " }

Step 3: Cut or tear the estradiol gel 0.1% packet as shown in Figure A.

{ "type": "p", "children": [], "text": "\nStep 3: Cut or tear the estradiol gel 0.1% packet as shown in Figure A. " }

Figure A

{ "type": "p", "children": [], "text": "\nFigure A\n" }

Step 4: Using your thumb and pointer (index) finger, squeeze the entire contents of the estradiol gel 0.1% packet onto the skin of the upper thigh as shown in Figure B.

{ "type": "p", "children": [], "text": "\nStep 4: Using your thumb and pointer (index) finger, squeeze the entire contents of the estradiol gel 0.1% packet onto the skin of the upper thigh as shown in Figure B." }

Figure B

{ "type": "p", "children": [], "text": "\nFigure B\n" }

Step 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 Figure C. It is not necessary to massage or rub in estradiol gel 0.1%.

{ "type": "p", "children": [], "text": "\nStep 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 Figure C. It is not necessary to massage or rub in estradiol gel 0.1%. " }

Figure C

{ "type": "p", "children": [], "text": "\nFigure C\n" }

Step 6: Allow the gel to dry completely before dressing.

{ "type": "p", "children": [], "text": "\nStep 6: Allow the gel to dry completely before dressing. " }

Step 7: Throw away (dispose) of the empty estradiol gel 0.1% packet in the trash.

{ "type": "p", "children": [], "text": "\nStep 7: Throw away (dispose) of the empty estradiol gel 0.1% packet in the trash. " }

Step 8: Wash your hands with soap and water immediately after applying estradiol gel 0.1% to remove any remaining gel and reduce the chance of transferring estradiol gel 0.1% to other people.

{ "type": "p", "children": [], "text": "\nStep 8: Wash your hands with soap and water immediately after applying estradiol gel 0.1% to remove any remaining gel and reduce the chance of transferring estradiol gel 0.1% to other people. " }

Important things to remember when using estradiol gel 0.1%

{ "type": "p", "children": [], "text": "\nImportant things to remember when using estradiol gel 0.1%\n" }

{ "type": "ul", "children": [ "Allow the gel to dry before dressing. Try to keep the area dry for as long as possible.", "Do not allow another person to come in contact with the area of skin where you applied the gel for at least 1 hour after you apply estradiol gel 0.1%.", "You should not have another person to apply the gel for you. However, if you need to have another person help you, have that person wear a disposable plastic glove to avoid direct contact with estradiol gel 0.1%.", "Do not apply estradiol gel 0.1% to your face, breast, or irritated skin.", "Never apply estradiol gel 0.1% in or around the vagina.", "\n\nEstradiol gel 0.1% contains alcohol. Alcohol based gels are flammable. Avoid fire, flame or smoking until the gel has dried.\n\n" ], "text": "" }

What should I do if I miss a dose?

{ "type": "p", "children": [], "text": "\nWhat should I do if I miss a dose?\n" }

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 estradiol gel 0.1% more than 1-time each day. If you accidentally spill some of the contents of an estradiol gel 0.1% packet, do not open a new estradiol gel 0.1% packet. Wait and apply your normal dose the next day.

{ "type": "p", "children": [], "text": "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 estradiol gel 0.1% more than 1-time each day. If you accidentally spill some of the contents of an estradiol gel 0.1% packet, do not open a new estradiol gel 0.1% packet. Wait and apply your normal dose the next day." }

What should I do if someone else is exposed to estradiol gel 0.1%?

{ "type": "p", "children": [], "text": "\nWhat should I do if someone else is exposed to estradiol gel 0.1%?\n" }

To reduce the chance of transfer to another person (or pet) let the estradiol gel 0.1% dry completely. Wash your hands with soap and water after application. If someone else is exposed to estradiol gel 0.1% by direct contact with the wet gel, have that person wash the area of contact with soap and water right away. This is especially important for men and children. The longer the gel is in contact with the skin before washing, the greater the chance that the other person (or pet) will absorb some of the estrogen hormone. This may harm them. In case of any signs or symptoms of estrogen exposure in the other person (or pet), contact your healthcare provider (or veterinarian, if appropriate).

{ "type": "p", "children": [], "text": "To reduce the chance of transfer to another person (or pet) let the estradiol gel 0.1% dry completely. Wash your hands with soap and water after application. If someone else is exposed to estradiol gel 0.1% by direct contact with the wet gel, have that person wash the area of contact with soap and water right away. This is especially important for men and children. The longer the gel is in contact with the skin before washing, the greater the chance that the other person (or pet) will absorb some of the estrogen hormone. This may harm them. In case of any signs or symptoms of estrogen exposure in the other person (or pet), contact your healthcare provider (or veterinarian, if appropriate)." }

What should I do if I get estradiol gel 0.1% in my eyes?

{ "type": "p", "children": [], "text": "\nWhat should I do if I get estradiol gel 0.1% in my eyes?\n" }

If you get estradiol gel 0.1% in your eyes, flush your eyes right away with lukewarm tap water. If you have concerns, contact your healthcare provider.

{ "type": "p", "children": [], "text": "If you get estradiol gel 0.1% 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 estradiol gel 0.1%?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of estradiol gel 0.1%?\n" }

Side effects are grouped by how serious they are and how often they happen when you are treated.

{ "type": "p", "children": [], "text": "\nSide effects are grouped by how serious they are and how often they happen when you are treated.\n" }

Serious, but less common side effects include:

{ "type": "p", "children": [], "text": "\nSerious, but less common side effects include:\n" }

<div class="scrollingtable"><table> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td valign="top"> <ul> <li> <p class="First">heart attack</p> </li> </ul> </td><td valign="top"> <ul> <li> <p class="First">high levels of fat (triglycerides) in your blood</p> </li> </ul> </td> </tr> <tr> <td valign="top"> <ul> <li> <p class="First">stroke</p> </li> </ul> </td><td valign="top"> <ul> <li> <p class="First">liver problems</p> </li> </ul> </td> </tr> <tr> <td valign="top"> <ul> <li> <p class="First">blood clots</p> </li> </ul> </td><td valign="top"> <ul> <li> <p class="First">changes in your thyroid hormone levels</p> </li> </ul> </td> </tr> <tr> <td valign="top"> <ul> <li> <p class="First">breast cancer</p> </li> </ul> </td><td valign="top"> <ul> <li> <p class="First">fluid retention</p> </li> </ul> </td> </tr> <tr> <td valign="top"> <ul> <li> <p class="First">cancer of the lining of the uterus (womb)</p> </li> </ul> </td><td valign="top"> <ul> <li> <p class="First">cancer change of endometriosis</p> </li> </ul> </td> </tr> <tr> <td valign="top"> <ul> <li> <p class="First">cancer of the ovary</p> </li> </ul> </td><td valign="top"> <ul> <li> <p class="First">enlargement of benign tumors of the uterus (“fibroids”)</p> </li> </ul> </td> </tr> <tr> <td valign="top"> <ul> <li> <p class="First">dementia</p> </li> </ul> </td><td valign="top"> <ul> <li> <p class="First">worsening swelling of face and tongue (angioedema)</p> </li> </ul> </td> </tr> <tr> <td valign="top"> <ul> <li> <p class="First">high or low blood calcium (hypercalcemia)</p> </li> </ul> </td><td valign="top"> <ul> <li> <p class="First">changes in certain laboratory test results such as high blood sugar</p> </li> </ul> </td> </tr> <tr> <td valign="top"> <ul> <li> <p class="First">gall bladder disease</p> </li> </ul> </td><td valign="top"></td> </tr> <tr> <td valign="top"> <ul> <li> <p class="First">visual abnormalities</p> </li> </ul> </td><td valign="top"></td> </tr> <tr class="Last"> <td valign="top"> <ul> <li> <p class="First">high blood pressure</p> </li> </ul> </td><td valign="top"></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">heart attack</p>\n</li>\n</ul>\n</td><td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">high levels of fat (triglycerides) in your blood</p>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">stroke</p>\n</li>\n</ul>\n</td><td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">liver problems</p>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">blood clots</p>\n</li>\n</ul>\n</td><td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">changes in your thyroid hormone levels</p>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">breast cancer</p>\n</li>\n</ul>\n</td><td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">fluid retention</p>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">cancer of the lining of the uterus (womb)</p>\n</li>\n</ul>\n</td><td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">cancer change of endometriosis</p>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">cancer of the ovary</p>\n</li>\n</ul>\n</td><td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">enlargement of benign tumors of the uterus (“fibroids”)</p>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">dementia</p>\n</li>\n</ul>\n</td><td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">worsening swelling of face and tongue (angioedema)</p>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">high or low blood calcium (hypercalcemia)</p>\n</li>\n</ul>\n</td><td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">changes in certain laboratory test results such as high blood sugar</p>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">gall bladder disease</p>\n</li>\n</ul>\n</td><td valign=\"top\"></td>\n</tr>\n<tr>\n<td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">visual abnormalities</p>\n</li>\n</ul>\n</td><td valign=\"top\"></td>\n</tr>\n<tr class=\"Last\">\n<td valign=\"top\">\n<ul>\n<li>\n<p class=\"First\">high blood pressure</p>\n</li>\n</ul>\n</td><td valign=\"top\"></td>\n</tr>\n</tbody>\n</table></div>" }

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

{ "type": "p", "children": [], "text": "\nCall your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:\n" }

{ "type": "ul", "children": [ "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", "\nswelling of face, lips, and tongue with or without red, itchy bumps\n" ], "text": "" }

The most common side effects of estradiol gel 0.1% include:

{ "type": "p", "children": [], "text": "\nThe most common side effects of estradiol gel 0.1% include:\n" }

{ "type": "ul", "children": [ "irregular vaginal bleeding or spotting", "breast tenderness", "vaginal yeast infection", "\nupper respiratory tract (nose, sinuses, pharynx or larynx) infection\n" ], "text": "" }

These are not all the possible side effects of estradiol gel 0.1%. For more information, ask your healthcare provider or pharmacist for advice about side effects. Tell your healthcare provider if you have any side effects that bother you or do not go away.

{ "type": "p", "children": [], "text": "These are not all the possible side effects of estradiol gel 0.1%. For more information, ask your healthcare provider or pharmacist for advice about side effects. Tell your healthcare provider if you have any side effects that bother you or do not go away." }

You may report side effects to  Xiromed, LLC. at 844-XIROMED (844-947-6633) or to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "You may report side effects to  Xiromed, LLC. at 844-XIROMED (844-947-6633) or to FDA at 1-800-FDA-1088." }

What can I do to lower my chances of a serious side effect with estradiol gel 0.1%?

{ "type": "p", "children": [], "text": "\nWhat can I do to lower my chances of a serious side effect with estradiol gel 0.1%?\n" }

{ "type": "ul", "children": [ "Talk with your healthcare provider regularly about whether you should continue using estradiol gel 0.1%.", "If you have a uterus, talk to your healthcare provider about whether the addition of a progestogen is right for you.", "\nIn general, the addition of a progestogen is recommended for a woman 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 estradiol gel 0.1%.\n", "Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. ", "\nIf 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.\n", "\nIf 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.\n" ], "text": "" }

Ask your healthcare provider for ways to lower your chances of getting heart disease.

{ "type": "p", "children": [], "text": "Ask your healthcare provider for ways to lower your chances of getting heart disease." }

How should I store estradiol gel 0.1%?

{ "type": "p", "children": [], "text": "\nHow should I store estradiol gel 0.1%?\n" }

Store estradiol gel 0.1% packets at room temperature, 68° to 77 °F (20° to 25 °C).

{ "type": "p", "children": [], "text": "Store estradiol gel 0.1% packets at room temperature, 68° to 77 °F (20° to 25 °C)." }

Keep estradiol gel 0.1% and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep estradiol gel 0.1% and all medicines out of the reach of children.\n" }

General information about safe and effective use of estradiol gel 0.1%.

{ "type": "p", "children": [], "text": "\nGeneral information about safe and effective use of estradiol gel 0.1%.\n" }

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use estradiol gel 0.1% for a condition for which it was not prescribed. Do not give estradiol gel 0.1% to other people, even if they have the same symptoms that you have. It may harm them.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use estradiol gel 0.1% for a condition for which it was not prescribed. Do not give estradiol gel 0.1% to other people, even if they have the same symptoms that you have. It may harm them." }

This leaflet provides a summary of the most important information about estradiol gel 0.1%. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your healthcare provider or pharmacist for information about estradiol gel 0.1% that is written for health professionals.

{ "type": "p", "children": [], "text": "This leaflet provides a summary of the most important information about estradiol gel 0.1%. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your healthcare provider or pharmacist for information about estradiol gel 0.1% that is written for health professionals." }

What are the ingredients in estradiol gel 0.1%?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in estradiol gel 0.1%?\n" }

Active ingredient: estradiol.

{ "type": "p", "children": [], "text": "\nActive ingredient: estradiol." }

Inactive ingredients: carbomer, ethanol, propylene glycol, purified water, and triethanolamine.

{ "type": "p", "children": [], "text": "\nInactive ingredients: carbomer, ethanol, propylene glycol, purified water, and triethanolamine." }

Contains: 58.6% alcohol.

{ "type": "p", "children": [], "text": "\nContains: 58.6% alcohol." }

How is estradiol gel 0.1% Supplied?

{ "type": "p", "children": [], "text": "\nHow is estradiol gel 0.1% Supplied?\n" }

Estradiol gel 0.1% is supplied in individual foil packets, each one containing a single day's dose.

{ "type": "p", "children": [], "text": "Estradiol gel 0.1% is supplied in individual foil packets, each one containing a single day's dose." }

Manufactured by Laboratorios Leon Farma, S.A. P.I de Navatejera, Calle la Vallina, s/n, 24193 Villaquilambre, Leon, Spain

{ "type": "p", "children": [], "text": "Manufactured by Laboratorios Leon Farma, S.A. P.I de Navatejera, Calle la Vallina, s/n, 24193 Villaquilambre, Leon, Spain " }

Distributed by Xiromed, LLC Florham Park, NJ 07932 www.xiromed.com Customer Service: 844-XIROMED (844-947-6633)

{ "type": "p", "children": [], "text": "Distributed by \nXiromed, LLC\nFlorham Park, NJ 07932 www.xiromed.com Customer Service: 844-XIROMED (844-947-6633)\n" }

Product of Spain

{ "type": "p", "children": [], "text": "Product of Spain" }

PI-145-03 Revised: 06/2025

{ "type": "p", "children": [], "text": "PI-145-03 Revised: 06/2025" }

This Patient Information has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration." }

PRINCIPAL DISPLAY PANEL - 1.25 mg Packet Carton

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL - 1.25 mg Packet Carton\n" }

NDC 70700-195-35

{ "type": "p", "children": [], "text": "NDC 70700-195-35" }

Estadiol Gel 0.1% - 1.25 mg

{ "type": "p", "children": [], "text": "Estadiol Gel 0.1% - 1.25 mg\n" }

30 packets 1.25 g gel provides 1.25 mg estradiol/packet

{ "type": "p", "children": [], "text": "30 packets 1.25 g gel provides 1.25 mg estradiol/packet " }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Xiromed LLC.

{ "type": "p", "children": [], "text": "Xiromed LLC." }

PRINCIPAL DISPLAY PANEL - 1 mg Packet Carton

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL - 1 mg Packet Carton\n" }

NDC 70700-145-35

{ "type": "p", "children": [], "text": "NDC 70700-145-35" }

Estadiol Gel 0.1% - 1 mg

{ "type": "p", "children": [], "text": "Estadiol Gel 0.1% - 1 mg\n" }

30 packets 1 g gel provides 1 mg estradiol/packet

{ "type": "p", "children": [], "text": "30 packets 1 g gel provides 1 mg estradiol/packet " }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Xiromed LLC.

{ "type": "p", "children": [], "text": "Xiromed LLC." }

PRINCIPAL DISPLAY PANEL - 0.75 mg Packet Carton

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL - 0.75 mg Packet Carton\n" }

NDC 70700-194-35

{ "type": "p", "children": [], "text": "NDC 70700-194-35" }

Estadiol Gel 0.1% - 0.75 mg

{ "type": "p", "children": [], "text": "Estadiol Gel 0.1% - 0.75 mg\n" }

30 packets 0.75 g gel provides 0.75 mg estradiol/packet

{ "type": "p", "children": [], "text": "30 packets 0.75 g gel provides 0.75 mg estradiol/packet " }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Xiromed LLC.

{ "type": "p", "children": [], "text": "Xiromed LLC." }

PRINCIPAL DISPLAY PANEL - 0.5 mg Packet Carton

{ "type": "p", "children": [], "text": "PRINCIPAL DISPLAY PANEL - 0.5 mg Packet Carton" }

NDC 70700-144-35

{ "type": "p", "children": [], "text": "NDC 70700-144-35" }

Estradiol Gel 0.1%- 0.5 mg

{ "type": "p", "children": [], "text": "\nEstradiol Gel 0.1%- 0.5 mg\n" }

30 packets 0.5 g gel provides 0.5 mg estradiol/packet

{ "type": "p", "children": [], "text": "30 packets 0.5 g gel provides 0.5 mg estradiol/packet " }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Xiromed LLC.

{ "type": "p", "children": [], "text": "Xiromed LLC." }

PRINCIPAL DISPLAY PANEL - 0.25 mg Packet Carton

{ "type": "p", "children": [], "text": "PRINCIPAL DISPLAY PANEL - 0.25 mg Packet Carton" }

NDC 70700-143-35

{ "type": "p", "children": [], "text": "NDC 70700-143-35" }

Estradiol Gel 0.1% - 0.25 mg

{ "type": "p", "children": [], "text": "\nEstradiol Gel 0.1% - 0.25 mg\n" }

30 packets 0.25 g gel provides 0.25 mg estradiol/packet

{ "type": "p", "children": [], "text": "30 packets 0.25 g gel provides 0.25 mg estradiol/packet " }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Xiromed, LLC.

{ "type": "p", "children": [], "text": "Xiromed, LLC." }