DailyMed Label: IMVEXXY

DailyMed Label: Imvexxy

2024

DailyMed Prescription

Imvexxy

estradiol

Mayne Pharma

NDC: 68308-747

NDC: 68308-747

NDC: 68308-747

NDC: 68308-747

NDC: 68308-747

NDC: 68308-747

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 C 18 H 24 O 2 with a molecular weight of 272.38. 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. Chemical Structure

IMVEXXY is an estrogen indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. ( 1 ):

Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, consider addition of a progestogen to reduce the risk of endometrial cancer. Generally, a woman without a uterus does not need to use a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women with a history of endometriosis may need a progestogen [see Warnings and Precautions (5.3 , 5.15) ]. Use estrogen-alone, or in combination with a progestogen, at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Re-evaluate postmenopausal women periodically as clinically appropriate to determine if treatment is still necessary. Administer IMVEXXY intravaginally: 1 vaginal insert daily for 2 weeks, followed by 1 insert twice weekly (for example, Monday and Thursday). ( 2.1 ) 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. Vaginal inserts: 4 mcg or 10 mcg estradiol. ( 3 )

IMVEXXY is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding [see Warning and Precautions (5.3) ]. Breast cancer or a history of breast cancer [see Warnings and Precautions (5.3) ]. Estrogen-dependent neoplasia [see Warnings and Precautions (5.3) ]. Active DVT, PE, or history of these conditions [see Warnings and Precautions (5.2) ]. Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions [see Warnings and Precautions (5.2) ]. Known anaphylactic reaction, angioedema, or hypersensitivity to IMVEXXY. Hepatic impairment or disease. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. Undiagnosed abnormal genital bleeding ( 4 , 5.3 ) Breast cancer or a history of breast cancer ( 4 , 5.3 ) Estrogen-dependent neoplasia ( 4 , 5.3 ) Active DVT, PE, or history of these conditions ( 4 , 5.2 ) Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions ( 4 , 5.2 ) Known anaphylactic reaction, angioedema, or hypersensitivity to IMVEXXY ( 4 ) Hepatic impairment or disease ( 4 , 5.11 ) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 )

Estrogens increase the risk of gallbladder disease ( 5.5 ) Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia, or cholestatic jaundice occurs. ( 5.6 , 5.7 , 5.10 , 5.11 ) Monitor thyroid function in women on thyroid replacement hormone therapy ( 5.12 , 5.19 ) 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 placebo 2 [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 years 3 [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 persisted 4 [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-years 8 [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-years 8 [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 women 8 [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. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and betathromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone. Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels. Impaired glucose tolerance.

The following serious adverse reactions are discussed elsewhere in the labeling:

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. Inducers and inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. ( 7 )

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 women 8 [see Warnings and Precautions (5.4) , and Clinical Studies (14.3) ].

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. IMVEXXY 4 mcg 8 inserts NDC 68308-747-08 IMVEXXY 4 mcg 18 inserts NDC 68308-747-18 IMVEXXY 10 mcg 8 inserts NDC 68308-748-08 IMVEXXY 10 mcg 18 inserts NDC 68308-748-18 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.]

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 C avg (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 Table 2: Arithmetic Mean (SD) of Estradiol and Estrone Pharmacokinetic Parameters Following 14 Daily Doses – Unadjusted for Baseline Estradiol Estrone C max (pg/mL) C avg (0—24) (pg/mL) C max (pg/mL) C avg (0—24) (pg/mL) 4 mcg 4.8 (2.3) 3.6 (1.8) 16.0 (5.5) 13.6 (4.8) 10 mcg 7.3 (2.4) 4.6 (2.3) 23.9 (13.5) 19.3 (10.2) Placebo 5.5 (3.4) 4.3 (2.8) 22.8 (10.9) 17.8 (7.5) 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. Figure 1 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). 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) Most Bothersome Moderate to Severe Symptom at Baseline IMVEXXY 4 mcg (N = 151) IMVEXXY 10 mcg (N = 154) Placebo (N = 163) 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 > 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 Dyspareunia Baseline Mean (SD) 2.7 (0.48) 2.6 (0.48) 2.7 (0.46) LS Mean Change from Baseline (SE) -1.52 (0.071) -1.69 (0.071) -1.28 (0.070) p-value vs. placebo 0.0149 <0.0001 ----- 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. Table 4: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. Event Relative Risk CE vs Placebo (95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ) CE N = 5,310 Placebo N = 5,429 Absolute Risk per 10,000 Women-Years CHD events Results are based on centrally adjudicated data for an average follow-up of 7.1 years. Non-fatal MI CHD death 0.95 (0.78-1.16) 0.91 (0.73-1.14) 1.01 (0.71-1.43) 54 40 16 57 43 16 All Strokes Ischemic stroke 1.33 (1.05-1.68) 1.55(1.19-2.01) 45 38 33 25 Deep vein thrombosis , Not included in "global index." 1.47 (1.06-2.06) 23 15 Pulmonary embolism 1.37 (0.90-2.07) 14 10 Invasive breast cancer 0.80 (0.62-1.04) 28 34 Colorectal cancer 1.08 (0.75-1.55) 17 16 Hip fracture 0.65 (0.45-0.94) 12 19 Vertebral fractures , 0.64 (0.44-0.93) 11 18 Lower arm/wrist fracture , 0.58 (0.47-0.72) 35 59 Total fractures , 0.71 (0.64-0.80) 144 197 Death due to other causes Results are based on an average follow-up of 6.8 years. , All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.08 (0.88-1.32) 53 50 Overall mortality , 1.04 (0.88-1.22) 79 75 Global Index 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. 1.02 (0.92-1.13) 206 201 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. Table 5: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. . Results are based on centrally adjudicated data. Event Relative Risk CE/MPA vs Placebo (95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ) CE/MPA N = 8.506 Placebo N = 8,102 Absolute Risk per 10,000 Women-Years CHD events Non-fatal MI CHD death 1.23 (0.99-1.53) 1.28 (1.00-1.63) 1.10 (0.70-1.75) 41 31 8 34 25 8 All Strokes Ischemic stroke 1.31 (1.03-1.68) 1.44 (1.09-1.90) 33 26 25 18 Deep vein thrombosis Not included in "global index." 1.95 (1.43-2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive breast cancer Includes metastatic and non-metastatic breast cancer with the exception of in situ cancer. 1.24 (1.01-1.54) 41 33 Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancer 0.81 (0.48-1.36) 6 7 Cervical cancer 1.44 (0.47-4.42) 2 1 Hip fracture 0.67 (0.47-0.96) 11 16 Vertebral fractures 0.65 (0.46-0.92) 11 17 Lower arm/wrist fracture 0.71 (0.59-0.85) 44 62 Total fractures 0.76 (0.69-0.83) 152 199 Overall mortality , All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.00 (0.83-1.19) 52 52 Global Index 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. 1.13 (1.02-1.25) 184 165 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) ].

PATIENT INFORMATION IMVEXXY (ĭm vex' ee) (estradiol vaginal inserts) 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. What is the most important information I should know about IMVEXXY (an estrogen hormone)? Using estrogen-alone may increase your chance of getting cancer of the uterus (womb). Report any unusual vaginal bleeding right away while you are using 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. Do not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline of brain function). Using estrogen-alone may increase your chances of getting strokes or blood clots. Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age and older. Do not use estrogens with progestogens to prevent heart disease, heart attacks, strokes or dementia. Using estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. Using estrogens with progestogens may increase your chance of getting dementia, based on a study of women 65 years of age and older. 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. You and your healthcare provider should talk regularly about whether you still need treatment with IMVEXXY. What is IMVEXXY? IMVEXXY is a prescription medicine that contains an estrogen hormone in a vaginal insert. What is IMVEXXY used for? IMVEXXY is used after menopause to treat moderate to severe painful intercourse, a symptom of changes in and around your vagina, due to menopause. Who should not use IMVEXXY? Do not start using IMVEXXY if you: have unusual vaginal bleeding. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. have been diagnosed with a bleeding disorder. currently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use IMVEXXY. currently have or have had blood clots. had a stroke or heart attack. currently have or have had liver problems. are allergic to IMVEXXY or any of its ingredients. See the list of ingredients in IMVEXXY at the end of this leaflet. Before you use IMVEXXY, tell your healthcare provider about all of your medical conditions, including if you: have any unusual vaginal bleeding. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding or spotting to find out the cause. have any other medical conditions that may become worse while you are using IMVEXXY. 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. are going to have surgery or will be on bed rest. You may need to stop using IMVEXXY. are pregnant or think you may be pregnant. Imvexxy is not for pregnant women. are breast feeding. The hormone in IMVEXXY can pass into your breast milk. 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 IMVEXXY works. 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. How should I use IMVEXXY? For detailed instructions, see the step-by-step instructions for using IMVEXXY at the end of this Patient Information. Use IMVEXXY exactly as your healthcare provider tells you to use it. IMVEXXY is a vaginal insert that you place in your vagina. IMVEXXY is only for use in the vagina. Do not take IMVEXXY by mouth (orally). Estrogens should be used at the lowest dose possible for your treatment and for only as long as needed. 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. 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. What are the possible side effects of IMVEXXY? Side effects are grouped by how serious they are and how often they happen when you are treated. Serious, but less common side effects could include: heart attack breast cancer dementia gallbladder disease high levels of fat (triglyceride) in your blood enlargement of benign tumors of the uterus ("fibroids") stroke cancer of the lining of the uterus (womb) high or low blood calcium visual abnormalities liver problems worsening of swelling of face and tongue (angioedema) in women with a history of angioedema  blood clots cancer of the ovary high blood pressure changes in your thyroid hormone levels Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you: new breast lumps unusual vaginal bleeding changes in vision or speech sudden, new, severe headaches severe pains in your chest or legs with or without shortness of breath, weakness, and fatigue Common side effects of IMVEXXY include: headache breast tenderness or pain nausea and vomiting 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. 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. What can I do to lower my chances of a serious side effect with IMVEXXY? Talk with your healthcare provider regularly about whether you should continue using IMVEXXY. 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. See your healthcare provider right away if you get vaginal bleeding while using ® IMVEXXY. 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. 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. General information about the safe and effective use of IMVEXXY. 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 What are the ingredients in IMVEXXY? Active ingredient: IMVEXXY (estradiol vaginal inserts) are small, light pink, tear-shaped inserts that contain estradiol. Inactive ingredients:  Each insert also contains 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. IMVEXXY is supplied in blister cartons of 18 or 8 vaginal inserts.

NDC 68308-747-08 Rx only Imvexxy ® 4 mcg (estradiol vaginal inserts) FOR VAGINAL USE ONLY 8 vaginal inserts mayne pharma PRINCIPAL DISPLAY PANEL - 8 Insert Blister Pack Carton