IMVEXXY

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning , Warnings and Precautions (5.2) ]. Malignant Neoplasms [see Boxed Warning , Warnings and Precautions (5.3) ] . The most common adverse reaction with IMVEXXY (incidence ≥ 3% and greater than placebo) is headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact TherapeuticsMD, Inc. at 1-888-228- 0150 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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. Table 1: Treatment-Emergent Adverse Reactions Reported at a Frequency of ≥ 3% and Numerical y More Common in Women Receiving IMVEXXY Preferred Term IMVEXXY 4 mcg (N = 191) IMVEXXY 10 mcg (N = 191) Placebo (N = 192) Nervous system disorders, n (%) Headache 7 (3.7) 5 (2.6) 6 (3.1) 6.2 Postmarketing Experience 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.

4 CONTRAINDICATIONS 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 )

11 DESCRIPTION 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

2 DOSAGE AND ADMINISTRATION 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 ) 2.1 Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, Due to Menopause 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.

1 INDICATIONS AND USAGE IMVEXXY is an estrogen indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause ( 1 ). 1.1 Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, Due to Menopause

10 OVERDOSAGE 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.

7 DRUG INTERACTIONS In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John's wort (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 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. 12.2 Pharmacodynamics 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. 12.3 Pharmacokinetics 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.

12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

12.2 Pharmacodynamics 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.

12.3 Pharmacokinetics 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.

20231212

8

3 DOSAGE FORMS AND STRENGTHS 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 estradiol estradiol estradiol Medium-chain triglycerides PEG-6 stearate PEG-32 stearate Glycol stearate Gelatin, unspecified Sorbitol Sorbitan Mannitol Glycerin FD&C Red No. 40 Titanium dioxide Water Ethyl acetate Propylene glycol Polyvinyl acetate phthalate Isopropyl alcohol Polyethylene glycol, unspecified Ammonia Alcohol Lecithin, soybean light pink TEAR 04 IMVEXXY estradiol estradiol estradiol Medium-chain triglycerides PEG-6 stearate PEG-32 stearate Glycol stearate Gelatin, unspecified Sorbitol Sorbitan Mannitol Glycerin FD&C Red No. 40 Titanium dioxide Water Ethyl acetate Propylene glycol Polyvinyl acetate phthalate Isopropyl alcohol Polyethylene glycol, unspecified Ammonia Alcohol Lecithin, soybean light pink TEAR 10

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

NDA208564

IMVEXXY

estradiol

50261-104

HUMAN PRESCRIPTION DRUG

VAGINAL

Principal Display Panel - Imvexxy 4 mcg 8 Count Carton Label NDC 50261-104-08 Rx only Imvexxy ® 4 mcg (estradiol vaginal inserts) TherapeuticsMD ® 8 vaginal inserts FOR VAGINAL USE ONLY Principal Display Panel - Imvexxy 4 mcg 8 Count Carton Label

Boxed Warning 11/2021 Warnings and Precautions, Malignant Neoplasms ( 5.3 ) 11/2023

17 PATIENT COUNSELING INFORMATION Advise women to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Vaginal Bleeding Inform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (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.

Instructions For Use IMVEXXY® (ĭm vex' ee) (estradiol vaginal inserts) 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? 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. Step 1: Push 1 IMVEXXY insert through the foil of the blister package. Figure A Step 2: Hold the IMVEXXY insert with the larger end between your fingers. Figure B 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. Figure C or Figure D If you have any questions, please ask your healthcare provider or pharmacist. How should I store IMVEXXY? Store IMVEXXY at room temperature between 68°F to 77°F (20°C to 25°C). IMVEXXY packaging is not child-resistant. Keep IMVEXXY and al medicines out of the reach of children. For information, go to TherapeuticsMD.com or call TherapeuticsMD, Inc. at 1-877-833- 0176 Manufactured for: TherapeuticsMD, Inc., Boca Raton, FL 33431 For patent information, go to TherapeuticsMD.com/patents IMVEXXY is a registered trademark of TherapeuticsMD, Inc. © TherapeuticsMD, Inc. All rights reserved. The Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration. Revised: 11/2023 Figure A Figure B Figure C Figure D

14 CLINICAL STUDIES 14.1 Effects on Moderate to Severe Dyspareunia in Postmenopausal Women 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 enrollee 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 ------ 14.2 Women's Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms. WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 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 A l 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 fractures , 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 A l 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 fractures 0.71 (0.59-0.85) 44 62 Total fractures 0.76 (0.69-0.83) 152 199 Overa l 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)]. 14.3 Women's Health Initiative Memory Study 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) ].

15 REFERENCES Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007; 297:1465-1477. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006; 166:357-365. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006; 166:772-780. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004; 292:1573-1580. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women with Hysterectomy. JAMA. 2006; 295:1647-1657. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003; 289:3243-3253. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003; 290:1739-1748. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004; 291:2947-2958. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women with Hysterectomy: Results from the Women's Health Initiative Randomized Trial. J Bone Miner Res. 2006; 21:817-828. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation. 2006; 113:2425-2434.

8.5 Geriatric Use 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) ] .

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

8.1 Pregnancy 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 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. 8.2 Lactation 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 breast- feeding 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. 8.4 Pediatric Use IMVEXXY is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population. 8.5 Geriatric Use 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) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 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 push- through 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 50261-104-08 IMVEXXY 4 mcg 18 inserts NDC 50261-104-18 IMVEXXY 10 mcg 8 inserts NDC 50261-110-08 IMVEXXY 10 mcg 18 inserts NDC 50261-110-18 Keep out of reach of children. Packages are not child-resistant. 16.2 Storage and Handling Store at 20°C to 25ºC (68°F to 77ºF), excursions permitted to 15ºC to 30ºC (59ºF to 86ºF). [See USP Controlled Room Temperature.]

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

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, and BREAST CANCER WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, and BREAST CANCER See full prescribing information for complete boxed warning. Estrogen-Alone Therapy There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens ( 5.3 ) The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) ( 5.2 ) The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older ( 5.4 ) Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia ( 5.2 , 5.4 ) Estrogen Plus Progestin Therapy The WHI estrogen plus progestin substudy reported increased risks of stroke, DVT, pumlonary embolism (PE) and myocardial infarction (MI) ( 5.2 ) The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer ( 5.3 ) The WHIMS estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older ( 5.4 ) Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia ( 5.2 , 5.4 ) Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. 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 [see Warnings and Precautions (5.3) ]. Cardiovascular Disorders and Probable Dementia The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo [see Warnings and Precautions (5.2) , and Clinical Studies (14.2) ]. The WHI Memory Study (WHIMS) estrogen-alone ancil ary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.4) , Use in Specific Populations (8.5) , and Clinical Studies (14.3) ]. Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.2 , 5.4) , and Clinical Studies (14.2 , 14.3) ] . Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.2) , and Clinical Studies (14.2) ]. The WHIMS estrogen plus progestin ancillary study of the WHI, reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.4) , Use in Specific Populations (8.5) , and Clinical Studies (14.3) ]. Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.2 , 5.4) , and Clinical Studies (14.2 , 14.3) ] . Breast Cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.3) , and Clinical Studies (14.2) ]. Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.