Premarin Vaginal

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) ] In a prospective, randomized, placebo-controlled, double-blind study, the most common adverse reactions ≥ 2 percent are headache, pelvic pain, vasodilation, breast pain, leucorrhea, metrorrhagia, vaginitis, vulvovaginal disorder ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 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 trial 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. In a 12-week, randomized, double-blind, placebo-controlled trial of PREMARIN Vaginal Cream (PVC), a total of 423 postmenopausal women received at least 1 dose of study medication and were included in all safety analyses: 143 women in the PVC-21/7 treatment group (0.5 g PVC daily for 21 days, then 7 days off), 72 women in the matching placebo treatment group; 140 women in the PVC-2×/wk treatment group (0.5 g PVC twice weekly), 68 women in the matching placebo treatment group. A 40-week, open-label extension followed, in which a total of 394 women received treatment with PVC, including those subjects randomized at baseline to placebo. In this study, the most common adverse reactions ≥ 1 percent in the double blind phase are shown below (Table 1) [see Clinical Studies (14.1) ] . Table 1: Number (%) of Patients Reporting Treatment Emergent Adverse Reactions ≥ 1 Percent Only Treatment Body System Body system totals are not necessarily the sum of individual adverse events, since a patient may report two or more different adverse reactions in the same body system. /Adverse Reaction PVC 21/7 N=143 Placebo 21/7 N=72 PVC 2×/week N=140 Placebo 2×/week N=68 Number (%) of Patients with Adverse Reaction Body As A Whole Abdominal Pain 1 (0.7) 1 (1.4) 0 1 (1.5) Headache 5 (3.5) 1 (1.4) 3 (2.1) 1 (1.5) Moniliasis 2 (1.4) 1 (1.4) 1 (0.7) 0 Pain 2 (1.4) 0 1 (0.7) 0 Pelvic Pain 4 (2.8) 2 (2.8) 4 (2.9) 0 Cardiovascular System Migraine 0 0 0 1 (1.5) Vasodilation 3 (2.1) 2 (2.8) 2 (1.4) 0 Musculoskeletal System Muscle Cramp 2 (1.4) 0 0 0 Nervous System Dizziness 1 (0.7) 0 0 1 (1.5) Skin and Appendages Acne 0 0 2 (1.4) 0 Erythema 0 1 (1.4) 0 0 Pruritus 2 (1.4) 1 (1.4) 1 (0.7) 0 Urogenital System Breast Enlargement 1 (0.7) 1 (1.4) 0 0 Breast Pain 7 (4.9) 0 3 (2.1) 0 Dysuria 2 (1.4) 0 0 0 Leukorrhea 3 (2.1) 1 (1.4) 4 (2.9) 5 (7.4) Metrorrhagia 0 0 0 2 (2.9) Urinary Frequency 0 1 (1.4) 0 0 Urinary Tract Infection 0 1 (1.4) 0 0 Urinary Urgency 1 (0.7) 1 (1.4) 0 0 Vaginal Hemorrhage 2 (1.4) 0 1 (0.7) 1 (1.5) Vaginal Moniliasis 2 (1.4) 0 0 0 Vaginitis 2 (1.4) 1 (1.4) 3 (2.1) 3 (4.4) Vulvovaginal Disorder 4 (2.8) 0 3 (2.1) 2 (2.9) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of PREMARIN Vaginal Cream. 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 Abnormal uterine bleeding or spotting, dysmenorrhea or pelvic pain, increase in size of uterine leiomyomata, vaginitis (including vaginal candidiasis), change in cervical secretion, cystitis-like syndrome, application site reactions of vulvovaginal discomfort, (including burning, irritation, and genital pruritus), endometrial hyperplasia, endometrial cancer, precocious puberty, leukorrhea. Breasts Tenderness, enlargement, pain, discharge, fibrocystic breast changes, breast cancer, gynecomastia in males. Cardiovascular Deep venous thrombosis, pulmonary embolism, myocardial infarction, stroke, increase in blood pressure. Gastrointestinal Nausea, vomiting, abdominal cramps, bloating, increased incidence of gallbladder disease. Skin Chloasma that may persist when drug is discontinued, loss of scalp hair, hirsutism, rash. Eyes Retinal vascular thrombosis, intolerance to contact lenses. Central Nervous System Headache, migraine, dizziness, mental depression, nervousness, mood disturbances, irritability, dementia. Miscellaneous Increase or decrease in weight, glucose intolerance, edema, arthralgias, leg cramps, changes in libido, urticaria, exacerbation of asthma, increased triglycerides, hypersensitivity. Additional postmarketing adverse reactions have been reported in patients receiving other forms of hormone therapy.

4 CONTRAINDICATIONS PREMARIN Vaginal Cream therapy should not be used in women with any of the following conditions: • Undiagnosed abnormal genital bleeding • Known, suspected, or history of breast cancer • Known or suspected estrogen-dependent neoplasia • Active DVT, PE, or a history of these conditions • Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions • Known anaphylactic reaction or angioedema to PREMARIN Vaginal Cream • Known liver dysfunction or disease • Known protein C, protein S or antithrombin deficiency or other known thrombophilic disorders • Known or suspected pregnancy • Undiagnosed abnormal genital bleeding ( 4 ) • Known, suspected, or history of breast cancer ( 4 , 5.3 ) • Known or suspected estrogen-dependent neoplasia ( 4 , 5.3 ) • Active DVT, PE, or a history of these conditions ( 4 , 5.2 ) • Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions ( 4 , 5.2 ) • Known anaphylactic reaction or angioedema to PREMARIN Vaginal Cream ( 5.16 , 5.17 ) • Known liver dysfunction or disease ( 4 , 5.10 ) • Known protein C, protein S, or antithrombin deficiency or other known thrombophilic disorders ( 4 ) • Known or suspected pregnancy ( 4 , 8.1 )

11 DESCRIPTION Each gram of PREMARIN (conjugated estrogens) Vaginal Cream contains 0.625 mg conjugated estrogens, USP in a nonliquefying base containing cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate, propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin, and mineral oil. PREMARIN Vaginal Cream is applied intravaginally. PREMARIN Vaginal Cream contains a mixture of conjugated estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as concomitant components, sodium sulfate conjugates, 17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin.

2 DOSAGE AND ADMINISTRATION Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be considered to reduce the risk of endometrial cancer. A woman without a uterus does not need a progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a progestin [see Warnings and Precautions (5.3 , 5.15) ] . Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. • Cyclic administration of 0.5 to 2 g intravaginally [daily for 21 days then off for 7 days] for Treatment of Atrophic Vaginitis and Kraurosis Vulvae ( 2. 1 ) • Cyclic administration of 0.5 g intravaginally [daily for 21 days then off for 7 days] for Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, due to Menopause ( 2. 2 ) • Twice-weekly administration of 0.5 g intravaginally [for example, Monday and Thursday] for Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, due to Menopause ( 2. 2 ) 2. 1 Treatment of Atrophic Vaginitis and Kraurosis Vulvae PREMARIN Vaginal Cream is administered intravaginally in a cyclic regimen (daily for 21 days and then off for 7 days). Generally, women should be started at the 0.5 g dosage strength. Dosage adjustments (0.5 to 2 g) may be made based on individual response [see Dosage Forms and Strengths (3) ] . 2. 2 Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, due to Menopause PREMARIN Vaginal Cream (0.5 g) is administered intravaginally in a twice-weekly (for example, Monday and Thursday) continuous regimen or in a cyclic regimen of 21 days of therapy followed by 7 days off of therapy [see Dosage Forms and Strengths (3) ] .

1 INDICATIONS AND USAGE PREMARIN (conjugated estrogens) Vaginal Cream is a mixture of estrogens indicated for: • Treatment of Atrophic Vaginitis and Kraurosis Vulvae ( 1.1 ) • Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, due to Menopause ( 1.2 ) 1.1 Treatment of Atrophic Vaginitis and Kraurosis Vulvae 1.2 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 PREMARIN therapy with institution of appropriate symptomatic care.

7 DRUG INTERACTIONS No drug interaction studies have been conducted for PREMARIN Vaginal Cream. Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism ( 7.1 ) 7.1 Metabolic Interactions In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John's wort ( Hypericum perforatum ) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice, may increase plasma concentrations of estrogens and may result in side effects.

5.21 Drug-Laboratory Test Interactions Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of 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) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T 4 levels (by column or by radioimmunoassay) or T 3 levels by radioimmunoassay. T 3 resin uptake is decreased, reflecting the elevated TBG. Free T 4 and free T 3 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 HDL 2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels. Impaired glucose tolerance.

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, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women. 12.2 Pharmacodynamics Currently, there are no pharmacodynamic data known for PREMARIN Vaginal Cream. 12.3 Pharmacokinetics Absorption Conjugated estrogens are water soluble and are well-absorbed through the skin, mucous membranes, and the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents first-pass metabolism. A bioavailability study was conducted in 24 postmenopausal women with atrophic vaginitis. The mean (SD) pharmacokinetic parameters for unconjugated estrone, unconjugated estradiol, total estrone, total estradiol and total equilin following 7 once-daily doses of PREMARIN Vaginal Cream 0.5 g is shown in Table 2. Table 2: Mean ± SD Pharmacokinetic Parameters of PREMARIN Following Daily Administration (7 Days) of PREMARIN Vaginal Cream 0.5 g in 24 Postmenopausal Women Pharmacokinetic Profiles of Unconjugated Estrogens PREMARIN Vaginal Cream 0.5 g PK Parameters Arithmetic Mean ± SD C max (pg/mL) T max (hr) AUC ss (pg•hr/mL) Estrone 42.0 ± 13.9 7.4 ± 6.2 826 ± 295 Baseline-adjusted estrone 21.9 ± 13.1 7.4 ± 6.2 365 ± 255 Estradiol 12.8 ± 16.6 8.5 ± 6.2 231 ± 285 Baseline-adjusted estradiol 9.14 ± 14.7 8.5 ± 6.2 161 ± 252 Pharmacokinetic Profiles of Conjugated Estrogens PREMARIN Vaginal Cream 0.5 g PK Parameters Arithmetic Mean ± SD C max (ng/mL) T max (hr) AUC ss (ng•hr/mL) Total estrone 0.60 ± 0.32 6.0 ± 4.0 9.75 ± 4.99 Baseline-adjusted total estrone 0.40 ± 0.28 6.0 ± 4.0 5.79 ± 3.7 Total estradiol 0.04 ± 0.04 7.7 ± 5.9 0.70 ± 0.42 Baseline-adjusted total estradiol 0.04 ± 0.04 7.7 ± 6.0 0.49 ± 0.38 Total equilin 0.12 ± 0.15 6.1 ± 4.7 3.09 ± 1.37 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 concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Use in Specific Populations No pharmacokinetic studies were conducted in specific populations, including patients with renal or hepatic impairment.

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, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.

12.2 Pharmacodynamics Currently, there are no pharmacodynamic data known for PREMARIN Vaginal Cream.

12.3 Pharmacokinetics Absorption Conjugated estrogens are water soluble and are well-absorbed through the skin, mucous membranes, and the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents first-pass metabolism. A bioavailability study was conducted in 24 postmenopausal women with atrophic vaginitis. The mean (SD) pharmacokinetic parameters for unconjugated estrone, unconjugated estradiol, total estrone, total estradiol and total equilin following 7 once-daily doses of PREMARIN Vaginal Cream 0.5 g is shown in Table 2. Table 2: Mean ± SD Pharmacokinetic Parameters of PREMARIN Following Daily Administration (7 Days) of PREMARIN Vaginal Cream 0.5 g in 24 Postmenopausal Women Pharmacokinetic Profiles of Unconjugated Estrogens PREMARIN Vaginal Cream 0.5 g PK Parameters Arithmetic Mean ± SD C max (pg/mL) T max (hr) AUC ss (pg•hr/mL) Estrone 42.0 ± 13.9 7.4 ± 6.2 826 ± 295 Baseline-adjusted estrone 21.9 ± 13.1 7.4 ± 6.2 365 ± 255 Estradiol 12.8 ± 16.6 8.5 ± 6.2 231 ± 285 Baseline-adjusted estradiol 9.14 ± 14.7 8.5 ± 6.2 161 ± 252 Pharmacokinetic Profiles of Conjugated Estrogens PREMARIN Vaginal Cream 0.5 g PK Parameters Arithmetic Mean ± SD C max (ng/mL) T max (hr) AUC ss (ng•hr/mL) Total estrone 0.60 ± 0.32 6.0 ± 4.0 9.75 ± 4.99 Baseline-adjusted total estrone 0.40 ± 0.28 6.0 ± 4.0 5.79 ± 3.7 Total estradiol 0.04 ± 0.04 7.7 ± 5.9 0.70 ± 0.42 Baseline-adjusted total estradiol 0.04 ± 0.04 7.7 ± 6.0 0.49 ± 0.38 Total equilin 0.12 ± 0.15 6.1 ± 4.7 3.09 ± 1.37 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 concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Use in Specific Populations No pharmacokinetic studies were conducted in specific populations, including patients with renal or hepatic impairment.

20230517

29

3 DOSAGE FORMS AND STRENGTHS Each gram contains 0.625 mg conjugated estrogens, USP. Combination package: Each contains a net wt. 1.06 oz (30 g) tube with plastic applicator(s) calibrated in 0.5 g increments to a maximum of 2 g. • Each gram contains 0.625 mg conjugated estrogens, USP ( 3 ) • Combination package: Each contains a net wt. 1.06 oz (30 g) tube with plastic applicator(s) calibrated in 0.5 g increments to a maximum of 2 g ( 3 )

Premarin Vaginal conjugated estrogens ESTROGENS, CONJUGATED ESTROGENS, CONJUGATED CETYL ALCOHOL WHITE WAX GLYCERYL MONOSTEARATE PROPYLENE GLYCOL MONOPALMITOSTEARATE METHYL STEARATE BENZYL ALCOHOL SODIUM LAURYL SULFATE GLYCERIN MINERAL OIL

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.

NDA020216

Premarin Vaginal

conjugated estrogens

0046-0872

HUMAN PRESCRIPTION DRUG

VAGINAL

5.20 Laboratory Tests Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe symptoms of vulvar and vaginal atrophy.

PRINCIPAL DISPLAY PANEL - 30 g Tube Label NDC 0046-0872-21 Premarin ® (conjugated estrogens) vaginal cream 0.625 mg/g Rx only Net Wt. 1.06 oz. (30 g) PRINCIPAL DISPLAY PANEL - 30 g Tube Label

Warnings and Precautions, Malignant Neoplasms ( 5.3 ) 11/2017

LAB-0498-7.0 Logo

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information and Instructions for Use). 17.1 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) ] . 17.2 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) ] . 17.3 Possible Less Serious but Common Adverse Reactions with Estrogen-Alone Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting.

14 CLINICAL STUDIES 14.1 Effects on Vulvar and Vaginal Atrophy A 12-week, prospective, randomized, double-blind placebo-controlled study was conducted to compare the safety and efficacy of 2 PREMARIN Vaginal Cream (PVC) regimens 0.5 g (0.3 mg CE) administered twice weekly and 0.5 g (0.3 mg CE) administered sequentially for 21 days on drug followed by 7 days off drug to matching placebo regimens in the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. The initial 12-week, double-blind, placebo-controlled phase was followed by an open-label phase to assess endometrial safety through week 52. The study randomized 423 generally healthy postmenopausal women between 44 to 77 years of age (mean 57.8 years), who at baseline had ≤ 5 percent superficial cells on a vaginal smear, a vaginal pH ≥ 5.0, and who identified a most bothersome moderate to severe symptom of vulvar and vaginal atrophy. The majority (92.2 percent) of the women were Caucasian (n = 390); 7.8 percent were Other (n = 33). All subjects were assessed for improvement in the mean change from baseline to Week 12 for the co-primary efficacy variables of: most bothersome symptom of vulvar and vaginal atrophy (defined as the moderate to severe symptom that had been identified by the woman as most bothersome to her at baseline); percentage of vaginal superficial cells and percentage of vaginal parabasal cells; and vaginal pH. In the 12-week, double-blind phase, a statistically significant mean change between baseline and Week 12 in the symptom of dyspareunia was observed for both of the PREMARIN Vaginal Cream regimens (0.5 g daily for 21 days, then 7 days off and 0.5 g twice weekly) compared to matching placebo, see Table 3 . Also demonstrated for each PREMARIN Vaginal Cream regimen compared to placebo was a statistically significant increase in the percentage of superficial cells at Week 12 (28 percent, 21/7 regimen and 26 percent, twice a week compared to 3 percent and 1 percent for matching placebo), a statistically significant decrease in parabasal cells (-61 percent, 21/7 regimen and -58 percent, twice a week compared to -21 percent and -7 percent for matching placebo) and statistically significant mean reduction between baseline and Week 12 in vaginal pH (-1.62, 21/7 regimen and -1.57, twice a week compared to -0.36 and -0.26 for matching placebo). Endometrial safety was assessed by endometrial biopsy for all randomly assigned subjects at week 52. For the 155 subjects (83 on the 21/7 regimen, 72 on the twice-weekly regimen) completing the 52-week period with complete follow-up and evaluable endometrial biopsies, there were no reports of endometrial hyperplasia or endometrial carcinoma. Table 3: Mean Change in Dyspareunia Severity Compared to Placebo MITT Population of Most Bothersome Symptom Score for Dyspareunia, LOCF Dyspareunia PVC 0.5 g 21/7 PVC 21/7 = apply PVC for 21 days and then 7 days of no therapy Placebo 0.5 g 21/7 PVC 0.5 g 2×/wk PVC 2×/wk = apply PVC twice a week Placebo 0.5 g 2×/wk Baseline n Mean (SD) 50 2.26 (0.99) n Mean (SD) 18 2.32 (0.88) n Mean (SD) 52 2.43 (0.76) n Mean (SD) 22 2.28 (1.04) Week 12 50 0.77 (1.05) 18 1.93 (1.03) 52 0.88 (0.96) 21 1.63 (1.16) Change from Baseline at Week 12 50 -1.48 (1.17) 18 -0.40 (1.01) 52 -1.55 (0.92) 21 -0.62 (1.23) P-value vs. Placebo <0.001 Comparison of PVC 21/7 with placebo 21/7 -- <0.001 Comparison of PVC 2×/wk with placebo 2×/wk -- 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 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 7.1 years, are presented in Table 4. Table 4: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of 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. 0.95 (0.78–1.16) 54 57 Non-fatal MI 0.91 (0.73–1.14) 40 43 CHD death 1.01 (0.71–1.43) 16 16 All Strokes 1.33 (1.05–1.68) 45 33 Ischemic stroke 1.55 (1.19–2.01) 38 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 Results are based on an average follow-up of 6.8 years. 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 , 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 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36–1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46–1.11)] . WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years. For those outcomes included in the WHI "global index" that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 5. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 5: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 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 1.23 (0.99–1.53) 41 34 Non-fatal MI 1.28 (1.00–1.63) 31 25 CHD death 1.10 (0.70–1.75) 8 8 All Strokes 1.31 (1.03–1.68) 33 25 Ischemic stroke 1.44 (1.09–1.90) 26 18 Deep vein 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 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, pulmonary embolism, 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 to 59 years of age, a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44–1.07)] . 14.3 Women's Health Initiative Memory Study The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) -alone on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83–2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer'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 percent were 65 to 69 years of age; 35 percent were 70 to 74 years; 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21–3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed 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 percent CI, 1.19–2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.4) , and Use in Specific Populations (8.5) ] .

15 REFERENCES 1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA . 2007;297:1465–1477. 2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med . 2006;166:357–365. 3. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med . 2006;166:772–780. 4. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA . 2004;292:1573–1580. 5. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA . 2006;295:1647–1657. 6. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA . 2003;289:3234–3253. 7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA . 2003;290:1739–1748. 8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA . 2004;291:2947–2958. 9. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women's Health Initiative Randomized Trial. J Bone Miner Res . 2006;21:817–828. 10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation . 2006;113:2425–2434.

8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing PREMARIN Vaginal Cream to determine whether those over 65 years of age differ from younger subjects in their response to PREMARIN Vaginal Cream. The Women's Health Initiative Studies In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Warnings and Precautions (5.2) , and Clinical Studies (14.2) ] . In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Warnings and Precautions (5.2 , 5.3) , and Clinical Studies (14.2) ] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.4) , 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) ] .

8.3 Nursing Mothers PREMARIN Vaginal Cream should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the breast milk of women receiving estrogen therapy. Caution should be exercised when PREMARIN Vaginal Cream is administered to a nursing woman.

8.4 Pediatric Use PREMARIN Vaginal Cream is not indicated in children. Clinical studies have not been conducted in the pediatric population.

8.1 Pregnancy PREMARIN Vaginal Cream should not be used during pregnancy [see Contraindications (4) ] . There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.

8 USE IN SPECIFIC POPULATIONS • Nursing Mothers: Estrogen administration to nursing women has been shown to decrease the quantity and quality of breast milk ( 8.3 ) • Geriatric Use: An increased risk of probable dementia in women over 65 years of age was reported in the Women's Health Initiative Memory ancillary studies of the Women's Health Initiative ( 5.4 , 8.5 ) 8.1 Pregnancy PREMARIN Vaginal Cream should not be used during pregnancy [see Contraindications (4) ] . There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy. 8.3 Nursing Mothers PREMARIN Vaginal Cream should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the breast milk of women receiving estrogen therapy. Caution should be exercised when PREMARIN Vaginal Cream is administered to a nursing woman. 8.4 Pediatric Use PREMARIN Vaginal Cream is not indicated in children. 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 PREMARIN Vaginal Cream to determine whether those over 65 years of age differ from younger subjects in their response to PREMARIN Vaginal Cream. The Women's Health Initiative Studies In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Warnings and Precautions (5.2) , and Clinical Studies (14.2) ] . In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Warnings and Precautions (5.2 , 5.3) , and Clinical Studies (14.2) ] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.4) , 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) ] . 8.6 Renal Impairment The effect of renal impairment on the pharmacokinetics of PREMARIN Vaginal Cream has not been studied. 8.7 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of PREMARIN Vaginal Cream has not been studied.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied PREMARIN (conjugated estrogens) Vaginal Cream—Each gram contains 0.625 mg conjugated estrogens, USP. Combination package: Each contains a net wt. of 1.06 oz (30 g) tube with plastic applicator(s) calibrated in 0.5 g increments to a maximum of 2 g (NDC 0046-0872-21). 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

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

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER and PROBABLE DEMENTIA Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.3) ] . Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.2 , 5.4) , and Clinical Studies (14.2 , 14.3) ] . 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 ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg) -alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.4) , Use in Specific Populations (8.5) , and Clinical Studies (14.3) ] . In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.2 , 5.4) , and Clinical Studies (14.2 , 14.3) ] . 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 or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.4) , Use in Specific Populations (8.5) , and Clinical Studies ( 14.3 )] . Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.3 ), and Clinical Studies (14.2) ] . In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER and PROBABLE DEMENTIA See full prescribing information for complete boxed warning. Estrogen-Alone Therap y • There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens ( 5.3 ) • Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia ( 5.2 , 5.4 ) • 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 ) Estrogen Plus Progestin Therapy • Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia ( 5.2 , 5.4 ) • The WHI estrogen plus progestin substudy reported increased risks of stroke, DVT, pulmonary 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 )