Premarin Vaginal

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

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 [see Boxed Warning ]. 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) ] .

5 WARNINGS AND PRECAUTIONS • Estrogens increase the risk of gallbladder disease ( 5.5 ) • Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs ( 5.6 , 5.7 , 5.10 , 5.11 ) • Monitor thyroid function in women on thyroid replacement therapy ( 5.12 , 5.21 ) 5.1 Risks from Systemic Absorption Systemic absorption occurs with the use of PREMARIN vaginal cream. The warnings, precautions, and adverse reactions associated with oral PREMARIN treatment should be taken into account. 5.2 Cardiovascular Disorders An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. Stroke In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) -alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in Year 1 and persisted [see Clinical Studies (14.2) ]. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg) -alone versus those receiving placebo (18 versus 21 per 10,000 women-years). 1 In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) [see Clinical Studies (14.2) ] . The increase in risk was demonstrated after the first year and persisted. 1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. Coronary Heart Disease In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo 2 [see Clinical Studies (14.2) ] . Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years). 1 In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years). 1 An increase in relative risk was demonstrated in Year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies (14.2) ]. In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established CHD. There were more CHD events in the CE plus MPA-treated group than in the placebo group in Year 1, but not during the subsequent years. Two thousand, three hundred and twenty-one (2,321) women from the original HERS …

4 CONTRAINDICATIONS PREMARIN vaginal cream is contraindicated in women with any of the following conditions: • Undiagnosed abnormal genital bleeding [see Warnings 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 a history of these conditions [see Warnings and Precautions (5.2) ] • Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions [see Warnings and Precautions (5.2) ] • Known anaphylactic reaction or angioedema to PREMARIN [see Warnings and Precautions (5.16, 5.17) ] • Hepatic impairment or disease [see Warnings and Precautions (5.11) ] • 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 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 ( 4 , 5.16 , 5.17 ) • Hepatic impairment or disease ( 4 , 5.11 ) • Protein C, protein S, or antithrombin deficiency or other known thrombophilic disorders ( 4 )

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.

8.1 Pregnancy Risk Summary PREMARIN vaginal cream is not indicated for use during pregnancy. There are no data with the use of PREMARIN vaginal cream in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

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% 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-2x/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% 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% 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 i…