DESCRIPTION SECTION.

11 DESCRIPTION. Each gram of PREMARIN (conjugated estrogens) Vaginal Cream contains 0.625 mg conjugated estrogens, USP in 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 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 mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as concomitant components, sodium sulfate conjugates, 17 -dihydroequilin, 17 -estradiol, and 17 -dihydroequilin.

ADVERSE REACTIONS SECTION.

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)] Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.2)] Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.3)] In prospective, randomized, placebo-controlled, double-blind study, the most common adverse reactions >= 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.In 12-week, randomized, double-blind, placebo-controlled trial of PREMARIN Vaginal Cream (PVC), total of 423 postmenopausal women received at least dose of study medication and were included in all safety analyses: 143 women in the PVC-21/7 treatment group (0.5 PVC daily for 21 days, then days off), 72 women in the matching placebo treatment group; 140 women in the PVC-2x/wk treatment group (0.5 PVC twice weekly), 68 women in the matching placebo treatment group. 40-week, open-label extension followed, in which total of 394 women received treatment with PVC, including those subjects randomized at baseline to placebo. In this study, the most common adverse reactions >= 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 >= Percent OnlyTreatmentBody SystemBody system totals are not necessarily the sum of individual adverse events, since patient may report two or more different adverse reactions in the same body system./Adverse ReactionPVC 21/7 N=143Placebo 21/7 N=72PVC 2x/week N=140Placebo 2x/weekN=68Number (%) of Patients with Adverse ReactionBody As WholeAbdominal Pain1 (0.7)1 (1.4)01 (1.5)Headache5 (3.5)1 (1.4)3 (2.1)1 (1.5)Moniliasis2 (1.4)1 (1.4)1 (0.7)0Pain2 (1.4)01 (0.7)0Pelvic Pain4 (2.8)2 (2.8)4 (2.9)0Cardiovascular SystemMigraine0001 (1.5)Vasodilation3 (2.1)2 (2.8)2 (1.4)0Musculoskeletal SystemMuscle Cramp2 (1.4)000Nervous SystemDizziness1 (0.7)001 (1.5)Skin and AppendagesAcne002 (1.4)0Erythema01 (1.4)00Pruritus2 (1.4)1 (1.4)1 (0.7)0Urogenital SystemBreast Enlargement1 (0.7)1 (1.4)00Breast Pain7 (4.9)03 (2.1)0Dysuria2 (1.4)000Leukorrhea3 (2.1)1 (1.4)4 (2.9)5 (7.4)Metrorrhagia0002 (2.9)Urinary Frequency01 (1.4)00Urinary Tract Infection01 (1.4)00Urinary Urgency1 (0.7)1 (1.4)00Vaginal Hemorrhage2 (1.4)01 (0.7)1 (1.5)Vaginal Moniliasis2 (1.4)000Vaginitis2 (1.4)1 (1.4)3 (2.1)3 (4.4)Vulvovaginal Disorder4 (2.8)03 (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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Genitourinary SystemAbnormal 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.BreastsTenderness, enlargement, pain, discharge, fibrocystic breast changes, breast cancer, gynecomastia in males.CardiovascularDeep venous thrombosis, pulmonary embolism, myocardial infarction, stroke, increase in blood pressure.GastrointestinalNausea, vomiting, abdominal cramps, bloating, increased incidence of gallbladder disease.SkinChloasma that may persist when drug is discontinued, loss of scalp hair, hirsutism, rash.EyesRetinal vascular thrombosis, intolerance to contact lenses.Central Nervous SystemHeadache, migraine, dizziness, mental depression, nervousness, mood disturbances, irritability, dementia.MiscellaneousIncrease 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.

BOXED WARNING SECTION.

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER and PROBABLE DEMENTIA. Estrogen-Alone TherapyEndometrial CancerThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens. Adding progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be 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 DementiaEstrogen-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 Womens 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 TherapyCardiovascular Disorders and Probable DementiaEstrogen 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 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 CancerThe 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 DEMENTIASee full prescribing information for complete boxed warning.Estrogen-Alone TherapyThere is an increased risk of endometrial cancer in woman with 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 Womens 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 TherapyEstrogen 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). There is an increased risk of endometrial cancer in woman with 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 Womens 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 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).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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.

CLINICAL PHARMACOLOGY SECTION.

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 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 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. AbsorptionConjugated 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 once-daily doses of PREMARIN Vaginal Cream 0.5 is shown in Table 2.Table 2: Mean +- SD Pharmacokinetic Parameters of PREMARIN Following Daily Administration (7 Days) of PREMARIN Vaginal Cream 0.5 in 24 Postmenopausal WomenPharmacokinetic Profiles of Unconjugated EstrogensPREMARIN Vaginal Cream 0.5 gPK ParametersArithmetic Mean +- SDCmax(pg/mL)Tmax(hr)AUCss(pgohr/mL)Estrone42.0 +- 13.97.4 +- 6.2826 +- 295Baseline-adjusted estrone21.9 +- 13.17.4 +- 6.2365 +- 255Estradiol12.8 +- 16.68.5 +- 6.2231 +- 285Baseline-adjusted estradiol9.14 +- 14.78.5 +- 6.2161 +- 252Pharmacokinetic Profiles of Conjugated EstrogensPREMARIN Vaginal Cream 0.5 gPK ParametersArithmetic Mean +- SDCmax(ng/mL)Tmax(hr)AUCss(ngohr/mL)Total estrone0.60 +- 0.326.0 +- 4.09.75 +- 4.99Baseline-adjusted total estrone0.40 +- 0.286.0 +- 4.05.79 +- 3.7Total estradiol0.04 +- 0.047.7 +- 5.90.70 +- 0.42Baseline-adjusted total estradiol0.04 +- 0.047.7 +- 6.00.49 +- 0.38Total equilin0.12 +- 0.156.1 +- 4.73.09 +- 1.37. DistributionThe 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. MetabolismExogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in 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 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, significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as circulating reservoir for the formation of more active estrogens. ExcretionEstradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Use in Specific PopulationsNo pharmacokinetic studies were conducted in specific populations, including patients with renal or hepatic impairment.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Effects on Vulvar and Vaginal Atrophy. 12-week, prospective, randomized, double-blind placebo-controlled study was conducted to compare the safety and efficacy of PREMARIN Vaginal Cream (PVC) regimens 0.5 (0.3 mg CE) administered twice weekly and 0.5 (0.3 mg CE) administered sequentially for 21 days on drug followed by 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 <= percent superficial cells on vaginal smear, vaginal pH >= 5.0, and who identified 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, 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 daily for 21 days, then days off and 0.5 twice weekly) compared to matching placebo, see Table 3. Also demonstrated for each PREMARIN Vaginal Cream regimen compared to placebo was statistically significant increase in the percentage of superficial cells at Week 12 (28 percent, 21/7 regimen and 26 percent, twice week compared to percent and percent for matching placebo), statistically significant decrease in parabasal cells (-61 percent, 21/7 regimen and -58 percent, twice 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 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, LOCFDyspareuniaPVC0.5 g21/7PVC 21/7 apply PVC for 21 days and then days of no therapy Placebo0.5 g21/7 PVC0.5 g2x/wkPVC 2x/wk apply PVC twice week Placebo0.5 g2x/wk BaselinenMean (SD)50 2.26 (0.99) nMean (SD)18 2.32 (0.88) nMean (SD)52 2.43 (0.76) nMean (SD)22 2.28 (1.04) Week 1250 0.77 (1.05) 18 1.93 (1.03) 52 0.88 (0.96) 21 1.63 (1.16) Change fromBaseline at Week 1250 -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 2x/wk with placebo 2x/wk --. 14.2 Womens 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. 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 SubstudyThe 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 WHIAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. EventRelative RiskCE vs. Placebo(95% nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons.)CEn 5,310Placebon 5,429Absolute Risk per 10,000 Women-YearsCHD eventsResults are based on centrally adjudicated data for an average follow-up of 7.1 years. 0.95 (0.78-1.16)5457 Non-fatal MI0.91 (0.73-1.14)4043 CHD death1.01 (0.71-1.43)1616All Strokes 1.33 (1.05-1.68)4533 Ischemic stroke 1.55 (1.19-2.01)3825Deep vein thrombosis Not included in global index. 1.47 (1.06-2.06)2315Pulmonary embolism 1.37 (0.90-2.07)1410Invasive breast cancer 0.80 (0.62-1.04)2834Colorectal cancerResults are based on an average follow-up of 6.8 years. 1.08 (0.75-1.55)1716Hip fracture 0.65 (0.45-0.94)1219Vertebral fractures 0.64 (0.44-0.93)1118Lower arm/wrist fractures 0.58 (0.47-0.72)3559Total fractures 0.71 (0.64-0.80)144197Death 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)5350Overall mortality 1.04 (0.88-1.22)7975Global IndexA subset of the events was combined in 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)206201For 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 fewer hip fractures.9 The absolute excess risk of events included in the global index was non-significant 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 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 SubstudyThe 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 more CHD events, more strokes, 10 more PEs, and more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were fewer colorectal cancers and 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 YearsAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. Results are based on centrally adjudicated data. EventRelative RiskCE/MPA vs. Placebo(95% nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons.)CE/MPAn 8,506Placebon 8,102Absolute Risk per 10,000 Women-YearsCHD events1.23 (0.99-1.53)4134 Non-fatal MI 1.28 (1.00-1.63)3125 CHD death 1.10 (0.70-1.75)88All Strokes1.31 (1.03-1.68)3325 Ischemic stroke 1.44 (1.09-1.90)2618Deep vein thrombosisNot included in global index. 1.95 (1.43-2.67)2613Pulmonary embolism2.13 (1.45-3.11)188Invasive breast cancerIncludes metastatic and non-metastatic breast cancer, with the exception of in situ cancer. 1.24 (1.01-1.54)4133Colorectal cancer0.61 (0.42-0.87)1016Endometrial cancer 0.81 (0.48-1.36)67Cervical cancer 1.44 (0.47-4.42)21Hip fracture0.67 (0.47-0.96)1116Vertebral fractures 0.65 (0.46-0.92)1117Lower arm/wrist fractures 0.71 (0.59-0.85)4462Total fractures 0.76 (0.69-0.83)152199Overall MortalityAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.00 (0.83-1.19)5252Global IndexA subset of the events was combined in 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)184165Timing 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, non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44-1.07)].. 14.3 Womens 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 Alzheimers 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 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)].

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. PREMARIN Vaginal Cream therapy should not be used in women with any of the following conditions:Undiagnosed abnormal genital bleedingKnown, suspected, or history of breast cancerKnown or suspected estrogen-dependent neoplasiaActive DVT, PE, or history of these conditionsActive arterial thromboembolic disease (for example, stroke and MI), or history of these conditionsKnown anaphylactic reaction or angioedema to PREMARIN Vaginal CreamKnown liver dysfunction or diseaseKnown protein C, protein or antithrombin deficiency or other known thrombophilic disordersKnown or suspected pregnancy. Undiagnosed abnormal genital bleeding. Known, suspected, or history of breast cancer. Known or suspected estrogen-dependent neoplasia. Active DVT, PE, or history of these conditions. Active arterial thromboembolic disease (for example, stroke and MI), or history of these conditions. Known anaphylactic reaction or angioedema to PREMARIN Vaginal Cream. Known liver dysfunction or disease. Known protein C, protein 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 history of these conditions (4, 5.2)Active arterial thromboembolic disease (for example, stroke and MI), or 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). 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 history of these conditions (4, 5.2). Active arterial thromboembolic disease (for example, stroke and MI), or 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).

SPL PATIENT PACKAGE INSERT SECTION.

FDA-Approved Patient LabelingPREMARIN(R) (prem-uh-rin) (Conjugated estrogens) Vaginal CreamRead this PATIENT INFORMATION before you start using PREMARIN Vaginal Cream and read what you get each time you refill your PREMARIN Vaginal Cream prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.. What is the most important information should know about PREMARIN Vaginal Cream (an estrogen mixture)Using estrogen-alone may increase your chance of getting cancer of the uterus (womb) Report any unusual vaginal bleeding right away while you are using PREMARIN Vaginal Cream. Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia (decline in brain function)Using estrogen-alone may increase your chances of getting strokes or blood clotsUsing estrogen-alone may increase your chance of getting dementia, based on study of women age 65 years of age or olderDo not use estrogens with progestins to prevent heart disease, heart attacks, strokes or dementiaUsing estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clotsUsing estrogens with progestins may increase your chance of getting dementia, based on study of women age 65 years of age or olderYou and your healthcare provider should talk regularly about whether you still need treatment with PREMARIN Vaginal Cream. Using estrogen-alone may increase your chance of getting cancer of the uterus (womb) Report any unusual vaginal bleeding right away while you are using PREMARIN Vaginal Cream. Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.. Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia (decline in brain function). Using estrogen-alone may increase your chances of getting strokes or blood clots. Using estrogen-alone may increase your chance of getting dementia, based on study of women age 65 years of age or older. Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or dementia. Using estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. Using estrogens with progestins may increase your chance of getting dementia, based on study of women age 65 years of age or older. You and your healthcare provider should talk regularly about whether you still need treatment with PREMARIN Vaginal Cream. What is PREMARIN Vaginal CreamPREMARIN Vaginal Cream is medicine that contains mixture of estrogen hormones.What is PREMARIN Vaginal Cream used forPREMARIN Vaginal Cream is used after menopause to:Treat menopausal changes in and around the vaginaYou and your healthcare provider should talk regularly about whether you still need treatment with PREMARIN Vaginal Cream to control these problems.Treat painful intercourse caused by menopausal changes of the vaginaWho should not use PREMARIN Vaginal CreamDo not start using PREMARIN Vaginal Cream if you:Have unusual vaginal bleedingCurrently have or have had certain cancersEstrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use PREMARIN Vaginal Cream.Had stroke or heart attackCurrently have or have had blood clotsCurrently have or have had liver problemsHave been diagnosed with bleeding disorderAre allergic to PREMARIN Vaginal Cream or any of its ingredientsSee the list of ingredients in PREMARIN Vaginal Cream at the end of this leaflet.Think you may be pregnantTell your healthcare provider:If you have unusual vaginal bleedingVaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.About all of your medical problemsYour healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.About all the medicines you takeThis includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how PREMARIN Vaginal Cream works. PREMARIN Vaginal Cream may also affect how your other medicines work.If you are going to have surgery or will be on bedrestYou may need to stop using PREMARIN Vaginal Cream.If you are breast feedingThe estrogen hormones in PREMARIN Vaginal Cream can pass into your breast milk.How should use PREMARIN Vaginal CreamPREMARIN Vaginal Cream is cream that you place in your vagina with the applicator provided with the cream. Take the dose recommended by your healthcare provider and talk to him or her about how well that dose is working for youEstrogens should be used at the lowest dose possible for your treatment only as long as needed. You and your healthcare provider should talk regularly (for example, every to months) about the dose you are taking and whether you still need treatment with PREMARIN Vaginal CreamoStep 1. Remove cap from tube. oStep 2. Screw nozzle end of applicator onto tube (Figure A). Figure Step 3. Gently squeeze tube from the bottom to force sufficient cream into the barrel to provide the prescribed dose. Use the marked stopping points on the applicator to measure the correct dose, as prescribed by your healthcare provider (Figure B). Figure Step 4. Unscrew applicator from tube. Step 5. Lie on back with knees drawn up. To deliver medication, gently insert applicator deeply into vagina and press plunger downward to its original position (Figure C). Figure Step 6. TO CLEANSE: Pull plunger to remove it from barrel. Wash with mild soap and warm water (Figure D). DO NOT BOIL OR USE HOT WATER.Figure DWhat are the possible side effects of PREMARIN Vaginal CreamPREMARIN Vaginal Cream is only used in and around the vagina; however, the risks associated with oral estrogens should be taken into account.Side effects are grouped by how serious they are and how often they happen when you are treated.Serious, but less common side effects include:Heart attackStroke Blood clots DementiaBreast cancerCancer of the lining of the uterus (womb)Cancer of the ovaryHigh blood pressureHigh blood sugarGallbladder diseaseLiver problemsEnlargement of benign tumors of the uterus (fibroids)Severe allergic reactionCall your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:New breast lumpsUnusual vaginal bleedingChanges in vision or speechSudden new severe headachesSevere pains in your chest or legs with or without shortness of breath, weakness and fatigueSwollen lips, tongue or faceLess serious, but common side effects include:HeadacheBreast painIrregular vaginal bleeding or spottingStomach or abdominal cramps, bloatingNausea and vomitingHair lossFluid retentionVaginal yeast infectionReactions from inserting PREMARIN Vaginal Cream, such as vaginal burning, irritation, and itchingThese are not all the possible side effects of PREMARIN Vaginal Cream. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report side effects to Pfizer Inc. at 1-800-438-1985 or to FDA at 1-800-FDA-1088.What can do to lower my chances of getting serious side effect with PREMARIN Vaginal CreamTalk with your healthcare provider regularly about whether you should continue using PREMARIN Vaginal CreamIf you have uterus, talk with your healthcare provider about whether the addition of progestin is right for youThe addition of progestin is generally recommended for woman with uterus to reduce the chance of getting cancer of the uterus. See your healthcare provider right away if you get vaginal bleeding while using PREMARIN Vaginal Cream.Have pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often.If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease Ask your healthcare provider for ways to lower your chances for getting heart disease.General information about the safe and effective use of PREMARIN Vaginal CreamMedicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use PREMARIN Vaginal Cream for conditions for which it was not prescribed. Do not give PREMARIN Vaginal Cream to other people, even if they have the same symptoms you have. It may harm them.Keep PREMARIN Vaginal Cream out of the reach of children.Latex or rubber condoms, diaphragms and cervical caps may be weakened and fail when they come into contact with PREMARIN Vaginal Cream. This leaflet provides summary of the most important information about PREMARIN Vaginal Cream. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about PREMARIN Vaginal Cream that is written for health professionals.What are the ingredients in PREMARIN Vaginal CreamPREMARIN Vaginal Cream contains mixture of conjugated estrogens, which are mixture of sodium estrone sulfate and sodium equilin sulfate and other components, including sodium sulfate conjugates: 17 -dihydroequilin, 17 -estradiol, and 17 -dihydroequilin. PREMARIN Vaginal Cream also contains cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate, propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin, and mineral oil.PREMARIN (conjugated estrogens) Vaginal Cream--Each gram contains 0.625 mg conjugated estrogens, USP.Combination package: Each contains net wt. of 1.06 oz (30 g) tube with plastic applicator(s) calibrated in 0.5 increments to maximum of g (NDC 0046-0872-21).Store at 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].This products label may have been updated. For current full prescribing information, please visit www.pfizer.com.LAB-0519-6.0Rev 09/2018. Treat menopausal changes in and around the vaginaYou and your healthcare provider should talk regularly about whether you still need treatment with PREMARIN Vaginal Cream to control these problems.. Treat painful intercourse caused by menopausal changes of the vagina. Have unusual vaginal bleeding. Currently have or have had certain cancersEstrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use PREMARIN Vaginal Cream.. Had stroke or heart attack. Currently have or have had blood clots. Currently have or have had liver problems. Have been diagnosed with bleeding disorder. Are allergic to PREMARIN Vaginal Cream or any of its ingredientsSee the list of ingredients in PREMARIN Vaginal Cream at the end of this leaflet.. Think you may be pregnant. If you have unusual vaginal bleedingVaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.. About all of your medical problemsYour healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.. About all the medicines you takeThis includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how PREMARIN Vaginal Cream works. PREMARIN Vaginal Cream may also affect how your other medicines work.. If you are going to have surgery or will be on bedrestYou may need to stop using PREMARIN Vaginal Cream.. If you are breast feedingThe estrogen hormones in PREMARIN Vaginal Cream can pass into your breast milk.. Take the dose recommended by your healthcare provider and talk to him or her about how well that dose is working for you. Estrogens should be used at the lowest dose possible for your treatment only as long as needed. You and your healthcare provider should talk regularly (for example, every to months) about the dose you are taking and whether you still need treatment with PREMARIN Vaginal Cream. oStep 1. Remove cap from tube. oStep 2. Screw nozzle end of applicator onto tube (Figure A). Figure A. Step 3. Gently squeeze tube from the bottom to force sufficient cream into the barrel to provide the prescribed dose. Use the marked stopping points on the applicator to measure the correct dose, as prescribed by your healthcare provider (Figure B). Figure . Step 4. Unscrew applicator from tube. Step 5. Lie on back with knees drawn up. To deliver medication, gently insert applicator deeply into vagina and press plunger downward to its original position (Figure C). Figure C. Step 6. TO CLEANSE: Pull plunger to remove it from barrel. Wash with mild soap and warm water (Figure D). DO NOT BOIL OR USE HOT WATER.. DO NOT BOIL OR USE HOT WATER.. Heart attack. Stroke Blood clots Dementia. Breast cancer. Cancer of the lining of the uterus (womb). Cancer of the ovary. High blood pressure. High blood sugar. Gallbladder disease. Liver problems. Enlargement of benign tumors of the uterus (fibroids). Severe allergic reaction. New breast lumps. Unusual vaginal bleeding. Changes in vision or speech. Sudden new severe headaches. Severe pains in your chest or legs with or without shortness of breath, weakness and fatigue. Swollen lips, tongue or face. Less serious, but common side effects include:. Headache. Breast pain. Irregular vaginal bleeding or spotting. Stomach or abdominal cramps, bloating. Nausea and vomiting. Hair loss. Fluid retention. Vaginal yeast infection. Reactions from inserting PREMARIN Vaginal Cream, such as vaginal burning, irritation, and itching. Talk with your healthcare provider regularly about whether you should continue using PREMARIN Vaginal Cream. If you have uterus, talk with your healthcare provider about whether the addition of progestin is right for youThe addition of progestin is generally recommended for woman with uterus to reduce the chance of getting cancer of the uterus. See your healthcare provider right away if you get vaginal bleeding while using PREMARIN Vaginal Cream.. Have pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often.. If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease Ask your healthcare provider for ways to lower your chances for getting heart disease.. Figure A. Figure B. Figure C. Figure D. Logo.

SPL UNCLASSIFIED SECTION.

1.1 Treatment of Atrophic Vaginitis and Kraurosis Vulvae.

STORAGE AND HANDLING SECTION.

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

DOSAGE & ADMINISTRATION SECTION.

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

DOSAGE FORMS & STRENGTHS SECTION.

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

DRUG & OR LABORATORY TEST INTERACTIONS SECTION.

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), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels.Impaired glucose tolerance.

DRUG INTERACTIONS SECTION.

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. Johns wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in 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.

GERIATRIC USE SECTION.

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 Womens Health Initiative StudiesIn the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was 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 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 Womens Health Initiative Memory StudyIn the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.4), and Clinical Studies (14.3)].Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see Warnings and Precautions (5.4), and Clinical Studies (14.3)].

HOW SUPPLIED SECTION.

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 net wt. of 1.06 oz (30 g) tube with plastic applicator(s) calibrated in 0.5 increments to maximum of g (NDC 0046-0872-21).. 16.2 Storage and Handling. Store at 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

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.

LABORATORY TESTS SECTION.

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.

MECHANISM OF ACTION SECTION.

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 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 negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.

NONCLINICAL TOXICOLOGY SECTION.

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.

NURSING MOTHERS SECTION.

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 nursing woman.

OVERDOSAGE SECTION.

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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 30 Tube Label. NDC 0046-0872-21Premarin(R) (conjugated estrogens)vaginal cream0.625mg/gRx onlyNet Wt. 1.06 oz.(30 g). PRINCIPAL DISPLAY PANEL 30 Tube Label.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

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

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionConjugated 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 once-daily doses of PREMARIN Vaginal Cream 0.5 is shown in Table 2.Table 2: Mean +- SD Pharmacokinetic Parameters of PREMARIN Following Daily Administration (7 Days) of PREMARIN Vaginal Cream 0.5 in 24 Postmenopausal WomenPharmacokinetic Profiles of Unconjugated EstrogensPREMARIN Vaginal Cream 0.5 gPK ParametersArithmetic Mean +- SDCmax(pg/mL)Tmax(hr)AUCss(pgohr/mL)Estrone42.0 +- 13.97.4 +- 6.2826 +- 295Baseline-adjusted estrone21.9 +- 13.17.4 +- 6.2365 +- 255Estradiol12.8 +- 16.68.5 +- 6.2231 +- 285Baseline-adjusted estradiol9.14 +- 14.78.5 +- 6.2161 +- 252Pharmacokinetic Profiles of Conjugated EstrogensPREMARIN Vaginal Cream 0.5 gPK ParametersArithmetic Mean +- SDCmax(ng/mL)Tmax(hr)AUCss(ngohr/mL)Total estrone0.60 +- 0.326.0 +- 4.09.75 +- 4.99Baseline-adjusted total estrone0.40 +- 0.286.0 +- 4.05.79 +- 3.7Total estradiol0.04 +- 0.047.7 +- 5.90.70 +- 0.42Baseline-adjusted total estradiol0.04 +- 0.047.7 +- 6.00.49 +- 0.38Total equilin0.12 +- 0.156.1 +- 4.73.09 +- 1.37. DistributionThe 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. MetabolismExogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in 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 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, significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as circulating reservoir for the formation of more active estrogens. ExcretionEstradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Use in Specific PopulationsNo pharmacokinetic studies were conducted in specific populations, including patients with renal or hepatic impairment.

PREGNANCY SECTION.

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.

RECENT MAJOR CHANGES SECTION.

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

REFERENCES SECTION.

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 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;289:3234-3253. 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 Womens Health Initiative Randomized Trial. Bone Miner Res. 2006;21:817-828. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Womens Health Initiative. Circulation. 2006;113:2425-2434. 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 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;289:3234-3253. 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 Womens Health Initiative Randomized Trial. Bone Miner Res. 2006;21:817-828. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Womens Health Initiative. Circulation. 2006;113:2425-2434.

USE IN SPECIFIC POPULATIONS SECTION.

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 Womens Health Initiative Memory ancillary studies of the Womens Health Initiative (5.4, 8.5). 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 Womens Health Initiative Memory ancillary studies of the Womens 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 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 Womens Health Initiative StudiesIn the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was 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 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 Womens Health Initiative Memory StudyIn the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.4), and Clinical Studies (14.3)].Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see Warnings and Precautions (5.4), and Clinical Studies (14.3)].. 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.

WARNINGS AND PRECAUTIONS SECTION.

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). 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 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.. StrokeIn the WHI estrogen-alone substudy, 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 and persisted [see Clinical Studies (14.2)]. Should 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, 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 stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.. Coronary Heart DiseaseIn 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 placebo2 [see Clinical Studies (14.2)].Subgroup analyses of women 50 to 59 years of age suggest 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 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 trend toward decreasing relative risk was reported in years through [see Clinical Studies (14.2)]. In postmenopausal women with documented heart disease (n 2,763), average 66.7 years of age, in controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during subsequent years. Two thousand, three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall.. Venous ThromboembolismIn the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily CE (0.625 mg) -alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first years3 [see Clinical Studies (14.2)]. Should VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately.In the WHI estrogen plus progestin substudy, statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus per 10,000 women-years) were also demonstrated. The increase in VTE risk was observed during the first year and persisted4 [see Clinical Studies (14.2)]. Should VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. If feasible, estrogens should be discontinued at least to weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.. 5.3 Malignant Neoplasms. Endometrial CancerAn increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in woman with uterus. The reported endometrial cancer risk among unopposed estrogen users is about to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than year. The greatest risk appears to be associated with prolonged use, with increased risks of 15- to 24-fold for to 10 years or more, and this risk has been shown to persist for at least to 15 years after estrogen therapy is discontinued.Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. 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. There is no evidence that the use of natural estrogens results in different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding progestin to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be precursor to endometrial cancer.In 52-week clinical trial using PREMARIN Vaginal Cream alone (0.5 inserted twice weekly or daily for 21 days, then off for days), there was no evidence of endometrial hyperplasia or endometrial carcinoma.. Breast CancerThe most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg) -alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] [see Clinical Studies (14.2)].The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups6 [see Clinical Studies (14.2)].Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.The use of estrogen-alone and estrogen plus progestin therapy has been reported to result in an increase in abnormal mammograms, requiring further evaluation.All women should receive yearly breast examinations by healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.. Ovarian CancerThe WHI estrogen plus progestin substudy reported statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24). The absolute risk for CE plus MPA versus placebo was versus cases per 10,000 women-years.7 meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than years [median of years] vs. greater than years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within years before cancer diagnosis) was 1.37 (95% CI 1.27-1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.. 5.4 Probable Dementia In the WHIMS estrogen-alone ancillary study of WHI, population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg) -alone or placebo.After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8 [see Use in Specific Populations (8. 5), and Clinical Studies (14.3)].In the WHIMS estrogen plus progestin ancillary study of WHI, population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.After an average follow-up of years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8 [see Use in Specific Populations (8. 5), and Clinical Studies (14.3)].When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see Use in Specific Populations (8.5), and Clinical Studies (14.3)].. 5.5 Gallbladder Disease. 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.. 5.6 Hypercalcemia. Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.. 5.7 Visual Abnormalities. Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.. 5.8 Addition of Progestin When Woman Has Not Had Hysterectomy. Studies of the addition of progestin for 10 or more days of cycle of estrogen administration, or daily with estrogen in continuous regimen, have reported lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be precursor to endometrial cancer.There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.. 5.9 Elevated Blood Pressure In small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In large, randomized, placebo-controlled clinical trial, generalized effect of estrogen therapy on blood pressure was not seen. 5.10 Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.. 5.11 Hepatic Impairment and/or Past History of Cholestatic Jaundice. Estrogens may be poorly metabolized in women with impaired liver function. For women with history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued.. 5.12 Hypothyroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.. 5.13 Fluid Retention. Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogen-alone is prescribed.. 5.14 Hypocalcemia. Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. 5.15 Exacerbation of Endometriosis. few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.. 5.16 Anaphylactic Reaction and Angioedema. Cases of anaphylaxis, which develop within minutes to hours after taking orally-administered PREMARIN and require emergency management, have been reported in the postmarketing setting. Skin (hives, pruritus, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) involvement has been noted. Angioedema involving the tongue, larynx, face, and feet requiring medical intervention has occurred postmarketing in patients taking orally-administered PREMARIN. If angioedema involves the tongue, glottis, or larynx, airway obstruction may occur. Patients who develop an anaphylactic reaction with or without angioedema after treatment with oral PREMARIN should not receive oral PREMARIN again. 5.17 Hereditary Angioedema. Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. 5.18 Exacerbation of Other Conditions. Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.. 5.19 Effects on Barrier Contraception. PREMARIN Vaginal Cream exposure has been reported to weaken latex condoms. The potential for PREMARIN Vaginal Cream to weaken and contribute to the failure of condoms, diaphragms, or cervical caps made of latex or rubber should be considered.. 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. 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), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels.Impaired glucose tolerance.