NDC 0046-1104 Premarin

Estrogens, Conjugated

NDC Product Code 0046-1104

NDC CODE: 0046-1104

Proprietary Name: Premarin What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Estrogens, Conjugated What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This medication is a female hormone. It is used by women to help reduce symptoms of menopause (such as hot flashes, vaginal dryness). These symptoms are caused by the body making less estrogen. If you are using this medication to treat symptoms only in and around the vagina, products applied directly inside the vagina should be considered before medications that are taken by mouth, absorbed through the skin, or injected. Certain estrogen products may also be used by women after menopause to prevent bone loss (osteoporosis). However, there are other medications (such as raloxifene, bisphosphonates including alendronate) that are also effective in preventing bone loss and may be safer. These medications should be considered for use before estrogen treatment. Certain estrogen products may also be used by men and women to treat cancers (certain types of prostate cancer, breast cancer that has spread to other parts of the body) and by women who are not able to produce enough estrogen (for example, due to hypogonadism, primary ovarian failure).

Product Characteristics

Color(s):
BLUE (C48333 - BLUE)
BROWN (C48332 - MAROON)
YELLOW (C48330 - YELLOW)
Shape: OVAL (C48345)
Size(s):
10 MM
14 MM
Imprint(s):
PREMARIN;045
PREMARIN;0625
PREMARIN;125
Score: 1

NDC Code Structure

NDC 0046-1104-81

Package Description: 100 TABLET, FILM COATED in 1 BOTTLE

NDC 0046-1104-91

Package Description: 1 BOTTLE in 1 CARTON > 1000 TABLET, FILM COATED in 1 BOTTLE

NDC Product Information

Premarin with NDC 0046-1104 is a a human prescription drug product labeled by Wyeth Pharmaceuticals Llc, A Subsidiary Of Pfizer Inc.. The generic name of Premarin is estrogens, conjugated. The product's dosage form is tablet, film coated and is administered via oral form.

Labeler Name: Wyeth Pharmaceuticals Llc, A Subsidiary Of Pfizer Inc.

Dosage Form: Tablet, Film Coated - A solid dosage form that contains medicinal substances with or without suitable diluents and is coated with a thin layer of a water-insoluble or water-soluble polymer.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Premarin Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • ESTROGENS, CONJUGATED 1.25 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • TRIBASIC CALCIUM PHOSPHATE (UNII: 91D9GV0Z28)
  • HYDROXYPROPYL CELLULOSE (1200000 MW) (UNII: RFW2ET671P)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • POWDERED CELLULOSE (UNII: SMD1X3XO9M)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)
  • SUCROSE (UNII: C151H8M554)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
  • CARNAUBA WAX (UNII: R12CBM0EIZ)
  • HYPROMELLOSE 2208 (15000 MPA.S) (UNII: Z78RG6M2N2)
  • HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)
  • HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W)
  • TRIBASIC CALCIUM PHOSPHATE (UNII: 91D9GV0Z28)
  • HYDROXYPROPYL CELLULOSE (1200000 MW) (UNII: RFW2ET671P)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • POWDERED CELLULOSE (UNII: SMD1X3XO9M)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)
  • SUCROSE (UNII: C151H8M554)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
  • FD&C RED NO. 40 (UNII: WZB9127XOA)
  • CARNAUBA WAX (UNII: R12CBM0EIZ)
  • HYPROMELLOSE 2208 (15000 MPA.S) (UNII: Z78RG6M2N2)
  • HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)
  • HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W)
  • TRIBASIC CALCIUM PHOSPHATE (UNII: 91D9GV0Z28)
  • HYDROXYPROPYL CELLULOSE (1200000 MW) (UNII: RFW2ET671P)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • POWDERED CELLULOSE (UNII: SMD1X3XO9M)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)
  • SUCROSE (UNII: C151H8M554)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)
  • FD&C YELLOW NO. 6 (UNII: H77VEI93A8)
  • CARNAUBA WAX (UNII: R12CBM0EIZ)
  • HYPROMELLOSE 2208 (15000 MPA.S) (UNII: Z78RG6M2N2)
  • HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)
  • HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Estrogen - [EPC] (Established Pharmacologic Class)
  • Estrogen Receptor Agonists - [MoA] (Mechanism of Action)
  • Estrogens -
  • Conjugated (USP) - [CS]

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Wyeth Pharmaceuticals Llc, A Subsidiary Of Pfizer Inc.
Labeler Code: 0046
FDA Application Number: NDA004782 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 09-01-2004 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Information for Patients

Estrogen

Estrogen is pronounced as (ess' troe jen)

Why is estrogen medication prescribed?
Estrogen is used to treat hot flushes ('hot flashes'; sudden strong feelings of heat and sweating) in women who are experiencing menopause ('change of life', the end of m...
[Read More]

* Please review the disclaimer below.

Premarin Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Other

Estrogen-Alone Therapy

Endometrial CancerThere is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2)].

Cardiovascular Disorders and Probable DementiaEstrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 14.6)].The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo[see Warnings and Precautions (5.1), and Clinical Studies (14.5)].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 (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.6)].In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens.Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Estrogen Plus Progestin Therapy

Cardiovascular Disorders and Probable DementiaEstrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 14.6)].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 (5.1), and Clinical Studies (14.5)].The WHIMS estrogen plus progestin ancillary study of the WHI, reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.6)].

Breast CancerThe WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.5)].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.

Limitation of UseWhen prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, topical vaginal products should be considered.

Limitation of UseWhen prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

StrokeIn 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 (14.5)]. 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).1In 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 (14.5)]. 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 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 (14.5)]. 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).1In 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 (14.5)].In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established CHD. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand, three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE (0.625 mg) plus MPA (2.5 mg) group and the placebo group in HERS, HERS II, and overall.

Venous Thromboembolism (VTE)In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE), was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years3 [see Clinical Studies (14.5)]. Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately. In the WHI estrogen plus progestin substudy, a 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 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted4 [see Clinical Studies (14.5)]. Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Endometrial CancerAn increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 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 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women using estrogen-alone or estrogen plus 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 a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

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 (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80]5 [see Clinical Studies (14.5)]. 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 a 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.6 Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups [see Clinical Studies (14.5)]. Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 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 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 has been reported to result in an increase in abnormal mammograms, requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

Ovarian CancerThe WHI estrogen plus progestin substudy reported a 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 4 versus 3 cases per 10,000 women-years.7A 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 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27–1.48), 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.

Genitourinary systemAbnormal uterine bleeding; dysmenorrheal or pelvic pain, increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis, change in cervical secretion, ovarian cancer, endometrial hyperplasia, endometrial cancer, leukorrhea.

BreastsTenderness, enlargement, pain, discharge, galactorrhea, fibrocystic breast changes, breast cancer, gynecomastia in males.

CardiovascularDeep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, stroke, increase in blood pressure.

GastrointestinalNausea, vomiting, abdominal pain, bloating, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis, enlargement of hepatic hemangiomas, ischemic colitis.

SkinChloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, loss of scalp hair, hirsutism, pruritus, rash.

EyesRetinal vascular thrombosis, intolerance to contact lenses.

Central nervous systemHeadache, migraine, dizziness , mental depression, nervousness, mood disturbances, irritability, exacerbation of epilepsy, dementia, possible growth potentiation of benign meningioma.

MiscellaneousIncrease or decrease in weight, glucose intolerance, aggravation of porphyria, edema, arthralgias, leg cramps, changes in libido, urticaria, exacerbation of asthma, increased triglycerides, hypersensitivity.

The Women's Health Initiative StudyIn the WHI estrogen-alone substudy (daily CE 0.625 mg-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.5)]. In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg]), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies (14.5)].

The Women's 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 (5.3), and Clinical Studies (14.6)]. 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 (5.3), and Clinical Studies (14.6)].

AbsorptionConjugated estrogens are water-soluble and are absorbed from the gastrointestinal tract after release from the drug formulation. The PREMARIN tablet releases conjugated estrogens slowly over several hours. Table 2 summarizes the mean pharmacokinetic parameters for unconjugated and conjugated estrogens following administration of 1 × 0.625 mg and 1 × 1.25 mg tablets to healthy postmenopausal women.

Food effect: The pharmacokinetics of PREMARIN 0.45 mg and 1.25 mg tablets were assessed following a single dose with a high-fat breakfast and with fasting administration. The Cmax and AUC of estrogens were altered approximately 3–13%. The changes to Cmax and AUC are not considered clinically meaningful, therefore PREMARIN may be taken without regard to meals. TABLE 2: PHARMACOKINETIC PARAMETERS FOR PREMARINPharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 × 0.625 mgPK Parameter Arithmetic Mean (%CV)Cmax (pg/mL)tmax (h)t1/2 (h)AUC (pg∙h/mL)Estrone87 (33)9.6 (33)50.7 (35)5557 (59)Baseline-adjusted estrone64 (42)9.6 (33)20.2 (40)1723 (52)Equilin31 (38)7.9 (32)12.9 (112)602 (54)Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 × 0.625 mgPK Parameter Arithmetic Mean (%CV)Cmax (ng/mL)tmax (h)t1/2 (h)AUC (ng∙h/mL)Total Estrone2.7 (43)6.9 (25)26.7 (33)75 (52)Baseline-adjusted total estrone2.5 (45)6.9 (25)14.8 (35)46 (48)Total Equilin1.8 (56)5.6 (45)11.4 (31)27 (56)Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 × 1.25 mgPK Parameter Arithmetic Mean (%CV)Cmax (pg/mL)tmax (h)t1/2 (h)AUC (pg∙h/mL)Estrone124 (30)10.0 (32)38.1 (37)6332 (44)Baseline-adjusted estrone102 (35)10.0 (32)19.7 (48)3159 (53)Equilin59 (43)8.8 (36)10.9 (47)1182 (42)Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 × 1.25 mgPK Parameter Arithmetic Mean (%CV)Cmax (ng/mL)tmax (h)t1/2 (h)AUC (ng∙h/mL)Total Estrone4.5 (39)8.2 (58)26.5 (40)109 (46)Baseline-adjusted total estrone4.3 (41)8.2 (58)17.5 (41)87 (44)Total equilin2.9 (42)6.8 (49)12.5 (34)48 (51)

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 sex hormone-binding globulin (SHBG) and albumin.

MetabolismExogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

ExcretionEstradiol, estrone, and estriol are excreted in the urine, along with glucuronide and sulfate conjugates.

Use in Specific PopulationsNo pharmacokinetic studies were conducted with Premarin in specific populations, including patients with renal or hepatic impairment.

Health and Osteoporosis, Progestin and Estrogen (HOPE) StudyThe HOPE study was a double-blind, randomized, placebo/active-drug-controlled, multicenter study of healthy postmenopausal women with an intact uterus. Subjects (mean age 53.3 ± 4.9 years) were 2.3 ± 0.9 years on average since menopause and took one 600 mg tablet of elemental calcium (Caltrate™) daily. Subjects were not given Vitamin D supplements. They were treated with PREMARIN 0.625 mg, 0.45 mg, 0.3 mg, or placebo. Prevention of bone loss was assessed by measurement of bone mineral density (BMD), primarily at the anteroposterior lumbar spine (L2 to L4). Secondarily, BMD measurements of the total body, femoral neck, and trochanter were also analyzed. Serum osteocalcin, urinary calcium, and N-telopeptide were used as bone turnover markers (BTM) at cycles 6, 13, 19, and 26.

Intent-to-treat subjectsAll active treatment groups showed significant differences from placebo in each of the four BMD endpoints at cycles 6, 13, 19, and 26. The mean percent increases in the primary efficacy measure (L2 to L4 BMD) at the final on-therapy evaluation (cycle 26 for those who completed and the last available evaluation for those who discontinued early) were 2.46 percent with 0.625 mg, 2.26 percent with 0.45 mg, and 1.13 percent with 0.3 mg. The placebo group showed a mean percent decrease from baseline at the final evaluation of 2.45 percent. These results show that the lower dosages of PREMARIN were effective in increasing L2 to L4 BMD compared with placebo, and therefore support the efficacy of the lower doses.The analysis for the other three BMD endpoints yielded mean percent changes from baseline in femoral trochanter that were generally larger than those seen for L2 to L4, and changes in femoral neck and total body that were generally smaller than those seen for L2 to L4. Significant differences between groups indicated that each of the PREMARIN treatments was more effective than placebo for all three of these additional BMD endpoints. With regard to femoral neck and total body, the active treatment groups all showed mean percent increases in BMD, while placebo treatment was accompanied by mean percent decreases. For femoral trochanter, each of the PREMARIN dose groups showed a mean percent increase that was significantly greater than the small increase seen in the placebo group. The percent changes from baseline to final evaluation are shown in Table 4. TABLE 4: PERCENT CHANGE IN BONE MINERAL DENSITY: COMPARISON BETWEEN ACTIVE AND PLACEBO GROUPS IN THE INTENT-TO-TREAT POPULATION, LOCFRegion Evaluated Treatment GroupIdentified by dosage (mg) of PREMARIN or placebo.No. of SubjectsBaseline (g/cm2) Mean ± SDChange from Baseline (%) Adjusted Mean ± SEp-Value vs. PlaceboL2 to L4 BMD0.625831.17 ± 0.152.46 ± 0.37<0.0010.45911.13 ± 0.152.26 ± 0.35<0.0010.3871.14 ± 0.151.13 ± 0.36<0.001Placebo851.14 ± 0.14-2.45 ± 0.36Total Body BMD0.625841.15 ± 0.080.68 ± 0.17<0.0010.45911.14 ± 0.080.74 ± 0.16<0.0010.3871.14 ± 0.070.40 ± 0.17<0.001Placebo851.13 ± 0.08-1.50 ± 0.17Femoral Neck BMD0.625840.91 ± 0.141.82 ± 0.45<0.0010.45910.89 ± 0.131.84 ± 0.44<0.0010.3870.86 ± 0.110.62 ± 0.45<0.001Placebo850.88 ± 0.14-1.72 ± 0.45Femoral Trochanter BMD0.625840.78 ± 0.133.82 ± 0.58<0.0010.45910.76 ± 0.123.16 ± 0.560.0030.3870.75 ± 0.103.05 ± 0.570.005Placebo850.75 ± 0.120.81 ± 0.58Figure 1 shows the cumulative percentage of subjects with changes from baseline equal to or greater than the value shown on the x-axis.Figure 1. CUMULATIVE PERCENT OF SUBJECTS WITH CHANGES FROM BASELINE IN SPINE BMD OF GIVEN MAGNITUDE OR GREATER IN PREMARIN AND PLACEBO GROUPSThe mean percent changes from baseline in L2 to L4 BMD for women who completed the bone density study are shown with standard error bars by treatment group in Figure 2. Significant differences between each of the PREMARIN dosage groups and placebo were found at cycles 6, 13, 19, and 26.Figure 2. ADJUSTED MEAN (SE) PERCENT CHANGE FROM BASELINE AT EACH CYCLE IN SPINE BMD: SUBJECTS COMPLETING IN PREMARIN GROUPS AND PLACEBOThe bone turnover markers, serum osteocalcin and urinary N-telopeptide, significantly decreased (p < 0.001) in all active-treatment groups at cycles 6, 13, 19, and 26 compared with the placebo group. Larger mean decreases from baseline were seen with the active groups than with the placebo group. Significant differences from placebo were seen less frequently in urine calcium.

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 5.TABLE 5: 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.Event Relative RiskCE vs. Placebo CEn = 5,310 Placebon = 5,429 (95% nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons.) Absolute Risk per 10,000 Women-Years CHD 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 Stroke1.33 (1.05–1.68) 4533  Ischemic stroke1.55 (1.19–2.01)3825Deep vein thrombosis,Not included in "global index."1.47 (1.06–2.06) 2315Pulmonary embolism1.37 (0.90–2.07) 14 10 Invasive breast cancer0.80 (0.62–1.04) 2834Colorectal cancerResults are based on an average follow-up of 6.8 years. 1.08 (0.75–1.55) 1716 Hip fracture0.65 (0.45–0.94) 12 19Vertebral 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/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 a "global index" defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. 1.02 (0.92–1.13) 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 7 fewer hip fractures.9 The absolute excess risk of events included in the "global index" was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow up of 7.1 years. See Table 5.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.10Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50–59 years of age, a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 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 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the estrogen plus progestin 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 6. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.TABLE 6: 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.Relative Risk CE/MPA vs. Placebo CE/MPAn = 8,506 Placebon = 8,102 Event(95% nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons. )Absolute Risk per 10,000 Women-Years CHD events 1.23 (0.99–1.53) 4134  Non-fatal MI1.28 (1.00–1.63)3125  CHD death1.10 (0.70–1.75)88All Strokes1.31 (1.03–1.68) 3325  Ischemic stroke1.44 (1.09–1.90)2618Deep vein thrombosisNot included in "global index."1.95 (1.43–2.67) 2613Pulmonary embolism2.13 (1.45–3.11) 18 8Invasive 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 cancer0.81 (0.48–1.36) 67 Cervical cancer1.44 (0.47–4.42) 21Hip fracture0.67 (0.47–0.96) 1116 Vertebral fractures0.65 (0.46–0.92) 1117Lower arm/wrist fractures0.71 (0.59–0.85) 4462 Total fractures0.76 (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 a "global index" defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.1.13 (1.02–1.25) 184 165 Timing of the initiation of estrogen therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50–59 years of age, a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI 0.44–1.07)].

LAB-0467-6.0

2 Dosage And Administration

Generally, when estrogen therapy is prescribed for a postmenopausal woman with a uterus, a progestin should be considered to reduce the risk of endometrial cancer [see Boxed Warning].A woman without a uterus does not need progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a progestin [see Warnings and Precautions (5.2, 5.16)]. 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. PREMARIN may be taken without regard to meals.

2.1 Treatment Of Moderate To Severe Vasomotor Symptoms Due To Menopause

Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg PREMARIN daily. Subsequent dosage adjustment may be made based upon the individual patient response. This dose should be periodically reassessed by the healthcare provider.PREMARIN therapy may be given continuously, with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by 5 days off drug), as is medically appropriate on an individual basis.

2.2 Treatment Of Moderate To Severe Symptoms Of Vulvar And Vaginal Atrophy Due To Menopause

Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg PREMARIN daily. Subsequent dosage adjustment may be made based upon the individual patient response. This dose should be periodically reassessed by the healthcare provider.PREMARIN therapy may be given continuously, with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by 5 days off drug), as is medically appropriate on an individual basis.

2.3 Treatment Of Hypoestrogenism Due To Hypogonadism, Castration, Or Primary Ovarian Failure

PREMARIN therapy should be initiated and maintained with the lowest effective dose to achieve clinical goals. Female hypogonadism: 0.3 mg or 0.625 mg daily, administered cyclically (e.g., three weeks on and one week off). Doses are adjusted depending on the severity of symptoms and responsiveness of the endometrium [see Clinical Studies (14.4)].Female castration or primary ovarian failure: 1.25 mg daily, cyclically. Adjust dosage, upward or downward, according to severity of symptoms and response of the patient. For maintenance, adjust dosage to lowest level that will provide effective control.

2.4 Treatment Of Breast Cancer (For Palliation Only) In Appropriately Selected Women And Men With Metastatic Disease

Suggested dosage is 10 mg three times daily, for a period of at least three months.

2.5 Treatment Of Advanced Androgen-Dependent Carcinoma Of The Prostate (For Palliation Only)

1.25 mg to 2 × 1.25 mg three times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as by symptomatic improvement of the patient.

2.6 Prevention Of Postmenopausal Osteoporosis

PREMARIN therapy may be given continuously, with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by 5 days off drug), as is medically appropriate on an individual basis.Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg PREMARIN daily. Subsequent dosage adjustment may be made based upon the individual clinical and bone mineral density responses. This dose should be periodically reassessed by the healthcare provider.

3 Dosage Forms And Strengths

PREMARIN (conjugated estrogens tablets, USP)Tablet StrengthTablet Shape/ColorImprint 0.3 mgoval/greenPREMARIN 0.30.45 mgoval/bluePREMARIN 0.450.625 mgoval/maroonPREMARIN 0.6250.9 mgoval/whitePREMARIN 0.91.25 mgoval/yellowPREMARIN 1.25

4 Contraindications

  • PREMARIN therapy is contraindicated in individuals with any of the following conditions: Undiagnosed abnormal genital bleedingKnown, suspected, or history of breast cancer except in appropriately selected patients being treated for metastatic disease Known or suspected estrogen-dependent neoplasiaActive DVT, PE, or a history of these conditionsActive arterial thromboembolic disease (for example stroke and MI), or a history of these conditionsKnown anaphylactic reaction or angioedema with Premarin Known liver impairment or diseaseKnown protein C, protein S or antithrombin deficiency, or other known thrombophilic disorders. Known or suspected pregnancy

5.1 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 or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

5.3 Probable Dementia

In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 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 (14.6)].In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 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 (14.6)].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 (14.6)].

5.4 Gallbladder Disease

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

5.5 Hypercalcemia

Estrogen administration may lead to severe hypercalcemia in patients 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.

5.6 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 a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.

5.7 Anaphylactic Reaction And Angioedema

Cases of anaphylaxis, which developed within minutes to hours after taking PREMARIN and require emergency medical management, have been reported in the postmarketing setting. Skin (hives, pruritis, 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, hands, and feet requiring medical intervention has occurred postmarketing in patients taking 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 PREMARIN should not receive PREMARIN again.

5.8 Addition Of A Progestin When A Woman Has Not Had A Hysterectomy

Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.

5.9 Elevated Blood Pressure

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of 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 patients with impaired liver function. For women with a 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 individuals with hypoparathyroidism as estrogen-induced hypocalcemia may occur.

5.15 Hereditary Angioedema

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

5.16 Exacerbation Of Endometriosis

A 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.

5.17 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.

5.18 Laboratory Tests

Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy. Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian failure.

5.19 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) levels leading to increased circulating total thyroid hormone levels 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.

6 Adverse Reactions

  • The following serious adverse reactions are discussed elsewhere in labeling:Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)]Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)]

6.1 Clinical Study Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.During the first year of a 2-year clinical trial with 2,333 postmenopausal women with a uterus between 40 and 65 years of age (88 percent Caucasian), 1,012 women were treated with conjugated estrogens, and 332 were treated with placebo. Table 1 summarizes treatment-related adverse reactions that occurred at a rate of ≥ 1 percent in any treatment group.Table 1: TREATMENT RELATED ADVERSE REACTIONS AT A FREQUENCY ≥ 1 PERCENTPREMARIN0.625 mg(n=348)PREMARIN0.45 mg (n=338)PREMARIN0.3 mg(n=326)Placebo(n=332)Body as a whole  Abdominal pain38 (11)28 (8)30 (9)21 (6)  Asthenia 16 (5)8 (2)14 (4)3 (1)  Back pain 18 (5)11 (3)13 (4)4 (1)  Chest pain 2 (1)3 (1)4 (1)2 (1)  Generalized edema 7 (2)6 (2)4 (1)8 (2)  Headache 45 (13)47 (14)44 (13)46 (14)  Moniliasis 5 (1)4 (1)4 (1)1 (0)  Pain 17 (5)10 (3)12 (4)14 (4)  Pelvic pain 10 (3)9 (3)8 (2)4 (1)Cardiovascular system   Hypertension 4 (1)4 (1)7 (2)5 (2)  Migraine 7 (2)1 (0)03 (1)  Palpitation 3 (1)3 (1)3 (1)4 (1)  Vasodilatation 2 (1)2 (1)3 (1)5 (2)Digestive system   Constipation 7 (2)6 (2)4 (1)3 (1)  Diarrhea 4 (1)5 (1)5 (2)8 (2)  Dyspepsia 7 (2)5 (1)6 (2)14 (4)  Eructation 1 (0)1 (0)4 (1)1 (0)  Flatulence 22 (6)18 (5)13 (4)8 (2)  Increased appetite 4 (1)1 (0)1 (0)2 (1)  Nausea 16 (5)10 (3)15 (5)16 (5)Metabolic and nutritional   Hyperlipidemia 2 (1)4 (1)3 (1)2 (1)  Peripheral edema 5 (1)2 (1)4 (1)3 (1)  Weight gain 11 (3)10 (3)8 (2)14 (4)Musculoskeletal system  Arthralgia 6 (2)3 (1)2 (1)5 (2)  Leg cramps 10 (3)5 (1)9 (3)4 (1)  Myalgia 2 (1)1 (0)4 (1)1 (0)Nervous system  Anxiety 6 (2)4 (1)2 (1)4 (1)  Depression 17 (5)15 (4)10 (3)17 (5)  Dizziness9 (3)7 (2)4 (1)5 (2)  Emotional lability 3 (1)4 (1)5 (2)8 (2)  Hypertonia 1 (0)1 (0)5 (2)3 (1)  Insomnia 16 (5)10 (3)13 (4)14 (4)  Nervousness 9 (3)12 (4)2 (1)6 (2)Skin and appendages  Acne 3 (1)1 (0)8 (2)3 (1)  Alopecia 6 (2)6 (2)5 (2)2 (1)  Hirsutism 4 (1)2 (1)1 (0)0  Pruritus 11 (3)11 (3)10 (3)3 (1)  Rash 6 (2)3 (1)1 (0)2 (1)  Skin discoloration 4 (1)2 (1)01 (0)  Sweating 4 (1)1 (0)3 (1)4 (1)Urogenital system   Breast disorder 6 (2)3 (1)3 (1)6 (2)  Breast enlargement 3 (1)4 (1)7 (2)3 (1)  Breast neoplasm 4 (1)4 (1)7 (2)7 (2)  Breast pain 37 (11)39 (12)24 (7)26 (8)  Cervix disorder 8 (2)4 (1)5 (2)0  Dysmenorrhea 12 (3)10 (3)4 (1)2 (1)  Endometrial disorder 4 (1)2 (1)2 (1)0  Endometrial hyperplasia 16 (5)8 (2)1 (0)0  Leukorrhea 17 (5)17 (5)12 (4)6 (2)  Metrorrhagia 11 (3)4 (1)3 (1)1 (0)  Urinary tract infection 1 (0)2 (1)1 (0)4 (1)  Uterine fibroids enlarged 6 (2)1 (0)2 (1)2 (1)  Uterine spasm 11 (3)5 (1)3 (1)2 (1)  Vaginal dryness 1 (0)2 (1)1 (0)6 (2)  Vaginal hemorrhage 46 (13)13 (4)6 (2)0  Vaginal moniliasis 14 (4)10 (3)12 (4)5 (2)  Vaginitis 18 (5)7 (2)9 (3)1 (0)

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during post-approval use of PREMARIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible always to reliably estimate their frequency or establish a causal relationship to drug exposure.

7 Drug Interactions

Data from a single-dose drug-drug interaction study involving conjugated estrogens and medroxyprogesterone acetate indicate that the pharmacokinetic disposition of both drugs is not altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been conducted with conjugated estrogens.

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

PREMARIN 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 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 mothers receiving estrogen-alone therapy. Caution should be exercised when PREMARIN is administered to a nursing woman.

8.4 Pediatric Use

Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established.Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration.Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the normal pubertal process and induce gynecomastia.

8.5 Geriatric Use

There have not been sufficient numbers of geriatric patients involved in studies utilizing PREMARIN to determine whether those over 65 years of age differ from younger subjects in their response to PREMARIN.

8.6 Renal Impairment

The effect of renal impairment on the pharmacokinetics of PREMARIN has not been studied.

8.7 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of PREMARIN has not been studied.

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.

11 Description

PREMARIN® (conjugated estrogens tablets, USP) for oral administration contains a mixture of conjugated estrogens purified from pregnant mares' urine and consists of the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains concomitant components as sodium sulfate conjugates, 17α-dihydroequilin, 17α estradiol, and 17β-dihydroequilin. Tablets for oral administration are available in 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg strengths of conjugated estrogens.PREMARIN 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg tablets also contain the following inactive ingredients: calcium phosphate tribasic, carnauba wax, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, powdered cellulose, sucrose, and titanium dioxide. Each tablet strength contains the following colors: Tablet strengthTablet color contains0.3 mgD&C Yellow No. 10 and FD&C Blue No. 20.45 mgFD&C Blue No. 20.625 mgFD&C Blue No. 2 and FD&C Red No. 400.9 mgD&C Red No. 30 and D&C Red No. 71.25 mgBlack iron oxide, D&C Yellow No. 10 and FD&C Yellow No. 6PREMARIN tablets comply with USP Dissolution Test criteria, as outlined below:PREMARIN 1.25 mg tabletsUSP Dissolution Test 4PREMARIN 0.3 mg, 0.45 mg and 0.625 mg tabletsUSP Dissolution Test 5PREMARIN 0.9 mg tabletsUSP Dissolution Test 6

12.1 Mechanism Of Action

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

12.2 Pharmacodynamics

There are no pharmacodynamic data for PREMARIN.

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.

14.1 Effects On Vasomotor Symptoms

In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2,805 postmenopausal women (average age 53.3 ± 4.9 years) were randomly assigned to one of eight treatment groups of either placebo or conjugated estrogens, with or without medroxyprogesterone acetate. Efficacy for vasomotor symptoms was assessed during the first 12 weeks of treatment in a subset of symptomatic women (n = 241) who had at least seven moderate to severe hot flushes daily, or at least 50 moderate to severe hot flushes during the week before randomization. PREMARIN (0.3 mg, 0.45 mg, and 0.625 mg tablets) was shown to be statistically better than placebo at weeks 4 and 12 for relief of both frequency and severity of moderate to severe vasomotor symptoms. Table 3 shows the adjusted mean number of hot flushes in the PREMARIN 0.3 mg, 0.45 mg, and 0.625 mg and placebo groups during the initial 12-week period.Table 3: SUMMARY TABULATION OF THE NUMBER OF HOT FLUSHES PER DAY – MEAN VALUES AND COMPARISONS BETWEEN THE ACTIVE TREATMENT GROUPS AND THE PLACEBO GROUP: PATIENTS WITH AT LEAST 7 MODERATE TO SEVERE FLUSHES PER DAY OR AT LEAST 50 PER WEEK AT BASELINE, LAST OBSERVATION CARRIED FORWARD (LOCF) Treatment (No. of Patients)---------------No. of Hot Flushes/Day---------------Time Period (week)Baseline Mean ± SDObserved Mean ± SDMean Change ± SDp-Values vs PlaceboBased on analysis of covariance with treatment as factor and baseline as covariate.0.625 mg CE (n = 27)412.29 ± 3.891.95 ± 2.77-10.34 ± 4.73<0.0011212.29 ± 3.890.75 ± 1.82-11.54 ± 4.62<0.0010.45 mg CE (n = 32)412.25 ± 5.045.04 ± 5.31-7.21 ± 4.75<0.0011212.25 ± 5.042.32 ± 3.32-9.93 ± 4.64<0.0010.3 mg CE (n = 30)413.77 ± 4.784.65 ± 3.71-9.12 ± 4.71<0.0011213.77 ± 4.782.52 ± 3.23-11.25 ± 4.60<0.001Placebo (n = 28)411.69 ± 3.877.89 ± 5.28-3.80 ± 4.71-1211.69 ± 3.875.71 ± 5.22-5.98 ± 4.60-

14.2 Effects On Vulvar And Vaginal Atrophy

Results of vaginal maturation indexes at cycles 6 and 13 showed that the differences from placebo were statistically significant (p < 0.001) for all treatment groups. (conjugated estrogens alone and conjugated estrogens/medroxyprogesterone acetate treatment groups).

14.4 Effects On Female Hypogonadism

In clinical studies of delayed puberty due to female hypogonadism, breast development was induced by doses as low as 0.15 mg. The dosage may be gradually titrated upward at 6-to 12 month intervals as needed to achieve appropriate bone age advancement and eventual epiphyseal closure. Clinical studies suggest that doses of 0.15 mg, 0.3 mg, and 0.6 mg are associated with mean ratios of bone age advancement to chronological age progression (ΔBA/ΔCA) of 1.1, 1.5, and 2.1, respectively. (PREMARIN in the dose strength of 0.15 mg is not available commercially). Available data suggest that chronic dosing with 0.625 mg is sufficient to induce artificial cyclic menses with sequential progestin treatment and to maintain bone mineral density after skeletal maturity is achieved.

14.5 Women's Health Initiative Studies

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms.

14.6 Women's Health Initiative Memory Study

The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)- alone on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI 0.83–2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo groups 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 (5.3), and Use in Specific Populations (8.5)]. The WHIMS estrogen plus progestin ancillary study enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years; 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA was 2.05 (95 percent CI, 1.21–3.48). The absolute risk of probable dementia for CE (0.625 mg) plus MPA (2.5 mg) 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 both the treatment and placebo groups 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 (5.3), 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 (5.3), and Use in Specific Populations (8.5)].

15 References

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

16.1 How Supplied

  • PREMARIN (conjugated estrogens tablets, USP)— Each oval green tablet contains 0.3 mg, in bottles of 100 (NDC 0046-1100-81) and 1,000 (NDC 0046-1100-91). — Each oval blue tablet contains 0.45 mg, in bottles of 100 (NDC 0046-1101-81).— Each oval maroon tablet contains 0.625 mg, in bottles of 100 (NDC 0046-1102-81) and 1,000 (NDC 0046-1102-91). — Each oval white tablet contains 0.9 mg, in bottles of 100 (NDC 0046-1103-81).— Each oval yellow tablet contains 1.25 mg, in bottles of 100 (NDC 0046-1104-81) and 1,000 (NDC 0046-1104-91).The appearance of these tablets is a trademark of Wyeth LLC.

16.2 Storage And Handling

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].Dispense in a well-closed container, as defined in the USP.

17 Patient Counseling Information

See FDA-approved patient labeling (Patient Information).

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 (5.2)].

17.2 Possible Serious Adverse Reactions With Estrogens

Inform postmenopausal women of possible serious adverse reactions of estrogen therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions (5.1, 5.2, 5.3)].

17.3 Possible Less Serious But Common Adverse Reactions With Estrogens

Inform postmenopausal women of possible less serious but common adverse reactions of estrogen therapy such as headache, breast pain and tenderness, nausea and vomiting.

Patient Information

PREMARIN®(prem-uh-rin)(Conjugated estrogen tablets, USP)Read this PATIENT INFORMATION before you start taking PREMARIN and read what you get each time you refill your PREMARIN prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What Is The Most Important Information I Should Know About Premarin (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 bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find the cause.Do not use estrogen-alone to prevent heart disease, heart attacks, or dementia (decline of 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 a study of women 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 a study of women 65 years of age or olderYou and your healthcare provider should talk regularly about whether you still need treatment with PREMARIN

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