1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause

1.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause

1.3 Treatment of Hypoestrogenism due to Hypogonadism, Castration or Primary Ovarian Failure

1.4 Treatment of Breast Cancer (for Palliation Only) in Appropriately Selected Women and Men with Metastatic Disease

1.5 Treatment of Advanced Androgen-Dependent Carcinoma of the Prostate (for Palliation Only)

1.6 Prevention of Postmenopausal Osteoporosis

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.

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.

5.2 Malignant Neoplasms

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.

6.1 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.

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.

7.1 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.

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.

12.3 Pharmacokinetics

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.

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).

14.3 Effects on Bone Mineral Density

Intent-to-treat subjects

All 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, LOCF

Region Evaluated Treatment Group*	No. of Subjects	Baseline (g/cm2) Mean ± SD	Change from Baseline (%) Adjusted Mean ± SE	p-Value vs. Placebo
* Identified by dosage (mg) of PREMARIN or placebo.
L2 to L4 BMD
0.625	83	1.17 ± 0.15	2.46 ± 0.37	<0.001
0.45	91	1.13 ± 0.15	2.26 ± 0.35	<0.001
0.3	87	1.14 ± 0.15	1.13 ± 0.36	<0.001
Placebo	85	1.14 ± 0.14	-2.45 ± 0.36
Total Body BMD
0.625	84	1.15 ± 0.08	0.68 ± 0.17	<0.001
0.45	91	1.14 ± 0.08	0.74 ± 0.16	<0.001
0.3	87	1.14 ± 0.07	0.40 ± 0.17	<0.001
Placebo	85	1.13 ± 0.08	-1.50 ± 0.17
Femoral Neck BMD
0.625	84	0.91 ± 0.14	1.82 ± 0.45	<0.001
0.45	91	0.89 ± 0.13	1.84 ± 0.44	<0.001
0.3	87	0.86 ± 0.11	0.62 ± 0.45	<0.001
Placebo	85	0.88 ± 0.14	-1.72 ± 0.45
Femoral Trochanter BMD
0.625	84	0.78 ± 0.13	3.82 ± 0.58	<0.001
0.45	91	0.76 ± 0.12	3.16 ± 0.56	0.003
0.3	87	0.75 ± 0.10	3.05 ± 0.57	0.005
Placebo	85	0.75 ± 0.12	0.81 ± 0.58

Figure 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 GROUPS

The 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 PLACEBO

The 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.

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)].

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).

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Each oval maroon tablet contains 0.625 mg, in bottles of 100 (NDC 0046-1102-81) and 1,000 (NDC 0046-1102-91).

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Each oval white tablet contains 0.9 mg, in bottles of 100 (NDC 0046-1103-81).

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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.

17.1 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.

LAB-0467-8.0

What is PREMARIN?

PREMARIN is a medicine that contains a mixture of estrogen hormones.

What is PREMARIN used for?

PREMARIN is used after menopause to:

•

Reduce moderate to severe hot flashes
Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes the "change of life" or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes "surgical menopause."
When the estrogen levels begin dropping, some women get very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating ("hot flashes" or "hot flushes"). In some women the symptoms are mild, and they will not need to take estrogens. In other women, symptoms can be more severe.

•

Treat menopausal changes in and around the vagina
You and your healthcare provider should talk regularly about whether you still need treatment with PREMARIN to control these problems. If you use PREMARIN only to treat your menopausal changes in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.

•

Help reduce your chances of getting osteoporosis (thin weak bones)
Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use PREMARIN only to prevent osteoporosis due to menopause, talk with your healthcare provider about whether a different treatment or medicine without estrogens might be better for you.
Weight-bearing exercise, like walking or running, and taking calcium (1500 mg/day of elemental calcium) and vitamin D (400–800 IU/day) supplements may also lower your chances of getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your healthcare provider before starting them.
You and your healthcare provider should talk regularly about whether you still need treatment with PREMARIN.

PREMARIN is also used to:

•

Treat certain conditions in women before menopause if their ovaries do not make enough estrogen naturally.

•

Ease symptoms of certain cancers that have spread through the body, in men and women

Who should not take PREMARIN?

Do not take PREMARIN if you:

•

Have unusual vaginal bleeding

•

Currently have or have had certain cancers
Estrogens 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.

•

Had a stroke or heart attack

•

Currently have or have had blood clots

•

Currently have or have had liver problems

•

Have been diagnosed with a bleeding disorder

•

Are allergic to PREMARIN or any of its ingredients
See the end of this leaflet for a list of ingredients in PREMARIN.

•

Think you may be pregnant

Tell your healthcare provider

•

If you have any unusual vaginal bleeding
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 out the cause.

•

About all of your medical problems
Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.

•

About all the medicines you take
This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how PREMARIN works. PREMARIN may also affect how your other medicines work.

•

If you are going to have surgery or will be on bedrest
You may need to stop taking PREMARIN.

•

If you are breastfeeding
The hormones in PREMARIN can pass into your milk.

How should I take PREMARIN?

•

Take one PREMARIN tablet at the same time each day

•

If you miss a dose, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your normal schedule. Do not take 2 doses at the same time.

•

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 3 to 6 months) about the dose you are taking and whether you still need treatment with PREMARIN.

•

If you see something that resembles a tablet in your stool, talk to your healthcare provider.

•

Take PREMARIN with or without food.

What are the possible side effects of PREMARIN?

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 attack

•

Stroke

•

Blood clots

•

Dementia

•

Breast cancer

•

Cancer of the lining of the uterus (womb)

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Cancer of the ovary

•

High blood pressure

•

High blood sugar

•

Gallbladder disease

•

Liver problems

•

Enlargement of benign tumors of the uterus ("fibroids")

•

Severe allergic reactions

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

•

New breast lumps

•

Unusual vaginal bleeding

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Changes in vision or speech

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Sudden new severe headaches

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Severe pains in your chest or legs with or without shortness of breath, weakness and fatigue

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Swollen lips, tongue and face

Less serious, but common side effects include:

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Headache

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Breast pain

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Irregular vaginal bleeding or spotting

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Stomach/abdominal cramps/bloating

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Nausea and vomiting

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Hair loss

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Fluid retention

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Vaginal yeast infection

These are not all the possible side effects of PREMARIN. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What can I do to lower my chances of getting a serious side effect with PREMARIN?

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Talk with your healthcare provider regularly about whether you should continue taking PREMARIN

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If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you. The addition of a progestin is generally recommended for women with a uterus to reduce the chance of getting cancer of the uterus (womb).

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See your health care provider right away if you get vaginal bleeding while taking PREMARIN

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Have a 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.

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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 of getting heart disease.

General information about the safe and effective use of PREMARIN

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take PREMARIN for conditions for which it was not prescribed. Do not give PREMARIN to other people, even if they have the same symptoms you have. It may harm them.

Keep PREMARIN out of the reach of children

This leaflet provides a summary of the most important information about PREMARIN. If you would like more information, talk with your healthcare provider or pharmacist.

What are the ingredients in PREMARIN?

PREMARIN contains a mixture of conjugated estrogens, which are a mixture of sodium estrone sulfate and sodium equilin sulfate and other components including sodium sulfate conjugates, 17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin.

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, hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sucrose and titanium dioxide.

The tablets come in different strengths and each strength tablet is a different color. The color ingredients are:

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0.3 mg tablet (green color): D&C Yellow No. 10 and FD&C Blue No. 2.

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0.45 mg tablet (blue color): FD&C Blue No. 2.

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0.625 mg tablet (maroon color): FD&C Blue No. 2 and FD&C Red No. 40.

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0.9 mg tablet (white color): D&C Red No. 30 and D&C Red No. 7.

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1.25 mg tablet (yellow color): black iron oxide, D&C Yellow No. 10, and FD&C Yellow No. 6.

The appearance of these tablets is a trademark of Wyeth LLC.

Store at Controlled Room Temperature 20° – 25°C (68° – 77°F).

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

LAB-0515-6.0

Revised February/2024