Premarin

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, 17αdihydroequilin, 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 strength	Tablet color contains
0.3 mg	D&C Yellow No. 10 and FD&C Blue No. 2
0.45 mg	FD&C Blue No. 2
0.625 mg	FD&C Blue No. 2 and FD&C Red No. 40
0.9 mg	D&C Red No. 30 and D&C Red No. 7
1.25 mg	Black iron oxide, D&C Yellow No. 10 and FD&C Yellow No. 6
PREMARIN tablets comply with USP Dissolution Test criteria, as outlined below:
PREMARIN 1.25 mg tablets	USP Dissolution Test 4
PREMARIN 0.3 mg, 0.45 mg and 0.625 mg	USP Dissolution Test 5
tablets
PREMARIN 0.9 mg tablets	USP Dissolution Test 6

 

The following serious adverse reactions are discussed elsewhere in labeling:

• Cardiovascular Disorders [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
• Malignant Neoplasms [see BOXED WARNING, WARNINGS AND PRECAUTIONS]

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 PERCENT

	PREMARIN0.625 mg (n=348)	PREMARIN0.45 mg (n=338)	PREMARIN0.3 mg (n=326)	Placebo (n=332)
Body as a whole
Abdominal pain	38 (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)	0	3 (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)
Dizziness	9 (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)	0	1 (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)

 

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.

Genitourinary system

Abnormal 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.

Breasts

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

Cardiovascular

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

Gastrointestinal

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

Skin

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

Eyes

Retinal vascular thrombosis, intolerance to contact lenses.

Central nervous system

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

Miscellaneous

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

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.

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.

WarningS

Included as part of the PRECAUTIONS section.

Precautions

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.

Stroke

In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies]. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.

Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).¹

In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) [see Clinical Studies]. The increase in risk was demonstrated after the first year and persisted.¹ Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

Coronary Heart Disease

In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo² [see Clinical Studies].

Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).¹

In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).¹ An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies].

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]. 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]. 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.

Malignant Neoplasms

Endometrial Cancer

An 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 Cancer

The 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].

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].

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 Cancer

The 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.⁷ In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies, and some report no association.

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, and Clinical Studies].

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, and Clinical Studies].

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, and Clinical Studies].

Gallbladder Disease

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

Hypocalcemia

Estrogen therapy should be used with caution in individuals with hypoparathyroidism as estrogen-induced hypocalcemia may occur.

Hereditary Angioedema

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

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.

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.

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.

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.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION).

Vaginal Bleeding

Inform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare provider as soon as possible [see WARNINGS AND PRECAUTIONS].

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].

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.

Nonclinical Toxicology

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.

Use In Specific Populations

Pregnancy

PREMARIN should not be used during pregnancy [see CONTRAINDICATIONS]. 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.

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.

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.

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.

The Women’s Health Initiative Study

In the WHI estrogen-alone substudy (daily CE 0.625 mg-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies].

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].

The Women’s Health Initiative Memory Study

In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see WARNINGS AND PRECAUTIONS, and Clinical Studies].

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, and Clinical Studies].

Renal Impairment

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

Hepatic Impairment

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

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;291:29472958.

Overdose

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.

Contraindications

PREMARIN therapy is contraindicated in individuals with any of the following conditions:

• Undiagnosed abnormal genital bleeding
• Known, suspected, or history of breast cancer except in appropriately selected patients being treated for metastatic disease
• Known or suspected estrogen-dependent neoplasia
• Active DVT, PE, or a history of these conditions
• Active arterial thromboembolic disease (for example stroke and MI), or a history of these conditions
• Known anaphylactic reaction or angioedema with Premarin
• Known liver impairment or disease
• Known protein C, protein S or antithrombin deficiency, or other known thrombophilic disorders.
• Known or suspected pregnancy

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.

Pharmacodynamics

There are no pharmacodynamic data for PREMARIN.

Pharmacokinetics

Absorption

Conjugated 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 x 0.625 mg and 1 x 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 PREMARIN

Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 x 0.625 mg
PK Parameter
Arithmetic Mean (%CV)	Cmax (pg/mL)	tmax (h)	t½ (h)	AUC (pg•h/mL)
Estrone	87 (33)	9.6 (33)	50.7 (35)	5557 (59)
Baseline- adjusted estrone	64 (42)	9.6 (33)	20.2 (40)	1723 (52)
Equilin	31 (38)	7.9 (32)	12.9 (112)	602 (54)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 x 0.625 mg
PK Parameter
Arithmetic Mean (%CV)	Cmax (ng/mL)	tmax (h)	t½ (h)	AUC (ng•h/mL)
Total Estrone	2.7 (43)	6.9 (25)	26.7 (33)	75(52)
Baseline-adjusted total estrone	2.5 (45)	6.9 (25)	14.8 (35)	46 (48)
Total Equilin	1.8 (56)	5.6 (45)	11.4 (31)	27 (56)
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 x 1.25 mg
PK Parameter
Arithmetic Mean (%CV)	Cmax (pg/mL)	tmax (h)	t½ (h)	AUC (pg•h/mL)
Estrone	124 (30)	10.0 (32)	38.1 (37)	6332 (44)
Baseline- adjusted estrone	102 (35)	10.0 (32)	19.7 (48)	3159 (53)
Equilin	59 (43)	8.8 (36)	10.9 (47)	1182 (42)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 x 1.25 mg
PK Parameter
Arithmetic Mean (%CV)	Cmax (ng/mL)	tmax (h)	t½ (h)	AUC (ng•h/mL)
Total Estrone	4.5 (39)	8.2 (58)	26.5 (40)	109 (46)
Baseline-adjusted total estrone	4.3 (41)	8.2 (58)	17.5 (41)	87 (44)
Total equilin	2.9 (42)	6.8 (49)	12.5 (34)	48 (51)

 

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin.

Metabolism

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

Excretion

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

Use In Specific Populations

No pharmacokinetic studies were conducted with Premarin in specific populations, including patients with renal or hepatic impairment.

Clinical Studies

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 ± SD	Observed Mean ± SD	Mean Change ± SD	p-Values vs Placeboa
0.625 mg CE (n = 27)
4	12.29 ± 3.89	1.95 ± 2.77	-10.34 ± 4.73	< 0.001
12	12.29 ± 3.89	0.75 ± 1.82	-11.54 ± 4.62	< 0.001
0.45 mg CE (n = 32)
4	12.25 ± 5.04	5.04 ± 5.31	-7.21 ± 4.75	< 0.001
12	12.25 ± 5.04	2.32 ± 3.32	-9.93 ± 4.64	< 0.001
0.3 mg CE (n = 30)
4	13.77 ± 4.78	4.65 ± 3.71	-9.12 ± 4.71	< 0.001
12	13.77 ± 4.78	2.52 ± 3.23	-11.25 ± 4.60	< 0.001
Placebo (n = 28)
4	11.69 ± 3.87	7.89 ± 5.28	-3.80 ± 4.71	–
12	11.69 ± 3.87	5.71 ± 5.22	-5.98 ± 4.60	–
a Based on analysis of covariance with treatment as factor and baseline as covariate.

 

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).

Effects On Bone Mineral Density

Health And Osteoporosis, Progestin And Estrogen (HOPE) Study

The 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 Ntelopeptide were used as bone turnover markers (BTM) at cycles 6, 13, 19, and 26.

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 Groupa	No. of Subjects	Baseline (g/cm²) Mean ± SD	Change from Baseline (%) Adjusted Mean ± SE	p-Value vs. 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
a Identified by dosage (mg) of PREMARIN or placebo.

 

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.

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 (BA/CA) 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.

Women’s Health Initiative Studies

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

WHI Estrogen-Alone Substudy

The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen alone in predetermined primary endpoints.

Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 7.1 years, are presented in Table 5.

TABLE 5: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN ALONE SUBSTUDY OF WHI^a

Event	Relative Risk CE vs. Placebo (95% nCIb)	CE n = 5,310	Placebo n = 5,429
		Absolute Risk per 10,000 Women-Years
CHD eventsc	0.95 (0.78-1.16)	54	57
Non-fatal MIc	0.91 (0.73-1.14)	40	43
CHD deathc	1.01 (0.71-1.43)	16	16
All Strokec	1.33 (1.05-1.68)	45	33
Ischemic strokec	1.55 (1.19-2.01)	38	25
Deep vein thrombosisc,d	1.47 (1.06-2.06)	23	15
Pulmonary embolismc	1.37 (0.90-2.07)	14	10
Invasive breast cancerc	0.80 (0.62-1.04)	28	34
Colorectal cancere	1.08 (0.75-1.55)	17	16
Hip fracturec	0.65 (0.45-0.94)	12	19
Vertebral fracturesc,d	0.64 (0.44-0.93)	11	18
Lower arm/wrist fracturesc,d	0.58 (0.47-0.72)	35	59
Total fracturesc,d	0.71 (0.64-0.80)	144	197
Death due to other causese,f	1.08 (0.88-1.32)	53	50
Overall mortalityc,d	1.04 (0.88-1.22)	79	75
Global Indexg	1.02 (0.92-1.13)	206	201
aAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. c Results are based on centrally adjudicated data for an average follow-up of 7.1 years. d Not included in “global index.” e Results are based on an average follow-up of 6.8 years. f All deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease. g A subset of the events was combined in a “global index” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.

 

For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures.⁹ The absolute excess risk of events included in the “global index” was a nonsignificant 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.¹⁰

Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50-59 years of age, a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI 0.46-1.11)].

WHI Estrogen Plus Progestin Substudy

The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years.

For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the 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 YEARS^a,b

Event	Relative Risk CE/MPA vs. Placebo (95% nCIc)	CE/MPA n = 8,506	Placebo n = 8,102
		Absolute Risk per 10,000 Women- Years
CHD events	1.23 (0.99-1.53)	41	34
Non-fatal MI	1.28 (1.00-1.63)	31	25
CHD death	1.10 (0.70-1.75)	8	8
All Strokes	1.31 (1.03-1.68)	33	25
Ischemic stroke	1.44 (1.09-1.90)	26	18
Deep vein thrombosisd	1.95 (1.43-2.67)	26	13
Pulmonary embolism	2.13 (1.45-3.11)	18	8
Invasive breast cancere	1.24 (1.01-1.54)	41	33
Colorectal cancer	0.61 (0.42-0.87)	10	16
Endometrial cancerd	0.81 (0.48-1.36)	6	7
Cervical cancerd	1.44 (0.47-4.42)	2	1
Hip fracture	0.67 (0.47-0.96)	11	16
Vertebral fracturesd	0.65 (0.46-0.92)	11	17
Lower arm/wrist fracturesd	0.71 (0.59-0.85)	44	62
Total fracturesd	0.76 (0.69-0.83)	152	199
Overall Mortalityf	1.00 (0.83-1.19)	52	52
Global Indexg	1.13 (1.02-1.25)	184	165
aAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Results are based on centrally adjudicated data. c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. d Not included in “global index.” e Includes metastatic and non-metastatic breast cancer, with the exception of in situ cancer. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g A subset of the events was combined in a “global index” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.

 

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)].

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, and Use in Specific Populations].

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, and Use in Specific Populations].

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, and Use in Specific Populations].

REFERENCES

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.