Premarin®

(conjugated estrogens) Tablets, USP
WARNINGS
ENDOMETRIAL CANCER
Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. (See WARNINGS, Malignant neoplasms, Endometrial cancer.)
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. (See Clinical Studies and WARNINGS, Cardiovascular disorders and Dementia.)
The estrogen alone substudy of the Women’s Health Initiative (WHI) reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 6.8 years and 7.1 years, respectively, of treatment with daily oral conjugated estrogens (CE 0.625 mg), relative to placebo. (See Clinical Studies and WARNINGS, Cardiovascular disorders.)
The estrogen plus progestin substudy of WHI reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and DVT in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily CE 0.625 mg combined with medroxyprogesterone acetate (MPA 2.5 mg), relative to placebo. (See Clinical Studies and WARNINGS, Cardiovascular disorders and Malignant neoplasms, Breast cancer.)
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE 0.625 mg alone and during 4 years of treatment with daily CE 0.625 mg combined with MPA 2.5 mg, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See Clinical Studies and WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)
In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
DRUG DESCRIPTION
What are the possible side effects of conjugated estrogens (Cenestin, Enjuvia, Premarin)?
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Stop taking this medication and call your doctor at once if you have any of these serious side effects:
chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;
sudden numbness or weakness, especially on one side of the body;
sudden…
Read All Potential Side Effects and See Pictures of Premarin »
Premarin® (conjugated estrogens tablets, USP) for oral administration contains a mixture of conjugated estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares’ urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as concomitant components, as sodium sulfate conjugates, 17α-dihydroequilin, 17α- estradiol, and 17β-dihydroequilin. Tablets for oral administration are available in 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg strengths of conjugated estrogens.
Premarin 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg tablets also contain the following inactive ingredients: calcium phosphate tribasic, hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sucrose, and titanium dioxide.
– 0.3 mg tablets also contain: D&C Yellow No. 10 and FD&C Blue No. 2.
– 0.45 mg tablets also contain: FD&C Blue No. 2.
– 0.625 mg tablets also contain: FD&C Blue No. 2 and FD&C Red No. 40.
– 0.9 mg tablets also contain: D&C Red No. 30 and D&C Red No. 7.
– 1.25 mg tablets also contain: 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 tablets USP Dissolution Test 5
Premarin 0.9 mg tablets USP Dissolution Test 6
Last reviewed on RxList: 3/28/2008
Premarin Indications & Dosage

INDICATIONS
Premarin therapy is indicated in the:
Treatment of moderate to severe vasomotor symptoms due to menopause.
Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.
Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. (See Clinical Studies)
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.
DOSAGE AND ADMINISTRATION
When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (for example at 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS). For women with a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
Premarin may be taken without regard to meals.
For treatment of moderate to severe vasomotor symptoms and/or moderate to severe symptoms of vulvar and vaginal atrophy due to menopause:

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

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 five days off drug), as is medically appropriate on an individualized basis.
For prevention of postmenopausal osteoporosis:

When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. 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.

Premarin therapy may be given continuously, with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by five days off drug), as is medically appropriate on an individualized basis.
For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure:

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.

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.

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.
For 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.
For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only:

1.25 mg to 2 x 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.
HOW SUPPLIED
Premarin (conjugated estrogens tablets, USP)
– Each oval yellow tablet contains 1.25 mg, in bottles of 100 (NDC 0046-1104-81) and 1,000 (NDC 0046-1104-91).
– Each oval white tablet contains 0.9 mg, in bottles of 100 (NDC 0046-1103-81).
– Each oval maroon tablet contains 0.625 mg, in bottles of 100 (NDC 0046-1102-81) and 1,000 (NDC 0046-1102-91).
– Each oval blue tablet contains 0.45 mg, in bottles of 100 (NDC 0046-1101-81).
– Each oval green tablet contains 0.3 mg, in bottles of 100 (NDC 0046-1100-81) and 1,000 (NDC 0046-1100-91).
The appearance of these tablets is a trademark of Wyeth Pharmaceuticals.
Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].
Dispense in a well-closed container, as defined in the USP.
Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101. Rev March 2008. FDA Rev date: 3/3/2008
Last reviewed on RxList: 3/28/2008
Premarin Side Effects & Drug Interactions

SIDE EFFECTS
See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.
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 practice.
During the first year of a 2-year clinical trial with 2,333 postmenopausal women between 40 and 65 years of age (88% Caucasian), 1,012 women were treated with conjugated estrogens and 332 were treated with placebo. Table 6 summarizes adverse events that occurred at a rate of ≥ 5%.
TABLE 6: NUMBER (%) OF PATIENTS REPORTING ≥ 5% TREATMENT EMERGENT ADVERSE EVENTS
Conjugated Estrogens Treatment Group
Body System 0.625 mg 0.45 mg 0.3 mg Placebo
Adverse event (n = 348) (n = 338) (n = 326) (n = 332)
Any adverse event 323 (93%) 305 (90%) 292 (90%) 281 (85%)
Body as a Whole
Abdominal pain 56 (16%) 50 (15%) 54 (17%) 37 (11%)
Accidental injury 21 (6%) 41 (12%) 20 (6%) 29 (9%)
Asthenia 25 (7%) 23 (7%) 25 (8%) 16 (5%)
Back pain 49 (14%) 43 (13%) 43 (13%) 39 (12%)
Flu syndrome 37 (11%) 38 (11%) 33 (10%) 35 (11%)
Headache 90 (26%) 109 (32%) 96 (29%) 93 (28%)
Infection 61 (18%) 75 (22%) 74 (23%) 74 (22%)
Pain 58 (17%) 61 (18%) 66 (20%) 61 (18%)
Digestive System
Diarrhea 21 (6%) 25 (7%) 19 (6%) 21 (6%)
Dyspepsia 33 (9%) 32 (9%) 36 (11%) 46 (14%)
Flatulence 24 (7%) 23 (7%) 18 (6%) 9 (3%)
Nausea 32 (9%) 21 (6%) 21 (6%) 30 (9%)
TABLE 6. NUMBER (%) OF PATIENTS REPORTING ≥ 5% TREATMENT EMERGENT ADVERSE EVENTS
Conjugated Estrogens Treatment Group
Body System 0.625 mg 0.45 mg 0.3 mg Placebo
Adverse event (n = 348) (n = 338) (n = 326) (n = 332)
Musculoskeletal System
Arthralgia 47 (14%) 42 (12%) 22 (7%) 39 (12%)
Leg cramps 19 (5%) 23 (7%) 11 (3%) 7 (2%)
Myalgia 18 (5%) 18 (5%) 29 (9%) 25 (8%)
Nervous System
Depression 25 (7%) 27 (8%) 17 (5%) 22 (7%)
Dizziness 19 (5%) 20 (6%) 12 (4%) 17 (5%)
Insomnia 21 (6%) 25 (7%) 24 (7%) 33 (10%)
Nervousness 12 (3%) 17 (5%) 6 (2%) 7 (2%)
Respiratory System
Cough increased 13 (4%) 22 (7%) 14 (4%) 14 (4%)
Pharyngitis 35 (10%) 35 (10%) 40 (12%) 38 (11%)
Rhinitis 21 (6%) 30 (9%) 31 (10%) 42 (13%)
Sinusitis 22 (6%) 36 (11%) 24 (7%) 24 (7%)
Upper respiratory infection 42 (12%) 34 (10%) 28 (9%) 35 (11%)
Skin and Appendages
Pruritus 14 (4%) 17 (5%) 16 (5%) 7 (2%)
Urogenital System
Breast pain 38 (11%) 41 (12%) 24 (7%) 29 (9%)
Leukorrhea 18 (5%) 22 (7%) 13 (4%) 9 (3%)
Vaginal hemorrhage 47 (14%) 14 (4%) 7 (2%) 0
Vaginal moniliasis 20 (6%) 18 (5%) 17 (5%) 6 (2%)
Vaginitis 24 (7%) 20 (6%) 16 (5%) 4 (1%)
The following additional adverse reactions have been reported with estrogen and/or progestin therapy:
Genitourinary system
Abnormal uterine bleeding/spotting
Dysmenorrhea/pelvic pain
Increase in size of uterine leiomyomata
Vaginitis, including vaginal candidiasis
Change in amount of cervical secretion
Change in cervical ectropion
Ovarian cancer
Endometrial hyperplasia
Endometrial cancer
Breasts
Tenderness, enlargement, pain, discharge, galactorrhea
Fibrocystic breast changes
Breast cancer
Cardiovascular
Deep and superficial venous thrombosis
Pulmonary embolism
Thrombophlebitis
Myocardial infarction
Stroke
Increase in blood pressure
Gastrointestinal
Nausea, vomiting
Abdominal cramps, 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
Hemorrhagic eruption
Loss of scalp hair
Hirsutism
Pruritus, rash
Eyes
Retinal vascular thrombosis Intolerance to contact lenses
Central Nervous System
Headache
Migraine
Dizziness
Mental depression
Exacerbation of chorea
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, angioedema, anaphylactoid/anaphylactic reactions
Hypocalcemia (preexisting condition)
Exacerbation of asthma
Increased triglycerides
DRUG INTERACTIONS
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 anti-factor 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. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentrations, increased triglyceride levels.
Impaired glucose tolerance.
Last reviewed on RxList: 3/28/2008
Premarin Warnings & Precautions

WARNINGS
See BOXED WARNINGS.
Cardiovascular disorders
An increased risk of stroke and deep vein thrombosis (DVT) has been reported with estrogen alone therapy.
An increased risk of stroke, DVT, pulmonary embolism, and myocardial infarction has been reported with estrogen plus progestin therapy.
Should any of these events occur or be suspected, estrogens with or without progestins should be discontinued immediately.
Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.
Stroke
In the Women’s Health Initiative (WHI) estrogen alone substudy, a statistically significant increased risk of stroke was reported in women receiving daily conjugated estrogens (CE 0.625 mg) compared to placebo (44 versus 32 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted. (See Clinical Studies)
In the estrogen plus progestin substudy of WHI, a statistically significant increased risk of stroke was reported in women receiving daily CE 0.625 mg plus medroxyprogesterone acetate (MPA 2.5 mg) compared to placebo (31 versus 24 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. (See Clinical Studies)
Coronary heart disease
In the estrogen alone substudy of WHI, no overall effect on coronary heart disease (CHD) events (defined as nonfatal myocardial infarction [MI], silent MI, or CHD death) was reported in women receiving estrogen alone compared to placebo. (See Clinical Studies)
In the estrogen plus progestin substudy of WHI, no statistically significant increase of CHD events was reported in women receiving CE/MPA compared to placebo (39 versus 33 per 10,000 women years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), 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/MPA 2.5 mg demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year one, 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/MPA group and the placebo group in the HERS, the HERS II, and overall.
Venous thromboembolism (VTE)
In the estrogen alone substudy of WHI, the risk of VTE (DVT and pulmonary embolism [PE]), was reported to be increased for women receiving daily CE 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 years. (See Clinical Studies)
In the estrogen plus progestin substudy of WHI, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE/MPA compared to 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 persisted. (See Clinical Studies)
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 women with a uterus. The reported endometrial cancer risk among unopposed estrogen users with an intact uterus 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 the 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 plus progestin therapy is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal 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 this issue in estrogen alone users is the Women’s Health Initiative (WHI) substudy of daily conjugated estrogens (CE 0.625 mg). In the estrogen alone substudy of WHI, after an average of 7.1 years of follow-up, daily CE 0.625 mg was not associated with an increased risk of invasive breast cancer ( relative risk [RR] 0.80, 95 percent nominal confidence interval [nCI] 0.62-1.04). (See Clinical Studies.)
The most important randomized clinical trial providing information about this issue in estrogen plus progestin users is the Women’s Health Initiative (WHI) substudy of daily CE 0.625 mg plus medroxyprogesterone acetate (MPA 2.5 mg). In the estrogen plus progestin substudy, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer in women who took daily CE/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 (95 percent nCI 1.01-1.54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo, respectively. 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/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 estrogen plus progestin compared with placebo. In the same substudy , invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA 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)
The results from observational studies are generally consistent with those of 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.
Dementia
In the estrogen alone Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily conjugated estrogens (CE 0.625 mg) or placebo. In the estrogen plus progestin WHIMS substudy, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE 0.625 mg plus medroxyprogesterone acetate (MPA 2.5 mg) or placebo.
In the estrogen alone substudy, 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-years. (See Clinical Studies and PRECAUTIONS, Geriatric Use.)
In the estrogen plus progestin substudy, after an average follow-up of 4 years, 40 women in the CE/MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE/MPA versus placebo was 2.05 (95 percent CI 1.21-3.48). The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years. (See Clinical Studies and PRECAUTIONS, Geriatric Use.)
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). Since both substudies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and PRECAUTIONS, Geriatric Use.)
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.
PRECAUTIONS
General
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: a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (lowering HDL, raising LDL) and impairment of glucose tolerance.
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. Blood pressure should be monitored at regular intervals during estrogen use.
Hypertriglyceridemia
In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. Consider discontinuation of treatment if pancreatitis or other complications develop.
In the HOPE study, the mean percent increase from baseline in serum triglycerides after one year of treatment with Premarin 0.625 mg, 0.45 mg, and 0.3 mg compared with placebo were 34.3, 30.2, 25.1, and 10.7, respectively. After two years of treatment, the mean percent changes were 47.6, 32.5, 19.0, and 5.5, respectively.
Impaired liver function and past history of cholestatic jaundice
Estrogens may be poorly metabolized in patients with impaired liver function. For patients 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. Patients 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. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients 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. Patients with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.
Hypocalcemia
Estrogens should be used with caution in individuals with severe hypocalcemia.
Ovarian cancer
The estrogen plus progestin substudy of WHI reported a non-statistically significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95 percent nCI 0.77 – 3.24). The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of 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.
Exacerbation of endometriosis
Endometriosis may be exacerbated with administration of estrogen therapy.
A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients 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 patients with these conditions.
Patient Information
Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients for whom they prescribe Premarin.
Laboratory Tests
Serum follicle stimulating hormone 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
(See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
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.
Pregnancy
Premarin should not be used during pregnancy. (See CONTRAINDICATIONS.)
Nursing Mothers
Premarin should not be used during lactation. Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug.
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. (See INDICATIONS and DOSAGE AND ADMINISTRATION.)
Geriatric Use
With respect to efficacy in the approved indications, 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.
In the estrogen alone substudy of the Women’s Health Initiative (WHI) study, 46 percent (n=4,943) were 65 years of age and older, while 7.1 percent (n=767) were 75 years of age and older. There was a higher relative risk (daily conjugated estrogens [CE 0.625 mg] versus placebo) of stroke in women less than 75 years of age compared to women 75 years and older.
In the estrogen alone Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women, 65 to 79 years of age , was randomized to daily CE 0.625 mg or placebo. After an average follow-up of 5.2 years, the relative risk (CE versus placebo) of probable dementia was 1.49 (95 percent CI 0.83-2.66). The absolute risk of developing probable dementia with estrogen alone was 37 versus 25 cases per 10,000 women- years compared with placebo.
Of the total number of subjects in the estrogen plus progestin substudy of the Women’s Health Initiative study, 44 percent (n=7,320) were 65 years of age and older, while 6.6 percent (n=1,095) were 75 years and older. In women 75 years of age and older compared to women less than 74 years of age, there was a higher relative risk of nonfatal stroke and invasive breast cancer in the estrogen plus progestin group versus placebo. In women greater than 75, the increased risk of nonfatal stroke and invasive breast cancer observed in the estrogen plus progestin group compared to placebo was 75 versus 24 per 10,000 women-years and 52 versus 12 per 10,000 women years, respectively.
In the estrogen plus progestin substudy of WHIMS, a population of 4,532 postmenopausal women, 65 to 79 years of age, was randomized to daily CE 0.625 mg/MPA 2.5 mg or placebo. In the estrogen plus progestin group, after an average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of probable dementia was 2.05 (95 percent CI 1.21-3.48). The absolute risk of developing probable dementia with CE/MPA was 45 versus 22 cases per 10,000 women-years compared with placebo.
Seventy-nine percent of the cases of probable dementia occurred in women that were older than 70 for the CE alone group, and 82 percent of the cases of probable dementia occurred in women who were older than 70 in the CE/MPA group. The most common classification of probable dementia in both the treatment groups and placebo groups was Alzheimer’s disease.
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). Since both substudies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)
Last reviewed on RxList: 3/28/2008
Premarin Overdosage & Contraindications

OVERDOSE
Overdosage of estrogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in females. Treatment of overdose consists of discontinuation of Premarin together with institution of appropriate symptomatic care.
CONTRAINDICATIONS
Premarin therapy should not be used in individuals with any of the following conditions:
Undiagnosed abnormal genital bleeding.
Known, suspected, or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease.
Known or suspected estrogen-dependent neoplasia.
Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
Active or recent (within the past year) arterial thromboembolic disease (for example, stroke, myocardial infarction).
Liver dysfunction or disease.
Known hypersensitivity to any of the ingredients in Premarin.
Known or suspected pregnancy.
Last reviewed on RxList: 3/28/2008
Premarin Clinical Pharmacology

CLINICAL PHARMACOLOGY
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 by 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 follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.
Pharmacokinetics
Absorption
Conjugated estrogens are water-soluble and are well-absorbed from the gastrointestinal tract after release from the drug formulation. The Premarin tablet releases conjugated estrogens slowly over several hours. Table 1 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.
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.
TABLE 1. PHARMACOKINETIC PARAMETERS FOR PREMARIN
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 x 0.625 mg
PK Parameter Cmax tmax t1/2 AUC
Arithmetic Mean (%CV) (pg/mL) (h) (h) (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 Cmax tmax t1/2 AUC
Arithmetic Mean (%CV) (ng/mL) (h) (h) (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 Cmax tmax t1/2 AUC
Arithmetic Mean (%CV) (pg/mL) (h) (h) (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 Cmax tmax t1/2 AUC
Arithmetic Mean (%CV) (ng/mL) (h) (h) (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 the 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 proportion 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.
Special Populations
No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.
Drug Interactions
Data from a single-dose drug-drug interaction study involving conjugated estrogens and medroxyprogesterone acetate indicate that the pharmacokinetic dispositions of both drugs are not altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been conducted with conjugated estrogens.
In vitro and in vivostudies 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 preparations (Hypericum perforatum), 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.
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, receiving 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 the frequency and severity of moderate to severe vasomotor symptoms. Table 2 shows the adjusted mean number of hot flushes in the Premarin 0.3 mg, 0.45 mg, and 0.625 mg and placebo treatment groups over the initial 12-week period.
TABLE 2. 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 N-telopeptide 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 3. TABLE 3. 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 aIdentified 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. Women's Health Initiative Studies The Women's Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of either the use of daily oral conjugated estrogens (CE 0.625 mg) alone or in combination with medroxyprogesterone acetate (MPA 2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction [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, pulmonary embolism (PE), endometrial cancer (only in CE/MPA substudy), colorectal cancer, hip fracture, or death due to other causes. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms. The 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 age of 63 years, 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 6.8 years, are presented in Table 4. TABLE 4. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN ALONE SUBSTUDY OF WHI Event Relative Risk CE vs. Placebo (95% nCIa) Placebo n = 5,429 CE n = 5,310 Absolute Risk per 10,000 Women-Years CHD eventsb 0.95 (0.79-1.16) 56 53 Non-fatal MIb 0.91 (0.73-1.14) 43 4 0 CHD deathb 1.01 (0.71-1.43) 16 16 Strokeb 1.37 (1.09-1.73) 33 45 Ischemicb 1.55 (1.19-2.01) 25 38 Deep vein thrombosisb,d 1.47 (1.06-2.06) 15 23 Pulmonary embolismb 1.37 (0.90-2.07) 10 14 Invasive breast cancerb 0.80 (0.62-1.04) 34 28 Colorectal cancerc 1.08 (0.75-1.55) 16 17 Hip fracturec 0.61 (0.41-0.91) 17 11 Vertebral fracturesc,d 0.62 (0.42-0.93) 17 11 Total fracturesc,d 0.70 (0.63-0.79) 195 139 Death due to other causesc,e 1.08 (0.88-1.32) 50 53 Overall mortalityc,d 1.04 (0.88-1.22) 78 81 Global Indexc,f 1.01 (0.91-1.12) 190 192 aNominal confidence intervals unadjusted for multiple looks and multiple comparisons. b Results are based on centrally adjudicated data for an average follow-up of 7.1 years' cResults are based on an average follow-up of 6.8 years. dNot included in Global Index. eAll deaths, except from breast or colorectal cancer, definite/probable CHD, PE orcerebrovascular disease. f A subset of the events was combined in a "global index," defined as the earliest occurrence ofCHD 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 were 12 more strokes while the absolute risk reduction per 10,000 women-years was 6 fewer hip fractures. The absolute excess risk of events included in the "global index" was a nonsignificant 2 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.) Final centrally adjudicated results for CHD events and centrally adjudicated results for invasive breast cancer incidence from the estrogen alone substudy, after an average follow-up of 7.1 years, reported 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 (see Table 4). 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 of ischemic stroke, and this excess was present in all subgroups of women examined (see Table 4). The estrogen plus progestin substudy was also stopped early. According to the predefined stopping rule, after an average follow-up of 5.2 years of treatment, the increased risk of 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 (relative risk [RR] 1.15, 95 percent nCI 1.03-1.28). 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/MPA were 6 more CHD events, 7 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 7 fewer colorectal cancers and 5 fewer hip fractures. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.) Results of the estrogen plus progestin substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 5. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. TABLE 5. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARSa Event Relative Risk CE/MPA vs. Placebo (95% nCIb) Placebo n = 8,102 CE/MPA n = 8,506 Absolute Risk per 10,000 Women-years CHD events 1.24 (1.00-1.54) 33 39 Non-fatal MI 1.28 (1.00-1.63) 25 31 CHD death 1.10 (0.70-1.75) 8 8 All strokes 1.31 (1.02-1.68) 24 31 Ischemic Stroke 1.44 (1.09-1.90) 18 26 Deep vein thrombosis 1.95 (1.43-2.67) 13 26 Pulmonary embolism 2.13 (1.45-3.11) 8 18 Invasive breast cancerc 1.24 (1.01-1.54) 33 41 Invasive colorectal cancer 0.56 (0.38-0.81) 16 9 Endometrial cancer 0.81 (0.48-1.36) 7 6 Cervical cancer 1.44 (0.47-4.42) 1 2 Hip fracture 0.67 (0.47-0.96) 16 11 Vertebral fractures 0.65 (0.46-0.92) 17 11 Lower arm/wrist fractures 0.71 (0.59-0.85) 62 44 Total fractures 0.76 (0.69-0.83) 199 152 aResults are based on centrally adjudicated data. Mortality data was not part of the adjudicated data; however, data at 5.2 years of follow-up showed no difference between the groups in terms of all-cause mortality (RR 0.98, 95 percent nCI 0.82-1.18). bNominal confidence intervals unadjusted for multiple looks and multiple comparisons. cIncludes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. Women's Health Initiative Memory Study The estrogen alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45 percent, age 65 to 69 years; 36 percent, 70 to 74 years; 19 percent, 75 years of age and older) to evaluate the effects of daily CE 0.625 mg on the incidence of probable dementia (primary outcome) compared with placebo. After an average follow-up of 5.2 years, 28 women in the estrogen alone group (37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the estrogen alone group was 1.49 (95 percent CI 0.83-2.66) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.) The estrogen plus progestin WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent, age 65 to 69 years; 35 percent, 70 to 74 years; 18 percent, 75 years of age and older) to evaluate the effects of daily CE/MPA 0.625 mg conjugated estrogens/2.5 mg medroxyprogesterone acetate on the incidence of probable dementia (primary outcome) compared with placebo. After an average follow-up of 4 years, 40 women in the estrogen plus progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95 percent CI 1.21-3.48) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.) 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 BOXED WARNINGS, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.) Last reviewed on RxList: 3/28/2008 Premarin Medication Guide PATIENT INFORMATION Premarin® (conjugated estrogens) Tablets, USP Read this PATIENT INFORMATION before you start taking Premarin and read what you get each time you refill your Premarin prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about Premarin (an estrogen mixture)? Estrogens increase the chance of getting cancer of the uterus. Report any unusual vaginal bleeding right away while you are taking Premarin. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. Do not use estrogens with or without progestins to prevent heart disease, heart attacks, strokes, or dementia. Using estrogens, with or without progestins, may increase your chance of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens, with or without progestins, may increase your chance of getting dementia, based on a study of women age 65 years or older. You and your healthcare provider should talk regularly about whether you still need treatment with Premarin. What is Premarin? Premarin is a medicine that contains a mixture of estrogen hormones. 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. You and your healthcare provider should talk regularly about whether you still need treatment with Premarin. Treat moderate to severe dryness, itching, and burning, 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 dryness, itching, and burning 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. You and your healthcare provider should talk regularly about whether you should continue with Premarin. Weight-bearing exercise, like walking or running, and taking calcium and vitamin D supplements may also lower your chances for getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your healthcare provider before starting them. 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 start taking 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 take Premarin. Had a stroke or heart attack in the past year. Currently have or have had blood clots. Currently have or have had liver problems. Are allergic to Premarin tablets or any of its ingredients. See the list of ingredients in Premarin at the end of this leaflet. Think you may be pregnant. Tell your healthcare provider: If you are breast feeding. The hormones in Premarin can pass into your milk. 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), migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. About all the medicines you take, including 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 estrogens. 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. 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: Breast cancer Cancer of the uterus Stroke Heart attack Blood clots Dementia Gallbladder disease Ovarian cancer High blood pressure Liver problems High blood sugar Enlargement of benign tumors of the uterus ("fibroids") Some of the warning signs of these serious side effects include: Breast lumps Unusual vaginal bleeding Dizziness and faintness Changes in speech Severe headaches Chest pain Shortness of breath Pains in your legs Changes in vision Vomiting Yellowing of the skin, eyes or nail beds Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptoms that concern you. Less serious but common side effects include: Headache Breast pain Irregular vaginal bleeding or spotting Stomach/abdominal cramps, bloating Nausea and vomiting Hair loss Fluid retention Vaginal yeast infection These are not all the possible side effects of Premarin. For more information, ask your healthcare provider or pharmacist. What can I do to lower my chances of getting a serious side effect with Premarin? Talk with your healthcare provider regularly about whether you should continue taking Premarin. If you have a uterus, talk to your healthcare provider about whether the addition of a progestin (a different prescribed hormone medication) 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. See your healthcare provider right away if you get vaginal bleeding while taking Premarin. Have a breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease. General information about the safe and effective use of Premarin 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. You can ask for information about Premarin that is written for health professionals. You can get more information by calling the toll free number 800-934-5556 begin_of_the_skype_highlighting 800-934-5556 end_of_the_skype_highlighting. 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: - 0.3 mg tablet (green color): D&C Yellow No. 10 and FD&C Blue No. 2. - 0.45 mg tablet (blue color): FD&C Blue No. 2. - 0.625 mg tablet (maroon color): FD&C Blue No. 2 and FD&C Red No. 40. - 0.9 mg tablet (white color): D&C Red No. 30 and D&C Red No. 7. - 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 Pharmaceuticals. This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556 begin_of_the_skype_highlighting 1-800-934-5556 end_of_the_skype_highlighting. Last reviewed on RxList: 3/28/2008 Premarin Consumer IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you. ESTROGENS - ORAL (ESS-trow-jens) COMMON BRAND NAME(S): Cenestin, Enjuvia, Ogen, Premarin WARNING: Estrogens given alone and with another hormone (progestin) for replacement therapy after menopause have sometimes caused rare but very serious side effects. Discuss the risks and benefits of hormone treatment and your personal health history with your doctor. Estrogens have been reported to increase the chance of cancer of the uterus (endometrial cancer). Taking a progestin with estrogen decreases this risk. Tell your doctor immediately if you have any unusual vaginal bleeding. Estrogens may also increase your risk of cancer of the ovaries, stroke, dementia, and serious blood clots in the legs. Estrogen given in combination with progestin can infrequently cause heart disease (e.g., heart attacks), stroke, serious blood clots (pulmonary embolism and deep venous thrombosis), dementia, and cancer of the breast. Some of these risks appear to depend on the length of time this drug is used and the amount of estrogen per dose. Therefore, this medication should be used for the shortest possible length of time at the lowest effective dose, so you can obtain the benefits and reduce the chance of serious side effects from long-term treatment. Discuss the details with your doctor and check with him/her regularly (e.g., every 3 to 6 months) to see if you still need to take this medication. Estrogen treatment alone does not appear to increase your risk of breast cancer when used for up to 7 years after menopause. However, talk to your doctor about the risks if you need to take estrogen for a longer period. Products that contain estrogen should not be used to prevent heart disease or dementia. If you use this drug for an extended period, you should have a complete physical exam at regular intervals (e.g., once a year) or as directed by your doctor. See Notes section. USES: This medication is a female hormone and is usually given to women who no longer produce the amount of estrogen they produced before menopause. It is a very effective treatment for reducing a common menopause symptom (intense feelings of warmth and sweating known as hot flashes). If you need treatment only for vaginal menopause symptoms (e.g., vaginal dryness), products applied directly inside the vagina should be considered before medications that are taken by mouth, absorbed through the skin, or injected. Certain estrogen products may also be used to prevent bone loss (osteoporosis) in people at high risk who cannot take non-estrogen drugs. There are several other medications (e.g., raloxifene, bisphosphonates such as alendronate) that are safe and effective to prevent or treat bone loss. These medicines should be considered for use before estrogen treatment. Certain estrogen products may also be used to treat certain cancers in men and women (e.g., certain types of metastatic breast cancer, prostate cancer) and other conditions as determined by your doctor. HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start using this medication and each time you get a refill. If you have any questions, consult your doctor or pharmacist. Take this medication by mouth as directed by your doctor. It may be taken with or without food. You may take it with food or immediately after a meal to prevent stomach upset. Take this medication regularly in order to get the most benefit from it. Remember to take it at the same time(s) each day as directed. Dosage is based on your medical condition and response to treatment. Follow your dosing schedule carefully. Inform your doctor if your condition does not improve or worsens. Premarin Consumer (continued) SIDE EFFECTS: Dizziness, lightheadedness, headache, stomach upset, bloating, nausea, weight changes, increased/decreased interest in sex, or breast tenderness may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly. Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects. Tell your doctor immediately if any of these unlikely but serious side effects occur: mental/mood changes (e.g., severe depression, memory loss), breast lumps, swelling of hands/feet, unusual vaginal bleeding (e.g., spotting, breakthrough bleeding, prolonged/recurrent bleeding), unusual vaginal discharge/itching/odor, yellowing eyes/skin, stomach/abdominal pain, persistent nausea/vomiting, dark urine, worsening of seizures, signs of worsening diabetes control (e.g., increased thirst and urination). This medication may infrequently cause serious problems such as heart attacks, stroke, and blood clots. Seek immediate medical attention if you experience any of the following: chest/jaw/left arm pain, sudden severe headache, weakness on one side of the body, confusion, slurred speech, sudden vision changes (e.g., double vision, loss of vision), pain/redness/swelling of legs, trouble breathing, coughing up blood, sudden dizziness/fainting. A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing. This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist. In the US - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 begin_of_the_skype_highlighting 1-800-FDA-1088 end_of_the_skype_highlighting. In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345 begin_of_the_skype_highlighting 1-866-234-2345 end_of_the_skype_highlighting. PRECAUTIONS: Before taking this medication, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: vaginal bleeding of unknown cause, certain cancers (e.g., breast cancer-especially non-metastatic type, cancer of the uterus or ovaries), current/history of blood clots, history of stroke or heart attack, liver disease. Before using this medication, tell your doctor or pharmacist your medical history, especially of: family medical history (especially breast lumps and cancer), asthma, diabetes, seizures, migraine headaches, heart disease (e.g., high blood pressure, congestive heart failure), kidney disease, underactive thyroid (hypothyroidism), a certain hormone problem (hypoparathyroidism), mineral imbalance (low calcium blood level), mental/mood disorders (e.g., dementia, depression), high blood pressure during pregnancy (toxemia), yellowing eyes/skin (cholestatic jaundice) during pregnancy or with past estrogen use, uterus problems (e.g., uterine fibroids, endometriosis), high blood cholesterol/fat (triglyceride) levels, gallbladder disease, obesity, certain blood disorder (porphyria), lupus. This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages. If you are nearsighted or wear contact lenses, you may develop vision problems or trouble wearing your contact lenses. Contact your eye doctor if these problems occur. This drug may cause a patchy darkening of the skin on the face (melasma). Sunlight may worsen this darkening. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors. Do not smoke cigarettes or use tobacco. Estrogens combined with smoking further increase your risk for stroke, blood clots, high blood pressure, and heart attacks, especially in women older than 35. If you will be having surgery or will be confined to a chair or bed for a long time (e.g., a long plane flight), tell your doctor beforehand. Special precautions may need to be taken because of the increased risk for blood clots. Caution is advised if this medicine is used in children. It may affect their growth/development. Discuss the possible effects of this medication with your doctor, and monitor your child's growth periodically. This medication must not be used during pregnancy. It may result in birth defects or cancer later in the child's life. If you become pregnant or think you may be pregnant, tell your doctor immediately. This medication is not effective for preventing a miscarriage and should not be used for this purpose. Small amounts of this medication pass into breast milk. This drug may reduce the quality and amount of breast milk produced. Consult your doctor before breast-feeding. Premarin Consumer (continued) DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first. This drug should not be used with the following medications because very serious interactions may occur: anastrozole, exemestane. If you are currently using either of these medications listed above, tell your doctor or pharmacist before starting estrogens. Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription products you may use, especially of: "blood thinners" (anticoagulants such as warfarin), corticosteroids (e.g., prednisone), raloxifene, tamoxifen, drugs affecting liver enzymes that remove estrogens from your body (such as St. John's wort, phenobarbital, phenytoin, rifamycins including rifabutin, azole antifungals including itraconazole, macrolide antibiotics including erythromycin, certain anti-seizure medications including carbamazepine). This product can affect the results of certain lab tests. Make sure laboratory personnel and all your doctors know you use this drug. This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222 begin_of_the_skype_highlighting 1-800-222-1222 end_of_the_skype_highlighting. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe nausea/vomiting, unusual vaginal bleeding. NOTES: Do not share this medication with others. Keep all medical and laboratory appointments. You should have a complete physical examination that includes blood pressure measurements and breast/pelvic examinations at regular intervals (e.g., once a year) or as directed by your doctor. Follow your doctor's instructions on how to examine your own breasts and report any lumps immediately. You should also be regularly screened for cervical cancer (e.g., Pap test) and have periodic mammograms as determined by your doctor. Consult your doctor for more details. Lifestyle changes that help promote healthy bones include increasing weight-bearing exercise, stopping smoking, limiting alcohol, and eating well-balanced meals that contain adequate calcium and vitamin D. Since you may also need to take calcium and vitamin D supplements and make lifestyle changes, consult your doctor for specific advice. Additional lifestyle changes (e.g., reducing stress, eating a low fat/low salt diet, losing weight if you are overweight) to control or prevent high blood pressure, high cholesterol, and diabetes help to prevent heart disease and strokes. Keep your mind active with mental exercises to help prevent dementia. Discuss with your doctor lifestyle changes that might benefit you. You can also manage hot flashes by keeping a cool body temperature (e.g., using a fan, drinking cool beverages, dressing lightly/in layers, avoiding hot/spicy foods). Limiting caffeine and alcohol, exercising regularly, and learning relaxation techniques may help reduce hot flashes. Vaginal lubricants can help lessen discomfort during intercourse. MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up. STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets. Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.