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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.
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 (conjugated estrogens) 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 (conjugated estrogens) tablets comply with USP Dissolution Test criteria as outlined below:
Premarin (conjugated estrogens) 1.25 mg tablets USP
Dissolution Test 4
Premarin (conjugated estrogens) 0.3 mg, 0.45 mg and 0.625 mg tablets USP
Dissolution Test 5
Premarin (conjugated estrogens) 0.9 mg tablets USP
Dissolution Test 6
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:
Read All Potential Side Effects and See Pictures of Premarin »
Before taking this medication, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.
Before using this medication, tell your doctor or pharmacist your medical history, especially of: vaginal bleeding of unknown cause, certain cancers (such as breast cancer, cancer of the uterus/ovaries), blood clots, stroke, heart disease (such as heart attack), liver disease, kidney disease, family medical history (especially breast lumps, cancer, blood clots, angioedema), blood clotting disorders (such as protein C or protein S deficiency), high blood pressure, diabetes, high cholesterol/triglyceride levels,...
Last reviewed on RxList: 3/28/2008
This monograph has been modified to include the generic and brand name in many instances.
Premarin (conjugated estrogens) therapy is indicated in the:
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.
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 (conjugated estrogens) may be taken without regard to meals.
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
This monograph has been modified to include the generic and brand name in many instances.
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:
Last reviewed on RxList: 3/28/2008
This monograph has been modified to include the generic and brand name in many instances.
See BOXED WARNINGS.
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.
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)
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.
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.
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.
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.
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.)
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
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.
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.
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.
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.
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 (conjugated estrogens) 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.
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.
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.
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.
Estrogens should be used with caution in individuals with severe hypocalcemia.
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.
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.
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.
Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients for whom they prescribe Premarin (conjugated estrogens) .
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.
(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.
Premarin (conjugated estrogens) should not be used during pregnancy. (See CONTRAINDICATIONS.)
Premarin (conjugated estrogens) 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.
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.)
With respect to efficacy in the approved indications, there have not been sufficient numbers of geriatric patients involved in studies utilizing Premarin (conjugated estrogens) to determine whether those over 65 years of age differ from younger subjects in their response to Premarin (conjugated estrogens) .
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
This monograph has been modified to include the generic and brand name in many instances.
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 (conjugated estrogens) together with institution of appropriate symptomatic care.
Premarin (conjugated estrogens) therapy should not be used in individuals with any of the following conditions:
Last reviewed on RxList: 3/28/2008
This monograph has been modified to include the generic and brand name in many instances.
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.
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 (conjugated estrogens) 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 (conjugated estrogens)
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) |
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.
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.
Estradiol, estrone, and estriol are excreted in the urine, along with glucuronide and sulfate conjugates.
No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.
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.
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 (conjugated estrogens) (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 (conjugated estrogens) 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. |
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).
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 (conjugated estrogens) 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.
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 (conjugated estrogens) 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 (conjugated estrogens) 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 (conjugated estrogens) 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.
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 (conjugated estrogens) dosage groups and placebo were found at cycles 6, 13, 19, and 26.
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.
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. |
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
This monograph has been modified to include the generic and brand name in many instances.
Premarin®
(conjugated estrogens) Tablets, USP
Read this PATIENT INFORMATION before you start taking Premarin (conjugated estrogens) and read what you get each time you refill your Premarin (conjugated estrogens) 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 (conjugated estrogens) (an estrogen mixture)?
Report any unusual vaginal bleeding right away while you are taking Premarin (conjugated estrogens) . 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.
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 (conjugated estrogens) .
What is Premarin (conjugated estrogens) ?
Premarin (conjugated estrogens) is a medicine that contains a mixture of estrogen hormones.
Premarin (conjugated estrogens) is used after menopause to:
Premarin (conjugated estrogens) is also used to:
Who should not take Premarin (conjugated estrogens) ?
Do not start taking Premarin (conjugated estrogens) if you:
Tell your healthcare provider:
How should I take Premarin (conjugated estrogens) ?
What are the possible side effects of Premarin (conjugated estrogens) ?
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:
Some of the warning signs of these serious side effects include:
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:
These are not all the possible side effects of Premarin (conjugated estrogens) . 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 (conjugated estrogens) ?
General information about the safe and effective use of Premarin (conjugated estrogens)
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Premarin (conjugated estrogens) for conditions for which it was not prescribed. Do not give Premarin (conjugated estrogens) to other people, even if they have the same symptoms you have. It may harm them.
Keep Premarin (conjugated estrogens) out of the reach of children.
This leaflet provides a summary of the most important information about Premarin (conjugated estrogens) . If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Premarin (conjugated estrogens) that is written for health professionals. You can get more information by calling the toll free number 800-934-5556.
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 (conjugated estrogens) 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.
Last reviewed on RxList: 3/28/2008
This monograph has been modified to include the generic and brand name in many instances.
IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.
ESTROGENS - ORAL
(ES-troe-jenz)
COMMON BRAND NAME(S): Cenestin, Enjuvia, Estrace, Femtrace, Ogen, Premarin
WARNING: Estrogens, either used alone or with another hormone (progestin), have rarely caused very serious side effects. Discuss the risks and benefits of hormone treatment with your doctor. Estrogens should not be used to prevent heart disease or dementia.
Estrogens can increase the risk of cancer of the uterus (endometrial cancer). Taking a progestin as directed by your doctor can help decrease this risk. Tell your doctor right away if you have any unusual vaginal bleeding.
In postmenopausal women, estrogens can increase the risk of cancer of the ovaries, stroke, dementia, and serious blood clots in the legs. Estrogens alone do not appear to increase the risk of breast cancer when used for up to 7 years. Estrogen, when used with a progestin, can increase the risk of heart disease (such as heart attacks), stroke, serious blood clots in the lungs/legs, dementia, and cancer of the breast/ovaries.
The risk for serious side effects may depend on the dose of estrogen and the length of time it is used. Therefore, this medication should be used at the lowest effective dose and for the shortest amount of time. Discuss the use of this medication with your doctor and check with him/her regularly (for example, every 3 to 6 months) to see if you still need to take this medication. If you will be taking this medication long-term, you should have regular complete physical exams (for example, once a year) as directed by your doctor. See also Notes section.
USES: This medication is a female hormone. It is used by women to help reduce symptoms of menopause (such as hot flashes, vaginal dryness). These symptoms are caused by the body making less estrogen. If you are using this medication to treat symptoms only in and around the vagina, products applied directly inside the vagina should be considered before medications that are taken by mouth, absorbed through the skin, or injected.
Certain estrogen products may also be used by women after menopause to prevent bone loss (osteoporosis). However, there are other medications (such as raloxifene, bisphosphonates including alendronate) that are also effective in preventing bone loss and may be safer. These medications should be considered for use before estrogen treatment.
Certain estrogen products may also be used by men and women to treat cancers (certain types of prostate cancer, breast cancer that has spread to other parts of the body) and by women who are not able to produce enough estrogen (for example, due to hypogonadism, primary ovarian failure).
HOW TO USE: Read the Patient Information Leaflet if available from your pharmacist before you start using this medication and each time you get a refill. If you have any questions, ask your doctor or pharmacist.
Take this medication by mouth with or without food as directed by your doctor. You may take it with food or right after a meal to prevent stomach upset.
The dosage is based on your medical condition and response to treatment.
Take this medication regularly to get the most benefit from it. To help you remember, take it at the same time(s) each day as directed. Follow your dosing schedule carefully. Do not increase your dose or take this medication more often or for a longer time than directed.
Tell your doctor if your condition does not improve or if it worsens.
Stomach upset, nausea/vomiting, bloating, breast tenderness, headache, or weight changes 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 right away if you have any serious side effects, including: mental/mood changes (such as depression, memory loss), breast lumps, unusual vaginal bleeding (such as spotting, breakthrough bleeding, prolonged/recurrent bleeding), increased or new vaginal irritation/itching/odor/discharge, severe stomach/abdominal pain, persistent nausea/vomiting, yellowing eyes/skin, dark urine, swelling hands/ankles/feet, increased thirst/urination.
This medication may rarely cause serious problems from blood clots (such as heart attacks, strokes, deep vein thrombosis, pulmonary embolism). Get medical help right away if you have any serious side effects, including: chest/jaw/left arm pain, unusual sweating, sudden/severe headache, weakness on one side of the body, confusion, slurred speech, sudden vision changes (such as partial/complete blindness), pain/redness/swelling of legs, tingling/weakness/numbness in the arms/legs, trouble breathing, coughing up blood, sudden dizziness/fainting.
A very serious allergic reaction to this product is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: 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.
In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.
PRECAUTIONS: Before taking this medication, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.
Before using this medication, tell your doctor or pharmacist your medical history, especially of: vaginal bleeding of unknown cause, certain cancers (such as breast cancer, cancer of the uterus/ovaries), blood clots, stroke, heart disease (such as heart attack), liver disease, kidney disease, family medical history (especially breast lumps, cancer, blood clots, angioedema), blood clotting disorders (such as protein C or protein S deficiency), high blood pressure, diabetes, high cholesterol/triglyceride levels, obesity, lupus, underactive thyroid (hypothyroidism), mineral imbalance (low or high level of calcium in the blood), a certain hormone problem (hypoparathyroidism), uterus problems (such as fibroids, endometriosis), gallbladder disease, asthma, seizures, migraine headaches, a certain blood disorder (porphyria), mental/mood disorders (such as dementia, depression).
Do not smoke or use tobacco. Estrogens combined with smoking further increases your risk of stroke, blood clots, high blood pressure, and heart attack, especially in women older than 35.
Tell your doctor if you just had or will be having surgery, or if you will be confined to a chair or bed for a long time (such as a long plane flight). These conditions increase your risk of getting blood clots, especially if you are taking an estrogen product. You may need to stop this medication for a time or take special precautions.
This drug may cause blotchy, dark areas of the skin on the face (melasma). Sunlight may worsen this effect. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.
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.
Children may be more sensitive to the side effects of this drug. It may affect their growth/development. Discuss the possible effects of this medication with the doctor, and monitor your child's growth periodically.
This medication must not be used during pregnancy. If you become pregnant or think you may be pregnant, tell your doctor immediately.
This medication passes into breast milk. It may reduce the quality and amount of breast milk produced. Consult your doctor before breast-feeding.
Some products that may interact with this drug include: aromatase inhibitors (such as anastrozole, exemestane, letrozole), fulvestrant, raloxifene, tamoxifen, toremifene.
This medication may interfere with certain laboratory tests (including metyrapone test), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.
OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. 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 regular medical and laboratory appointments. You should have regular complete physical exams (for example, once a year) which include laboratory and medical tests (such as blood pressure, breast exam/mammogram, pelvic exam, pap smear) to monitor your progress and check for side effects. Follow your doctor's instructions for examining your own breasts, and report any lumps right away. Consult your doctor for more details.
Preventing or controlling high blood pressure, high cholesterol, and diabetes can help to reduce your chances of heart disease and stroke. Lifestyle changes that can help to control or prevent these diseases include reducing stress, eating a low fat/salt diet, losing weight if overweight, exercising regularly, and stopping smoking. Keep your mind active with mental exercises (such as reading, solving crossword puzzles) to help prevent dementia. Talk to your doctor about lifestyle changes that might benefit you.
Lifestyle changes that may help reduce hot flashes include stopping smoking, dressing lightly or in layers, avoiding/limiting certain foods (spicy foods, caffeine, alcohol), reducing stress, and exercising regularly.
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.
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 away from light and moisture. Do not store in the bathroom. Keep all medications 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.
Information last revised April 2011 Copyright(c) 2011 First DataBank, Inc.
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
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