Conjugated estrogens (oral)
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
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Black Box Warning
|
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA Estrogen-Alone Therapy Endometrial Cancer
See full prescribing information for complete Boxed Warning.
Estrogen-Alone Therapy
Estrogen Plus Progestin Therapy
|
Overview
Conjugated estrogens (oral) is a hormone that is FDA approved for the treatment of vasomotor symptoms due to menopause, symptoms of vulvar and vaginal atrophy due to menopause, hypogonadism, castration or primary ovarian failure, breast cancer (for palliation only), androgen-dependent carcinoma of the prostate. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, vasodilatation, chloasma, hirsutism, injection site reaction, pruritus, weight change, abdominal pain, bloating, diarrhea, flatulence, nausea, vomiting, backache, leg cramp, asthenia, headache, migraine, depression, disturbance in mood, disorder of menstruation, pain of breast, vaginitis, withdrawal bleeding, cough, and pharyngitis.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indication
- 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.
- 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
- 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. 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.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Conjugated estrogens (oral) in adult patients.
Non–Guideline-Supported Use
Bleeding, Renal Failure
- Dosing Information
- 10–50 mg IV/IM per day
Gender Identity Disorder
- Dosing Information
- 10 mg IV/IM
Hemorrhagic Cystitis
- Dosing Information
- 5–50 mg IV
Postcoital Contraception
- Dosing Information
- A single 50 mg intravenous (IV) dose, followed by a second 50 mg IV dose 24 hours later.
Postoperative Hemorrhage
- Dosing Information
- 1 mg/kg IV
Turner Syndrome
- Dosing Information
- 0.375 mg/kg IV
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Conjugated estrogens (oral) in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Conjugated estrogens (oral) in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Conjugated estrogens (oral) in pediatric patients.
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.
Warnings
|
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA Estrogen-Alone Therapy Endometrial Cancer
See full prescribing information for complete Boxed Warning.
Estrogen-Alone Therapy
Estrogen Plus Progestin Therapy
|
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.
- 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.
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.
- 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.
- 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.
- 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
- 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 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.
- 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.
- 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.
- Gallbladder Disease
- 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.
- 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.
- Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.
Adverse Reactions
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in 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%.
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- 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.
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Conjugated estrogens (oral) in the drug label.
Drug Interactions
There is limited information regarding Conjugated estrogens (oral) Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
- PREMARIN should not be used during pregnancy
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Conjugated estrogens (oral) in women who are pregnant.
Labor and Delivery
- 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.
Nursing Mothers
There is no FDA guidance on the use of Conjugated estrogens (oral) with respect to nursing mothers.
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.
Geriatic 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.
Gender
There is no FDA guidance on the use of Conjugated estrogens (oral) with respect to specific gender populations.
Race
There is no FDA guidance on the use of Conjugated estrogens (oral) with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Conjugated estrogens (oral) in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Conjugated estrogens (oral) in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Conjugated estrogens (oral) in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Conjugated estrogens (oral) in patients who are immunocompromised.
Administration and Monitoring
Administration
Monitoring
There is limited information regarding Monitoring of Conjugated estrogens (oral) in the drug label.
IV Compatibility
There is limited information regarding IV Compatibility of Conjugated estrogens (oral) in the drug label.
Overdosage
- 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.
Pharmacology
Mechanism of Action
- Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogen 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.
Structure
- 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:
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Pharmacodynamics
There is limited information regarding Pharmacodynamics of Conjugated estrogens (oral) in the drug label.
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.
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Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Conjugated estrogens (oral) in the drug label.
Clinical Studies
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How Supplied
- :
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Storage
Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F)
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
- Read this PATIENT INFORMATION which describes the benefit and major risks of your treatment, as well as how and when treatment should be used. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
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Precautions with Alcohol
- Alcohol-Conjugated estrogens (oral) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
- PREMARIN®[2]
Look-Alike Drug Names
There is limited information regarding Conjugated estrogens (oral) Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.
- ↑ 1.0 1.1 1.2 1.3 1.4 Davies, BE (April 2010). "Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations" (PDF). The Journal of antimicrobial chemotherapy. 65 Suppl 2: ii5–ii10. doi:10.1093/jac/dkq015. PMC 2835511. PMID 20215135.
- ↑ "PREMARIN - estrogens, conjugated tablet, film coated".