Conjugated Estrogens
estrogens, conjugated · Tablet, Film Coated · Oral
• There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens ( 5.2 )
• Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 )
• Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) ( 5.1 )
• The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older ( 5.3 ) Estrogen Plus Progestin Therapy
• Estrogen plus progestin therapy should not be used for the…
Uses
Conjugated Estrogens Tablets are a mixture of estrogens indicated for:
• Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause ( 1.1 )
• Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause ( 1.2 )
• Treatment of Hypoestrogenism due to Hypogonadism, Castration or Primary Ovarian Failure ( 1.3 )
• Treatment of Breast Cancer (for Palliation Only) in Appropriately Selected Women and Men with Metastatic Disease ( 1.4 )
• Treatment of Advanced Androgen-Dependent Carcinoma of the Prostate (for Palliation Only) ( 1.5 )
• Prevention of Postmenopausal Osteoporosis ( 1.6 ) 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause 1.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Limitations of Use When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, topical vaginal products should be considered. 1.3 Treatment of Hypoestrogenism due to Hypogonadism, Castration or Primary Ovarian Failure 1.4 Treatment of Breast Cancer (for Palliation Only) in Appropriately Selected Women and Men with Metastatic Disease 1.5 Treatment of Advanced Androgen-Dependent Carcinoma of the Prostate (for Palliation Only) 1.6 Prevention of Postmenopausal Osteoporosis Limitations of Use When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered.
Dosage and administration
Generally, when estrogen therapy is prescribed for a postmenopausal woman with a uterus, a progestin should be considered to reduce the risk of endometrial cancer [see Boxed Warning ]. A woman without a uterus does not need progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a progestin [see Warnings and Precautions (5.2, 5.16) ] . 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. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. Conjugated Estrogens Tablets may be taken without regard to meals.
• Daily administration of 0.3, 0.45, 0.625, 0.9, and 1.25 mg ( 2.1 , 2.2 , 2.3 , 2.5 , 2.6 )
• Cyclic administration of 0.3, 0.625, and 1.25 mg ( 2.1 , 2.2 , 2.3 ) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg Conjugated Estrogens Tablets daily. Subsequent dosage adjustment may be made based upon the individual patient response. This dose should be periodically reassessed by the healthcare provider. Conjugated Estrogens Tablets therapy may be given continuously, with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by 5 days off drug), as is medically appropriate on an individual basis. 2.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg Conjugated Estrogens Tablets daily. Subsequent dosage adjustment may be made based upon the individual patient response. This dose should be periodically reassessed by the healthcare provider. Conjugated Estrogens Tablets therapy may be given continuously, with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by 5 days off drug), as is medically appropriate on an individual basis. 2.3 Treatment of Hypoestrogenism due to Hypogonadism, Castration, or Primary Ovarian Failure Conjugated Estrogens Tablets therapy should be initiated and maintained with the lowest effective dose to achieve clinical goals. Female hypogonadism: 0.3 mg or 0.625 mg daily, administered cyclically (e.g., three weeks on and one week off). Doses are adjusted depending on the severity of symptoms and responsiveness of the endometrium [see Clinical Studies (14.4) ] . Female castration or primary ovarian failure: 1.25 mg daily, cyclically. Adjust dosage, upward or downward, according to severity of symptoms and response of the patient. For maintenance, adjust dosage to lowest level that will provide effective control. 2.4 Treatment of Breast Cancer (for Palliation Only) in Appropriately Selected Women and Men with Metastatic Disease Suggested dosage is 10 mg three times daily, for a period of at least three months. 2.5 Treatment of Advanced Androgen-Dependent Carcinoma of the Prostate (for Palliation Only) 1.25 mg to 2 × 1.25 mg three times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as by symptomatic improvement of the patient. 2.6 Prevention of Postmenopausal Osteoporosis Conjugated Estrogens Tablets therapy may be given continuously, with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by 5 days off drug), as is medically appropriate on an individual basis. Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg Conjugated Estrogens Tablets 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.
Dosage forms and strengths
Conjugated Estrogens Tablets, USP Tablet Strength Tablet Shape/Color Imprint 0.3 mg oval/green PREMARIN 0.3 0.45 mg oval/blue PREMARIN 0.45 0.625 mg oval/maroon PREMARIN 0.625 0.9 mg oval/white PREMARIN 0.9 1.25 mg oval/yellow PREMARIN 1.25 Tablets: 0.3, 0.45, 0.625, 0.9, and 1.25 mg ( 3 )
Contraindications
Conjugated Estrogens Tablets therapy is contraindicated in individuals with any of the following conditions:
• Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.2) ]
• Breast cancer or a history of breast cancer except in appropriately selected patients being treated for metastatic disease [see Warnings and Precautions (5.2) ]
• Estrogen-dependent neoplasia [see Warnings and Precautions (5.2) ]
• Active DVT, PE, or a history of these conditions [see Warnings and Precautions (5.1) ]
• Active arterial thromboembolic disease (for example stroke and MI), or a history of these conditions [see Warnings and Precautions (5.1) ]
• Known anaphylactic reaction or angioedema with Conjugated Estrogens Tablets [see Warnings and Precautions (5.7 , 5.15 )]
• Hepatic impairment or disease [see Warnings and Precautions (5.11) ]
• Protein C, protein S or antithrombin deficiency, or other known thrombophilic disorders.
• Undiagnosed abnormal genital bleeding ( 4 )
• Breast cancer or history of breast cancer except in appropriately selected patients being treated for metastatic diseases ( 4 , 5.2 )
• Estrogen-dependent neoplasia ( 4 , 5.2 )
• Active DVT, PE, or a history of these conditions ( 4 , 5.1 )
• Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions ( 4 , 5.1 )
• Known anaphylactic reaction or angioedema with Conjugated Estrogens Tablets ( 5.7 , 5.15 )
• Hepatic impairment or disease ( 4 , 5.11 )
• Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 )
Warnings and precautions
• Estrogens increase the risk of gallbladder disease ( 5.4 )
• Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs ( 5.5 , 5.6 , 5.10 , 5.11 )
• Monitor thyroid function in patients on thyroid replacement therapy ( 5.12 , 5.19 ) 5.1 Cardiovascular Disorders An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. Stroke In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in Year 1 and persisted [see Clinical Studies (14.5) ] . Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years). 1 In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) [see Clinical Studies (14.5) ] . The increase in risk was demonstrated after the first year and persisted. 1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. Coronary Heart Disease In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo 2 [see Clinical Studies (14.5)] . Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years). 1 In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years). 1 An increase in relative risk was demonstrated in Year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies (14.5) ] . In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established CHD. There were more CHD events in the CE plus MPA‑treated group than in the placebo group in Year 1, but not during the subsequent years. Two thousand, three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE (0.625 mg) plus MPA (2.5 mg) group and the placebo group in HERS, HERS II, and overall. Venous Thromboembolism (VTE) In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE), was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years 3 [see Clinical Studies (14.5) ] . Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately. In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted 4 [see Clinical Studies (14.5) ] . Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 5.2 Malignant Neoplasms Endometrial Cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year.
Side effects
The following serious adverse reactions are discussed elsewhere in labeling:
• Cardiovascular Disorders [see Boxed Warning , Warnings and Precautions (5.1) ]
• Malignant Neoplasms [see Boxed Warning , Warnings and Precautions (5.2) ] Most common adverse reactions (≥5%) are: abdominal pain, asthenia, pain, back pain, headache, flatulence, nausea, depression, insomnia, breast pain, endometrial hyperplasia, leucorrhea, vaginal hemorrhage, and vaginitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Prasco Laboratories at 1-866-525-0688 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Study Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. During the first year of a 2-year clinical trial with 2,333 postmenopausal women with a uterus between 40 and 65 years of age (88% Caucasian), 1,012 women were treated with CE, and 332 were treated with placebo. Table 1 summarizes treatment-related adverse reactions that occurred at a rate of ≥1% in any treatment group. Table 1: Treatment-Related Adverse Reactions at a Frequency ≥1% Conjugated Estrogens Tablets 0.625 mg (n=348) Conjugated Estrogens Tablets 0.45 mg (n=338) Conjugated Estrogens Tablets 0.3 mg (n=326) Placebo (n=332) Body as a whole Abdominal pain 38 (11) 28 (8) 30 (9) 21 (6) Asthenia 16 (5) 8 (2) 14 (4) 3 (1) Back pain 18 (5) 11 (3) 13 (4) 4 (1) Chest pain 2 (1) 3 (1) 4 (1) 2 (1) Generalized edema 7 (2) 6 (2) 4 (1) 8 (2) Headache 45 (13) 47 (14) 44 (13) 46 (14) Moniliasis 5 (1) 4 (1) 4 (1) 1 (0) Pain 17 (5) 10 (3) 12 (4) 14 (4) Pelvic pain 10 (3) 9 (3) 8 (2) 4 (1) Cardiovascular system Hypertension 4 (1) 4 (1) 7 (2) 5 (2) Migraine 7 (2) 1 (0) 0 3 (1) Palpitation 3 (1) 3 (1) 3 (1) 4 (1) Vasodilatation 2 (1) 2 (1) 3 (1) 5 (2) Digestive system Constipation 7 (2) 6 (2) 4 (1) 3 (1) Diarrhea 4 (1) 5 (1) 5 (2) 8 (2) Dyspepsia 7 (2) 5 (1) 6 (2) 14 (4) Eructation 1 (0) 1 (0) 4 (1) 1 (0) Flatulence 22 (6) 18 (5) 13 (4) 8 (2) Increased appetite 4 (1) 1 (0) 1 (0) 2 (1) Nausea 16 (5) 10 (3) 15 (5) 16 (5) Metabolic and nutritional Hyperlipidemia 2 (1) 4 (1) 3 (1) 2 (1) Peripheral edema 5 (1) 2 (1) 4 (1) 3 (1) Weight gain 11 (3) 10 (3) 8 (2) 14 (4) Musculoskeletal system Arthralgia 6 (2) 3 (1) 2 (1) 5 (2) Leg cramps 10 (3) 5 (1) 9 (3) 4 (1) Myalgia 2 (1) 1 (0) 4 (1) 1 (0) Nervous system Anxiety 6 (2) 4 (1) 2 (1) 4 (1) Depression 17 (5) 15 (4) 10 (3) 17 (5) Dizziness 9 (3) 7 (2) 4 (1) 5 (2) Emotional lability 3 (1) 4 (1) 5 (2) 8 (2) Hypertonia 1 (0) 1 (0) 5 (2) 3 (1) Insomnia 16 (5) 10 (3) 13 (4) 14 (4) Nervousness 9 (3) 12 (4) 2 (1) 6 (2) Skin and appendages Acne 3 (1) 1 (0) 8 (2) 3 (1) Alopecia 6 (2) 6 (2) 5 (2) 2 (1) Hirsutism 4 (1) 2 (1) 1 (0) 0 Pruritus 11 (3) 11 (3) 10 (3) 3 (1) Rash 6 (2) 3 (1) 1 (0) 2 (1) Skin discoloration 4 (1) 2 (1) 0 1 (0) Sweating 4 (1) 1 (0) 3 (1) 4 (1) Urogenital system Breast disorder 6 (2) 3 (1) 3 (1) 6 (2) Breast enlargement 3 (1) 4 (1) 7 (2) 3 (1) Breast neoplasm 4 (1) 4 (1) 7 (2) 7 (2) Breast pain 37 (11) 39 (12) 24 (7) 26 (8) Cervix disorder 8 (2) 4 (1) 5 (2) 0 Dysmenorrhea 12 (3) 10 (3) 4 (1) 2 (1) Endometrial disorder 4 (1) 2 (1) 2 (1) 0 Endometrial hyperplasia 16 (5) 8 (2) 1 (0) 0 Leukorrhea 17 (5) 17 (5) 12 (4) 6 (2) Metrorrhagia 11 (3) 4 (1) 3 (1) 1 (0) Urinary tract infection 1 (0) 2 (1) 1 (0) 4 (1) Uterine fibroids enlarged 6 (2) 1 (0) 2 (1) 2 (1) Uterine spasm 11 (3) 5 (1) 3 (1) 2 (1) Vaginal dryness 1 (0) 2 (1) 1 (0) 6 (2) Vaginal hemorrhage 46 (13) 13 (4) 6 (2) 0 Vaginal moniliasis 14 (4) 10 (3) 12 (4) 5 (2) Vaginitis 18 (5) 7 (2) 9 (3) 1 (0) 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of Conjugated Estrogens Tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible always to reliably estimate their frequency or establish a causal relationship to drug exposure. Genitourinary system Abnormal uterine bleeding; dysmenorrheal or pelvic pain, increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis, change in cervical secretion, ovarian cancer, endometrial hyperplasia, endometrial cancer, leukorrhea. Breasts Tenderness, enlargement, pain, discharge, galactorrhea, fibrocystic breast changes, breast cancer, gynecomastia in males. Cardiovascular Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, stroke, increase in blood pressure. Gastrointestinal Nausea, vomiting, abdominal pain, bloating, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis, enlargement of hepatic hemangiomas, ischemic colitis. Skin Chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, loss of scalp hair, hirsutism, pruritus, rash. Eyes Retinal vascular thrombosis, intolerance to contact lenses. Central nervous system Headache, migraine, dizziness , mental depression, nervousness, mood disturbances, irritability, exacerbation of epilepsy, dementia, possible growth potentiation of benign meningioma. Miscellaneous Increase or decrease in weight, glucose intolerance, aggravation of porphyria, edema, arthralgias, leg cramps, changes in libido, urticaria, exacerbation of asthma, increased triglycerides, hypersensitivity.
Drug interactions
Data from a single-dose drug-drug interaction study involving CE and MPA indicate that the pharmacokinetic disposition of both drugs is not altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been conducted with CE. Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism ( 7.1 ) 7.1 Metabolic Interactions In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John's Wort ( Hypericum perforatum ) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice, may increase plasma concentrations of estrogens and may result in side effects.
Use in specific populations
• Lactation: Estrogen administration to lactating women has been shown to decrease the quantity and quality of breast milk ( 8.2 )
• Geriatric Use: An increased risk of probable dementia in women over 65 years of age was reported in the Women's Health Initiative Memory ancillary studies of the Women's Health Initiative ( 5.3 , 8.5 ) 8.1 Pregnancy Risk Summary Conjugated Estrogens Tablets are not indicated for use during pregnancy. There are no data with the use of Conjugated Estrogens in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary Estrogens and progestins and metabolites are present in human milk. These hormones can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. The developmental and health benefits of breast‑feeding should be considered along with the mother’s clinical need for Conjugated Estrogens Tablets and any potential adverse effects on the breast-fed child from Conjugated Estrogens Tablets or from the underlying maternal condition. 8.4 Pediatric Use Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established. Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration. Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the normal pubertal process and induce gynecomastia. 8.5 Geriatric Use There have not been sufficient numbers of geriatric patients involved in studies utilizing Conjugated Estrogens Tablets to determine whether those over 65 years of age differ from younger subjects in their response to Conjugated Estrogens Tablets. The Women's Health Initiative Study In the WHI estrogen-alone substudy (daily CE 0.625 mg-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.5) ] . In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies (14.5) ] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.3) , and Clinical Studies (14.6) ] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions (5.3) , and Clinical Studies (14.6) ]. 8.6 Renal Impairment The effect of renal impairment on the pharmacokinetics of Conjugated Estrogens Tablets has not been studied. 8.7 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of Conjugated Estrogens Tablets has not been studied.
Pregnancy
8.1 Pregnancy Risk Summary Conjugated Estrogens Tablets are not indicated for use during pregnancy. There are no data with the use of Conjugated Estrogens in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Pediatric use
8.4 Pediatric Use Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established. Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration. Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the normal pubertal process and induce gynecomastia.
Geriatric use
8.5 Geriatric Use There have not been sufficient numbers of geriatric patients involved in studies utilizing Conjugated Estrogens Tablets to determine whether those over 65 years of age differ from younger subjects in their response to Conjugated Estrogens Tablets. The Women's Health Initiative Study In the WHI estrogen-alone substudy (daily CE 0.625 mg-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.5) ] . In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies (14.5) ] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.3) , and Clinical Studies (14.6) ] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions (5.3) , and Clinical Studies (14.6) ].
Overdosage
Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Conjugated Estrogens Tablets therapy with institution of appropriate symptomatic care.
Description
Conjugated Estrogens Tablets, USP for oral administration contain a mixture of CE purified from pregnant mares' urine and consists of the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains concomitant components as sodium sulfate conjugates, 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 CE. Conjugated Estrogens Tablets 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg also contain the following inactive ingredients: calcium phosphate tribasic, carnauba wax, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, powdered cellulose, sucrose, and titanium dioxide. Each tablet strength contains the following colors: Tablet strength Tablet color contains 0.3 mg D&C Yellow No. 10 and FD&C Blue No. 2 0.45 mg FD&C Blue No. 2 0.625 mg FD&C Blue No. 2 and FD&C Red No. 40 0.9 mg D&C Red No. 30 and D&C Red No. 7 1.25 mg Black iron oxide, D&C Yellow No. 10 and FD&C Yellow No. 6 Conjugated Estrogens Tablets comply with USP Dissolution Test criteria, as outlined below: Conjugated Estrogens Tablets 1.25 mg USP Dissolution Test 4 Conjugated Estrogens Tablets 0.3 mg, 0.45 mg and 0.625 mg USP Dissolution Test 5 Conjugated Estrogens Tablets 0.9 mg USP Dissolution Test 6
Mechanism of action
12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.
How supplied
16.1 How Supplied Conjugated Estrogens Tablets, USP
• Each oval green tablet contains 0.3 mg, in bottles of 100 (NDC 66993-295-02).
• Each oval blue tablet contains 0.45 mg, in bottles of 100 (NDC 66993-296-02).
• Each oval maroon tablet contains 0.625 mg, in bottles of 100 (NDC 66993-297-02).
• Each oval white tablet contains 0.9 mg, in bottles of 100 (NDC 66993-298-02).
• Each oval yellow tablet contains 1.25 mg, in bottles of 100 (NDC 66993-299-02). The appearance of these tablets is a trademark of Wyeth LLC. 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a well-closed container, as defined in the USP.
Storage
16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a well-closed container, as defined in the USP.
Patient information
Advise the patients to read the FDA-approved patient labeling ( Patient Information ). 17.1 Vaginal Bleeding Inform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.2) ] . 17.2 Possible Serious Adverse Reactions with Estrogens Inform postmenopausal women of possible serious adverse reactions of estrogen therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] . 17.3 Possible Less Serious but Common Adverse Reactions with Estrogens Inform postmenopausal women of possible less serious but common adverse reactions of estrogen therapy such as headache, breast pain and tenderness, nausea and vomiting. Distributed by Prasco Laboratories Mason, OH 45040 USA LAB 1631-1.0 Prasco logo
Label text from the FDA structured product label by Prasco Laboratories (revised Feb 27, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Estrogens, Conjugated in 5 products
Conjugated Estrogens NDC products (5)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 66993-295 | Estrogens, Conjugated .3 mg/1 Tablet, Film Coated | Prasco Laboratories | NDA AUTHORIZED GENERIC |
| 66993-296 | Estrogens, Conjugated .45 mg/1 Tablet, Film Coated | Prasco Laboratories | NDA AUTHORIZED GENERIC |
| 66993-297 | Estrogens, Conjugated .625 mg/1 Tablet, Film Coated | Prasco Laboratories | NDA AUTHORIZED GENERIC |
| 66993-298 | Estrogens, Conjugated .9 mg/1 Tablet, Film Coated | Prasco Laboratories | NDA AUTHORIZED GENERIC |
| 66993-299 | Estrogens, Conjugated 1.25 mg/1 Tablet, Film Coated | Prasco Laboratories | NDA AUTHORIZED GENERIC |
Frequently asked questions
What is Conjugated Estrogens used for?
Conjugated Estrogens Tablets are a mixture of estrogens indicated for: • Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause ( 1.1 ) • Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause ( 1.2 ) • Treatment of Hypoestrogenism due to Hypogonadism, Castration or Primary Ovarian Failure ( 1.3 ) • Treatment of Breast Cancer (for Palliation Only) in…
What are the side effects of Conjugated Estrogens?
The following serious adverse reactions are discussed elsewhere in labeling: • Cardiovascular Disorders [see Boxed Warning , Warnings and Precautions (5.1) ] • Malignant Neoplasms [see Boxed Warning , Warnings and Precautions (5.2) ] Most common adverse reactions (≥5%) are: abdominal pain, asthenia, pain, back pain, headache, flatulence, nausea, depression, insomnia, breast pain, endometrial… See the full label for the complete list.
Who makes Conjugated Estrogens?
Conjugated Estrogens is listed by 1 labeler in the FDA NDC directory, including Prasco Laboratories.