lack of awareness Estrogens, Conjugated Class: Estrogens ATC Class: G03CA57 VA Class: HS300 Brands: Cenestin, Duavee, Enjuvia, Premarin, Premphase, Prempro Warning(s) Estrogens increase the risk of endometrial cancer in postmenopausal women. 101 104 105 106 107 121 (See Endometrial Cancer under Cautions.) Do not use estrogens with or without progestins for prevention of cardiovascular disease 101 104 105 106 107 121 (see Cardiovascular Risk Reduction under Uses and Cardiovascular Disorders under Cautions) or dementia (see Alzheimer s Disease under Uses). 101 104 105 107 The Women s Health Initiative (WHI) study of estrogen alone reported increased risks of stroke and DVT in postmenopausal women receiving approximately 7 years of therapy with conjugated estrogens 0.625 mg daily. 101 104 105 107 The WHI study of estrogen plus progestin reported increased risks of MI, stroke, invasive breast cancer, pulmonary embolism, and DVT in postmenopausal women receiving ≥5 years of therapy with conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily. 101 104 105 106 107 The WHI Memory Study (WHIMS) reported increased risk of developing probable dementia in postmenopausal women ≥65 years of age receiving long-term therapy (4 5 years) with conjugated estrogens in conjunction with medroxyprogesterone acetate or conjugated estrogens alone. 101 104 105 107 Not known whether this finding also applies to younger postmenopausal women. 101 104 105 107 Other dosages of conjugated estrogens with medroxyprogesterone and other combinations or dosage forms of estrogens with progestin not studied in WHI trials; in the absence of comparable data, assume risks are similar. 101 104 105 107 Prescribe estrogens (with or without progestins) at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. 101 104 105 106 107 Introduction Mixture of estrogens available either as preparations that meet current official USP standards (i.e., conjugated estrogens USP) 101 105 107 108 109 or as nonofficial preparations (i.e., synthetic conjugated estrogens A and synthetic conjugated estrogens B, which are prepared synthetically from plant sources). 106 108 109 121 122 Uses for Estrogens, Conjugated Use of estrogens alone in postmenopausal women generally is referred to as estrogen replacement therapy (ERT); use of estrogens in combination with progestins usually is referred to as hormone replacement therapy (HRT) or postmenopausal hormone therapy. b Another therapeutic option involves use of estrogens in combination with an estrogen agonist-antagonist; this combination referred to as a tissue-selective estrogen complex (TSEC). 263 ERT Management of moderate to severe vasomotor symptoms associated with menopause. 101 106 107 121 262 266 Management of severe vaginal dryness, pain with sexual intercourse, and vulvar and vaginal atrophy associated with menopause. 101 105 106 107 266 If used solely for this indication, consider use of topical vaginal preparations. 101 105 106 107 266 Osteoporosis Prevention of osteoporosis. 100 101 107 262 Used adjunctively with other measures (e.g., diet, calcium, vitamin D, weight-bearing exercise, physical therapy) to retard further bone loss and progression of osteoporosis in postmenopausal women. 100 101 107 Estrogens are effective for prevention of osteoporosis but are associated with a number of adverse effects. 100 101 107 If prevention of postmenopausal osteoporosis is the sole indication for therapy, consider alternative therapy (e.g., alendronate, raloxifene, risedronate). 101 107 112 Has been effective in the treatment of osteoporosis in postmenopausal women. Formerly recommended as first-line therapy; however, recommendations on appropriate use of HRT have been revised based on WHI study findings. (See Boxed Warning.) Evaluate risks and benefits of long-term HRT use in the management of osteoporosis, taking into account the increased risk of breast cancer and cardiovascular disease, availability of other pharmacologic modalities (e.g., alendronate, calcitonin, calcium, raloxifene, risedronate, vitamin D), and life-style factors that can be modified. 101 107 Has been used in a limited number of anorexic women with chronic amenorrhea to reduce calcium loss † and, thereby, reduce risk of osteoporosis. Corticosteroid-induced Osteoporosis Has been used to prevent bone loss in postmenopausal women receiving low- to moderate-dose corticosteroid therapy † . Hypoestrogenism Treatment of hypoestrogenism secondary to hypogonadism, castration, or primary ovarian failure. 101 Used for induction of puberty in adolescents with pubertal delay due to hypogonadism. 101 Metastatic Breast Carcinoma Palliative treatment of metastatic breast cancer in selected women and men. 101 One of several second-line agents. a Prostate Carcinoma Palliative treatment of advanced androgen-dependent prostate carcinoma. 101 Abnormal Uterine Bleeding Treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology. 104 Cardiovascular Risk Reduction † ERT or HRT does not decrease the incidence of cardiovascular disease. 101 105 106 107 AHA, American College of Obstetricians and Gynecologists, FDA, and manufacturers recommend that hormone therapy not be used to prevent heart disease in healthy women (primary prevention) or to protect women with preexisting heart disease (secondary prevention). Alzheimer s Disease Prior use of HRT, but not current HRT unless such use exceeds 10 years, associated with reduced risk of Alzheimer s disease † . Estrogens have not been shown to prevent progression of Alzheimer s disease; American Academy of Neurology recommends that estrogens not be used for treatment of Alzheimer s disease. Initiation of ERT or HRT in women ≥65 years of age not associated with an improvement in cognitive function. Some women receiving ERT or HRT experience detrimental effects. Incidence of probable dementia in women receiving ERT or HRT was higher than that in women receiving placebo. (See Boxed Warning.) Use of ERT or HRT to prevent dementia or cognitive decline in women ≥65 years of age is not recommended. Postpartum Breast Engorgement Used in the past for prevention of postpartum breast engorgement † ; FDA has withdrawn approval of estrogen-containing drugs for this indication, since estrogens have not been shown to be safe for this use. 110 (See Lactation under Cautions.) Pregnancy Not effective for any purpose during pregnancy; use contraindicated in pregnant women. 101 104 105 106 107 121 (See Pregnancy under Cautions.) Estrogens, Conjugated Dosage and Administration General A progestin generally is added to estrogen therapy (HRT) in women with an intact uterus. 101 104 105 107 121 Addition of a progestin for ≥10 days per cycle of estrogen or daily with estrogen reduces incidence of endometrial hyperplasia and attendant risk of endometrial carcinoma in women with an intact uterus. 101 104 105 107 121 As an alternative to progestin, use of bazedoxifene (an estrogen agonist-antagonist) in fixed combination with conjugated estrogens reduces risk of endometrial hyperplasia. 261 262 263 ERT is appropriate in women who have undergone a hysterectomy (to avoid unnecessary exposure to progestins). 101 104 105 107 121 Administration Conjugated estrogens USP usually administered orally; may also administer intravaginally or by deep IM or slow IV injection. 101 104 105 107 Administer synthetic conjugated estrogens A and synthetic conjugated estrogens B orally. 106 121 Estrogen therapy generally is administered in a continuous daily dosage regimen or, alternatively, in a cyclic regimen. 101 105 107 When administered cyclically, estrogen usually is given once daily for 3 weeks followed by 1 week without the drug or once daily for 25 days followed by 5 days off; regimen is repeated as necessary. 101 105 When parenteral administration of conjugated estrogens USP is required, IV injection is preferred because of the more rapid response compared with IM injection. 104 Oral Administration Oral preparations containing medroxyprogesterone acetate in combination with conjugated estrogens USP as monophasic or biphasic regimens are commercially available in a mnemonic dispensing package to aid user in complying with the prescribed dosage schedule. 107 Oral preparation containing bazedoxifene acetate in fixed combination with conjugated estrogens is commercially available in a 30-day package including 2 blister packs of 15 tablets each. 262 IV Administration For solution and drug compatibility information, see Compatibility under Stability. Administer by direct IV injection. 104 Reconstitution Reconstitute vial containing 25 mg of conjugated estrogens USP with 5 mL of sterile water for injection. 104 Do not shake vigorously. 104 Administer immediately after reconstitution. 104 Rate of Administration Administer slowly (to avoid flushing reaction). 104 IM Administration Administer by deep IM injection. 104 Reconstitution Reconstitute vial containing 25 mg of conjugated estrogens USP with 5 mL of sterile water for injection. 104 Do not shake vigorously. 104 Administer immediately after reconstitution. 104 Vaginal Administration Administer intravaginally as a vaginal cream. 105 Dosage Individualize dosage according to the condition being treated and the tolerance and therapeutic response of the patient. 101 104 105 106 107 121 To minimize risk of adverse effects, use the lowest possible effective dosage. 101 104 105 106 107 121 Because of the potential increased risk of cardiovascular events, breast cancer, and venous thromboembolic events, limit estrogen, estrogen/progestin, or conjugated estrogens in fixed combination with bazedoxifene to the lowest effective doses and shortest duration of therapy consistent with treatment goals and risks for the individual woman. 101 104 105 107 121 262 Periodically reevaluate use of estrogen, estrogen/progestin, or conjugated estrogens in fixed combination with bazedoxifene (i.e., at 3- to 6-month intervals). 101 104 105 107 121 262 Pediatric Patients Hypoestrogenism Oral Conjugated estrogens USP: 0.15 mg daily may induce breast development. 101 Increase dosage at 6- to 12-month intervals to achieve appropriate bone age advancement and epiphyseal closure. 101 Conjugated estrogens USP: 0.625 mg daily (with progestins) sufficient to induce artificial cyclic menses and to maintain bone mineral density (BMD) after skeletal maturity. 101 Adults Estrogen Replacement Therapy Vasomotor Symptoms Oral Conjugated estrogens USP: Initially, 0.3 mg daily continuously or in cyclic regimen (25 days on, 5 days off). 101 Adjust dosage based on patient response. 101 Synthetic conjugated estrogens A: Initially, 0.45 mg daily. 106 May increase dosage up to 1.25 mg daily. 106 Synthetic conjugated estrogens B: Initially, 0.3 mg daily. 121 266 May increase dosage up to 1.25 mg daily. 266 Adjust dosage based on patient response. 121 266 Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro ), monophasic regimen: Initially, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily. 107 Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily. 107 Conjugated estrogens USP with medroxyprogesterone acetate (Premphase ), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; medroxyprogesterone acetate 5 mg daily on days 15 28 of the cycle. 107 Conjugated estrogens in fixed combination with bazedoxifene acetate: Conjugated estrogens 0.45 mg with bazedoxifene 20 mg once daily. 262 Vulvar and Vaginal Atrophy Oral Conjugated estrogens USP: Initially, 0.3 mg daily continuously or in cyclic regimen (25 days on, 5 days off). 101 Adjust dosage based on patient response. 101 Synthetic conjugated estrogens A: 0.3 mg daily. 106 Synthetic conjugated estrogens B: 0.3 mg daily. 266 Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro ), monophasic regimen: Initially, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily. 107 Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily. 107 Conjugated estrogens USP with medroxyprogesterone acetate (Premphase ), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; medroxyprogesterone acetate 5 mg daily on days 15 28 of the cycle. 107 Vaginal Conjugated estrogens USP: 0.5 2 g daily in cyclic regimen (3 weeks on, 1 week off). 105 Osteoporosis Prevention in Postmenopausal Women Oral Conjugated estrogens USP: Initially, 0.3 mg daily continuously or in cyclic regimen (25 days on, 5 days off). 101 Adjust dosage based on clinical and BMD response. 101 Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro ), monophasic regimen: Initially, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily. 107 Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily. 107 Adjust dosage based on clinical and BMD response. 107 Conjugated estrogens USP with medroxyprogesterone acetate (Premphase ), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; medroxyprogesterone acetate 5 mg daily on days 15 28 of the cycle. 107 Conjugated estrogens in fixed combination with bazedoxifene acetate: Conjugated estrogens 0.45 mg with bazedoxifene 20 mg once daily. 262 Hypoestrogenism Female Hypogonadism Oral Conjugated estrogens USP: 0.3 0.625 mg daily in a cyclic regimen (3 weeks on, 1 week off). 101 Adjust dosage based on symptom severity and endometrial responsiveness. 101 Female Castration or Primary Ovarian Failure Oral Conjugated estrogens USP: 1.25 mg daily in a cyclic regimen. 101 Adjust dosage based on symptom severity and clinical response. 101 Metastatic Breast Carcinoma Oral Conjugated estrogens USP: 10 mg 3 times daily for ≥3 months. 101 Prostate Carcinoma Oral Conjugated estrogens USP: 1.25 2.5 mg 3 times daily. 101 Abnormal Uterine Bleeding IV or IM Conjugated estrogens USP: 25 mg; can repeat dose in 6 12 hours. 104 Cautions for Estrogens, Conjugated Contraindications Undiagnosed abnormal genital bleeding. 101 104 105 106 107 121 262 Known or suspected breast cancer or history of breast cancer (except when used for palliative treatment of metastatic disease in appropriately selected individuals). 101 104 105 106 107 121 262 Known or suspected estrogen-dependent neoplasia. 101 104 105 106 107 121 262 Active DVT or pulmonary embolism; history of DVT or pulmonary embolism. 101 104 105 106 107 121 262 Active or recent (within past year) arterial thromboembolic disease (e.g., stroke, MI). 101 104 105 106 107 121 262 Liver disease or impairment. 101 104 105 107 121 262 Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. 262 264 265 266 267 Known or suspected pregnancy. 101 104 105 106 107 121 262 Known hypersensitivity to estrogen or any ingredient in the formulation. 101 104 105 106 107 121 262 Warnings/Precautions Warnings Cardiovascular Disorders Estrogen/progestin therapy associated with increased risk of MI, stroke, DVT, and pulmonary embolism. 101 104 105 106 107 112 113 114 121 Estrogen therapy associated with increased risk of stroke and DVT. 101 104 105 107 262 (See Boxed Warning.) Discontinue estrogens immediately if any of these events occur or are suspected. 101 104 105 106 107 121 Use of ERT or HRT is not advised in women with a history of stroke or transient ischemic attacks. (See Contraindications under Cautions.) Appropriately manage risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, obesity) and/or venous thromboembolism (personal or family history of venous thromboembolism, obesity, systemic lupus erythematosus). 101 104 105 106 107 121 (See Contraindications under Cautions.) Discontinue estrogens, whenever feasible, at least 4 6 weeks prior to surgery that is associated with an increased risk of thromboembolism or during prolonged immobilization. 101 104 105 106 107 121 262 Endometrial Cancer Use of unopposed estrogen therapy in women who have a uterus is associated with increased risk of endometrial cancer. 101 104 105 106 107 121 262 Clinical surveillance and evaluation are essential. 101 104 105 106 107 121 Perform diagnostic tests to rule out malignancy in women with undiagnosed, persistent or recurring abnormal vaginal bleeding. 101 104 105 106 107 121 Incidence of endometrial hyperplasia is reduced substantially when progestins are used concomitantly. 101 104 105 106 107 121 Concomitant use of estrogen agonist/antagonist bazedoxifene also reduces risk of endometrial hyperplasia associated with conjugated estrogens. 262 Breast Cancer HRT associated with increased risk of breast cancer 101 104 105 106 107 112 113 114 121 or increase in abnormal mammograms requiring further evaluation. 262 All postmenopausal women should receive yearly breast examinations by a clinician and perform monthly self-examinations. 101 104 105 106 107 121 262 Schedule periodic mammography based on patient age and risk factors. 101 104 105 106 107 121 262 Dementia ERT or HRT in women ≥65 years of age has been associated with increased risk of developing probable dementia. 101 104 105 107 121 262 Whether these findings apply to younger women is unknown. 101 104 105 107 121 (See Alzheimer s Disease under Uses.) Gallbladder Disease ERT associated with increased risk of gallbladder disease requiring surgery. 101 104 105 106 107 121 262 Hypercalcemia Estrogens may cause severe hypercalcemia in patients with breast cancer and bone metastases. 101 104 105 106 107 121 Discontinue the drug and initiate appropriate therapy to reduce serum calcium concentrations if hypercalcemia occurs. 101 104 105 106 107 121 Ocular Effects Retinal thrombosis reported. 101 104 105 106 107 121 262 Discontinue pending examination if sudden partial or complete loss of vision or sudden onset of proptosis, diplopia, or migraine occurs. 101 104 105 107 121 262 Discontinue estrogens if papilledema or retinal vascular lesions noted on examination. 101 104 105 106 107 104 105 121 262 General Precautions Elevated BP Rarely, substantial increases in BP attributed to idiosyncratic reactions to estrogen. 101 104 105 106 107 121 262 ERT generally is not associated with elevated BP. 101 104 105 107 121 Monitor BP at regular intervals. 101 104 105 106 107 121 Hypertriglyceridemia Estrogen therapy may be associated with increases in plasma triglyceride concentrations resulting in pancreatitis in women with increased serum lipids. 101 104 105 106 107 121 262 Consider discontinuance of therapy if pancreatitis occurs. 262 264 265 266 Fluid Retention Estrogens may cause some degree of fluid retention; use with caution and careful monitoring in patients with conditions that might be aggravated by fluid retention (e.g., cardiac or renal impairment). 101 104 105 106 107 121 262 Hypocalcemia Use with caution in patients with hypoparathyroidism since estrogen-induced hypocalcemia may occur. 101 104 105 106 107 121 262 264 265 266 Hereditary Angioedema Estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. 262 264 265 266 267 Ovarian Cancer Long-term estrogen therapy associated with increased incidence of ovarian cancer in some epidemiologic studies. 101 104 105 106 107 121 262 Other studies did not show a clinically important association. 101 104 105 106 107 121 262 Endometriosis Estrogens may exacerbate endometriosis. 101 104 105 106 107 121 Malignant transformation of residual endometrial implants reported rarely in women receiving unopposed estrogen following hysterectomy. 101 104 105 107 Consider the addition of progestin in women with residual endometriosis following hysterectomy. 101 104 105 107 121 Other Conditions Estrogens may exacerbate asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas; use with caution in patients with these conditions. 101 104 105 107 121 262 Precautions Specific to Vaginal Administration Exposure to conjugated estrogens USP vaginal cream may weaken latex condoms. 105 Consider the potential for the cream to weaken and contribute to protective failure of latex or rubber condoms, diaphragms, or cervical caps. 105 Use of Fixed Combinations When a progestin is used in conjunction with estrogen therapy, consider the cautions, precautions, and contraindications associated with progestin therapy. 107 a When bazedoxifene is used in combination with conjugated estrogens, consider the usual cautions, precautions, contraindications, and interactions associated with bazedoxifene. 262 Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug in the fixed combination. 262 Specific Populations Pregnancy Category X. 101 104 105 106 107 121 262 (See Contraindications under Cautions.) In utero exposure of females to diethylstilbestrol (DES [no longer commercially available in US]) is associated with increased risk of vaginal adenosis, squamous cell dysplasia of the cervix, and clear-cell vaginal cancer in later life. b In utero exposure of males to DES is associated with an increased risk of genital abnormalities and possibly testicular cancer later in life. b Women who receive DES during pregnancy may be at increased risk of breast cancer; causal relationship unproven. b Lactation Administration of estrogens to nursing women has been associated with decreased amounts and lower quality of milk. 101 104 105 106 107 121 262 Detectable amounts of estrogens have been identified in milk of women receiving these drugs. 101 104 105 106 107 121 262 Caution advised. 101 104 105 106 107 121 Conjugated estrogens/bazedoxifene in fixed combination not recommended for use in nursing women. 262 Pediatric Use Estrogen therapy has been used for induction of puberty in adolescents with some forms of pubertal delay. 101 Safety and efficacy of estrogens in children not otherwise established. 101 104 105 107 121 Use estrogen therapy with caution and careful monitoring if bone growth is not yet complete, since estrogens may cause premature epiphyseal closure. 101 Estrogen therapy in prepubertal girls induces premature breast development and vaginal cornification and may induce vaginal bleeding. 101 Estrogen therapy in boys may modify the normal pubertal process. 101 Geriatric Use No substantial differences in safety in women ≥65 years of age compared with younger women; increased incidence of stroke and invasive breast cancer reported in women≥75 years of age compared with younger women. 101 104 105 107 Conjugated estrogens/bazedoxifene in fixed combination not recommended for use in women ≥75 years of age. 262 Possible increased risk of developing probable dementia in women ≥65 years of age. (See Dementia under Cautions.) 101 104 105 107 Clinical studies of estrogens alone or in combination with a progestin did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients. 101 104 105 107 Hepatic Impairment Estrogens may be poorly metabolized in patients with hepatic impairment. 101 104 105 106 107 121 (See Contraindications under Cautions.) Caution advised in patients with a history of cholestatic jaundice associated with previous estrogen use or with pregnancy; discontinue if jaundice recurs. 101 104 105 106 107 121 Renal Impairment Use with caution. 101 104 105 107 121 (See Fluid Retention under Cautions.) Common Adverse Effects Abdominal pain, asthenia, flatulence, leg cramps, pruritus, vaginal hemorrhage, vaginitis, vaginal moniliasis. 101 107 Interactions for Estrogens, Conjugated Appears to be metabolized partially by CYP3A4. 101 104 105 106 107 121 Drugs Affecting Hepatic Microsomal Enzymes CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma estrogen concentrations). 101 104 105 106 107 121 CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma estrogen concentrations). 101 104 105 106 107 121 Specific Drugs and Foods Drug or Food Interaction Comments Anticoagulants, oral Possible decreased anticoagulant action b Monitor; increase warfarin dosage if required b Antifungals, azoles (itraconazole, ketoconazole) Possible increased plasma estrogen concentrations; increased potential for adverse effects 101 104 105 106 107 121 Carbamazepine Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding 101 104 105 106 107 121 Corticosteroids (hydrocortisone) Enhanced anti-inflammatory effects in patients with chronic inflammatory skin disease b Observe for signs of excessive corticosteroid effects; adjust corticosteroid dosage when initiating or discontinuing estrogen b Grapefruit juice Possible increased plasma estrogen concentrations; increased potential for adverse effects 101 104 105 106 107 121 Macrolide antibiotics (clarithromycin, erythromycin) Possible increased plasma estrogen concentrations; increased potential for adverse effects 101 104 105 106 107 121 Medroxyprogesterone Interaction unlikely 101 106 107 Phenobarbital Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding 101 104 105 106 107 121 Rifampin Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding 101 104 105 106 107 121 Ritonavir Possible increased plasma estrogen concentrations; increased potential for adverse effects 101 104 105 106 107 121 St. John s wort ( Hypericum perforatum ) Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding 101 104 105 106 107 121 Thyroid agents Increased thyroid-binding globulin concentrations 101 104 105 106 107 121 Increased dosages of thyroid replacement agents may be needed; monitor thyroid function 101 104 105 106 107 121 Estrogens, Conjugated Pharmacokinetics Absorption Bioavailability Conjugated estrogens are well absorbed through mucous membranes and from the GI tract. 101 104 105 106 107 121 Food Conjugated estrogens USP: High-fat meal does not affect extent of oral absorption. 107 Synthetic conjugated estrogens A: Effect of food unknown. 106 Synthetic conjugated estrogens B: Effects of food unknown. 121 Distribution Extent Widely distributed; highest concentrations found in sex hormone target organs. 101 104 105 106 107 121 Plasma Protein Binding 50 80%. b Elimination Metabolism Metabolized in the liver; the kidney, gonads, and muscle tissue involved to some extent. b Estrogens metabolized partially by CYP3A4. 101 104 105 106 107 121 Extensive metabolic conversion takes place in the liver (e.g., estradiol converted to estrone, both converted to estriol). 101 104 105 106 107 121 Estrogens undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. 101 104 105 106 107 121 Elimination Route Estrogens and their metabolites excreted mainly in urine. 101 104 106 107 121 Half-life Conjugated estrogens: 10 28 hours. 101 106 107 Stability Storage Oral Tablets 20 25 C (may be exposed to 15 30 C). 101 106 107 121 Parenteral Powder for Injection 2 8 C. 104 Vaginal Cream 20 25 C (may be exposed to 15 30 C). 105 Compatibility For information on systemic interactions resulting from concomitant use, see Interactions. Parenteral Stated to be incompatible with protein hydrolysate, ascorbic acid, or any solution with an acid pH. 104 Solution Compatibility 104 Compatible Dextrose solutions Invert sugar solutions Sodium chloride 0.9% Drug Compatibility Y-Site CompatibilityHID Compatible Heparin sodium with hydrocortisone sodium succinate Potassium chloride Vitamin B complex with C Actions Conjugated estrogens USP is a mixture of conjugated equine estrogens obtained from natural sources and occurring as the sodium salts of the water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mare s urine. 101 It is a mixture of sodium estrone sulfate and sodium equilin sulfate that also contains 17α-dihydroequilin, 17α-estradiol, 17β-dihydroequilin, equilenin, 17α-dihydroequilenin, 17β-dihydroequilenin, δ 8,9 -dehydroestrone, and 17β-estradiol. 101 Synthetic conjugated estrogens A is a mixture of conjugated estrogens prepared synthetically from plant sources (i.e., soy and yams). 106 It contains the sodium salts of water-soluble estrogen sulfates blended into a 9-component mixture of estrone sulfate and sodium equilin sulfate as well as the concomitant components 17α-dihydroequilin, 17α-estradiol, 17β-dihydroequilin, 17α-dihydroequilenin, 17β-dihydroequilenin, equilenin, and 17β-estradiol as sodium sulfate conjugates. 106 Synthetic conjugated estrogens B is a mixture of conjugated estrogens prepared synthetically from plant sources. 121 122 It contains the sodium salts of water-soluble estrogen sulfates blended into a 10-component mixture of estrone sulfate and sodium equilin sulfate as well as the concomitant components 17α-dihydroequilin, 17α-estradiol, 17β-dihydroequilin, 17α-dihydroequilenin, 17β-dihydroequilenin, equilenin, 17β-estradiol, and δ 8,9 -dehydroestrone as sodium sulfate conjugates. 121 This mixture contains the 10 estrogenic substances present in currently available commercial preparations of conjugated estrogens USP. 121 Exogenous estrogens elicit, to varying degrees, all the pharmacologic responses usually produced by endogenous estrogens. a Advice to Patients Importance of providing patient a copy of the manufacturer s patient information. 101 104 105 106 107 121 Risk of cancer of the uterus in postmenopausal women. 101 104 105 106 107 121 Importance of reporting any unusual vaginal bleeding to clinicians. 101 104 105 106 107 121 Risk of MI, stroke, breast cancer, and venous thromboembolism. 101 104 105 106 107 121 Importance of not using estrogens to prevent heart disease, MI, or strokes. 101 104 105 106 107 121 Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. 101 104 105 106 107 121 Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as concomitant illnesses. 101 104 105 106 107 121 Importance of informing patients of other important precautionary information. 101 104 105 106 107 121 (See Cautions.) Preparations Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations. Conjugated Estrogens USP Routes Dosage Forms Strengths Brand Names Manufacturer Oral Tablets 0.3 mg Premarin Pfizer 0.45 mg Premarin Pfizer 0.625 mg Premarin Pfizer 0.9 mg Premarin Pfizer 1.25 mg Premarin Pfizer Parenteral For injection 25 mg Premarin Intravenous Pfizer Vaginal Cream 0.0625% Premarin Pfizer Conjugated Estrogens Combinations Routes Dosage Forms Strengths Brand Names Manufacturer Oral Tablets 0.45 mg with Bazedoxifene Acetate 20 mg (of bazedoxifene) Duavee Pfizer Tablets, monophasic regimen 0.3 mg with Medroxyprogesterone acetate 1.5 mg (28 tablets) Prempro Pfizer 0.45 mg with Medroxyprogesterone acetate 1.5 mg (28 tablets) Prempro Pfizer 0.625 mg with Medroxyprogesterone Acetate 2.5 mg (28 tablets) Prempro Pfizer 0.625 mg with Medroxyprogesterone Acetate 5 mg (28 tablets) Prempro Pfizer Tablets, biphasic regimen 0.625 mg (14 tablets Premarin ) and 0.625 mg with Medroxyprogesterone Acetate 5 mg (14 tablets) Premphase Pfizer Conjugated Estrogens A, Synthetic Routes Do is incredibly
confer with Estrogens, Conjugated cut
EmoticonEmoticon