Estrogens, Conjugated (Synthetic A or B)
Pronouncation: (ES-tra-jenz, CON-ju-gate-ed)Class: Estrogens
Trade Names:
Cenestin
- Tablets 0.3 mg (conjugated estrogens, synthetic A)
- Tablets 0.45 mg (conjugated estrogens, synthetic A)
- Tablets 0.625 mg (conjugated estrogens, synthetic A)
- Tablets 0.9 mg (conjugated estrogens, synthetic A)
- Tablets 1.25 mg (conjugated estrogens, synthetic A)
Trade Names:
Enjuvia
- Tablets 0.3 mg (conjugated estrogens, synthetic B)
- Tablets 0.45 mg (conjugated estrogens, synthetic B)
- Tablets 0.625 mg (conjugated estrogens, synthetic B)
- Tablets 1.25 mg (conjugated estrogens, synthetic B)
Pharmacology
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Feedback for Estrogens, Synthetic Conjugated, A or B
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Estrogens are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Circulating estrogens modulate the pituitary secretion of the gonadotropins luteinizing hormone and follicle-stimulating hormone through a negative-feedback mechanism and estrogen replacement therapy acts to reduce the elevated levels of these hormones seen in postmenopausal women.
Pharmacokinetics
Absorption
Well absorbed from the GI tract. Absorbed slowly from the product over a period of several hours.
Distribution
Widely distributed in the body and generally found in higher concentrations in sex hormone target organs. Largely bound to sex hormone–binding globulin and albumin.
Metabolism
Partially metabolized by CYP3A4. Metabolized mainly in the liver (estradiol converted to estrone and both are converted to estriol, a major urinary metabolite). Estrogens undergo enterohepatic recirculation via sulfate and glucuronide conjugates in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption.
Elimination
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
Special Populations
No pharmacokinetic studies have been conducted in special populations, including patients with renal or hepatic function impairment.
Indications and Usage
Treatment of moderate to severe symptoms associated with menopause; treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause (0.3 mg only).
Contraindications
Known or suspected pregnancy; undiagnosed abnormal genital bleeding; known or suspected cancer of the breast; 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 (eg, stroke, MI); liver dysfunction or disease; hypersensitivity to estrogens.
Dosage and Administration
MenopauseAdults
PO
Conjugated estrogens, synthetic AStart with 0.45 mg/day and titrate dose based on response.
Conjugated estrogens, synthetic BStart with 0.3 mg/day, titrate dose based on patient response. Use the lowest effective dose for the shortest duration consistent with the treatment goals and risk.
Vulvar and Vaginal AtrophyAdults
PO 0.3 mg/day.
General Advice
Administer prescribed dose without regard to meals. Administer with food if GI upset occurs.
Storage/Stability
Store tablets at controlled room temperature (68° to 77°F).
Drug Interactions
Corticosteroids (eg, prednisone)Increased pharmacologic and toxicologic effects of corticosteroids may occur.
Hydantoins (eg, phenytoin)Loss of seizure control or decreased estrogenic effects may occur.
Inducers of CYP3A4 (eg, carbamazepine, phenobarbital, rifampin, St. John's wort)Estrogen concentration may be decreased, reducing the efficacy and changing the uterine bleeding profile.
Inhibitors of CYP3A4 (eg, clarithromycin, erythromycin, grapefruit juice, itraconazole, ketoconazole, ritonavir)May elevate estrogen concentrations, increasing the risk of adverse reactions.
Thyroid hormones (eg, levothyroxine)Serum-free thyroxine concentrations may be decreased, increasing serum thyrotropin concentrations and the need for thyroid hormone.
Laboratory Test Interactions
Accelerated PT, PTT, and platelet aggregation time with increased clotting factor activity; increased platelets; decreased anti-factor Xa and antithrombin III; increased thyroid-binding globulin (TBG) leading to increased total circulating thyroid hormone; increased plasma HDL, reduced LDL cholesterol, and increased triglycerides; impaired glucose tolerance; reduced response to metyrapone test; increased corticosteroid binding globulin and sex hormone binding globulin; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased antithrombin III activity, increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity; decreased T3 resin uptake; decreased free hormone concentrations; other plasma proteins may be increased (eg, angiotensinogen/resin substrate).
Adverse Reactions
CNS
Headache (68%); paresthesia (33%); dizziness (11%); anxiety, hypertonia, paresthesia (6%).
EENT
Rhinitis (7%).
GI
Abdominal pain (28%); nausea (12%); dyspepsia (10%); flatulence, vomiting (7%); constipation, diarrhea (6%).
Genitourinary
Breast pain (29%); endometrial thickening (19%); metrorrhagia (14%); dysmenorrhea, vaginitis (8%).
Metabolic-Nutritional
Weight increase (6%).
Musculoskeletal
Back pain (14%); leg cramps (10%).
Respiratory
Upper respiratory tract infection (13%); bronchitis, sinusitis (7%); increased cough (6%).
Miscellaneous
Pain (19%); infection (14%); accidental injury (8%); flu syndrome (7%).
Precautions
WarningsCV and other risksEstrogens with or without progestins should not be used for prevention of CV disease. The Women's Health Initiative (WHI) study reported increased risk of MI, stoke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women 50 to 79 yr of age during 5.6 yr of treatment with oral conjugated estrogens 0.625 mg combined with medroxyprogesterone acetate 2.5 mg compared with placebo. DementiaA substudy of WHI, the WHI Memory Study, reported increased risk of developing probable dementia in postmenopausal women 65 yr of age or older during 4 yr of treatment with oral conjugated estrogens plus medroxyprogesterone acetate compared with placebo. It is unknown if this finding applies to younger postmenopausal women or women taking estrogen alone. Endometrial cancerClose clinical surveillance of all women taking estrogens is important. The use of unopposed estrogen in women with intact uteri has been associated with an increased risk of endometrial cancer. 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. |
MonitorMonitor blood glucose in diabetic patients when starting or changing the dose of the drug. Baseline examinationsEnsure breast, abdominal, and pelvic examinations and Pap smear have been completed and documented before starting therapy and annually thereafter during prolonged therapy. |
Pregnancy
Contraindicated in pregnancy.
Lactation
Excreted in breast milk. May reduce quantity and quality of breast milk.
Children
Safety not established.
Elderly
Insufficient data to determine if clinical response of subjects older than 65 yr of age is different from younger subjects.
Special Risk Patients
Because asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas may be exacerbated by estrogens, use with caution.
Breast cancer
Use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. Use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.
Elevated BP
Substantial increases in BP have been attributed to idiosyncratic reactions to estrogens. Assess BP at beginning of therapy and periodically during treatment.
Endometriosis
May be exacerbated with administration of estrogens.
Fluid retention
Because estrogens may cause fluid retention, carefully monitor patients with conditions influenced by fluid retention (eg, cardiac dysfunction, renal function impairment).
Gallbladder
Increased risk of gallbladder disease requiring surgery.
History of cholestatic jaundice
Use with caution and discontinue if there is recurrence.
Hypercalcemia
Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases.
Hypertriglyceridemia
In patients with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations in plasma triglycerides, leading to pancreatitis and other complications.
Hypocalcemia
Use with caution.
Hypothyroidism
Estrogen administration leads to increased TBG levels. Ensure thyroid function is periodically monitored in patients with hypothyroidism and thyroid replacement dose is adjusted, if necessary, to maintain free thyroid levels in an acceptable range.
Liver function impairment
Estrogens may be poorly metabolized in patients with impaired liver function.
Ovarian cancer
Estrogen plus progestin has been reported to increase the risk of cancer.
Surgery/Immobilization
Consider discontinuing therapy during periods of prolonged immobilization and, if possible, 4 to 6 wk before surgery that is associated with an increased risk of thromboembolic disease.
Tapering/Withdrawal
Ensure attempts are made every 3ߙto 6 mo to discontinue therapy or reduce the dose of medication.
Visual abnormalities
Retinal vascular thrombosis may occur, leading to loss of vision, sudden onset of proptosis, diplopia, or migraine.
Overdosage
Symptoms
Nausea, vomiting, withdrawal bleeding.
Patient Information
- Advise patient to review patient information leaflet before starting therapy and with each refill.
- Advise patient that dose may be adjusted periodically to obtain max benefits.
- Advise patient to be prepared to regularly (eg, every 3 to 6 mo) talk with health care provider about whether the dose of medication needs to be adjusted or if the medication is no longer needed and can be stopped.
- Instruct patient to take as prescribed and not to change the dose or stop taking the medicine unless advised to do so by health care provider.
- Advise patient to take prescribed dose once daily without regard to meals, but to take with food if stomach upset occurs.
- Advise patient that if a dose is missed, to take it as soon as remembered. However, if it is nearing time for the next scheduled dose, skip the missed dose and take only the next regularly scheduled dose. Advise patient to not double the dose to catch up.
- Instruct diabetic patients to monitor blood glucose more frequently when drug is started or dose is changed and to inform health care provider of significant changes in readings.
- Review nonhormonal modalities that help prevent osteoporosis: 1,500 mg/day of calcium, vitamin D supplementation, exercise.
- Teach patient proper method of breast self-examination and advise patient to perform monthly.
- Instruct patient to immediately report any of the following to health care provider: pain in groin or calves, chest pain, difficulty breathing or unexplained shortness of breath, abnormal vaginal bleeding, breast lumps, sudden severe headache, dizziness or fainting, vision or speech problems, weakness or numbness of arms or legs, severe abdominal pain or swelling, yellowing of skin or eyes, severe depression.
- Advise patient that follow-up visits and examinations, including Pap smear at least once a year, will be required to monitor therapy and to keep appointments.
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Postmenopausal Symptoms, Oophorectomy, Osteoporosis, Abnormal Uterine Bleeding, Prostate Cancer, Atrophic Vaginitis, Atrophic Urethritis, Hypoestrogenism, Breast Cancer -- Palliative, Primary Ovarian Failure
