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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

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

Menopause
Adults

PO

Conjugated estrogens, synthetic A

Start with 0.45 mg/day and titrate dose based on response.

Conjugated estrogens, synthetic B

Start 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 Atrophy
Adults

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

Warnings

CV and other risks

Estrogens 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.

Dementia

A 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 cancer

Close 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.


Monitor

Monitor blood glucose in diabetic patients when starting or changing the dose of the drug.

Baseline examinations

Ensure 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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