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Trade Names:
Cenestin
- Tablets 0.3 mg (synthetic conjugated estrogens, A)
- Tablets 0.45 mg (synthetic conjugated estrogens, A)
- Tablets 0.625 mg (synthetic conjugated estrogens, A)
- Tablets 0.9 mg (synthetic conjugated estrogens, A)
- Tablets 1.25 mg (synthetic conjugated estrogens, A)

Trade Names:
Enjuvia
- Tablets 0.3 mg
- Tablets 0.45 mg
- Tablets 0.625 mg (synthetic conjugated estrogens, B)
- Tablets 1.25 mg (synthetic conjugated estrogens, B)

Mechanism of Action

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 (LH) and follicle stimulating hormone (FSH) 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

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.

Indications and Usage

Treatment of moderate to severe symptoms associated with menopause (synthetic conjugated estrogens, A or B); moderate to severe symptoms of vulvar and vaginal atrophy (synthetic conjugated estrogens, A 0.3 mg only).

Contraindications

Known or suspected pregnancy; undiagnosed abnormal genital bleeding; known or suspected 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 (eg, stroke); liver dysfunction or disease; hypersensitivity to estrogens.

Dosage and Administration

PO Synthetic conjugated estrogens, A: Start with 0.45 mg/day and titrate up to 1.25 mg/day based on response.

Synthetic conjugated estrogens, 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.

PO Synthetic conjugated estrogens, A: 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

Estrogen concentration may be decreased, reducing the efficacy and changing the uterine bleeding profile.

May elevate estrogen concentrations, increasing the risk of adverse reactions.

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.

Adverse Reactions

The following adverse reactions occurred in at least 5% of patients.

Cardiovascular

Palpitation, vasodilation.

CNS

Anxiety, asthenia, depression, dizziness, headache, hypertonia, insomnia, nervousness, paresthesia, vertigo.

GI

Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, nausea, vomiting.

Genitourinary

Breast pain, dysmenorrhea, endometrial thickening, metrorrhagia, vaginitis.

Metabolic

Peripheral edema, weight increase.

Musculoskeletal

Arthralgia, leg cramps, myalgia.

Respiratory

Bronchitis, cough, pharyngitis, rhinitis, sinusitis, upper respiratory infection.

Miscellaneous

Accidental injury, back pain, fever, flu syndrome, infection, pain, rash.

Precautions

Pregnancy

Contraindicated in pregnancy.

Lactation

Excreted in breast milk. May reduce quantity and quality of breast milk.

Children

Safety not established.

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.

CV disorders

Estrogen and estrogen/progestin therapy has been associated with an increased risk of CV events (eg, MI, stroke, venous thromboembolism, pulmonary embolism). In the Women's Health Initiative (WHI) study, an increase in number of strokes and venous thromboembolism has been observed in women taking conjugated estrogens compared with placebo. In addition, in women taking conjugated estrogens/medroxyprogesterone acetate an increased risk of coronary heart disease events was observed in the first year and an increase in stroke was observed after the first year. Both persisted.

Cholestatic jaundice history

Use with caution and discontinue if there is recurrence.

Dementia

In the WHI study, the risk of dementia was increased in women receiving conjugated estrogens/medroxyprogesterone acetate.

Elevated BP

Substantial increases in BP have been attributed to idiosyncratic reactions to estrogens. Assess BP at beginning of therapy and periodically during treatment. Notify health care provider of significant increases.

Endometrial cancer

Use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. Use of estrogen plus progestin has been reported to reduce the risk of endometrial hyperplasia, which is a precursor to endometrial cancer.

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 or renal function impairment).

Gallbladder

Increased risk of gallbladder disease requiring surgery.

Glucose intolerance

Monitor blood sugar in diabetic patient when drug is started or dose is changed. Report significant changes to health care provider. A worsening of glucose tolerance has occurred.

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 thyroid-binding globulin levels. Ensure thyroid function is periodically monitored in patient with hypothyroidism, and thyroid replacement dose is adjusted, if necessary, to maintain free thyroid levels in an acceptable range.

Impaired liver function

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 3 to 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.

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 change the dose or stop taking the medicine unless advised 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 patient 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.