Ogen (Estropipate)

OGEN®

Pharmacia & Upjohn

Estropipate

Estrogen

Action And Clinical Pharmacology: Estropipate is a natural estrogenic substance prepared from purified crystalline estrone, solubilized as the sulfate and stabilized with piperazine. It is appreciably soluble in water and has almost no odor or taste. The amount of piperazine in estropipate is not sufficient to exert a pharmacological action. Its addition ensures solubility, stability and uniform potency of the estrone sulfate.

Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics. They promote growth and development of the vagina, uterus and fallopian tubes, and enlargement of the breasts. Indirectly, they contribute to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination, growth of axillary and pubic hair, and pigmentation of the nipples and genitals. Along with other hormones such as progesterone, estrogens are intricately involved in the process of menstruation. Estrogens also affect the release of pituitary gonadotropins.

Estropipate owes its therapeutic action to estrone, one of the three principal estrogenic steroid hormones of man: estradiol, estrone and estriol. Estradiol is rapidly hydrolysed in the body to estrone, which in turn may be hydrated to the less active estriol. These transformations occur readily, mainly in the liver, where there is also free interconversion between estrone and estradiol.

A depletion of endogenous estrogens occurs postmenopausally as a result of a decline in ovarian function, and may cause symptomatic vulvovaginal atrophy.

Gastrointestinal absorption of orally administered estrogens is usually prompt and complete. Inactivation of estrogens in the body occurs mainly in the liver. During cyclic passage through the liver, estrogens are degraded to less active estrogenic compounds and conjugated with sulfuric and glucuronic acids. Estrone is 50 to 80% bound to protein as it circulates in the blood, usually as a conjugate with sulfate.

In the normal menstrual cycle, the mean daily excretion of endogenous estrogens at the midovulatory maximum has been found to be 29 µg of estriol, 21 µg of estrone and 8 µg of estradiol (total, 58 µg). In normal women, after menopause, the average daily excretion of these 3 estrogens totals only 6 µg.

In studies of postmenopausal women with low bone density, it has been shown that therapy with estropipate, concomitant with other preventative measures such as an appropriate diet, calcium supplementation and exercise, can prevent further bone loss.

Indications And Clinical Uses: The treatment of menopausal and postmenopausal symptoms.

Contra-Indications: Estrogens should not be administered to patients with active hepatic dysfunction or disease, especially of the obstructive type; or a personal history of breast or endometrial cancer, except in special circumstances, or in patients with endometrial hyperplasia unless a progestogen is administered concomitantly.

The drug is also contraindicated in the following situations: undiagnosed vaginal bleeding; a history of cerebrovascular accidents, coronary thrombosis, or in the presence of classical migraine; a history of thrombophlebitis or thromboembolic disease; partial or complete loss of vision or diplopia due to ophthalmic vascular disease, and suspected pregnancy.

Manufacturers’ Warnings In Clinical States: Before estrogens are administered, the patient should have a complete physical examination including a blood pressure determination. Breasts and pelvic organs should be examined and a Papanicolaou smear should be taken. Baseline tests should include those for blood glucose, calcium, triglycerides and cholesterol, and liver function.

The first follow-up examination should be done preferably within 6 months after initiation of treatment. Thereafter, examinations should be made once a year and should include those procedures outlined above.

If any surgical procedures are performed, the pathologist should be advised of the patient’s therapy when specimens are sent for examination. Liver function tests should be made periodically in subjects who have, or are suspected of having, hepatic disease.

An increased risk of endometrial hyperplasia and carcinoma in postmenopausal women exposed to exogenous estrogens for long periods has been reported. The risk appears to depend on both duration of treatment and on estrogen dose. If abnormal vaginal bleeding occurs during therapy, diagnostic aspiration biopsy or curettage should be performed to rule out the possibility of uterine malignancy.

Patients who develop visual disturbances, classical migraine, transient aphasia, paralysis, or loss of consciousness, should discontinue medication.

Although the estrogen content of oral contraceptive therapy have been associated with an increased risk of various thromboembolic, thrombotic and vascular diseases, to date no such increased risk in postmenopausal users of estrogens has been described. Nevertheless, this does not rule out the possibility that such an increase may be present in women who have underlying risk factors or who are receiving relatively large doses of estrogens. Therefore, if the patient develops any sign of phlebitis or thrombotic complications (thrombophlebitis, retinal thrombosis, cerebral embolism and pulmonary embolism), medication should be discontinued immediately.

Precautions: Development or sudden enlargement, pain, or tenderness of uterine fibroids requires discontinuation of medication.

Estrogen may cause fluid retention. Where this may be undesirable such as in cardiac or renal dysfunction, epilepsy or asthma, particular caution is indicated.

Elevation of blood pressure in previously normotensive or hypertensive patients necessitates cessation of medication.

Diabetic patients or those with a predisposition to diabetes should be observed closely to detect any alterations in carbohydrate metabolism.

When liver or endocrine function tests are indicated, the results should not be considered reliable unless therapy has been discontinued for 2 to 4 months.

Adverse Reactions: Although not all of the following adverse reactions have been specifically associated with estropipate, they have been reported with estrogens generally and may be encountered when giving any estrogen. Some of these (indicated in brackets) have been documented with oral contraceptives specifically, and have not to now been associated with cyclic menopausal or postmenopausal estrogen therapy.

Gastrointestinal: nausea, (anorexia, vomiting, abdominal cramps, bloating), cholestatic jaundice, increase or decrease in body weight.

Genitourinary: sodium and water retention, breakthrough bleeding, spotting and withdrawal bleeding, increased cervical mucus, endometrial hyperplasia, reactivation of endometriosis, (cystitis-like syndrome).

Endocrine: breast swelling and tenderness, increased blood sugar levels, and decreased glucose tolerance. In males: gynecomastia, reduced potency and feminization.

CNS: headaches, increase or decrease of libido, (nervousness, mental depression, dizziness, fatigue, irritability).

Dermatologic – Hypersensitivity: allergic reactions and rashes, chloasma (loss of scalp hair, hemorrhagic eruption, itching, erythema nodosum, erythema multiforme, pigmentation of the skin).

Cardiovascular: an increase in blood pressure in susceptible individuals, aggravation of migraine headaches.

Hematologic: A statistically significant association has been demonstrated between the use of oral contraceptive preparations containing estrogens and the following serious reactions: thrombophlebitis, pulmonary embolism and cerebral thrombosis. Although available evidence is suggestive of an association, such a relationship has been neither confirmed nor refuted for the following serious reactions: coronary thrombosis and neuro-ocular lesions (e.g., retinal thrombosis and optic neuritis); altered coagulation tests (increase in prothrombin and Factors VII, VIII, IX, X).

Miscellaneous: premenstrual-like syndrome, precipitation or aggravation of porphyria cutanea tarda in predisposed individuals.

Symptoms And Treatment Of Overdose: Symptoms: Excessive doses may result in nausea, vomiting and abdominal cramps, headache, dizziness and general malaise. tag_Treatment

Treatment: Remove all of the ingested drug by gastric lavage and give symptomatic treatment.

Dosage And Administration: In general, estrogen should be given cyclically (21 to 25 days followed by a 5- to 7-day rest period) and in some cases with progestogen or androgen to avoid overstimulation of breast and endometrial tissues. Withdrawal bleeding commonly occurs toward the end of the rest period. The addition of sufficient progestogen to promote conversion of the endometrium is mandatory in those patients who are receiving sufficient unopposed estrogen to cause vaginal bleeding or endometrial hyperplasia. Obviously, abnormal vaginal bleeding in such patients is an indication for prompt diagnostic measures.

Estropipate is administered orally. As with most drugs, the dosage should be adjusted to the minimum required to control symptoms and the requirement for estrogen therapy should be reassessed periodically.

Estropipate is indicated for a variety of estrogen deficiency states. The usual daily dose is 0.75 to 3.0 mg of estropipate (Ogen 0.625, Ogen 1.25, Ogen 2.5 calculated as sodium estrone sulfate). Titrate dosage as necessary according to the individual patient’s clinical response.

Availability And Storage: 0.625 mg: Each yellow-colored, oval, scored tablet, embossed with “U” and “3772” on left and right halves, contains: estropitate 0.75 mg (calculated as sodium estrone sulfate 0.625 mg). Blisters of 20. Cartons of 5 blisters. Bottles of 100.

1.25 mg: Each peach-colored oval, scored tablet, embossed with “U” and “3773” on left and right halves, contains: estropitate 1.5 mg (calculated as sodium estrone sulfate 1.25 mg). Blisters of 20. Cartons of 5 blisters. Bottles of 100.

2.5 mg: Each blue-colored, oval scored tablet, embossed with “U” and “3774” on left and right halves, contains: estropitate 3.0 mg (calculated as sodium estrone sulfate 2.5 mg). Blisters of 20. Cartons of 5 blisters. Bottles of 100.

Nonmedicinal ingredients: blue dye #2 (2.5 mg only), hydrogenated vegetable oil wax, hydroxypropyl cellulose, lactose, magnesium stearate, microcrystalline cellulose, potassium phosphate dibasic, silicon dioxide, sodium starch glycolate, tromethamine, yellow dye #6 (0.625 and 1.25 mg only) and yellow dye #10 (0.625 mg only).

Tablets of all 3 dosage levels are grooved to provide dosage flexibility.

OGEN® Pharmacia & Upjohn Estropipate Estrogen

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