Premarin Vaginal Cream (Conjugated Estrogens)

PREMARIN® VAGINAL CREAM

Wyeth-Ayerst

Conjugated Estrogens

Vaginitis Therapy

Action And Clinical Pharmacology: Conjugated estrogens are a mixture of estrogens obtained exclusively from natural sources occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares’ urine. It contains estrone, equilin, and 17a-dihydroequilin, together with smaller amounts of 17a-estradiol, equilenin, and 17a-dihydroequilenin as salts of their sulfate esters.

Metabolic and Somatic Effects: Estrogens are responsible for the development and maintenance of the female reproductive system and secondary sex characteristics. Estrogens cause growth and development of the vagina, uterus and fallopian tubes, and the enlargement of the breasts. Indirectly, estrogens contribute to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, cause changes in the epiphyses of the long bones producing pubertal growth spurt and termination, axillary and pubic hair growth, and pigmentation of the nipples and genitals.

Estrogens affect calcium and phosphorus metabolism and are involved in maintaining normal bone structure. In prolonged estrogen deficiency states, the administration of estrogens may alter associated degenerative bone changes.

Effect on Menstruation: An ebb and rise of the female gonadal hormone produces the normal menstrual cycle. In the pre- and anovulatory cycle, estrogens are the primary determinants for the onset of menstruation. Estrogens do not induce ovulation. Estrogen levels rise during the first half of the menstrual cycle. At midpoint in the second half of the cycle, the corpus luteum produces high levels of both estrogens and progesterone. Decline of estrogenic activity at the end of the menstrual cycle commonly brings on menstruation, although the cessation of progesterone secretion is the most important factor in this phase of the mature ovulatory cycle.

Effects on Nervous System: Estrogens also affect the psychologic and emotional aspects of feminine behavior. As estrogen levels increase during the menstrual cycle, women experience a sense of well-being and vigor. In the postmenopausal period, after the decline of endogenous estrogen production, estrogen administration aids in relieving nervous symptoms, such as anxiety, depression and irritability.

Indications And Clinical Uses: The treatment of atrophic vaginitis, dyspareunia and kraurosis vulvae.

For many years it has been known that topical or vaginal estrogen therapy would stimulate cell growth and development, improving the epithelial thickness of the vaginal mucosa and increasing secretions. Recent reports have shown that the intravaginal use of topical estrogen creams produces even higher blood estrogen levels than comparable oral doses. Therefore, precautions recommended with oral estrogen administration should also be observed with this route.

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.

Premarin is also contraindicated in the following situations: undiagnosed vaginal bleeding; a history of cerebrovascular accident, 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; when pregnancy is suspected.

Manufacturers’ Warnings In Clinical States: Before administration the patient should have a complete physical examination including blood pressure determination. Breasts, and pelvic organs should be examined and a Papanicolaou smear taken.

The first followup 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.

If abnormal vaginal bleeding occurs during therapy, diagnostic aspiration biopsy or curettage should be performed to rule out the possibility of uterine malignancy.

Although the estrogen content or oral contraceptive therapy has 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 detected. Nevertheless, the physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, retinal thrombosis, cerebral embolism, and pulmonary embolism). If these occur or are suspected, estrogen therapy should be discontinued immediately.

In patients with metastatic carcinoma and hypercalcemia, estrogen medication should be used with caution.

Three independent retrospective studies have reported an association between postmenopausal oral estrogen therapy and an increased risk of endometrial carcinoma. These studies, however, lacked information regarding certain important intrinsic risk factors of the patients (especially pretreatment endogenous hormonal status) and the mode of administration of estrogen. The potential relationship of estrogen to endometrial carcinoma under clinical conditions has to be considered. However, a cause and effect relationship between estrogen administration and endometrial carcinoma cannot be established by these data at this time.

Precautions: Estrogen may cause sodium and water retention. Where this may be undesirable such as in cardiac or renal dysfunction, epilepsy, or asthma, particular caution is indicated.

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

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

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.

Note: Preliminary studies conducted by the Health Protection Branch have demonstrated that Premarin cream may react with the latex rubber of certain mechanical barrier devices used for prevention of sexually transmitted diseases and pregnancy (diaphragms and condoms).

Adverse Reactions: The following adverse reactions have been reported with the use of estrogens in general. Some of these (indicated in brackets) have been documented with oral contraceptives specifically, and have not, to date been associated with cyclic menopausal or postmenopausal conjugated estrogen therapy.

Gastrointestinal: nausea, (anorexia, vomiting, abdominal cramps, bloating), cholestatic jaundice and increase 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 and Metabolic: 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, (mental depression, nervousness, dizziness, fatigue, irritability).

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

Cardiovascular: an increase in blood pressure in susceptible individuals and 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).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Excessive doses may result in nausea, vomiting and abdominal cramps, headache, dizziness and general malaise. Treatment should be discontinued and symptomatic treatment given.

Dosage And Administration: Administered cyclically for short-term use only: For the treatment of atrophic vaginitis, dyspareunia or kraurosis vulvae.

In patients with severe cases of atrophic vaginitis, the mucosa should first be conditioned with a short course of oral therapy, 1.25 mg daily for approximately 10 days. Vaginal treatment should be instituted at the lowest effective dosage, and the requirement for estrogen therapy reassessed regularly. In patients already receiving oral therapy, the oral dosage may be reduced taking into account the potential absorption from the vaginal medication. The degree of atrophy is directly responsible for the level of absorption and should be the guiding factor in dose adjustment.

Two to 4 g daily, intravaginally or topically, depending on the severity of the condition. Administration should be cyclic (e.g. 3 weeks on and 1 week off).

Appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding.

Availability And Storage: Each g of white, vaginal cream contains: 625 µg (0.625 mg) of conjugated estrogens CSD in a nonliquefying cream base. Nonmedicinal ingredients: cetyl alcohol, cetyl esters wax, glycerin, glyceryl monostearate, methyl stearate, mineral oil light, phenylethyl alcohol, propylene glycol monostearate, sodium lauryl sulfate, water purified and white wax. Gluten-, paraben-, sugar-, sulfite- and tartrazine-free. Tubes of 42.5 g with calibrated plastic applicator.

PREMARIN® VAGINAL CREAM Wyeth-Ayerst Conjugated Estrogens Vaginitis Therapy

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