Conjugated estrogens for vaginal administration is a mixture of estrogens, obtained exclusively from natural sources, blended to represent the average composition of material derived from pregnant mares’ urine. It contains the sodium salts of water-soluble sulfate esters of estrone, equilin, and 17 alpha-dihydroequilin, together with smaller amounts of 17 alpha-estradiol, equilenin, 17 alpha-dihydroequilenin, 17 beta-dihydroequilin, 17 beta-dihydroequilenin, 17 beta-estradiol, and delta 8,9-dehydroestrone.

Pharmacology

Estrogens are important in the development and maintenance of the female urogenital 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 associated with the pubertal growth spurt and its termination, growth of axillary and pubic hair, and pigmentation of the nipples and genital tissues. However, in the preovulatory or anovulatory cycle, estrogen is the primary determinant in the onset menstruation. Eestrogen also affects the release of pituitary gonadotropins. The pharmacologic effects of conjugated estrogens are similar to those of endogenous estrogens. In responsive tissues (female urogenital organs, breasts, hypothalamus, pituitary) estrogens enter the cell and are transported into the nucleus. As a result of estrogenic activity, specific RNA and protein synthesis occurs.

Osteoporosis associated with estrogen deficiency: Estrogen replacement therapy is the most effective single modality for the prevention of osteoporosis (loss of bone mass) in postmenopausal women. Estrogen reduces bone resorption and retards or halts postmenopausal bone loss. One clinical study demonstrated that even when estrogen was started as late as fifteen years after menopause, further loss of bone mass was prevented but no restoration of bone mass was observed. The effect on bone mass conservation is sustained only as long as conjugated estrogen therapy is continued. Different ethnic groups are at different risk for osteoporosis.

Atrophic vaginitis and Kraurosis Vulvae: Atrophic vaginitis and Kraurosis Vulvae associated with estrogen deficiency. In the absence of estrogen stimulation, the vulvar and vaginal tissues shrink, the vaginal walls become thin and dry, and rugal folds disappear. Tenderness and pruritus, with resulting dysuria and dyspareunia, may occur. Fissures and ulcerations of tissue with spotting or bleeding may result from coitus. These changes are reversible with the administration of estrogen replacement therapy.

Female Hypoestrogenism: Estrogen replacement therapy is indicated in hypoestrogenism related to female hypogonadism or primary ovarian failure. Primary ovarian failure starting early in life will lead to delayed closure of the epiphyses and retarded bone maturation. Long term estrogen deficiency in any age group will usually lead to osteoporosis (for efficacy with estrogen replacement therapy see osteoporosis). Estrogen therapy is associated with the appearance of female characteristics in these patients.

Conjugated Estrogen cream is indicated in the following indications-

• Moderate-to-severe vasomotor symptoms associated with estrogen deficiency.
• Prevention and management of osteoporosis associated with estrogen deficiency.
• Atrophic vaginitis and Kraurosis Vulvae.
• Female hypoestrogenism.
• Treatment of moderate to severe Dyspareunia.

Atrophic Vaginitis and Kraurosis Vulvae: Administer cyclic regimen (daily for 21 days followed by 7 days off) intravaginally. Start at 0.5 gm dosage strength; may adjust dosage (0.5 to 2 gm) based on individual response.

Moderate to Severe Dyspareunia: Treats symptom of vulvar and vaginal atrophy due to menopause 0.5 gm intravaginally in a twice-weekly (eg, Monday and Thursday) continuously or in a cyclic regimen of daily administration for 21 days followed by 7 days off.

Administration

Step 1: Remove cap from tube.

Step 2: Screw nozzle end of applicator onto tube.

Step 3: Gently squeeze tube from the bottom to force sufficient cream into the barrel to provide the prescribed dose.

Step 4: Unscrew applicator from tube.

Step 5: Place the applicator into the vaginal opening.

Step 6: To deliver medication, press plunger downward.

To cleanse: Pull plunger to remove it from barrel. Wash with mild soap and warm water. Do not boil.

• Known or suspected cancer of the breast.
• Known or suspected estrogen-dependent neoplasia.
• Known or suspected pregnancy.
• Undiagnosed abnormal genital bleeding.
• Active thrombophlebitis or thromboembolic disorders.
• Hypersensitivity to any of the components of Conjugated Estrogen vaginal cream.

The most serious adverse reactions associated with the use of estrogen are indicated under Warnings and Precautions. The following additional adverse reactions have been reported with estrogenic therapy.

• Genitourinary System: Breakthrough bleeding, spotting, change in menstrual flow, amenorrhea.
• Breasts: Tenderness, enlargement, secretion.
• Gastrointestinal: Nausea, vomiting, abdominal cramps, bloating, cholestatic jaundice.
• Skin: Chloasma or melasma which may persist when drug is discontinued, alopecia, rash.
• Eyes: Steepening of the corneal curvature; intolerance to contact lenses.
• Central Nervous System: Headache, migraine, dizziness; chorea.
• Miscellaneous: Increase or decrease in weight; edema; changes in libido, aggravation of porphyria.

Common side effects include Headache, Breast pain, Irregular vaginal bleeding or spotting, stomach or abdominal cramps, bloating, Nausea and vomiting, Hair loss, Fluid retention, Vaginal yeast infection, Reactions from inserting Conjugated Estrogen Vaginal Cream, such as vaginal burning, irritation and itching.

Uncommon side Effects Heart attack, Stroke, Blood clots, Dementia, Breast cancer, Cancer of the lining of the uterus (womb), Cancer of the ovary, High blood pressure, High blood sugar, Gallbladder disease, Enlargement of benign tumors of the uterus

(fibroids), Severe allergic reaction.

Overdose Effects

Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Conjugated Estrogen therapy with institution of appropriate symptomatic care.

Estrogen therapy without the addition of a progestogen in women with a uterus has been reported to increase the risk of endometrial hyperplasia/carcinoma. The risk appears to depend on both duration of treatment and estrogen dose. The patient should be reassessed at least on an annual basis. Studies have indicated a reduced risk of endometrial cancer when a progestogen is administered with estrogen replacement therapy. There are possible additional risks which may be associated with the inclusion of a progestogen in hormone replacement therapy regimens. These include adverse effects on carbohydrate and lipid metabolism. An increased risk of gallbladder disease in women receiving postmenopausal estrogen has been reported. Some studies have suggested a possible increased incidence of breast cancer in those women on estrogen therapy taking higher doses for prolonged periods of time. Women on this therapy should have regular breast examinations and should be instructed in breast self-examination. Doses of Conjugated Estrogen used should not exceed the recommended doses.

A complete medical and family history should be obtained prior to the initiation of any estrogen therapy. The pretreatment and periodic physical examinations should include special reference to blood pressure, breasts, abdomen, and pelvic organs, and should include a Papanicolaou smear. Where no pathologic cause is found for abnormal vaginal bleeding, dose reduction of cycling may be indicated. Women on estrogen replacement therapy have not been reported to have an increased risk of thrombophlebitis and/or thromboembolic disease. However, there is insufficient information regarding women who have a history of thromboembolic disease to determine risk. Estrogen may be poorly metabolized in patients with impaired liver function and they should be administered with caution in such patients

Pregnancy & Lactation

Estrogen should not be used during pregnancy. Estrogen therapy during pregnancy is associated with an increased risk of congenital defects in the reproductive organs of the male and female fetus, an increased risk of vaginal adenosis, squamous cell dysplasia of the cervix, and vaginal cancer in the female later in life. There is no indication for estrogen therapy during pregnancy. Estrogens are effective in the prevention or treatment of threatened or habitual abortion.

As a general principle, the administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk.