conjugated estrogens, vaginal (Rx)

Brand and Other Names:Premarin Vaginal Cream
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

vaginal cream

  • 0.625mg/g
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Atrophic Vaginitis and Kraurosis Vulvae

Administered intravaginally in a cyclic regimen (daily for 21 days and then off for 7 days)

Typically started at the 0.5 g dosage strength; dosage adjustments (0.5 to 2 g) may be made based on individual response

Dyspareunia

Indicated for treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy due to menopause

0.5 g intravaginally in a twice-weekly (eg, Monday and Thursday) continuous regimen or in a cyclic regimen of 21 days of therapy followed by 7 days off of therapy

Dosing Considerations

Generally, when estrogen is prescribed for postmenopausal women with a uterus, a progestin should also be considered to reduce the risk of endometrial cancer

Women without a uterus do not need a progestin; in some cases, however, hysterectomized women with a history of endometriosis may need a progestin

Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual

Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

Administration

Plastic applicator calibrated in 0.5 g increments to a maximum of 2 g

Not indicated

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Interactions

Interaction Checker

and conjugated estrogens, vaginal

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            Adverse Effects

            1-10%

            Breast pain (4.9%)

            Headache (3.5%)

            Pelvic pain (2.8%)

            Vulvovaginal disorder (2.8%)

            Vasodilation (2.1%)

            Leukorrhea (2.1%)

            Moniliasis (1.4%)

            Pain (1.4%)

            Muscle cramps (1.4%)

            Pruritus (1.4%)

            Dysuria (1.4%)

            Vaginal hemorrhage (1.4%)

            Vaginitis (1.4%)

            <1%

            Abdominal pain

            Dizziness

            Breast enlargement

            Urinary urgency

            Postmarketing Reports

            Genitourinary system: Abnormal uterine bleeding or spotting, dysmenorrhea or pelvic pain, increase in size of uterine leiomyomata, vaginitis (including vaginal candidiasis), change in cervical secretion, cystitis-like syndrome, application site reactions of vulvovaginal discomfort, (including burning, irritation, and genital pruritus), endometrial hyperplasia, endometrial cancer, precocious puberty, leukorrhea

            Breasts: Tenderness, enlargement, pain, discharge, fibrocystic breast changes, breast cancer, gynecomastia in males

            Cardiovascular: DVT, PE, MI, stroke, increased BP

            Gastrointestinal: Nausea, vomiting, abdominal cramps, bloating, increased incidence of gallbladder disease

            Skin: Chloasma that may persist when drug is discontinued, loss of scalp hair, hirsutism, rash

            Eyes: Retinal vascular thrombosis, intolerance to contact lenses

            Central nervous system: Headache, migraine, dizziness, mental depression, nervousness, mood disturbances, irritability, dementia

            Miscellaneous: Increase or decrease in weight, glucose intolerance, edema, arthralgias, leg cramps, changes in libido, urticaria, exacerbation of asthma, increased triglycerides, hypersensitivity

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            Warnings

            Black Box Warnings

            Endometrial cancer

            • Estrogens increase risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens
            • Close clinical surveillance of all women taking estrogens is important
            • Adequate 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
            • There is no evidence that the use of "natural" estrogens results in a different endometrial risk profile than the use of synthetic estrogens at equivalent estrogen doses

            Breast cancer

            • Using conjugated estrogens in combination with medroxyprogesterone increases risk of invasive breast cancer

            Cardiovascular risks

            • Estrogens with progestins should not be used to prevent cardiovascular disease
            • Estrogens plus progestins: Women’s Health Initiative (WHI) Estrogen Plus Progestin substudy reported increased risks of myocardial infarction (MI), stroke, invasive breast cancer, pulmonary embolism (PE), and deep vein thrombosis (DVT) in postmenopausal women (aged 50-79 years) during 5.6 years of treatment with daily PO conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) in comparison with placebo
            • strogens alone: A substudy of the WHI study reported increased risk for stroke and DVT in postmenopausal women (aged 50-79 years) during 6.8 years of treatment with daily PO conjugated estrogens (0.625 mg) alone in comparison with placebo

            Dementia risks

            • Estrogens with or without progestins should not be used to prevent dementia
            • Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI study, reported increased risk of developing probable dementia in postmenopausal women aged ≥65 years during 4 years of treatment with daily PO conjugated estrogens (0.625) mg combined with medroxyprogesterone acetate (2.5 mg) in comparison with placebo
            • Estrogens alone: A substudy of the WHIMS reported increased risk of developing probable dementia in postmenopausal women aged ≥65 years during 5.2 years of treatment with daily PO conjugated estrogens (0.625 mg) alone in comparison with placebo
            • Unknown whether these findings apply to younger postmenopausal women

            Dose and duration

            • In the absence of comparable data, these risks should be assumed to be similar for other doses of conjugated estrogens and medroxyprogesterone acetate, as well as for other combinations and dosage forms of estrogens and progestins
            • Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective dosage and for the shortest duration consistent with treatment goals and individual risks

            Contraindications

            Undiagnosed abnormal genital bleeding

            Known, suspected, or history of breast cancer

            Known or suspected estrogen-dependent neoplasia

            Active DVT, PE, or a history of these conditions

            Active arterial thromboembolic disease (eg, stroke, MI), or a history of these conditions

            Known anaphylactic reaction or angioedema to conjugated estrogen preparations

            Known liver dysfunction or disease

            Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders

            Known or suspected pregnancy

            Cautions

            Systemic absorption occurs with use of vaginal cream

            Risk of cardiovascular, endometrial cancer, breast cancer, and dementia; see Black Box Warnings

            Estrogens increase the risk of gallbladder disease

            Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs Monitor thyroid function in women on thyroid replacement therapy

            May cause fluid retention May exacerbate residual endometriosis post-hysterectomy

            Rare cases of anaphylaxis and angioedema reported; may exacerbate symptoms of hereditary angioedema

            May cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas

            Premarin cream may weaken latex condoms; the potential for the vaginal cream to weaken and contribute to the failure of condoms, diaphragms, or cervical caps made of latex or rubber should be considered

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            Pregnancy & Lactation

            Pregnancy Category: X

            Lactation: Distributed in human breast milk; caution when breast feeding, estrogens may decrease the quantity and quality of milk

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Estrogens act through binding to nuclear receptors in estrogen-responsive tissues

            Absorption

            Peak plasma concentration: 42 pg/mL (estrone); 12.8 pg/mL (estradiol)

            Peak plasma time: 7.4 hr (estrone); 8.5 hr (estradiol)

            AUC: 826 pg•hr/mL (estrone); 231 pg•hr/mL (estradiol)

            Distribution

            Protein binding: Largely bound to sex hormone binding globulin (SHBG) and albumin

            Widely distributed throughout body, higher concentration in sex hormone target organs

            Metabolism

            Liver

            Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite

            Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption

            Elimination

            Excretion: Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.