Dosing and uses of Premarin Vaginal Cream (conjugated estrogens, vaginal)
Adult dosage forms and strengths
vaginal cream
- 0.625mg/g
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
Pediatric dosage forms and strengths
Not indicated
Premarin Vaginal Cream (conjugated estrogens, vaginal) adverse (side) 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
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
Pregnancy and 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.
Pharmacology of Premarin Vaginal Cream (conjugated estrogens, vaginal)
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
