Dosing and uses of Premarin (estrogens conjugated)
Adult dosage forms and strengths
tablet
- 0.3mg
- 0.45mg
- 0.625mg
- 0.9mg
- 1.25mg
powder for injection
- 25mg
Menopausal Vasomotor Symptoms, Atrophic Vaginitis/Kraurosis Vulvae
0.3 mg PO once daily in either continuous daily regimen or cyclic regimen (25 days on, 5 days off); adjusted PRN; use lowest dose that control symptoms; may be given daily if medical assessment warrants it
Female Hypogonadism
0.3-0.625 mg PO once daily in cyclic regimen (3 weeks on, 1 week off); may be titrated every 6-12 months; adjusted PRN; add progestin treatment should be added to maintain bone mineral density once skeletal maturity achieved
Osteoporosis
Prophylaxis
0.3 mg PO once daily in cyclic regimen (25 days on, 5 days off); adjusted PRN based on clinical response; may be given daily if medical assessment warrants it; administer lowest effective dose
May also be used in combination with medroxyprogesterone acetate
Prostate Cancer
Palliation only
1.25-2.5 mg PO q8hr
Abnormal Uterine Bleeding
25 mg IV/IM; repeated in 6-12 hours PRN or 25 mg IV repeated q4hr for 24 hr; if no response after 2 doses, re-evaluate therapy
Alternative regimen: 10-20 mg/day PO divided q4hr
May administer low dose medroxyprogesterone acetate with therapy or following therapy
Cyclic therapy: 25 days on, 5 days off; either 3 weeks on, 1 week off
Female Castration/Primary Ovarian Failure
1.25 mg PO once daily in cyclic regimen (25 days on, 5 days off); adjusted PRN; administer lowest effective dose
Breast Cancer Palliation
Metastatic disease in selected patients (males and females):10 mg PO q8hr for ≥3 months
Uremic Bleeding (Off-label)
0.6 mg/kg/day IV for 5 days
Pediatric dosage forms and strengths
Safety and efficacy not established
Premarin (estrogens conjugated) adverse (side) effects
>10%
Abdominal pain (15-17%)
Back pain (13-14%)
Breast enlargement
Breast tenderness (7-12%)
Headache (26-32%)
Arthralgia (7-14%)
Pharyngitis (10-12%)
Sinusitis (6-11%)
Diarrhea (6-7%)
1-10%
Depression (5-8%)
Dizziness (4-6%)
Nervousness (2-5%)
Flatulence (6-7%)
Vaginitis (5-7%)
Leukorrhea (4-7%)
Leg cramps (3-7%)
Increased cough (4-7%)
Pruritus (4-5%)
Frequency not defined
Amenorrhea
Breakthrough bleeding
Corneal curvation change
Melasma
Spotting
Vaginal moniliasis
Weight changes
Warnings
Black box warnings
Estrogens increase risk of endometrial cancer
- 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
Increased risk of breast cancer
- Using conjugated estrogens in combination with medroxyprogesterone increases risk of invasive breast cancer
Cardiovascular risks
- Estrogens with or without 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
- Estrogens 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 & 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
Known anaphylactic reaction or angioedema
Known protein C, protein S, or antithrombin deficiency; other known thrombophilic disorders
Active or history of breast cancer
Arterial thromboembolic disease (stroke, MI), thrombophlebitis, DVT/PE, thrombogenic valvular disease
Liver disease, liver tumors
Uncontrolled hypertension, diabetes mellitus with vascular involvement, jaundice with previous oral contraceptive use
Estrogen-dependent neoplasia
Undiagnosed abnormal vaginal bleeding
Cautions
Use caution in diabetes mellitus, hyperlipidemias, hypertension, hypothyroidism, advanced age, hepatic or renal impairment, uterine leiomyomata, porphyria, patients with defects of lipoprotein metabolism, hypertriglyceridemia, ovarian cancer, systemic lupus erhythematosus, exacerbation of endometriosis or other conditions, smoking, diseases exacerbated by fluid retention
Discontinue if any of the following develop: Jaundice, signs of venous thromboembolism, visual problems (may cause contact lens intolerance), massive blood pressure increase, major surgery or prolonged immobilization occurring in 4 weeks, new migraine, depression, papilledema or retinal vascular lesions observed on examination
Women with protein C or S deficiency (inherited thrombophilia), may have increased risk of venous thromboembolism
Conditions exacerbated by fluid retention (asthma, epilepsy, migraines, cardiac or renal dysfunction)
Risk of hypercalcemia in patients with breast cancer and bone metastases
Increased risk of ovarian and endometrial cancer
Long-term postmenopausal estrogen treatment has been associated with increased risk of breast cancer, MI, stroke, DVT/PE, and dementia
Patients on warfarin or other oral anticoagulants: Estrogens increase thromboembolic risk; increase in anticoagulant dosage may be warranted
Discontinue therapy if pancreatitis occurs; estrogen compounds generally associated with increased triglyceride levels
Cases of anaphylaxis and angioedema have been reported; exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema
Pregnancy and lactation
Pregnancy category: X
Lactation: Use controversial; estrogens are excreted into breast milk in small quantities; use with caution
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 (estrogens conjugated)
Mechanism of action
Replaces endogenous estrogen; important for development and maintenance of female reproductive system and secondary sexual characteristics
Antiandrogenic effect provides benefit in prostate cancer
Absorption
Bioavailability: Readily absorbed from gastrointestinal (GI) tract
Onset: 2-4 weeks (PO-menopause)
Peak plasma time: 7 hr (PO)
Distribution
Protein bound: 80%
Metabolism
Metabolized in liver to inactive sulfates and glucuronides
Metabolites: Estradiol, estrone, estrioL
Elimination
Excretion: Mainly in urine as conjugates with small amount of unchanged drug; most estrogens are also excreted in bile and undergo enterohepatic recycling
Administration
IV Incompatibilities
Additive, syringe, Y-site: Ascorbic acid, acidic solutions, protein hydrolysate
IV Compatibilities
Solution: D5W, NS, invert sugar solutions
Y-site: Heparin/hydrocortisone, potassium chloride, vitamins B and C
IV Preparation
Reconstitute with 5 mL of diluent provided
First withdraw air from vial, then add diluent slowly and aseptically with gentle agitation
Stable at 2-8°C for 60 days
Do not use if agent darkens or precipitates
IV/IM Administration
IM: Acceptable
IV: Administer slowly to avoid flushing reaction
Infusion not recommended; injection into running infusion can be performed
Storage
Refrigerate reconstituted injection
Intact vials are stable for 24 months at room temperature
