Included as part of the "PRECAUTIONS" Section
Risks From Systemic Absorption
Systemic absorption occurs with the use of PREMARIN Vaginal Cream. The warnings, precautions,
and adverse reactions associated with oral PREMARIN treatment should be taken into account.
An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk
of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. Should any of these
occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately.
Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use,
hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal
history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed
In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in
women 50 to 79 years of age receiving daily CE (0.625 mg) -alone compared to women in the same age
group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was
demonstrated in year 1 and persisted [see Clinical Studies]. Should a stroke occur or be suspected,
estrogen-alone therapy should be discontinued immediately.
Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those
women receiving CE (0.625 mg) -alone versus those receiving placebo (18 versus 21 per 10,000
In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was
reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to
women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) [see Clinical Studies]. The increase in risk was demonstrated after the first year and persisted. Should a stroke
occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.
Coronary Heart Disease
In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined
as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to
placebo2 [see Clinical Studies].
Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in
CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since
menopause (8 versus 16 per 10,000 women-years).1
In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of
CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women
receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in relative risk was
demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5
[see Clinical Studies].
In postmenopausal women with documented heart disease (n = 2,763), average 66.7 years of age, in a
controlled clinical trial of secondary prevention of cardiovascular disease (Heart and
Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg)
demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE
plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established
coronary heart disease. There were more CHD events in the CE plus MPA-treated group than in the
placebo group in year 1, but not during subsequent years. Two thousand, three hundred and twenty-one
(2,321) women from the original HERS trial agreed to participate in an open label extension of HERS,
HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall.
Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group
in HERS, HERS II, and overall.
In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving
daily CE (0.625 mg) -alone compared to placebo (30 versus 22 per 10,000 women-years), although
only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years).
The increase in VTE risk was demonstrated during the first 2 years3 [see Clinical Studies]. Should
a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately.
In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was
reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving
placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT
(26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also
demonstrated. The increase in VTE risk was observed during the first year and persisted4 [see Clinical Studies]. Should a VTE occur or be suspected, estrogen plus progestin therapy should be
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type
associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy
in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is
about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on
estrogen dose. Most studies show no significant increased risk associated with use of estrogens for
less than 1 year. The greatest risk appears to be associated with prolonged use, with increased risks of
15- to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15
years after estrogen therapy is discontinued.
Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is
important. Adequate diagnostic measures, including directed or random endometrial sampling when
indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed
persistent or recurring abnormal genital bleeding.
There is no evidence that the use of natural estrogens results in a different endometrial risk profile than
synthetic estrogens of equivalent estrogen dose. Adding a progestin to postmenopausal estrogen
therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to
In a 52-week clinical trial using PREMARIN Vaginal Cream alone (0.5 g inserted twice weekly or daily
for 21 days, then off for 7 days), there was no evidence of endometrial hyperplasia or endometrial
The most important randomized clinical trial providing information about breast cancer in estrogenalone
users is the WHI substudy of daily CE (0.625 mg) -alone. In the WHI estrogen-alone substudy,
after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of
invasive breast cancer [relative risk (RR) 0.80]5 [see Clinical Studies].
The most important randomized clinical trial providing information about breast cancer in estrogen plus
progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up
of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer
in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus
progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer
was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA
compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of
invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years,
for CE plus MPA compared with placebo. Among women who reported no prior use of hormone
therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36
cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy,
invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a
more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group.
Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic
factors, such as histologic subtype, grade and hormone receptor status did not differ between the
groups6 [see Clinical Studies].
Consistent with the WHI clinical trial, observational studies have also reported an increased risk of
breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone
therapy, after several years of use. The risk increased with duration of use, and appeared to return to
baseline over about 5 years after stopping treatment (only the observational studies have substantial data
on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and
became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy.
However, these studies have not generally found significant variation in the risk of breast cancer among
different estrogen plus progestin combinations, doses, or routes of administration.
The use of estrogen-alone and estrogen plus progestin therapy has been reported to result in an
increase in abnormal mammograms, requiring further evaluation.
All women should receive yearly breast examinations by a healthcare provider and perform monthly
breast self-examinations. In addition, mammography examinations should be scheduled based on patient
age, risk factors, and prior mammogram results.
The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of
ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE
plus MPA versus placebo was 1.58 (95 percent CI, 0.77–3.24). The absolute risk for CE plus MPA
versus placebo was 4 versus 3 cases per 10,000 women-years.7 In some epidemiologic studies, the use
of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been
associated with an increased risk of ovarian cancer . However, the duration of exposure associated with
increased risk is not consistent across all epidemiologic studies, and some report no association.
In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65
to 79 years of age was randomized to daily CE (0.625 mg) -alone or placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the
placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-
alone versus placebo was 1.49 (95 percent CI, 0.83–2.66). The absolute risk of probable dementia for
CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8 [see Use In Specific Populations, and Clinical Studies].
In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal
women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.
After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the
placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE
plus MPA versus placebo was 2.05 (95 percent CI, 1.21–3.48). The absolute risk of probable dementia
for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8 [see Use In Specific Populations, and Clinical Studies].
When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary
studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable
dementia was 1.76 (95 percent CI, 1.19–2.60). Since both ancillary studies were conducted in women 65
to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see Use In Specific Populations, and Clinical Studies].
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women
receiving estrogens has been reported.
Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone
metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken
to reduce the serum calcium level.
Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication
pending examination if there is sudden partial or complete loss of vision, or a sudden onset of
proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions,
estrogens should be permanently discontinued.
Addition Of A Progestin When A Woman Has Not Had A Hysterectomy
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily
with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia
than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to
There are, however, possible risks that may be associated with the use of progestins with estrogens
compared to estrogen-alone regimens. These include an increased risk of breast cancer.
Elevated Blood Pressure
In a small number of case reports, substantial increases in blood pressure have been attributed to
idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a
generalized effect of estrogen therapy on blood pressure was not seen.
In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations
of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis
Hepatic Impairment And/Or Past History Of Cholestatic Jaundice
Estrogens may be poorly metabolized in women with impaired liver function. For women with a history
of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be
exercised, and in the case of recurrence, medication should be discontinued.
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal
thyroid function can compensate for the increased TBG by making more thyroid hormone, thus
maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid
hormone replacement therapy who are also receiving estrogens may require increased doses of their
thyroid replacement therapy. These women should have their thyroid function monitored in order to
maintain their free thyroid hormone levels in an acceptable range.
Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced
by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogen-alone is
Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced
hypocalcemia may occur.
Exacerbation Of Endometriosis
A few cases of malignant transformation of residual endometrial implants have been reported in women
treated post-hysterectomy with estrogen-alone therapy. For women known to have residual
endometriosis post-hysterectomy, the addition of progestin should be considered.
Anaphylactic Reaction And Angioedema
Cases of anaphylaxis, which develop within minutes to hours after taking orally-administered
PREMARIN and require emergency management, have been reported in the postmarketing setting. Skin
(hives, pruritus, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or
gastrointestinal tract (abdominal pain, vomiting) involvement has been noted.
Angioedema involving the tongue, larynx, face, and feet requiring medical intervention has occurred
postmarketing in patients taking orally-administered PREMARIN. If angioedema involves the tongue,
glottis, or larynx, airway obstruction may occur. Patients who develop an anaphylactic reaction with or
without angioedema after treatment with oral PREMARIN should not receive oral PREMARIN again.
Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.
Exacerbation Of Other Conditions
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria,
systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with
Effects On Barrier Contraception
PREMARIN Vaginal Cream exposure has been reported to weaken latex condoms. The potential for
PREMARIN Vaginal Cream to weaken and contribute to the failure of condoms, diaphragms, or
cervical caps made of latex or rubber should be considered.
Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the
management of moderate to severe symptoms of vulvar and vaginal atrophy.
Drug-Laboratory Test Interactions
Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased
platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X
complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and
antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen
activity; increased plasminogen antigen and activity.
Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as
measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by
radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4and free T3
concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of
Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG),
sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex
steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be
decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin,
Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations,
reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels.
Impaired glucose tolerance.
Patient Counseling Information
See FDA-Approved Patient Labeling (PATIENT INFORMATION and Instructions for Use).
Inform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare
provider as soon as possible [see WARNINGS AND PRECAUTIONS].
Possible Serious Adverse Reactions With Estrogen-Alone Therapy
Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy
including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see WARNINGS AND PRECAUTIONS].
Possible Less Serious But Common Adverse Reactions With Estrogen-Alone Therapy
Inform postmenopausal women of possible less serious but common adverse reactions of estrogenalone
therapy such as headache, breast pain and tenderness, nausea and vomiting.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term continuous administration of natural and synthetic estrogens in certain animal species
increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
Use In Specific Populations
PREMARIN Vaginal Cream should not be used during pregnancy [see CONTRAINDICATIONS]. There
appears to be little or no increased risk of birth defects in children born to women who have used
estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.
PREMARIN Vaginal Cream should not be used during lactation. Estrogen administration to nursing
women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of
estrogens have been identified in the breast milk of women receiving estrogen therapy. Caution should
be exercised when PREMARIN Vaginal Cream is administered to a nursing woman.
PREMARIN Vaginal Cream is not indicated in children. Clinical studies have not been conducted in the
There have not been sufficient numbers of geriatric women involved in clinical studies utilizing
PREMARIN Vaginal Cream to determine whether those over 65 years of age differ from younger
subjects in their response to PREMARIN Vaginal Cream.
The Women's Health Initiative Studies
In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher
relative risk of stroke in women greater than 65 years of age [see WARNINGS AND PRECAUTIONS, and Clinical Studies].
In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo),
there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65
years of age [see WARNINGS AND PRECAUTIONS, and Clinical Studies].
The Women's Health Initiative Memory Study
In the WHIMS ancillary studies ancillary studies of postmenopausal women 65 to 79 years of age, there
was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen
plus progestin when compared to placebo [see WARNINGS AND PRECAUTIONS, and Clinical Studies].
Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether
these findings apply to younger postmenopausal women8 [see WARNINGS AND PRECAUTIONS, and Clinical Studies].
The effect of renal impairment on the pharmacokinetics of PREMARIN Vaginal Cream has not been
The effect of hepatic impairment on the pharmacokinetics of PREMARIN Vaginal Cream has not been
1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age
and Years Since Menopause. JAMA. 2007;297:1465–1477.
2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med.
3. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus.
Arch Int Med. 2006;166:772–780.
4. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573–
5. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography
Screening in Postmenopausal Women With Hysterectomy. JAMA. 2006;295:1647–1657.
6. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in
Healthy Postmenopausal Women. JAMA. 2003;289:3234–3253.
7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated
Diagnostic Procedures. JAMA. 2003;290:1739–1748.
8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild
Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947–2958.