There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. 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.

Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia.

The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women with daily oral conjugated estrogens (CE) 0.625mg alone relative to placebo. The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism, stroke, and myocardial infarction in postmenopausal women with daily oral CE 0.625mg combined with medroxyprogesterone acetate (MPA) 2.5mg relative to placebo. 

The WHI Memory Study (WHIMS) reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older, in both the estrogen alone and estrogen plus progestin arms. It is unknown whether these findings apply to younger postmenopausal women.

The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.

In the absence of comparable data, these risks should be assumed to be similar for other doses of CE or CE and MPA, and other dosage forms of estrogen or combinations and dosage forms of estrogens and progestins. 

Estrogens with or without progestins should be prescribed at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman.

In a 12-week, double-blind phase,

• 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 (for example, stroke and MI), or a history of these conditions
• Known anaphylactic reaction or angioedema to Premarin Vaginal Cream
• Known liver dysfunction or disease
• Known protein C, protein S or antithrombin deficiency or other known thrombophilic disorders
• Known or suspected pregnancy

In a 12-week, double-blind, placebo-controlled study with a 40-week open-label extension phase,

• Endometrial safety was assessed by endometrial biopsy for all randomly assigned subjects at week 52

The safety of Premarin Vaginal Cream beyond 52 weeks at any dose is not well known. The data on this page are not intended to minimize the risk of endometrial hyperplasia and associated neoplasms included as part of the Women's Health Initiative (WHI) BOXED warning for all estrogen therapies. The decision as to whether or not to add a progestin to the unopposed estrogen in Premarin Vaginal Cream should be left up to the physician’s clinical judgment based on the individual patient’s risks.

Results from a 12-week, randomized, double-blind, placebo-controlled trial that evaluated the efficacy and safety of Premarin Vaginal Cream in generally healthy postmenopausal women aged 44 to 77 years (N=423), who at baseline had ≤5% superficial cells on a vaginal smear, a vaginal pH ≥5.0, and who identified a most bothersome moderate to severe symptom of vulvar and vaginal atrophy. Premarin Vaginal Cream was administered using 2 dosing regimens: 0.5 g twice weekly and 0.5 g once daily (21 days on/7 days off). The study consisted of an initial 12-week trial followed by an open-label extension to assess endometrial safety through week 52.

Primary end points were the changes from baseline in Vaginal Maturation Index, vaginal pH, and severity of patient-reported most bothersome symptom at week 12. Participants defined the severity of their most bothersome symptom on the following scale: 1=mild, 2=moderate, 3=severe. For most women, dyspareunia was identified as the most bothersome symptom at baseline. Weekly severity score is an average of the daily scores.^1,2