Summary of Changes to Contraindications and Warnings

BOXED WARNING

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

• Cardiovascular Disorders
  • Stroke
  • Coronary Heart Disease
  • Venous Thromboembolism (VTE)
• Malignant Neoplasms
  • Endometrial Cancer
• Addition of a Progestin When a Woman Has Not Had a Hysterectomy
• Hypocalcemia

ADVERSE REACTIONS

• Clinical Study Experience
  • Initial Section
  • Table 1
• Postmarketing Experience
  • Genitourinary System
    • precocious puberty (added)
  • Breasts
    • gynecomastia in males (added)
  • Miscellaneous
    • hypersensitivity (added)

DRUG INTERACTIONS

• Metabolic Interactions

USE IN SPECIFIC POPULATIONS

• Pregnancy
• Nursing Mothers
• Pediatric Use
• Geriatric Use
  • The Women's Health Initiative Study

PATIENT COUNSELING INFORMATION

• Vaginal Bleeding
• Possible Serious Adverse Reactions With Estrogens
• Possible Less Serious But Common Adverse Reactions With Estrogens

PATIENT COUNSELING INFORMATION (new subsection)

PATIENT PACKAGE INSERT

• What is Premarin Vaginal Cream used for?
• Who should not use Premarin Vaginal Cream?
• Tell your healthcare provider...
• How should I use Premarin Vaginal Cream?
• Some of the warning signs of these serious side effects include...
• Less serious, but common, side effects include...
• What can I do to lower my chances of getting a serious side effect with Premarin Vaginal Cream?
• General Information about the safe and effective use of Premarin Vaginal Cream

(See highlighted label for specific changes.)

BOXED WARNING

WARNING: ENDOMETRIAL CANCER,
CARDIOVASCULAR DISORDERS AND PROBABLE DEMENTIA FOR ESTROGEN- ALONE THERAPY

ENDOMETRIAL CANCER

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 [see Warnings and Precautions (5.3)].

CONTRAINDICATIONS

Premarin Vaginal Cream therapy should not be used in women with any of the following conditions:

...Active arterial thromboembolic disease (for example, stroke, and myocardial infarction), or a history of these conditions...

WARNINGS AND PRECAUTIONS

Cardiovascular Disorders:

Stroke

...Should a stroke occur or be suspected, estrogens 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) versus those receiving placebo (18 versus 21 per 10,000 women-years)...

Coronary Heart Disease

...Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE 0.625 mg compared to placebo) in women with less than 10 years since
menopause (8 versus 16 per 10,000 women-years)...

Venous Thromboembolism (VTE)

...Should a VTE occur or be suspected, estrogens should be discontinued immediately...

Malignant Neoplasms:

Endometrial Cancer

...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 carcinoma.

Addition of a Progestin When a Woman Has Not Had a Hysterectomy:

...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.

Hypocalcemia:

Estrogens should be used with caution in individuals with hypoparathyroidism as estrogen-induced hypocalcemia may occur.