Estrogens,side effects

The following serious adverse reactions are discussed elsewhere in labeling:

Cardiovascular Disorders

Malignant Neoplasms Most common adverse reactions (≥5%) are: abdominal pain, asthenia, pain, back pain, headache, flatulence, nausea, depression, insomnia, breast pain, endometrial hyperplasia, leucorrhea, vaginal hemorrhage, and vaginitis. To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical

Study Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. During the first year of a 2-year clinical trial with 2,333 postmenopausal women with a uterus between 40 and 65 years of age (88% Caucasian), 1,012 women were treated with CE, and 332 were treated with placebo. Table 1 summarizes treatment-related adverse reactions that occurred at a rate of ≥1% in any treatment group.

Table 1: Treatment-Related Adverse Reactions at a Frequency ≥1% PREMARIN 0.625 mg (n=348) PREMARIN 0.45 mg (n=338) PREMARIN 0.3 mg (n=326) Placebo (n=332) Body as a whole Abdominal pain 38 28 30 21 Asthenia 16 8 14 3 Back pain 18 11 13 4 Chest pain 2 3 4 2 Generalized edema 7 6 4 8 Headache 45 47 44 46 Moniliasis 5 4 4 1 Pain 17 10 12 14 Pelvic pain 10 9 8 4 Cardiovascular system Hypertension 4 4 7 5 Migraine 7 1 0 3 Palpitation 3 3 3 4 Vasodilatation 2 2 3 5 Digestive system Constipation 7 6 4 3 Diarrhea 4 5 5 8 Dyspepsia 7 5 6 14 Eructation 1 1 4 1 Flatulence 22 18 13 8 Increased appetite 4 1 1 2 Nausea 16 10 15 16 Metabolic and nutritional Hyperlipidemia 2 4 3 2 Peripheral edema 5 2 4 3 Weight gain 11 10 8 14 Musculoskeletal system Arthralgia 6 3 2 5 Leg cramps 10 5 9 4 Myalgia 2 1 4 1 Nervous system Anxiety 6 4 2 4 Depression 17 15 10 17 Dizziness 9 7 4 5 Emotional lability 3 4 5 8 Hypertonia 1 1 5 3 Insomnia 16 10 13 14 Nervousness 9 12 2 6 Skin and appendages Acne 3 1 8 3 Alopecia 6 6 5 2 Hirsutism 4 2 1 0 Pruritus 11 11 10 3 Rash 6 3 1 2 Skin discoloration 4 2 0 1 Sweating 4 1 3 4 Urogenital system Breast disorder 6 3 3 6 Breast enlargement 3 4 7 3 Breast neoplasm 4 4 7 7 Breast pain 37 39 24 26 Cervix disorder 8 4 5 0 Dysmenorrhea 12 10 4 2 Endometrial disorder 4 2 2 0 Endometrial hyperplasia 16 8 1 0 Leukorrhea 17 17 12 6 Metrorrhagia 11 4 3 1 Urinary tract infection 1 2 1 4 Uterine fibroids enlarged 6 1 2 2 Uterine spasm 11 5 3 2 Vaginal dryness 1 2 1 6 Vaginal hemorrhage 46 13 6 0 Vaginal moniliasis 14 10 12 5 Vaginitis 18 7 9 1

6.2 Postmarketing

Experience The following additional adverse reactions have been identified during post-approval use of PREMARIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible always to reliably estimate their frequency or establish a causal relationship to drug exposure. Genitourinary system Abnormal uterine bleeding; dysmenorrheal or pelvic pain, increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis, change in cervical secretion, ovarian cancer, endometrial hyperplasia, endometrial cancer, leukorrhea. Breasts Tenderness, enlargement, pain, discharge, galactorrhea, fibrocystic breast changes, breast cancer, gynecomastia in males. Cardiovascular Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, stroke, increase in blood pressure. Gastrointestinal Nausea, vomiting, abdominal pain, bloating, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis, enlargement of hepatic hemangiomas, ischemic colitis. Skin Chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, loss of scalp hair, hirsutism, pruritus, rash. Eyes Retinal vascular thrombosis, intolerance to contact lenses. Central nervous system Headache, migraine, dizziness, mental depression, nervousness, mood disturbances, irritability, exacerbation of epilepsy, dementia, possible growth potentiation of benign meningioma. Miscellaneous Increase or decrease in weight, glucose intolerance, aggravation of porphyria, edema, arthralgias, leg cramps, changes in libido, urticaria, exacerbation of asthma, increased triglycerides, hypersensitivity.