Estradiolside effects

The following serious adverse reactions are discussed elsewhere in the labeling:

Cardiovascular Disorders.

Malignant Neoplasms. Most common adverse reactions (incidence > 5 percent) are vaginal bleeding and breast tenderness. To report SUSPECTED ADVERSE REACTIONS, contact Millicent at 1-877-810-2101 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical

Trials 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 practice. In a 13-week clinical trial that included 225 postmenopausal women treated with Femring and 108 women treated with placebo vaginal rings, adverse reactions that occurred at a rate of ≥ 2 percent are summarized in Table 1. Table 1. Incidence of Adverse Reactions Occurring in ≥ 2 Percent of Subjects Presented in Descending Frequency of Preferred Term AE = adverse event; NOS = not otherwise specified Adverse Event Placebo (n = 108) Estradiol 0.05 mg/day (n = 113) Estradiol 0.10 mg/day (n = 112) n (percent) n (percent) n (percent) Headache (NOS) 10 8 11 Intermenstrual Bleeding 2 9 11 Vaginal Candidiasis 3 7 12 Breast Tenderness 2 7 12 Back Pain 4 7 4 Abdominal Distension 3 8 3 Sinusitis (NOS) 2 2 4 Uterine Pain 1 2 5 Urinary Tract Infection (NOS) 2 1 4

6.2 Postmarketing

Experience 1. A few cases of toxic shock syndrome (TSS) have been reported in women using vaginal rings. TSS is a rare, but serious disease that may cause death. Warning signs of TSS include fever, nausea, vomiting, diarrhea, muscle pain, dizziness, faintness, or a sunburn-rash on face and body. 2. Cases of ring adherence to the vaginal or bladder wall, making ring removal difficult, have been reported in women using vaginal rings and may require surgical removal of the device. Women should be carefully evaluated for vaginal or bladder wall ulceration or erosion. Cases of vaginal erosion and vaginal ulceration have been reported with other estradiol vaginal rings. If an ulceration or erosion has occurred, consideration should be given to leaving the ring out and not replacing it until healing is complete to prevent the ring from adhering to the vaginal tissue. 3. A few cases of bowel obstruction associated with vaginal ring use have been reported. Persistent abdominal complaints consistent with obstruction should be carefully evaluated. 4. A few cases of inadvertent ring insertion into the urinary bladder, which may require surgical removal, have been reported for women using vaginal rings. Persistent unexplained urinary symptoms should be carefully evaluated. The following additional adverse reactions have been identified during post-approval use of Femring. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Genitourinary system Uterine cancer, vaginal hemorrhage, ovarian cyst, irregular menstruation, metrorrhagia, menorrhagia, dysmenorrhea, uterine enlargement. Breasts Breast cancer, fibrocystic breast disease, breast disorder, breast mass, breast enlargement, breast pain, nipple pain, breast discharge. Cardiovascular Chest pain, increased blood pressure, irregular heart rate, pulmonary embolism, cerebrovascular accident (stroke), hemiparesis, transient ischemic attack, thrombosis. Gastrointestinal Abdominal pain, pancreatitis, cholecystitis, cholelithiasis, vomiting. Skin Generalized erythema, erythema multiforme, erythema nodosum, rash, hirsutism, pruritis. Eyes Blindness, contact lens intolerance. Central Nervous System Dizziness, headache, depression, nervousness, mood disturbances, irritability. Miscellaneous Medical device complication, back pain, angioedema, weight increased/decreased, edema, libido increased/decreased, urticaria, hypersensitivity, anaphylaxis.