5 WARNINGS AND PRECAUTIONS
5.1 Venous Thromboembolism
In clinical trials, EVISTA-treated women had an increased risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism). Other venous thromboembolic events also could occur. A less serious event, superficial thrombophlebitis, also has been reported more frequently with EVISTA than with placebo. The greatest risk for deep vein thrombosis and pulmonary embolism occurs during the first 4 months of treatment, and the magnitude of risk appears to be similar to the reported risk associated with use of hormone therapy. Because immobilization increases the risk for venous thromboembolic events independent of therapy, EVISTA should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and EVISTA therapy should be resumed only after the patient is fully ambulatory. In addition, women taking EVISTA should be advised to move about periodically during prolonged travel. The risk-benefit balance should be considered in women at risk of thromboembolic disease for other reasons, such as congestive heart failure, superficial thrombophlebitis, and active malignancy [see Contraindications and Adverse Reactions] .
5.2 Death Due to Stroke
In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, an increased risk of death due to stroke was observed after treatment with EVISTA. During an average follow-up of 5.6 years, 59 (1.2%) EVISTA-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (22 versus 15 per 10,000 women-years; hazard ratio 1.49; 95% confidence interval, 1.00-2.24; p=0.0499). There was no statistically significant difference between treatment groups in the incidence of stroke (249 in EVISTA [4.9%] versus 224 placebo [4.4%]). EVISTA had no significant effect on all-cause mortality. The risk-benefit balance should be considered in women at risk for stroke, such as prior stroke or transient ischemic attack (TIA), atrial fibrillation, hypertension, or cigarette smoking [see Clinical Studies] .
5.3 Cardiovascular Disease
EVISTA should not be used for the primary or secondary prevention of cardiovascular disease. In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with raloxifene for 5 years [see Clinical Studies] .
5.4 Premenopausal Use
There is no indication for premenopausal use of EVISTA. Safety of EVISTA in premenopausal women has not been established and its use is not recommended.
5.5 Hepatic Impairment
EVISTA should be used with caution in patients with hepatic impairment. Safety and efficacy have not been established in patients with hepatic impairment [see Clinical Pharmacology] .
5.6 Concomitant Estrogen Therapy
The safety of concomitant use of EVISTA with systemic estrogens has not been established and its use is not recommended.
5.7 History of Hypertriglyceridemia when Treated with Estrogens
Limited clinical data suggest that some women with a history of marked hypertriglyceridemia (>5.6 mmol/L or >500 mg/dL) in response to treatment with oral estrogen or estrogen plus progestin may develop increased levels of triglycerides when treated with EVISTA. Women with this medical history should have serum triglycerides monitored when taking EVISTA.
5.8 Renal Impairment
EVISTA should be used with caution in patients with moderate or severe renal impairment. Safety and efficacy have not been established in patients with moderate or severe renal impairment [see Clinical Pharmacology] .
5.9 History of Breast Cancer
EVISTA has not been adequately studied in women with a prior history of breast cancer.
5.10 Use in Men
There is no indication for the use of EVISTA in men. EVISTA has not been adequately studied in men and its use is not recommended.
5.11 Unexplained Uterine Bleeding
Any unexplained uterine bleeding should be investigated as clinically indicated. EVISTA-treated and placebo-treated groups had similar incidences of endometrial proliferation [see Clinical Studies (14.1, 14.2)] .
5.12 Breast Abnormalities
Any unexplained breast abnormality occurring during EVISTA therapy should be investigated. EVISTA does not eliminate the risk of breast cancer [see Clinical Studies] .
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category X. EVISTA should not be used in women who are or may become pregnant [see Contraindications] .
8.3 Nursing Mothers
EVISTA should not be used by lactating women [see Contraindications] . It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when raloxifene is administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
Of the total number of patients in placebo-controlled clinical studies of EVISTA, 61% were 65 and over, while 15.5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on clinical trials, there is no need for dose adjustment for geriatric patients [see Clinical Pharmacology] .
8.6 Renal Impairment
EVISTA should be used with caution in patients with moderate or severe renal impairment [see Warnings and Precautions and Clinical Pharmacology] .
8.7 Hepatic Impairment
EVISTA should be used with caution in patients with hepatic impairment [see Warnings and Precautions and Clinical Pharmacology] .