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During clinical trials, the most common treatment-related adverse event associated with use of raloxifene was hot flashes (7.8% to 28.7%). Hot flashes were usually reported within the first 6 months of treatment and were not different from placebo thereafter. In controlled clinical trials, drug discontinuation due to hot flashes was similar among patients receiving raloxifene (1.7%) and those receiving placebo (2.2%). Sweating or hyperhidrosis occurred in 2.5% to 3.1% of patients taking raloxifene vs. 1.7% to 2% of patients taking placebo.[29603]

In placebo-controlled clinical trials, raloxifene was associated with an increased risk of venous thromboembolism (VTE), defined as deep vein thrombosis, pulmonary embolism (PE) compared to placebo. An increased risk for and superficial thrombo-phlebitis also occurred. During an average of 2.6 years of drug exposure in patients taking raloxifene for the treatment of osteoporosis, VTE occurred in about 1 of 100 patients treated with raloxifene (HR 2.4, 95% CI 1.2 to 4.5). In patients with an increased risk for major coronary events (RUTH trial), VTE occurred in 2% of patients receiving raloxifene vs. 1.4% of patients taking placebo. The greatest risk occurs within the first 4 months of treatment. Of note, the increased risk of venous thromboembolism is similar in magnitude to that reported with hormone replacement therapy. The mechanisms by which raloxifene increases VTE is unknown. Unlike estrogens, raloxifene does not appear to enhance fibrinolysis. Varicose vein was reported in 2.2% of patients taking raloxifene vs. 1.5% of patients taking placebo in clinical trials. Adverse reactions reported very rarely since market introduction include retinal vein occlusion (retinal thrombosis) and death associated with VTE.[29603]

Raloxifene may increase the risk for death from stroke in at-risk patients. In the Raloxifene Use for The Heart (RUTH) trial of postmenopausal women with documented coronary artery disease or at increased risk for coronary events, an increased risk of death due to stroke was observed after treatment with raloxifene relative to placebo. During an average follow-up of 5.6 years, 59 (1.2%) raloxifene-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (22 vs. 15 per 10,000 women-years; hazard ratio 1.49; 95% CI, 1 to 2.24; p = 0.0499). There was no statistically significant difference between treatment groups in the overall incidence of stroke (4.9% for raloxifene vs. 4.4% for placebo). Raloxifene use had no significant effect on all-cause mortality.[29603] [32460] In the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial, the risk of stroke was found to be similar between tamoxifen and raloxifene, with annual rates of 1.39 per 1,000 patients taking tamoxifen and 1.33 per 1,000 patients taking raloxifene.[32250]

Cardiovascular related adverse events reported during clinical trials of raloxifene and occurring at rates higher than with placebo included chest pain (unspecified) (2.8% to 4%), syncope (2.3%), and peripheral edema (3.3% to 14.1%).[29603]

Arthralgia (10.7% to 15.5%) and muscle cramps, specifically leg cramps, were some of the most commonly reported treatment-related adverse events in patients taking raloxifene (5.9% to 12.1%) and occurring at an incidence greater than with placebo. Other reported musculoskeletal adverse events with raloxifene include myalgia (7.7%), arthritis (4%), and tendon disorder (3.6%).[29603]

Central nervous system reactions that have been reported during raloxifene clinical trials at rates higher than with placebo include headache (9.2%), migraine (2.4%), mental depression (6.4%), insomnia (5.5%), vertigo (4.1%), neuralgia or neuropathic pain (2.4%), and hypoesthesia (2.1%).[29603]

Gastrointestinal (GI) adverse events that have been reported during clinical trials of raloxifene at incidences higher than with placebo include nausea (9.7% to 24.6%), diarrhea (7.2%), dyspepsia (5.9%), vomiting (3.4% to 4.8%), flatulence (3.1%), abdominal pain (6.6%), cholelithiasis (3.3%), gastroenteritis (2.6%), and gastrointestinal disorder (3.3%).[29603]

Urogenital adverse reactions that have been reported during raloxifene clinical trials at rates higher than with placebo include vaginitis (4.3%), leukorrhea (3.3%), uterine disorder (3.3%), endometrial disorder (3.1%), and vaginal bleeding (2.5%). The incidence of vaginal bleeding is significantly lower in patients treated with raloxifene vs. those treated with hormone replacement therapy (6.2% for raloxifene vs. 64.2 to 88.5% for hormone replacement therapy). Although breast pain (mastalgia) has been reported in 4.4% of women treated with raloxifene for osteoporosis prevention, the incidence was significantly lower than the incidence in patients treated with hormone replacement therapy (29.7 to 37.5%); further, the incidence and severity of mastalgia was similar when comparing patients taking raloxifene to placebo.[29603] In placebo-controlled osteoporosis prevention trials, endometrial thickness was evaluated every 6 months in 831 women. Endometrial thickness measurements in raloxifene-treated women were indistinguishable from placebo.[25061] The incidence of endometrial cancer and ovarian cancer were similar between patients taking raloxifene and placebo.[29603]

Rash (unspecified) (5.5%) has been reported during clinical trials of raloxifene.[29603]

Weight gain (8.8%) has been reported during clinical trials of raloxifene.[29603]

Infectious and/or respiratory-related adverse reactions that have been reported during clinical trials of raloxifene and at incidences higher than placebo include infection (11% to 15.1%); examples of specific infections include sinusitis (7.9% to 10.3%), rhinitis (10.2%), bronchitis (9.5%), pharyngitis (5.3% to 7.6%), laryngitis (2.2%), influenza (13.5% to 14.6%), urinary tract infection (4%), conjunctivitis (2.2%), and cystitis (3.3% to 4.6%). Increased cough (6% to 9.3%) and fever (3.1% to 3.9%) have also been reported.[29603]

Raloxifene is contraindicated in patients with acute thromboembolism or a past history of thromboembolic disease. The risk and benefit of raloxifene therapy should be considered carefully in patients at risk for thromboembolic events due to other reasons, such as congestive heart failure, superficial thrombophlebitis, and active neoplastic disease. An increased risk of thromboembolic events has been observed in women taking raloxifene. The greatest risk for thromboembolic events 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 estrogen-containing hormone therapy. In clinical trials, raloxifene-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 raloxifene than with placebo. Because immobilization increases the risk for venous thromboembolic events independent of therapy, the drug should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgery recovery, prolonged bed rest). Raloxifene should be resumed only after a patient is fully ambulatory. In addition, women taking raloxifene should be advised to move about periodically during prolonged travel.[29603]

Do not use raloxifene for the primary or secondary prevention of cardiovascular disease. Raloxifene should be used with caution in women with a history of cardiac disease or at increased for stroke including those with previous cerebrovascular disease [e.g., previous stroke or transient ischemic attack (TIA)], atrial fibrillation, hypertension, or tobacco smoking. In a clinical trial of postmenopausal women with documented coronary artery disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with raloxifene for 5 years. Raloxifene use had no significant effect on coronary events (e.g., death from coronary causes, nonfatal myocardial infarction, or hospitalization for acute coronary syndromes). Mortality is increased secondary to stroke after treatment with raloxifene. During an average follow-up of 5.6 years, 59 (1.2%) raloxifene-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (22 vs. 15 per 10,000 women-years; hazard ratio 1.49; 95% CI, 1 to 2.24; p = 0.0499). There was no statistically significant difference between treatment groups in the incidence of stroke (4.9% for raloxifene vs. 4.4% for placebo). Raloxifene use had no significant effect on all-cause mortality.[29603]

Raloxifene should be used with caution in patients with hepatic disease. Safety and efficacy have not been established in patients with hepatic impairment. In patients with mild hepatic impairment (Child Pugh A, serum bilirubin 0.6 to 2 mg/dL), the clearance of raloxifene was reduced 56% and plasma raloxifene concentrations were approximately 150% higher than those in healthy volunteers and correlated with total bilirubin concentrations. The pharmacokinetics of raloxifene have not been evaluated in patients with moderate or severe hepatic insufficiency.[29603]

Raloxifene should be used with caution in patients with moderate or severe renal impairment, as evidenced by a creatinine clearance (CrCl) of 50 mL/minute or less. Safety and efficacy have not been established in patients with moderate or severe renal impairment or renal failure.[29603]

Any unexplained uterine or vaginal bleeding occurring in a female taking raloxifene should be investigated as clinically indicated. Raloxifene is not associated with endometrial hyperplasia. Raloxifene-treated and placebo-treated groups had similar incidences of endometrial proliferation.[29603]

Raloxifene has not been adequately studied in patients with a prior history of breast cancer. While raloxifene is approved to reduce the risk of invasive breast cancer in postmenopausal women, it is not approved for the treatment of invasive breast cancer, to reduce the risk of non-invasive breast cancer, nor to reduce the risk of recurrence of breast cancer. Furthermore, there are no data regarding the effects of raloxifene on invasive breast cancer risk in women with inherited mutations (e.g., BRCA1, BRCA2). Any unexplained breast abnormality occurring during raloxifene therapy should be investigated as raloxifene use does not eliminate the risk of breast cancer. Patients should have breast exams and mammograms before starting raloxifene and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with the drug.[29603]

Women with a history of marked hypertriglyceridemia (more than 5.6 mmol/L or more than 500 mg/dL) in response to treatment with oral estrogen or estrogen plus progestin therapy should have serum triglycerides monitored during raloxifene therapy. Limited clinical data suggests that these women may develop increased levels of triglycerides during raloxifene treatment.[29603]

Raloxifene is contraindicated in women during pregnancy. The safety of raloxifene in premenopausal women has not been established. Use in premenopausal women is not recommended due to concern of inadvertent drug exposure during pregnancy and the risk of fetal harm. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal studies have demonstrated a potential for fetal harm. In rabbit studies, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred in rabbits at doses greater than or equal to 0.1 mg/kg (0.04 times or more the human dose based on surface area, mg/m²), and hydrocephaly was observed in fetuses at doses greater than or equal to 10 mg/kg (4 times or more the human dose based on BSA). In rat studies, retardation of fetal development and developmental abnormalities (wavy ribs, kidney cavitation) occurred at doses greater than or equal to 1 mg/kg (0.2 times or more the human dose based on BSA). Treatment of rats at doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on BSA) during gestation and lactation produced effects that included delayed and disrupted parturition; decreased neonatal survival and altered physical development; sex- and age-specific reductions in growth and changes in pituitary hormone content; and decreased lymphoid compartment size in offspring. At 10 mg/kg, raloxifene disrupted parturition, which resulted in maternal and progeny death and morbidity. Effects in adult offspring (4 months of age) included uterine hypoplasia and reduced fertility; however, no ovarian or vaginal pathology was observed.[29603]

Raloxifene is contraindicated in women who are breast-feeding due to the potential risk to a nursing infant, although it is not known if the drug is excreted in human milk.[29603]

The reproductive and developmental effects observed in animal studies are consistent with the estrogen receptor activity of raloxifene. In female animals, raloxifene disrupted estrous cycles and inhibited ovulation. These effects of raloxifene were reversible. Raloxifene also delayed and disrupted embryo implantation, resulting in prolonged gestation and reduced litter size. It is unknown if reproductive risk or issues relating to infertility would occur in humans.[29603]

Safety and effectiveness of raloxifene in pediatric patients have not been established. Raloxifene is not recommended for use in infants, children, adolescents, or premenopausal females.[29603]