raloxifene hydrochloride 60 MG Oral Tablet [Evista]

INDICATIONS AND USAGE Raloxifene hydrochloride tablets are an estrogen agonist/antagonist indicated for: Treatment and prevention of osteoporosis in postmenopausal women. ( 1.1 ) Reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis. ( 1.2 ) Reduction in risk of invasive breast cancer in postmenopausal women at high risk for invasive breast cancer. ( 1.3 ) Important Limitations: Raloxifene hydrochloride tablets are not indicated for the treatment of invasive breast cancer, reduction of the risk of recurrence of breast cancer, or reduction of risk of noninvasive breast cancer. ( 1.3 ) 1.1 Treatment and Prevention of Osteoporosis in Postmenopausal Women Raloxifene hydrochloride tablets are indicated for the treatment and prevention of osteoporosis in postmenopausal women [ see Clinical Studies ( 14.1 , 14.2 ) ]. 1.2 Reduction in the Risk of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis Raloxifene hydrochloride tablets are indicated for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis [ see Clinical Studies ( 14.3 ) ]. 1.3 Reduction in the Risk of Invasive Breast Cancer in Postmenopausal Women at High Risk of Invasive Breast Cancer Raloxifene hydrochloride tablets are indicated for the reduction in risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer [ see Clinical Studies ( 14.4 ) ]. The effect in the reduction in the incidence of breast cancer was shown in a study of postmenopausal women at high risk for breast cancer with a 5-year planned duration with a median follow-up of 4.3 years [ see Clinical Studies ( 14.4 ) ]. Twenty-seven percent of the participants received drug for 5 years. The long-term effects and the recommended length of treatment are not known. High risk of breast cancer is defined as at least one breast biopsy showing lobular carcinoma in situ (LCIS) or atypical hyperplasia, one or more first-degree relatives with breast cancer, or a 5-year predicted risk of breast cancer ≥1.66% (based on the modified Gail model). Among the factors included in the modified Gail model are the following: current age, number of first-degree relatives with breast cancer, number of breast biopsies, age at menarche, nulliparity or age of first live birth. Healthcare professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-800-545-5979. Currently, no single clinical finding or test result can quantify risk of breast cancer with certainty. After an assessment of the risk of developing breast cancer, the decision regarding therapy with raloxifene hydrochloride tablets should be based upon an individual assessment of the benefits and risks. Raloxifene hydrochloride tablets do not eliminate the risk of breast cancer. Patients should have breast exams and mammograms before starting raloxifene hydrochloride tablets and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with raloxifene hydrochloride tablets. Important Limitations of Use for Breast Cancer Risk Reduction There are no data available regarding the effect of raloxifene hydrochloride tablets on invasive breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of raloxifene hydrochloride tablets. Raloxifene hydrochloride tablets are not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence. Raloxifene hydrochloride tablets are not indicated for the reduction in the risk of noninvasive breast cancer.

DOSAGE AND ADMINISTRATION 60 mg tablet orally once daily. ( 2.1 ) 2.1 Recommended Dosing The recommended dosage is one raloxifene hydrochloride tablets, USP 60 mg daily, which may be administered any time of day without regard to meals [see Clinical Pharmacology ( 12.3 )] . For the indications in risk of invasive breast cancer the optimum duration of treatment is not known [see Clinical Studies ( 14.3 , 14.4 )] . 2.2 Recommendations for Calcium and Vitamin D Supplementation For either osteoporosis treatment or prevention, supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Total daily intake of calcium above 1500 mg has not demonstrated additional bone benefits while daily intake above 2000 mg has been associated with increased risk of adverse effects, including hypercalcemia and kidney stones. The recommended intake of vitamin D is 400 to 800 IU daily. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home bound, or chronically ill) may need additional vitamin D supplements. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered.

WARNINGS AND PRECAUTIONS Venous Thromboembolism : Increased risk of deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. Discontinue use 72 hours prior to and during prolonged immobilization. ( 5.1 , 6.1 ) Death Due to Stroke : Increased risk of death due to stroke occurred in a trial in postmenopausal women with documented coronary heart disease or at increased risk for major coronary events. No increased risk of stroke was seen in this trial. Consider risk-benefit balance in women at risk for stroke. ( 5.2 , 14.5 ) Cardiovascular Disease : Raloxifene hydrochloride tablets should not be used for the primary or secondary prevention of cardiovascular disease. ( 5.3 , 14.5 ) Premenopausal Women : Use is not recommended. ( 5.4 ) Hepatic Impairment : Use with caution. ( 5.5 ) Concomitant Use with Systemic Estrogens : Not recommended. ( 5.6 ) Hypertriglyceridemia : If previous treatment with estrogen resulted in hypertriglyceridemia, monitor serum triglycerides. ( 5.7 ) 5.1 Venous Thromboembolism In clinical trials, raloxifene hydrochloride tablets-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 hydrochloride 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, raloxifene hydrochloride tablets should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and raloxifene hydrochloride tablets therapy should be resumed only after the patient is fully ambulatory. In addition, women taking raloxifene hydrochloride tablets 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 ( 4.1 ) and Adverse Reactions ( 6.1 )] . 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 raloxifene hydrochloride tablets. During an average follow-up of 5.6 years, 59 (1.2%) raloxifene hydrochloride tablets-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 to 2.24; p=0.0499). There was no statistically significant difference between treatment groups in the incidence of stroke (249 in raloxifene hydrochloride tablets [4.9%] versus 224 placebo [4.4%]). Raloxifene hydrochloride tablets 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 ( 14.5 )] . 5.3 Cardiovascular Disease Raloxifene hydrochloride tablets 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 ( 14.5 )] . 5.4 Premenopausal Use There is no indication for premenopausal use of raloxifene hydrochloride tablets. Safety of raloxifene hydrochloride tablets in premenopausal women has not been established and its use is not recommended. Additionally, there is concern regarding inadvertent drug exposure in pregnancy in women of reproductive potential who become pregnant, due to risk of fetal harm [see Use in Specific Populations ( 8.1 )] . 5.5 Hepatic Impairment Raloxifene hydrochloride tablets 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 ( 12.3 )] . 5.6 Concomitant Estrogen Therapy The safety of concomitant use of raloxifene hydrochloride tablets 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 raloxifene hydrochloride tablets. Women with this medical history should have serum triglycerides monitored when taking raloxifene hydrochloride tablets. 5.8 Renal Impairment Raloxifene hydrochloride tablets 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 ( 12.3 )] . 5.9 History of Breast Cancer Raloxifene hydrochloride tablets 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 raloxifene hydrochloride tablets in men. Raloxifene hydrochloride tablets 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. Raloxifene hydrochloride tablets-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 raloxifene hydrochloride tablets therapy should be investigated. Raloxifene hydrochloride tablets does not eliminate the risk of breast cancer [see Clinical Studies ( 14.4 )] .

CONTRAINDICATIONS Active or past history of venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. ( 4.1 ) Pregnancy, women who may become pregnant, and nursing mothers. ( 4.2 , 8.1 , 8.3 ) 4.1 Venous Thromboembolism Raloxifene hydrochloride tablets, USP is contraindicated in women with active or past history of venous thromboembolism (VTE), including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis [see Warnings and Precautions ( 5.1 )] . 4.2 Pregnancy, Women Who May Become Pregnant, and Nursing Mothers Raloxifene hydrochloride tablets, USP is contraindicated in pregnancy, in women who may become pregnant, and in nursing mothers [see Use in Specific Populations ( 8.1 , 8.3 )] . Raloxifene hydrochloride tablets, USP may cause fetal harm when administered to a pregnant woman. 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. In rabbit studies, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred in rabbits at doses ≥0.1 mg/kg (≥0.04 times the human dose based on surface area, mg/m 2 ), and hydrocephaly was observed in fetuses at doses ≥10 mg/kg (≥4 times the human dose based on surface area, mg/m 2 ). In rat studies, retardation of fetal development and developmental abnormalities (wavy ribs, kidney cavitation) occurred at doses ≥1 mg/kg (≥0.2 times the human dose based on surface area, mg/m 2 ). Treatment of rats at doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on surface area, mg/m 2 ) 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.

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Raloxifene is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM). The biological actions of raloxifene are largely mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). The agonistic or antagonistic action of raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promoters. Raloxifene appears to act as an estrogen agonist in bone. It decreases bone resorption and bone turnover, increases bone mineral density (BMD) and decreases fracture incidence. Preclinical data demonstrate that raloxifene is an estrogen antagonist in uterine and breast tissues. These results are consistent with findings in clinical trials, which suggest that raloxifene hydrochloride lacks estrogen-like effects on the uterus and breast tissue. 12.2 Pharmacodynamics Decreases in estrogen levels after oophorectomy or menopause lead to increases in bone resorption and accelerated bone loss. Bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses. In addition to loss of estrogen, this imbalance between resorption and formation may be due to age-related impairment of osteoblasts or their precursors. In some women, these changes will eventually lead to decreased bone mass, osteoporosis, and increased risk for fractures, particularly of the spine, hip, and wrist. Vertebral fractures are the most common type of osteoporotic fracture in postmenopausal women. In both the osteoporosis treatment and prevention trials, raloxifene hydrochloride tablets therapy resulted in consistent, statistically significant suppression of bone resorption and bone formation, as reflected by changes in serum and urine markers of bone turnover (e.g., bone-specific alkaline phosphatase, osteocalcin, and collagen breakdown products). The suppression of bone turnover markers was evident by 3 months and persisted throughout the 36-month and 24-month observation periods. In a 31-week, open-label, radiocalcium kinetics study, 33 early postmenopausal women were randomized to treatment with once-daily raloxifene hydrochloride tablets 60 mg, cyclic estrogen/progestin (0.625 mg conjugated estrogens daily with 5 mg medroxyprogesterone acetate daily for the first 2 weeks of each month [hormone therapy]), or no treatment. Treatment with either raloxifene hydrochloride tablets or hormone therapy was associated with reduced bone resorption and a positive shift in calcium balance (-82 mg Ca/day and +60 mg Ca/day, respectively, for raloxifene hydrochloride tablets and –162 mg Ca/day and +91 mg Ca/day, respectively, for hormone therapy). There were small decreases in serum total calcium, inorganic phosphate, total protein, and albumin, which were generally of lesser magnitude than decreases observed during estrogen or hormone therapy. Platelet count was also decreased slightly and was not different from estrogen therapy. 12.3 Pharmacokinetics The disposition of raloxifene has been evaluated in more than 3000 postmenopausal women in selected raloxifene osteoporosis treatment and prevention clinical trials, using a population approach. Pharmacokinetic data also were obtained in conventional pharmacology studies in 292 postmenopausal women. Raloxifene exhibits high within-subject variability (approximately 30% coefficient of variation) of most pharmacokinetic parameters. Table 3 summarizes the pharmacokinetic parameters of raloxifene. Absorption — Raloxifene is absorbed rapidly after oral administration. Approximately 60% of an oral dose is absorbed, but presystemic glucuronide conjugation is extensive. Absolute bioavailability of raloxifene is 2%. The time to reach average maximum plasma concentration and bioavailability are functions of systemic interconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites. Administration of raloxifene HCl with a standardized, high-fat meal increases the absorption of raloxifene (C max 28% and AUC 16%), but does not lead to clinically meaningful changes in systemic exposure. Raloxifene hydrochloride tablets can be administered without regard to meals. Distribution — Following oral administration of single doses ranging from 30 to 150 mg of raloxifene HCl, the apparent volume of distribution is 2348 L/kg and is not dose dependent. Raloxifene and the monoglucuronide conjugates are highly (95%) bound to plasma proteins. Raloxifene binds to both albumin and α1-acid glycoprotein, but not to sex-steroid binding globulin. Metabolism — Biotransformation and disposition of raloxifene in humans have been determined following oral administration of 14 C-labeled raloxifene. Raloxifene undergoes extensive first-pass metabolism to the glucuronide conjugates: raloxifene-4´-glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4´-diglucuronide. No other metabolites have been detected, providing strong evidence that raloxifene is not metabolized by cytochrome P450 pathways. Unconjugated raloxifene comprises less than 1% of the total radiolabeled material in plasma. The terminal log-linear portions of the plasma concentration curves for raloxifene and the glucuronides are generally parallel. This is consistent with interconversion of raloxifene and the glucuronide metabolites. Following intravenous administration, raloxifene is cleared at a rate approximating hepatic blood flow. Apparent oral clearance is 44.1 L/kg•hr. Raloxifene and its glucuronide conjugates are interconverted by reversible systemic metabolism and enterohepatic cycling, thereby prolonging its plasma elimination half-life to 27.7 hours after oral dosing. Results from single oral doses of raloxifene predict multiple-dose pharmacokinetics. Following chronic dosing, clearance ranges from 40 to 60 L/kg•hr. Increasing doses of raloxifene HCl (ranging from 30 to 150 mg) result in slightly less than a proportional increase in the area under the plasma time concentration curve (AUC). Excretion — Raloxifene is primarily excreted in feces, and less than 0.2% is excreted unchanged in urine. Less than 6% of the raloxifene dose is eliminated in urine as glucuronide conjugates. Table 3: Summary of Raloxifene Pharmacokinetic Parameters in a Healthy Postmenopausal Woman C max a,b (ng/mL)/ (mg/kg) t 1/2 (hr) a AUC 0-∞ a,b (ng•hr/mL)/ (mg/kg) CL/F a (L/kg•hr) V/F a (L/kg) a Abbreviations: C max = maximum plasma concentration, t 1/2 = half-life, AUC = area under the curve, CL = clearance, V = volume of distribution, F = bioavailability, CV = coefficient of variation. b Data normalized for dose in mg and body weight in kg. c Range of observed half–life Single Dose Mean 0.5 27.7 27.2 44.1 2348 CV a (%) 52 10.7 to 273 c 44 46 52 Multiple Dose Mean 1.36 32.5 24.2 47.4 2853 CV a (%) 37 15.8 to 86.6 c 36 41 56 Special Populations Pediatric — The pharmacokinetics of raloxifene has not been evaluated in a pediatric population [see Use in Specific Populations (8.4) ]. Geriatric — No differences in raloxifene pharmacokinetics were detected with regard to age (range 42 to 84 years) [see Use in Specific Populations (8.5) ]. Gender — Total extent of exposure and oral clearance, normalized for lean body weight, are not significantly different between age-matched female and male volunteers. Race — Pharmacokinetic differences due to race have been studied in 1712 women, including 97.5% White, 1.0% Asian, 0.7% Hispanic, and 0.5% Black in a osteoporosis treatment trial and in 1053 women, including 93.5% White, 4.3% Hispanic, 1.2% Asian, and 0.5% Black in a osteoporosis prevention trials.. There were no discernible differences in raloxifene plasma concentrations among these groups; however, the influence of race cannot be conclusively determined. Renal Impairment — In a osteoporosis treatment