Raloxifene Hydrochloride

1 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.

2 DOSAGE AND ADMINISTRATION 60 mg tablet orally once daily. (2.1) 2.1 Recommended Dosing The recommended dosage is one 60 mg raloxifene hydrochloride tablet 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 1,500 mg/day of elemental calcium. Total daily intake of calcium above 1,500 mg has not demonstrated additional bone benefits while daily intake above 2,000 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.

5 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 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-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 should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and raloxifene hydrochloride therapy should be resumed only after the patient is fully ambulatory. In addition, women taking raloxifene hydrochloride 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. During an average follow-up of 5.6 years, 59 (1.2%) raloxifene hydrochloride-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 [4.9%] versus 224 placebo [4.4%]). Raloxifene hydrochloride 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 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. Safety of raloxifene hydrochloride 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 …

4 CONTRAINDICATIONS Active or past history of venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. (4.1) Pregnancy. (4.2, 8.1 ) 4.1 Venous Thromboembolism Raloxifene hydrochloride 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 Raloxifene hydrochloride is contraindicated for use in pregnancy, as it may cause fetal harm [see Use in Specific Populations (8.1) ] .

7 DRUG INTERACTIONS Cholestyramine: Use with raloxifene hydrochloride is not recommended. Reduces the absorption and enterohepatic cycling of raloxifene. (7.1, 12.3) Warfarin: Monitor prothrombin time when starting or stopping raloxifene hydrochloride. (7.2, 12.3) Highly Protein-Bound Drugs: Use with raloxifene hydrochloride with caution. Highly protein-bound drugs include diazepam, diazoxide, and lidocaine. Raloxifene hydrochloride is more than 95% bound to plasma proteins. (7.3, 12.3) 7.1 Cholestyramine Concomitant administration of cholestyramine with raloxifene hydrochloride is not recommended. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect. Raloxifene hydrochloride should not be co-administered with other anion exchange resins [see Clinical Pharmacology (12.3) ] . 7.2 Warfarin If raloxifene hydrochloride is given concomitantly with warfarin or other warfarin derivatives, prothrombin time should be monitored more closely when starting or stopping therapy with raloxifene hydrochloride [see Clinical Pharmacology (12.3) ] . 7.3 Other Highly Protein-Bound Drugs Raloxifene hydrochloride should be used with caution with certain other highly protein-bound drugs such as diazepam, diazoxide, and lidocaine. Although not examined, raloxifene hydrochloride might affect the protein binding of other drugs. Raloxifene is more than 95% bound to plasma proteins [see Clinical Pharmacology (12.3) ] . 7.4 Systemic Estrogens The safety of concomitant use of raloxifene hydrochloride with systemic estrogens has not been established and its use is not recommended. 7.5 Other Concomitant Medications Raloxifene hydrochloride can be concomitantly administered with ampicillin, amoxicillin, antacids, corticosteroids, and digoxin [see Clinical Pharmacology (12.3) ] . The concomitant use of raloxifene hydrochloride and lipid-lowering agents has not been studied.

8.1 Pregnancy Risk Summary Raloxifene hydrochloride is contraindicated for use in pregnant women, and is not indicated for use in females of reproductive potential. Based on mechanism of action, raloxifene hydrochloride may block the important functions that estrogen has during all stages of pregnancy [see Clinical Pharmacology (12.1) ] . Limited data with raloxifene hydrochloride use in pregnant women are insufficient to inform any drug associated risks for births defects or miscarriage. In rabbits and rats dosed during organogenesis or during gestation and lactation, raloxifene hydrochloride produced multiple adverse reproductive and developmental effects, including abortion; fetal anomalies; and delayed or disrupted parturition leading to maternal and neonatal mortality, at doses less than or similar to the maximum recommended human dose (based on human body surface area comparison). Data Animal Data In the developmental and reproductive toxicity studies conducted with raloxifene hydrochloride, numerous adverse effects were observed in multiple animal species. In rabbits dosed during organogenesis, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred at doses ≥ 0.1 mg/kg (≥ 0.04 times the human dose based on surface area, mg/m 2 ). In rats dosed during organogenesis, retardation of fetal growth 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 during gestation and lactation with doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on surface area, mg/m 2 ) 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, the disruption of parturition resulted in maternal and progeny morbidity and death. Effects in adult offspring (4 months of age) included uterine hypoplasia and reduced fertility; however, no ovarian or vaginal pathology was observed.

6 ADVERSE REACTIONS Adverse reactions (> 2% and more common than with placebo) include: hot flashes, leg cramps, peripheral edema, flu syndrome, arthralgia, sweating. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical studies 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. The data described below reflect exposure to raloxifene hydrochloride in 8,429 patients who were enrolled in placebo-controlled trials, including 6,666 exposed for 1 year and 5,685 for at least 3 years. Osteoporosis Treatment Clinical Trial (MORE) — The safety of raloxifene in the treatment of osteoporosis was assessed in a large (7,705 patients) multinational, placebo-controlled trial. Duration of treatment was 36 months, and 5,129 postmenopausal women were exposed to raloxifene (2,557 received 60 mg/day, and 2,572 received 120 mg/day). The incidence of all-cause mortality was similar among groups: 23 (0.9%) placebo, 13 (0.5%) raloxifene hydrochloride-treated (raloxifene hydrochloride 60 mg), and 28 (1.1%) raloxifene hydrochloride 120 mg women died. Therapy was discontinued due to an adverse reaction in 10.9% of raloxifene hydrochloride-treated women and 8.8% of placebo-treated women. Venous Thromboembolism: The most serious adverse reaction related to raloxifene hydrochloride was VTE (deep venous thrombosis, pulmonary embolism, and retinal vein thrombosis). During an average of study-drug exposure of 2.6 years, VTE occurred in about 1 out of 100 patients treated with raloxifene hydrochloride. Twenty-six raloxifene hydrochloride-treated women had a VTE compared to 11 placebo-treated women, the hazard ratio was 2.4 (95% confidence interval, 1.2, 4.5), and the highest VTE risk was during the initial months of treatment. Common adverse reactions considered to be related to raloxifene hydrochloride therapy were hot flashes and leg cramps. Hot flashes occurred in about one in 10 patients on raloxifene hydrochloride and were most commonly reported during the first 6 months of treatment and were not different from placebo thereafter. Leg cramps occurred in about one in 14 patients on raloxifene hydrochloride. Placebo-Controlled Osteoporosis Prevention Clinical Trials — The safety of raloxifene has been assessed primarily in 12 Phase 2 and Phase 3 studies with placebo, estrogen, and estrogen-progestin therapy control groups. The duration of treatment ranged from 2 to 30 months, and 2,036 women were exposed to raloxifene hydrochloride (371 patients received 10 to 50 mg/day, 828 received 60 mg/day, and 837 received from 120 to 600 mg/day). Therapy was discontinued due to an adverse reaction in 11.4% of 581 raloxifene hydrochloride-treated women and 12.2% of 584 placebo-treated women. Discontinuation rates due to hot flashes did not differ significantly between raloxifene hydrochloride and placebo groups (1.7% and 2.2%, respectively). Common adverse reactions considered to be drug-related were hot flashes and leg cramps. Hot flashes occurred in about one in four patients on raloxifene hydrochloride versus about one in six on placebo. The first occurrence of hot flashes was most commonly reported during the first 6 months of treatment. Table 1 lists adverse reactions occurring in either the osteoporosis treatment or in five prevention placebo-controlled clinical trials at a frequency ≥ 2% in either group and in more raloxifene hydrochloride-treated women than in placebo-treated women. Adverse reactions are shown without attribution of causality. The majority of adverse reactions occurring during the studies were mild and generally did not require discontinuation of therapy. Table 1: Adverse Reactions Occurring in Placebo-Controlled Osteoporosi…