Raloxifene Hydrochloride

1 INDICATIONS AND USAGE Raloxifene hydrochloride is 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 does 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 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.

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 Northstar Rx LLC at 1-800-206-7821 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 8429 patients who were enrolled in placebo-controlled trials, including 6666 exposed for 1 year and 5685 for at least 3 years. Osteoporosis Treatment Clinical Trial (MORE) — The safety of raloxifene in the treatment of osteoporosis was assessed in a large (7705 patients) multinational, placebo-controlled trial. Duration of treatment was 36 months, and 5129 postmenopausal women were exposed to raloxifene hydrochloride (2557 received 60 mg/day, and 2572 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 2036 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 Osteoporosis Clinical Trials at a Frequency ≥ 2% and in More Raloxifene Hydrochloride-Treated (60 mg Once Daily) Women than Placebo-Treated Women a Treatment Prevention Raloxifene Hydrochloride (N=2557) % Placebo (N=2576) % Raloxifene Hydrochloride (N=581) % Placebo (N=584) % a A: Placebo incidence greater than or equal to raloxifene hydrochloride incidence; B: Less than 2% incidence and more frequent with raloxifene hydrochloride. b Includes only patients with an intact uterus: Prevention Trials: raloxifene hydrochloride, n=354, Placebo, n=364; Treatment Trial: raloxifene hydrochloride, n=1948, Placebo, n=1999. c Actual terms most frequently referred to endometrial fluid. Body as a Whole Infection A A 15.1 14.6 Flu Syndrome 13.5 11.4 14.6 13.5 Headache 9.2 8.5 A A Leg Cramps 7 3.7 5.9 1.9 Chest Pain A A 4 3.6 Fever 3.9 3.8 3.1 2.6 Cardiovascular System Hot Flashes 9.7 6.4 24.6 18.3 Migraine A A 2.4 2.1 Syncope 2.3 2.1 B B Varicose Vein 2.2 1.5 A A Digestive System Nausea 8.3 7.8 8.8 8.6 Diarrhea 7.2 6.9 A A Dyspepsia A A 5.9 5.8 Vomiting 4.8 4.3 3.4 3.3 Flatulence A A 3.1 2.4 Gastrointestinal Disorder A A 3.3 2.1 Gastroenteritis B B 2.6 2.1 Metabolic and Nutritional Weight Gain A A 8.8 6.8 Peripheral Edema 5.2 4.4 3.3 1.9 Musculoskeletal System Arthralgia 15.5 14 10.7 10.1 Myalgia A A 7.7 6.2 Arthritis A A 4 3.6 Tendon Disorder 3.6 3.1 A A Nervous System Depression A A 6.4 6 Insomnia A A 5.5 4.3 Vertigo 4.1 3.7 A A Neuralgia 2.4 1.9 B B Hypesthesia 2.1 2 B B Respiratory System Sinusitis 7.9 7.5 10.3 6.5 Rhinitis 10.2 10.1 A A Bronchitis 9.5 8.6 A A Pharyngitis 5.3 5.1 7.6 7.2 Cough Increased 9.3 9.2 6 5.7 Pneumonia A A 2.6 1.5 Laryngitis B B 2.2 1.4 Skin and Appendages Rash A A 5.5 3.8 Sweating 2.5 2 3.1 1.7 Special Senses Conjunctivitis 2.2 1.7 A A Urogenital System Vaginitis A A 4.3 3.6 Urinary Tract Infection A A 4 3.9 Cystitis 4.6 4.5 3.3 3.1 Leukorrhea A A 3.3 1.7 Uterine Disorder b, c 3.3 2.3 A A Endometrial Disorder b B B 3.1 1.9 Vaginal Hemorrhage 2.5 2.4 A A Urinary Tract Disorder 2.5 2.1 A A Comparison of Raloxifene Hydrochloride and Hormone Therapy — Raloxifene hydrochloride was compared with estrogen-progestin therapy in three clinical trials for prevention of osteoporosis. Table 2 shows adverse reactions occurring more frequently in one treatment group and at an incidence ≥2% in any group. Adverse reactions are shown without attribution of causality. Table 2: Adverse Reactions Reported in the Clinical Trials for Osteoporosis Prevention with Raloxifene Hydrochloride (60 mg Once Daily) and Continuous Combined or Cyclic Estrogen Plus Progestin (Hormone Therapy) at an Incidence ≥2% in any Treatment Group a Raloxifene Hydrochloride (N=317) % Hormone Therapy- Continuous Combined b (N=96) % Hormone Therapy-Cyclic c (N=219) % a These data are from both blinded and open-label studies. b Continuous Combined Hormone Therapy = 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate. c Cyclic Hormone Therapy = 0.625 mg conjugated estrogens for 28 days with concomitant 5 mg medroxyprogesterone acetate or 0.15 mg norgestrel on Days 1 through 14 or 17 through 28. d Includes only patients with an intact uterus: raloxifene hydrochloride, n=290; Hormone Therapy-Continuous Combined, n=67; Hormone Therapy-Cyclic, n=217. Urogenital Breast Pain 4.4 37.5 29.7 Vaginal Bleeding d 6.2 64.2 88.5 Digestive Flatulence 1.6 12.5 6.4 Cardiovascular Hot Flashes 28.7 3.1 5.9 Body as a Whole Infection 11 0 6.8 Abdominal Pain 6.6 10.4 18.7 Chest Pain 2.8 0 0.5 Breast Pain — Across all placebo-controlled trials, raloxifene hydrochloride was indistinguishable from placebo with regard to frequency and severity of breast pain and tenderness. Raloxifene hydrochloride was associated with less breast pain and tenderness than reported by women receiving estrogens with or without added progestin. Gynecologic Cancers — Raloxifene hydrochloride-treated and placebo-treated groups had similar incidences of endometrial cancer and ovarian cancer. Placebo-Controlled Trial of Postmenopausal Women at Increased Risk for Major Coronary Events (RUTH) — The safety of raloxifene hydrochloride (60 mg once daily) was assessed in a placebo-controlled multinational trial of 10,101 postmenopausal women (age range 55 to 92) with documented coronary heart disease (CHD) or multiple CHD risk factors. Median study drug exposure was 5.1 years for both treatment groups [see Clinical Studies (14.3) ] . Therapy was discontinued due to an adverse reaction in 25% of 5044 raloxifene hydrochloride-treated women and 24% of 5057 placebo-treated women. The incidence per year of all-cause mortality was similar between the raloxifene (2.07%) and placebo (2.25%) groups. Adverse reactions reported more frequently in raloxifene hydrochloride-treated women than in placebo-treated women included peripheral edema (14.1% raloxifene versus 11.7% placebo), muscle spasms/leg cramps (12.1% raloxifene versus 8.3% placebo), hot flashes (7.8% raloxifene versus 4.7% placebo), venous thromboembolic events (2% raloxifene versus 1.4% placebo), and cholelithiasis (3.3% raloxifene versus 2.6% placebo) [see Clinical Studies (14.3 , 14.5) ] . Tamoxifen-Controlled Trial of Postmenopausal Women at Increased Risk for Invasive Breast Cancer (STAR) — The safety of raloxifene hydrochloride 60 mg/day versus tamoxifen 20 mg/day over 5 years was assessed in 19,747 postmenopausal women (age range 35 to 83 years) in a randomized, double-blind trial. As of 31 December 2005, the median follow-up was 4.3 years. The safety profile of raloxifene was similar to that in the placebo-controlled raloxifene trials [see Clinical Studies (14.4) ] . 6.2 Postmarketing Experience 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. Adverse reactions reported very rarely since market introduction include retinal vein occlusion, stroke, and death associated with venous thromboembolism (VTE).

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 hydrochloride 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 can be administered without regard to meals. Distribution — Following oral administration of single doses ranging from 30 to 150 mg of raloxifene hydrochloride, 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 α 1 -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 hydrochloride (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 the 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% Asian, 0.7% Hispanic, and 0.5% Black in the osteoporosis treatment trial and in 1053 women, including 93.5% White, 4.3% Hispanic, 1.2% Asian, and 0.5% Black in the 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 the osteoporosis treatment and prevention trials, raloxifene concentrations in women with mild renal impairment are similar to women with normal creatinine clearance. When a single dose of 120 mg raloxifene hydrochloride was administered to 10 renally impaired males [7 moderate impairment (CrCl = 31 to 50 mL/min); 3 severe impairment (CrCl ≤30 mL/min)] and to 10 healthy males (CrCl >80 mL/min), plasma raloxifene concentrations were 122% (AUC 0-∞ ) higher in renally impaired patients than those of healthy volunteers. Raloxifene should be used with caution in patients with moderate or severe renal impairment [see Warnings and Precautions (5.8) and Use in Specific Populations (8.6) ] . Hepatic Impairment — The disposition of raloxifene was compared in 9 patients with mild (Child-Pugh Class A) hepatic impairment (total bilirubin ranging from 0.6 to 2 mg/dL) to 8 subjects with normal hepatic function following a single dose of 60 mg raloxifene hydrochloride. Apparent clearance of raloxifene was reduced 56% and the half-life of raloxifene was not altered in patients with mild hepatic impairment. Plasma raloxifene concentrations were approximately 150% higher than those in healthy volunteers and correlated with total bilirubin concentrations. The pharmacokinetics of raloxifene has not been studied in patients with moderate or severe hepatic impairment. Raloxifene should be used with caution in patients with hepatic impairment [see Warnings and Precautions (5.5) and Use in Specific Populations (8.7) ] . Drug Interactions Cholestyramine — Cholestyramine, an anion exchange resin, causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene after a single dose. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect [see Drug Interactions (7.1) ] . Warfarin — In vitro , raloxifene did not interact with the binding of warfarin. The concomitant administration of raloxifene hydrochloride and warfarin, a coumarin derivative, has been assessed in a single-dose study. In this study, raloxifene had no effect on the pharmacokinetics of warfarin. However, a 10% decrease in prothrombin time was observed in the single-dose study. In the osteoporosis treatment trial, there were no clinically relevant effects of warfarin co-administration on plasma concentrations of raloxifene [see Drug Interactions (7.2) ] . Other Highly Protein-Bound Drugs — In the osteoporosis treatment trial, there were no clinically relevant effects of co-administration of other highly protein-bound drugs (e.g., gemfibrozil) on plasma concentrations of raloxifene. In vitro , raloxifene did not interact with the binding of phenytoin, tamoxifen, or warfarin ( see above) [see Drug Interactions (7.3) ] . Ampicillin and Amoxicillin — Peak concentrations of raloxifene and the overall extent of absorption are reduced 28% and 14%, respectively, with co-administration of ampicillin. These reductions are consistent with decreased enterohepatic cycling associated with antibiotic reduction of enteric bacteria. However, the systemic exposure and the elimination rate of raloxifene were not affected. In the osteoporosis treatment trial, co-administration of amoxicillin had no discernible differences in plasma raloxifene concentrations [see Drug Interactions (7.5) ] . Antacids — Concomitant administration of calcium carbonate or aluminum and magnesium hydroxide-containing antacids does not affect the systemic exposure of raloxifene [see Drug Interactions (7.5) ] . Corticosteroids — The chronic administration of raloxifene in postmenopausal women has no effect on the pharmacokinetics of methylprednisolone given as a single oral dose [see Drug Interactions (7.5) ] . Digoxin — Raloxifene has no effect on the pharmacokinetics of digoxin [see Drug Interactions (7.5) ] . Cyclosporine — Concomitant administration of raloxifene hydrochloride with cyclosporine has not been studied. Lipid-Lowering Agents — Concomitant administration of raloxifene hydrochloride with lipid-lowering agents has not been studied.