RALOXIFENE HYDROCHLORIDE

Raloxifene HCl, USP is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM) that belongs to the benzothiophene class of compounds. The chemical structure is: The chemical designation is methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[ b ]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]-, hydrochloride. Raloxifene HCl, USP has the molecular formula C 28 H 27 NO 4 S•HCl, which corresponds to a molecular weight of 510.05. Raloxifene HCl, USP is an off-white to pale-yellow solid that is very slightly soluble in water. Raloxifene HCl, USP is supplied in a tablet dosage form for oral administration. Each raloxifene HCl tablet, USP contains 60 mg of raloxifene HCl, USP, which is the molar equivalent of 55.71 mg of free base. Inactive ingredients include anhydrous lactose, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, silicon dioxide and titanium dioxide. Chemical Structure

Raloxifene HCl tablets, USP 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 HCl tablets, USP 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 (HCl) tablets, USP 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 HCl tablets, USP 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 HCl tablets, USP 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 HCl tablets, USP should be based upon an individual assessment of the benefits and risks. Raloxifene HCl tablets, USP does not eliminate the risk of breast cancer. Patients should have breast exams and mammograms before starting raloxifene HCl tablets, USP and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with raloxifene HCl tablets, USP. Important Limitations of Use for Breast Cancer Risk Reduction There are no data available regarding the effect of raloxifene HCl tablets, USP on invasive breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of raloxifene HCl tablets, USP. Raloxifene HCl tablets, USP are not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence. Raloxifene HCl tablets, USP are not indicated for the reduction in the risk of noninvasive breast cancer.

60 mg tablet orally once daily. (2.1) 2.1 Recommended Dosing The recommended dosage is one 60 mg raloxifene HCl tablet, USP 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.

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 HCl, 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 Raloxifene hydrochloride is contraindicated for use in pregnancy, as it may cause fetal harm [see Use in Specific Populations (8.1)].

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 AvKARE at 1-855-361-3993; email [email protected]; 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 HCl 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 (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 HCl-treated (raloxifene 60 mg) and 28 (1.1%) raloxifene 120 mg women died. Therapy was discontinued due to an adverse reaction in 10.9% of raloxifene HCl-treated women and 8.8% of placebo-treated women. Venous Thromboembolism: The most serious adverse reaction related to raloxifene HCl 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 HCl. Twenty-six raloxifene HCl-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 HCl therapy were hot flashes and leg cramps. Hot flashes occurred in about one in 10 patients on raloxifene HCl 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 HCl. 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 (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 HCl-treated women and 12.2% of 584 placebo-treated women. Discontinuation rates due to hot flashes did not differ significantly between raloxifene HCl 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 HCl 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 HCl-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 HCl-Treated (60 mg Once Daily) Women than Placebo-Treated Women a Treatment Prevention Raloxifene HCl N=2557 % Placebo N=2576 % Raloxifene HCl N=581 % Placebo N=584 % 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 3.7 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 a A: Placebo incidence greater than or equal to raloxifene HCl incidence; B: Less than 2% incidence and more frequent with raloxifene HCl. b Includes only patients with an intact uterus: Prevention Trials: Raloxifene HCl, n=354, Placebo, n=364; Treatment Trial: Raloxifene HCl, n=1948, Placebo, n=1999. c Actual terms most frequently referred to endometrial fluid. Comparison of Raloxifene HCl and Hormone Therapy —Raloxifene HCl 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 HCl (60 mg Once Daily) and Continuous Combined or Cyclic Estrogen Plus Progestin (Hormone Therapy) at an Incidence ≥2% in any Treatment Group a Raloxifene HCl (N=317) % Hormone Therapy- Continuous Combined b (N=96) % Hormone Therapy- Cyclic c (N=219) % 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 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 HCl, n=290; Hormone Therapy-Continuous Combined, n=67; Hormone Therapy-Cyclic, n=217. Breast Pain — Across all placebo-controlled trials, raloxifene HCl was indistinguishable from placebo with regard to frequency and severity of breast pain and tenderness. Raloxifene HCl was associated with less breast pain and tenderness than reported by women receiving estrogens with or without added progestin. Gynecologic Cancers — Raloxifene HCl-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 HCl (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 HCl-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 HCl-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 HCl 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).

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