1 INDICATIONS AND USAGE Raloxifene hydrochloride tablet, USP 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 is 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, 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 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 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.

Important Limitations of Use for Breast Cancer Risk Reduction There are no data available regarding the effect of raloxifene hydrochloride 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.

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.

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 Cipla Ltd.

at 1-866-604-3268 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 tablets 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 a 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 tablets-treated (raloxifene HCl 60 mg), and 28 (1.1%) raloxifene HCl 120 mg women died.

Therapy was discontinued due to an adverse reaction in 10.9% of raloxifene hydrochloride tablets-treated women and 8.8% of placebo-treated women.

Venous Thromboembolism: The most serious adverse reaction related to raloxifene hydrochloride tablets 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 tablets.

Twenty-six raloxifene hydrochloride tablets-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 tablets therapy were hot flashes and leg cramps.

Hot flashes occurred in about one in 10 patients on raloxifene hydrochloride tablets 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 tablets.

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 HCl (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 osteoporosis treatment or in five prevention placebo-controlled clinical trials at a frequency ≥2.0% 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 ≥2.0% and in more Raloxifene Hydrochloride Tablets-Treated (60 mg Once Daily) Women than Placebo-Treated Women A: Placebo incidence greater than or equal to raloxifene hydrochloride tablets incidence; B: Less than 2% incidence and more frequent with raloxifene hydrochloride tablets.

Treatment Prevention Raloxifene hydrochloride tablets (N=2557) % Placebo (N=2576) % Raloxifene Hydrochloride tablets (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 7.0 3.7 5.9 1.9 Chest Pain A A 4.0 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 14.0 10.7 10.1 Myalgia A A 7.7 6.2 Arthritis A A 4.0 3.6 Tendon Disorder 3.6 3.1 A A Nervous System Depression A A 6.4 6.0 Insomnia A A 5.5 4.3 Vertigo 4.1 3.7 A A Neuralgia 2.4 1.9 B B Hypesthesia 2.1 2.0 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 6.0 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 2.0 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 4.0 3.9 Cystitis 4.6 4.5 3.3 3.1 Leukorrhea A A 3.3 1.7 Uterine Disorder Includes only patients with an intact uterus: Prevention Trials: Raloxifene hydrochloride tablets, n=354, Placebo, n=364; Treatment Trial: Raloxifene hydrochloride Tablets, n=1948, Placebo, n=1999.

, Actual terms most frequently referred to endometrial fluid.

3.3 2.3 A A Endometrial Disorder 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 tablets were 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 ≥ 2.0% 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 Tablets (60 mg Once Daily) and Continuous Combined or Cyclic Estrogen Plus Progestin (Hormone Therapy) at an Incidence ≥2.0% in any Treatment Group These data are from both blinded and open-label studies.

Raloxifene Hydrochloride tablets (N=317) % Hormone Therapy-Continuous Combined Continuous Combined Hormone Therapy = 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate.

(N=96) % Hormone Therapy-Cyclic 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.

(N=219) % Urogenital Breast Pain 4.4 37.5 29.7 Vaginal Bleeding Includes only patients with an intact uterus: Raloxifene Hydrochloride Tablets, n=290; Hormone Therapy-Continuous Combined, n=67; Hormone Therapy-Cyclic, n=217.

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 was indistinguishable from placebo with regard to frequency and severity of breast pain and tenderness.

Raloxifene was associated with less breast pain and tenderness than reported by women receiving estrogens with or without added progestin.

Gynecologic Cancers — Raloxifene-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 (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-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-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 (2.0% 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 35-83 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).