Raloxifene

Raloxifene hydrochloride tablet, USP is an estrogen agonist/antagonist indicated for: Treatment and prevention of osteoporosis in postmenopausal women. Reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis. . Reduction in risk of invasive breast cancer in postmenopausal women at high risk for invasive breast cancer. 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.

1.1Treatment and Prevention of Osteoporosis in Postmenopausal Women

Raloxifene hydrochloride tablets, USP are indicated for the treatment and prevention of osteoporosis in postmenopausal women .

1.2Reduction 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 .

1.3Reduction 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 . 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 . 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.

2 DOSAGE AND ADMINISTRATION 60 mg tablet orally once daily.

2.1Recommended Dosing The

recommended dosage is one 60 mg raloxifene hydrochloride tablet daily, which may be administered any time of day without regard to meals . For the indications in risk of invasive breast cancer the optimum duration of treatment is not known .

2.2Recommendations 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 400-800 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.

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. Hepatic Impairment: Use with caution. Concomitant Use with Systemic Estrogens: Not recommended. Hypertriglyceridemia: If previous treatment with estrogen resulted in hypertriglyceridemia, monitor serum triglycerides.

5.1Venous 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 tablets 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 .

5.2Death 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 an 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 .

5.3Cardiovascular 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 .

5.4Premenopausal 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 .

5.5Hepatic 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 .

5.6Concomitant Estrogen Therapy The

safety of concomitant use of raloxifene hydrochloride tablets with systemic estrogens has not been established and its use is not recommended.

5.7History 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.

5.8Renal 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 .

5.9History of Breast Cancer Raloxifene

hydrochloride tablets have not been adequately studied in women with a prior history of breast cancer.

5.10Use in Men There

is no indication for the use of raloxifene hydrochloride tablets in men. Raloxifene hydrochloride tablets have not been adequately studied in men and its use is not recommended.

5.11Unexplained 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 .

5.12Breast Abnormalities Any

unexplained breast abnormality occurring during raloxifene hydrochloride tablets therapy should be investigated. Raloxifene hydrochloride does not eliminate the risk of breast cancer .

Active or past history of venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. Pregnancy (4.2 , 8.1)

4.1Venous Thromboembolism Raloxifene

hydrochloride tablets are contraindicated in women with active or past history of venous thromboembolism (VTE), including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis .

4.2Pregnancy Raloxifene

hydrochloride tablets are contraindicated in pregnancy, as it may cause fetal harm .

8.1Pregnancy 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 . 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.

Adverse reactions (>2% and more common than with placebo) include: hot flashes, leg cramps, peripheral edema, flu syndrome, arthralgia, sweating. 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

6.1Clinical 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

14.6Flu Syndrome

13.5 11.4 14.6

13.5Headache

9.2 8.5 A A Leg Cramps 7.0 3.7 5.9

1.9Chest Pain A A

4.0

3.6Fever

3.9 3.8 3.1

2.6Cardiovascular System Hot Flashes

9.7 6.4 24.6

18.3Migraine A A

2.4

2.1Syncope

2.3 2.1 B B Varicose Vein 2.2 1.5 A A Digestive System Nausea 8.3 7.8 8.8

8.6Diarrhea

7.2 6.9 A A Dyspepsia A A 5.9

5.8Vomiting

4.8 4.3 3.4

3.3Flatulence A A

3.1

2.4Gastrointestinal Disorder A A

3.3

2.1Gastroenteritis B B

2.6

2.1Metabolic and Nutritional Weight Gain A A

8.8

6.8Peripheral Edema

5.2 4.4 3.3

1.9Musculoskeletal System Arthralgia

15.5 14.0 10.7

10.1Myalgia A A

7.7

6.2Arthritis A A

4.0

3.6Tendon Disorder

3.6 3.1 A A Nervous System Depression A A 6.4

6.0Insomnia A A

5.5

4.3Vertigo

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

6.5Rhinitis

10.2 10.1 A A Bronchitis 9.5 8.6 A A Pharyngitis 5.3 5.1 7.6

7.2Cough Increased

9.3 9.2 6.0

5.7Pneumonia A A

2.6

1.5Laryngitis B B

2.2

1.4Skin and Appendages Rash A A

5.5

3.8Sweating

2.5 2.0 3.1

1.7Special Senses Conjunctivitis

2.2 1.7 A A Urogenital System Vaginitis A A 4.3

3.6Urinary Tract Infection A A

4.0

3.9Cystitis

4.6 4.5 3.3

3.1Leukorrhea A A

3.3

1.7Uterine 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

1.9Vaginal 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

29.7Vaginal 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

88.5Digestive Flatulence

1.6 12.5

6.4Cardiovascular Hot Flashes

28.7 3.1

5.9Body as a Whole Infection

11 0

6.8Abdominal Pain

6.6 10.4

18.7Chest Pain

2.8 0

0.5Breast 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 . 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) . 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 .

6.2Postmarketing 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).