Raloxifene

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.

Tablets (not scored): 60 mg ( 3 ) 60 mg, White film coated round biconvex tablets (not scored) de-bossed with IG on one side and 256 on the other.

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 tablets are 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 tablets are contraindicated in pregnancy, as it may cause fetal harm [see Use in Specific Populations (8.1) ] .

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 Diseas e: 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. ( 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 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 [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 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 a 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 [see Clinical Studies (14.5) ].

5.3 Cardiovascular 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 [see Clinical Studies (14.5) ].

5.4 Premenopausal 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 [see Use in Specific Populations (8.1) ].

5.5 Hepatic 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 [see Clinical Pharmacology (12.3) ].

5.6 Concomitant Estrogen Therapy The safety of concomitant use of raloxifene hydrochloride tablets with systemic estrogens has not been established and its use is not recommended.

5.7 History 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.

5.8 Renal 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 [see Clinical Pharmacology (12.3) ].

5.9 History of Breast Cancer Raloxifene hydrochloride tablets have not been adequately studied in women with a prior history of breast cancer.

5.10 Use 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.

5.11 Unexplained 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 [see Clinical Studies (14.1 , 14.2 )]

5.12 Breast Abnormalities Any unexplained breast abnormality occurring during raloxifene hydrochloride tablets therapy should be investigated. Raloxifene hydrochloride does not eliminate the risk of breast cancer [see Clinical Studies ( 14.4 )].

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 USA, Inc 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 the 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 Treatment Prevention Raloxifene hydrochloride tablets (N=2557) % Placebo (N=2576) % Raloxifene Hydrochloride tablets (N=581) % Placebo (N=584) % a A: Placebo incidence greater than or equal to raloxifene hydrochloride tablets incidence; B: Less than 2% incidence and more frequent with raloxifene hydrochloride tablets. b 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. 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 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 a Raloxifene Hydrochloride tablets (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 Tablets, 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 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. […]

Cholestyramine: Use with raloxifene hydrochloride tablets 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 tablets. ( 7.2 , 12.3 ) Highly Protein-Bound Drugs: Use with Raloxifene hydrochloride tablets 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 tablets is not recommended. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect. Raloxifene hydrochloride tablets should not be co-administered with other anion exchange resins [see Clinical Pharmacology (12.3) ].

7.2 Warfarin If raloxifene hydrochloride tablets are given concomitantly with warfarin or other warfarin derivatives, prothrombin time should be monitored more closely when starting or stopping therapy with raloxifene hydrochloride tablets [see Clinical Pharmacology (12.3) ].

7.3 Other Highly Protein-Bound Drugs Raloxifene hydrochloride tablets should be used with caution with certain other highly protein-bound drugs such as diazepam, diazoxide, and lidocaine. Although not examined, raloxifene hydrochloride tablets 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 tablets with systemic estrogens has not been established and its use is not recommended.

7.5 Other Concomitant Medications Raloxifene hydrochloride tablets can be concomitantly administered with ampicillin, amoxicillin, antacids, corticosteroids, and digoxin [see Clinical Pharmacology (12.3) ]. The concomitant use of raloxifene hydrochloride tablets and lipid-lowering agents has not been studied.

Pediatric Use: Safety and effectiveness not established. ( 8.4 )

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.

8.2 Lactation Risk Summary Raloxifene hydrochloride tablets are not indicated for use in females of reproductive potential. There is no information on the presence of raloxifene in human milk, the effects on the breastfed child, or the effects on milk production. However, based on mechanism of action, raloxifene hydrochloride may block the important functions that estrogen has in mammary tissue during lactation [see Clinical Pharmacology (12.1) ] .

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Of the total number of patients in placebo-controlled clinical studies of raloxifene hydrochloride tablets, 61% were 65 and over, while 15.5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on clinical trials, there is no need for dose adjustment for geriatric patients [see Clinical Pharmacology (12.3) ].

8.6 Renal Impairment Raloxifene hydrochloride tablets should be used with caution in patients with moderate or severe renal impairment [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3) ].

8.7 Hepatic Impairment Raloxifene hydrochloride tablets should be used with caution in patients with hepatic impairment [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3) ].

Raloxifene is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM). The biological actions of raloxifene are largely mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). The agonistic or antagonistic action of raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promoters. Raloxifene appears to act as an estrogen agonist in bone. It decreases bone resorption and bone turnover, increases bone mineral density (BMD) and decreases fracture incidence. Preclinical data demonstrate that raloxifene is an estrogen antagonist in uterine and breast tissues. These results are consistent with findings in clinical trials, which suggest that raloxifene hydrochloride lacks estrogen-like effects on the uterus and breast tissue.