Raloxifene: uses, appearance and warnings

Raloxifene hydrochloride tablets 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 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 do 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.

60 mg tablets are white to off-white, elliptical shaped, film-coated tablets debossed with “AN057” on one side and plain on the other side. Tablets (not scored): 60 mg (3)

16.1 How Supplied Raloxifene hydrochloride tablets USP, 60 mg are supplied as white to off-white, elliptical shaped, film–coated tablets debossed with “AN057” on one side and plain on the other side. They are available as follows: Bottles of 30: NDC 65162-057-03 Bottles of 90: NDC 65162-057-09 Bottles of 100: NDC 65162-057-10 Bottles of 500: NDC 65162-057-50 Bottles of 1000: NDC 65162-057-11 Bottles of 2000: NDC 65162-057-33 16.2 Storage and Handling Store at controlled room temperature, 20º to 25ºC (68º to 77ºF) [ see USP]. The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20º to 25ºC (68º to 77ºF); that results in a mean kinetic temperature calculated to be not more than 25ºC; and that allows for excursions between 15º to 30ºC (59º and 86ºF) that are experienced in pharmacies, hospitals and warehouses. Dispense in tight containers.

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 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) ] .

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 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 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 should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and raloxifene hydrochloride therapy should be resumed only after the patient is fully ambulatory. In addition, women taking raloxifene hydrochloride 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. During an average follow-up of 5.6 years, 59 (1.2%) raloxifene hydrochloride-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 the incidence of stroke (249 in raloxifene hydrochloride [4.9%] versus 224 placebo [4.4%]). Raloxifene hydrochloride 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 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. Safety of raloxifene hydrochloride 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 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 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. Women with this medical history should have serum triglycerides monitored when taking raloxifene hydrochloride. 5.8 Renal Impairment Raloxifene hydrochloride 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 has 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 in men. Raloxifene hydrochloride has 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-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 therapy should be investigated. …

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 Amneal Pharmaceuticals at 1-877-835-5472 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 8,429 patients who were enrolled in placebo-controlled trials, including 6,666 exposed for 1 year and 5,685 for at least 3 years. …

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