RALOXIFENE Drug Interactions: What You Need to Know

INTERACTIONS

• 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.2 Warfarin If raloxifene hydrochloride is given concomitantly with warfarin or other warfarin derivatives, prothrombin time should be monitored more closely when starting or stopping therapy with raloxifene hydrochloride <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.3 Other Highly Protein-Bound Drugs Raloxifene hydrochloride should be used with caution with certain other highly protein-bound drugs such as diazepam, diazoxide, and lidocaine. Although not examined, raloxifene hydrochloride might affect the protein binding of other drugs. Raloxifene is more than 95% bound to plasma proteins <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.4 Systemic Estrogens The safety of concomitant use of raloxifene hydrochloride with systemic estrogens has not been established and its use is not recommended.

7.5 Other Concomitant Medications Raloxifene hydrochloride can be concomitantly administered with ampicillin, amoxicillin, antacids, corticosteroids, and digoxin <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . The concomitant use of raloxifene hydrochloride and lipid-lowering agents has not been studied.

Drug Interactions

Cholestyramine — Cholestyramine, an anion exchange resin, causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene after a single dose. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect [see Drug Interactions ( 7.1 )] . Warfarin — In vitro , raloxifene did not interact with the binding of warfarin. The concomitant administration of raloxifene hydrochloride and warfarin, a coumarin derivative, has been assessed in a single-dose study. In this study, raloxifene had no effect on the pharmacokinetics of warfarin. However, a 10% decrease in prothrombin time was observed in the single-dose study. In the osteoporosis treatment trial, there were no clinically relevant effects of warfarin co-administration on plasma concentrations of raloxifene [see Drug Interactions ( 7.2 )] .

Other Highly

Protein-Bound Drugs — In the osteoporosis treatment trial, there were no clinically relevant effects of co-administration of other highly protein-bound drugs (e.g., gemfibrozil) on plasma concentrations of raloxifene. In vitro , raloxifene did not interact with the binding of phenytoin, tamoxifen, or warfarin ( see above) [see Drug Interactions ( 7.3 )] . Ampicillin and Amoxicillin — Peak concentrations of raloxifene and the overall extent of absorption are reduced 28% and 14%, respectively, with co-administration of ampicillin. These reductions are consistent with decreased enterohepatic cycling associated with antibiotic reduction of enteric bacteria. However, the systemic exposure and the elimination rate of raloxifene were not affected. In the osteoporosis treatment trial, co-administration of amoxicillin had no discernible differences in plasma raloxifene concentrations [see Drug Interactions ( 7.5 )] . Antacids — Concomitant administration of calcium carbonate or aluminum and magnesium hydroxide-containing antacids does not affect the systemic exposure of raloxifene [see Drug Interactions ( 7.5 )] . Corticosteroids — The chronic administration of raloxifene in postmenopausal women has no effect on the pharmacokinetics of methylprednisolone given as a single oral dose [see Drug Interactions ( 7.5 )] . Digoxin — Raloxifene has no effect on the pharmacokinetics of digoxin [see Drug Interactions ( 7.5 )] . Cyclosporine — Concomitant administration of raloxifene hydrochloride with cyclosporine has not been studied. Lipid-Lowering Agents — Concomitant administration of raloxifene hydrochloride with lipid-lowering agents has not been studied.

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 hydrochloride tablets, USP is contraindicated in women with active or past history of venous thromboembolism (VTE), including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> .

4.2 Pregnancy, Women Who May Become Pregnant, and Nursing Mothers Raloxifene hydrochloride tablets, USP is contraindicated in pregnancy, in women who may become pregnant, and in nursing mothers <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span> . Raloxifene hydrochloride tablets, USP may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. In rabbit studies, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred in rabbits at doses ≥0.1 mg/kg (≥0.04 times the human dose based on surface area, mg/m 2 ), and hydrocephaly was observed in fetuses at doses ≥10 mg/kg (≥4 times the human dose based on surface area, mg/m 2 ). In rat studies, retardation of fetal development 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 at doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on surface area, mg/m 2 ) during gestation and lactation 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, raloxifene disrupted parturition, which resulted in maternal and progeny death and morbidity. Effects in adult offspring (4 months of age) included uterine hypoplasia and reduced fertility; however, no ovarian or vaginal pathology was observed.

AND PRECAUTIONS 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. ( 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 tablets-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 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 <span class="opacity-50 text-xs">[see Contraindications ( 4.1 ) and Adverse Reactions ( 6.1 )]</span> .

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 the 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.5 )]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.5 )]</span> .

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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

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 (&gt;5.6 mmol/L or &gt;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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

5.9 History of Breast Cancer Raloxifene hydrochloride tablets 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 tablets in men. Raloxifene hydrochloride tablets 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 tablets-treated and placebo-treated groups had similar incidences of endometrial proliferation <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 , 14.2 )]</span> .

5.12 Breast Abnormalities Any unexplained breast abnormality occurring during raloxifene hydrochloride tablets therapy should be investigated. Raloxifene hydrochloride tablets does not eliminate the risk of breast cancer <span class="opacity-50 text-xs">[see Clinical Studies ( 14.4 )]</span> .