Renal Impairment — In the osteoporosis treatment and prevention trials, raloxifene concentrations in women with mild renal impairment are similar to women with normal creatinine clearance. When a single dose of 120 mg raloxifene HCl was administered to 10 renally impaired males [7 moderate impairment (CrCl = 3 -50 mL/min); 3 severe impairment (CrCl ≤ 30 mL/min)] and to 10 healthy males (CrCl > 80 mL/min), plasma raloxifene concentrations were 122% (AUC_0-∞) higher in renally impaired patients than those of healthy volunteers. Raloxifene should be used with caution in patients with moderate or severe renal impairment [see Warnings and PRECAUTIONS and Use in Specific Populations].

Hepatic Impairment — The disposition of raloxifene was compared in 9 patients with mild (Child-Pugh Class A) hepatic impairment (total bilirubin ranging from 0.6 to 2 mg/dL) to 8 subjects with normal hepatic function following a single dose of 60 mg raloxifene HCl. Apparent clearance of raloxifene was reduced 56% and the half- life of raloxifene was not altered in patients with mild hepatic impairment. Plasma raloxifene concentrations were approximately 150% higher than those in healthy volunteers and correlated with total bilirubin concentrations. The pharmacokinetics of raloxifene has not been studied in patients with moderate or severe hepatic hepatic impairment. Raloxifene should be used with caution in patients with hepatic impairment [see Warnings and PRECAUTIONS and Use in Specific Populations].

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].

Warfarin — In vitro, raloxifene did not interact with the binding of warfarin. The concomitant administration of EVISTA 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].

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].

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].

Antacids — Concomitant administration of calcium carbonate or aluminum and magnesium hydroxide- containing antacids does not affect the systemic exposure of raloxifene [see DRUG INTERACTIONS].

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].

Digoxin — Raloxifene has no effect on the pharmacokinetics of digoxin [see DRUG INTERACTIONS].

Cyclosporine — Concomitant administration of EVISTA with cyclosporine has not been studied.

Lipid-lowering agents — Concomitant administration of EVISTA with lipid-lowering agents has not been studied.

Animal Toxicology and/or Pharmacology

The skeletal effects of raloxifene treatment were assessed in ovariectomized rats and monkeys. In rats, raloxifene prevented increased bone resorption and bone loss after ovariectomy. There were positive effects of raloxifene on bone strength, but the effects varied with time. Cynomolgus monkeys were treated with raloxifene or conjugated estrogens for 2 years. In terms of bone cycles, this is equivalent to approximately 6 years in humans. Raloxifene and estrogen suppressed bone turnover and increased BMD in the lumbar spine and in the central cancellous bone of the proximal tibia. In this animal model, there was a positive correlation between vertebral compressive breaking force and BMD of the lumbar spine.

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