Drug Interaction Report

MONITOR: Coadministration with inhibitors of P-glycoprotein (P-gp) may increase the plasma concentrations of daunorubicin and idarubicin, both of which are substrates of the efflux transporter also known as ABCB1 or MDR1. The interaction has been studied with cyclosporine, a potent P-gp inhibitor, in attempt to overcome multidrug resistance in MDR1-overexpressing tumors. In a randomized study to test whether cyclosporine can enhance the antileukemia effect of anthracyclines, cyclosporine was found to significantly reduce the frequency of resistance to induction chemotherapy consisting of sequential cytarabine and daunorubicin (31% vs. 47%). The addition of cyclosporine also increased relapse-free and overall survival, particularly in patients with moderate or high P-gp expression. Pharmacokinetically, steady-state mean serum concentrations of daunorubicin and its active metabolite, daunorubicinol, were significantly higher (approximately 2-fold and 4-fold, respectively) in patients receiving cyclosporine. Although there was no significant difference in the frequency or severity of stomatitis or renal toxicity (as measured by creatinine elevation), grade 4 hyperbilirubinemia and grade 3 nausea occurred more frequently in patients receiving cyclosporine than in controls (31% vs. 4% and 11% vs. 3%, respectively). In a pharmacokinetic study of 27 patients with acute myelogenous leukemia receiving induction chemotherapy with idarubicin and cytarabine, the systemic exposure (AUC) to idarubicin and idarubicinol was increased by 77% and 182%, respectively, in patients administered cyclosporine 10 mg/kg daily compared to controls due to a 40% reduction in total body clearance. The interaction was also reported in another study in which increases in the AUC of idarubicin and idarubicinol were associated with increased levels of toxicity.

MANAGEMENT: Caution is advised if daunorubicin or idarubicin is prescribed in combination with a P-gp inhibitor. Patients should be closely monitored for increased adverse effects including cardiotoxicity and myelosuppression.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of atorvastatin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. When a single 40 mg dose of atorvastatin was coadministered with 240 mL of grapefruit juice, atorvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 16% and 37%, respectively. Greater increases in Cmax (up to 71%) and/or AUC (up to 2.5 fold) have been reported with excessive consumption of grapefruit juice (>=750 mL to 1.2 liters per day). Clinically, high levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death.

ADJUST DOSING INTERVAL: Fibres such as oat bran and pectin may diminish the pharmacologic effects of HMG-CoA reductase inhibitors by interfering with their absorption from the gastrointestinal tract.

MANAGEMENT: Patients receiving therapy with atorvastatin should limit their consumption of grapefruit juice to no more than 1 liter per day. Patients should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed. In addition, patients should either refrain from the use of oat bran and pectin or, if concurrent use cannot be avoided, to separate the administration times by at least 2 to 4 hours.