Drug Interaction Report

GENERALLY AVOID: Coadministration of a macrolide immunosuppressant with certain HMG-CoA reductase inhibitors may result in elevated plasma concentrations of both due to competitive inhibition of CYP450 3A4 metabolism. High levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity including rhabdomyolysis, which can be fatal. In one case report, severe rhabdomyolysis complicated by acute renal transplant failure occurred in a diabetic woman whose drug regimen at the time of hospital admission consisted of tacrolimus, azathioprine, prednisolone, felodipine, citalopram, aspirin, insulin, simvastatin, and fusidic acid. The patient developed muscle pain accompanied by a grossly elevated serum creatine kinase level several weeks after simvastatin was increased from 10 to 20 mg/day and fusidic acid was initiated to treat soft tissue infection and osteomyelitis of a toe. She recovered after discontinuation of simvastatin and fusidic acid and institution of supportive therapy. Simvastatin was later replaced with fluvastatin, and fusidic acid was administered on another occasion without incident. The authors suggest that use of tacrolimus with simvastatin at a dosage exceeding 10 mg/day may increase the risk of rhabdomyolysis. The use of fusidic acid may have presented an additional risk factor in the case patient. In another report, a transplant patient developed significantly elevated sirolimus serum trough levels following addition of atorvastatin to her regimen. No adverse effects were reported, but a 50% reduction in sirolimus dosage was required.

MANAGEMENT: In general, lovastatin, red yeast rice (which contains lovastatin), and simvastatin should preferably be avoided in patients treated with sirolimus or tacrolimus due to the potential for serious interaction. Atorvastatin may be used with caution, although the dosage should start low, and immunosuppressant blood levels should be closely monitored. Pravastatin and fluvastatin are probably the safest alternatives, since they are not metabolized by CYP450 3A4. All patients treated with HMG-CoA reductase inhibitors should be advised to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.

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.

ADJUST DOSING INTERVAL: Consumption of food can decrease the rate and extent of gastrointestinal absorption of sirolimus. Also, the consumption of grapefruit juice may result in increased sirolimus trough concentrations.

MANAGEMENT: Experts recommend that this drug be taken either at least one hour prior to eating or consistently with or without food to avoid variations in sirolimus blood levels. The manufacturer recommends against using grapefruit juice for dilution of sirolimus doses. Patients should be monitored for clinical and laboratory evidence of altered immunosuppressant effects.