Drug interactions between Gengraf and Lipitor

ADJUST DOSE: Coadministration with cyclosporine may significantly increase the plasma concentrations of some HMG-CoA reductase inhibitors and/or their pharmacologically active metabolites. The mechanism is cyclosporine inhibition of intestinal and hepatic CYP450 3A4, the isoenzyme responsible for the metabolic clearance of HMG-CoA reductase inhibitors like atorvastatin, lovastatin acid, and simvastatin acid. In addition, atorvastatin and its metabolites are substrates of the OATP1B1 transporter, which is also inhibited by cyclosporine. 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. Use of simvastatin and lovastatin with cyclosporine has resulted in musculoskeletal toxicity, and the risk may be increased with dosages greater than 10 and 20 mg/day, respectively. The interaction has also been reported with atorvastatin and resulted in rhabdomyolysis. Atorvastatin AUC increased 8.7-fold during concurrent administration of atorvastatin 10 mg/day and cyclosporine 5.2 mg/kg/day.


MANAGEMENT: The benefits of the use of atorvastatin, lovastatin, simvastatin, and red yeast rice (which contains lovastatin) in patients receiving cyclosporine should be carefully weighed against the potential risks. If the combination is prescribed, lower dosages of the HMG-CoA reductase inhibitor should be considered. Product labeling for simvastatin states that therapy should start at 5 mg/day and not exceed 10 mg/day when used in combination with cyclosporine. Similarly, lovastatin labeling recommends that therapy begin at 10 mg/day and not exceed 20 mg/day when prescribed with cyclosporine. The dosage of atorvastatin should not exceed 10 mg/day during coadministration. Fluvastatin, pravastatin, and rosuvastatin are probably safer alternatives in patients receiving cyclosporine, 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.