Drug Interactions between pravastatin and Prezcobix

ADJUST DOSE: Coadministration with darunavir/ritonavir may increase the plasma concentrations of pravastatin. The mechanism of interaction has not been described. In 14 study subjects, administration of pravastatin (40 mg single dose) in combination with darunavir/ritonavir (600 mg/100 mg twice a day) increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of pravastatin by 63% and 81%, respectively, compared to administration without darunavir/ritonavir. Pravastatin AUC increased by up to 5-fold in some patients.

MANAGEMENT: Because high levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity including severe myopathy and rhabdomyolysis, pravastatin should be initiated at the lowest possible dosage when prescribed with darunavir/ritonavir. The dosage may be increased gradually based on clinical response. 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.

MONITOR: Coadministration with cobicistat may increase the plasma concentrations of most HMG-CoA reductase inhibitors (i.e., statins) to varying degrees. Cobicistat is a potent inhibitor of CYP450 3A4 and can significantly increase exposure to statins that are primarily metabolized by the isoenzyme (e.g., atorvastatin, lovastatin, simvastatin). Cobicistat may also inhibit the OATP 1B1- and 1B3- mediated hepatic uptake of statins, thus even those that are not metabolized by CYP450 3A4 may be affected. 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.

MANAGEMENT: Caution is advised when statins are prescribed with cobicistat-containing regimens. The lowest starting dosage of the statin is recommended, then titrated as needed based on clinical response and tolerance. Some statins such as lovastatin and simvastatin are contraindicated for use with cobicistat. All patients receiving statin therapy 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.