Drug Interactions between Crestor and elbasvir / grazoprevir

ADJUST DOSE: Coadministration with elbasvir-grazoprevir may significantly increase the plasma concentrations of HMG-CoA reductase inhibitors (statins) that are substrates of the CYP450 3A4 isoenzyme and/or breast cancer resistance protein (BCRP) transporter. Grazoprevir is reported to be a relatively weak inhibitor of CYP450 3A4 in vivo, and both elbasvir and grazoprevir are inhibitors of BCRP at the intestinal level in humans. In 16 study subjects, administration of a single 10 mg dose of atorvastatin (CYP450 3A4 substrate) during treatment with elbasvir-grazoprevir 50 mg-200 mg once daily increased atorvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) by 4.3- and 1.9-fold, respectively, compared to administration of atorvastatin alone. Likewise, when a single 10 mg dose of rosuvastatin (BCRP substrate) was coadministered with elbasvir-grazoprevir in 12 study subjects, rosuvastatin Cmax and AUC increased by 5.5- and 2.3-fold, respectively. High levels of statin or 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. No data are available for fluvastatin, lovastatin and simvastatin, but similar interactions with elbasvir-grazoprevir should be expected. The pharmacokinetics of elbasvir and grazoprevir were not significantly affected by either atorvastatin or rosuvastatin.

MANAGEMENT: Caution is advised when statins such as atorvastatin, rosuvastatin, fluvastatin, lovastatin, and simvastatin are prescribed with elbasvir-grazoprevir. Atorvastatin dosage should not exceed 20 mg/day and rosuvastatin dosage should not exceed 10 mg/day according to the product labeling for elbasvir-grazoprevir. The lowest effective dose of fluvastatin, lovastatin, or simvastatin should be used; some authorities recommend a maximum daily dose of 20 mg of these statins. In contrast, pitavastatin and pravastatin do not have clinically relevant interactions with elbasvir-grazoprevir, and no dosage adjustments are necessary. 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.

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