Drug Interactions between fluvastatin and sofosbuvir / velpatasvir / voxilaprevir

ADJUST DOSE: Coadministration with sofosbuvir/velpatasvir/voxilaprevir may increase the plasma concentrations of all statins including atorvastatin, fluvastatin, lovastatin, and simvastatin. The proposed mechanism is inhibition of organic anion transporting polypeptide (OATP) 1B1-mediated hepatic uptake of statins by velpatasvir and voxilaprevir. Although the interaction has not been studied specifically with atorvastatin, fluvastatin, lovastatin or simvastatin, it has been reported with other statins that are also substrates of OATP1B1. High levels of HMG-CoA reductase inhibitory activity in plasma may be 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 during concomitant administration of atorvastatin, fluvastatin, lovastatin, simvastatin, or red yeast rice (which contains lovastatin) with sofosbuvir/velpatasvir/voxilaprevir. The lowest approved dosage of the statin should be used. If higher dosages are required, the lowest effective statin dosage should be prescribed based on a risk/benefit assessment.

MONITOR: Coadministration with inhibitors of organic anion transporting polypeptides (OATP) 1B1 and/or 1B3 may increase the plasma concentrations of voxilaprevir, which is a substrate of the hepatic uptake transporters. When a single 100 mg dose of voxilaprevir was administered with a single 600 mg dose of the potent OATP 1B1/1B3 inhibitor cyclosporine (n=24), mean voxilaprevir peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 19.0- and 9.4-fold, respectively. Inhibition of P-glycoprotein (P-gp)- and breast cancer resistance protein (BCRP)-mediated intestinal transport and CYP450 3A4-mediated metabolism of voxilaprevir may also contribute to the overall interaction with cyclosporine. The safety of such high levels of voxilaprevir has not been established.

MANAGEMENT: Caution and monitoring are advised when voxilaprevir is used with OATP 1B1 or 1B3 inhibitors.