Coadministration has not been studied but may increase atorvastatin concentrations due to inhibition of P-gp and/or BCRP by ledipasvir. A dose reduction of atorvastatin may be required. Statin-associated adverse events such as myopathy should be closely monitored.

Coadministration with rifaximin has not been studied but there is a low potential for interaction. In vitro studies suggest that rifaximin is a substrate of CYP3A4, P-gp, and OATP1, as well as a weak inducer of CYP3A4 and weak inhibitor of P-gp. Concentrations of rifaximin may increase due to inhibition of P-gp by ledipasvir but the clinical significance of this is unclear as systemic absorption of rifaximin is minimal.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydroxyzine is metabolised by alcohol dehydrogenase and CYP mediated pathways but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro. [Note, as hydroxyzine elimination is impaired in patients with hepatic dysfunction, daily dose or dose frequency should be reduced in patients with impaired liver function.]

Midazolam is metabolised by CYP3A4 but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro. Coadministration with a single dose of ledipasvir alone increased midazolam Cmax by 7% and decreased AUC by 1%. Coadministration with ledipasvir once daily decreased midazolam Cmax and AUC by 5% and 11%, respectively. These changes are not clinically relevant and no effect is expected on ledipasvir/sofosbuvir concentrations. No dose adjustment of ledipasvir/sofosbuvir or midazolam is required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Estradiol is metabolized by CYPs 3A4 and 1A2, and is glucuronidated, but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro.