Drug Interactions between esomeprazole / naproxen and sofosbuvir / velpatasvir / voxilaprevir

GENERALLY AVOID: Coadministration of velpatasvir with proton pump inhibitors may reduce its gastrointestinal absorption. Velpatasvir exhibits pH-dependent solubility, with increased solubility at lower pH. In 60 healthy volunteers, mean velpatasvir peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 37% and 36%, respectively, when a single 400 mg-100 mg dose of sofosbuvir-velpatasvir was administered simultaneously with omeprazole 20 mg once daily. Interestingly, mean sofosbuvir Cmax and AUC also decreased by 34% and 29%, respectively, although its solubility is not known to be pH-dependent. When omeprazole 20 mg once daily was given 12 hours before the sofosbuvir-velpatasvir dose, mean velpatasvir Cmax and AUC decreased by 57% and 55%, respectively, while mean sofosbuvir Cmax and AUC decreased by 45% and 44%, respectively. Similar results were observed for velpatasvir when omeprazole 20 mg once daily was given 2 hours before the sofosbuvir-velpatasvir dose, or when omeprazole 40 mg once daily was given 4 hours after the sofosbuvir-velpatasvir dose. When omeprazole 20 mg once daily was administered 4 hours after the sofosbuvir-velpatasvir dose, mean velpatasvir Cmax decreased by 33% and AUC decreased by 26%.

MANAGEMENT: Concomitant use of sofosbuvir-velpatasvir with proton-pump inhibitors should generally be avoided. If coadministration is required, sofosbuvir-velpatasvir should be administered with food and taken 4 hours before the proton-pump inhibitor at a maximum daily dose equivalent to omeprazole 20 mg. Use with other proton-pump inhibitors has not been studied.

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GENERALLY AVOID: Theoretically, proton pump inhibitors may decrease the gastrointestinal absorption of enteric-coated naproxen, which requires an acidic environment for dissolution. The proposed mechanism is an increase in gastric pH (i.e. decreased gastric acidity) induced by proton pump inhibitors. In patients treated with proton pump inhibitors, the possibility of a reduced or subtherapeutic response to enteric-coated naproxen should be considered.

MANAGEMENT: Concomitant use of these drugs is generally not recommended.

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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.

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