Drug Interactions between naldemedine and sofosbuvir / velpatasvir / voxilaprevir

MONITOR: Coadministration with moderate inhibitors of CYP450 3A4 and/or moderate or potent inhibitors of P-glycoprotein (P-gp) may increase the plasma concentrations of naldemedine, which is primarily metabolized by CYP450 3A4 to nor-naldemedine and to a minor extent by UGT1A3 to naldemedine 3-G. Both metabolites have demonstrated antagonistic activity for opioid receptors, but with less potency than the parent drug. Naldemedine is also a substrate of the P-gp efflux transporter. According to the product labeling, administration of naldemedine with 200 mg once daily itraconazole, a potent CYP450 3A4 and P-gp inhibitor, increased naldemedine peak plasma concentration (Cmax) by 12% and systemic exposure (AUC) by 191% compared to naldemedine administered alone. When administered with 200 mg once daily fluconazole, a moderate CYP450 3A4 inhibitor, naldemedine Cmax and AUC increased by 38% and 90%, respectively. When administered with a single 600 mg dose of cyclosporine, a potent P-gp but weak CYP450 3A4 inhibitor, naldemedine Cmax and AUC increased by 45% and 78%, respectively. Increased exposure to naldemedine may precipitate opioid withdrawal symptoms such as hyperhidrosis, lacrimation, rhinorrhea, chills, diarrhea, abdominal pain, anxiety, insomnia, irritability, restlessness, and yawning.

MANAGEMENT: Caution is advised during concomitant use of naldemedine with moderate inhibitors of CYP450 3A4 and/or moderate or potent inhibitors of P-glycoprotein (P-gp). Patients should be closely monitored for potential opioid withdrawal symptoms as well as other adverse effects of naldemedine.

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.

MONITOR: Coadministration with moderate inhibitors of CYP450 3A4 and/or moderate or potent inhibitors of P-glycoprotein (P-gp) may increase the plasma concentrations of naldemedine, which is primarily metabolized by CYP450 3A4 to nor-naldemedine and to a minor extent by UGT1A3 to naldemedine 3-G. Both metabolites have demonstrated antagonistic activity for opioid receptors, but with less potency than the parent drug. Naldemedine is also a substrate of the P-gp efflux transporter. According to the product labeling, administration of naldemedine with 200 mg once daily itraconazole, a potent CYP450 3A4 and P-gp inhibitor, increased naldemedine peak plasma concentration (Cmax) by 12% and systemic exposure (AUC) by 191% compared to naldemedine administered alone. When administered with 200 mg once daily fluconazole, a moderate CYP450 3A4 inhibitor, naldemedine Cmax and AUC increased by 38% and 90%, respectively. When administered with a single 600 mg dose of cyclosporine, a potent P-gp but weak CYP450 3A4 inhibitor, naldemedine Cmax and AUC increased by 45% and 78%, respectively. Increased exposure to naldemedine may precipitate opioid withdrawal symptoms such as hyperhidrosis, lacrimation, rhinorrhea, chills, diarrhea, abdominal pain, anxiety, insomnia, irritability, restlessness, and yawning.

MANAGEMENT: Caution is advised during concomitant use of naldemedine with moderate inhibitors of CYP450 3A4 and/or moderate or potent inhibitors of P-glycoprotein (P-gp). Patients should be closely monitored for potential opioid withdrawal symptoms as well as other adverse effects of naldemedine.