Drug Interactions between amiodarone and sofosbuvir / velpatasvir / voxilaprevir

GENERALLY AVOID: Severe, life-threatening, symptomatic bradycardia has been reported during coadministration of amiodarone with ledipasvir-sofosbuvir or with sofosbuvir taken in combination with another direct acting antiviral for the treatment of hepatitis C, such as daclatasvir or simeprevir. The mechanism of interaction has not been delineated. Postmarketing adverse event reports include one death due to cardiac arrest, three patients requiring placement of a pacemaker to regulate cardiac rhythm, and other patients who recovered following discontinuation of either the hepatitis C drugs or amiodarone, or both. Bradycardia has generally occurred within hours to days, but in some cases up to 2 weeks after initiating hepatitis C antiviral treatment. Additional risk factors may include concomitant use of beta blockers, underlying cardiac comorbidities, and advanced liver disease.

MANAGEMENT: Concomitant use of amiodarone with sofosbuvir-containing hepatitis C antiviral treatment is not recommended. However, if coadministration is unavoidable, some authorities recommend cardiac monitoring in an inpatient hospital setting for the first 48 hours, followed by subsequent cardiac monitoring every day for at least the first 2 weeks of treatment. Similar cardiac monitoring is recommended for patients in whom amiodarone was discontinued just prior to starting hepatitis C antiviral treatment due to the long half-life of amiodarone. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate symptomatic bradycardia such as dizziness, lightheadedness, confusion, memory problems, fainting, malaise, weakness, excessive tiredness, palpitation, chest pain, irregular heart rhythm, shortness of breath, or syncope.

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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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