78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 Oistration (FDA) issued a safety announcement of serious slowing of the heart rate when the class III antiarrhythmic drug amiodarone was used with hepatitis C treatment containing sofosbuvir in combination with another direct-acting antiviral (DAA). The announcement was based on a total of 9 postmarketing reports of bradycardia either submitted by Gilead Sciences, the manufacturer of sofosbuvir, or recorded in the FDA Adverse Event Reporting System database. Two of the patients taking sofosbuvir and daclatasvir are reported in this issue of Gastroenterology. In this editorial, we discuss the potential mechanism of the proposed drug–drug interaction with amiodarone, how it may have occurred despite intensive evaluation of drug–drug interactions during clinical development of current DAAs, and the lessons to be learned from these observations. From the FDA announcement and Gilead’s Dear Doctor letter, the following information can be retrieved: in a total of 9 patients, bradycardia was observed and was fatal in 1 patient; 3 others needed a pacemaker insertion. In 6 of the 9 patients, symptoms occurred within 24 hours after the first dose of therapy for hepatitis C virus (HCV) infection; in the other 3 patients, this occurred between 2 and 12 days. All patients were on amiodarone; 7 of them also took a b-blocker. HCV therapy consisted of sofosbuvir in all 9 cases to which was added daclatasvir in 5, ledipasvir in 3, and simeprevir in 1. All patients stopped HCV therapy after bradycardia was diagnosed. However, 3 patients were rechallenged with HCV therapy while amiodarone was continued and this resulted in recurrence of symptomatic bradycardia. In 1 patient, amiodarone was discontinued and after 8 weeks a rechallenge with HCV therapy was asymptomatic. Although Renet et al do not specifically mention this, we assume that the 2 patients on sofosbuvir with daclatasvir reported in this issue of Gastroenterology are included in the case series mentioned by the FDA. Several pieces of evidence are available to estimate the probable causality between use of HCV therapy and the occurrence of symptomatic bradycardia in patients concurrently taking amiodarone (Table 1; Naranjo et al). First, in 3 patients a rechallenge with HCV therapy led to
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