154 Current Drug Safety, 2012, Vol. 7, No. 2 comparators in both the PO (3 [0.1%] moxifloxacin, 4 [0.1%] comparators) and IV/PO (19 [1.4%] moxifloxacin, 15 [1.1%] comparators) groups. Only one of these events in the IV/PO group (comparators) was considered drug-related. Incidences of treatment-emergent cardiac AEs with fatal outcome were also similar in patients 65 years in both the PO (9 [0.4%] moxifloxacin, 12 [0.5%] comparators) and IV/PO (32 [2.3%] moxifloxacin, 37 [2.8%] comparators) groups. Three events in the IV/PO group, all receiving comparator treatment, were considered drug-related. Incidence of Cardiac AEs Considered Surrogates for TdP/QTc Prolongation Potential The overall incidence of treatment-emergent cardiac AEs considered potential surrogates for TdP/QTc prolongation was lower in the PO group than the IV/PO group, probably reflecting differences in severity of illness and underlying conditions (Table 4). There was no evidence of any excess of cardiac AEs with moxifloxacin versus comparators in either the PO or IV/PO groups. In addition, the incidence of specific cardiac events was similar in the moxifloxacin and comparator groups. Across the PO and IV/PO groups, 14 moxifloxacin- and 14 comparator-treated patients developed a ventricular arrhythmia, ventricular fibrillation, or ventricular tachycardia. Ten of these cases were drug-related (6 moxifloxacin, 4 comparators). Cardiac arrest or cardiorespiratory arrest was reported in 16 moxifloxacin- Haverkamp et al. (PO 3; IV/PO 13) and 18 comparator-treated (PO 2; IV/PO 16) patients, the majority of them being treated for CAP, HAP, or aspiration pneumonia. Of the 16 moxifloxacin- treated patients, six had existing cardiac comorbidity, two had an underlying respiratory disease, and eight had comorbidities including hypertension, diabetes, renal impairment, and/or alcohol abuse. In the comparator arm, 13 patients had an existing cardiac comorbidity, three had underlying respiratory disease, and two had both cardiac comorbidities and underlying respiratory disease. There was only one case of TdP reported in the clinical studies; this occurred in a patient treated with an IV/PO comparator agent. This elderly patient, who was enrolled in a CAP study, was administered levofloxacin 500 mg once daily. Looking specifically at treatment-emergent events considered potential surrogates for TdP/QTc prolongation and the incidence of loss of consciousness and syncope, numbers were low and similar for moxifloxacin and comparator agents given either PO or IV/PO (Table 4). Cardiac AEs that were potential surrogates for TdP/QTc prolongation and had a fatal outcome were reported in 8/10,613 moxifloxacin patients and 6/10,685 comparator- treated patients in the PO group and 13/3431 moxifloxacin- vs 17/3415 comparator-treated patients in the IV/PO group. Of these events, one in the PO comparator group was considered drug-related (death following respiratory arrest as the consequence of septicemia), while in the IV/PO group, Table 4. Treatment-Emergent Events Considered Potential Surrogates for TdP/QTc Prolongation: Pooled Data from Phase II to IV Randomized Active-Controlled Studies with Moxifloxacin PO Studies, nb (%) Moxifloxacin (Nc = 10613) Comparatorsd (N = 10685) IV/PO Studies, n (%) Moxifloxacin (N = 3431) Comparatorsd (N = 3415) System Organ Class • MedDRAa Preferred Term Any event Cardiac disorders • Cardiac arrest • Cardiac flutter • Cardiorespiratory arrest • Torsade de pointes • Ventricular arrhythmia • Ventricular fibrillation • Ventricular tachycardia General disorders and administration • Death • Sudden death • Sudden cardiac death Nervous system disorders • Loss of consciousness • Syncope Surgical and medicinal procedures • Resuscitation PO = oral administration; IV/PO = sequential intravenous/oral administration. aStandardized Medical Dictionary for Regulatory Activities (MedDRA) Query. bn = number of patients with event. cN = total number of patients in group. dFor a list of comparators see Table 1. 25 (0.2) 1 (< 0.1) 2 (< 0.1) 2 (< 0.1) 0 (0) 2 (< 0.1) 1 (< 0.1) 0 (0) 2 (< 0.1) 2 (< 0.1) 0 (0) 4 (< 0.1) 9 (< 0.1) 0 (0) 23 (0.2) 1 (< 0.1) 1 (< 0.1) 1 (< 0.1) 0 (0) 0 (0) 0 (0) 2 (< 0.1) 2 (< 0.1) 1 (< 0.1) 0 (0) 5 (< 0.1) 10 (< 0.1) 0 (0) 37 (1.1) 9 (0.3) 0 (0) 4 (0.1) 0 (0) 0 (0) 0 (0) 11 (0.3) 2 (< 0.1) 2 (< 0.1) 1 (< 0.1) 0 (0.0) 6 (0.2) 2 (< 0.1) 36 (1.1) 11 (0.3) 0 (0) 5 (0.1) 1 (< 0.1) 3 (< 0.1) 1 (< 0.1) 8 (0.2) 0 (–) 2 (< 0.1) 0 (0.0) 1 (< 0.1) 5 (0.1) 0 (0)