Update on the Cardiac Safety of Moxifloxacin one in the moxifloxacin arm (ventricular tachycardia as a complication of acute myocardial infarction and respiratory failure) and two (cardiorespiratory arrest in two patients) in the comparator groups were considered drug-related. Incidence of Cardiac AEs Considered Potential Surrogates for TdP/QTc Prolongation in High-Risk Subsets of Patients Four high-risk subsets of patients were included in this analysis: patients on initial IV treatment with CAP requiring admittance to the ICU and/or mechanical ventilation, patients with a prolonged baseline QTcB interval (> 450 ms in men, > 470 ms in women), women, and patients 65 years old. Of the 6662 patients with CAP in the safety population, 316 had CAP requiring ICU admission and/or mechanical ventilation and initial IV treatment (149 moxifloxacin, 167 comparators). Cardiac AE profiles for these patients were similar in the moxifloxacin and comparator groups (Table 5) and no deaths were observed in either group during follow- up. Treatment-emergent cardiac AEs were reported in 55 (36.9%) moxifloxacin- and 59 (35.3%) comparator-treated patients. Looking specifically at treatment-emergent cardiac AEs considered potential surrogates for TdP/QTc prolongation, seven (4.7%) were reported for moxifloxacin- treated patients and eight (4.8%) for comparator-treated patients (Table 5). Table 5. Patients with Serious Community-Acquired Pneumonia Requiring Intensive Care Support or Mechanical Ventilation: Treatment-Emergent Cardiac Events Considered Potential Surrogates for TdP/QTc Prolongation System Organ Class • MedDRAa preferred term Any event Cardiac disorders • Cardiac arrest • Cardiorespiratory arrest • Ventricular tachycardia Moxifloxacin Nb = 149 nc (%) Comparatorsd N = 167 n (%) 7 (4.7) 3 (2.0) 0 (0) 3 (2.0) 8 (4.8) 3 (1.8) 1 (< 0.1) 4 (2.4) Surgical and medicinal procedures • Resuscitation 1 (0.7) 0 (0) aStandardized Medical Dictionary for Regulatory Activities (MedDRA) Query. bN = total number of patients with serious CAP requiring intensive care support or mechanical ventilation. cn = number of patients with event. dFor a list of comparators see Table 1. Three groups of patients with a prolonged QTcB interval at baseline were assessed: PO patients, IV/PO CAP patients and IV/PO cSSSI patients. Among the 145 PO patients with data available (71 in the moxifloxacin group and 74 in the comparator group), there were two treatment-emergent cardiac AEs considered potential surrogates for TdP/QTc prolongation in each group: cardiac flutter and syncope in the moxifloxacin group and cardiac flutter and loss of consciousness in the comparator group. No deaths were observed. No events were seen in the IV/PO cSSSI Current Drug Safety, 2012, Vol. 7, No. 2 155 population, while in the IV/PO CAP population (n = 221 with available data) there was one event in the moxifloxacin group (sudden death) and two in the comparator group (cardiac arrest and ventricular tachycardia). Of the 14,262 women enrolled in the study, 21 (10 moxifloxacin, 11 comparators) in PO studies and 22 (11 moxifloxacin, 11 comparators) in IV/PO studies experienced treatment-emergent cardiac AEs considered potential surrogates for TdP/QTc prolongation, with similar cardiac AE profiles being observed between arms (Table 6). In the IV/PO group there was one death (moxifloxacin) and two sudden deaths (comparator group) reported in women patients. In the 7561 patients 65 years old, treatment-emergent cardiac AEs considered potential surrogates for TdP/QTc prolongation were experienced by 16 (9 moxifloxacin, 7 comparators) in PO studies and 46 (24 moxifloxacin, 22 comparators) in IV/PO studies, with no apparent differences between groups. Two deaths (moxifloxacin IV/PO group), one sudden cardiac death (moxifloxacin IV/PO group) and six sudden deaths (PO: 1 moxifloxacin, 1 comparators; IV/PO: 2 moxifloxacin, 2 comparators) occurred in the subgroup of patients 65 years old. Absolute QTcB and QTcF Values at Baseline and Changes after PO and IV/PO Treatment with Antimicrobials Disposition of patients with ECG recordings at baseline and post-baseline is presented in Fig. (1) for the three populations outlined above (PO, IV/PO CAP, and IV/PO cSSSI). There was wide overlap in the interquartile range for all populations and a wide range in individual QTcB intervals both at baseline and post-baseline, with minimum QTcB values of 273–352 ms and maximum values of 492– 590 ms for PO and IV/PO populations (Fig. 2). Baseline QTcB data for all three populations (PO, IV/PO CAP, and IV/PO cSSSI) were similar with mean QTcB intervals for both treatment arms in the range of 414–421 ms with a standard deviation (SD) of about 27 ms (Table 7). In addition to QTcB values, baseline QTcF values were also found to be similar among the two treatment groups for each population (in the range of 391–405 ms and a standard deviation of about 27 ms). QTcF values at baseline were lower than corresponding QTcB values in all groups (the overcorrection on heart rates associated with the Fridericia’s formula being probably less pronounced than that of the Bazett’s formula) and slightly higher in the PO studies than in the IV/PO studies in both treatment arms; a difference possibly occurring due to higher heart rates in the hospitalized patients treated with sequential IV/PO therapy. As expected, moxifloxacin produced a small mean QTcB prolongation (Table 7). In PO studies post-baseline prolongation in the order of 6.4 ms was seen, while in IV/PO studies the average prolongation ranged from 6.1 to 10.1 ms on Day 1 post-dose and from 4.4 to 6.6 ms on Day 3 post- dose. In contrast, a mean 0.6 ms change was seen post-dose in the PO comparator treatment group, while in IV/PO studies prolongation ranged from -1.3 to 1.8 ms on Day 1 post-dose and from -3.9 to -3.2 ms on Day 3 post-dose.