156 Current Drug Safety, 2012, Vol. 7, No. 2 Haverkamp et al. Table 6. Women and Patients 65 Years: Treatment-Emergent Events Considered Potential Surrogates for TdP/QTc Prolongation 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 • Sudden cardiac death General disorders and administration • Death • Sudden death Nervous system disorders • Loss of consciousness • Syncope Women Patients 65 years PO Studies, nb (%) IV/PO Studies, n (%) PO Studies, nb (%) IV/PO studies, n (%) Moxifloxacin Comparatorsd Moxifloxacin Comparatorsd Moxifloxacin Comparators Moxifloxacin Comparators (Nc = 5773) (N = 5817) (N = 1349) (N = 1323) (N = 2451) (N = 2403) (N = 1373) (N = 1334) 10 (0.2) 0 (0) 1 (< 0.1) 1 (< 0.1) 0 (0) 2 (< 0.1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (< 0.1) 5 (< 0.1) 11 (0.2) 1 (< 0.1) 0 (0) 1 (< 0.1) 0 (0) 0 (0) 0 (0) 1 (< 0.1) 0 (0) 0 (0) 0 (0) 1 (< 0.1) 7 (0.1) 11 (0.8) 4 (0.3) 0 (0) 1 (< 0.1) 0 (0) 0 (0) 0 (0) 4 (0.3) 0 (0) 1 (< 0.1) 0 (0) 0 (0) 1 (< 0.1) 11(0.8) 4 (0.3) 0 (0) 2 (< 0.1) 1 (< 0.1) 0 (0) 0 (0) 1 (< 0.1) 0 (0) 0 (0) 2 (< 0.1) 1 (< 0.1) 0 (0) 9 (0.4) 1 (< 0.1) 1 (< 0.1) 2 (< 0.1) 0 (0) 1 (< 0.1) 1 (< 0.1) 0 (0) 0 (0) 0 (0) 1 (< 0.1) 0 (0) 2 (< 0.1) 7 (0.3) 0 (0) 1 (< 0.1) 1 (< 0.1) 0 (0) 0 (0) 0 (0) 1 (< 0.1) 0 (0) 0 (0) 1 (< 0.1) 1 (< 0.1) 2 (< 0.1) 24 (1.7) 4 (0.3) 0 (0) 2 (0.1) 0 (0) 0 (0) 0 (0) 9 (0.7) 1 (< 0.1) 2 (0.1) 2 (0.1) 0 (0) 4 (0.3) 22 (1.6) 6 ( 0.4) 0 (0) 5 (0.4) 1 (< 0.1) 3 (0.2) 0 (0) 3 (0.2) 0 (0) 0 (0) 2 (0.1) 0 (0) 3 (0.2) 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. Calculation of QTcF confirms the QTcB data in the PO group, where the QTc change from baseline to post-baseline was similar when calculated as QTcB or QTcF with both moxifloxacin (6.4 ± 25.5 ms vs 7.5 ± 24.8 ms, respectively) and comparators (0.6 ± 23.1 ms vs 2.0 ± 21.8 ms) (Table 7). Larger differences were seen between QTcF and QTcB- calculated values in hospitalized patients with tachycardia in the IV/PO CAP group. Here, in group C the change from baseline to Day 3 with moxifloxacin treatment was 13.3 ± 25.6 ms when calculated using QTcF and 5.7 ± 26.3 ms when calculated using QTcB. Corresponding values for comparators were 4.3 ± 26.8 ms and -3.5 ± 27.6 ms, respecti- vely. In the IV/PO cSSSI group, the change from baseline to Day 3 in group C with moxifloxacin treatment was 9.9 ± 20.1 ms when calculated using QTcF and 4.4 ± 21.5 ms when calculated using QTcB. Corresponding values for comparators were 1.8 ± 17.3 ms and -3.6 ± 20.2 ms, respecti- vely. A similar trend was observed in group A patients on Day 3 in IV/PO CAP, and IV/PO cSSSI studies, also in both treatment groups. Concerning those patients in group B and group A on Day 1 in the sequential IV/PO studies, no differences were seen between QTcF and QTcB-calculated values in either treatment arm. QTcB Changes in Subgroups at Higher Risk of Cardiac AEs In women and patients 65 years old, there was some variation in the extent of QTcB changes. Changes in the moxifloxacin group ranged from 6.2 to 12.7 ms in women and from 1.8 to 12.4 ms in patients 65 years (Table 8). Conversely, in the comparator group, changes in women ranged from -8.7 to 1.5 ms and from -4.0 to 2.8 ms in patients 65 years (Table 8). In moxifloxacin-treated patients of group A, although QT prolongation after the first IV dose (on Day 1) was slightly higher in the IV/PO CAP population than in the IV/PO cSSSI population for both women (12.7 vs 7.4 ms, respectively, in Group A) and patients 65 years old (12.4 vs 8.2 ms), QTcB changes by Day 3 in the IV/PO CAP group were similar to the post-baseline levels seen in the PO population (7.8 ms in women and 7.6 ms in patients 65 years old), and only 1–2 ms higher than that observed in the overall study population (6.6 ms). Changes from baseline to Day 1 in group B patients and from baseline to Day 3 in group C patients were similar to those seen in group A on Day 1 and Day 3, respectively. DISCUSSION The major finding of the analysis was that moxifloxacin treatment resulted in an expected small prolongation of the QTc interval which did not translate into an increased risk of TdP or other ventricular arrhythmias. This data is in agreement with a recent assessment carried out by the EMA PhVWP confirming that moxifloxacin has a potential to prolong the QTc interval in patients [30]. The low potential of prolongation of the QTc interval has been considered greater for moxifloxacin than for other fluoroquinolones (i.e. ciprofloxacin, levofloxacin). A mean prolongation at steady state of the ECG QTc interval by 4–7 ms is a well-known effect of moxifloxacin [11]. As with all drugs that affect the QTc interval [31, 32],