Current Drug Safety, 2012, 7, 149-163 149 Update on the Cardiac Safety of Moxifloxacin Wilhelm Haverkamp*,1, Frank Kruesmann2, Anna Fritsch2, David van Veenhuyzen3 and Pierre Arvis4 1Department of Cardiology, Campus Virchow Clinic, Charité University Medicine Berlin, Berlin, Germany 2Bayer Pharma AG, Wuppertal, Germany 3Bayer HealthCare, Montville, NJ, USA 4Bayer HealthCare, Loos, France Abstract: Cardiac safety was compared in patients receiving moxifloxacin and other antimicrobials in a large patient population from Phase II–IV randomized active-controlled clinical trials. Moxifloxacin 400 mg once-daily monotherapy was administered orally (PO) or sequentially (intravenous/oral, IV/PO). Across 64 trials, 21,298 patients received PO therapy (10,613 moxifloxacin, 10,685 comparators) while 6846 received sequential IV/PO therapy (3431 moxifloxacin, 3415 comparators). Treatment-emergent cardiac adverse event (AE) rates were similar for moxifloxacin and comparators in PO (6.6% vs 5.8%) and IV/PO (11.0% vs 12.0%) trials. Treatment-emergent cardiac adverse drug reactions were rare in PO (moxifloxacin 3.2% vs comparators 2.4%) and IV/PO (moxifloxacin 1.4% vs comparators 1.5%) patients. There were five (<0.02%) treatment-emergent drug-related deaths due to cardiac events out of 28,144 patients; one PO patient died treated with comparators, one patient died treated with IV/PO moxifloxacin, and three patients died after treatment with IV/PO comparators. Only one case of treatment-related non-fatal torsade de pointes occurred in the comparator arm. Incidence rates of cardiac AEs remained low in populations at elevated risk of cardiac events predisposed to QTc prolongation (i.e. community-acquired pneumonia patients admitted to the intensive care unit and/or mechanical ventilation, patients with documented prolongation of baseline QTc interval, women, and patients 65 years old). There was no evidence of unexpected cardiac events. After moxifloxacin treatment, an expected small prolongation in QTcB and QTcF was found. This analysis of numerous clinical trials shows the favorable cardiac safety profile of moxifloxacin, when used appropriately and according to its label, versus other antibiotics. Keywords: Cardiac safety, comparator antimicrobials, moxifloxacin, oral therapy, Phase II–IV clinical trials, QTc prolongation, sequential intravenous/oral therapy. INTRODUCTION Many non-anti-arrhythmic drugs, such as antipsychotics (e.g. pimozide, sertindole, ziprasidone, quetiapine, haloperidol, thioridazine) [1-4], antihistamines (e.g. astemizole, terfenadine) [3], and antimicrobials/antimalarials (e.g. erythromycin, ketoconazole, chloroquine, halofantrine) [3-6] are known to prolong the cardiac repolarization phase, i.e. the QT interval of the surface electrocardiogram. Prolonged repolarization has the potential to increase the risk of cardiac events such as ventricular arrhythmias [1], including the potentially life-threatening ventricular tachycardia known as torsade de pointes (TdP) [3, 7], and cardiac arrest. QT prolongation has been observed with several classes of antimicrobials [7], including macrolides (e.g. clarithromycin, erythromycin) [7], ketolides (telithromycin) [7, 8], and fluoroquinolones (e.g. ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin, sparfloxacin) [7, 9-13]. The potential to cause TdP appears to be higher for macrolides, when given intravenously, than for fluoroquinolones [7, 14]. Within each class, the agents seem to differ in their potential to cause such cardiac events [15]. *Address correspondence to this author at the Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Medizinische Klinik mit Schwerpunkt Kardiologie, Augustenburger Platz 1, D-13353 Berlin, Germany; Tel: +49 30 450 553 366; Fax: +49 30 450 553 994; E-mail: wilhelm.haverkamp@charite.de It is well established that moxifloxacin produces a predictable small prolongation of the corrected QT (QTc) interval [11] by reversible and dose-dependent but weak blockage of the rapidly activating delayed rectifier potassium channel, IKr [16] or human cloned counterpart, the hERG potassium channels [17]. The predictability of moxifloxacin- induced QTc changes has led to its use as a positive control in thorough Phase I QT/QTc studies [18, 19]. However, despite the observed QTc prolongation with moxifloxacin, there is no evidence that its use is associated with an increase in the overall number of cardiac events [11, 20-24]. Even in a high-risk population of elderly patients with community- acquired pneumonia (CAP), sequential intravenous/oral (IV/PO) treatment with moxifloxacin has a good cardiac rhythm safety profile, comparable to that of levofloxacin [25]. The objective of this analysis was to investigate the cardiac safety of moxifloxacin and to compare it with a range of other antimicrobials in a large patient population. The data presented here cover cardiac safety findings from 64 of the 65 Bayer-sponsored Phase II to IV randomized, active-controlled clinical trials with moxifloxacin 400 mg, including indications requiring oral (PO) administration and those where sequential IV/PO therapy could be used. One Phase II trial included only patients with cirrhotic liver disease, and was excluded from the analysis due to enrolment of very different patients compared with other studies (most patients had a Child-Pugh C cirrhosis, which is a contraindication for the use of moxifloxacin). Several of 1574-8863/12 $58.00+.00 © 2012 Bentham Science Publishers