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      Moxifloxacin Safety : An Analysis of 14 Years of Clinical Data

      research-article
        , ,
      Drugs in R&d
      Springer International Publishing

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          Abstract

          Background

          Moxifloxacin, a fluoroquinolone antibiotic, is used for the treatment of respiratory tract, pelvic inflammatory disease, skin, and intra-abdominal infections. Its safety profile is considered favorable in most reviews but has been challenged with respect to rare but potentially fatal toxicities (e.g. hepatic, cardiac, or skin reactions).

          Objective

          To analyze and compare the safety profile of moxifloxacin versus comparators in the entire clinical database of the manufacturer.

          Setting

          Data on the valid-for-safety population from phase II–IV actively controlled studies (performed between 1996 and 2010) were analyzed. Studies were either double blind (n = 22 369) or open label (n = 7635) and included patients with indications that have been approved in at least one country [acute bacterial sinusitis, acute exacerbation of chronic bronchitis, community-acquired pneumonia, uncomplicated pelvic inflammatory disease, complicated and uncomplicated skin and skin structure infections, and complicated intra-abdominal infections] (n = 27 824) and patients with other indications (n = 2180), using the recommended daily dose (400 mg) and route of administration (oral, intravenous/oral, intravenous only). The analysis included patients at risk (age ≥65 years, diabetes mellitus, renal impairment, hepatic impairment, cardiac disorders, or body mass index <18 kg/m 2). Patients with known contraindications were excluded from enrollment by study protocol design, but any patient having entered a study, even if inappropriately, was included in the analysis.

          Main Outcome Measure

          Crude incidences and relative risk estimates (Mantel-Haenszel analysis) of patients with any adverse event (AE), adverse drug reaction (ADR), serious AE (SAE), serious ADR (SADR), treatment discontinuation due to an AE or ADR, and fatal outcomes related to an AE or ADR.

          Results

          Overall incidence rates of AEs were globally similar in the moxifloxacin and comparator groups. By filtering the data for differences in disfavor of moxifloxacin (i) at ≥2.5% for events with an incidence ≥2.5% or at ≥2-fold for events with an incidence <2.5% in one or both groups and (ii) affecting ≥10 patients in either group, we observed slightly more (i) AEs in double-blind intravenous-only and open-label oral studies, (ii) SAEs in double-blind intravenous-only studies, (iii) ADRs and SADRs in open-label oral studies, (iv) SADRs in open-label intravenous/oral studies, and (v) premature discontinuation due to AEs in open-label intravenous-only studies. The actual numbers of SADRs (in all studies) were small, with clinically relevant differences noted only in intravenous/oral studies and mainly driven by ‘gastrointestinal disorders’ (15 versus 7 patients) and ‘changes observed during investigations’ (23 versus 7 patients [asymptomatic QT prolongation: 11 versus 4 patients in double-blind studies]). Analysis by comparator (including another fluoroquinolone) did not reveal medically relevant differences, even in patients at risk. Incidence rates of hepatic disorders, tendon disorders, clinical surrogates of QT prolongation, serious cutaneous reactions, and Clostridium difficile-associated diarrhea were similar with moxifloxacin and comparators.

          Conclusion

          The safety of moxifloxacin is essentially comparable to that of standard therapies for patients receiving the currently registered dosage and for whom contraindications and precautions of use (as in the product label) are taken into account.

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          Most cited references56

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          Guidelines for the management of adult lower respiratory tract infections - Full version

          This document is an update of Guidelines published in 2005 and now includes scientific publications through to May 2010. It provides evidence-based recommendations for the most common management questions occurring in routine clinical practice in the management of adult patients with LRTI. Topics include management outside hospital, management inside hospital (including community-acquired pneumonia (CAP), acute exacerbations of COPD (AECOPD), acute exacerbations of bronchiectasis) and prevention. Background sections and graded evidence tables are also included. The target audience for the Guideline is thus all those whose routine practice includes the management of adult LRTI.
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            Practice guidelines for the diagnosis and management of skin and soft-tissue infections.

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              Estimation of a common effect parameter from sparse follow-up data.

              Breslow (1981, Biometrika 68, 73-84) has shown that the Mantel-Haenszel odds ratio is a consistent estimator of a common odds ratio in sparse stratifications. For cohort studies, however, estimation of a common risk ratio or risk difference can be of greater interest. Under a binomial sparse-data model, the Mantel-Haenszel risk ratio and risk difference estimators are consistent in sparse stratifications, while the maximum likelihood and weighted least squares estimators are biased. Under Poisson sparse-data models, the Mantel-Haenszel and maximum likelihood rate ratio estimators have equal asymptotic variances under the null hypothesis and are consistent, while the weighted least squares estimators are again biased; similarly, of the common rate difference estimators the weighted least squares estimators are biased, while the estimator employing "Mantel-Haenszel" weights is consistent in sparse data. Variance estimators that are consistent in both sparse data and large strata can be derived for all the Mantel-Haenszel estimators.
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                Author and article information

                Contributors
                tulkens@facm.ucl.ac.be
                Journal
                Drugs R D
                Drugs R D
                Drugs in R&d
                Springer International Publishing (Cham )
                1174-5886
                1179-6901
                18 December 2012
                18 December 2012
                June 2012
                : 12
                : 2
                : 71-100
                Affiliations
                [ ]Pharmacologie cellulaire et moléculaire & Centre de Pharmacie clinique, Louvain Drug Research Institute, Université catholique de Louvain, avenue E. Mounier 73 Bte B1.73.05, B-1200 Brussels, Belgium
                [ ]Bayer Santé SAS, Loos, France
                [ ]Bayer Pharma AG, Wuppertal, Germany
                Article
                12020071
                10.2165/11634300-000000000-00000
                3585838
                22715866
                36862386-7d58-4153-a71c-315d2b2e9e6f
                © Krenzelok & Royal, publisher and licensee Springer International Publishing AG 2012
                History
                Categories
                Original Research Article
                Custom metadata
                © Krenzelok & Royal, publisher and licensee Springer International Publishing AG 2012

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