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Moxifloxacin safety: an analysis of 14 years of clinical data.

Tulkens PM, Arvis P, Kruesmann F - Drugs R D (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Pharmacologie cellulaire et molculaire Centre de Pharmacie clinique, Louvain Drug Research Institute, Universit catholique de Louvain, Brussels, Belgium. tulkens@facm.ucl.ac.be

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/m2). 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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Related in: MedlinePlus

Summary of safety data for patients valid for the safety analysis, treated with moxifloxacin or a comparator and stratified by route of administration (oral only; intravenous followed by oral [sequential]; intravenous only) and by study design. An asterisk (*) indicates differences observed between treatment groups in disfavor of moxifloxacin that were ≥2.5% for events with an incidence ≥2.5% in both groups or ≥2-fold for events with an incidence <2.5% in one or both groups and for which the number of patients experiencing an event was ≥10 in either group
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Tab3: Summary of safety data for patients valid for the safety analysis, treated with moxifloxacin or a comparator and stratified by route of administration (oral only; intravenous followed by oral [sequential]; intravenous only) and by study design. An asterisk (*) indicates differences observed between treatment groups in disfavor of moxifloxacin that were ≥2.5% for events with an incidence ≥2.5% in both groups or ≥2-fold for events with an incidence <2.5% in one or both groups and for which the number of patients experiencing an event was ≥10 in either group

Mentions: Table III shows the summary of the safety data for all patients, subdivided between double-blind studies and open-label studies, respectively. As for any drug, a gradual decrease in the incidence of events was seen when looking from all AEs down to ADRs and further to SADRs. To help identify the highest incidence rates and imbalances between the treatment groups affecting a specific event, the data were filtered, and situations are highlighted where (i) there was a 2-fold difference between treatment arms for events with an incidence <2.5% in either of the treatment groups or a ≥2.5% difference between treatments for events with an incidence ≥2.5% in both groups and (ii) the number of patients experiencing an event was ≥10 in either treatment group. With these filters, the differences between moxifloxacin and comparators were related to (i) AEs and SAEs in the intravenous double-blind studies; and (ii) AEs, ADRs, and SADRs in the oral studies, SADRs in the intravenous/oral studies, and premature discontinuation due to AE in the intravenous open-label studies. Concerning SADRs reported in open-label oral and intravenous/oral studies, the numbers of patients with such events were small in each treatment group (moxifloxacin 12 [0.7%] versus comparator 5 [0.2%] in the oral studies; moxifloxacin 42 [2.7%] versus comparator 19 [1.2%] in the intravenous/oral studies). In the intravenous/oral studies, the difference in incidence rates (1.5%) was driven by gastrointestinal disorders (mostly diarrhea: 8 cases [0.5%] for moxifloxacin versus 1 case [<0.1%] for comparator) and results of investigations (10 cases [0.6%] for moxifloxacin versus 1 case [<0.1%] for comparator), including asymptomatic prolongation of the QT interval.


Moxifloxacin safety: an analysis of 14 years of clinical data.

Tulkens PM, Arvis P, Kruesmann F - Drugs R D (2012)

Summary of safety data for patients valid for the safety analysis, treated with moxifloxacin or a comparator and stratified by route of administration (oral only; intravenous followed by oral [sequential]; intravenous only) and by study design. An asterisk (*) indicates differences observed between treatment groups in disfavor of moxifloxacin that were ≥2.5% for events with an incidence ≥2.5% in both groups or ≥2-fold for events with an incidence <2.5% in one or both groups and for which the number of patients experiencing an event was ≥10 in either group
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585838&req=5

Tab3: Summary of safety data for patients valid for the safety analysis, treated with moxifloxacin or a comparator and stratified by route of administration (oral only; intravenous followed by oral [sequential]; intravenous only) and by study design. An asterisk (*) indicates differences observed between treatment groups in disfavor of moxifloxacin that were ≥2.5% for events with an incidence ≥2.5% in both groups or ≥2-fold for events with an incidence <2.5% in one or both groups and for which the number of patients experiencing an event was ≥10 in either group
Mentions: Table III shows the summary of the safety data for all patients, subdivided between double-blind studies and open-label studies, respectively. As for any drug, a gradual decrease in the incidence of events was seen when looking from all AEs down to ADRs and further to SADRs. To help identify the highest incidence rates and imbalances between the treatment groups affecting a specific event, the data were filtered, and situations are highlighted where (i) there was a 2-fold difference between treatment arms for events with an incidence <2.5% in either of the treatment groups or a ≥2.5% difference between treatments for events with an incidence ≥2.5% in both groups and (ii) the number of patients experiencing an event was ≥10 in either treatment group. With these filters, the differences between moxifloxacin and comparators were related to (i) AEs and SAEs in the intravenous double-blind studies; and (ii) AEs, ADRs, and SADRs in the oral studies, SADRs in the intravenous/oral studies, and premature discontinuation due to AE in the intravenous open-label studies. Concerning SADRs reported in open-label oral and intravenous/oral studies, the numbers of patients with such events were small in each treatment group (moxifloxacin 12 [0.7%] versus comparator 5 [0.2%] in the oral studies; moxifloxacin 42 [2.7%] versus comparator 19 [1.2%] in the intravenous/oral studies). In the intravenous/oral studies, the difference in incidence rates (1.5%) was driven by gastrointestinal disorders (mostly diarrhea: 8 cases [0.5%] for moxifloxacin versus 1 case [<0.1%] for comparator) and results of investigations (10 cases [0.6%] for moxifloxacin versus 1 case [<0.1%] for comparator), including asymptomatic prolongation of the QT interval.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Pharmacologie cellulaire et molculaire Centre de Pharmacie clinique, Louvain Drug Research Institute, Universit catholique de Louvain, Brussels, Belgium. tulkens@facm.ucl.ac.be

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/m2). 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.

Show MeSH
Related in: MedlinePlus