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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

Serious adverse events presented by system organ class in 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). A single asterisk (*) indicates differences observed between groups 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 (calculations were made using the number of patients [no rounding]; in the event of a  value for one treatment, only situations where ≥2 cases were observed in the other treatment group are indicated); the symbol is placed to the right of the value observed for the drug in disfavor. A double asterisk (**) indicates differences observed between treatment groups according to the same rule and where the number of patients experiencing an event was ≥10 in either group; the symbols are placed to the right of the value observed for the drug in disfavor
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Tab5: Serious adverse events presented by system organ class in 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). A single asterisk (*) indicates differences observed between groups 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 (calculations were made using the number of patients [no rounding]; in the event of a value for one treatment, only situations where ≥2 cases were observed in the other treatment group are indicated); the symbol is placed to the right of the value observed for the drug in disfavor. A double asterisk (**) indicates differences observed between treatment groups according to the same rule and where the number of patients experiencing an event was ≥10 in either group; the symbols are placed to the right of the value observed for the drug in disfavor

Mentions: Treatment-emergent SAEs are presented by SOCs for combined double-blind and open-label studies in table V. In the oral population, the overall incidence of SAEs (4.0% versus 3.9% in moxifloxacin- and comparator-treated patients) and those within the SOCs were very similar in the treatment groups. More SAEs were reported in the intravenous/oral studies in both treatment groups (moxifloxacin 595 [17.3%] versus comparator 527 [15.4%]), as expected given the increased severity of the disease. The SOCs associated with the highest incidences of events in both treatment groups, were ‘infections and infestations’ (moxifloxacin 219 [6.4%] versus comparator 165 [4.8%]) and ‘respiratory, thoracic, and mediastinal disorders’ (moxifloxacin 129 [3.8%] versus comparator 143 [4.2%]). Serious ‘cardiac disorders’ in the population treated by the intravenous/oral routes were reported with a similar incidence in the two groups (moxifloxacin 84 [2.4%] versus comparator 89 [2.6%]). In the intravenous-only trials, the overall rates were 7.9% and 6.0% in moxifloxacin- and comparator-treated patients, respectively, with SAEs from the SOC ‘infections and infestations’ being predominant (moxifloxacin 38 [4.1%] versus comparator 23 [2.5%]).


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

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

Serious adverse events presented by system organ class in 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). A single asterisk (*) indicates differences observed between groups 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 (calculations were made using the number of patients [no rounding]; in the event of a  value for one treatment, only situations where ≥2 cases were observed in the other treatment group are indicated); the symbol is placed to the right of the value observed for the drug in disfavor. A double asterisk (**) indicates differences observed between treatment groups according to the same rule and where the number of patients experiencing an event was ≥10 in either group; the symbols are placed to the right of the value observed for the drug in disfavor
© Copyright Policy
Related In: Results  -  Collection

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

Tab5: Serious adverse events presented by system organ class in 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). A single asterisk (*) indicates differences observed between groups 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 (calculations were made using the number of patients [no rounding]; in the event of a value for one treatment, only situations where ≥2 cases were observed in the other treatment group are indicated); the symbol is placed to the right of the value observed for the drug in disfavor. A double asterisk (**) indicates differences observed between treatment groups according to the same rule and where the number of patients experiencing an event was ≥10 in either group; the symbols are placed to the right of the value observed for the drug in disfavor
Mentions: Treatment-emergent SAEs are presented by SOCs for combined double-blind and open-label studies in table V. In the oral population, the overall incidence of SAEs (4.0% versus 3.9% in moxifloxacin- and comparator-treated patients) and those within the SOCs were very similar in the treatment groups. More SAEs were reported in the intravenous/oral studies in both treatment groups (moxifloxacin 595 [17.3%] versus comparator 527 [15.4%]), as expected given the increased severity of the disease. The SOCs associated with the highest incidences of events in both treatment groups, were ‘infections and infestations’ (moxifloxacin 219 [6.4%] versus comparator 165 [4.8%]) and ‘respiratory, thoracic, and mediastinal disorders’ (moxifloxacin 129 [3.8%] versus comparator 143 [4.2%]). Serious ‘cardiac disorders’ in the population treated by the intravenous/oral routes were reported with a similar incidence in the two groups (moxifloxacin 84 [2.4%] versus comparator 89 [2.6%]). In the intravenous-only trials, the overall rates were 7.9% and 6.0% in moxifloxacin- and comparator-treated patients, respectively, with SAEs from the SOC ‘infections and infestations’ being predominant (moxifloxacin 38 [4.1%] versus comparator 23 [2.5%]).

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