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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

Adverse drug reactions occurring in either treatment group in ≧0.5% of 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 (double blind, open label). Numbers in bold italic text correspond to events with an incidence ≥5% in either treatment group. 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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Tab4: Adverse drug reactions occurring in either treatment group in ≧0.5% of 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 (double blind, open label). Numbers in bold italic text correspond to events with an incidence ≥5% in either treatment group. 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: ADRs occurring in at least 0.5% of patients in either treatment group are shown in table IV. In the oral population enrolled in double-blind studies, the most common ADRs were nausea (moxifloxacin 602 [6.8%] versus comparator 457 [5.3%]), diarrhea (moxifloxacin 432 [4.9%] versus comparator 334 [3.9%]), dizziness (moxifloxacin 247 [2.8%] versus comparator 198 [2.3%]), headache (moxifloxacin 165 [1.9%] versus comparator 177 [2.0%]), and vomiting (moxifloxacin 162 [1.8%] versus comparator 150 [1.7%]). Only dysgeusia (moxifloxacin 66 [0.7%] versus comparator 171 [2.0%]) and increased GGT (moxifloxacin 11 [0.1%] versus comparator 30 [0.3%]) met the criteria set by the double filter used in table III. In the double-blind intravenous/oral population, diarrhea was the most common ADR (moxifloxacin 96 [5.1%] versus comparator 95 [5.1%]). Differences affected fewer than 10 patients in each treatment group, except for vomiting (moxifloxacin 13 [0.7%] versus comparator 26 [1.4%]). In the double-blind intravenous population, increased lipase (moxifloxacin 14 [2.4%] versus comparator 18 [3.2%]) and increased GGT (moxifloxacin 13 [2.2%] versus comparator 18 [3.2%]) were the most common ADRs, and only nausea showed a difference in disfavor of moxifloxacin versus comparator (12 [2.0%] versus 3 [0.5%], respectively) according to the double filter. In the open-label oral studies, nausea (moxifloxacin 77 [4.3%] versus comparator 44 [2.2%]) and diarrhea (moxifloxacin 54 [3.0%] versus comparator 141 [6.9%]) were again the most common ADRs across therapy arms, followed by dizziness (moxifloxacin 30 [1.7%] versus comparator 4 [0.2%]), upper abdominal pain (moxifloxacin 23 [1.3%] versus comparator 20 [1.0%]), and vomiting (moxifloxacin 20 [1.1%] versus comparator 14 [0.7%]), all experienced by >1% of patients in the moxifloxacin arm. Application of the double filter to the open-label oral population showed that diarrhea was more frequent with comparators (moxifloxacin 54 [3.0%] versus comparator 141 [6.9%]), whereas dizziness (moxifloxacin 30 [1.7%] versus comparator 4 [0.2%]), rash (moxifloxacin 16 [0.9%] versus comparator 8 [0.4%]), dysgeusia (moxifloxacin 13 [0.7%] versus comparator 2 [<0.1%]), and somnolence (moxifloxacin 10 [0.6%] versus comparator 2 [<0.1%]) were more frequent with moxifloxacin. In the open-label intravenous/oral population, diarrhea was the most common ADR for both moxifloxacin and comparator (61 [4.0%] and 60 [3.8%], respectively). Differences in disfavor of moxifloxacin versus comparator that met the double filter criteria concerned QT prolongation (moxifloxacin 19 [1.2%] versus comparator 3 [0.2%]) and dizziness (moxifloxacin 10 [0.6%] versus comparator 2 [0.1%]). For patients treated with intravenous therapy in the open-label population, all ADRs occurred in <10 patients in both treatment groups at low incidence rates, i.e. nausea (moxifloxacin 5 [1.4%] versus comparator 2 [0.6%]), dizziness (moxifloxacin 6 [1.7%] versus comparator 6 [1.7%]), increased ALT (moxifloxacin 9 [2.6%] versus comparator 8 [2.3%]), and rash (moxifloxacin 8 [2.3%] versus comparator 3 [0.9%]).


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

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

Adverse drug reactions occurring in either treatment group in ≧0.5% of 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 (double blind, open label). Numbers in bold italic text correspond to events with an incidence ≥5% in either treatment group. 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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Related In: Results  -  Collection

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

Tab4: Adverse drug reactions occurring in either treatment group in ≧0.5% of 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 (double blind, open label). Numbers in bold italic text correspond to events with an incidence ≥5% in either treatment group. 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: ADRs occurring in at least 0.5% of patients in either treatment group are shown in table IV. In the oral population enrolled in double-blind studies, the most common ADRs were nausea (moxifloxacin 602 [6.8%] versus comparator 457 [5.3%]), diarrhea (moxifloxacin 432 [4.9%] versus comparator 334 [3.9%]), dizziness (moxifloxacin 247 [2.8%] versus comparator 198 [2.3%]), headache (moxifloxacin 165 [1.9%] versus comparator 177 [2.0%]), and vomiting (moxifloxacin 162 [1.8%] versus comparator 150 [1.7%]). Only dysgeusia (moxifloxacin 66 [0.7%] versus comparator 171 [2.0%]) and increased GGT (moxifloxacin 11 [0.1%] versus comparator 30 [0.3%]) met the criteria set by the double filter used in table III. In the double-blind intravenous/oral population, diarrhea was the most common ADR (moxifloxacin 96 [5.1%] versus comparator 95 [5.1%]). Differences affected fewer than 10 patients in each treatment group, except for vomiting (moxifloxacin 13 [0.7%] versus comparator 26 [1.4%]). In the double-blind intravenous population, increased lipase (moxifloxacin 14 [2.4%] versus comparator 18 [3.2%]) and increased GGT (moxifloxacin 13 [2.2%] versus comparator 18 [3.2%]) were the most common ADRs, and only nausea showed a difference in disfavor of moxifloxacin versus comparator (12 [2.0%] versus 3 [0.5%], respectively) according to the double filter. In the open-label oral studies, nausea (moxifloxacin 77 [4.3%] versus comparator 44 [2.2%]) and diarrhea (moxifloxacin 54 [3.0%] versus comparator 141 [6.9%]) were again the most common ADRs across therapy arms, followed by dizziness (moxifloxacin 30 [1.7%] versus comparator 4 [0.2%]), upper abdominal pain (moxifloxacin 23 [1.3%] versus comparator 20 [1.0%]), and vomiting (moxifloxacin 20 [1.1%] versus comparator 14 [0.7%]), all experienced by >1% of patients in the moxifloxacin arm. Application of the double filter to the open-label oral population showed that diarrhea was more frequent with comparators (moxifloxacin 54 [3.0%] versus comparator 141 [6.9%]), whereas dizziness (moxifloxacin 30 [1.7%] versus comparator 4 [0.2%]), rash (moxifloxacin 16 [0.9%] versus comparator 8 [0.4%]), dysgeusia (moxifloxacin 13 [0.7%] versus comparator 2 [<0.1%]), and somnolence (moxifloxacin 10 [0.6%] versus comparator 2 [<0.1%]) were more frequent with moxifloxacin. In the open-label intravenous/oral population, diarrhea was the most common ADR for both moxifloxacin and comparator (61 [4.0%] and 60 [3.8%], respectively). Differences in disfavor of moxifloxacin versus comparator that met the double filter criteria concerned QT prolongation (moxifloxacin 19 [1.2%] versus comparator 3 [0.2%]) and dizziness (moxifloxacin 10 [0.6%] versus comparator 2 [0.1%]). For patients treated with intravenous therapy in the open-label population, all ADRs occurred in <10 patients in both treatment groups at low incidence rates, i.e. nausea (moxifloxacin 5 [1.4%] versus comparator 2 [0.6%]), dizziness (moxifloxacin 6 [1.7%] versus comparator 6 [1.7%]), increased ALT (moxifloxacin 9 [2.6%] versus comparator 8 [2.3%]), and rash (moxifloxacin 8 [2.3%] versus comparator 3 [0.9%]).

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