Safety profile of oral and intravenous moxifloxacin: cumulative data from clinical trials and postmarketing studies.

BACKGROUND: The established safety profile of the fluoroquinolones has been disrupted in the past decade by the detection of low-frequency but potentially serious adverse events that have led to the license suspension, voluntary withdrawal, or restricted use of specific members of the class. Moxifloxacin is a broad-spectrum, advanced-generation fluoroquinolone that has potent activity against respiratory tract infections in adults in both oral and IV formulations. OBJECTIVE: The goal of this article was to provide an overview of the cumulative safety data on both oral and IV moxifloxacin, including data from the most recent clinical trials and postmarketing studies. METHODS: Data from clinical trials of moxifloxacin were captured from an electronic database maintained by the manufacturer. Safety data for oral moxifloxacin were obtained from 30 Phase II/III comparator studies (n = 7,368 moxifloxacin, n = 5,687 comparators), 1 Phase IV study (n = 18,374), and 4 postmarketing observational studies (n = 27,756). Safety data for IV moxifloxacin were obtained from 2 Phase III comparator studies (n = 550 maxifloxacin, n = 579 comparators). In addition, pharmacokinetic data were reviewed. RESULTS: In Phase II/III comparator studies, gastrointestinal complaints were the most common adverse drug reactions (ADRs) associated with both formulations of moxifloxacin, with nausea occurring in 7.1% and 3.1% of patients receiving oral and IV moxifloxacin, respectively, and diarrhea occurring in 5.2% and 6.2% of patients. Discontinuation rates due to ADRs with oral and IV moxifloxacin were 2.7% and 6.0%, and mortality rates were 0.3% and 4.0%. Similar rates of withdrawal and mortality were observed in the comparator groups. There was no evidence that moxifloxacin caused disturbances in glucose metabolism in patients with or without diabetes mellitus, and there was no evidence of an increased risk for cardiovascular adverse events. Pharmacokinetic analyses indicated that dose adjustment of moxifloxacin does not appear to be necessary in elderly patients, those with renal dysfunction, or those with mild to moderate hepatic impairment. The pharmacokinetics of moxifloxacin have not been studied in patients with severe hepatic insufficiency. Moxifloxacin does not interact with a number of commonly prescribed drugs, although its absorption is decreased by concomitant administration of iron and cationic antacids. CONCLUSIONS: Based on evidence from >7000 patients in clinical trials and >46,000 patients in postmarketing studies, moxifloxacin is generally well tolerated. Its lack of significant drug interactions in target groups makes it an option in diabetic patients or the elderly, as well as in those with renal impairment.

Moxifloxacin and glucose homeostasis: a pooled-analysis of the evidence from clinical and postmarketing studies.

BACKGROUND: Recently, clinical data has emerged suggesting that the fluoroquinolone, gatifloxacin, can affect glucose homeostosis through an unknown mechanism. In order to explore the potential effects of moxifloxacin on glucose metabolism in humans, a pooled analysis of phase II/III clinical trials and postmarketing studies was performed and compared with results from an investigation in laboratory animals. METHODS: A pooled analysis of 30 (26 controlled, 4 uncontrolled) oral and two intravenous/oral prospective, controlled phase II/III moxifloxacin studies was performed to evaluate the frequency of hyper- and hypoglycaemic episodes and glucose-related adverse events and adverse reactions (i.e. those considered to be drug related) versus comparator antimicrobials (penicillins, cephalosporins, macrolides, doxycycline, fluoroquinolones). Similar evaluations were conducted on data pooled from five postmarketing surveillance studies. In addition, potential effects of supratherapeutic doses of moxifloxacin on blood glucose and plasma insulin levels in fed and fasted rats were assessed in comparison with those of gatifloxacin, levofloxacin and glibenclamide (glyburide). RESULTS: The phase II/III database was comprised of 14,731 patients (8474 moxifloxacin, 6257 comparator antimicrobial). There were no drug-related hypoglycaemic adverse events reported for moxifloxacin in either the oral or intravenous/oral database. Two drug-related hypoglycaemic adverse events were reported in the oral comparator group, both following administration of levofloxacin and both of mild severity; one drug-related hypoglycaemic adverse event was reported in the intravenous/oral comparator group after trovafloxacin administration. Drug-related hyperglycaemic adverse events were reported in seven (<0.1%) moxifloxacin and 1 (<0.1%) comparator-treated patients in the oral study database, none of these cases were considered serious and six of the seven moxifloxacin cases were graded as mild and required no countermeasures. There were no cases of drug-related hyperglycaemic events in any patient enrolled in the intravenous/oral studies. Coadministration of oral antidiabetic drugs with moxifloxacin or comparator antimicrobials did not change the rate of blood glucose increases or decreases in diabetic patients. Data from five moxifloxacin postmarketing studies (46 130 subjects) reported no episodes of hypoglycaemia and two non-drug-related hyperglycaemic episodes. Data from animal studies revealed that supratherapeutic doses of moxifloxacin and levofloxacin did not affect blood glucose or plasma insulin levels in both fed and fasted rats, whereas gatifloxacin decreased both blood glucose and plasma insulin in a dose-dependent manner in fed rats only. The reference compound glibenclamide increased insulin and decreased glucose levels as expected. CONCLUSIONS: Hyperglycaemic or hypoglycaemic adverse reactions were reported rarely in studies with oral or sequential intravenous/oral moxifloxacin, and incidence was comparable in moxifloxacin and comparator groups. Changes in glucose metabolism were also similar in diabetic patients treated with moxifloxacin compared with those patients without diabetes mellitus. This comprehensive analysis of the datapool for moxifloxacin phase II/III clinical trials and postmarketing studies suggests that moxifloxacin administration has no clinically relevant effect on blood glucose homeostasis.

An economic evaluation of sequential i.v./po moxifloxacin therapy compared to i.v./po co-amoxiclav with or without clarithromycin in the treatment of community-acquired pneumonia.

STUDY OBJECTIVE: To evaluate costs, clinical consequences, and cost-effectiveness from a German and French health-care system perspective of sequential i.v./po moxifloxacin monotherapy compared to co-amoxiclav with or without clarithromycin (AMC +/- CLA) in patients with community-acquired pneumonia (CAP) who required parenteral treatment. METHODS: Costs and consequences over 21 days were evaluated based on clinical cure rates 5 to 7 days after treatment and health resource use reported for the TARGET multinational, prospective, randomized, open-label trial. This trial compared sequential i.v./po monotherapy with moxifloxacin (400 mg qd) to i.v./po co-amoxiclav (1.2 g i.v./625 mg po tid) with or without clarithromycin (500 mg bid) for 7 to 14 days in hospitalized patients with CAP. Since no country-by-treatment interaction was found in spite of some country differences for length of hospital stays, resource data (antimicrobial treatment, hospitalization, and out-of-hospital care) from all centers were pooled and valued using German and French unit prices to estimate CAP-related cost to the German Sickness Funds and French public health-care sector, respectively. RESULTS: Compared to AMC +/- CLA, treatment with moxifloxacin resulted in 5.3% more patients achieving clinical cure 5 to 7 days after therapy (95% confidence interval [CI], 1.2 to 11.8%), increased speed of response (1 day sooner for median time to first return to apyrexia, p = 0.008), and a reduction in hospital stay by 0.81 days (95% CI, - 0.01 to 1.63) within the 21-day time frame. Treatment with moxifloxacin resulted in savings of 266 euro and 381 euro for Germany and France respectively, primarily due to the shorter length of hospital stay. Cost-effectiveness acceptability curves show moxifloxacin has a > or = 95% chance of being cost saving from French and German health-care perspectives, and higher probability of being cost-effective at acceptability thresholds up to 2,000 euro per additional patient cured. CONCLUSION: i.v./po monotherapy with moxifloxacin shows clinical benefits including increased speed of response and is cost-effective compared to i.v./po AMC +/- CLA in the treatment of CAP.