Moxifloxacin Injection - Scientific Information
|Manufacture:||Fresenius Kabi USA, LLC|
|Condition:||Bacterial Infection, Bronchitis, Cutaneous Bacillus anthracis, Intraabdominal Infection, Plague, Plague Prophylaxis, Pneumonia, Sinusitis, Skin and Structure Infection, Skin or Soft Tissue Infection, Tuberculosis, Active|
|Ingredients:||Moxifloxacin, sodium acetate-trihydrate, disodium sulfate, sulfuric acid, water for injection|
Moxifloxacin is a synthetic broad spectrum antibacterial agent for intravenous administration. Moxifloxacin, a fluoroquinolone, is available as a buffered salt of 1-cyclopropyl-7-[(S,S)-2,8- diazabicyclo[4.3.0]non-8-yl]-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3 quinoline carboxylic acid. It is a slightly yellow to yellow crystalline substance. Its chemical structure is as follows:
Moxifloxacin injection is sterile solution for infusion in a ready-to-use flexible plastic container.
|Moxifloxacin*||Active ingredient||400 mg*|
|Sodium acetate (added as a trihydrate)||Tonicity adjuster||1,702.5 mg|
|Disodium sulfate||Tonicity adjuster||2,840 mg|
|Sulfuric acid **||pH adjustment||As needed|
|Water for injection||vehicle||q.s. 250 mL|
* 400 mg moxifloxacin equivalent to 5 mg of moxifloxacin hydrochloride.
**The pH may have been adjusted with sulfuric acid. The pH is 5.0 to 6.0.
Each mL contains 1.6 mg of moxifloxacin.
The appearance of the intravenous solution is clear. The plastic container is fabricated from a specially designed multilayer plastic (freeflex). Solution is in contact with the polypropylene layer of this container and can leach out certain chemical components of the plastic in very small amounts within the expiration period. The leachable compounds were all within acceptable limits based on animal toxicology studies.
Moxifloxacin injection contains approximately 52.5 mEq (1,207 mg) of sodium in 250 mL.
Mechanism of Action
Moxifloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology].
The mean (±SD) pharmacokinetic parameters of moxifloxacin following single and multiple dose of 400 mg moxifloxacin given by 1 hour intravenous infusion are summarized in Table 1. The mean (± SD) elimination half-life from plasma is 12 ± 1.3 hours; steady-state is achieved after at least three days with a 400 mg once daily regimen. The absolute bioavailability of moxifloxacin is approximately 90 percent. When switching from intravenous to oral formulation, no dosage adjustment is necessary [see Dosage and Administration].
|Single Dose IV|
|Healthy young male/female (n = 56)||3.9 ± 0.9||39.3 ± 8.6||8.2 to 15.4a|
|Patients (n = 118)|
| Male (n = 64)|
Female (n = 54)
< 65 years (n = 58)
≥ 65 years (n = 60)
|4.4 ± 3.7|
4.5 ± 2
4.6 ± 4.2
4.3 ± 1.3
|Multiple Dose IV|
| Healthy young male (n = 8)|
Healthy elderly (n =12; 8 male, 4 female)
|4.2 ± 0.8|
6.1 ± 1.3
|38 ± 4.7|
48.2 ± 0.9
|14.8 ± 2.2|
10.1 ± 1.6
|Patientsb (n = 107)|
| Male (n = 58)|
Female (n = 49)
< 65 years (n = 52)
≥ 65 years (n = 55)
|4.2 ± 2.6|
4.6 ± 1.5
4.1 ± 1.4
4.7 ± 2.7
a Range of means from different studies
b Expected Cmax (concentration obtained around the time of the end of the infusion)
Moxifloxacin is approximately 30 to 50% bound to serum proteins, independent of drug concentration. The volume of distribution of moxifloxacin ranges from 1.7 to 2.7 L/kg. Moxifloxacin is widely distributed throughout the body, with tissue concentrations often exceeding plasma concentrations.
Moxifloxacin has been detected in the saliva, nasal and bronchial secretions, mucosa of the sinuses, skin blister fluid, subcutaneous tissue, skeletal muscle, and abdominal tissues and fluids following oral or intravenous administration of 400 mg. Moxifloxacin concentrations measured post-dose in various tissues and fluids following a 400 mg oral or intravenous dose are summarized in Table 2. The rates of elimination of moxifloxacin from tissues generally parallel the elimination from plasma.
|Tissue or Fluid||N||Plasma Concentration|
|Tissue or Fluid Concentration|
(mcg/mL or mcg/g)
|3.3 ± 0.7|
3.3 ± 0.7
3.3 ± 0.7
|61.8 ± 27.3|
5.5 ± 1.3
24.4 ± 14.7
|21.2 ± 10|
1.7 ± 0.3
8.7 ± 6.1
| Maxillary Sinus Mucosa|
Anterior Ethmoid Mucosa
|3.7 ± 1.1b|
3.7 ± 1.1b
3.7 ± 1.1b
|7.6 ± 1.7|
8.8 ± 4.3
9.8 ± 4.5
|2 ± 0.3|
2.2 ± 0.6
2.6 ± 0.6
| Blister Fluid|
|3 ± 0.5c|
2.3 ± 0.4d
2.3 ± 0.4d
|2.6 ± 0.9|
0.9 ± 0.3e
0.9 ± 0.2e
|0.9 ± 0.2|
0.4 ± 0.6
0.4 ± 0.1
| Abdominal tissue|
|2.9 ± 0.5|
2.3 ± 0.5
2.7 ± 0.7
|7.6 ± 2|
|2.7 ± 0.8|
1.6 ± 0.7
0.8 ± 0.4
a All moxifloxacin concentrations were measured 3 hours after a single 400 mg dose, except the abdominal tissue and exudate concentrations which were measured at 2 hours post-dose and the sinus concentrations which were measured 3 hours post-dose after 5 days of dosing.
b N = 5 c N = 7 d N = 12
e Reflects only non-protein bound concentrations of drug.
Approximately 52% of an oral or intravenous dose of moxifloxacin is metabolized via glucuronide and sulfate conjugation. The cytochrome P450 system is not involved in moxifloxacin metabolism, and is not affected by moxifloxacin. The sulfate conjugate (M1) accounts for approximately 38% of the dose, and is eliminated primarily in the feces. Approximately 14% of an oral or intravenous dose is converted to a glucuronide conjugate (M2), which is excreted exclusively in the urine. Peak plasma concentrations of M2 are approximately 40% those of the parent drug, while plasma concentrations of M1 are generally less than 10% those of moxifloxacin.
In vitro studies with cytochrome (CYP) P450 enzymes indicate that moxifloxacin does not inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2, suggesting that moxifloxacin is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.
Approximately 45% of an oral or intravenous dose of moxifloxacin is excreted as unchanged drug (~20% in urine and ~25% in feces). A total of 96% ± 4% of an oral dose is excreted as either unchanged drug or known metabolites. The mean (± SD) apparent total body clearance and renal clearance are 12 ± 2 L/hr and 2.6 ± 0.5 L/hr, respectively.
Pharmacokinetics in Specific Populations
Following oral administration of 400 mg moxifloxacin for 10 days in 16 elderly (8 male; 8 female) and 17 young (8 male; 9 female) healthy volunteers, there were no age-related changes in moxifloxacin pharmacokinetics. In 16 healthy male volunteers (8 young; 8 elderly) given a single 200 mg dose of oral moxifloxacin, the extent of systemic exposure (AUC and Cmax) was not statistically different between young and elderly males and elimination half-life was unchanged. No dosage adjustment is necessary based on age. In large phase III studies, the concentrations around the time of the end of the infusion in elderly patients following intravenous infusion of 400 mg were similar to those observed in young patients [see Use in Specific Populations].
The pharmacokinetics of moxifloxacin in pediatric subjects has not been studied [see Use in Specific Populations].
Following oral administration of 400 mg moxifloxacin daily for 10 days to 23 healthy males (19 to 75 years) and 24 healthy females (19 to 70 years), the mean AUC and Cmax were 8% and 16% higher, respectively, in females compared to males. There are no significant differences in moxifloxacin pharmacokinetics between male and female subjects when differences in body weight are taken into consideration.
A 400 mg single dose study was conducted in 18 young males and females. The comparison of moxifloxacin pharmacokinetics in this study (9 young females and 9 young males) showed no differences in AUC or Cmax due to gender. Dosage adjustments based on gender are not necessary.
Steady-state moxifloxacin pharmacokinetics in male Japanese subjects were similar to those determined in Caucasians, with a mean Cmax of 4.1 mcg/mL, an AUC24 of 47 mcg/mL, and an elimination half-life of 14 hours, following 400 mg p.o. daily.
The pharmacokinetic parameters of moxifloxacin are not significantly altered in mild, moderate, severe, or end-stage renal disease. No dosage adjustment is necessary in patients with renal impairment, including those patients requiring hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD).
In a single oral dose study of 24 patients with varying degrees of renal function from normal to severely impaired, the mean peak concentrations (Cmax) of moxifloxacin were reduced by 21% and 28% in the patients with moderate (CLCR ≥ 30 and ≤ 60 mL/min) and severe (CLCR < 30 mL/min) renal impairment, respectively. The mean systemic exposure (AUC) in these patients was increased by 13%. In the moderate and severe renally impaired patients, the mean AUC for the sulfate conjugate (M1) increased by 1.7-fold (ranging up to 2.8-fold) and mean AUC and Cmax for the glucuronide conjugate (M2) increased by 2.8-fold (ranging up to 4.8-fold) and 1.4-fold (ranging up to 2.5-fold), respectively [see Use in Specific Populations].
The pharmacokinetics of single dose and multiple dose moxifloxacin were studied in patients with CLCR < 20 mL/min on either hemodialysis or continuous ambulatory peritoneal dialysis (8 HD, 8 CAPD). Following a single 400 mg oral dose, the AUC of moxifloxacin in these HD and CAPD patients did not vary significantly from the AUC generally found in healthy volunteers. Cmax values of moxifloxacin were reduced by about 45% and 33% in HD and CAPD patients, respectively, compared to healthy, historical controls. The exposure (AUC) to the sulfate conjugate (M1) increased by 1.4- to 1.5-fold in these patients. The mean AUC of the glucuronide conjugate (M2) increased by a factor of 7.5, whereas the mean Cmax values of the glucuronide conjugate (M2) increased by a factor of 2.5 to 3, compared to healthy subjects. The sulfate and the glucuronide conjugates of moxifloxacin are not microbiologically active, and the clinical implication of increased exposure to these metabolites in patients with renal disease including those undergoing HD and CAPD has not been studied.
Oral administration of 400 mg QD moxifloxacin for 7 days to patients on HD or CAPD produced mean systemic exposure (AUCss) to moxifloxacin similar to that generally seen in healthy volunteers.
Steady-state Cmax values were about 22% lower in HD patients but were comparable between CAPD patients and healthy volunteers. Both HD and CAPD removed only small amounts of moxifloxacin from the body (approximately 9% by HD, and 3% by CAPD). HD and CAPD also removed about 4% and 2% of the glucuronide metabolite (M2), respectively.
No dosage adjustment is recommended for mild, moderate, or severe hepatic insufficiency (Child-Pugh Classes A, B, or C). However, due to metabolic disturbances associated with hepatic insufficiency, which may lead to QT prolongation, moxifloxacin should be used with caution in these patients [see Warnings and Precautions and Use in Specific Populations].
In 400 mg single oral dose studies in 6 patients with mild (Child-Pugh Class A) and 10 patients with moderate (Child-Pugh Class B) hepatic insufficiency, moxifloxacin mean systemic exposure (AUC) was 78% and 102%, respectively, of 18 healthy controls and mean peak concentration (Cmax) was 79% and 84% of controls.
The mean AUC of the sulfate conjugate of moxifloxacin (M1) increased by 3.9-fold (ranging up to 5.9- fold) and 5.7-fold (ranging up to 8-fold) in the mild and moderate groups, respectively. The mean Cmax of M1 increased by approximately 3-fold in both groups (ranging up to 4.7- and 3.9-fold). The mean AUC of the glucuronide conjugate of moxifloxacin (M2) increased by 1.5-fold (ranging up to 2.5-fold) in both groups. The mean Cmax of M2 increased by 1.6- and 1.3-fold (ranging up to 2.7- and 2.1-fold), respectively. The clinical significance of increased exposure to the sulfate and glucuronide conjugates has not been studied. In a subset of patients participating in a clinical trial, the plasma concentrations of moxifloxacin and metabolites determined approximately at the moxifloxacin Tmax following the first intravenous or oral moxifloxacin dose in the Child-Pugh Class C patients (n = 10) were similar to those in the Child-Pugh Class A/B patients (n = 5), and also similar to those observed in healthy volunteer studies.
A study of the skin response to ultraviolet (UVA and UVB) and visible radiation conducted in 32 healthy volunteers (8 per group) demonstrated that moxifloxacin does not show phototoxicity in comparison to placebo. The minimum erythematous dose (MED) was measured before and after treatment with moxifloxacin (200 mg or 400 mg once daily), lomefloxacin (400 mg once daily), or placebo. In this study, the MED measured for both doses of moxifloxacin were not significantly different from placebo, while lomefloxacin significantly lowered the MED.
It is difficult to ascribe relative photosensitivity/phototoxicity among various fluoroquinolones during actual patient use because other factors play a role in determining a subject’s susceptibility to this adverse event such as: a patient’s skin pigmentation, frequency and duration of sun and artificial ultraviolet light (UV) exposure, wearing of sunscreen and protective clothing, the use of other concomitant drugs and the dosage and duration of fluoroquinolone therapy [see Warnings and Precautions, Adverse Reactions, and Patient Counseling Information].
The following drug interactions were studied in healthy volunteers or patients.
Digoxin, itraconazole, morphine, probenecid, ranitidine, theophylline and warfarin did not significantly affect the pharmacokinetics of moxifloxacin. These results and the data from in vitro studies suggest that moxifloxacin is unlikely to significantly alter the metabolic clearance of drugs metabolized by CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2 enzymes.
Moxifloxacin had no clinically significant effect on the pharmacokinetics of atenolol, digoxin, glyburide, itraconazole, oral contraceptives, theophylline, cyclosporine and warfarin [see Drug Interactions].
In a crossover study involving 24 healthy volunteers (12 male; 12 female), the mean atenolol AUC following a single oral dose of 50 mg atenolol with placebo was similar to that observed when atenolol was given concomitantly with a single 400 mg oral dose of moxifloxacin. The mean Cmax of single dose atenolol decreased by about 10% following co-administration with a single dose of moxifloxacin.
No significant effect of moxifloxacin (400 mg once daily for two days) on digoxin (0.6 mg as a single dose) AUC was detected in a study involving 12 healthy volunteers. The mean digoxin Cmax increased by about 50% during the distribution phase of digoxin. This transient increase in digoxin Cmax is not viewed to be clinically significant. Moxifloxacin pharmacokinetics were similar in the presence or absence of digoxin. No dosage adjustment for moxifloxacin or digoxin is required when these drugs are administered concomitantly.
In diabetics, glyburide (2.5 mg once daily for two weeks pretreatment and for five days concurrently) mean AUC and Cmax were 12% and 21% lower, respectively, when taken with moxifloxacin (400 mg once daily for five days) in comparison to placebo. Nonetheless, blood glucose levels were decreased slightly in patients taking glyburide and moxifloxacin in comparison to those taking glyburide alone, suggesting no interference by moxifloxacin on the activity of glyburide. These interaction results are not viewed as clinically significant.
In a study involving 11 healthy volunteers, there was no significant effect of itraconazole (200 mg once daily for 9 days), a potent inhibitor of cytochrome P4503A4, on the pharmacokinetics of moxifloxacin (a single 400 mg dose given on the 7th day of itraconazole dosing). In addition, moxifloxacin was shown not to affect the pharmacokinetics of itraconazole.
No significant effect of morphine sulfate (a single 10 mg intramuscular dose) on the mean AUC and Cmax of moxifloxacin (400 mg single dose) was observed in a study of 20 healthy male and female volunteers.
A placebo-controlled study in 29 healthy female subjects showed that moxifloxacin 400 mg daily for 7 days did not interfere with the hormonal suppression of oral contraception with 0.15 mg levonorgestrel/0.03 mg ethinylestradiol (as measured by serum progesterone, FSH, estradiol, and LH), or with the pharmacokinetics of the administered contraceptive agents.
Probenecid (500 mg twice daily for two days) did not alter the renal clearance and total amount of moxifloxacin (400 mg single dose) excreted renally in a study of 12 healthy volunteers.
No significant effect of ranitidine (150 mg twice daily for three days as pretreatment) on the pharmacokinetics of moxifloxacin (400 mg single dose) was detected in a study involving 10 healthy volunteers.
No significant effect of moxifloxacin (200 mg every twelve hours for 3 days) on the pharmacokinetics of theophylline (400 mg every twelve hours for 3 days) was detected in a study involving 12 healthy volunteers. In addition, theophylline was not shown to affect the pharmacokinetics of moxifloxacin.
The effect of co-administration of a 400 mg dose of moxifloxacin with theophylline has not been studied, but it is not expected to be clinically significant based on in vitro metabolic data showing that moxifloxacin does not inhibit the CYP1A2 isoenzyme.
No significant effect of moxifloxacin (400 mg once daily for eight days) on the pharmacokinetics of R- and S-warfarin (25 mg single dose of warfarin sodium on the fifth day) was detected in a study involving 24 healthy volunteers. No significant change in prothrombin time was observed [see Adverse Reactions and Drug Interactions].
Mechanism of Action
The bactericidal action of moxifloxacin results from inhibition of the topoisomerase II (DNA gyrase) and topoisomerase IV required for bacterial DNA replication, transcription, repair, and recombination. It appears that the C8-methoxy moiety contributes to enhanced activity and lower selection of resistant mutants of Gram-positive bacteria compared to the C8-H moiety. The presence of the bulky bicycloamine substituent at the C-7 position prevents active efflux, associated with the NorA or pmrA genes seen in certain Gram-positive bacteria.
Mechanism of Resistance
The mechanism of action for fluoroquinolones, including moxifloxacin, is different from that of macrolides, beta-lactams, aminoglycosides, or tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to moxifloxacin. Resistance to fluoroquinolones occurs primarily by a mutation in topoisomerase II (DNA gyrase) or topoisomerase IV genes, decreased outer membrane permeability or drug efflux. In vitro resistance to moxifloxacin develops slowly via multiple-step mutations. Resistance to moxifloxacin occurs in vitro at a general frequency of between 1.8 x 10-9 to < 1 x 10-11 for Gram-positive bacteria.
Cross-resistance has been observed between moxifloxacin and other fluoroquinolones against Gram-negative bacteria. Gram-positive bacteria resistant to other fluoroquinolones may, however, still be susceptible to moxifloxacin. There is no known cross-resistance between moxifloxacin and other classes of antimicrobials.
Moxifloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage].
- Enterococcus faecalis
- Staphylococcus aureus
- Streptococcus anginosus
- Streptococcus constellatus
- Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP]**)
- Streptococcus pyogenes
**MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as PRSP (Penicillin-resistant S. pneumoniae), and are isolates resistant to two or more of the following antibacterial drugs: penicillin (MIC) ≥ 2 mcg/mL), 2nd generation cephalosporins (for example, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.
- Enterobacter cloacae
- Escherichia coli
- Haemophilus influenzae
- Haemophilus parainfluenzae
- Proteus mirabilis
- Bacteroides fragilis
- Peptostreptococcus species
- Chlamydophila pneumoniae
- Mycoplasma pneumoniae
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to 1 mcg/mL for moxifloxacin. However, the efficacy of moxifloxacin in treating clinical infections due to these bacteria has not been established in adequate and well controlled clinical trials.
- Staphylococcus epidermidis
- Streptococcus agalactiae
- Streptococcus viridans group
- Citrobacter freundii
- Legionella pneumophila
- Fusobacterium species
- Prevotella species
Susceptibility Tests Methods
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth and/or agar).1 The MIC values should be interpreted according to the criteria in Table 3.
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size prove should be determined using a standardized test method.2,3 This procedure uses paper disks impregnated with 5 mcg moxifloxacin to test the susceptibility of bacteria to moxifloxacin. The disc diffusion interpretive criteria are provided in Table 3.
For anaerobic bacteria, the susceptibility to moxifloxacin can be determined by a standardized test method.4 The MIC values obtained should be interpreted according to the criteria provided in Table 3.
|MIC (mcg/mL)||Zone Diameter (mm)|
|Enterobacteriacae||≤ 2||4||≥ 8||≥ 19||16 to 18||≤ 15|
|Enterococcus faecalis||≤ 1||2||≥ 4||≥ 18||15 to 17||≤ 14|
|Staphylococcus aureus||≤ 2||4||≥ 8||≥ 19||16 to 18||≤ 15|
|Haemophilus influenzae||≤ 1||a||a||≥ 18||a||a|
|Haemophilus parainfluenzae||≤ 1||a||a||≥ 18||a||a|
|Streptococcus pneumoniae||≤ 1||2||≥ 4||≥ 18||15 to 17||≤ 14|
|Streptococcus species||≤ 1||2||≥ 4||≥ 18||15 to 17||≤ 14|
|Anaerobic bacteria||≤ 2||4||≥ 8||-||-||-|
S=susceptible, I=Intermediate, and R=resistant.
a The current absence of data on moxifloxacin-resistant isolates precludes defining any results other than “Susceptible”. Isolates yielding test results (MIC or zone diameter) other than susceptible, should be submitted to a reference laboratory for additional testing.
A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug product can be used.
This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay and the techniques of the individuals performing the test.1,2,3,4 Standard moxifloxacin powder should provide the following range of MIC values noted in Table 4. For the diffusion technique using the 5 mcg moxifloxacin disk, the criteria in Table 4 should be achieved.
MIC range (mcg/mL)
Zone Diameter (mm)
Enterococcus faecalis ATCC 29212
0.06 to 0.5
0.008 to 0.06
28 to 35
Haemophilus influenzae ATCC 49247
0.008 to 0.03
31 to 39
Staphylococcus aureus ATCC 29213
0.015 to 0.06
Staphylococcus aureus ATCC 25923
28 to 35
Streptococcus pneumoniae ATCC 49619
0.06 to 0.25
25 to 31
0.125 to 0.5
1 to 4
0.125 to 0.5
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long term studies in animals to determine the carcinogenic potential of moxifloxacin have not been performed.
Moxifloxacin was not mutagenic in 4 bacterial strains (TA 98, TA 100, TA 1535, TA 1537) used in the Ames Salmonella reversion assay. As with other quinolones, the positive response observed with moxifloxacin in strain TA 102 using the same assay may be due to the inhibition of DNA gyrase. Moxifloxacin was not mutagenic in the CHO/HGPRT mammalian cell gene mutation assay. An equivocal result was obtained in the same assay when v79 cells were used. Moxifloxacin was clastogenic in the v79 chromosome aberration assay, but it did not induce unscheduled DNA synthesis in cultured rat hepatocytes. There was no evidence of genotoxicity in vivo in a micronucleus test or a dominant lethal test in mice.
Moxifloxacin had no effect on fertility in male and female rats at oral doses as high as 500 mg/kg/day, (approximately 12 times the maximum recommended human dose based on body surface area), or at intravenous doses as high as 45 mg/kg/day, (approximately equal to the maximum recommended human dose based on body surface area). At 500 mg/kg orally there were slight effects on sperm morphology (head-tail separation) in male rats and on the estrous cycle in female rats.
Animal Toxicology and/or Pharmacology
Quinolones have been shown to cause arthropathy in immature animals. In studies in juvenile dogs oral doses of moxifloxacin ≥ 30 mg/kg/day (approximately 1.5 times the maximum recommended human dose based upon systemic exposure) for 28 days resulted in arthropathy. There was no evidence of arthropathy in mature monkeys and rats at oral doses up to 135 and 500 mg/kg/day, respectively.
Moxifloxacin at an oral dose of 300 mg/kg did not show an increase in acute toxicity or potential for CNS toxicity (for example, seizures) in mice when used in combination with NSAIDs such as diclofenac, ibuprofen, or fenbufen. Some quinolones have been reported to have proconvulsant activity that is exacerbated with concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs).
A QT-prolonging effect of moxifloxacin was found in dog studies, at plasma concentrations about five times the human therapeutic level. The combined infusion of sotalol, a Class III antiarrhythmic agent, with moxifloxacin induced a higher degree of QTc prolongation in dogs than that induced by the same dose (30 mg/kg) of moxifloxacin alone. Electrophysiological in vitro studies suggested an inhibition of the rapid activating component of the delayed rectifier potassium current (IKr) as an underlying mechanism.
No signs of local intolerability were observed in dogs when moxifloxacin was administered intravenously. After intra-arterial injection, inflammatory changes involving the peri-arterial soft tissue were observed suggesting that intra-arterial administration of moxifloxacin should be avoided.
Acute Bacterial Exacerbation of Chronic Bronchitis
Moxifloxacin tablets (400 mg once daily for five days) were evaluated for the treatment of acute bacterial exacerbation of chronic bronchitis in a randomized, double-blind, controlled clinical trial conducted in the US. This study compared moxifloxacin with clarithromycin (500 mg twice daily for 10 days) and enrolled 629 patients. Clinical success was assessed at 7 to 17 days post-therapy. The clinical success for moxifloxacin was 89% (222/250) compared to 89% (224/251) for clarithromycin.
|Streptococcus pneumoniae||16/16 (100%)||20/23 (87%)|
|Haemophilus influenzae||33/37 (89%)||36/41 (88%)|
|Haemophilus parainfluenzae||16/16 (100%)||14/14 (100%)|
|Moraxella catarrhalis||29/34 (85%)||24/24 (100%)|
|Staphylococcus aureus||15/16 (94%)||6/8 (75%)|
|Klebsiella pneumoniae||18/20 (90%)||10/11 (91%)|
The microbiological eradication rates (eradication plus presumed eradication) in moxifloxacin-treated patients were Streptococcus pneumoniae 100%, Haemophilus influenzae 89%, Haemophilus parainfluenzae 100%, Moraxella catarrhalis 85%, Staphylococcus aureus 94%, and Klebsiella pneumoniae 85%.
Community Acquired Pneumonia
A randomized, double-blind, controlled clinical trial was conducted in the US to compare the efficacy of moxifloxacin tablets (400 mg once daily) to that of high-dose clarithromycin (500 mg twice daily) in the treatment of patients with clinically and radiologically documented community acquired pneumonia. This study enrolled 474 patients (382 of whom were valid for the efficacy analysis conducted at the 14 to 35 day follow-up visit). Clinical success for clinically evaluable patients was 95% (184/194) for moxifloxacin and 95% (178/188) for high dose clarithromycin.
A randomized, double-blind, controlled trial was conducted in the US and Canada to compare the efficacy of sequential IV/PO moxifloxacin 400 mg QD for 7 to 14 days to an IV/PO fluoroquinolone control (trovafloxacin or levofloxacin) in the treatment of patients with clinically and radiologically documented community acquired pneumonia. This study enrolled 516 patients, 362 of whom were valid for the efficacy analysis conducted at the 7 to 30 day post-therapy visit. The clinical success rate was 86% (157/182) for moxifloxacin therapy and 89% (161/180) for the fluoroquinolone comparators.
An open-label ex-US study that enrolled 628 patients compared moxifloxacin to sequential IV/PO amoxicillin/clavulanate (1.2 g IV q8h/625 mg PO q8h) with or without high-dose IV/PO clarithromycin (500 mg BID). The intravenous formulations of the comparators are not FDA approved. The clinical success rate at Day 5 to 7 for moxifloxacin therapy was 93% (241/258) and demonstrated superiority to amoxicillin/clavulanate ± clarithromycin (85%, 239/280) [95% C.I. of difference in success rates between moxifloxacin and comparator (2.9%, 13.2%)]. The clinical success rate at the 21 to 28 days post-therapy visit for moxifloxacin was 84% (216/258), which also demonstrated superiority to the comparators (74%, 208/280) [95% C.I. of difference in success rates between moxifloxacin and comparator (2.6%, 16.3%)].
The clinical success rates by pathogen across four CAP studies are presented in Table 6.
Community Acquired Pneumonia Caused by Multi-Drug Resistant Streptococcus pneumoniae (MDRSP)
Moxifloxacin was effective in the treatment of community acquired pneumonia (CAP) caused by multi- drug resistant MDRSP* isolates. Of 37 microbiologically evaluable patients with MDRSP isolates, 35 patients (95%) achieved clinical and bacteriological success post-therapy. The clinical and bacteriological success rates based on the number of patients treated are shown in Table 7.
* MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as PRSP (Penicillin-resistant pneumoniae), and are isolates resistant to two or more of the following antibiotics: penicillin (MIC ≥ 2 mcg/mL), 2nd generation cephalosporins (for example, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.
|Screening Susceptibility||Clinical Success||Bacteriological Success|
|2nd generation cephalosporin-resistant||25/26||96%c||25/26||96%c|
a n = number of patients successfully treated; N = number of patients with MDRSP (from a total of 37 patients)
b n = number of patients successfully treated (presumed eradication or eradication);
N = number of patients with MDRSP (from a total of 37 patients)
c One patient had a respiratory isolate that was resistant to penicillin and cefuroxime but a blood isolate that was intermediate to penicillin and cefuroxime. The patient is included in the database based on the respiratory isolate.
d Azithromycin, clarithromycin, and erythromycin were the macrolide antimicrobials tested.
Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in Table 8.
|S. pneumoniae with MDRSP||Clinical Success||Bacteriological Eradication Rate|
|Resistant to 2 antimicrobials||12/13 (92.3%)||12/13 (92.3%)|
|Resistant to 3 antimicrobials||10/11 (90.9%)a||10/11 (90.9%)a|
|Resistant to 4 antimicrobials||6/6 (100%)||6/6 (100%)|
|Resistant to 5 antimicrobials||7/7 (100%)a||7/7 (100%)a|
|Bacteremia with MDRSP||9/9 (100%)||9/9 (100%)|
a One patient had a respiratory isolate resistant to 5 antimicrobials and a blood isolate resistant to 3 antimicrobials. The patient was included in the category resistant to 5 antimicrobials.
Acute Bacterial Sinusitis
In a controlled double-blind study conducted in the US, moxifloxacin tablets (400 mg once daily for ten days) were compared with cefuroxime axetil (250 mg twice daily for ten days) for the treatment of acute bacterial sinusitis. The trial included 457 patients valid for the efficacy analysis. Clinical success (cure plus improvement) at the 7 to 21 day post-therapy test of cure visit was 90% for moxifloxacin and 89% for cefuroxime.
An additional non-comparative study was conducted to gather bacteriological data and to evaluate microbiological eradication in adult patients treated with moxifloxacin 400 mg once daily for seven days. All patients (n = 336) underwent antral puncture in this study. Clinical success rates and eradication/presumed eradication rates at the 21 to 37 day follow-up visit were 97% (29 out of 30) for Streptococcus pneumoniae, 83% (15 out of 18) for Moraxella catarrhalis, and 80% (24 out of 30) for Haemophilus influenzae.
Uncomplicated Skin and Skin Structure Infections
A randomized, double-blind, controlled clinical trial conducted in the US compared the efficacy of moxifloxacin 400 mg once daily for seven days with cephalexin HCl 500 mg three times daily for seven days. The percentage of patients treated for uncomplicated abscesses was 30%, furuncles 8%, cellulitis 16%, impetigo 20%, and other skin infections 26%. Adjunctive procedures (incision and drainage or debridement) were performed on 17% of the moxifloxacin-treated patients and 14% of the comparator treated patients. Clinical success rates in evaluable patients were 89% (108/122) for moxifloxacin and 91% (110/121) for cephalexin HCl.
Complicated Skin and Skin Structure Infections
Two randomized, active controlled trials of cSSSI were performed. A double-blind trial was conducted primarily in North America to compare the efficacy of sequential IV/PO moxifloxacin 400 mg QD for 7 to 14 days to an IV/PO beta-lactam/beta-lactamase inhibitor control in the treatment of patients with cSSSI. This study enrolled 617 patients, 335 of which were valid for the efficacy analysis. A second open-label International study compared moxifloxacin 400 mg QD for 7 to 21 days to sequential IV/PO beta-lactam/beta-lactamase inhibitor control in the treatment of patients with cSSSI. This study enrolled 804 patients, 632 of which were valid for the efficacy analysis. Surgical incision and drainage or debridement was performed on 55% of the moxifloxacin-treated and 53% of the comparator treated patients in these studies and formed an integral part of therapy for this indication.
Success rates varied with the type of diagnosis ranging from 61% in patients with infected ulcers to 90% in patients with complicated erysipelas. These rates were similar to those seen with comparator drugs. The overall success rates in the evaluable patients and the clinical success by pathogen are shown in Tables 9 and 10.
|95% Confidence Interval*|
|North America||125/162 (77.2%)||141/173 (81.5%)||(-14.4%, 2%)|
|International||254/315 (80.6%)||268/317 (84.5%)||(-9.4%, 2.2%)|
* of difference in success rates between moxifloxacin and comparator (moxifloxacin - comparator)
|106/129 (82.2%)||120/137 (87.6%)|
|Escherichia coli||31/38 (81.6%)||28/33 (84.8%)|
|Klebsiella pneumoniae||11/12 (91.7%)||7/10 (70%)|
|Enterobacter cloacae||9/11 (81.8%)||4/7 (57.1%)|
a methicillin susceptibility was only determined in the North American Study
Complicated Intra-Abdominal Infections
Two randomized, active controlled trials of cIAI were performed. A double-blind trial was conducted primarily in North America to compare the efficacy of sequential IV/PO moxifloxacin 400 mg QD for 5 to 14 days to IV/piperacillin/tazobactam followed by PO amoxicillin/clavulanic acid in the treatment of patients with cIAI, including peritonitis, abscesses, appendicitis with perforation, and bowel perforation. This study enrolled 681 patients, 379 of which were considered clinically evaluable. A second open-label international study compared moxifloxacin 400 mg QD for 5 to 14 days to IV ceftriaxone plus IV metronidazole followed by PO amoxicillin/clavulanic acid in the treatment of patients with cIAI. This study enrolled 595 patients, 511 of which were considered clinically evaluable. The clinically evaluable population consisted of subjects with a surgically confirmed complicated infection, at least 5 days of treatment and a 25 to 50 day follow-up assessment for patients at the Test of Cure visit. The overall clinical success rates in the clinically evaluable patients are shown in Table 11.
|95% Confidence Intervala|
|North America (overall)||146/183 (79.8%)||153/196 (78.1%)||(-7.4%, 9.3%)|
|Abscess||40/57 (70.2%)||49/63 (77.8%)b||NAc|
|Non-abscess||106/126 (84.1%)||104/133 (78.2%)||NA|
|International (overall)||199/246 (80.9%)||218/265 (82.3%)||(-8.9%, 4.2%)|
|Abscess||73/93 (78.5%)||86/99 (86.9%)||NA|
|Non-abscess||126/153 (82.4%)||132/166 (79.5%)||NA|
a of difference in success rates between moxifloxacin and comparator (moxifloxacin – comparator)
b Excludes 2 patients who required additional surgery within the first 48 hours.
c NA – not applicable