CLINICAL PHARMACOLOGY
Mechanism of Action
Levofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology].
Pharmacokinetics
The mean ± SD pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following oral tablet, oral solution, or intravenous (IV) doses of LEVAQUIN® are summarized in Table 10.
Table 10: Mean ± SD Levofloxacin PK Parameters
Regimen |
Cmax
|
Tmax
|
AUC |
CL/Fclearance/bioavailability
|
Vd/Fvolume of distribution/bioavailability
|
t1/2
|
CLR
|
(mcg/mL) |
(h) |
(mcg∙h/mL) |
(mL/min) |
(L) |
(h) |
(mL/min) |
ND=not determined. |
Single dose
|
250 mg oral tablet
|
2.8 ± 0.4 |
1.6 ± 1.0 |
27.2 ± 3.9 |
156 ± 20 |
ND |
7.3 ± 0.9 |
142 ± 21 |
500 mg oral tablet
|
5.1 ± 0.8 |
1.3 ± 0.6 |
47.9 ± 6.8 |
178 ± 28 |
ND |
6.3 ± 0.6 |
103 ± 30 |
500 mg oral solutionhealthy males and females 19–55 years of age.
|
5.8 ± 1.8 |
0.8 ± 0.7 |
47.8 ± 10.8 |
183 ± 40 |
112 ± 37.2 |
7.0 ± 1.4 |
ND |
500 mg IV
|
6.2 ± 1.0 |
1.0 ± 0.1 |
48.3 ± 5.4 |
175 ± 20 |
90 ± 11 |
6.4 ± 0.7 |
112 ± 25 |
750 mg oral tablet
|
9.3 ± 1.6 |
1.6 ± 0.8 |
101 ± 20 |
129 ± 24 |
83 ± 17 |
7.5 ± 0.9 |
ND |
750 mg IV
|
11.5 ± 4.0
|
ND |
110 ± 40 |
126 ± 39 |
75 ± 13 |
7.5 ± 1.6 |
ND |
Multiple dose
|
500 mg every 24h oral tablet
|
5.7 ± 1.4 |
1.1 ± 0.4 |
47.5 ± 6.7 |
175 ± 25 |
102 ± 22 |
7.6 ± 1.6 |
116 ± 31 |
500 mg every 24h IV
|
6.4 ± 0.8 |
ND |
54.6 ± 11.1 |
158 ± 29 |
91 ± 12 |
7.0 ± 0.8 |
99 ± 28 |
500 mg or 250 mg every 24h IV, patients with bacterial infection500 mg every 48h for patients with moderate renal impairment (CLCR 20–50 mL/min) and infections of the respiratory tract or skin
|
8.7± 4.0
|
ND |
72.5 ± 51.2
|
154 ± 72 |
111 ± 58 |
ND |
ND |
750 mg every 24h oral tablet
|
8.6 ± 1.9 |
1.4 ± 0.5 |
90.7 ± 17.6 |
143 ± 29 |
100 ± 16 |
8.8 ± 1.5 |
116 ± 28 |
750 mg every 24h IV
|
12.1 ± 4.1
|
ND |
108 ± 34 |
126 ± 37 |
80 ± 27 |
7.9 ± 1.9 |
ND |
500 mg oral tablet single dose, effects of gender and age:
|
Malehealthy males 22–75 years of age
|
5.5 ± 1.1 |
1.2 ± 0.4 |
54.4 ± 18.9 |
166 ± 44 |
89 ± 13 |
7.5 ± 2.1 |
126 ± 38 |
Femalehealthy females 18–80 years of age
|
7.0 ± 1.6 |
1.7 ± 0.5 |
67.7 ± 24.2 |
136 ± 44 |
62 ± 16 |
6.1 ± 0.8 |
106 ± 40 |
Youngyoung healthy male and female subjects 18–36 years of age
|
5.5 ± 1.0 |
1.5 ± 0.6 |
47.5 ± 9.8 |
182 ± 35 |
83 ± 18 |
6.0 ± 0.9 |
140 ± 33 |
Elderlyhealthy elderly male and female subjects 66–80 years of age
|
7.0 ± 1.6 |
1.4 ± 0.5 |
74.7 ± 23.3 |
121 ± 33 |
67 ± 19 |
7.6 ± 2.0 |
91 ± 29 |
500 mg oral single dose tablet, patients with renal insufficiency:
|
CLCR 50–80 mL/min |
7.5 ± 1.8 |
1.5 ± 0.5 |
95.6 ± 11.8 |
88 ± 10 |
ND |
9.1 ± 0.9 |
57 ± 8 |
CLCR 20–49 mL/min |
7.1 ± 3.1 |
2.1 ± 1.3 |
182.1 ± 62.6 |
51 ± 19 |
ND |
27 ± 10 |
26 ± 13 |
CLCR <20 mL/min |
8.2 ± 2.6 |
1.1 ± 1.0 |
263.5 ± 72.5 |
33 ± 8 |
ND |
35 ± 5 |
13 ± 3 |
Hemodialysis |
5.7 ± 1.0 |
2.8 ± 2.2 |
ND |
ND |
ND |
76 ± 42 |
ND |
CAPD |
6.9 ± 2.3 |
1.4 ± 1.1 |
ND |
ND |
ND |
51 ± 24 |
ND |
Absorption
Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak plasma concentrations are usually attained one to two hours after oral dosing. The absolute bioavailability of levofloxacin from a 500 mg tablet and a 750 mg tablet of LEVAQUIN® are both approximately 99%, demonstrating complete oral absorption of levofloxacin. Following a single intravenous dose of LEVAQUIN® to healthy volunteers, the mean ± SD peak plasma concentration attained was 6.2 ± 1.0 mcg/mL after a 500 mg dose infused over 60 minutes and 11.5 ± 4.0 mcg/mL after a 750 mg dose infused over 90 minutes. LEVAQUIN® Oral Solution and Tablet formulations are bioequivalent.
Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral or IV dosing regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once-daily dosage regimen. The mean ± SD peak and trough plasma concentrations attained following multiple once-daily oral dosage regimens were approximately 5.7 ± 1.4 and 0.5 ± 0.2 mcg/mL after the 500 mg doses, and 8.6 ± 1.9 and 1.1 ± 0.4 mcg/mL after the 750 mg doses, respectively. The mean ± SD peak and trough plasma concentrations attained following multiple once-daily IV regimens were approximately 6.4 ± 0.8 and 0.6 ± 0.2 mcg/mL after the 500 mg doses, and 12.1 ± 4.1 and 1.3 ± 0.71 mcg/mL after the 750 mg doses, respectively. Oral administration of a 500 mg dose of LEVAQUIN® with food prolongs the time to peak concentration by approximately 1 hour and decreases the peak concentration by approximately 14% following tablet and approximately 25% following oral solution administration. Therefore, LEVAQUIN® Tablets can be administered without regard to food. It is recommended that LEVAQUIN® Oral Solution be taken 1 hour before or 2 hours after eating.
The plasma concentration profile of levofloxacin after IV administration is similar and comparable in extent of exposure (AUC) to that observed for LEVAQUIN® Tablets when equal doses (mg/mg) are administered. Therefore, the oral and IV routes of administration can be considered interchangeable (see Figure 2 and Figure 3).
Figure 2: Mean Levofloxacin Plasma Concentration vs. Time Profile: 750 mg
|
|
Figure 3: Mean Levofloxacin Plasma Concentration vs. Time Profile: 500 mg
|
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Distribution
The mean volume of distribution of levofloxacin generally ranges from 74 to 112 L after single and multiple 500 mg or 750 mg doses, indicating widespread distribution into body tissues. Levofloxacin reaches its peak levels in skin tissues and in blister fluid of healthy subjects at approximately 3 hours after dosing. The skin tissue biopsy to plasma AUC ratio is approximately 2 and the blister fluid to plasma AUC ratio is approximately 1 following multiple once-daily oral administration of 750 mg and 500 mg doses of LEVAQUIN®, respectively, to healthy subjects. Levofloxacin also penetrates well into lung tissues. Lung tissue concentrations were generally 2- to 5-fold higher than plasma concentrations and ranged from approximately 2.4 to 11.3 mcg/g over a 24-hour period after a single 500 mg oral dose.
In vitro, over a clinically relevant range (1 to 10 mcg/mL) of serum/plasma levofloxacin concentrations, levofloxacin is approximately 24 to 38% bound to serum proteins across all species studied, as determined by the equilibrium dialysis method. Levofloxacin is mainly bound to serum albumin in humans. Levofloxacin binding to serum proteins is independent of the drug concentration.
Metabolism
Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to its enantiomer, D-ofloxacin. Levofloxacin undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. Following oral administration, approximately 87% of an administered dose was recovered as unchanged drug in urine within 48 hours, whereas less than 4% of the dose was recovered in feces in 72 hours. Less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans. These metabolites have little relevant pharmacological activity.
Excretion
Levofloxacin is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin given orally or intravenously. The mean apparent total body clearance and renal clearance range from approximately 144 to 226 mL/min and 96 to 142 mL/min, respectively. Renal clearance in excess of the glomerular filtration rate suggests that tubular secretion of levofloxacin occurs in addition to its glomerular filtration. Concomitant administration of either cimetidine or probenecid results in approximately 24% and 35% reduction in the levofloxacin renal clearance, respectively, indicating that secretion of levofloxacin occurs in the renal proximal tubule. No levofloxacin crystals were found in any of the urine samples freshly collected from subjects receiving LEVAQUIN®.
Geriatric
There are no significant differences in levofloxacin pharmacokinetics between young and elderly subjects when the subjects' differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of LEVAQUIN® to healthy elderly subjects (66–80 years of age), the mean terminal plasma elimination half-life of levofloxacin was about 7.6 hours, as compared to approximately 6 hours in younger adults. The difference was attributable to the variation in renal function status of the subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by age. LEVAQUIN® dose adjustment based on age alone is not necessary [see Use in Specific Populations].
Pediatrics
The pharmacokinetics of levofloxacin following a single 7 mg/kg intravenous dose were investigated in pediatric patients ranging in age from 6 months to 16 years. Pediatric patients cleared levofloxacin faster than adult patients, resulting in lower plasma exposures than adults for a given mg/kg dose. Subsequent pharmacokinetic analyses predicted that a dosage regimen of 8 mg/kg every 12 hours (not to exceed 250 mg per dose) for pediatric patients 6 months to 17 years of age would achieve comparable steady state plasma exposures (AUC0–24 and Cmax) to those observed in adult patients administered 500 mg of levofloxacin once every 24 hours.
Gender
There are no significant differences in levofloxacin pharmacokinetics between male and female subjects when subjects' differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of LEVAQUIN® to healthy male subjects, the mean terminal plasma elimination half-life of levofloxacin was about 7.5 hours, as compared to approximately 6.1 hours in female subjects. This difference was attributable to the variation in renal function status of the male and female subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by the gender of the subjects. Dose adjustment based on gender alone is not necessary.
Race
The effect of race on levofloxacin pharmacokinetics was examined through a covariate analysis performed on data from 72 subjects: 48 white and 24 non-white. The apparent total body clearance and apparent volume of distribution were not affected by the race of the subjects.
Renal Impairment
Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in adult patients with impaired renal function (creatinine clearance < 50 mL/min), requiring dosage adjustment in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating that supplemental doses of LEVAQUIN® are not required following hemodialysis or CAPD [see Dosage and Administration
,
Use in Specific Populations].
Hepatic Impairment
Pharmacokinetic studies in hepatically impaired patients have not been conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin are not expected to be affected by hepatic impairment [see Use in Specific Populations].
Bacterial Infection
The pharmacokinetics of levofloxacin in patients with serious community-acquired bacterial infections are comparable to those observed in healthy subjects.
Drug-Drug Interactions
The potential for pharmacokinetic drug interactions between LEVAQUIN® and antacids, warfarin, theophylline, cyclosporine, digoxin, probenecid, and cimetidine has been evaluated [see Drug Interactions (7) ].
Microbiology
Mechanism of Action
Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair and recombination.
Mechanism of Resistance
Fluoroquinolone resistance can arise through mutations in defined regions of DNA gyrase or topoisomerase IV, termed the Quinolone-Resistance Determining Regions (QRDRs), or through altered efflux.
Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from aminoglycosides, macrolides and β-lactam antibiotics, including penicillins. Fluoroquinolones may, therefore, be active against bacteria resistant to these antimicrobials.
Resistance to levofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-10). Cross-resistance has been observed between levofloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to levofloxacin.
Activity in vitro and in vivo
Levofloxacin has in vitro activity against Gram-negative and Gram-positive bacteria.
Levofloxacin has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections as described in
Indications and Usage (1)
:
-
Gram-Positive Bacteria
-
Enterococcus faecalis
-
Staphylococcus aureus (methicillin-susceptible isolates)
-
Staphylococcus epidermidis (methicillin-susceptible isolates)
-
Staphylococcus saprophyticus
-
Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP]MDRSP (Multi-drug resistant Streptococcus pneumoniae) isolates are isolates resistant to two or more of the following antibiotics: penicillin (MIC ≥2 mcg/mL), 2nd generation cephalosporins, e.g., cefuroxime; macrolides, tetracyclines and trimethoprim/sulfamethoxazole.)
-
Streptococcus pyogenes
-
Gram-Negative Bacteria
-
Enterobacter cloacae
-
Escherichia coli
-
Haemophilus influenzae
-
Haemophilus parainfluenzae
-
Klebsiella pneumoniae
-
Legionella pneumophila
-
Moraxella catarrhalis
-
Proteus mirabilis
-
Pseudomonas aeruginosa
-
Serratia marcescens
-
Other Bacteria
-
Chlamydophila pneumoniae
-
Mycoplasma pneumoniae
The following in vitro data are available, but their clinical significance is unknown: Levofloxacin exhibits in vitro minimum inhibitory concentrations (MIC values) of 2 mcg/mL or less against most (≥90%) isolates of the following microorganisms; however, the safety and effectiveness of LEVAQUIN® in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.
-
Gram-Positive Bacteria
-
Staphylococcus haemolyticus
-
β-hemolytic Streptococcus (Group C/F)
-
β-hemolytic Streptococcus (Group G)
-
Streptococcus agalactiae
-
Streptococcus milleri
-
Viridans group streptococci
-
Bacillus anthracis
-
Gram-Negative Bacteria
-
Acinetobacter baumannii
-
Acinetobacter lwoffii
-
Bordetella pertussis
-
Citrobacter koseri
-
Citrobacter freundii
-
Enterobacter aerogenes
-
Enterobacter sakazakii
-
Klebsiella oxytoca
-
Morganella morganii
-
Pantoea agglomerans
-
Proteus vulgaris
-
Providencia rettgeri
-
Providencia stuartii
-
Pseudomonas fluorescens
-
Yersinia pestis
-
Anaerobic Gram-Positive Bacteria
-
Clostridium perfringens
Susceptibility Tests
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in the 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.
Dilution techniques:
Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC values should be determined using a standardized procedure. Standardized procedures are based on a dilution method1,2,4 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of levofloxacin powder. The MIC values should be interpreted according to the criteria outlined in Table 11.
Diffusion techniques:
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg levofloxacin to test the susceptibility of bacteria to levofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg levofloxacin disk should be interpreted according to the criteria outlined in Table 11.
Table 11: Susceptibility Test Interpretive Criteria for Levofloxacin
|
Minimum Inhibitory Concentrations (mcg/mL) |
Disk Diffusion (zone diameter in mm) |
S = Susceptible, I = Intermediate, R = Resistant |
Pathogen
|
S
|
I
|
R
|
S
|
I
|
R
|
Enterobacteriaceae
|
≤2 |
4 |
≥8 |
≥17 |
14–16 |
≤13 |
Enterococcus faecalis
|
≤2 |
4 |
≥8 |
≥17 |
14–16 |
≤13 |
Staphylococcus species |
≤2 |
4 |
≥8 |
≥17 |
14–16 |
≤13 |
Pseudomonas aeruginosa
|
≤2 |
4 |
≥8 |
≥17 |
14–16 |
≤13 |
Haemophilus influenzae
|
≤2 |
--The current absence of data on resistant isolates precludes defining any categories other than "Susceptible." Isolates yielding MIC/zone diameter results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing.
|
-- |
≥17 |
-- |
-- |
Haemophilus parainfluenzae
|
≤2 |
-- |
-- |
≥17 |
-- |
-- |
Streptococcus pneumoniae
|
≤2 |
4 |
≥8 |
≥17 |
14–16 |
≤13 |
Streptococcus pyogenes
|
≤2 |
4 |
≥8 |
≥17 |
14–16 |
≤13 |
Yersinia pestis4
|
≤0.25 |
-- |
-- |
-- |
-- |
-- |
Bacillus anthracis4
|
≤0.25 |
-- |
-- |
-- |
-- |
-- |
A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. 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 drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Quality Control:
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 levofloxacin powder should provide the range of MIC values noted in Table 12. For the diffusion technique using the 5 mcg disk, the criteria in Table 12 should be achieved.
Table 12: Quality Control Ranges for Susceptibility Testing
Microorganism |
Microorganism QC Number |
MIC (mcg/mL) |
Disk Diffusion (zone diameter in mm) |
Enterococcus faecalis
|
ATCC 29212 |
0.25 – 2 |
-- |
Escherichia coli
|
ATCC 25922 |
0.008 – 0.06 |
29 – 37 |
Escherichia coli
|
ATCC 35218 |
0.015 – 0.06 |
-- |
Haemophilus influenzae
|
ATCC 49247 |
0.008 – 0.03 |
32 – 40 |
Pseudomonas aeruginosa
|
ATCC 27853 |
0.5 – 4 |
19 – 26 |
Staphylococcus aureus
|
ATCC 29213 |
0.06 – 0.5 |
-- |
Staphylococcus aureus
|
ATCC 25923 |
-- |
25 – 30 |
Streptococcus pneumoniae
|
ATCC 49619 |
0.5 – 2 |
20 – 25 |
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a lifetime bioassay in rats, levofloxacin exhibited no carcinogenic potential following daily dietary administration for 2 years; the highest dose (100 mg/kg/day) was 1.4 times the highest recommended human dose (750 mg) based upon relative body surface area. Levofloxacin did not shorten the time to tumor development of UV-induced skin tumors in hairless albino (Skh-1) mice at any levofloxacin dose level and was therefore not photo-carcinogenic under conditions of this study. Dermal levofloxacin concentrations in the hairless mice ranged from 25 to 42 mcg/g at the highest levofloxacin dose level (300 mg/kg/day) used in the photo-carcinogenicity study. By comparison, dermal levofloxacin concentrations in human subjects receiving 750 mg of LEVAQUIN® averaged approximately 11.8 mcg/g at Cmax.
Levofloxacin was not mutagenic in the following assays: Ames bacterial mutation assay (S. typhimurium and E. coli), CHO/HGPRT forward mutation assay, mouse micronucleus test, mouse dominant lethal test, rat unscheduled DNA synthesis assay, and the mouse sister chromatid exchange assay. It was positive in the in vitro chromosomal aberration (CHL cell line) and sister chromatid exchange (CHL/IU cell line) assays.
Levofloxacin caused no impairment of fertility or reproductive performance in rats at oral doses as high as 360 mg/kg/day, corresponding to 4.2 times the highest recommended human dose based upon relative body surface area and intravenous doses as high as 100 mg/kg/day, corresponding to 1.2 times the highest recommended human dose based upon relative body surface area.
Animal Toxicology and/or Pharmacology
Levofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see Warnings and Precautions]. In immature dogs (4–5 months old), oral doses of 10 mg/kg/day for 7 days and intravenous doses of 4 mg/kg/day for 14 days of levofloxacin resulted in arthropathic lesions. Administration at oral doses of 300 mg/kg/day for 7 days and intravenous doses of 60 mg/kg/day for 4 weeks produced arthropathy in juvenile rats. Three-month old beagle dogs dosed orally with levofloxacin at 40 mg/kg/day exhibited clinically severe arthrotoxicity resulting in the termination of dosing at Day 8 of a 14-day dosing routine. Slight musculoskeletal clinical effects, in the absence of gross pathological or histopathological effects, resulted from the lowest dose level of 2.5 mg/kg/day (approximately 0.2-fold the pediatric dose based upon AUC comparisons). Synovitis and articular cartilage lesions were observed at the 10 and 40 mg/kg dose levels (approximately 0.7-fold and 2.4-fold the pediatric dose, respectively, based on AUC comparisons). Articular cartilage gross pathology and histopathology persisted to the end of the 18-week recovery period for those dogs from the 10 and 40 mg/kg/day dose levels.
When tested in a mouse ear swelling bioassay, levofloxacin exhibited phototoxicity similar in magnitude to ofloxacin, but less phototoxicity than other quinolones.
While crystalluria has been observed in some intravenous rat studies, urinary crystals are not formed in the bladder, being present only after micturition and are not associated with nephrotoxicity.
In mice, the CNS stimulatory effect of quinolones is enhanced by concomitant administration of non-steroidal anti-inflammatory drugs.
In dogs, levofloxacin administered at 6 mg/kg or higher by rapid intravenous injection produced hypotensive effects. These effects were considered to be related to histamine release.
In vitro and in vivo studies in animals indicate that levofloxacin is neither an enzyme inducer nor inhibitor in the human therapeutic plasma concentration range; therefore, no drug metabolizing enzyme-related interactions with other drugs or agents are anticipated.
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