LEVOFLOXACIN- levofloxacin_tablet

Levofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology ( 12. 4 The mean +/- SD pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following oral tablet, oral solution, or intravenous (IV) doses of Levofloxacin are summarized in Table 8. Table8:Mean+/-SDLevofloxacinPKParameters 1 2 3 4 5 6 7 8 9 10 11 12 *Absolute bioavailability; F=0. 08 from a 500 mg tablet and F=0. 06 from a 750 mg tablet; ND=not determined Regimen C max T max AUC CL/F * Vd/F dagger t1/2 CLR (mcg/mL) (h) (mcg∙h/mL) (mL/min) (L) (h) (mL/min) Single dose 250 mg oral tablet 3 2. 9 156 +/- 20 ND 7. 9 142 +/- 21 500 mg oral tablet 3* 5. 8 178 +/- 28 ND 6. 6 103 +/- 30 500 mg oral solution 12 5. 8 183 +/- 40 112 +/- 37. 4 ND 500 mg IV 3 6. 4 175 +/- 20 90 +/- 11 6. 7 112 +/- 25 750 mg oral tablet 5* 9. 8 101 +/- 20 129 +/- 24 83 +/- 17 7. 9 ND 750 mg IV 5 11. 0 4 ND 110 +/- 40 126 +/- 39 75 +/- 13 7. 6 ND Multiple dose 500 mg every 24h oral tablet 3 5. 7 175 +/- 25 102 +/- 22 7. 6 116 +/- 31 500 mg every 24h IV 3 6. 1 158 +/- 29 91 +/- 12 7. 8 99 +/- 28 500 mg or 250 mg every 24h IV, patients with bacterial infection 6 8. 2 7 154 +/- 72 111 +/- 58 ND ND 750 mg every 24h oral tablet 5 8. 6 143 +/- 29 100 +/- 16 8. 5 116 +/- 28 750 mg every 24h IV 5 12. 1 4 ND 108 +/- 34 126 +/- 37 80 +/- 27 7. 9 ND 500 mg oral tablet single dose, effects of gender and age: Male 8 5. 9 166 +/- 44 89 +/- 13 7. 1 126 +/- 38 Female 9 7. 2 136 +/- 44 62 +/- 16 6. 8 106 +/- 40 Young 10 5. 8 182 +/- 35 83 +/- 18 6. 9 140 +/- 33 Elderly 11 7. 3 121 +/- 33 67 +/- 19 7. 0 91 +/- 29 500 mg oral single dose tablet, patients with renal insufficiency: CLCR 50en dash80 mL/min 7. 8 88 +/- 10 ND 9. 9 57 +/- 8 CLCR 20en dash49 mL/min 7. 6 51 +/- 19 ND 27 +/- 10 26 +/- 13 CLCR <20 mL/min 8. 5 33 +/- 8 ND 35 +/- 5 13 +/- 3 Hemodialysis 5. 2 ND ND ND 76 +/- 42 ND CAPD 6. 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 levofloxacin are both approximately 99%, demonstrating complete oral absorption of levofloxacin. Following a single intravenous dose of levofloxacin to healthy volunteers, the mean +/- SD peak plasma concentration attained was 6. 0 mcg/mL after a 500 mg dose infused over 60 minutes and 11. 0 mcg/mL after a 750 mg dose infused over 90 minutes. Levofloxacin 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. 2 mcg/mL after the 500 mg doses, and 8. 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. 2 mcg/mL after the 500 mg doses, and 12. 71 mcg/mL after the 750 mg doses, respectively. Oral administration of a 500 mg dose of levofloxacin 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, levofloxacin Tablets can be administered without regard to food. It is recommended that levofloxacin 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 levofloxacin 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: 750mg Figure 3: Mean Levofloxacin Plasma Concentration vs. Time Profile: 500mg 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 levofloxacin, 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. 3 mcg/g over a 24-hour period after a single 500 mg oral dose. In vitro 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 levofloxacin. 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 levofloxacin to healthy elderly subjects (66 en dash 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. Levofloxacin dose adjustment based on age alone is not necessary [see Use in Specific Populations ( 8. 5 ) 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 (AUC 0en dash24 max 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 levofloxacin 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 levofloxacin are not required following hemodialysis or CAPD [see Dosage and Administration ( 2. 3 ) Use in Specific Populations ( 8. 6 ) Hepatic Impairment Pharmacokinetic studies in hepatically impaired patients have not been conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin is not expected to be affected by hepatic impairment [see Use in Specific Populations ( 8. 7 ) 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 levofloxacin and antacids, warfarin, theophylline, cyclosporine, digoxin, probenecid, and cimetidine has been evaluated [see Drug Interactions ( 7 ) Figure01 Figure 02 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 beta-lactam antibiotics, including penicillins. Fluoroquinolones may, therefore, be active against bacteria resistant to these antimicrobials. Resistance to levofloxacin due to spontaneous mutation in vitro -9 -10 Activity in vitro and in vivo Levofloxacin has in vitro 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 Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus pneumoniae 1) Streptococcus pyogenes 1 Streptococcus pneumoniae 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 but their clinical significance is unknown : in vitro Gram-Positive Bacteria Staphylococcus haemolyticus beta-hemolytic Streptococcus beta-hemolytic Streptococcus 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 method 1, 2, 4 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 procedure 2, 3 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 9. Table9:Susceptibility TestInterpretiveCriteriaforLevofloxacin dagger Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameter in mm) Pathogen S I R S I R Enterobacteriaceae <=2 4 >=8 >=17 14en dash16 <=13 Enterococcus faecalis <=2 4 >=8 >=17 14en dash16 <=13 Staphylococcus <=2 4 >=8 >=17 14en dash16 <=13 Pseudomonas aeruginosa <=2 4 >=8 >=17 14en dash16 <=13 Haemophilus influenzae <=2 -- dagger -- >=17 -- -- Haemophilus parainfluenzae <=2 -- -- >=17 -- -- Streptococcus pneumoniae <=2 4 >=8 >=17 14en dash16 <=13 Streptococcus pyogenes <=2 4 >=8 >=17 14en dash16 <=13 Yersinia pestis 4 <=0. 25 -- -- -- -- -- Bacillus anthracis 4 <=0. 25 -- -- -- -- -- S = Susceptible, I = Intermediate, R = Resistant A report of Susceptible Intermediate Resistant 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 Table10:QualityControlforSusceptibilityTesting Microorganism Microorganism QC Number MIC (mcg/mL) Disk Diffusion (zone diameter in mm) Enterococcus faecalis ATCC 29212 0. 25 en dash 2 -- Escherichia coli ATCC 25922 0. 008 en dash 0. 06 29 en dash 37 Escherichia coli ATCC 35218 0. 015 en dash 0. 06 -- Haemophilus influenzae ATCC 49247 0. 03 32 en dash 40 Pseudomonas aeruginosa ATCC 27853 0. 5 en dash 4 19 en dash 26 Staphylococcus aureus ATCC 29213 0. 06 en dash 0. 5 -- Staphylococcus aureus ATCC 25923 -- 25 en dash 30 Streptococcus pneumoniae ATCC 49619 0. 5 en dash 2 20 en dash 25.

Levofloxacin is a fluoroquinolone antibacterial indicated in adults (>=18 years of age) with infections caused by designated, susceptible bacteria ( 1 12. 4 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of levofloxacin tablets and other antibacterial drugs, levofloxacin tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria (1. Levofloxacin are indicated for the treatment of adults (>=18 years of age) with mild, moderate, and severe infections caused by susceptible isolates of the designated microorganisms in the conditions listed in this section. Levofloxacin is indicated for the treatment of nosocomial pneumonia due to methicillin susceptible Staphylococcus aureus Pseudomonas aeruginosa Serratia marcescens Escherichia coli Klebsiella pneumoniae Haemophilus influenzae Streptococcus pneumoniae Pseudomonas aeruginosa [see Clinical Studies ( 14. 1 Levofloxacin is indicated for the treatment of community-acquired pneumonia due to methicillin-susceptible Staphylococcus aureus Streptococcus pneumoniae Streptococcus pneumoniae Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumoniae Moraxella catarrhalis Chlamydophila pneumoniae Legionella pneumophila Mycoplasma pneumoniae [see Dosage and Administration ( 2. 1 and Clinical Studies ( 14. 2 MDRSP isolates are strains resistant to two or more of the following antibacterials: penicillin (MIC >=2 mcg/mL), 2nd generation cephalosporins, e. , cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole. Levofloxacin is indicated for the treatment of community-acquired pneumonia due to Streptococcus pneumoniae Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae Chlamydophila pneumoniae see Dosage and Administration ( 2. 3 Levofloxacin s indicated for the treatment of complicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus Enterococcus faecalis Streptococcus pyogenes Proteus mirabilis [see Clinical Studies ( 14. 5 ) Levofloxacin is indicated for the treatment of uncomplicated skin and skin structure infections (mild to moderate) including abscesses, cellulitis, furuncles, impetigo, pyoderma, wound infections, due to methicillin-susceptible Staphylococcus aureus Streptococcus pyogenes Levofloxacin is indicated for the treatment of chronic bacterial prostatitis due to Escherichia coli Enterococcus faecalis Staphylococcus epidermidis [see Clinical Studies ( 14. 6 Levofloxacin is indicated for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. [see Dosage and Administration ( 2. 2 and Clinical Studies ( 14. 9 Levofloxacin is indicated for treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis (Y. pestis) [see Dosage and Administration ( 2. 10 Levofloxacin is indicated for the treatment of complicated urinary tract infections due to Escherichia coli Klebsiella pneumoniae Proteus mirabilis [see Clinical Studies ( 14. 7 Levofloxacin is indicated for the treatment of complicated urinary tract infections (mild to moderate) due to Enterococcus faecalis Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa [see Clinical Studies ( 14. 8 Levofloxacin s indicated for the treatment of acute pyelonephritis caused by Escherichia coli, including cases with concurrent bacteremia [ see Clinical Studies ( 14. 8 Levofloxacin is indicated for the treatment of uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae, or Staphylococcus saprophyticus. Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions (5. 15)] and for some patients uncomplicated urinary tract infection is self-limiting, reserve levofloxacin for treatment of uncomplicated urinary tract infections in patients who have no alternative treatment options. Levofloxacin is indicated for the treatment of acute bacterial exacerbation of chronic bronchitis (ABECB) due to methicillin-susceptible Staphylococcus aureus Streptococcus pneumoniae Haemophilus influenzae Haemophilus parainfluenzae Moraxella catarrhalis [see Clinical Studies (14. 4) Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [ see Warnings and Precautions (5. 15) Levofloxacin is indicated for the treatment of acute bacterial sinusitis due to Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis [see Clinical Studies ( 14. 4 Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [ see Warnings and Precautions (5. 14) To reduce the development of drug-resistant bacteria and maintain the effectiveness of levofloxacin and other antibacterial drugs, levofloxacin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Culture and susceptibility testing Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to levofloxacin [ see Microbiology (12. 4) As with other drugs in this class, some isolates of Pseudomonas aeruginosa.

1 Type of Infection Dose Every 24 hours Duration (days) Nosocomial Pneumonia 1. 1 750mg 7-14 Community Acquired Pneumonia 1. 2 500mg 7-14 Community Acquired Pneumonia 1. 3 750mg 5 Complicated Skin and Skin Structure 1. 4 750mg 7-14 Uncomplicated SSSI 1. 5 500mg 7-10 Chronic Bacterial Prostatitis 1. 6 500mg 28 Inhalation Anthrax (Post Exposure) 1. 7 Adults and Pediatric Patients > 50kg 500mg 60 Pediatric Patients < 50 kg and >= 6 months of age 8 mg/kg BID 60 Plague (1. 8) Adults and Pediatric Patients > 50kg 500mg 10 to 14 Pediatric Patients < 50 kg and >= 6 months of age 8 mg/kg BID 10 to 14 Complicated Urinary Tract Infection 1. 11 750mg 5 Complicated Urinary Tract Infection 1. 11 250mg 10 Uncomplicated Urinary Tract Infection 1. 12 250mg 3 Acute Bacterial Exacerbation of Chronic 1. 13 500mg 7 Acute Bacterial Sinusitis 1. 14 750mg 5 500mg 10-14 2. 3 The usual dose of levofloxacin tablets is 250 mg, 500 mg, or 750 mg administered orally every 24 hours, as indicated by infection and described in Table 1. These recommendations apply to patients with creatinine clearance >= 50 mL/min. For patients with creatinine clearance <50 mL/min, adjustments to the dosing regimen are required [see Dosage and Administration ( 2. 3 Table 1: Dosage in Adult Patients with Normal Renal Function (creatinine clearance >= 50 mL/min) * [see Indications and Usage (1)] dagger double dagger Staphylococcus aureus, Streptococcus pneumoniae Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae [see Indications and Usage (1. 2)] section Streptococcus pneumoniae Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Indications and Usage (1. 3)] paragraph Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis E. coli # Enterococcus faecalis, Enterococcus cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa; E. coli Þ ß [see Warnings and Precautions (5. 10), Use in Specific Populations (8. 4), and Clinical Studies (14. à Yersinia pestis Type of Infection* Dosed Every 24 hours Duration (days) dagger Nosocomial Pneumonia 750 mg 7-14 Community Acquired Pneumonia double dagger 500 mg 7-14 Community Acquired Pneumonia section 750 mg 5 Complicated Skin and Skin Structure Infections (SSSI) 750 mg 7en dash14 Uncomplicated SSSI 500 mg 7en dash10 Chronic Bacterial Prostatitis 500 mg 28 Inhalational Anthrax (Post-Exposure), adult and pediatric patients > 50 kg Þ,ß 500 mg see 60 ß Pediatric patients < 50 kg and >= 6 months of age Þ,ß Table 2 below (2. 2) 60 ß Plague, adult and pediatric patients > 50 kg à 500 mg see 10 to 14 Pediatric patients < 50 kg and >= 6 months of age Table 2 below (2. 2) 10 to 14 750 mg 5 Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) # 250 mg 10 Uncomplicated Urinary Tract Infection 250 mg 3 Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB) 500 mg 7 Acute Bacterial Sinusitis (ABS) 750 mg 5 500 mg 10en dash14 The dosage in pediatric patients >= 6 months of age is described below in Table 2. Table 2: Dosage in Pediatric Patients >= 6 months of age * dagger double dagger section paragraph Type of Infection* Dose Freq. Once every Duration dagger Inhalational Anthrax (post-exposure) double dagger, section Pediatric patients > 50 kg 500 mg 24 hr 60 days section Pediatric patients < 50 kg and >= 6 months of age 8 mg/kg 12 hr 60 days section Plagueparagraph Pediatric patients > 50 kg 500 mg 24 hr 10 to 14 days Pediatric patients < 50 kg and >= 6 months of age 8 mg/kg 12 hr 10 to 14 days Administer levofloxacin with caution in the presence of renal insufficiency. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of levofloxacin may be reduced. No adjustment is necessary for patients with a creatinine clearance >= 50 mL/min. In patients with impaired renal function (creatinine clearance <50 mL/min), adjustment of the dosage regimen is necessary to avoid the accumulation of levofloxacin due to decreased clearance [see Use in Specific Populations ( 8. 6 Table 3 shows how to adjust dose based on creatinine clearance. DosageAdjustmentinAdultPatientswithRenalImpairment(creatinineclearance<50mL/min) Dosage in Normal Renal Function Every 24 hours Creatinine Clearance 20 to 49 mL/min Creatinine Clearance 10 to 19 mL/min Hemodialysis or Chronic Ambulatory Peritoneal Dialysis (CAPD) 750 mg 750 mg every 750 mg initial dose, 750 mg initial dose, then 500 mg 500 mg initial dose, 500 mg initial dose, 500 mg initial dose, then 250 mg No dosage 250 mg every 48 No information on dosing Levofloxacin tablets should be administered at least two hours before or two hours after antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine chewable/buffered tablets or the pediatric powder for oral solution [see Drug Interactions ( 7. 1 and Patient Counseling Information ( Error! Hyperlink reference not valid. )] Food and Levofloxacin Tablets Levofloxacin Tablets can be administered without regard to food. Hydration for Patients Receiving Levofloxacin Tablets Adequate hydration of patients receiving oral levofloxacin should be maintained to prevent the formation of highly concentrated urine. Crystalluria and cylindruria have been reported with quinolones [see Adverse Reactions ( 6. 1 Patient Counseling Information ( Error! Hyperlink reference not valid.

The most common reactions (>=3%) were nausea, headache, diarrhea, insomnia, constipation and dizziness ( 6. 2 To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd, at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www. gov/medwatch The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: Disabling and Potentially Irreversible Serious Adverse Reactions [see Warnings and Precautions (5. 1)] see Warnings and Precautions (5. 2)] see Warnings and Precautions (5. 3 see Warnings and Precautions (5. 4 [seeWarningsandPrecautions( 5. 5 [seeWarningsandPrecautions( 5. 6 [seeWarningsandPrecautions( 5. 7 [seeWarningsandPrecautions( 5. 8 Clostridiumdifficile [seeWarningsandPrecautions( 5. 9 [seeWarningsandPrecautions( 5. 10 [seeWarningsandPrecautions( 5. 11 [seeWarningsandPrecautions( 5. 12 [seeWarningsandPrecautions( 5. 13 [seeWarningsandPrecautions( 5. 14 Crystalluria and cylindruria have been reported with quinolones, including levofloxacin. Therefore, adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of a highly concentrated urine [see Dosage and Administration ( 2. 5 Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to levofloxacin in 7537 patients in 29 pooled Phase 3 clinical trials. The population studied had a mean age of 50 years (approximately 74% of the population was < 65 years of age), 50% were male, 71% were Caucasian, 19% were Black. Patients were treated with levofloxacin for a wide variety of infectious diseases [see Indications and Usage ( 1 The overall incidence, type and distribution of adverse reactions was similar in patients receiving levofloxacin doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation of levofloxacin due to adverse drug reactions occurred in 4. 3% of patients overall, 3. 8% of patients treated with the 250 mg and 500 mg doses and 5. 4% of patients treated with the 750 mg dose. The most common adverse drug reactions leading to discontinuation with the 250 and 500 mg doses were gastrointestinal (1. 4%), primarily nausea (0. 6%); vomiting (0. 4%); dizziness (0. 3%); and headache (0. The most common adverse drug reactions leading to discontinuation with the 750 mg dose were gastrointestinal (1. 2%), primarily nausea (0. 6%), vomiting (0. 5%); dizziness (0. Adverse reactions occurring in >=1% of levofloxacin-treated patients and less common adverse reactions, occurring in 0. 1 to <1% of levofloxacin-treated patients, are shown in Table 4 and Table 5, respectively. The most common adverse drug reactions (>=3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness. Table4:Common(>=1%)AdverseReactionsReportedinClinicalTrialswithLevofloxacin * dagger System/Organ Class Adverse Reaction %(N=7537) Infections and Infestations moniliasis 1 Psychiatric Disorders insomnia * [seeWarningsand Precautions ( 5. 4 4 Nervous System Disorders headache, [seeWarningsand Precautions ( 5. 4 6 Respiratory Thoracic and Mediastinal Disorders dyspnea [seeWarningsandPrecautions ( 5. 7 1 Gastrointestinal Disorders nausea 7 diarrhea 5 constipation 3 abdominal pain 2 vomiting 2 dyspepsia 2 Skin and Subcutaneous Tissue Disorders rash [seeWarningsandPrecautions( 5. 7 2 Reproductive System and Breast Disorders vaginitis 1 dagger General Disorders and Administration Site Conditions edema 1 injection site reaction 1 chest pain 1 Table5:LessCommon(0. 1to1%)AdverseReactionsReportedinClinicalTrialswithLevofloxacin(N=7537) * System/Organ Class Adverse Reaction Infections and Infestations genital moniliasis Blood and Lymphatic System Disorders anemia, thrombocytopenia, granulocytopenia [seeWarningsandPrecautions( 5. 6 Immune System Disorders allergic reaction [seeWarningsandPrecautions( 5. 7 ] Metabolism and Nutrition Disorders hyperglycemia, hypoglycemia [seeWarningsandPrecautions( 5. 12 Psychiatric Disorders Anxiety, agitation, confusion, depression, hallucination, nightmare * [see 5. 4 ] * * Nervous System Disorders Tremor, convulsions [seeWarningsandPrecautions( 5. 4 [seeWarningsandPrecautions( 5. 3 * Respiratory Thoracic and Mediastinal Disorders epistaxis Cardiac Disorders cardiac arrest, palpitation, ventricular tachycardia, ventricular arrhythmia Vascular Disorders phlebitis Gastrointestinal Disorders Gastritis, stomatitis, pancreatitis, esophagitis, gastroenteritis, glossitis, pseudomembraneous/ C. difficile colitis [seeWarningsandPrecautions( 5. 9 Hepatobiliary Disorders abnormal hepatic function, Skin and Subcutaneous Tissue Disorders urticaria [seeWarningsandPrecautions( 5. 7 Musculoskeletal and Connective Tissue Disorders arthralgia, tendinitis [seeWarningsandPrecautions( 5. 2 Renal and Urinary Disorders abnormal renal function, [seeWarningsandPrecautions( 5. 6 In clinical trials using multiple-dose therapy, ophthalmologic abnormalities, including cataracts and multiple punctate lenticular opacities, have been noted in patients undergoing treatment with quinolones, including levofloxacin. The relationship of the drugs to these events is not presently established. Table 6 lists adverse reactions that have been identified during post-approval use of levofloxacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimating their frequency or establishing a causal relationship to drug exposure. Table6:PostmarketingReportsofAdverseDrugReactions System/Organ Class Adverse Reaction Blood and Lymphatic System Disorders Pancytopenia, [seeWarningsandPrecautions( 5. 6 Immune System Disorders hypersensitivity reactions, sometimes fatal including: [seeWarningsandPrecautions( 5. 7 ] Psychiatric Disorders Psychosis, [seeWarningsandPrecautions( 5. 4 Nervous System Disorders exacerbation of myasthenia gravis [seeWarningsandPrecautions( 5. 5 [seeWarningsandPrecautions( 5. 3 See Warning and Precautions ( 5. 4 Eye Disorders Uveitis, Ear and Labyrinth Disorders Hypoacusis, Cardiac Disorders isolated reports of torsade de pointes, [seeWarnings andPrecautions( 5. 10 Vascular Disorders vasodilatation Respiratory Thoracic and Mediastinal Disorders isolated reports of allergic pneumonitis [seeWarningsandPrecautions( 5. 6 Hepatobiliary Disorders hepatic failure (including fatal cases), [seeWarningsand Precautions( 5. 8 ] Skin and Subcutaneous Tissue Disorders bullous eruptions to include: [seeWarningsandPrecautions( 5. 6) [seeWarningsand Precautions( 5. 13) Musculoskeletal and Connective Tissue Disorders tendon rupture, [seeWarningsandPrecautions( 5. 2 Renal and Urinary Disorders interstitial nephritis [seeWarningsandPrecautions( 5. 6 General Disorders and Administration Site Conditions multi-organ failure, Investigations prothrombin time prolonged,.

Known hypersensitivity to levofloxacin or other quinolones ( 4 5. 7 Levofloxacin is contraindicated in persons with known hypersensitivity to levofloxacin, or other quinolone antibacterials [see Warnings and Precautions ( 5.

Geriatrics: 5. 5 17 Pediatrics: 5. 9 Pregnancy Category C. Levofloxacin was not teratogenic in rats at oral doses as high as 810 mg/kg/day which corresponds to 9. 4 times the highest recommended human dose based upon relative body surface area, or at intravenous doses as high as 160 mg/kg/day corresponding to 1. 9 times the highest recommended human dose based upon relative body surface area. The oral dose of 810 mg/kg/day to rats caused decreased fetal body weight and increased fetal mortality. No teratogenicity was observed when rabbits were dosed orally as high as 50 mg/kg/day which corresponds to 1. 1 times the highest recommended human dose based upon relative body surface area, or when dosed intravenously as high as 25 mg/kg/day, corresponding to 0. 5 times the highest recommended human dose based upon relative body surface area. There are, however, no adequate and well-controlled studies in pregnant women. Levofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on data on other fluoroquinolones and very limited data on levofloxacin, it can be presumed that levofloxacin will be excreted in human milk. Because of the potential for serious adverse reactions from levofloxacin in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. [see Warnings and Precautions ( 5. 11 and Animal Toxicology and/or Pharmacology ( 13. 2 Inhalational Anthrax (Post-Exposure) Levofloxacin is indicated in pediatric patients 6 months of age and older, for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate. The safety of levofloxacin in pediatric patients treated for more than 14 days has not been studied. [see Indications and Usage ( 1. 7 Dosage and Administration ( 2. 2 and Clinical Studies ( 14. 9 Plague Levofloxacin is indicated in pediatric patients, 6 months of age and older, for treatment of plague, including pneumonic and septicemic plague due to Yersinia pestis (Y. pestis) and prophylaxis for plague. Efficacy studies of levofloxacin could not be conducted in humans with pneumonic plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals. The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate [ see Indications and Usage ( 1. 10 Safety and effectiveness in pediatric patients below the age of six months have not been established. Adverse Events In clinical trials, 1534 children (6 months to 16 years of age) were treated with oral and intravenous levofloxacin. Children 6 months to 5 years of age received levofloxacin 10 mg/kg twice a day and children greater than 5 years of age received 10 mg/kg once a day (maximum 500 mg per day) for approximately 10 days. A subset of children in the clinical trials (1340 levofloxacin-treated and 893 non-fluoroquinolone-treated) enrolled in a prospective, long-term surveillance study to assess the incidence of protocol-defined musculoskeletal disorders (arthralgia, arthritis, tendinopathy, gait abnormality) during 60 days and 1 year following the first dose of the study drug. Children treated with levofloxacin had a significantly higher incidence of musculoskeletal disorders when compared to the non-fluoroquinolone-treated children as illustrated in Table 7. Follow-up Period Levofloxacin N = 1340 Non-Fluoroquinolone Non-Fluoroquinolone: ceftriaxone, amoxicillin/ clavulanate, clarithromycin N = 893 p-value 2-sided Fisher's Exact Test 60 days 28 (2. 038 1 year There were 1199 levofloxacin-treated and 804 non-fluoroquinolone-treated children who had a one-year evaluation visit. However, the incidence of musculoskeletal disorders was calculated using all reported events during the specified period for all children enrolled regardless of whether they completed the 1-year evaluation visit. 025 Arthralgia was the most frequently occurring musculoskeletal disorder in both treatment groups. Most of the musculoskeletal disorders in both groups involved multiple weight-bearing joints. Disorders were moderate in 8/46 (17%) children and mild in 35/46 (76%) levofloxacin-treated children and most were treated with analgesics. The median time to resolution was 7 days for levofloxacin-treated children and 9 for non-fluoroquinolone-treated children (approximately 80% resolved within 2 months in both groups). No child had a severe or serious disorder and all musculoskeletal disorders resolved without sequelae. Vomiting and diarrhea were the most frequently reported adverse events, occurring in similar frequency in the levofloxacin-treated and non-fluoroquinolone-treated children. In addition to the events reported in pediatric patients in clinical trials, events reported in adults during clinical trials or post-marketing experience [see Adverse Reactions ( 6 Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as levofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing levofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue levofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see Boxed Warning; Warnings and Precautions ( 5. 8 and Adverse Reactions ( 6. 3 In phase 3 clinical trials, 1,945 levofloxacin-treated patients (26%) were >= 65 years of age. Of these, 1,081 patients (14%) were between the ages of 65 and 74 and 864 patients (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Severe, and sometimes fatal, cases of hepatotoxicity have been reported post-marketing in association with levofloxacin. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. Levofloxacin should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Warnings and Precautions ( 5. 8 Elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using levofloxacin with concomitant drugs that can result in prolongation of the QT interval (e. , Class IA or Class III antiarrhythmics) or in patients with risk factors for torsade de pointes (e. , known QT prolongation, uncorrected hypokalemia) [see Warnings and Precautions ( 5. 10 The pharmacokinetic properties of levofloxacin in younger adults and elderly adults do not differ significantly when creatinine clearance is taken into consideration. However, since the drug is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology ( 12. 3 Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in 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 levofloxacin are not required following hemodialysis or CAPD [see Dosage and Administration ( 2. 3 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.

RECENT MAJOR CHANGES
Boxed Warning 6/2016 Indications and Usage (1) 6/2016 Dosage and Administration (2) 6/2016 Warnings and Precautions (5) 6/2016
DRUG INTERACTIONS
Interacting Drug Interaction Multivalent cation-containing Absorption of levofloxacin is decreased 2. 1 Warfarin Effect may be enhanced. 2 Antidibetic agents Carefully monitor blood glucose ( 5. 3 While the chelation by divalent cations is less marked than with other fluoroquinolones, concurrent administration of levofloxacin Tablets with antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc may interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired. Tablets with antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamins preparations with zinc or didanosine may substantially interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired. These agents should be taken at least two hours before or two hours after oral levofloxacin administration. No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for R- and S- warfarin was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of warfarin on levofloxacin absorption and disposition was observed. However, there have been reports during the postmarketing experience in patients that levofloxacin enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent warfarin and levofloxacin use have been associated with episodes of bleeding. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if levofloxacin is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Adverse Reactions ( 6. 3 Patient Counseling Information ( Error! Hyperlink reference not valid. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with fluoroquinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered [see Warnings and Precautions ( 5. 12 Adverse Reactions ( 6. 2 Patient Counseling Information ( Error! Hyperlink reference not valid. The concomitant administration of a non-steroidal anti-inflammatory drug with a fluoroquinolone, including levofloxacin, may increase the risk of CNS stimulation and convulsive seizures [see Warnings and Precautions ( 5. 4 No significant effect of levofloxacin on the plasma concentrations, AUC, and other disposition parameters for theophylline was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of theophylline on levofloxacin absorption and disposition was observed. However, concomitant administration of other fluoroquinolones with theophylline has resulted in prolonged elimination half-life, elevated serum theophylline levels, and a subsequent increase in the risk of theophylline-related adverse reactions in the patient population. Therefore, theophylline levels should be closely monitored and appropriate dosage adjustments made when levofloxacin is co-administered. Adverse reactions, including seizures, may occur with or without an elevation in serum theophylline levels [see Warnings and Precautions ( 5. 4 No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for cyclosporine was detected in a clinical study involving healthy volunteers. However, elevated serum levels of cyclosporine have been reported in the patient population when co-administered with some other fluoroquinolones. Levofloxacin C max e max No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for digoxin was detected in a clinical study involving healthy volunteers. Levofloxacin absorption and disposition kinetics were similar in the presence or absence of digoxin. Therefore, no dosage adjustment for levofloxacin or digoxin is required when administered concomitantly. No significant effect of probenecid or cimetidine on the C max R Some fluoroquinolones, including levofloxacin, may produce false-positive urine screening results for opiates using commercially available immunoassay kits. Confirmation of positive opiate screens by more specific methods may be necessary.

OVERDOSAGE
In the event of an acute overdosage, the stomach should be emptied. The patient should be observed and appropriate hydration maintained. Levofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis. Levofloxacin exhibits a low potential for acute toxicity. Mice, rats, dogs and monkeys exhibited the following clinical signs after receiving a single high dose of levofloxacin: ataxia, ptosis, decreased locomotor activity, dyspnea, prostration, tremors, and convulsions. Doses in excess of 1500 mg/kg orally and 250 mg/kg IV produced significant mortality in rodents.
NONCLINICAL TOXICOLOGY
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 levofloxacin averaged approximately 11. 8 mcg/g at Cmax. Levofloxacin was not mutagenic in the following assays: Ames bacterial mutation assay ( S. typhimurium E. coli) 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. Levofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see Warnings and Precautions ( 5. 11 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 in vivo.
CLINICAL STUDIES
Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a multicenter, randomized, open-label study comparing intravenous levofloxacin (750 mg once daily) followed by oral levofloxacin (750 mg once daily) for a total of 7en dash15 days to intravenous imipenem/cilastatin (500en dash1000 mg every 6en dash8 hours daily) followed by oral ciprofloxacin (750 mg every 12 hours daily) for a total of 7en dash15 days. Levofloxacin-treated patients received an average of 7 days of intravenous therapy (range: 1en dash16 days); comparator-treated patients received an average of 8 days of intravenous therapy (range: 1en dash19 days). Overall, in the clinically and microbiologically evaluable population, adjunctive therapy was empirically initiated at study entry in 56 of 93 (60. 2%) patients in the levofloxacin arm and 53 of 94 (56. 4%) patients in the comparator arm. The average duration of adjunctive therapy was 7 days in the levofloxacin arm and 7 days in the comparator. In clinically and microbiologically evaluable patients with documented Pseudomonas aeruginosa S. aureus Clinical success rates in clinically and microbiologically evaluable patients at the post-therapy visit (primary study endpoint assessed on day 3en dash15 after completing therapy) were 58. 1% for levofloxacin and 60. 6% for comparator. The 95% CI for the difference of response rates (Levofloxacin minus comparator) was [-17. The microbiological eradication rates at the post-therapy visit were 66. 7% for levofloxacin and 60. The 95% CI for the difference of eradication rates (levofloxacin minus comparator) was [-8. Clinical success and microbiological eradication rates by pathogen are detailed in Table 11. Table11:ClinicalSuccessRatesandMicrobiologicalEradicationRates(NosocomialPneumonia) * S. aureus dagger double dagger Pathogen N Levofloxacin No. (%) of Patients Microbiologic/Clinical Outcomes N Imipenem/Cilastatin No. (%) of Patients Microbiologic/Clinical Outcomes MSSA * 21 14 (66. 9) 19 13 (68. aeruginosa dagger 17 10 (58. 7) 17 5 (29. marcescens 11 9 (81. coli 12 10 (83. 3) 11 7 (63. pneumoniae double dagger 11 9 (81. influenzae 16 13 (81. 5) 15 14 (93. pneumoniae 4 3 (75. 1) Adult inpatients and outpatients with a diagnosis of community-acquired bacterial pneumonia were evaluated in 2 pivotal clinical studies. In the first study, 590 patients were enrolled in a prospective, multi-center, unblinded randomized trial comparing levofloxacin 500 mg once daily orally or intravenously for 7 to 14 days to ceftriaxone 1 to 2 grams intravenously once or in equally divided doses twice daily followed by cefuroxime axetil 500 mg orally twice daily for a total of 7 to 14 days. Patients assigned to treatment with the control regimen were allowed to receive erythromycin (or doxycycline if intolerant of erythromycin) if an infection due to atypical pathogens was suspected or proven. Clinical and microbiologic evaluations were performed during treatment, 5 to 7 days post-therapy, and 3 to 4 weeks post-therapy. Clinical success (cure plus improvement) with levofloxacin at 5 to 7 days post-therapy, the primary efficacy variable in this study, was superior (95%) to the control group (83%). The 95% CI for the difference of response rates (Levofloxacin minus comparator) was [-6, 19]. In the second study, 264 patients were enrolled in a prospective, multi-center, non-comparative trial of 500 mg levofloxacin administered orally or intravenously once daily for 7 to 14 days. Clinical success for clinically evaluable patients was 93%. For both studies, the clinical success rate in patients with atypical pneumonia due to Chlamydophila pneumoniae Mycoplasma pneumoniae Legionella pneumophila Microbiologic eradication rates across both studies are presented in Table 12. Table12:BacteriologicalEradicationRatesacross2CommunityAcquiredPneumoniaClinicalStudies Pathogen No. Pathogens Bacteriological Eradication Rate (%) H. influenzae 55 98 S. pneumoniae 83 95 S. aureus 17 88 M. catarrhalis 18 94 H. parainfluenzae 19 95 K. pneumoniae 10 100 Community-Acquired Pneumonia Due to Multi-Drug Resistant Streptococcus pneumoniae Levofloxacin was effective for the treatment of community-acquired pneumonia caused by multi-drug resistant Streptococcus pneumoniae Table13:ClinicalandBacterialSuccessRatesforLevofloxacin-TreatedMDRSPinCommunityAcquiredPneumoniaPatients(PopulationValidforEfficacy) Screening Susceptibility Clinical Success Bacteriological Success One patient had a respiratory isolate that was resistant to tetracycline, cefuroxime, macrolides and TMP/SMX and intermediate to penicillin and a blood isolate that was intermediate to penicillin and cefuroxime and resistant to the other classes. The patient is included in the database based on respiratory isolate. n/N n=the number of microbiologically evaluable patients who were clinical successes; N=number of microbiologically evaluable patients in the designated resistance group. % n/N n=the number of MDRSP isolates eradicated or presumed eradicated in microbiologically evaluable patients; N=number of MDRSP isolates in a designated resistance group. % Penicillin-resistant 16/17 94. 1 2nd generation 31/32 96. 9 Macrolide-resistant 28/29 96. 6 Trimethoprim/ 17/19 89. 5 Tetracycline-resistant 12/12 100 12/12 100 Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in Table 14. Table14:ClinicalSuccessandBacteriologicEradicationRatesforResistantStreptococcuspneumoniae(CommunityAcquiredPneumonia) Type of Resistance Clinical Success Bacteriologic Eradication Resistant to 2 antibacterials 17/18 (94. 4%) 17/18 (94. 4%) Resistant to 3 antibacterials 14/15 (93. 3%) 14/15 (93. 3%) Resistant to 4 antibacterials 7/7 (100%) 7/7 (100%) Resistant to 5 antibacterials 0 0 Bacteremia with MDRSP 8/9 (89%) 8/9 (89%) To evaluate the safety and efficacy of the higher dose and shorter course of levofloxacin, 528 outpatient and hospitalized adults with clinically and radiologically determined mild to severe community-acquired pneumonia were evaluated in a double-blind, randomized, prospective, multicenter study comparing levofloxacin 750 mg, IV or orally, every day for five days or levofloxacin 500 mg IV or orally, every day for 10 days. Clinical success rates (cure plus improvement) in the clinically evaluable population were 90. 9% in the levofloxacin 750 mg group and 91. 1% in the levofloxacin 500 mg group. The 95% CI for the difference of response rates (levofloxacin 750 minus levofloxacin 500) was [-5. In the clinically evaluable population (31en dash38 days after enrollment) pneumonia was observed in 7 out of 151 patients in the levofloxacin 750 mg group and 2 out of 147 patients in the levofloxacin 500 mg group. Given the small numbers observed, the significance of this finding cannot be determined statistically. The microbiological efficacy of the 5-day regimen was documented for infections listed in Table 15. Table15:BacteriologicalEradicationRates(Community-AcquiredPneumonia) S. pneumoniae 19/20 (95%) Haemophilus influenzae 12/12 (100%) Haemophilus parainfluenzae 10/10 (100%) Mycoplasma pneumoniae 26/27 (96%) Chlamydophila pneumoniae 13/15 (87%) Levofloxacin is approved for the treatment of acute bacterial sinusitis (ABS) using either 750 mg by mouth × 5 days or 500 mg by mouth once daily × 10en dash14 days. To evaluate the safety and efficacy of a high dose short course of levofloxacin, 780 outpatient adults with clinically and radiologically determined acute bacterial sinusitis were evaluated in a double-blind, randomized, prospective, multicenter study comparing levofloxacin 750 mg by mouth once daily for five days to levofloxacin 500 mg by mouth once daily for 10 days. Clinical success rates (defined as complete or partial resolution of the pre-treatment signs and symptoms of ABS to such an extent that no further antibiotic treatment was deemed necessary) in the microbiologically evaluable population were 91. 4% (139/152) in the levofloxacin 750 mg group and 88. 6% (132/149) in the levofloxacin 500 mg group at the test-of-cure (TOC) visit (95% CI [-4. 0] for levofloxacin 750 mg minus levofloxacin 500 mg). Rates of clinical success by pathogen in the microbiologically evaluable population who had specimens obtained by antral tap at study entry showed comparable results for the five- and ten-day regimens at the test-of-cure visit 22 days post treatment (see Table 16). Table16:ClinicalSuccessRatebyPathogenattheTOCinMicrobiologicallyEvaluableSubjectsWhoUnderwentAntralPuncture(AcuteBacterialSinusitis) Pathogen Levofloxacin 750 mg × 5 days Levofloxacin 500 mg × 10 days Streptococcus pneumoniae Note: Forty percent of the subjects in this trial had specimens obtained by sinus endoscopy. The efficacy data for subjects whose specimen was obtained endoscopically were comparable to those presented in the above table. 6%) 26/27 (96. 3%) Haemophilus influenzae 19/21 (90. 5%) 25/27 (92. 6%) Moraxella catarrhalis 10/11 (90. 9%) 13/13 (100%) Three hundred ninety-nine patients were enrolled in an open-label, randomized, comparative study for complicated skin and skin structure infections. The patients were randomized to receive either levofloxacin 750 mg once daily (IV followed by oral), or an approved comparator for a median of 10 +/- 4. As is expected in complicated skin and skin structure infections, surgical procedures were performed in the levofloxacin and comparator groups. Surgery (incision and drainage or debridement) was performed on 45% of the levofloxacin-treated patients and 44% of the comparator-treated patients, either shortly before or during antibiotic treatment and formed an integral part of therapy for this indication. Among those who could be evaluated clinically 2en dash5 days after completion of study drug, overall success rates (improved or cured) were 116/138 (84. 1%) for patients treated with levofloxacin and 106/132 (80. 3%) for patients treated with the comparator. Success rates varied with the type of diagnosis ranging from 68% in patients with infected ulcers to 90% in patients with infected wounds and abscesses. These rates were equivalent to those seen with comparator drugs. Adult patients with a clinical diagnosis of prostatitis and microbiological culture results from urine sample collected after prostatic massage (VB3) or expressed prostatic secretion (EPS) specimens obtained via the Meares-Stamey procedure were enrolled in a multicenter, randomized, double-blind study comparing oral levofloxacin 500 mg, once daily for a total of 28 days to oral ciprofloxacin 500 mg, twice daily for a total of 28 days. The primary efficacy endpoint was microbiologic efficacy in microbiologically evaluable patients. A total of 136 and 125 microbiologically evaluable patients were enrolled in the levofloxacin and ciprofloxacin groups, respectively. The microbiologic eradication rate by patient infection at 5en dash18 days after completion of therapy was 75. 0% in the levofloxacin group and 76. 8% in the ciprofloxacin group (95% CI [-12. 98] for levofloxacin minus ciprofloxacin). The overall eradication rates for pathogens of interest are presented in Table 17. Table17:BacteriologicalEradicationRates(ChronicBacterialProstatitis) Levofloxacin (N=136) Ciprofloxacin (N=125) Pathogen N Eradication N Eradication E. coli 15 14 (93. 3%) 11 9 (81. faecalis 54 39 (72. 2%) 44 33 (75. epidermidis Eradication rates shown are for patients who had a sole pathogen only; mixed cultures were excluded. 8%) 14 11 (78. 6%) Eradication rates for S. epidermidis Clinical success (cure + improvement with no need for further antibiotic therapy) rates in microbiologically evaluable population 5en dash18 days after completion of therapy were 75. 0% for levofloxacin-treated patients and 72. 8% for ciprofloxacin-treated patients (95% CI [-8. 27] for levofloxacin minus ciprofloxacin). Clinical long-term success (24en dash45 days after completion of therapy) rates were 66. 7% for the levofloxacin-treated patients and 76. 9% for the ciprofloxacin-treated patients (95% CI [-23. 89] for levofloxacin minus ciprofloxacin). To evaluate the safety and efficacy of the higher dose and shorter course of levofloxacin, 1109 patients with cUTI and AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the US from November 2004 to April 2006 comparing levofloxacin 750 mg IV or orally once daily for 5 days (546 patients) with ciprofloxacin 400 mg IV or 500 mg orally twice daily for 10 days (563 patients). Patients with AP complicated by underlying renal diseases or conditions such as complete obstruction, surgery, transplantation, concurrent infection or congenital malformation were excluded. Efficacy was measured by bacteriologic eradication of the baseline organism(s) at the post-therapy visit in patients with a pathogen identified at baseline. The post-therapy (test-of-cure) visit occurred 10 to 14 days after the last active dose of levofloxacin and 5 to 9 days after the last dose of active ciprofloxacin. The bacteriologic cure rates overall for levofloxacin and control at the test-of-cure (TOC) visit for the group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the group of patients in the mITT population who closely followed the protocol (Microbiologically Evaluable) are summarized in Table 18. Table18:BacteriologicalEradicationatTest-of-Cure Levofloxacin 750 mg orally or IV once daily for 5 days Ciprofloxacin 400 mg IV/500 mg orally twice daily for 10 days Overall Difference [95% CI] n/N % n/N % Levofloxacin- Ciprofloxacin mITT Population The mITT population included patients who received study medication and who had a positive (>=10 CFU/mL) urine culture with no more than 2 uropathogens at baseline. Patients with missing response were counted as failures in this analysis. Overall 252/333 75. 7 239/318 75. 1) cUTI 168/230 73. 0 157/213 73. 7 AP 84/103 81. 6 82/105 78. 1 Microbiologically Evaluable Population The Microbiologically Evaluable population included patients with a confirmed diagnosis of cUTI or AP, a causative organism(s) at baseline present at >= 10 CFU/mL, a valid test-of-cure urine culture, no pathogen isolated from blood resistant to study drug, no premature discontinuation or loss to follow-up, and compliance with treatment (among other criteria). Overall 228/265 86. 0 215/241 89. 5] cUTI 154/185 83. 2 144/165 87. 3 AP 74/80 92. 4 Microbiologic eradication rates in the Microbiologically Evaluable population at TOC for individual pathogens recovered from patients randomized to levofloxacin treatment are presented in Table 19. Table19:BacteriologicalEradicationRatesforIndividualPathogensRecoveredFromPatientsRandomizedtoLevofloxacin750mgQDfor5DaysTreatment Pathogen Bacteriological Eradication Rate (n/N) % Escherichia coli The predominant organism isolated from patients with AP was E. coli 155/172 90 Klebsiella pneumoniae 20/23 87 Proteus mirabilis 12/12 100 To evaluate the safety and efficacy of the 250 mg dose, 10 day regimen of levofloxacin, 567 patients with uncomplicated UTI, mild-to-moderate cUTI, and mild-to-moderate AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the US from June 1993 to January 1995 comparing levofloxacin 250 mg orally once daily for 10 days (285 patients) with ciprofloxacin 500 mg orally twice daily for 10 days (282 patients). Patients with a resistant pathogen, recurrent UTI, women over age 55 years, and with an indwelling catheter were initially excluded, prior to protocol amendment which took place after 30% of enrollment. Microbiological efficacy was measured by bacteriologic eradication of the baseline organism(s) at 1en dash12 days post-therapy in patients with a pathogen identified at baseline. The bacteriologic cure rates overall for levofloxacin and control at the test-of-cure (TOC) visit for the group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the group of patients in the mITT population who closely followed the protocol (Microbiologically Evaluable) are summarized in Table 20. Table20:BacteriologicalEradicationOverall(cUTIorAP)atTest-Of-Cure The Microbiologically Evaluable population included mITT patients who met protocol-specified evaluability criteria. Levofloxacin 250 mg once daily for 10 days Ciprofloxacin 500 mg twice daily for 10 days n/N % n/N % mITT Population 1en dash9 days post-therapy for 30% of subjects enrolled prior to a protocol amendment; 5en dash12 days post-therapy for 70% of subjects. 3 184/219 84. 0 Microbiologically Evaluable Population The mITT population included patients who had a pathogen isolated at baseline. 7 159/171 93. 0 The effectiveness of levofloxacin for this indication is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin has not been tested in humans for the post-exposure prevention of inhalation anthrax. The mean plasma concentrations of levofloxacin associated with a statistically significant improvement in survival over placebo in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage regimens [see Indications and Usage ( 1. 13 Dosage and Administration ( 2. Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. The mean (+/- SD) steady state peak plasma concentration in human adults receiving 500 mg orally or intravenously once daily is 5. 8 mcg/mL, respectively; and the corresponding total plasma exposure (AUC 0en dash24 [see Clinical Pharmacology ( 12. 3 In adults, the safety of levofloxacin for treatment durations of up to 28 days is well characterized. However, information pertaining to extended use at 500 mg daily up to 60 days is limited. Prolonged levofloxacin therapy in adults should only be used when the benefit outweighs the risk. In pediatric patients, the safety of levofloxacin for treatment durations of more than 14 days has not been studied. An increased incidence of musculoskeletal adverse events (arthralgia, arthritis, tendinopathy, gait abnormality) compared to controls has been observed in clinical studies with treatment duration of up to 14 days. Long-term safety data, including effects on cartilage, following the administration of levofloxacin to pediatric patients is limited [see Warnings and Precautions ( 5. 10 Use in Specific Populations ( 8. 4 A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 49 LD 50 6 50 B. anthracis max 0en dash24 Efficacy studies of levofloxacin could not be conducted in humans with pneumonic plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals. The mean plasma concentrations of levofloxacin associated with a statistically significant improvement in survival over placebo in an African green monkey model of pneumonic plague are reached or exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage regimens [see Indications and Usage ( 1. 2 Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. 8 mcg/mL, respectively; and the corresponding total plasma exposure (AUC0-24) is 47. h/mL, respectively. The predicted steady-state pharmacokinetic parameters in pediatric patients ranging in age from 6 months to 17 years receiving 8 mg/kg orally every 12 hours (not to exceed 250 mg per dose) were calculated to be comparable to those observed in adults receiving 500 mg orally once daily [see Clinical Pharmacology ( 12. 3 A placebo-controlled animal study in African green monkeys exposed to an inhaled mean dose of 65 LD 50 50 0-24 9. Animals were randomized to receive either a 10-day regimen of i. levofloxacin or placebo beginning within 6 hrs of the onset of telemetered fever (>= 39 o subsequent daily blood cultures from Day 4 through Day 7 were negative.
REFERENCES
1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. Approved Standard - 9th ed. CLSI Document M7-A9, CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA, 2012. 2. CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22nd Informational Supplement. CLSI Document M100 - S22, 2012. 3. CLSI Performance Standards for Antimicrobial Disk Susceptibility Tests. Approved Standard - 11th ed. CLSI M2-A11, 2012. 4. CLSI. Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline - 2nd ed. CLSI Document M45-A2, 2010.

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