LEVOFLOXACIN- levofloxacin_tablet, film coated

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 doses of levofloxacin are summarized in Table 10. Table 8Mean +/-SD Levofloxacin PK Parameters Regimen C max T max AUC (mcgh/mL) CL/F 1 Vd/F 2 (L) t 1/2 CL R 1 2 3 4 5 6 7 8 * ND=not determined. 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 +/- 30 750 mg oral tablet 4* 9. 8 101 +/- 20 129 +/- 24 83 +/- 17 7. 9 ND Multiple dose 500 mg every 24h oral tablet 3 5. 7 175 +/- 25 102 +/- 22 7. 6 116 +/- 31 750 mg every 24h oral tablet 4 8. 6 143 +/- 29 100 +/- 16 8. 5 116 +/- 28 500 mg oral tablet single dose, effects of gender and age: Male 5 5. 9 166 +/- 44 89 +/- 13 7. 1 126 +/- 38 Female 6 7 +/- 1. 2 136 +/- 44 62 +/- 16 6. 8 106 +/- 40 Young 7 5. 8 182 +/- 35 83 +/- 18 6 +/- 0. 9 140 +/- 33 Elderly 8 7 +/- 1. 3 121 +/- 33 67 +/- 19 7. 6 +/- 2 91 +/- 29 500 mg oral single dose tablet, patients with renal insufficiency: CLCR 50 to 80 mL/min 7. 8 88 +/- 10 ND 9. 9 57 +/- 8 CLCR 20 to 49 mL/min 7. 6 51 +/- 19 ND 27 +/- 10 26 +/- 13 CLCR < 20 mL/min 8. 1 +/- 1 263. 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. 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. 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 administration. Therefore, levofloxacin tablets can be administered without regard to food. 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: 750 mg Figure 3 Mean Levofloxacin Plasma Concentration vs. Time Profile: 500 mg 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 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 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 to 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 0-24 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. 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 are 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 Structured product formula for Levofloxacin Structured product formula for Levofloxacin 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 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: Levofloxacin exhibits in vitro Gram-Positive Bacteria Staphylococcus haemolyticus beta-hemolytic Streptococcus beta-hemolytic Streptococcus Streptococcus agalactiae Streptococcus milleri Bacillus anthracis Viridans group streptococci 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 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 11. Table 9Susceptibility Test Interpretive Criteria for Levofloxacin Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameter in mm) S = Susceptible, I = Intermediate, R = Resistant dagger Pathogen S I R S I R Enterobacteriaceae <= 2 4 >= 8 >= 17 14 to 16 <= 13 Enterococcus faecalis <= 2 4 >= 8 >= 17 14 to 16 <= 13 Staphylococcus <= 2 4 >= 8 >= 17 14 to 16 <= 13 Pseudomonas aeruginosa <= 2 4 >= 8 >= 17 14 to 16 <= 13 Haemophilus influenzae <= 2 -- dagger -- >= 17 -- -- Haemophilus parainfluenzae <= 2 -- -- >= 17 -- -- Streptococcus pneumoniae <= 2 4 >= 8 >= 17 14 to 16 <= 13 Streptococcus pyogenes <= 2 4 >= 8 >= 17 14 to 16 <= 13 Yersinia pestis 4 <= 0. 25 -- -- -- -- -- Bacillus anthracis 4 <= 0. 25 -- -- -- -- -- 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 Table 10Quality Control Ranges for Susceptibility Testing Microorganism Microorganism QC Number MIC (mcg/mL) Disk Diffusion (zone diameter in mm) Enterococcus faecalis ATCC 29212 0. 25 to 2 -- Escherichia coli ATCC 25922 0. 06 29 to 37 Escherichia coli ATCC 35218 0. 06 -- Haemophilus influenzae ATCC 49247 0. 03 32 to 40 Pseudomonas aeruginosa ATCC 27853 0. 5 to 4 19 to 26 Staphylococcus aureus ATCC 29213 0. 5 -- Staphylococcus aureus ATCC 25923 -- 25 to 30 Streptococcus pneumoniae ATCC 49619 0. 5 to 2 20 to 25.

Levofloxacinare a fluoroquinolone antibacterial indicated in adults (>= 18 years of age) with infections caused by designated, susceptible bacteria ( 1 12. 12 1. 11 1. 13 1. 14 To reduce the development of drug-resistant bacteria and maintain the effectiveness of levofloxacin tabletsand other antibacterial drugs, levofloxacin tabletsshould 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. Levofloxacin tablets 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. 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 Levofloxacin tablet 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 tablet 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. 2 MDRSP isolates are isolates resistant to two or more of the following antibacterials: penicillin (MIC >= 2 mcg/mL), 2 nd Levofloxacin tablet is indicated for the treatment of community-acquired pneumonia due to Streptococcus pneumoniae Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Dosage and Administration ( 2. 3 Levofloxacin tablet is indicated for the treatment of acute bacterial sinusitis due to Streptococcus pneumoniae Haemophilus influenzae, Moraxella catarrhalis [see Clinical Studies ( 14. 4 Levofloxacin tablet is indicated for the treatment of acute bacterial exacerbation of chronic bronchitis due to methicillin-susceptible Staphylococcus aureus Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis Levofloxacin tablet is 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 tablet 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 tablet is indicated for the treatment of chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, Staphylococcus epidermidis [see Clinical Studies ( 14. 6 Levofloxacin tablet is indicated for the treatment of complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis [see Clinical Studies ( 14. 7 Levofloxacin tablet 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 tablet is indicated for the treatment of acute pyelonephritis caused by Escherichia coli [see Clinical Studies ( 14. 8 Levofloxacin tabletis indicated for the treatment of uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae, Staphylococcus saprophyticus Levofloxacin tabletis 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. 9 Levofloxacin tablet is indicated for treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis Y. pestis see Dosage and Administration ( 2. 2 ) and Clinical Studies ( 14.

1 Type of Infection Dose Every 24 hours Duration (days) Nosocomial Pneumonia ( Error! Hyperlink reference not valid. 750 mg 7 to 14 Community Acquired Pneumonia ( 1. 2 500 mg 7 to 14 Community Acquired Pneumonia ( 1. 3 750 mg 5 Acute Bacterial Sinusitis ( 1. 4 750 mg 5 500 mg 10 to 14 Acute Bacterial Exacerbation of Chronic Bronchitis ( 1. 5 500 mg 7 Complicated Skin and Skin Structure Infections (SSSI) ( 1. 6 750 mg 7 to 14 Uncomplicated SSSI ( 1. 7 500 mg 7 to 10 Chronic Bacterial Prostatitis ( 1. 8 500 mg 28 Complicated Urinary Tract Infection ( 1. 11 750 mg 5 Complicated Urinary Tract Infection ( 1. 11 250 mg 10 Uncomplicated Urinary Tract Infection ( 1. 12 250 mg 3 Inhalational Anthrax (Post-Exposure) ( 1. 13 500 mg 60 Pediatric Patients < 50 kg and >= 6 months of age 8 mg/kg BID (not to exceed 250 mg/dose) 60 Plague ( 1. 14 500 mg 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 1Dosage in Adult Patients with Normal Renal Function (creatinine clearance >= 50 mL/min) Type of Infection * Dosed Every 24 hours Duration (days) dagger *Due to the designated pathogens [see Indications and Usage ( 1 dagger double daggerDue to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae [see Indications and Usage ( 1. 2 sectionDue to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), 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. This indication is based on a surrogate endpoint. Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit [see Clinical Studies ( 14. 9 ßThe safety of levofloxacin tablets in adults for durations of therapy beyond 28 days or in pediatric patients for durations beyond 14 days has not been studied. An increased incidence of musculoskeletal adverse events compared to controls has been observed in pediatric patients [see Warnings and Precautions ( 5. 9 a Yersinia pestis Nosocomial Pneumonia 750 mg 7 to 14 Community Acquired Pneumonia double dagger 500 mg 7 to 14 Community Acquired Pneumonia section 750 mg 5 Acute Bacterial Sinusitis 750 mg 5 500 mg 10 to 14 Acute Bacterial Exacerbation of Chronic Bronchitis 500 mg 7 Complicated Skin and Skin Structure Infections (SSSI) 750 mg 7 to 14 Uncomplicated SSSI 500 mg 7 to 10 Chronic Bacterial Prostatitis 500 mg 28 Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) paragraph 750 mg 5 Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) # 250 mg 10 Uncomplicated Urinary Tract Infection 250 mg 3 Inhalational Anthrax (Post-Exposure), adult and pediatric patients > 50 kg Þ, ß Þ, ß 500 mg 60 ß ß Plague, adult and pediatric patients > 50 kg a 500 mg 10 to 14 The dosage in pediatric patients >= 6 months of age is described below in Table 2. Table 2Dosage in Pediatric Patients >= 6 months of age Type of Infection * Dose Freq. Once every Duration dagger *Due to Bacillus anthracis [see Indications and Usage ( 1. 14 dagger double daggerDrug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B. 9 sectionThe safety of levofloxacin tablets in pediatric patients for durations of therapy beyond 14 days has not been studied. 9 paragraph Yersinia pestis. Inhalational Anthrax (post-exposure) double dagger,section 500 mg section Pediatric patients < 50 kg and >= 6 months of age 8 mg/kg 12 hr 60 days section Plague paragraph Pediatric patients > 50 kg 500 mg 24 hr 10 to 14 days Pediatric patients < 50 kg and >= 6 months of age 8 mg/kg (not to exceed 250 mg per dose) 12 hr 10 to 14 days Administer levofloxacin tabletswith 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. Table 3Dosage Adjustment in Adult Patients with Renal Impairment (creatinine clearance < 50 mL/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, then 500 mg every 48 hours 750 mg initial dose, then 500 mg every 48 hours 500 mg 500 mg initial dose, then 250 mg every 24 hours 500 mg initial dose, then 250 mg every 48 hours 500 mg initial dose, then 250 mg every 48 hours 250 mg No dosage adjustment required 250 mg every 48 hours. If treating uncomplicated UTI, then no dosage adjustment is required No information on dosing adjustment is available Levofloxacin Tablets 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 [see Drug Interactions ( 7. 2 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 ( 17.

The most common reactions (>= 3%) were nausea, headache, diarrhea, insomnia, constipation and dizziness ( 6. 2 To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals USA Inc. at 1-877-993-8779 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: Tendon Effects [see Warnings and Precautions ( 5. 10 5. 11 5. 12 5. 13 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 levofloxacinin 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 levofloxacinfor 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 levofloxacindue 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 6 and Table 7, respectively. The most common adverse drug reactions (>= 3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness. Table 4Common (>= 1%) Adverse Reactions Reported in Clinical Trials with levofloxacin System/Organ Class Adverse Reaction % (N=7537) * dagger Infections and Infestations moniliasis 1 Psychiatric Disorders Insomnia* [see Warnings and Precautions ( 5. 6 4 Nervous System Disorders headache dizziness [see Warnings and Precautions ( 5. 6 6 Respiratory, Thoracic and Mediastinal Disorders dyspnea [see Warnings and Precautions ( 5. 3 1 Gastrointestinal Disorders nausea 7 Skin and Subcutaneous Tissue Disorders rash [see Warnings and Precautions ( 5. 3 2 Reproductive System and Breast Disorders vaginitis 1 dagger General Disorders and Administration Site Conditions edema 1 Table 5Less Common (0. 1 to 1%) Adverse Reactions Reported in Clinical Trials with levofloxacin (N=7537) System/Organ Class Adverse Reaction * Infections and Infestations genital moniliasis Blood and Lymphatic System Disorders anemia thrombocytopenia granulocytopenia [see Warnings and Precautions ( 5. 4 Immune System Disorders allergic reaction [See Warnings and Precautions ( 5. 4 Metabolism and Nutrition Disorders hyperglycemia hypoglycemia [see Warnings and Precautions ( 5. 11 hyperkalemia Psychiatric Disorders anxiety agitation confusion depression hallucination nightmare * [see Warnings and Precautions ( 5. 6 sleep disorder * anorexia abnormal dreaming * Nervous System Disorders tremor convulsions [see Warnings and Precautions ( 5. 6 paresthesia [see Warnings and Precautions ( 5. 8 vertigo hypertonia hyperkinesias abnormal gait somnolence * syncope 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 [see Warnings and Precautions ( 5. 7 Hepatobiliary Disorders abnormal hepatic function increased hepatic enzymes increased alkaline phosphatase Skin and Subcutaneous Tissue Disorders urticaria [see Warnings and Precautions ( 5. 3 Musculoskeletal and Connective Tissue Disorders arthralgia tendonitis [see Warnings and Precautions ( 5. 1 myalgia skeletal pain Renal and Urinary Disorders abnormal renal function acute renal failure [see Warnings and Precautions ( 5. 4 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 8 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, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible. Table 6Postmarketing Reports Of Adverse Drug Reactions System/Organ Class Adverse Reaction Blood and Lymphatic System Disorders pancytopenia aplastic anemia leukopenia hemolytic anemia [see Warnings and Precautions ( 5. 4 eosinophilia Immune System Disorders hypersensitivity reactions, sometimes fatal including: anaphylactic/anaphylactoid reactions anaphylactic shock angioneurotic edema serum sickness [see Warnings and Precautions ( 5. 4 Psychiatric Disorders psychosis paranoia isolated reports of suicide attempt and suicidal ideation [see Warnings and Precautions ( 5. 6 Nervous System Disorders exacerbation of myasthenia gravis [see Warnings and Precautions ( 5. 2 anosmia ageusia parosmia dysgeusia peripheral neuropathy (may be irreversible) [see Warnings and Precautions ( 5. 8 isolated reports of encephalopathy abnormal electroencephalogram (EEG) dysphonia pseudotumor cerebri [see Warnings and Precautions ( 5. 6 Eye Disorders Uveitis vision disturbance, including diplopia visual acuity reduced vision blurred scotoma Ear and Labyrinth Disorders hypoacusis tinnitus Cardiac Disorders isolated reports of torsade de pointes electrocardiogram QT prolonged [see Warnings and Precautions ( 5. 9 Vascular Disorders vasodilatation Respiratory, Thoracic and Mediastinal Disorders isolated reports of allergic pneumonitis [see Warnings and Precautions ( 5. 4 Hepatobiliary Disorders hepatic failure (including fatal cases) hepatitis jaundice [see Warnings and Precautions ( 5. 5 Skin and Subcutaneous Tissue Disorders bullous eruptions to include: Stevens-Johnson Syndrome toxic epidermal necrolysis erythema multiforme [see Warnings and Precautions ( 5. 4 photosensitivity/phototoxicity reaction [see Warnings and Precautions ( 5. 12 leukocytoclastic vasculitis Musculoskeletal and Connective Tissue Disorders tendon rupture [see Warnings and Precautions ( 5. 1 muscle injury, including rupture rhabdomyolysis Renal and Urinary Disorders interstitial nephritis [see Warnings and Precautions ( 5. 4 General Disorders and Administration Site Conditions multi-organ failure pyrexia Investigations prothrombin time prolonged international normalized ratio prolonged muscle enzymes increased.

Known hypersensitivity to levofloxacinor other quinolones ( 4 5. 3 Levofloxacin tablet is contraindicated in persons with known hypersensitivity to levofloxacin, or other quinolone antibacterials [see Warnings and Precautions ( 5.

Geriatrics: 5. 5 17 Pediatrics: 5. 4 Error! Hyperlink reference not valid. 10 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. 10 Error! Hyperlink reference not valid. Pharmacokinetics following intravenous administration The pharmacokinetics of levofloxacin following a single intravenous dose were investigated in pediatric patients ranging in age from six 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 [see Clinical Pharmacology ( 12. 9 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. 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 [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 9. Table 7Incidence of Musculoskeletal Disorders in Pediatric Clinical Trial Follow-up Period Levofloxacin N = 1340 Non-Fluoroquinolone* N = 893 p-value dagger * dagger double dagger 60 days 28 (2. 038 1 year double dagger 46 (3. 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-fluoroqu inolone-treated children. In addition to the events reported in pediatric patients in clinical trials, events reported in adults during clinical trials or postmarketing 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 levofloxacinto 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. 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 postmarketing 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. 5 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. 9 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.

Interacting Drug Interaction Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. 1 Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7. 2 Antidiabetic agents Carefully monitor blood glucose ( 5. 3 Levofloxacin Tablets 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 levofloxacinadministration. 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 levofloxacinenhances 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. 4 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 coadministered [see Warnings and Precautions ( 5. 4 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. 6 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 coadministered. Adverse reactions, including seizures, may occur with or without an elevation in serum theophylline levels [see Warnings and Precautions ( 5. 6 No significant effect of levofloxacinon 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 coadministered with some other fluoroquinolones. Levofloxacin C max e max ½ 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 ½ 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 ) max Levofloxacin was not mutagenic in the following assays: Ames bacterial mutation assay ( S. typhimurium E. coli), in vitro 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. 10 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 7 to 15 days to intravenous imipenem/cilastatin (500 to 1000 mg every 6 to 8 hours daily) followed by oral ciprofloxacin (750 mg every 12 hours daily) for a total of 7 to 15 days. levofloxacin-treated patients received an average of 7 days of intravenous therapy (range: 1 to 16 days); comparator-treated patients received an average of 8 days of intravenous therapy (range: 1 to 19 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 posttherapy visit (primary study endpoint assessed on day 3 to 15 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 posttherapy 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 13. Table 11Clinical Success Rates and Bacteriological Eradication Rates (Nosocomial Pneumonia) Pathogen N Levofloxacin No. (%) of Patients Microbiologic/ Clinical Outcomes N Imipenem/Cilastatin No. (%) of Patients Microbiologic/ Clinical Outcomes * S. aureus dagger double dagger 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)/3 (75) 7 5 (71. 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 posttherapy, and 3 to 4 weeks posttherapy. Clinical success (cure plus improvement) with levofloxacin at 5 to 7 days posttherapy, 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 Table 12Bacteriological Eradication Rates Across 2 Community Acquired Pneumonia Clinical Studies 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 nd Table 13Clinical and Bacterial Success Rates for levofloxacin -Treated MDRSP in Community Acquired Pneumonia Patients (Population Valid for Efficacy) Screening Susceptibility Clinical Success Bacteriological Success * * dagger double dagger n/N dagger % n/N double dagger % Penicillin-resistant 16/17 94. 1 2nd generation Cephalosporin resistant 31/32 96. 9 Macrolide-resistant 28/29 96. 6 Trimethoprim/ Sulfamethoxazole resistant 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 16. Table 14Clinical Success and Bacteriologic Eradication Rates for Resistant Streptococcus pneumoniae (Community Acquired Pneumonia) 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 Clinical success rates (cure plus improvement) in the clinically evaluable population were 90. 9% in the levofloxacin Table 15Bacteriological Eradication Rates (Community-Acquired Pneumonia) S. pneumonae 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 x 5 days or 500 mg by mouth once daily x 10 to 14 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. 2, 10] for levofloxacin 750 mg minus levofloxacin 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. Table 16Clinical Success Rate by Pathogen at the TOC in Microbiologically Evaluable Subjects Who Underwent Antral Puncture (Acute Bacterial Sinusitis) Pathogen Levofloxacin 750 mg x 5 days Levofloxacin 500 mg x 10 days * Streptococcus pneumoniae * 25/27 (92. 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 2 to 5 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 (VB 3 Table 17Bacteriological Eradication Rates (Chronic Bacterial Prostatitis) Levofloxacin (N=136) Ciprofloxacin (N=125) * mixed cultures were excluded. Pathogen N Eradication N Eradication E. coli 15 14 (93. 3%) 11 9 (81. faecalis 54 39 (72. 2%) 44 33 (75%) S. epidermidis * 11 9 (81. 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 5 to 18 days after completion of therapy were 75% for levofloxacin-treated patients and 72. 8% for ciprofloxacin-treated patients (95% CI [-8. 27] for levofloxacin minus ciprofloxacin). Clinical long-term success (24 to 45 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 20. Table 18Bacteriological Eradication at Test-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] * 5 dagger 5 n/N % n/N % Levofloxacin-Ciprofloxacin mITT Population * Overall (cUTI or AP) 252/333 75. 7 239/318 75. 1) cUTI 168/230 73 157/213 73. 7 AP 84/103 81. 6 82/105 78. 1 Microbiologically Evaluable Population dagger Overall (cUTI or AP) 228/265 86 215/241 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 21. Table 19Bacteriological Eradication Rates for Individual Pathogens Recovered From Patients Randomized to Levofloxacin750 mg QD for 5 Days Treatment Pathogen Bacteriological Eradication Rate (n/N) % * E. coli Escherichia 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 1 to 12 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 22. Table Bacteriological Eradication Overall (cUTI or AP) at Test-Of-Cure * Levofloxacin 250 mg once daily for 10 days Ciprofloxacin 500 mg twice daily for 10 days * dagger double dagger n/N % n/N % mITT Population dagger 174/209 83. 3 184/219 84 Microbiologically Evaluable Population double dagger 164/177 92. 7 159/171 93 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. 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 0-24 [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. 4 A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 49 LD 50 6 50 B. anthracis max 0-24 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. 3 A placebo-controlled animal study in African green monkeys exposed to an inhaled mean dose of 65 LD 50 50 Yersinia pestis Y. pestis 0-24 o Y.
REFERENCES
Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically th nd th nd
Medication Guide
Levofloxacin (LEE voe FLOX a sin) Tablets, USP What is the most important information I should know about levofloxacin? Levofloxacin, a fluoroquinolone antibiotic, can cause serious side effects. Some of these serious side effects can happen at the same time and could result in death. If you have any of the following serious side effects while you take levofloxacin, get medical help right away. 1. Tendon rupture or swelling of the tendon (tendinitis). Tendon problems can happen in people of all ages who take levofloxacin Some tendon problems include pain, swelling, tears, and swelling of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites. o o o o o o The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can also happen with other tendons. You may need a different antibiotic that is not a fluoroquinolone to treat your infection. o o o 2. Changes in sensation and possible nerve damage (Peripheral Neuropathy). Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including levofloxacin. Stop taking levofloxacin immediately and talk to your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet: The nerve damage may be permanent. 3. Central Nervous System (CNS) effects. Seizures have been reported in people who take fluoroquinolone antibacterial medicines, including levofloxacin. Tell your healthcare provider if you have a history of seizures before you start taking levofloxacin. CNS side effects may happen as soon as after taking the first dose of levofloxacin. Stop taking levofloxacin immediately and talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior: 4. Worsening of myasthenia gravis (a problem that causes muscle weakness). Fluoroquinolones like levofloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Tell your healthcare provider if you have a history of myasthenia gravis before you start taking levofloxacin. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems. What is levofloxacin ? Levofloxacin is a fluoroquinolone antibiotic medicine used in adults age 18 years or older to treat certain infections caused by certain germs called bacteria. These bacterial infections include: Studies of levofloxacin for use in the treatment of plague and anthrax were done in animals only, because plague and anthrax could not be studied in people. Levofloxacin should not be used in patients with uncomplicated urinary tract infections, acute bacterial exacerbation of chronic bronchitis, or acute bacterial sinusitis if there are other treatment options available. Levofloxacin tablets are also used to treat children who weigh at least 66 pounds (or at least 30 kilograms) and may have breathed in anthrax germs, have plague, or been exposed to plague germs. It is not known if levofloxacin is safe and effective in children under 6 months of age. The safety and effectiveness in children treated with levofloxacin for more than 14 days is not known. Who should not take levofloxacin? Do not take levofloxacin Before you take levofloxacin, tell your healthcare provider about all of your medical conditions, including if you: Tell your healthcare provider about all the medicines you take, Levofloxacin and other medicines can affect each other causing side effects. Especially tell your healthcare provider if you take: o o o Ask your healthcare provider if you are not sure if any of your medicines are listed above. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take levofloxacin? o "What is the most important information I should know about levofloxacin?". o What are the possible side effects of levofloxacin? o What are the possible side effects of levofloxacin? o "What are the possible side effects of levofloxacin?". o Taking all of your levofloxacin doses will help make sure that all of the bacteria are killed. Taking all of your levofloxacin doses will help you lower the chance that the bacteria will become resistant to levofloxacin. If your infection does not get better while you take levofloxacin, it may mean that the bacteria causing your infection may be resistant to levofloxacin. If your infection does not get better, call your healthcare provider. If your infection does not get better, levofloxacin and other similar antibiotic medicines may not work for you in the future. What should I avoid while taking levofloxacin? What are the possible side effects of levofloxacin? Levofloxacin can cause serious side effects, including:. "What is the most important information I should know about levofloxacin?" Serious allergic reactions. Allergic reactions can happen in people taking fluoroquinolones, including levofloxacin, even after only 1 dose. Stop taking levofloxacin and get emergency medical help right away if you have any of the following symptoms of a severe allergic reaction: Skin rash may happen in people taking levofloxacin, even after only 1 dose. Stop taking levofloxacin at the first sign of a skin rash and call your healthcare provider. Skin rash may be a sign of a more serious reaction to levofloxacin. Liver damage (hepatotoxicity). Hepatotoxicity can happen in people who take levofloxacin. Call your healthcare provider right away if you have unexplained symptoms such as: Stop taking levofloxacin and tell your healthcare provider right away if you have yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to levofloxacin (a liver problem). Aortic aneurysm and dissection People who take fluoroquinolone medicines, including levofloxacin, have an increased risk of swelling of the large artery that carries blood from the heart to the body (aortic aneurysm) and tearing (dissection) of this artery. Tell your healthcare provider if you have ever been told that you have an aortic aneurysm. Get emergency medical help right away if you have sudden chest, stomach, or back pain. Intestine infection (Pseudomembranous colitis) Pseudomembranous colitis can happen with many antibiotics, including levofloxacin. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic. Serious heart rhythm changes (QT prolongation and torsades de pointes) Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. Levofloxacin may cause a rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people: Joint Problems Increased chance of problems with joints and tissues around joints in children can happen. Tell your child’s healthcare provider if your child has any joint problems during or after treatment with levofloxacin. Changes in blood sugar People who take levofloxacin and other fluoroquinolone medicines with oral anti-diabetes medicines or with insulin can get low blood sugar (hypoglycemia) and high blood sugar (hyperglycemia). Follow your healthcare provider’s instructions for how often to check your blood sugar. If you have diabetes and you get low blood sugar while taking levofloxacin, stop taking levofloxacin and call your healthcare provider right away. Your antibiotic medicine may need to be changed. Sensitivity to sunlight (photosensitivity) See "What should I avoid while taking levofloxacin?" The most common side effects of levofloxacin include: In children 6 months and older who take levofloxacin to treat anthrax disease or plague, vomiting is also common. Levofloxacin may cause false-positive urine screening results for opiates when testing is done with some commercially available kits. A positive result should be confirmed using a more specific test. These are not all the possible side effects of levofloxacin. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store levofloxacin? General information about the safe and effective use of levofloxacin Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use levofloxacin for a condition for which it is not prescribed. Do not give levofloxacin to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about levofloxacin. If you would like more information about levofloxacin, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about levofloxacin that is written for healthcare professionals. Please address medical inquiries to, MedicalAffairs@zydususa.com orTel.: 1-877-993-8779. What are the ingredients in levofloxacin tablets, USP? Active ingredients: Inactive ingredients: Trademarks are the property of their respective owners. This Medication Guide has been approved by the U.S. Food and Drug Administration. This product''s label may have been updated. For current full prescribing information, please visit www.zydususa.com.

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LEVOFLOXACIN- levofloxacin_tablet, film coated Product manual source documgent