LEVOFLOXACIN- levofloxacin_tablet, film coated

12.1 Mechanism of Action Levofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology(12.4)]. 12.3 Pharmacokinetics The mean +/-SD pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following administration of the oral tablets, are summarized in Table 8. Table 8: Mean +/-SD Levofloxacin PK Parameters Regimen Cmax (mcg/mL) Tmax (h) AUC (mcg·h/mL) CL/F1 (mL/min) Vd/F2 (L) t 1/2 (h) CLR (mL/ Single dose 250 mg oral tablet3 2.8 +/- 0.4 1.6 +/- 1.0 27.2 +/- 3.9 156 +/- 20 ND 7.3 +/- 0.9 142 +/- 21 500 mg oral tablet3* 5.1 +/- 0.8 1.3 +/- 0.6 47.9 +/- 6.8 178 +/- 28 ND 6.3 +/- 0.6 103 +/- 30 750 mg oral tablet4* 9.3 +/- 1.6 1.6 +/- 0.8 101 +/- 20 129 +/- 24 83 +/- 17 7.5 +/- 0.9 ND Multiple dose 500 mg every 24h oral tablet3 5.7 +/- 1.4 1.1 +/- 0.4 47.5 +/- 6.7 175 +/- 25 102 +/- 22 7.6 +/- 1.6 116 +/- 31 750 mg every 24h oral tablet4 8.6 +/- 1.9 1.4 +/- 0.5 90.7 +/- 17.6 143 +/- 29 100 +/- 16 8.8 +/- 1.5 116 +/- 28 500 mg oral tablet single dose, effects of gender and age: Male5 5.5 +/- 1.1 1.2 +/- 0.4 54.4 +/- 18.9 166 +/- 44 89 +/- 13 7.5 +/- 2.1 126 +/- 38 Female6 7.0 +/- 1.6 1.7 +/- 0.5 67.7 +/- 24.2 136 +/- 44 62 +/- 16 6.1 +/- 0.8 106 +/- 40 Young7 5.5 +/- 1.0 1.5 +/- 0.6 47.5 +/- 9.8 182 +/- 35 83 +/- 18 6.0 +/- 0.9 140 +/- 33 Elderly8 7.0 +/- 1.6 1.4 +/- 0.5 74.7 +/- 23.3 121 +/- 33 67 +/- 19 7.6 +/- 2.0 91 +/- 29 500 mg oral single dose tablet, patients with renal impairment: CLCR 50en dash80 mL/min 7.5 +/- 1.8 1.5 +/- 0.5 95.6 +/- 11.8 88 +/- 10 ND 9.1 +/- 0.9 57 +/- 8 CLCR 20en dash49 mL/min 7.1 +/- 3.1 2.1 +/- 1.3 182.1 +/- 62.6 51 +/- 19 ND 27 +/- 10 26 +/- 13 CLCR <20 mL/min 8.2 +/- 2.6 1.1 +/- 1.0 263.5 +/- 72.5 33 +/- 8 ND 35 +/- 5 13 +/- 3 Hemodialysis 5.7 +/- 1.0 2.8 +/- 2.2 ND ND ND 76 +/- 42 ND CAPD 6.9 +/- 2.3 1.4 +/- 1.1 ND ND ND 51 +/- 24 ND 1 clearance /bioavailability Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral or IV dosing regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once-daily dosage regimen. The mean +/- SD peak and trough plasma concentrations attained following multiple once-daily oral dosage regimens were approximately 5.7 +/- 1.4 and 0.5 +/- 0.2 mcg/mL after the 500 mg doses, and 8.6 +/- 1.9 and 1.1 +/- 0.4 mcg/mL after the 750 mg doses, respectively. The mean +/- SD peak and trough plasma concentrations attained following multiple once-daily IV regimens were approximately 6.4 +/- 0.8 and 0.6 +/- 0.2 mcg/mL after the 500 mg doses, and 12.1 +/- 4.1 and 1.3 +/- 0.71 mcg/mL after the 750 mg doses, respectively. Absorption 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. 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 2.4 to 11.3 mcg/g over a 24-hour period after a single 500 mg oral dose. In vitro, over a clinically relevant range (1 to 10 mcg/mL) of serum/plasma levofloxacin concentrations, levofloxacin is approximately 24 to 38% bound to serum proteins across all species studied, as determined by the equilibrium dialysis method. Levofloxacin is mainly bound to serum albumin in humans. Levofloxacin binding to serum proteins is independent of the drug concentration. Metabolism Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to its enantiomer, D-ofloxacin. Levofloxacin undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. Following oral administration, approximately 87% of an administered dose was recovered as unchanged drug in urine within 48 hours, whereas less than 4% of the dose was recovered in feces in 72 hours. Less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans. These metabolites have little relevant pharmacological activity. Excretion Levofloxacin is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin given orally or intravenously. The mean apparent total body clearance and renal clearance range from approximately 144 to 226 mL/min and 96 to 142 mL/min, respectively. Renal clearance in excess of the glomerular filtration rate suggests that tubular secretion of levofloxacin occurs in addition to its glomerular filtration. Concomitant administration of either cimetidine or probenecid results in approximately 24% and 35% reduction in the levofloxacin renal clearance, respectively, indicating that secretion of levofloxacin occurs in the renal proximal tubule. No levofloxacin crystals were found in any of the urine samples freshly collected from subjects receiving levofloxacin. Specific Populations 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)]. The pharmacokinetics of levofloxacin following a single 7 mg/kg intravenous dose were investigated in pediatric patients ranging in age from 6 months to 16 years. Pediatric patients cleared levofloxacin faster than adult patients, resulting in lower plasma exposures than adults for a given mg/kg dose. Subsequent pharmacokinetic analyses predicted that a dosage regimen of 8 mg/kg every 12 hours (not to exceed 250 mg per dose) for pediatric patients 6 months to 17 years of age would achieve comparable steady state plasma exposures (AUC0-24 and Cmax) to those observed in adult patients administered 500 mg of levofloxacin once every 24 hours. Levofloxacin tablets can only be administered to pediatric patients with inhalational anthrax (post-exposure) or plague who are 30 kg or greater due to the limitations of the available strengths [see Dosage and Administration (2.2)] 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. 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. Patients with 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) and Use in Specific Populations (8.6)]. Patients with 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)] The pharmacokinetics of levofloxacin in patients with serious community-acquired bacterial infections are comparable to those observed in healthy subjects. The potential for pharmacokinetic drug interactions between levofloxacin and antacids warfarin, theophylline, cyclosporine, digoxin, probenecid, and cimetidine has been evaluated [see Drug Interactions (7)]. 12.4 Microbiology 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. 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 ⛚-lactam antibiotics, including penicillins. Fluoroquinolones may, therefore, be active against bacteria resistant to these antimicrobials. 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): Aerobic bacteria Enterococcus faecalis Staphylococcus epidermidis (methicillin-susceptible isolates) Staphylococcus saprophyticus Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP]1) Streptococcus pyogenes Gram-Negative Bacteria Escherichia coli Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumoniae Legionella pneumophila Moraxella catarrhalis Proteus mirabilis Pseudomonas aeruginosa Serratia marcescens Chlamydophila pneumoniae Mycoplasma pneumoniae The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentrations (MIC) less than or equal to the susceptible breakpoint for levofloxacin against isolates of similar genus or organism group. However, efficacy of levofloxacin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials. Aerobic bacteria beta-hemolytic Streptococcus (Group C/F) beta - hemolytic Streptococcus (Group G) Streptococcus agalactiae Streptococcus milleri 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 Anaerobic bacteria Susceptibility Tests

1 INDICATIONS & USAGE 1.1 Nosocomial Pneumonia Levofloxacin tablets are indicated in adult patients for the treatment of nosocomial pneumonia due to methicillinsusceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, or Streptococcus pneumoniae. Adjunctive therapy should be used as clinically indicated. Where Pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with an antipseudomonal beta-lactam is recommended [see Clinical Studies (14.1)]. 1.2 Community-Acquired Pneumonia: 7 to 14 day Treatment Regimen Levofloxacin tablets are indicated in adult patients for the treatment of community-acquired pneumonia due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multidrug-resistant Streptococcus pneumoniae [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or 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.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole. 1.3 Community-Acquired Pneumonia: 5-day Treatment Regimen Levofloxacin tablets are indicated in adult patients for the treatment of community-acquired pneumonia due to Streptococcus pneumoniae (excluding multi-drug-resistant strains [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Dosage and Administration (2.1)and Clinical Studies (14.3)]. 1.4 Complicated Skin and Skin Structure Infections Levofloxacin tablets are indicated in adult patients for the treatment of complicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, or Proteus mirabilis [see Clinical Studies (14.5)]. 1.5 Uncomplicated Skin and Skin Structure Infections Levofloxacin tablets are indicated in adult patients 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, or Streptococcus pyogenes. 1.6 Chronic Bacterial Prostatitis Levofloxacin tablets are indicated in adult patients for the treatment of chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or methicillin-susceptible Staphylococcus epidermidis [see Clinical Studies (14.6)]. 1.7 Inhalational Anthrax (Post-Exposure) Levofloxacin tablets are indicated for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis in adults and pediatric patients, 6 months of age and older [see Dosage and Administration (2.2)]. . The effectiveness of levofloxacin tablets are based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin tablets has not been tested in humans for the post-exposure prevention of inhalation anthrax. The safety of levofloxacin tablets in adults for durations of therapy beyond 28 days or in pediatric patients for durations of therapy beyond 14 days has not been studied. Prolonged levofloxacin tablets therapy should only be used when the benefit outweighs the risk [see Clinical Studies (14.9)]. 1.8 Plague Levofloxacin tablets are indicated for treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis (Y. pestis) and prophylaxis for plague in adults and pediatric patients, 6 months of age and older [see Dosage and Administration (2.2)]. Efficacy studies of levofloxacin tablets could not be conducted in humans with plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals [see Clinical Studies (14.10)]. 1.9 Complicated Urinary Tract Infections: 5-day Treatment Regimen Levofloxacin tablets are indicated in adult patients for the treatment of complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis [see Clinical Studies (14.7)]. 1.10 Complicated Urinary Tract Infections: 10-day Treatment Regimen Levofloxacin tablets are indicated in adult patients for the treatment of complicated urinary tract infections (mild to moderate) due to Enterococcus faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa [see Clinical Studies (14.8)]. 1.11 Acute Pyelonephritis: 5 or 10-day Treatment Regimen Levofloxacin tablets are indicated in adult patients for the treatment of acute pyelonephritis caused by Escherichia coli, including cases with concurrent bacteremia [see Clinical Studies (14.7, 14.8)]. 1.12 Uncomplicated Urinary Tract Infections Levofloxacin tablets are indicated in adult patients 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 (5.1-5.15)] and for some patients uncomplicated urinary tract infection is self-limiting, reserve levofloxacin tablets for treatment of uncomplicated urinary tract infections in patients who have no alternative treatment options. 1.13 Acute Bacterial Exacerbation of Chronic Bhronchitis Levofloxacin tablets are indicated in adult patients for the treatment of acute bacterial exacerbation of chronic bronchitis (ABECB) due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis. Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions (5.1-5.15)] and for some patients ABECB is self-limiting, reserve levofloxacin tablets, USP for treatment of ABECB in patients who have no alternative treatment options. 1.14 Acute Bacterial Sinusitis: 5-day and 10-14day Treatment Regimens Levofloxacin tablets are indicated in adult patients for the treatment of acute bacterial sinusitis (ABS) due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis [see Clinical Studies (14.4)]. Because fluoroquinolones, including levofloxacin have been associated with serious adverse reactions [see Warnings and Precautions (5.1-5.15)] and for some patients ABS is self-limiting, reserve levofloxacin tablets for treatment of ABS in patients who have no alternative treatment options. 1.15 Usage 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 As with other drugs in this class, some isolates of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with levofloxacin tablets. Culture and susceptibility testing performed periodically during therapy will provide information about the continued susceptibility of the pathogens to the antimicrobial agent and also the possible emergence of bacterial resistance

2.1 Dosage of Levofloxacin Tablets in Adult Patients with Creatinine Clearance > 50mL/minute These recommendations apply to patients with creatinine clearance >= 50 mL/minute. For patients with creatinine clearance less than 50 mL/min, adjustments to the dosing regimen are required [see Dosage and Administration (2.3)]. Table 1: Dosage of Levofloxacin Tablets in Adult Patients with Creatinine Clearance greater than or equal to 50 mL/minute) Type of Infection* Dosed Every 24 hours Duration (days)dagger Nosocomial Pneumonia 750 mg 7 to 14 Community Acquired Pneumoniadouble dagger 500 mgdouble dagger 7 to 14double dagger Community Acquired Pneumoniasection 750 mgsection 5section 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 Inhalational Anthrax (Post-Exposure), adult and pediatric patients weighing 50 kg Þ,ß or greater 500 mg 60ß Plague, adult and pediatric patients weighing 50 kg à or greater Pediatric patients weighing 30 kg to less than 50 kg 500 mg 10 to 14 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 Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB) 500 mg 7 Acute Bacterial Sinusitis (ABS) 750 mg 5 500 mg 10 to 14 * Due to the designated pathogens [see Indications and Usage (1)]. section Due 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 This regimen is indicated for cUTI due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and AP due to E. coli, including cases with concurrent bacteremia. # This regimen is indicated for cUTI due to Enterococcus faecalis, Enterococcus cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa; and for AP due to E. coli. Þ Drug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis. 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)]. ß The 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 (5.12), Use in Specific Populations (8.4), and Clinical Studies (14.9)]. Prolonged levofloxacin tablets therapy should only be used when the benefit outweighs the risk. à Drug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis. Higher doses of levofloxacin tablets typically used for treatment of pneumonia can be used for treatment of plague, if clinically indicated. 2.2 Dosage of Levofloxacin Tablets in Pediatric Patients with Inhalational Anthrax or Plague Type of Infection* Dose Frequency Durationdagger Inhalational Anthrax (post-exposure)double dagger,section Pediatric patients weighing 50 kg or greater 500 mg every 24 hours 60 dayssection Pediatric patients weighing 30 kg to less than 50kg 250 mg every 12 hours 60 dayssection Plagueparagraph Pediatric patients weighing 50 kg or greater 500 mg every 24 hours 10 to 14 days Pediatric patients weighing 30 kg to less than 50 kg 250 mg every 12 hours 10 to 14 days * Due to Bacillus anthracis [see Indications and Usage (1.13)] and Yersinia pestis [see Indications and Usage (1.14)]. dagger Sequential therapy (intravenous levofloxacin injection to oral levofloxacin tablets) may be instituted at the discretion of the healthcare provider. double dagger Begin levofloxacin tablets as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis. section The safety of levofloxacin tablets in pediatric patients for durations of therapy beyond 14 days has not been studied. [see Warnings and Precautions (5.12), Use in Specific Populations (8.4), and Clinical Studies (14.9)]. Begin levofloxacin tablets as soon as possible after suspected or confirmed exposure to Yersinia pestis. 2.3 Dosage Adjustment in Adults with Renal Impairment In patients with renal impairment (creatinine clearance less than 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)]. No adjustment is necessary for patients with a creatinine clearance greater than or equal to 50mL/minute Table 3 shows how to adjust dose based on creatinine clearance. Creatinine Clearance greater than or equal to 50 mL/ minute Creatinine Clearance Creatinine Clearance Hemodialysis or Chronic Ambulatory Peritoneal Dialysis (CAPD) 750 mg every 24 hours 750 mg every 48 hours 500 mg every 24 hours 250 mg every 24 hours No dosage adjustment required No information on dosing adjustment is available 2.4 Drug Interaction With Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins 2.5 Important Administration Instructions

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: 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)]. 6.1 Clinical Trial Experience 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)]. Patients received levofloxacin doses of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. Treatment duration was usually 3en dash14 days, and the mean number of days on therapy was 10 days. Table 4: Common (>=1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin# System/Organ ClassSystem/Organ Class Adverse ReactionAdverse Reaction % System/Organ Class Adverse Reaction % * N=7274 dagger N=3758 (women) # pool of studies included IV and oral administration Table 5: Less Common (0.1 to 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin (N=7537) System/Organ ClassSystem/Organ Class Adverse ReactionAdverse Reaction System/Organ Class Adverse Reaction Infections and Infestations genital moniliasis Blood and Lymphatic System Disorders anemia Immune System Disorders allergic reaction [See Warnings and Precautions (5.6,5.7)] Metabolism and Nutrition Disorders hyperglycemia Psychiatric Disorders anxiety Nervous System Disorders tremor Respiratory, Thoracic and Mediastinal Disorders epistaxis Cardiac Disorders cardiac arrest Vascular Disorders phlebitis Gastrointestinal Disorders gastritis Hepatobiliary Disorders abnormal hepatic function Skin and Subcutaneous Tissue Disorders urticaria [see Warnings and Precautions (5.7)] Musculoskeletal and Connective Tissue Disorders arthralgia Renal and Urinary Disorders abnormal renal function *N=7274 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. 6.2 Postmarketing Experience 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 estimate their frequency or establish a causal relationship to drug exposure. System/Organ ClassSystem/Organ Class Adverse ReactionAdverse Reaction System/Organ Class Adverse Reaction Blood and Lymphatic System Disorders pancytopenia Immune System Disorders hypersensitivity reactions, sometimes fatal including: Psychiatric Disorders psychosis Nervous System Disorders exacerbation of myasthenia gravis [see Warnings and Precautions (5.5)] Eye Disorders uveitis Ear and Labyrinth Disorders hypoacusis Cardiac Disorders isolated reports of torsade de pointes Vascular Disorders vasodilatation Respiratory, Thoracic and Mediastinal Disorders isolated reports of allergic pneumonitis [see Warnings and Precautions (5.6)] Hepatobiliary Disorders hepatic failure (including fatal cases) Musculoskeletal and Connective Tissue Disorders tendon rupture [see Warnings and Precautions (5.2)] Renal and Urinary Disorders interstitial nephritis [see Warnings and Precautions (5.6)] General Disorders and Administration Site Conditions multi-organ failure Investigations prothrombin time prolonged

Levofloxacin tablets are contraindicated in persons with known hypersensitivity to levofloxacin, or other quinolone antibacterials [see Warnings and Precautions (5.3)].

8.1 Pregnancy Risk Summary Published information from case reports, case control studies and observational studies on levofloxacin administered during pregnancy have not identified any drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of levofloxacin to pregnant rats and rabbits during organogenesis at doses up to 9.4 times and 1.1 times the maximum recommended human dose (MRHD), respectively, did not result in teratogenicity. Fetal toxicity was seen in the rat study, but was absent at doses up to 1.2 times the maximum recommended human dose (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Levofloxacin was not teratogenic in an embryofetal development study in rats treated during organogenesis with oral doses as high as 810 mg/kg/day which corresponds to 9.4 times the MRHD (based upon doses normalized for total body surface area). The oral dose of 810 mg/kg/day (high dose) to rats caused decreased fetal body weight and increased fetal mortality that was not seen at the next lower dose (mid-dose, 90 mg/kg/day, equivalent to 1.2 times the MRHD (based upon doses normalized for total body surface area). Maternal toxicity was limited to lower weight gain in the mid and high dose groups. No teratogenicity was observed in an embryofetal development study in rabbits dosed orally during organogenesis with doses as high as 50 mg/kg/day, which corresponds to 1.1 times the MRHD (based upon doses normalized for total body surface area). Maternal toxicity at that dose consisted of lower weight gain and decreased food consumption relative to controls and abortion in four of sixteen dams. 8.2 Lactation Risk Summary Published literature reports that levofloxacin is present in human milk following intravenous and oral administration (see Data). There is no information regarding effects of levofloxacin on milk production or the breastfed infant. Because of the potential risks of serious adverse reactions, in breastfed infants, for most indications, a lactating woman may consider pumping and discarding breast milk during treatment with levofloxacin and an additional two days (five half-lives) after the last dose. Alternatively, advise a lactating woman that breastfeeding is not recommended during treatment with levofloxacin and for an additional two days (five half-lives) after the last dose [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. However, for inhalation anthrax (post exposure), during an incident resulting in exposure to anthrax, the risk-benefit assessment of continuing breastfeeding while the mother (and potentially the infant) is (are) on levofloxacin may be acceptable [see Dosage and Administration (2.2), Pediatric Use (8.4), and Clinical Studies (14.2)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for levofloxacin and any potential adverse effects on the breastfed child from levofloxacin or from the underlying maternal condition. Data A published literature reports that peak levofloxacin human milk concentration was 8.2 mg/L at 5 hours after dosing in a woman who received 500 mg of intravenous, followed by oral, levofloxacin daily. For an infant fed exclusively with human milk (approximately 900 ml/day), an estimated maximum daily dose of levofloxacin through breastfeeding is 5 mg (i.e., approximately 1% of maternal daily dose). The above data come from a single case and may not be generalizable to the general population of lactating women. 8.4 Pediatric Use Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. [see Warnings and Precautions [5.12] 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) andClinical 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 (1.8), Dosage and Administration (2.2) and Clinical Studies (14.10)]. Safety and effectiveness of levofloxacin tablets in pediatric patients below the age of six months have not been established. Pharmacokinetics following intravenous administration Dosage in Pediatric Patients with Inhalational Anthrax or Plague Adverse Reactions Table 7: Incidence of Musculoskeletal Disorders in Pediatric Clinical Trial Follow-up Period Levofloxacin Non-Fluoroquinolone* p-valuedagger 60 days 28 (2.1%) 8 (0.9%) p = 0.038 1 yeardouble dagger 46 (3.4%) 16 (1.8%) p = 0.025 * Non-Fluoroquinolone: ceftriaxone, amoxicillin/clavulanate, clarithromycin 8.5 Geriatric Use 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 (5.2); 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.g., Class IA or Class III antiarrhythmics) or in patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia) [see Warnings and Precautions (5.11)]. 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)]. 8.6 Renal Impairment Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in patients with renal impairment (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)]. 8.7 Hepatic Impairment Pharmacokinetic studies in patients with hepatic impairment 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.

7.1 Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins 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 multivitamin 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. 7.2 Warfarin 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) and Patient Counseling Information (17)]. 7.3 Antidiabetic Agents 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 (5.13); Adverse Reactions (6.2) and Patient Counseling Information (17)]. 7.4 Non-Steroidal Anti-Inflammatory Drugs 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)]. 7.5 Theophylline 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)]. 7.6 Cyclosporine 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 Cmax and ke were slightly lower while Tmax and t½ were slightly longer in the presence of cyclosporine than those observed in other studies without concomitant medication. The differences, however, are not considered to be clinically significant. Therefore, no dosage adjustment is required for levofloxacin or cyclosporine when administered concomitantly. 7.7 Digoxin 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. 7.8 Probenecid and Cimetidine No significant effect of probenecid or cimetidine on the Cmax of levofloxacin was observed in a clinical study involving healthy volunteers. The AUC and t½ of levofloxacin were higher while CL/F and CLR were lower during concomitant treatment of levofloxacin with probenecid or cimetidine compared to levofloxacin alone. However, these changes do not warrant dosage adjustment for levofloxacin when probenecid or cimetidine is co-administered. 7.9 Interactions with Laboratory or Diagnostic Testing 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 (approximately 10 or 19 times MRHD in mice and rats, respectively) and 250 mg/kg IV produced significant mortality (estimated to be greater than or equal to 50%) in rodents.
Non Clinical Toxicology
13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility In a lifetime bioassay in rats, levofloxacin exhibited no carcinogenic potential following daily dietary administration for 2 years; the highest dose (100 mg/kg/day) was 1.4 times the Maximum Recommended Human Dose (MRHD) (750 mg) after normalization for total 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 and E. coli), CHO/HGPRT forward mutation assay, mouse micronucleus test, mouse dominant lethal test, rat unscheduled DNA synthesis assay, and the mouse sister chromatid exchange assay. It was positive in the in vitro chromosomal aberration (CHL cell line) and sister chromatid exchange (CHL/IU cell line) assays. Levofloxacin caused no impairment of fertility or reproductive performance in rats at oral doses as high as 360 mg/kg/day, corresponding to 4.2 times the MRHD and intravenous doses as high as 100 mg/kg/day, corresponding to 1.2 times the MRHD after normalization for total body surface area. 13.2 Animal Toxicology & or Pharmacology Levofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see Warnings and Precautions (5.12)]. In immature dogs (4en dash5 months old), oral doses of 10 mg/kg/day for 7 days and intravenous doses of 4 mg/kg/day for 14 days of levofloxacin resulted in arthropathic lesions. Administration at oral doses of 300 mg/kg/day for 7 days and intravenous doses of 60 mg/kg/day for 4 weeks produced arthropathy in juvenile rats. Three-month old beagle dogs dosed orally with levofloxacin at 40 mg/kg/day exhibited clinically severe arthrotoxicity resulting in the termination of dosing at Day 8 of a 14-day dosing routine (dosing was terminated in the low and mid-dose groups on Day 9 due to similar findings at the mid-dose). Slight musculoskeletal clinical effects, in the absence of gross pathological or histopathological effects, resulted from the lowest dose level of 2.5 mg/kg/day (approximately 0.2-fold the pediatric dose based upon AUC comparisons). Synovitis and articular cartilage lesions were observed at the 10 and 40 mg/kg dose levels (approximately 0.7-fold and 2.4-fold the pediatric dose, respectively, based on AUC comparisons). Articular cartilage gross pathology and histopathology persisted to the end of the 18-week recovery period for those dogs from the 10 and 40 mg/kg/day dose levels. The low and mid-dose groups in that study were also evaluated by electron microscopy, revealing compound-related ultrastructural effects in articular cartilage chondrocytes at the end of treatment and at the end of recovery in both of those doses.
Clinical Studies
14.1 Nosocomial Pneumonia 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). Pathogen N Levofloxacin No. (%) of Patients Microbiologic/Clinical Outcomes N Imipenem/Cilastatin No. (%) of Patients Microbiologic/Clinical Outcomes MSSA* 21 14 (66.7)/13 (61.9) 19 13 (68.4)/15(78.9) P. aeruginosadagger 17 10 (58.8)/11 (64.7) 17 5 (29.4)/7 (41.2) S. marcescens 11 9 (81.8)/7 (63.6) 7 2 (28.6)/3 (42.9) E. coli 12 10 (83.3)/7 (58.3) 11 7 (63.6 )/8 (72.7) K. pneumoniae dagger 11 9 (81.8)/5 (45.5) 7 6 (85.7)/3 (42.9) H. influenzae 16 13 (81.3)/10 (62.5) 15 14 (93.3)/11(73.3) S. pneumoniae 4 3 (75.0)/3 (75.0) 7 5 (71.4)/4 (57.1) * Methicillin-susceptible S. aureus 14.2 Community-Acquired Pneumonia: 7-14 day Treatment Regimen 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, and Legionella pneumophila were 96%, 96%, and 70%, respectively. Microbiologic eradication rates across both studies are presented in Table 10. Table 10: Bacteriological 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 10 100.0 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 (MDRSP). MDRSP isolates are isolates resistant to two or more of the following antibacterials: penicillin (MIC >=2 mcg/mL), 2nd generation cephalosporins (e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole). Of 40 microbiologically evaluable patients with MDRSP isolates, 38 patients (95.0%) achieved clinical and bacteriologic success at post-therapy. The clinical and bacterial success rates are shown in Table 11. Table 11: Clinical and Bacterial Success Rates for Levofloxacin-Treated MDRSP in Community Acquired Pneumonia Patients (Population Valid for Efficacy) Screening Susceptibility Clinical Success Bacteriological Success* n/Ndagger % n/Ndouble dagger % Penicillin-resistant 16/17 94.1 16/17 94.1 2nd generation Cephalosporin resistant 31/32 96.9 31/32 96.9 Macrolide-resistant 28/29 96.6 28/29 96.6 Trimethoprim/ Sulfamethoxazole resistant 17/19 89.5 17/19 89.5 Tetracycline-resistant 12/12 100 12/12 100 * 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. dagger n=the number of microbiologically evaluable patients who were clinical successes; N=number of microbiologically evaluable patients in the designated resistance group. double dagger n=the number of MDRSP isolates eradicated or presumed eradicated in microbiologically evaluable patients; N=number of MDRSP isolates in a designated resistance group. Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in Table 12. Table 12: Clinical 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%) 14.3 Community-Acquired Pneumonia: 5-day Treatment Regimen 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 [-5.9, 5.4]. 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 13. Table 13: Bacteriological Eradication Rates (Community-Acquired Pneumonia) 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%) 14.4 Acute Bacterial Sinusitis: 5-day and 10-14 day Treatment Regimens 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. 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 14). Table 14: Clinical Success Rate by Pathogen at the TOC in Microbiologically Evaluable Subjects Who Underwent Antral Puncture (Acute Bacterial Sinusitis) Table 14: Clinical Success Rate by Pathogen at the TOC in Microbiologically Evaluable Subjects Who Underwent Antral Puncture (Acute Bacterial Sinusitis) PathogenPathogen Levofloxacin Levofloxacin Table 14: Clinical Success Rate by Pathogen at the TOC in Microbiologically Evaluable Subjects Who Underwent Antral Puncture (Acute Bacterial Sinusitis) Pathogen Levofloxacin Levofloxacin 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%) * 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. 14.5 Complicated Skin and Skin Structure Infections 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 +/- 4.7 days. 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. 14.6 Chronic Bacterial Prostatitis 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 [-12.58, 8.98] for levofloxacin minus ciprofloxacin). The overall eradication rates for pathogens of interest are presented in Table 15. Levofloxacin (N=136) Ciprofloxacin (N=125) Pathogen N Eradication N Eradication E. coli 15 14 (93.3%) 11 9 (81.8%) E. faecalis 54 39 (72.2%) 44 33 (75.0%) S. epidermidis * 11 9 (81.8%) 14 11 (78.6%) * Eradication rates shown are for patients who had a sole pathogen only; mixed cultures were excluded. Eradication rates for S. epidermidis when found with other co-pathogens are consistent with rates seen in pure isolates. 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 [-8.87, 13.27] 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 [-23.40, 2.89] for levofloxacin minus ciprofloxacin). 14.7 Complicated Urinary Tract Infections and Acute Pyelonephritis: 5-day Treatment Regimen 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 16. Levofloxacin Ciprofloxacin 400 mg IV/500 mg orally twice daily for 10 days Overall Difference [95% CI] n/N % n/N % Levofloxacin Ciprofloxacin mITT Population* Overall (cUTI or AP) 252/333 75.7 239/318 75.2 0.5 (-6.1, 7.1) cUTI 168/230 73.0 157/213 73.7 AP 84/103 81.6 82/105 78.1 Microbiologically Evaluable Populationdagger Overall (cUTI or AP) 228/265 86.0 215/241 89.2 -3.2 [-8.9, 2.5] cUTI 154/185 83.2 144/165 87.3 AP 74/80 92.5 71/76 93.4 Pathogen Bacteriological Eradication Rate (n/N) % Escherichia coli* 155/172 90 Klebsiella pneumoniae 20/23 87 Proteus mirabilis 12/12 100 * The predominant organism isolated from patients with AP was E. coli: 91% (63/69) eradication in AP and 89% (92/103) in patients with cUTI. 14.8 Complicated Urinary Tract Infections and Acute Pyelonephritis: 10-day Treatment Regimen 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 18. Table 18: 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 n/N % n/N % mITT Population dagger 174/209 83.3 184/219 84.0 Microbiologically Evaluable Populationdouble dagger 164/177 92.7 159/171 93.0 * 1en dash9 days posttherapy for 30% of subjects enrolled prior to a protocol amendment; 5en dash12 days posttherapy for 70% of subjects. 14.9 Inhalational Anthrax (Post-Exposure) 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) and Dosage and Administration (2.1, 2.2)]. 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 5.7 +/- 1.4 and 6.4 +/- 0.8 mcg/mL, respectively; and the corresponding total plasma exposure (AUC0-24) is 47.5 +/- 6.7 and 54.6 +/- 11.1 mcg.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)]. Levofloxacin tablets can only be administered to pediatric patients with inhalational anthrax (post-exposure) or plague who are 30 kg or greater due to the limitations of the available strengths [see Dosage and Administration (2.2 )]. 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 (5.12) and Use in Specific Populations (8.4)]. A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 49 LD50 (~2.7 X 106) spores (range 17 - 118 LD50) of B. anthracis (Ames strain) was conducted. The minimal inhibitory concentration (MIC) of levofloxacin for the anthrax strain used in this study was 0.125 mcg/mL. In the animals studied, mean plasma concentrations of levofloxacin achieved at expected Tmax (1 hour post dose) following oral dosing to steady state ranged from 2.79 to 4.87 mcg/mL. Steady state trough concentrations at 24 hours post-dose ranged from 0.107 to 0.164 mcg/mL. Mean (SD) steady state AUC0-24 was 33.4 +/- 3.2 mcg.h/mL (range 30.4 to 36.0 mcg.h/mL). Mortality due to anthrax for animals that received a 30 day regimen of oral levofloxacin beginning 24 hrs post exposure was significantly lower (1/10), compared to the placebo group (9/10) [P=0.0011, 2-sided Fisher''s Exact Test]. The one levofloxacin treated animal that died of anthrax did so following the 30-day drug administration period. 14.10 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.
Medication Guide
MEDICATION GUIDE What is the most important information I should know about levofloxacin tablets? Levofloxacin tablets, 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. Tendon problems can happen in people who do not have the above risk factors when they take levofloxacin tablets. Other reasons that can increase your risk of tendon problems can include: The nerve damage may be permanent nosocomial pneumonia plague skin infections, complicated and uncomplicated acute kidney infection (pyelonephritis) have tendon problems. Levofloxacin tablets should not be used in people who have a history of tendon problems. are breastfeeding or plan to breastfeed. It is not known if levofloxacin passes into your breast milk. You should not breastfeed during treatment with levofloxacin and for 2 days after taking your last dose of levofloxacin. You may pump your breast milk and throw it away during treatment with levofloxacin and for 2 days after taking your last dose of levofloxacin. a blood thinner (warfarin, Coumadin, Jantoven). Ask your healthcare provider if you are not sure if any of your medicines are listed above. How should I take levofloxacin tablets? Drink plenty of fluids while you take levofloxacin tablets. Levofloxacin tablets can be taken with or without food. Do not skip any doses of levofloxacin tablets or stop taking it, even if you begin to feel better, until you finish your prescribed treatment unless: o you have a nerve problem. See “What is the most important information I should know about levofloxacin tablets?”. o you have a central nervous sytem problem. See “What is the most important information I should know about levofloxacin tablets?”. o you have a serious allergic reaction. See “What are the possible side effects of levofloxacin tablets?”. o your healthcare provider tells you to stop taking levofloxacin tablets Taking all of your levofloxacin tablets doses will help make sure that all of the bacteria are killed. Taking all of your levofloxacin tablets doses will help you lower the chance that the bacteria will become resistant to levofloxacin tablets. If your infection does not get better while you take levofloxacin tablets, it may mean that the bacteria causing your infection may be resistant to levofloxacin tablets. If your infection does not get better, call your healthcare provider. If your infection does not get better, levofloxacin tablets and other similar antibiotic medicines may not work for you in the future. If you take too much levofloxacin tablets, call your healthcare provider or get medical help right away. What are the possible side effects of levofloxacin tablets? Serious allergic reactions. Allergic reactions can happen in people taking fluoroquinolones, including levofloxacin tablets, even after only 1 dose. Stop taking levofloxacin tablets and get emergency medical help right away if you have any of the following symptoms of a severe allergic reaction: Intestine infection (Clostridium difficile-associated diarrhea). Clostridium difficile-associated diarrhea (CDAD) can happen with many antibiotics, including levofloxacin tablets. 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. CDAD can happen 2 or more months after you have finished your antibiotic. Joint Problems Sensitivity to sunlight (photosensitivity) In children 6 months and older who take levofloxacin to treat anthrax disease or plague, vomiting is also common. Store levofloxacin tablets at 20º to 25º C (68º to 77º F); excursions permitted to 15º to 30º C (59º to 86º F). General information about the safe and effective use of levofloxacin tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use levofloxacin tablets for a condition for which it is not prescribed. Do not give levofloxacin tablets 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 tablets. If you would like more information about levofloxacin tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about levofloxacin tablets that is written for health professionals. For more information, call 1-888-943-3210 Active ingredient: levofloxacin. Inactive ingredients: hypromellose, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, titanium dioxide, polysorbate 80. Levofloxacin tablets 250 mg also contain synthetic red iron oxide, levofloxacin tablets 500 mg also contain synthetic red and yellow iron oxides. The brands listed are trademarks of their respective owners. Manufactured for: Manufactured by: This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: August 2019

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LEVOFLOXACIN- levofloxacin_tablet, film coated Product manual source documgent