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 administration of the oral tablets, are summarized in Table 8. Table 8 Mean +/-SD Levofloxacin PK Parameters 1 2 3 4 5 6 7 8 * ND=not determined. Regimen C max T max AUC (mcg h/mL) CL/F 1 (mL/min) Vd/F 2 (L) t 1/2 CL R 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 impairment: 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 Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral or IV dosing regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once-daily dosage regimen. The mean +/- SD peak and trough plasma concentrations attained following multiple once-daily oral dosage regimens were approximately 5. 2 mcg/mL after the 500 mg doses, and 8. 4 mcg/mL after the 750 mg doses, respectively. The mean +/- SD peak and trough plasma concentrations attained following multiple once-daily IV regimens were approximately 6. 2 mcg/mL after the 500 mg doses, and 12. 71 mcg/mL after the 750 mg doses, respectively. Absorption Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak plasma concentrations are usually attained one to two hours after oral dosing. The absolute bioavailability of levofloxacin from a 500 mg tablet and a 750 mg tablet of levofloxacin are both approximately 99%, demonstrating complete oral absorption of levofloxacin. Following a single intravenous dose of levofloxacin to healthy volunteers, the mean +/- SD peak plasma concentration attained was 6. 0 mcg/mL after a 500 mg dose infused over 60 minutes and 11. 0 mcg/mL after a 750 mg dose infused over 90 minutes. Oral administration of a 500 mg dose of levofloxacin with food prolongs the time to peak concentration by approximately 1 hour and decreases the peak concentration by approximately 14% following tablet and approximately 25% following oral solution administration. Therefore, levofloxacin tablets can be administered without regard to food. 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. 3 mcg/g over a 24 hour period after a single 500 mg oral dose. In vitro Elimination 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 Geriatric Patients 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 Pediatric Patients 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 see Dosage and Administration ( 2. 2 Male and Female Subjects 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. Racial or Ethnic Groups 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. 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 Patients with Bacterial Infection The pharmacokinetics of levofloxacin in patients with serious community-acquired bacterial infections are comparable to those observed in healthy subjects. Drug Interaction Studies The potential for pharmacokinetic drug interactions between levofloxacin and antacids, warfarin, theophylline, cyclosporine, digoxin, probenecid, and cimetidine has been evaluated [see Drug Interactions ( 7 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. 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 Antimicrobial Activity 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 Aerobic bacteria Gram-Positive Bacteria Enterococcus faecalis Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus pneumoniae 1 Streptococcus pyogenes 1 Streptococcus pneumoniae nd Gram-Negative Bacteria Enterobacter cloacae Escherichia coli Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumoniae Legionella pneumophila Moraxella catarrhalis Proteus mirabilis Pseudomonas aeruginosa Serratia marcescens Other microorganisms Chlamydophila pneumoniae Mycoplasma pneumoniae The following in vitro in vitro Aerobic bacteria Gram-Positive Bacteria Staphylococcus haemolyticus beta-hemolytic Streptococcus beta-hemolytic Streptococcus Streptococcus agalactiae Streptococcus milleri Viridans group streptococci Bacillus anthracis Gram-Negative Bacteria Acinetobacter baumannii Acinetobacter lwoffii Bordetella pertussis Citrobacter koseri Citrobacter freundii Enterobacter aerogenes Enterobacter sakazakii Klebsiella oxytoca Morganella morganii Pantoea agglomerans Proteus vulgaris Providencia rettgeri Providencia stuartii Pseudomonas fluorescens Yersinia pestis Anaerobic Bacteria Gram-Positive Bacteria Clostridium perfringens Susceptibility Tests For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.

Levofloxacin 1 12. 12 1. 11 1. 13 1. 14 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 bacteria ( 1. 15 Levofloxacin tablet is indicated in adult patients 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 in adult patients 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 in adult patients 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 in adult patients 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 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 Streptococcus pyogenes Levofloxacin tablet is indicated in adult patients 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 inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis [see Dosage and Administration ( 2. 2 [see Clinical Studies ( 14. 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 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 Levofloxacin tablet is indicated in adult patients 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 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, Pseudomonas aeruginosa [see Clinical Studies ( 14. 8 Levofloxacin tablet is indicated in adult patients for the treatment of acute pyelonephritis caused by Escherichia coli [see Clinical Studies ( 14. 8 Levofloxacin tablet Escherichia coli, Klebsiella pneumoniae, Staphylococcus saprophyticus Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions ( 5 Levofloxacin tablet is 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 Moraxella catarrhalis Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions ( 5 Levofloxacin tablet is indicated in adult patients for the treatment of acute bacterial sinusitis (ABS) due to Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis [see Clinical Studies ( 14. 4 Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions ( 5 To reduce the development of drug-resistant bacteria and maintain the effectiveness of levofloxacin and other antibacterial drugs, levofloxacin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Culture and Susceptibility Testing Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to levofloxacin [see Microbiology ( 12. 4 As with other drugs in this class, some isolates of Pseudomonas aeruginosa.

2 Dosage in Adult and Pediatric Patients with Creatinine Clearance greater than or equal to 50 mL/minute ( 2. 2 Type of Infection Dose Every 24 hours Duration (days) Nosocomial Pneumonia ( 1. 1 750 mg 7 to 14 Community Acquired Pneumonia ( 1. 2 500 mg 7 to 14 Community Acquired Pneumonia ( 1. 3 750 mg 5 Complicated SSSI ( 1. 4 750 mg 7 to 14 Uncomplicated SSSI ( 1. 5 500 mg 7 to 10 Chronic Bacterial Prostatitis ( 1. 6 500 mg 28 Inhalational Anthrax (Post-Exposure) ( 1. 7 Adults and Pediatric Patients 50 kg or greater 500 mg 60 Pediatric Patients 30 kg to less than 50 kg (2. 2) 250 mg every 12 hours 60 Plague ( 1. 8 Adults and Pediatric Patients 50 kg or greater 500 mg 10 to 14 Pediatric Patients 30 kg to less than 50 kg (2. 2) 250 mg every 12 hours 10 to 14 Complicated UTI ( 1. 11 750 mg 5 Complicated UTI ( 1. 11 250 mg 10 Uncomplicated UTI ( 1. 12 250 mg 3 Acute Bacterial Exacerbation of Chronic Bronchitis ( 1. 13 500 mg 7 Acute Bacterial Sinusitis ( 1. 14 750 mg 5 500 mg 10 to 14 2. 3 The usual dose of levofloxacin tablets is 250 mg, 500 mg, or 750 mg administered orally every 24 hours, as indicated by infection and described in Table 1. These recommendations apply to patients with creatinine clearance >= 50 mL/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 * [see Indications and Usage ( 1 dagger double dagger Staphylococcus aureus, Streptococcus pneumoniae Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae [see Indications and Usage ( 1. 2 section Streptococcus pneumoniae Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, 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. anthracis [see Clinical Studies ( 14. 9 ß [see Warnings and Precautions ( 5. 9 à Yersinia pestis Type of Infection * Dosed Every 24 hours Duration (days) dagger Nosocomial Pneumonia 750 mg 7 to 14 Community Acquired Pneumonia double dagger 500 mg 7 to 14 Community Acquired Pneumonia section 750 mg 5 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 Þ, ß 500 mg 60 ß ß Plague, adult and pediatric patients weighing 50 kg à à 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 The dosage of levofloxacin tablets for inhalational anthrax (post-exposure) and plague in pediatric patients who weigh 30 kg or greater is described below in Table 2. Levofloxacin tablets cannot be administered to patients who weigh less than 30 kg because of the limitations of the available strength. Alternative formulations of levofloxacin may be considered for pediatric patients who weigh less than 30 kg. Table 2 Levofloxacin Tablets Dosage in Pediatric Patients Weighing 30 kg or greater with Inhalational Anthrax (Post-Exposure) and Plague* * Bacillus anthracis [see Indications and Usage ( 1. 14 dagger double dagger B. anthracis section [see Warnings and Precautions ( 5. 9 Yersinia pestis Type of Infection * Dose Frequency Duration dagger Inhalational Anthrax (post-exposure) double dagger,section Pediatric patients weighing 50 kg or greater 500 mg every 24 hours 60 days section Pediatric patients weighing 30 kg to less than 50 kg 250 mg every 12 hours 60 days section Plague paragraph 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 Administer levofloxacin tablets 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 Table 3 shows how to adjust dose based on creatinine clearance. Table 3 Dosage Adjustment in Adult Patients with Renal Impairment (Creatinine Clearance less than 50 mL/minute) Creatinine Clearance greater than or equal to 50 mL/minute Creatinine Clearance 20 to 49 mL/minute Creatinine Clearance 10 to 19 mL/minute Hemodialysis or Chronic Ambulatory Peritoneal Dialysis (CAPD) 750 mg every 24 hours 750 mg every 48 hours 750 mg initial dose, then 500 mg every 48 hours 750 mg initial dose, then 500 mg every 48 hours 500 mg every 24 hours 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 every 24 hours 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 should be administered at least two hours before or two hours after antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine chewable/buffered tablets or the pediatric powder for oral solution [see Drug Interactions ( 7. 1 17 Levofloxacin tablets can be administered without regard to food. If patients miss a dose, they should take it as soon as possible anytime up to 8 hours prior to their next scheduled dose. If less than 8 hours remain before the next dose, wait until their next scheduled dose. Adequate hydration of patients receiving 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.

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS,TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS
WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS See full prescribing information for complete boxed warning. Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together ( 5. 1 o Tendinitis and tendon rupture ( 5. 2 o Peripheral neuropathy ( 5. 3 o Central nervous system effects ( 5. 4 Discontinue levofloxacin immediately and avoid the use of fluoroquinolones, including levofloxacin, in patients who experience any of these serious adverse reactions ( 5. 1 Fluoroquinolones, including levofloxacin, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid levofloxacin [see Warnings and Precautions ( 5. 5 Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions ( 5 o Uncomplicated urinary tract infection ( 1. 12 o Acute bacterial exacerbation of chronic bronchitis ( 1. 13 o Acute bacterial sinusitis ( 1. 14 Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together [see Warnings and Precautions ( 5. 1 o Tendinitis and tendon rupture [see Warnings and Precautions ( 5. 2 o Peripheral neuropathy [see Warnings and Precautions ( 5. 3 o Central nervous system effects [see Warnings and Precautions ( 5. 4 Discontinue levofloxacin immediately and avoid the use of fluoroquinolones, including levofloxacin, in patients who experience any of these serious adverse reactions [see Warnings and Precautions ( 5. 1 Fluoroquinolones, including levofloxacin , may exacerbate muscle weakness in patients with myasthenia gravis. Avoid levofloxacin in patients with a known history of myasthenia gravis [see Warnings and Precautions ( 5. Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions ( 5 o Uncomplicated urinary tract infection [see Indications and Usage ( 1. 12 o Acute bacterial exacerbation of chronic bronchitis [see Indications and Usage ( 1. 13 o Acute bacterial sinusitis [see Indications and Usage ( 1.
ADVERSE REACTIONS
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: [see Warnings and Precautions ( 5. 1 [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. 4 [see Warnings and Precautions ( 5. 5 [see Warnings and Precautions ( 5. 6 [see Warnings and Precautions ( 5. 7 [see Warnings and Precautions ( 5. 8 [see Warnings and Precautions ( 5. 9 Clostridium difficile [see Warnings and Precautions ( 5. 10 [see Warnings and Precautions ( 5. 11 [see Warnings and Precautions ( 5. 12 [see Warnings and Precautions ( 5. 13 [see Warnings and Precautions ( 5. 14 [see Warnings and Precautions ( 5. 15 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 The most common reactions (>= 3%) were nausea, headache, diarrhea, insomnia, constipation and dizziness ( 6. 2 To report SUSPECTED ADVERSE REACTIONS, contact Viona Pharmaceuticals Inc. at 1-888-304-5011 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 [see Indications and Usage ( 1 The overall incidence, type and distribution of adverse reactions was similar in patients receiving levofloxacin doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation of levofloxacin Adverse reactions occurring in >= 1% of levofloxacin-treated patients and less common adverse reactions, occurring in 0. 1 to < 1% of levofloxacin-treated patients, are shown in Table 4 and Table 5, respectively. The most common adverse drug reactions (>= 3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness. Table4 Common ( >= 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin # * dagger # pool of studies included IV and oral administration System/Organ Class Adverse Reaction % (N=7,537) Infections and Infestations moniliasis 1 Psychiatric Disorders Insomnia * [see Warnings and Precautions ( 5. 4 4 Nervous System Disorders headache [see Warnings and Precautions ( 5. 4 6 Respiratory, Thoracic and Mediastinal Disorders dyspnea [see Warnings and Precautions ( 5. 7 1 Gastrointestinal Disorders nausea 7 Skin and Subcutaneous Tissue Disorders rash [see Warnings and Precautions ( 5. 7 2 Reproductive System and Breast Disorders vaginitis 1 dagger General Disorders and Administration Site Conditions edema 1 Table 5 Less Common (0. 1 to 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin (N=7,537) * System/Organ Class Adverse Reaction Infections and Infestations genital moniliasis Blood and Lymphatic System Disorders anemia thrombocytopenia granulocytopenia [see Warnings and Precautions ( 5. 6 Immune System Disorders allergic reaction [see Warnings and Precautions ( 5. 7 Metabolism and Nutrition Disorders hyperglycemia hypoglycemia [see Warnings and Precautions ( 5. 13 hyperkalemia Psychiatric Disorders anxiety agitation confusion depression hallucination nightmare * [see Warnings and Precautions ( 5. 4 sleep disorder * anorexia abnormal dreaming * Nervous System Disorders tremor convulsions [see Warnings and Precautions ( 5. 4 paresthesia [see Warnings and Precautions ( 5. 3 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 pseudomembranous/ C. difficile [see Warnings and Precautions ( 5. 10 Hepatobiliary Disorders abnormal hepatic function increased hepatic enzymes increased alkaline phosphatase Skin and Subcutaneous Tissue Disorders urticaria [see Warnings and Precautions ( 5. 7 Musculoskeletal and Connective Tissue Disorders arthralgia tendinitis [see Warnings and Precautions ( 5. 2 myalgia skeletal pain Renal and Urinary Disorders abnormal renal function acute renal failure [see Warnings and Precautions ( 5. 6 In clinical trials using multiple-dose therapy, ophthalmologic abnormalities, including cataracts and multiple punctate lenticular opacities, have been noted in patients undergoing treatment with quinolones, including levofloxacin. The relationship of the drugs to these events is not presently established. Table 6 lists adverse reactions that have been identified during post-approval use of levofloxacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Table 6 Postmarketing 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. 6 eosinophilia Immune System Disorders hypersensitivity reactions, sometimes fatal including: [see Warnings and Precautions ( 5. 7 Psychiatric Disorders psychosis paranoia isolated reports of suicidal ideation, suicide attempt and completed suicide [see Warnings and Precautions ( 5. 4 Nervous System Disorders exacerbation of myasthenia gravis [see Warnings and Precautions ( 5. 5 [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. 4 Eye Disorders uveitis Ear and Labyrinth Disorders hypoacusis tinnitus Cardiac Disorders isolated reports of torsade de pointes [see Warnings and Precautions ( 5. 11 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) hepatitis jaundice [see Warnings and Precautions ( 5. 8 Skin and Subcutaneous Tissue Disorders bullous eruptions to include: Stevens-Johnson Syndrome toxic epidermal necrolysis Acute Generalized Exanthematous Pustulosis (AGEP) fixed drug eruptions erythema multiforme [see Warnings and Precautions ( 5. 6 photosensitivity/phototoxicity reaction [see Warnings and Precautions ( 5. 14 leukocytoclastic vasculitis 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 international normalized ratio prolonged muscle enzymes increased.

Known hypersensitivity to levofloxacin 4 5. 7 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. 10 Lactation 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. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 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. 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. 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. , 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. Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species [see Warnings and Precautions ( 5. 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. 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. 8), Dosage and Administration ( 2. 10 Safety and effectiveness of levofloxacin in pediatric patients below the age of six months have not been established. 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 Dosage in Pediatric Patients with Inhalational Anthrax or Plague For the recommended levofloxacin tablet dosage in pediatric patients with inhalational anthrax or plague [see Dosage and Administration ( 2. 2 Adverse Reactions In clinical trials, 1,534 pediatric patients (6 months to 16 years of age) were treated with oral and intravenous levofloxacin. Pediatric patients 6 months to 5 years of age received levofloxacin 10 mg/kg twice a day and pediatric patients greater than 5 years of age received 10 mg/kg once a day (maximum 500 mg per day) for approximately 10 days. 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 A subset of pediatric patients in the clinical trials (1,340 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. Pediatric patients treated with levofloxacin had a significantly higher incidence of musculoskeletal disorders when compared to the non-fluoroquinolone-treated children as illustrated in Table 7. 2 Table 7 Incidence of Musculoskeletal Disorders in Pediatric Clinical Trial * dagger double dagger Follow-up Period Levofloxacin N = 1,340 Non-Fluoroquinolone* N = 893 p-value 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 pediatric patients and most were treated with analgesics. The median time to resolution was 7 days for levofloxacin-treated pediatric patients and 9 for non-fluoroquinolone-treated children (approximately 80% resolved within 2 months in both groups). No pediatric patient had a severe or serious disorder and all musculoskeletal disorders resolved without sequelae. Vomiting and diarrhea were the most frequently reported adverse reactions, occurring in similar frequency in the levofloxacin-treated and non-fluoroquinolone-treated pediatric patients. In addition to the adverse reactions reported in pediatric patients in clinical trials, adverse reactions reported in adults during clinical trials or post-marketing experience [see Adverse Reactions ( 6 Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as levofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing levofloxacin [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 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 [see Warnings and Precautions ( 5. 9 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. 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 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 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.

RECENT MAJOR CHANGES
Warnings and Precautions Hypersensitivity Reactions ( 5.7 06/2024
DRUG INTERACTIONS
Interacting Drug Interaction Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablets are taken within 2 hours of these products. 1 Warfarin Effect may be enhanced. Monitor prothrombin time, INR and watch for bleeding ( 7. 2 Antidiabetic agents Carefully monitor blood glucose ( 5. 3 While the chelation by divalent cations is less marked than with other fluoroquinolones, concurrent administration of levofloxacin tablets with antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc may interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired. Tablets with antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and 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 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 [see Adverse Reactions ( 6. 3 17 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. 2 17 The concomitant administration of a non-steroidal anti-inflammatory drug with a fluoroquinolone, including levofloxacin, may increase the risk of CNS stimulation and convulsive seizures [see Warnings and Precautions ( 5. 4 No significant effect of levofloxacin on the plasma concentrations, AUC, and other disposition parameters for theophylline was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of theophylline on levofloxacin absorption and disposition was observed. However, concomitant administration of other fluoroquinolones with theophylline has resulted in prolonged elimination half-life, elevated serum theophylline levels, and a subsequent increase in the risk of theophylline-related adverse reactions in the patient population. Therefore, theophylline levels should be closely monitored and appropriate dosage adjustments made when levofloxacin is co-administered. Adverse reactions, including seizures, may occur with or without an elevation in serum theophylline levels [see Warnings and Precautions ( 5. 4 No significant effect of levofloxacin 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 1,500 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.
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 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. Levofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see Warnings and Precautions (5. 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 1,000 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 post-therapy 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 post-therapy visit were 66. 7% for levofloxacin and 60. The 95% CI for the difference of eradication rates (levofloxacin minus comparator) was [-8. Clinical success and microbiological eradication rates by pathogen are detailed in Table 9. Table 9 Clinical Success Rates and Bacteriological Eradication Rates (Nosocomial Pneumonia) * S. aureus dagger double dagger Pathogen N Levofloxacin No. (%) of Patients Microbiologic/ Clinical Outcomes N Imipenem/Cilastatin No. (%) of Patients Microbiologic/ Clinical Outcomes MSSA * 21 14 (66. 9) 19 13 (68. aeruginosa dagger 17 10 (58. 7) 17 5 (29. marcescens 11 9 (81. coli 12 10 (83. 3) 11 7 (63. pneumoniae double dagger 11 9 (81. influenzae 16 13 (81. 5) 15 14 (93. pneumoniae 4 3 (75)/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 post-therapy, and 3 to 4 weeks post-therapy. Clinical success (cure plus improvement) with levofloxacin at 5 to 7 days post-therapy, the primary efficacy variable in this study, was superior (95%) to the control group (83%). The 95% CI for the difference of response rates (levofloxacin minus comparator) was [-6, 19]. In the second study, 264 patients were enrolled in a prospective, multi-center, non-comparative trial of 500 mg levofloxacin administered orally or intravenously once daily for 7 to 14 days. Clinical success for clinically evaluable patients was 93%. For both studies, the clinical success rate in patients with atypical pneumonia due to Chlamydophila pneumoniae, Mycoplasma pneumoniae Legionella pneumophila 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 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 11 Clinical and Bacterial Success Rates for Levofloxacin-Treated MDRSP in Community Acquired Pneumonia Patients (Population Valid for Efficacy) * dagger double dagger Screening Susceptibility Clinical Success Bacteriological Success * 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 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%) 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 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%) 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 (see Table 14). Table 14 Clinical 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 15 Bacteriological Eradication Rates (Chronic Bacterial Prostatitis) * mixed cultures were excluded. Levofloxacin (N=136) Ciprofloxacin (N=125) Pathogen N Eradication N Eradication E. coli 15 14 (93. 3%) 11 9 (81. faecalis 54 39 (72. 2%) 44 33 (75%) 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, 1,109 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. Table 16 Bacteriological Eradication at Test-of-Cure * 5 dagger 5 Levofloxacin 750 mg orally or IV once daily for 5 days Ciprofloxacin 400 mg IV/500 mg orally twice daily for 10 days Overall Difference [95% CI] n/N % n/N % Levofloxacin-Ciprofloxacin mITT Population * 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 17. Table 17 Bacteriological Eradication Rates for Individual Pathogens Recovered From Patients Randomized to Levofloxacin 750 mg QD for 5 Days Treatment * E. coli Pathogen Bacteriological Eradication Rate (n/N) % 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 18. Table 18 Bacteriological Eradication Overall (cUTI or AP) at Test-Of-Cure * * dagger double dagger 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 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 [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. 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. 14 and Dosage and Administration ( 2. 2 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.

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