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 Regimen C max T max AUC (mcg·h/mL) CL/F 1 Vd/F 2 t 1/2 CL R min) Single dose 250 mg oral tablet 3 2. 9 156 +/- 20 ND 7. 9 142 +/- 21 500 mg oral tablet 3* 5. 8 178 +/- 28 ND 6. 6 103 +/- 30 750 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. 2 136 +/- 44 62 +/- 16 6. 8 106 +/- 40 Young 7 5. 8 182 +/- 35 83 +/- 18 6. 9 140 +/- 33 Elderly 8 7. 3 121 +/- 33 67 +/- 19 7. 0 91 +/- 29 500 mg oral single dose tablet, patients with renal impairment: CLCR 50en dash80 mL/min 7. 8 88 +/- 10 ND 9. 9 57 +/- 8 CLCR 20en dash49 mL/min 7. 6 51 +/- 19 ND 27 +/- 10 26 +/- 13 CLCR <20 mL/min 8. 5 33 +/- 8 ND 35 +/- 5 13 +/- 3 Hemodialysis 5. 2 ND ND ND 76 +/- 42 ND CAPD 6. 1 ND ND ND 51 +/- 24 ND 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. 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 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 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. Elimination Metabolism Excretion 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 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. 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 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 Use in Specific Populations ( 8. 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 ]. 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 ⛚-lactam antibiotics, including penicillins. Fluoroquinolones may, therefore, be active against bacteria resistant to these antimicrobials. Resistance to levofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10 -9 -10 Antimicrobial Activity 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 Enterococcus faecalis Staphylococcus aureus (methicillin-susceptible isolates) Staphylococcus epidermidis (methicillin-susceptible isolates) Staphylococcus saprophyticus Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP] 1 Streptococcus pyogenes 1 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 data are available, but their clinical significance is unknown Aerobic bacteria Staphylococcus haemolyticus beta-hemolytic Streptococcus (Group C/F) beta - hemolytic Streptococcus (Group G) Streptococcus agalactiae Streptococcus milleri Viridans group streptococci Bacillus anthracis 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 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 tablets are fluoroquinolone antibacterial indicated in adults (18 years of age and older) with infections caused by designated, susceptible bacteria and in pediatric patients where indicated ( 1 12. 15 Levofloxacin tablets are 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, or Streptococcus pneumoniae. Adjunctive therapy should be used as clinically indicated. Where Pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with an anti-pseudomonal beta-lactam is recommended [see Clinical Studies ( 14. Levofloxacin tablets are 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 Dosage and Administration ( 2. 1 ) and Clinical Studies ( 14. 2 MDRSP isolates are isolates resistant to two or more of the following antibacterials: penicillin (MIC >=2 mcg/mL), 2 nd Levofloxacin tablets are indicated in adult patients for the treatment of community-acquired pneumonia due to Streptococcus pneumoniae Haemophilus influenzae Haemophilus parainfluenzae Mycoplasma pneumoniae Chlamydophila pneumoniae [see Dosage and Administration ( 2. 1 Clinical Studies ( 14. 3 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, Proteus mirabilis [see Clinical Studies ( 14. 5 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. Levofloxacin tablets are 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 tablets are 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 Prolonged levofloxacin tablets therapy should only be used when the benefit outweighs the risk [see Clinical Studies ( 14. 9 Levofloxacin tablets are indicated for treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis (Y. pestis) Dosage and Administration ( 2. 2 see Clinical Studies ( 14. 10 Levofloxacin tablets are 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 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 Pseudomonas aeruginosa [see Clinical Studies ( 14. 8 Levofloxacin tablets are indicated in adult patients for the treatment of acute pyelonephritis caused by Escherichia coli [see Clinical Studies ( 14. 8 Levofloxacin tablets are indicated in adult patients for the treatment of uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae, Staphylococcus saprophyticus. Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions ( 5. 15 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 Moraxella catarrhalis. [see Warnings and Precautions ( 5. 15 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. 15 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 see Microbiology ( 12. 4 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.

Administer levofloxacin tablets to pediatric patients weighing 30 kg and greater only ( 2. 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. 2 500 mg 60 Plague ( 1. 2 500 mg 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 Adjust dose for creatinine clearance less than 50 mL/minute ( 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) Type of Infection* Dosed Every 24 hours Duration (days) dagger Nosocomial Pneumonia 750 mg 7 to 14 Community Acquired Pneumonia double dagger 500 mg double dagger 7 to 14 double dagger Community Acquired Pneumonia section 750 mg section 5 section 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 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 Staphylococcus aureus, Streptococcus pneumoniae Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae see Indications and Usage ( 1. 2 section Due to Streptococcus pneumoniae Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, Chlamydophila pneumoniae see Indications and Usage ( 1. 3 paragraph This regimen is indicated for cUTI due to Escherichia coli, Klebsiella pneumoniae Proteus mirabilis E. coli # This regimen is indicated for cUTI due to Enterococcus faecalis, Enterococcus cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa E. coli Þ Drug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis 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. 9 à Drug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis 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* 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 50kg 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 * Due to Bacillus anthracis [see Indications and Usage ( 1. 13 Indications and Usage ( 1. 14 Warnings and Precautions ( 5. 9 Administer levofloxacin with caution in patients with renal impairment. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of levofloxacin may be reduced in these patients. [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 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 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 can be administered without regard to food. 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.

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS,TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS
Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together [ see Warnings and Precautions ( 5. 1 see Warnings and Precautions ( 5. 2 see Warnings and Precautions ( 5. 3 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. 5 Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [ see Warnings and Precautions (5. 15) see Indications and Usage ( 1. 12 see Indications and Usage ( 1. 13 see Indications and Usage ( 1. 14 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 in patients with a known history of myasthenia gravis [see Warnings and Precautions ( 5. 5 Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions ( 5. 15 o Uncomplicated urinary tract infection ( 1. 12 o Acute bacterial exacerbation of chronic bronchitis ( 1. 13 o Acute bacterial sinusitis ( 1.
ADVERSE REACTIONS
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: Disabling and Potentially Irreversible Serious Adverse Reactions [see Warnings and Precautions ( 5. 1 Tendinitis and Tendon Rupture [see Warnings and Precautions ( 5. 2 Peripheral Neuropathy [see Warnings and Precautions ( 5. 3 Central Nervous System Effects [see Warnings and Precautions ( 5. 4 Exacerbation of Myasthenia Gravis [see Warnings and Precautions ( 5. 5 Other Serious and Sometimes Fatal Reactions [see Warnings and Precautions ( 5. 6 Hypersensitivity Reactions [see Warnings and Precautions ( 5. 7 Hepatotoxicity [see Warnings and Precautions ( 5. 8 )] Risk of Aortic Aneurysm and Dissection [see Warnings and Precautions ( 5. 9 Clostridium difficile-Associated Diarrhea [see Warnings and Precautions ( 5. 10 Prolongation of the QT Interval [see Warnings and Precautions ( 5. 11 Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions ( 5. 12 Blood Glucose Disturbances [see Warnings and Precautions ( 5. 13 Photosensitivity/Phototoxicity [see Warnings and Precautions ( 5. 14 Development of Drug Resistant Bacteria [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 Macleods Pharma USA, Inc. , at 1-888-943-3210 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 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 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 % Infections and Infestations Psychiatric Disorders N=7274 [see Warnings and Precautions ( 5. 4 Nervous System Disorders [see Warnings and Precautions ( 5. 4 Respiratory, Thoracic and Mediastinal Disorders [see Warnings and Precautions ( 5. 7 Gastrointestinal Disorders Skin and Subcutaneous Tissue Disorders [see Warnings and Precautions ( 5. 7 Reproductive System and Breast Disorders N=3758 (women) General Disorders and Administration Site Conditions # 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 [see Warnings and Precautions ( 5. 6 Immune System Disorders allergic reaction [See Warnings and Precautions ( 5. 7 Metabolism and Nutrition Disorders hyperglycemia [see Warnings and Precautions ( 5. 13 ] Psychiatric Disorders anxiety [see Warnings and Precautions ( 5. 4 ] Nervous System Disorders tremor [see Warnings and Precautions ( 5. 4 ] see Warnings and Precautions ( 5. 3 Respiratory, Thoracic and Mediastinal Disorders epistaxis Cardiac Disorders cardiac arrest Vascular Disorders phlebitis Gastrointestinal Disorders gastritis [see Warnings and Precautions ( 5. 10 ] Hepatobiliary Disorders abnormal hepatic function Skin and Subcutaneous Tissue Disorders urticaria [see Warnings and Precautions ( 5. 7 ] Musculoskeletal and Connective Tissue Disorders arthralgia [see Warnings and Precautions ( 5. 2 ] Renal and Urinary Disorders abnormal renal function [see Warnings and Precautions ( 5. 6 ] *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. 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 ClassSystem/Organ Class Adverse ReactionAdverse Reaction System/Organ Class Adverse Reaction Blood and Lymphatic System Disorders pancytopenia [see Warnings and Precautions ( 5. 6 Immune System Disorders hypersensitivity reactions, sometimes fatal including: [see Warnings and Precautions ( 5. 7 ] Psychiatric Disorders psychosis [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 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) [see Warnings and Precautions 5. 8 ] Skin and Subcutaneous Tissue Disorders [see Warnings and Precautions ( 5. 6 ] [see Warnings and Precautions ( 5. 14 ] 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 Known hypersensitivity to levofloxacin tablets or other quinolones ( 4 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 2-4% 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. Risk Summary Published literature reports that levofloxacin is present in human milk following intravenous and oral administration ( see Data see Use in Specific Populations ( 8. 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 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. 12 and Animal Toxicology and/or Pharmacology ( 13. 2 I nhalational 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 Indications and Usage ( 1. 8 ), Dosage and Administration ( 2. 10 Safety and effectiveness of levofloxacin tablets in pediatric patients below the age of six months have not been established. Pharmacokinetics following intravenous administration Clinical Pharmacology ( 12. 9 Dosage in Pediatric Patients with Inhalational Anthrax or Plague Dosage and Administration ( 2. 2 Adverse Reactions In clinical trials, 1534 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 [see Dosage and Administration ( 2. 2 Table 7: Incidence of Musculoskeletal Disorders in Pediatric Clinical Trial Follow-up Period Levofloxacin Non-Fluoroquinolone* p-valuedagger 60 days 28 (2. 038 1 yeardouble dagger 46 (3. 025 * Non-Fluoroquinolone: ceftriaxone, amoxicillin/clavulanate, clarithromycin There were 1199 levofloxacin-treated and 804 non-fluoroquinolone-treated pediatric patients who had a one-year evaluation visit. However, the incidence of musculoskeletal disorders was calculated using all reported events during the specified period for all pediatric patients enrolled regardless of whether they completed the 1-year evaluation visit. Adverse Reactions ( 6 Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as levofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing levofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue levofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see Boxed Warning ; Warnings and Precautions ( 5. 2 ; and Adverse Reactions ( 6. 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. 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.

Interacting Drug Interacting Drug Interaction Interaction 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 ( 2. 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 administration. No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for R- and S- warfarin was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of warfarin on levofloxacin absorption and disposition was observed. However, there have been reports during the postmarketing experience in patients that levofloxacin enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent warfarin and levofloxacin use have been associated with episodes of bleeding. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if levofloxacin is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Adverse Reactions (6. 3) andPatient Counseling Information ( 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 on the peak plasma concentrations, AUC, and other disposition parameters for cyclosporine was detected in a clinical study involving healthy volunteers. However, elevated serum levels of cyclosporine have been reported in the patient population when co-administered with some other fluoroquinolones. Levofloxacin C max e max ½ No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for digoxin was detected in a clinical study involving healthy volunteers. Levofloxacin absorption and disposition kinetics were similar in the presence or absence of digoxin. Therefore, no dosage adjustment for levofloxacin or digoxin is required when administered concomitantly. No significant effect of probenecid or cimetidine on the C max ½ R Some fluoroquinolones, including levofloxacin, may produce false-positive urine screening results for opiates using commercially available immunoassay kits. Confirmation of positive opiate screens by more specific methods may be necessary.

OVERDOSAGE
In the event of an acute overdosage, the stomach should be emptied. The patient should be observed and appropriate hydration maintained. Levofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis. Levofloxacin exhibits a low potential for acute toxicity. Mice, rats, dogs and monkeys exhibited the following clinical signs after receiving a single high dose of levofloxacin: ataxia, ptosis, decreased locomotor activity, dyspnea, prostration, tremors, and convulsions. Doses in excess of 1500 mg/kg orally (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) 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 C max Levofloxacin was not mutagenic in the following assays: Ames bacterial mutation assay ( S. typhimurium E. coli) Levofloxacin caused no impairment of fertility or reproductive performance in rats at oral doses as high as 360 mg/kg/day, corresponding to 4. 2 times the 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.
CLINICAL STUDIES
Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a multicenter, randomized, open-label study comparing intravenous levofloxacin (750 mg once daily) followed by oral levofloxacin (750 mg once daily) for a total of 7en dash15 days to intravenous imipenem/cilastatin (500en dash1000 mg every 6en dash8 hours daily) followed by oral ciprofloxacin (750 mg every 12 hours daily) for a total of 7en dash15 days. Levofloxacin-treated patients received an average of 7 days of intravenous therapy (range: 1en dash16 days); comparator-treated patients received an average of 8 days of intravenous therapy (range: 1en dash19 days). Pseudomonas aeruginosa S. aureus Table 9: Clinical Success Rates and Bacteriological Eradication Rates (Nosocomial Pneumonia) Pathogen N Levofloxacin No. (%) of Patients Microbiologic/Clinical Outcomes N Imipenem/Cilastatin No. (%) of Patients Microbiologic/Clinical Outcomes MSSA Methicillin-susceptible S. aureus 21 14 (66. 9) 19 13 (68. aeruginosa See above text for use of combination therapy 17 10 (58. 7) 17 5 (29. marcescens 11 9 (81. coli 12 10 (83. 3) 11 7 (63. pneumoniae The observed differences in rates for the clinical and microbiological outcomes may reflect other factors that were not accounted for in the study 11 9 (81. influenzae 16 13 (81. 5) 15 14 (93. pneumoniae 4 3 (75. 1) Adult inpatients and outpatients with a diagnosis of community-acquired bacterial pneumonia were evaluated in 2 pivotal clinical studies. In the first study, 590 patients were enrolled in a prospective, multi-center, unblinded randomized trial comparing levofloxacin 500 mg once daily orally or intravenously for 7 to 14 days to ceftriaxone 1 to 2 grams intravenously once or in equally divided doses twice daily followed by cefuroxime axetil 500 mg orally twice daily for a total of 7 to 14 days. Patients assigned to treatment with the control regimen were allowed to receive erythromycin (or doxycycline if intolerant of erythromycin) if an infection due to atypical pathogens was suspected or proven. Clinical and microbiologic evaluations were performed during treatment, 5 to 7 days 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 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. , 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/N dagger % n/N double dagger % Penicillin-resistant 16/17 94. 1 2 nd 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 * 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 double dagger 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 Type of Resistance Clinical Success Bacteriologic Eradication Resistant to 2 antibacterials 17/18 (94. 4%) 17/18 (94. 4%) Resistant to 3 antibacterials 14/15 (93. 3%) 14/15 (93. 3%) Resistant to 4 antibacterials 7/7 (100%) 7/7 (100%) Resistant to 5 antibacterials 0 0 Bacteremia with MDRSP 8/9 (89%) 8/9 (89%) To evaluate the safety and efficacy of the higher dose and shorter course of levofloxacin, 528 outpatient and hospitalized adults with clinically and radiologically determined mild to severe community-acquired pneumonia were evaluated in a double-blind, randomized, prospective, multicenter study comparing levofloxacin 750 mg, IV or orally, every day for five days or levofloxacin 500 mg IV or orally, every day for 10 days. Clinical success rates (cure plus improvement) in the clinically evaluable population were 90. 9% in the levofloxacin 750 mg group and 91. 1% in the levofloxacin 500 mg group. The 95% CI for the difference of response rates (levofloxacin 750 minus levofloxacin 500) was [-5. In the clinically evaluable population (31en dash38 days after enrollment) pneumonia was observed in 7 out of 151 patients in the levofloxacin 750 mg group and 2 out of 147 patients in the levofloxacin 500 mg group. Given the small numbers observed, the significance of this finding cannot be determined statistically. The microbiological efficacy of the 5-day regimen was documented for infections listed in Table 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%) 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 Note: Forty percent of the subjects in this trial had specimens obtained by sinus endoscopy. The efficacy data for subjects whose specimen was obtained endoscopically were comparable to those presented in the above table. 6%) 26/27 (96. 3%) Haemophilus influenzae 19/21 (90. 5%) 25/27 (92. 6%) Moraxella catarrhalis 10/11 (90. 9%) 13/13 (100%) Three hundred ninety-nine patients were enrolled in an open-label, randomized, comparative study for complicated skin and skin structure infections. The patients were randomized to receive either levofloxacin 750 mg once daily (IV followed by oral), or an approved comparator for a median of 10 +/- 4. As is expected in complicated skin and skin structure infections, surgical procedures were performed in the levofloxacin and comparator groups. Surgery (incision and drainage or debridement) was performed on 45% of the levofloxacin-treated patients and 44% of the comparator treated patients, either shortly before or during antibiotic treatment and formed an integral part of therapy for this indication. Among those who could be evaluated clinically 2en dash5 days after completion of study drug, overall success rates (improved or cured) were 116/138 (84. 1%) for patients treated with levofloxacin and 106/132 (80. 3%) for patients treated with the comparator. Success rates varied with the type of diagnosis ranging from 68% in patients with infected ulcers to 90% in patients with infected wounds and abscesses. These rates were equivalent to those seen with comparator drugs. Adult patients with a clinical diagnosis of prostatitis and microbiological culture results from urine sample collected after prostatic massage (VB 3 Table 15: Bacteriological Eradication Rates (Chronic Bacterial Prostatitis Levofloxacin (N=136) Ciprofloxacin (N=125) Pathogen N Eradication N Eradication E. coli 15 14 (93. 3%) 11 9 (81. faecalis 54 39 (72. 2%) 44 33 (75. epidermidis Eradication rates shown are for patients who had a sole pathogen only; mixed cultures were excluded. 8%) 14 11 (78. 6%) Eradication rates for S. epidermidis Clinical success (cure + improvement with no need for further antibiotic therapy) rates in microbiologically evaluable population 5en dash18 days after completion of therapy were 75. 0% for levofloxacin-treated patients and 72. 8% for ciprofloxacin-treated patients (95% CI [-8. 27] for levofloxacin minus ciprofloxacin). Clinical long-term success (24en dash45 days after completion of therapy) rates were 66. 7% for the levofloxacin-treated patients and 76. 9% for the ciprofloxacin-treated patients (95% CI [-23. 89] for levofloxacin minus ciprofloxacin). To evaluate the safety and efficacy of the higher dose and shorter course of levofloxacin, 1109 patients with cUTI and AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the US from November 2004 to April 2006 comparing levofloxacin 750 mg IV or orally once daily for 5 days (546 patients) with ciprofloxacin 400 mg IV or 500 mg orally twice daily for 10 days (563 patients). Patients with AP complicated by underlying renal diseases or conditions such as complete obstruction, surgery, transplantation, concurrent infection or congenital malformation were excluded. Efficacy was measured by bacteriologic eradication of the baseline organism(s) at the post-therapy visit in patients with a pathogen identified at baseline. The post-therapy (test-of-cure) visit occurred 10 to 14 days after the last active dose of levofloxacin and 5 to 9 days after the last dose of active ciprofloxacin. The bacteriologic cure rates overall for levofloxacin and control at the test-of-cure (TOC) visit for the group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the group of patients in the mITT population who closely followed the protocol (Microbiologically Evaluable) are summarized in Table 16. Table 16: Bacteriological Eradication at Test-of-Cure 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. 1) cUTI 168/230 73. 0 157/213 73. 7 AP 84/103 81. 6 82/105 78. 1 Microbiologically Evaluable Population dagger Overall (cUTI or AP) 228/265 86. 0 215/241 89. 5] cUTI 154/185 83. 2 144/165 87. 3 AP 74/80 92. 4 * The mITT population included patients who received study medication and who had a positive (>=105 CFU/mL) urine culture with no more than 2 uropathogens at baseline. Patients with missing response were counted as failures in this analysis. dagger 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. 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 1en dash9 days posttherapy for 30% of subjects enrolled prior to a protocol amendment; 5en dash12 days posttherapy for 70% of subjects. Levofloxacin 250 mg once daily for 10 days Ciprofloxacin 500 mg twice daily for 10 days n/N % n/N % mITT Population The mITT population included patients who had a pathogen isolated at baseline. 3 184/219 84. 0 Microbiologically Evaluable Population The Microbiologically Evaluable population included mITT patients who met protocol-specified evaluability criteria. 7 159/171 93. 0 The effectiveness of levofloxacin for this indication is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin has not been tested in humans for the post-exposure prevention of inhalation anthrax. The mean plasma concentrations of levofloxacin associated with a statistically significant improvement in survival over placebo in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage regimens [see Indications and Usage ( 1. 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 Dosage and Administration ( 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. see Indications and Usage ( 1. 2 ] 0-24 see Clinical Pharmacology ( 12. 50 50 Yersinia pestis Y. pestis 0-24 o Y.
MEDICATION GUIDE
Medication Guide What is the most important information I should know about levofloxacin tablets? you should stop taking levofloxacin tablets immediately and get medical help right away. 1. Tendon rupture or swelling of the tendon (tendinitis). Tendon problems can happen in people of all ages who take levofloxacin tablets. Tendons are tough cords of tissue that connect muscles to bones. Some tendon problems include: pain swelling tears and swelling of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites. The risk of getting tendon problems while you take levofloxacin tablets is higher if you: are over 60 years of age are taking steroids (corticosteroids) have had a kidney, heart or lung transplant. 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: physical activity or exercise kidney failure tendon problems in the past, such as in people with rheumatoid arthritis (RA) Stop taking levofloxacin tablets immediately and get medical help right away at the first sign of tendon pain, swelling or inflammation. Avoid exercise and using the affected area. The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can also happen with other tendons. You may need a different antibiotic that is not a fluoroquinolone to treat your infection. Tendon rupture can happen while you are taking or after you have finished taking levofloxacin tablets. Tendon ruptures can happen within hours or days of taking levofloxacin tablets and have happened up to several months after people have finished taking their fluoroquinolone. Stop taking levofloxacin tablets immediately and get medical help right away if you get any of the following signs or symptoms of a tendon rupture: hear or feel a snap or pop in a tendon area bruising right after an injury in a tendon area unable to move the affected area or bear weight The tendon problems may be permanent. 2. Changes in sensation and possible nerve damage (Peripheral Neuropathy). pain numbness burning weakness tingling The nerve damage may be permanent 3. Central Nervous System (CNS) effects. seizures nightmares hear voices, see things, or sense things that are not there(hallucinations) feel lightheaded or dizzy feel more suspicious (paranoia) tremors suicidal thoughts or acts feel anxious or nervous headaches that will not go away, with or without blurred vision confusion memory problems depression false or strange thoughts or beliefs (delusion) reduced awareness of surroundings trouble sleeping The CNS changes may be permanent. 4. Worsening of myasthenia gravis (a problem that causes muscle weakness). What are levofloxacin tablets? nosocomial pneumonia plague community acquired pneumonia urinary tract infections, complicated and uncomplicated skin infections, complicated and uncomplicated acute kidney infection (pyelonephritis) chronic prostate infection acute sinus infection inhalation anthrax germs acute worsening or chronic bronchitis Studies of levofloxacin tablets for use in the treatment of plague and anthrax were done in animals only, because plague and anthrax could not be studied in people. Who should not take levofloxacin tablets? Do not take levofloxacin tablets Before you take levofloxacin tablets, tell your healthcare provider about all of your medical conditions, including if you: have tendon problems. Levofloxacin tablets should not be used in people who have a history of tendon problems. have a problem that causes muscle weakness (myasthenia gravis). Levofloxacin tablets should not be used in people who have a known history of myasthenia gravis. have a history of mental health problems, including depression. have central nervous system problems such as seizures (epilepsy). have nerve problems. Levofloxacin should not be used in people who have a history of a nerve problem called peripheral neuropathy. have or anyone in your family has an irregular heartbeat, especially a condition called “QT prolongation”. have low blood potassium (hypokalemia). have bone problems. have joint problems including rheumatoid arthritis (RA). have kidney problems. You may need a lower dose of levofloxacin tablets if your kidneys do not work well. have liver problems. have diabetes or problems with low blood sugar (hypoglycemia). are pregnant or plan to become pregnant. Levofloxacin tablets will harm your unborn child. are breastfeeding or plan to breastfeed. 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. If you are taking levofloxacin for inhalational anthrax, you and your healthcare provider should decide whether you can continue breastfeeding while taking levofloxacin. Tell your healthcare provider about all the medicines you take 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? Take levofloxacin exactly as your healthcare provider tells you to take it. Take levofloxacin at the same time each day. Drink plenty of fluids while you take levofloxacin. Levofloxacin can be taken with or without food. If you miss a dose of levofloxacin tablets and it is: o 8 hours or more less than 8 hours Do not skip any doses of levofloxacin or stop taking it, even if you begin to feel better, until you finish your prescribed treatment unless: What is the most important information I should know about levofloxacin ?” o you have a nerve problem. See “ What is the most important information I should know about levofloxacin ?”. o you have a central nervous system problem. See “ What is the most important information I should know about levofloxacin ?”. o you have a serious allergic reaction. See “ What are the possible side effects of levofloxacin ?”. o your healthcare provider tells you to stop taking levofloxacin 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 should I avoid while taking levofloxacin tablets? Levofloxacin tablets can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how levofloxacin tablets affects you. Avoid sunlamps, tanning beds, and try to limit your time in the sun. Levofloxacin tablets can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while you take levofloxacin tablets, call your healthcare provider right away. You should use sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight. What are the possible side effects of levofloxacin tablets? Levofloxacin tablets may cause serious side effects, including: What is the most important information I should know about levofloxacin tablets?” Serious allergic reactions. Liver damage (hepatotoxicity): Aortic aneurysm and dissection Intestine infection ( Clostridium difficile Serious heart rhythm changes (QT prolongation and torsades de pointes) Joint Problems Changes in blood sugar Sensitivity to sunlight (photosensitivity) What should I avoid while taking levofloxacin tablets In children 6 months and older who take levofloxacin to treat anthrax disease or plague, vomiting is also common. How should I store levofloxacin tablets? Store levofloxacin tablets at room temperature between 59°F to 86° F (15°C to 30°C). 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 or 1-855-926-3384 What are the ingredients in levofloxacin tablets? 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. Medication Guide available at:www.macleodspharma.com/usa Revised: January 2023

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