Levofloxacin in 5% Dextrose

INDICATIONS AND USAGE Levofloxacin injection is indicated for the treatment of adults (≥18 years of age) with mild, moderate, and severe infections caused by susceptible isolates of the designated microorganisms in the conditions listed in this section. Levofloxacin injection is indicated when intravenous administration offers a route of administration advantageous to the patient (e.g., patient cannot tolerate an oral dosage form). Levofloxacin injection is a fluoroquinolone antibacterial indicated in adults (≥18 years of age) with infections caused by designated, susceptible bacteria ( 1 , 12.4 ). Pneumonia: Nosocomial ( 1.1 ) and Community Acquired (1.2 , 1.3) Skin and Skin Structure Infections: Complicated (1.4) and Uncomplicated (1.5) Chronic bacterial prostatitis (1.6) Inhalational Anthrax, Post-Exposure (1.7) Plague (1.8) Urinary Tract Infections: Complicated (1.9 , 1.10) and Uncomplicated (1.12) Acute Pyelonephritis (1.11) Acute Bacterial Exacerbation of Chronic Bronchitis (1.13) Acute Bacterial Sinusitis ( 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 ). 1.1 Nosocomial Pneumonia Levofloxacin injection is indicated 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 β-lactam is recommended [see Clinical Studies (14.1) ] . 1.2 Community-Acquired Pneumonia: 7 to 14 day Treatment Regimen Levofloxacin injection is indicated for the treatment of community-acquired pneumonia due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant Streptococcus pneumoniae [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae [see Dosage and Administration (2.1) and Clinical Studies (14.2) ]. MDRSP isolates are isolates resistant to two or more of the following antibacterials: penicillin (MIC ≥2 mcg/mL), 2 nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole. 1.3 Community-Acquired Pneumonia: 5-day Treatment Regimen Levofloxacin injection is indicated for the treatment of community-acquired pneumonia due to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Dosage and Administration (2.1) and Clinical Studies (14.3) ]. 1.4 Complicated Skin and Skin Structure Infections Levofloxacin injection is indicated for the treatment of complicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, or Proteus mirabilis [see Clinical Studies (14.5) ]. 1.5 Uncomplicated Skin and Skin Structure Infections Levofloxacin injection is indicated for the treatment of uncomplicated skin and skin structure infections (mild to moderate) including abscesses, cellulitis, furuncles, impetigo, pyoderma, wound infections, due to methicillin-susceptible Staphylococcus aureus , or Streptococcus pyogenes . 1.6 Chronic Bacterial Prostatitis Levofloxacin injection is indicated for the treatment of chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or methicillin-susceptible Staphylococcus epidermidis [see Clinical Studies (14.6) ]. 1.7 Inhalational Anthrax (Post-Exposure) Levofloxacin injection is indicated for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. The effectiveness of levofloxacin injection is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin injection has not been tested in humans for the post-exposure prevention of inhalation anthrax. The safety of levofloxacin in adults for durations of therapy beyond 28 days or in pediatric patients for durations of therapy beyond 14 days has not been studied. Prolonged levofloxacin therapy should only be used when the benefit outweighs the risk [see Dosage and Administration (2.1 , 2.2) and Clinical Studies (14.9) ]. 1.8 Plague Levofloxacin injection is indicated for treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis ( Y. pestis ) and prophylaxis for plague in adults and pediatric patients, 6 months of age and older. Efficacy studies of levofloxacin 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 Dosage and Administration (2.1 , 2.2) and Clinical Studies (14.10) ]. 1.9 Complicated Urinary Tract Infections: 5-day Treatment Regimen Levofloxacin injection is indicated for the treatment of complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis [see Clinical Studies (14.7) ]. 1.10 Complicated Urinary Tract Infections: 10-day Treatment Regimen Levofloxacin injection is indicated for the treatment of complicated urinary tract infections (mild to moderate) due to Enterococcus faecalis , Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa [see Clinical Studies (14.8) ] . 1.11 Acute Pyelonephritis: 5 or 10-day Treatment Regimen Levofloxacin injection is indicated for the treatment of acute pyelonephritis caused by Escherichia coli , including cases with concurrent bacteremia [see Clinical Studies (14.7 , 14.8) ] . 1.12 Uncomplicated Urinary Tract Infections Levofloxacin injection is indicated for the treatment of uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae, or Staphylococcus saprophyticus . Because fluoroquinolones, including levofloxacin injection, have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1 to 5.15) ] and for some patients uncomplicated urinary tract infection is self-limiting, reserve levofloxacin injection for treatment of uncomplicated urinary tract infections in patients who have no alternative treatment options. 1.13 Acute Bacterial Exacerbation of Chronic Bronchitis Levofloxacin injection is indicated for the treatment of acute bacterial exacerbation of chronic bronchitis (ABECB) due to methicillin-susceptible Staphylococcus aureus , Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis . Because fluoroquinolones, including levofloxacin injection, have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1 to 5.15 )] and for some patients ABECB is self-limiting, reserve levofloxacin injection for treatment of ABECB in patients who have no alternative treatment options. 1.14 Acute Bacterial Sinusitis: 5-day and 10 to 14 day Treatment Regimens Levofloxacin injection is indicated 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 injection, have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1 to 5.15 )] and for some patients ABS is self-limiting, reserve levofloxacin injection for treatment of ABS in patients who have no alternative treatment options. 1.15 Usage To reduce the development

DOSAGE AND ADMINISTRATION Dosage in patients with normal renal function ( 2.1 ) 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 Skin and Skin Structure Infections (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 Pediatric Patients < 50 kg and ≥ 6 months of age 500 mg 8 mg/kg BID (not to exceed 250 mg/dose) 60 60 Plague ( 1.8 ) Adults and Pediatric Patients > 50 kg Pediatric Patients < 50 kg and ≥ 6 months of age 500 mg 8 mg/kg BID (not to exceed 250 mg/dose) 10 to 14 10 to 14 Complicated Urinary Tract Infection ( 1.9 ) or Acute Pyelonephritis (1.11) 750 mg 5 Complicated Urinary Tract Infection ( 1.10 ) or Acute Pyelonephritis (1.11) 250 mg 10 Uncomplicated Urinary Tract Infection ( 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 < 50 mL/min ( 2.3 , 8.6 , 12.3 ) IV Injection Premix: Slow IV infusion only, over 60 or 90 minutes depending on dose. Avoid rapid or bolus IV ( 2.5 ) Do not mix with other medications in IV line ( 2.6 ) 2.1 Dosage in Adult Patients with Normal Renal Function The usual dose of levofloxacin injection is 250 mg or 500 mg administered by slow infusion over 60 minutes every 24 hours or 750 mg administered by slow infusion over 90 minutes every 24 hours, as indicated by infection and described in Table 1. These recommendations apply to patients with creatinine clearance ≥ 50 mL/min. For patients with creatinine clearance <50 mL/min, adjustments to the dosing regimen are required [see Dosage and Administration (2.3) ] . Table 1: Dosage in Adult Patients with Normal Renal Function (creatinine clearance ≥ 50 mL/min) * Due to the designated pathogens [see Indications and Usage (1) ] . † Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician. ‡ Due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae [see Indications and Usage (1.2) ]. § Due to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Indications and Usage (1.3) ]. ¶ This regimen is indicated for cUTI due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and AP due to E. coli, including cases with concurrent bacteremia. # This regimen is indicated for cUTI due to Enterococcus faecalis, Enterococcus cloacae, Escherichia coli , Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa ; and for AP due to E. coli. Þ Drug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis . This indication is based on a surrogate endpoint. Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit [see Clinical Studies (14.9) ] . ß The safety of levofloxacin 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 (5.11) , Use in Specific Populations (8.4) , and Clinical Studies (14.9) ] . Prolonged levofloxacin therapy should only be used when the benefit outweighs the risk. à Drug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis . Higher doses of levofloxacin typically used for treatment of pneumonia can be used for treatment of plague, if clinically indicated. Type of Infection * Dosed Every 24 hours Duration (days) † Nosocomial Pneumonia 750 mg 7 to 14 Community Acquired Pneumonia ‡ 500 mg 7 to 14 Community Acquired Pneumonia § 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 > 50 kg Þ,ß Pediatric patients < 50 kg and ≥ 6 months of age Þ,ß 500 mg see Table 2 below (2.2) 60 ß 60 ß Plague, adult and pediatric patients > 50 kg à Pediatric patients < 50 kg and ≥ 6 months of age 500 mg see Table 2 below (2.2) 10 to 14 10 to 14 Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) ¶ 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 2.2 Dosage in Pediatric Patients The dosage in pediatric patients ≥ 6 months of age is described below in Table 2. Table 2: Dosage in Pediatric Patients ≥ 6 months of age Type of Infection * Dose Freq. Once every Duration † Inhalational Anthrax (post-exposure) ‡ , § Pediatric patients > 50 kg 500 mg 24 hr 60 days § Pediatric patients < 50 kg and ≥ 6 months of age 8 mg/kg (not to exceed 250 mg per dose) 12 hr 60 days § Plague ¶ Pediatric patients > 50 kg 500 mg 24 hr 10 to 14 days Pediatric patients < 50 kg and ≥ 6 months of age 8 mg/kg (not to exceed 250 mg per dose) 12 hr 10 to 14 days * Due to Bacillus anthracis [see Indications and Usage (1.13) ] and Yersinia pestis [see Indications and Usage (1.14) ]. † Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician. ‡ Drug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis . This indication is based on a surrogate endpoint. Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit [see Clinical Studies (14.9) ] § The safety of levofloxacin in pediatric patients for durations of therapy 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 (5.11) , Use in Specific Populations (8.4) , and Clinical Studies (14.9) ] . Prolonged levofloxacin therapy should only be used when the benefit outweighs the risk. ¶ Drug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis . 2.3 Dosage Adjustment in Adults with Renal Impairment Administer levofloxacin injection with caution in the presence of renal insufficiency. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of levofloxacin may be reduced. No adjustment is necessary for patients with a creatinine clearance ≥ 50 mL/min. In patients with impaired renal function (creatinine clearance < 50 mL/min), adjustment of the dosage regimen is necessary to avoid the accumulation of levofloxacin due to decreased clearance [see Use in Specific Populations (8.6) ] . Table 3 shows how to adjust dose based on creatinine clearance. Table 3: Dosage Adjustment in Adult Patients with Renal Impairment (creatinine clearance < 50 mL/min) Dosage in Normal Renal Function Every 24 hours Creatinine Clearance 20 to 49 mL/min Creatinine Clearance 10 to 19 mL/min Hemodialysis or Chronic Ambulatory Peritoneal Dialysis (CAPD) 750 mg 750 mg every 48 hours 750 mg initial dose, then 500 mg every 48 hours 750 mg initial dose, then 500 mg every 48 hours 500 mg 500 mg initial dose, then 250 mg every 24 hours 500 mg initial dose, then 250 mg every 48 hours 500 mg initial dose, then 250 m

WARNINGS AND PRECAUTIONS Anaphylactic reactions and allergic skin reactions, serious, occasionally fatal, may occur after first dose ( 4 , 5.7 ) Hematologic (including agranulocytosis, thrombocytopenia), and renal toxicities may occur after multiple doses ( 5.6 ) Hepatotoxicity: Severe, and sometimes fatal, hepatotoxicity has been reported. Discontinue immediately if signs and symptoms of hepatitis occur ( 5.8 ) Clostridium difficile -associated colitis: evaluate if diarrhea occurs ( 5.10 ) Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs that prolong the QT interval ( 5.11 , 8.5 ) 5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting levofloxacin. Patients of any age or without pre-existing risk factors have experienced these adverse reactions [see Warnings and Precautions (5.2 , 5.3 , 5.4) ] . Discontinue levofloxacin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including levofloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones. 5.2 Tendinitis and Tendon Rupture Fluoroquinolones, including levofloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages [see Warnings and Precautions (5.1) and Adverse Reactions (6.2) ] . This adverse reaction most frequently involves the Achilles tendon and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites. Tendinitis or tendon rupture can occur within hours or days of starting levofloxacin or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in those taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have been reported in patients taking fluoroquinolones who do not have the above risk factors. Discontinue levofloxacin immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. Avoid levofloxacin in patients who have a history of tendon disorders or tendon rupture [see Adverse Reactions (6.3) ; Patient Counseling Information (17) ] . 5.3 Peripheral Neuropathy Fluoroquinolones, including levofloxacin, have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including levofloxacin. Symptoms may occur soon after initiation of levofloxacin and may be irreversible in some patients [see Warnings and Precautions (5.1) and Adverse Reactions (6.1 , 6.2 )] . Discontinue levofloxacin immediately if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation. Avoid fluoroquinolones, including levofloxacin, in patients who have previously experienced peripheral neuropathy [see Adverse Reactions (6) , Patient Counseling Information (17) ]. 5.4 Central Nervous System Effects Psychiatric Adverse Reactions Fluoroquinolones, including levofloxacin, have been associated with an increased risk of psychiatric adverse reactions, including: toxic psychoses, hallucinations, or paranoia; depression, or suicidal thoughts; anxiety, agitation, restlessness, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; memory impairment. Attempted or completed suicide have been reported, especially in patients with a medical history of depression, or an underlying risk factor for depression. These reactions may occur following the first dose. If these reactions occur in patients receiving levofloxacin, discontinue levofloxacin and institute appropriate measures. Central Nervous System Adverse Reactions of Seizures, Increased Intracranial Pressure, and Tremors Fluoroquinolones, including levofloxacin, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (including pseudotumor cerebri), tremors, and lightheadedness. As with other fluoroquinolones, levofloxacin should be used with caution in patients with a known or suspected central nervous system (CNS) disorder that may predispose them to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose them to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction). If these reactions occur in patients receiving levofloxacin, discontinue levofloxacin and institute appropriate measures. [see Adverse Reactions (6) ; Drug Interactions (7.4 , 7.5 ); Patient Counseling Information (17) ]. 5.5 Exacerbation of Myasthenia Gravis Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Avoid levofloxacin in patients with a known history of myasthenia gravis [see Adverse Reactions (6.3) ; Patient Counseling Information (17) ] . 5.6 Other Serious and Sometimes Fatal Adverse Reactions Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with fluoroquinolones, including levofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome); vasculitis; arthralgia; myalgia; serum sickness; allergic pneumonitis; interstitial nephritis; acute renal insufficiency or failure; hepatitis; jaundice; acute hepatic necrosis or failure; anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities. Discontinue levofloxacin immediately at the first appearance of skin rash, jaundice, or any other sign of hypersensitivity and institute supportive measures [see Adverse Reactions (6) ; Patient Counseling Information (17) ]. 5.7 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy

CONTRAINDICATIONS Levofloxacin injection is contraindicated in persons with known hypersensitivity to levofloxacin, or other quinolone antibacterials [see Warnings and Precautions (5.3) ]. Known hypersensitivity to levofloxacin injection or other quinolones (4 , 5.7 )

DRUG INTERACTIONS Interacting Drug Interaction Multivalent cation-containing products including antacids, metal cations or didanosine Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1) Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2) Antidiabetic agents Carefully monitor blood glucose ( 5.13 , 7.3) 7.1 Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins Levofloxacin Injection There are no data concerning an interaction of intravenous fluoroquinolones with oral antacids, sucralfate, multivitamins, didanosine, or metal cations. However, no fluoroquinolone should be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line [see Dosage and Administration (2.5) ] . 7.2 Warfarin No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for R- and S-warfarin was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of warfarin on levofloxacin absorption and disposition was observed. However, there have been reports during the postmarketing experience in patients that levofloxacin enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent warfarin and levofloxacin use have been associated with episodes of bleeding. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if levofloxacin is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Adverse Reactions (6.3) ; Patient Counseling Information (17) ]. 7.3 Antidiabetic Agents Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with fluoroquinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered [see Warnings and Precautions (5.13) ; Adverse Reactions (6.2) ; Patient Counseling Information (17) ]. 7.4 Non-Steroidal Anti-Inflammatory Drugs The concomitant administration of a non-steroidal anti-inflammatory drug with a fluoroquinolone, including levofloxacin, may increase the risk of CNS stimulation and convulsive seizures [see Warnings and Precautions (5.4) ]. 7.5 Theophylline No significant effect of levofloxacin on the plasma concentrations, AUC, and other disposition parameters for theophylline was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of theophylline on levofloxacin absorption and disposition was observed. However, concomitant administration of other fluoroquinolones with theophylline has resulted in prolonged elimination half-life, elevated serum theophylline levels, and a subsequent increase in the risk of theophylline-related adverse reactions in the patient population. Therefore, theophylline levels should be closely monitored and appropriate dosage adjustments made when levofloxacin is co-administered. Adverse reactions, including seizures, may occur with or without an elevation in serum theophylline levels [see Warnings and Precautions (5.4) ]. 7.6 Cyclosporine No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for cyclosporine was detected in a clinical study involving healthy volunteers. However, elevated serum levels of cyclosporine have been reported in the patient population when co-administered with some other fluoroquinolones. Levofloxacin C max and k e were slightly lower while T max and t ½ were slightly longer in the presence of cyclosporine than those observed in other studies without concomitant medication. The differences, however, are not considered to be clinically significant. Therefore, no dosage adjustment is required for levofloxacin or cyclosporine when administered concomitantly. 7.7 Digoxin No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for digoxin was detected in a clinical study involving healthy volunteers. Levofloxacin absorption and disposition kinetics were similar in the presence or absence of digoxin. Therefore, no dosage adjustment for levofloxacin or digoxin is required when administered concomitantly. 7.8 Probenecid and Cimetidine No significant effect of probenecid or cimetidine on the C max of levofloxacin was observed in a clinical study involving healthy volunteers. The AUC and t 1/2 of levofloxacin were higher while CL/F and CL R were lower during concomitant treatment of levofloxacin with probenecid or cimetidine compared to levofloxacin alone. However, these changes do not warrant dosage adjustment for levofloxacin when probenecid or cimetidine is co-administered. 7.9 Interactions with Laboratory or Diagnostic Testing Some fluoroquinolones, including levofloxacin, may produce false-positive urine screening results for opiates using commercially available immunoassay kits. Confirmation of positive opiate screens by more specific methods may be necessary.

ADVERSE REACTIONS The most common reactions (≥3%) were nausea, headache, diarrhea, insomnia, constipation and dizziness (6.2) . To report SUSPECTED ADVERSE REACTIONS, contact Eugia US LLC at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Serious and Otherwise Important 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 Adverse 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) ] Hypotension has been associated with rapid or bolus intravenous infusion of levofloxacin. Levofloxacin should be infused slowly over 60 to 90 minutes, depending on dosage [see Dosage and Administration (2.5) ]. Crystalluria and cylindruria have been reported with quinolones, including levofloxacin. Therefore, adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of a highly concentrated urine [see Dosage and Administration (2.5) ]. 6.2 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to levofloxacin in 7537 patients in 29 pooled Phase 3 clinical trials. The population studied had a mean age of 50 years (approximately 74% of the population was < 65 years of age), 50% were male, 71% were Caucasian, 19% were Black. Patients were treated with levofloxacin for a wide variety of infectious diseases [see Indications and Usage (1)] . Patients received levofloxacin doses of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. Treatment duration was usually 3 to 14 days, and the mean number of days on therapy was 10 days. The overall incidence, type and distribution of adverse reactions was similar in patients receiving levofloxacin doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation of levofloxacin due to adverse drug reactions occurred in 4.3% of patients overall, 3.8% of patients treated with the 250 mg and 500 mg doses and 5.4% of patients treated with the 750 mg dose. The most common adverse drug reactions leading to discontinuation with the 250 and 500 mg doses were gastrointestinal (1.4%), primarily nausea (0.6%); vomiting (0.4%); dizziness (0.3%); and headache (0.2%). The most common adverse drug reactions leading to discontinuation with the 750 mg dose were gastrointestinal (1.2%), primarily nausea (0.6%), vomiting (0.5%); dizziness (0.3%); and headache (0.3%). 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. Table 4: Common (≥1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin * N = 7274 † N = 3758 (women) System/Organ Class Adverse Reaction % (N = 7537) Infections and Infestations moniliasis 1 Psychiatric Disorders insomnia * [see Warnings and Precautions (5.4) ] 4 Nervous System Disorders headache dizziness [see Warnings and Precautions (5.4) ] 6 3 Respiratory, Thoracic and Mediastinal Disorders dyspnea [see Warnings and Precautions (5.7) ] 1 Gastrointestinal Disorders nausea diarrhea constipation abdominal pain vomiting dyspepsia 7 5 3 2 2 2 Skin and Subcutaneous Tissue Disorders rash [see Warnings and Precautions (5.7) ] pruritus 2 1 Reproductive System and Breast Disorders vaginitis 1 † General Disorders and Administration Site Conditions edema injection site reaction chest pain 1 1 1 Table 5: Less Common (0.1 to 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin (N = 7537) * N = 7274 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 (5.6 , 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 colitis [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. 6.3 Postmarketing Experience Table 6 lists adverse reactions that have been identified during post-approval use of levofloxacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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: anaphylactic/anaphylactoid reactions anaphylactic shock angioneurotic edema serum sickness [see Warnings and Precautions (5.6 , 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) ] anosmia ageusia parosmia dysgeusia peripheral neuropathy (may be irreversible) [see Warnings and Precautio

Mechanism of Action Levofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology (12.4) ] .