LEVOFLOXACIN: 40,403 Adverse Event Reports & Safety Profile

Levofloxacin is a synthetic broad-spectrum antibacterial agent for oral and intravenous administration. Chemically, levofloxacin, a chiral fluorinated carboxyquinolone, is the pure (-)-(S)-enantiomer of the racemic drug substance ofloxacin. The chemical name is (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hemihydrate.

Figure

1: The Chemical Structure of Levofloxacin The empirical formula is C 18 H 20 FN 3 O 4 ∙ ½ H 2 O and the molecular weight is 370.38. Levofloxacin is a light yellowish-white to yellow-white crystal or crystalline powder. The molecule exists as a zwitterion at the pH conditions in the small intestine. The data demonstrate that from pH 0.6 to 5.8, the solubility of levofloxacin is essentially constant (approximately 100 mg/mL). Levofloxacin is considered soluble to freely soluble in this pH range, as defined by USP nomenclature. Above pH 5.8, the solubility increases rapidly to its maximum at pH 6.7 (272 mg/mL) and is considered freely soluble in this range. Above pH 6.7, the solubility decreases and reaches a minimum value (about 50 mg/mL) at a pH of approximately 6.9. Levofloxacin has the potential to form stable coordination compounds with many metal ions. This in vitro chelation potential has the following formation order: Al +3 >Cu +2 >Zn +2 >Mg +2 >Ca +2 . Excipients and Description of Dosage Forms The appearance of Levofloxacin Injection may range from a clear yellow to a clear greenish-yellow solution. This does not adversely affect product potency.

Levofloxacin

Injection in Single-Use Vials is a sterile, preservative-free aqueous solution of levofloxacin in Water for Injection, with pH ranging from 3.8 to 5.8.

Levofloxacin

Injection in 5% Dextrose (Premix) in Single-Use Flexible Containers is a sterile, preservative-free aqueous solution of levofloxacin with pH ranging from 3.8 to 5.8. This is a dilute, non-pyrogenic, nearly isotonic premixed solution that contains levofloxacin in 5% Dextrose (D W). Solutions of hydrochloric acid and sodium hydroxide may have been added to adjust the pH. The flexible container is fabricated from specially formulated non-plasticized, thermoplastic copolyester (CR3). The amount of water that can permeate from the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the flexible container can leach out certain of the container’s chemical components in very small amounts within the expiration period. The suitability of the container material has been confirmed by tests in animals according to USP biological tests for plastic containers.

Figure

1

AND USAGE Levofloxacin in 5% Dextrose 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 in 5% Dextrose 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 in 5% Dextrose 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 )

1.1 Nosocomial Pneumonia Levofloxacin in 5% Dextrose 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 in 5% Dextrose 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 ) and Clinical Studies ( 14.2 )]</span> . 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 in 5% Dextrose 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 ) and Clinical Studies ( 14.3 )]</span>.

1.4 Complicated Skin and Skin Structure Infections Levofloxacin in 5% Dextrose 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.5 )]</span>.

1.5 Uncomplicated Skin and Skin Structure Infections Levofloxacin in 5% Dextrose 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 in 5% Dextrose Injection is indicated for the treatment of chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or methicillin-susceptible Staphylococcus epidermidis <span class="opacity-50 text-xs">[see Clinical Studies ( 14.6 )]</span>.

1.7 Inhalational Anthrax (Post-Exposure) Levofloxacin in 5% Dextrose 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 is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin in 5% Dextrose Injection has not been tested in humans for the post-exposure prevention of inhalation anthrax. The safety of Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection 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 in 5% Dextrose 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 in 5% Dextrose Injection 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 , 2.2 ) and Clinical Studies ( 14.10 )]</span>.

1.9 Complicated Urinary Tract Infections: 5-day Treatment Regimen Levofloxacin in 5% Dextrose Injection is indicated for the treatment of complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis <span class="opacity-50 text-xs">[see Clinical Studies (14.7) ]</span>.

1.10 Complicated Urinary Tract Infections: 10-day Treatment Regimen Levofloxacin in 5% Dextrose 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.8) ]</span>.

1.11 Acute Pyelonephritis: 5 or 10-day Treatment Regimen Levofloxacin in 5% Dextrose Injection is indicated for the treatment of acute pyelonephritis caused by Escherichia coli , including cases with concurrent bacteremia <span class="opacity-50 text-xs">[see Clinical Studies (14.7, 14.8) ]</span>.

1.12 Uncomplicated Urinary Tract Infections Levofloxacin in 5% Dextrose 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 in 5% Dextrose Injection, have been associated with serious adverse reactions <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 - 5.15 )]</span> and for some patients uncomplicated urinary tract infection is self-limiting, reserve Levofloxacin in 5% Dextrose 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 in 5% Dextrose 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 in 5% Dextrose Injection, have been associated with serious adverse reactions <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 - 5.15 )]</span> and for some patients ABECB is self-limiting, reserve levofloxacin 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 in 5% Dextrose Injection is indicated for the treatment of acute bacterial sinusitis (ABS)due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis <span class="opacity-50 text-xs">[see Clinical Studies ( 14.4 )]</span>. Because fluoroquinolones, including Levofloxacin in 5% Dextrose Injection, have been associated with serious adverse reactions <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 - 5.15 )]</span> and for some patients ABS is self-limiting, reserve Levofloxacin in 5% Dextrose Injection for treatment of ABS in patients who have no alternative treatment options.

1.15 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Levofloxacin in 5% Dextrose Injection and other antibacterial drugs, Levofloxacin in 5% Dextrose Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Culture and susceptibility testing Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to levofloxacin <span class="opacity-50 text-xs">[see Microbiology ( 12.4 )]</span> . Therapy with Levofloxacin in 5% Dextrose Injection, may be initiated before results of these tests are known; once results become available, appropriate therapy should be selected. As with other drugs in this class, some isolates of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with levofloxacin. 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.

1.1 Nosocomial Pneumonia Levofloxacin in 5% Dextrose 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 in 5% Dextrose 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 ) and Clinical Studies ( 14.2 )]</span> . 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 in 5% Dextrose 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 ) and Clinical Studies ( 14.3 )]</span>.

1.4 Complicated Skin and Skin Structure Infections Levofloxacin in 5% Dextrose 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.5 )]</span>.

1.5 Uncomplicated Skin and Skin Structure Infections Levofloxacin in 5% Dextrose 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 in 5% Dextrose Injection is indicated for the treatment of chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or methicillin-susceptible Staphylococcus epidermidis <span class="opacity-50 text-xs">[see Clinical Studies ( 14.6 )]</span>.

1.7 Inhalational Anthrax (Post-Exposure) Levofloxacin in 5% Dextrose 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 is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin in 5% Dextrose Injection has not been tested in humans for the post-exposure prevention of inhalation anthrax. The safety of Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection 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 in 5% Dextrose 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 in 5% Dextrose Injection 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 , 2.2 ) and Clinical Studies ( 14.10 )]</span>.

1.9 Complicated Urinary Tract Infections: 5-day Treatment Regimen Levofloxacin in 5% Dextrose Injection is indicated for the treatment of complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis <span class="opacity-50 text-xs">[see Clinical Studies (14.7) ]</span>.

1.10 Complicated Urinary Tract Infections: 10-day Treatment Regimen Levofloxacin in 5% Dextrose 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.8) ]</span>.

1.11 Acute Pyelonephritis: 5 or 10-day Treatment Regimen Levofloxacin in 5% Dextrose Injection is indicated for the treatment of acute pyelonephritis caused by Escherichia coli , including cases with concurrent bacteremia <span class="opacity-50 text-xs">[see Clinical Studies (14.7, 14.8) ]</span>.

1.12 Uncomplicated Urinary Tract Infections Levofloxacin in 5% Dextrose 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 in 5% Dextrose Injection, have been associated with serious adverse reactions <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 - 5.15 )]</span> and for some patients uncomplicated urinary tract infection is self-limiting, reserve Levofloxacin in 5% Dextrose 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 in 5% Dextrose 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 in 5% Dextrose Injection, have been associated with serious adverse reactions <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 - 5.15 )]</span> and for some patients ABECB is self-limiting, reserve levofloxacin 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 in 5% Dextrose Injection is indicated for the treatment of acute bacterial sinusitis (ABS)due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis <span class="opacity-50 text-xs">[see Clinical Studies ( 14.4 )]</span>. Because fluoroquinolones, including Levofloxacin in 5% Dextrose Injection, have been associated with serious adverse reactions <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 - 5.15 )]</span> and for some patients ABS is self-limiting, reserve Levofloxacin in 5% Dextrose Injection for treatment of ABS in patients who have no alternative treatment options.

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) ( 1.6 ) 750 mg 7 to 14 Uncomplicated SSSI ( 1.7 ) 500 mg 7 to 10 Chronic Bacterial Prostatitis ( 1.8 ) 500 mg 28 Inhalational Anthrax (Post-Exposure) ( 1.13 ) 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 ( 1.14 ) 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 ( 1.5 ) 500 mg 7 Acute Bacterial Sinusitis (1.4 ) 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 in 5% Dextrose 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 &lt; 50 mL/min, adjustments to the dosing regimen are required <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> .

Table

1: Dosage in Adult Patients with Normal Renal Function (creatinine clearance ≥ 50 mL/min) 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 * 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 ( 5.12 ), 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.

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 ( 5.12 ), 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 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 &lt; 50 mL/min), adjustment of the dosage regimen is necessary to avoid the accumulation of levofloxacin due to decreased clearance <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) ]</span>.

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 mg every 48 hours 250 mg No dosage adjustment required 250 mg every 48 hours. If treating uncomplicated UTI, then no dosage adjustment is required No information on dosing adjustment is available

2.4 Drug Interaction with Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins Levofloxacin in 5% dextrose injection should not be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span> .

2.5 Administration Instructions Caution: Rapid or bolus intravenous infusion of levofloxacin has been associated with hypotension and must be avoided. Levofloxacin in 5% dextrose injection should be infused intravenously slowly over a period of not less than 60 or 90 minutes, depending on the dosage. Levofloxacin in 5% dextrose injection should be administered only by intravenous infusion. It is not for intramuscular, intrathecal, intraperitoneal, or subcutaneous administration. Hydration for Patients Receiving Levofloxacin in 5% Dextrose Injection Adequate hydration of patients receiving intravenous levofloxacin should be maintained to prevent the formation of highly concentrated urine. Crystalluria and cylindruria have been reported with quinolones <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 ) and Patient Counseling Information ( 17 )]</span>.

2.6 Preparation of Intravenous Product Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Because only limited data are available on the compatibility of levofloxacin in 5% dextrose injection with other intravenous substances, additives or other medications should not be added to Levofloxacin Injection Premix Solution in Single-Use Flexible Containers, or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of levofloxacin in 5% dextrose injection with an infusion solution compatible with levofloxacin in 5% dextrose injection and with any other drug(s) administered via this common line.

Levofloxacin Injection

Premix in Single-Use Flexible Containers (5 mg/mL) Levofloxacin in 5% dextrose injection is supplied in flexible containers within a foil overwrap. These contain a premixed, ready to use levofloxacin solution in 5% dextrose (D5W) for single-use.

The

50 mL premixed flexible container contains 250 mg/50 mL of levofloxacin solution.

The

100 mL premixed flexible container contains 500 mg/100 mL of levofloxacin solution.

The

150 mL premixed flexible container contains 750 mg/150 mL of levofloxacin solution. The concentration of each container is 5 mg/mL. No further dilution of these preparations is necessary. Because the premix flexible containers are for single-use only, any unused portion should be discarded. Instructions for the Use of Levofloxacin Injection Premix in Single-Use Flexible Containers: 1. Tear outer wrap at the notch and remove solution container. 2. Check the container for minute leaks by squeezing the inner bag firmly. If leaks are found, or if the seal is not intact, discard the solution, as the sterility may be compromised. 3. Do not use if the solution is cloudy or a precipitate is present. 4. Use sterile equipment. 5. WARNING: Do not use flexible containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete. Preparation for Administration: 1. Close flow control clamp of administration set. 2. Remove cover from port at bottom of container. 3. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. NOTE: See full directions on administration set carton. 4. Suspend container from hanger. 5. Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of Levofloxacin Injection Premix in Flexible Containers. 6. Open flow control clamp to expel air from set. Close clamp. 7. Regulate rate of administration with flow control clamp.

2.1 Dosage in Adult Patients with Normal Renal Function The usual dose of Levofloxacin in 5% Dextrose 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 &lt; 50 mL/min, adjustments to the dosing regimen are required <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> .

Table

1: Dosage in Adult Patients with Normal Renal Function (creatinine clearance ≥ 50 mL/min) 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 * 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 ( 5.12 ), 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.

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 ( 5.12 ), 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 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 &lt; 50 mL/min), adjustment of the dosage regimen is necessary to avoid the accumulation of levofloxacin due to decreased clearance <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) ]</span>.

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 mg every 48 hours 250 mg No dosage adjustment required 250 mg every 48 hours. If treating uncomplicated UTI, then no dosage adjustment is required No information on dosing adjustment is available

2.4 Drug Interaction with Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins Levofloxacin in 5% dextrose injection should not be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span> .

2.5 Administration Instructions Caution: Rapid or bolus intravenous infusion of levofloxacin has been associated with hypotension and must be avoided. Levofloxacin in 5% dextrose injection should be infused intravenously slowly over a period of not less than 60 or 90 minutes, depending on the dosage. Levofloxacin in 5% dextrose injection should be administered only by intravenous infusion. It is not for intramuscular, intrathecal, intraperitoneal, or subcutaneous administration. Hydration for Patients Receiving Levofloxacin in 5% Dextrose Injection Adequate hydration of patients receiving intravenous levofloxacin should be maintained to prevent the formation of highly concentrated urine. Crystalluria and cylindruria have been reported with quinolones <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 ) and Patient Counseling Information ( 17 )]</span>.

2.6 Preparation of Intravenous Product Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Because only limited data are available on the compatibility of levofloxacin in 5% dextrose injection with other intravenous substances, additives or other medications should not be added to Levofloxacin Injection Premix Solution in Single-Use Flexible Containers, or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of levofloxacin in 5% dextrose injection with an infusion solution compatible with levofloxacin in 5% dextrose injection and with any other drug(s) administered via this common line.

Levofloxacin Injection

Premix in Single-Use Flexible Containers (5 mg/mL) Levofloxacin in 5% dextrose injection is supplied in flexible containers within a foil overwrap. These contain a premixed, ready to use levofloxacin solution in 5% dextrose (D5W) for single-use.

The

50 mL premixed flexible container contains 250 mg/50 mL of levofloxacin solution.

The

100 mL premixed flexible container contains 500 mg/100 mL of levofloxacin solution.

The

150 mL premixed flexible container contains 750 mg/150 mL of levofloxacin solution. The concentration of each container is 5 mg/mL. No further dilution of these preparations is necessary. Because the premix flexible containers are for single-use only, any unused portion should be discarded. Instructions for the Use of Levofloxacin Injection Premix in Single-Use Flexible Containers: 1. Tear outer wrap at the notch and remove solution container. 2. Check the container for minute leaks by squeezing the inner bag firmly. If leaks are found, or if the seal is not intact, discard the solution, as the sterility may be compromised. 3. Do not use if the solution is cloudy or a precipitate is present. 4. Use sterile equipment. 5. WARNING: Do not use flexible containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete. Preparation for Administration: 1. Close flow control clamp of administration set. 2. Remove cover from port at bottom of container. 3. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. NOTE: See full directions on administration set carton. 4. Suspend container from hanger. 5. Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of Levofloxacin Injection Premix in Flexible Containers. 6. Open flow control clamp to expel air from set. Close clamp. 7. Regulate rate of administration with flow control clamp.

Levofloxacin ophthalmic solution is contraindicated in patients with a history of hypersensitivity to levofloxacin, to other quinolones, or to any of the components in this medication. Levofloxacin ophthalmic solution is contraindicated in patients with a history of hypersensitivity to levofloxacin, to other quinolones, or to any of the components in this medication. ( 4 )

REACTIONS The most common reactions (≥ 3%) were nausea, headache, diarrhea, insomnia, constipation and dizziness ( 6.2 ). To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 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 )]
• 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 in 5% Dextrose Injection. Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection. Therefore, adequate hydration of patients receiving Levofloxacin in 5% Dextrose Injection 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 5% Dextrose Injection in 7,537 patients in 29 pooled Phase 3 clinical trials. The population studied had a mean age of 50 years (approximately 74% of the population was &lt; 65 years of age), 50% were male, 71% were Caucasian, 19% were Black. Patients were treated with Levofloxacin in 5% Dextrose Injection for a wide variety of infectious diseases <span class="opacity-50 text-xs">[see Indications and Usage (1) ]</span> . Patients received Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation of Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection-treated patients and less common adverse reactions, occurring in 0.1 to &lt; 1% of Levofloxacin in 5% Dextrose Injection-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 System/Organ Class Adverse Reaction % (N = 7,537) Infections and Infestations moniliasis 1 Psychiatric Disorders insomnia* [see Warnings and Precautions ( 5.4 )] 4 Nervous System Disorders headache 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 * N = 7,274 † N = 3,758 (women)

Table

5: Less Common (0.1 to 1%)

Adverse Reactions

Reported in Clinical Trials with Levofloxacin (N=7,537)

System/Organ

Class Adverse Reaction Infections and Infestations genital moniliasis Blood and Lymphatic System Disorders anemia thrombocytopenia granulocytopenia [see Warnings and Precautions ( 5.6 )]

Immune System

Disorders allergic reaction [see Warnings and Precautions ( 5.6 , 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 )] * N = 7,274 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 Post-marketing Experience Table 6 lists adverse reactions that have been identified during post-approval use of Levofloxacin in 5% Dextrose Injection. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible.

Table

6: Post-marketing 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 suicide ideation, suicide attempt and completed suicide [see Warnings and Precautions ( 5.4 )]

Nervous System

Disorders exacerbation of myasthenia gravis [see Warnings and Precautions ( 5.2 )] anosmia ageusia parosmia dysgeusia peripheral neuropathy (may be irreversible) [see Warnings and Precautions ( 5.3 )] isolated reports of encephalopathy abnormal electroencephalogram (EEG) dysphonia pseudotumor cerebri [see Warnings and Precautions ( 5.4 )]

Eye

Disorders uveitis vision disturbance, including diplopia visual acuity reduced vision blurred scotoma Ear and Labyrinth Disorders hypoacusis tinnitus Cardiac Disorders isolated reports of torsades de pointes electrocardiogram QT prolonged [see Warnings and Precautions ( 5.11 )] tachycardia Vascular Disorders vasodilatation Respiratory, Thoracic and Mediastinal Disorders isolated reports of allergic pneumonitis [see Warnings and Precautions ( 5.6 )]

Hepatobiliary

Disorders hepatic failure (including fatal cases) hepatitis jaundice [see Warnings and Precautions ( 5.6 , 5.8 )] Skin and Subcutaneous Tissue Disorders bullous eruptions to include: Stevens-Johnson Syndrome toxic epidermal necrolysis Acute Generalized Exanthematous Pustulosis (AGEP) fixed drug eruptions erythema multiforme [see Warnings and Precautions ( 5.6 )] photosensitivity/phototoxicity reaction [see Warnings and Precautions ( 5.14 )] leukocytoclastic vasculitis Musculoskeletal and Connective Tissue Disorders tendon rupture [see Warnings and Precautions ( 5.2 )] muscle injury, including rupture rhabdomyolysis Renal and Urinary Disorders interstitial nephritis [see Warnings and Precautions ( 5.6 )]

General

Disorders and Administration Site Conditions multi-organ failure pyrexia Investigations prothrombin time prolonged international normalized ratio prolonged muscle enzymes increased

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 torsades 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 in 5% Dextrose Injection, 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 in 5% Dextrose Injection. Patients of any age or without pre-existing risk factors have experienced these adverse reactions <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 , 5.3 , 5.4 )]</span> .

Discontinue

Levofloxacin in 5% Dextrose Injection immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including Levofloxacin in 5% Dextrose Injection, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

5.2 Tendinitis and Tendon Rupture Fluoroquinolones, including Levofloxacin in 5% Dextrose Injection have been associated with an increased risk of tendinitis and tendon rupture in all ages <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.2 )]</span> . 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 in 5% Dextrose Injection 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 usually 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 in 5% Dextrose Injection 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 5% Dextrose Injection in patients who have a history of tendon disorders or tendon rupture [see Adverse Reactions ( 6.3 ) and Patient Counseling Information ( 17 )] .

5.3 Peripheral Neuropathy Fluoroquinolones, including Levofloxacin in 5% Dextrose Injection, 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 in 5% Dextrose Injection. Symptoms may occur soon after initiation of Levofloxacin in 5% Dextrose Injection and may be irreversible in some patients <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 , 6.2 )]</span> .

Discontinue

Levofloxacin in 5% Dextrose Injection 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 5% Dextrose Injection, 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 in 5% Dextrose Injection, 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 in 5% Dextrose Injection, discontinue Levofloxacin in 5% Dextrose Injection and institute appropriate measures.

Central Nervous System Adverse

Reactions of Seizures, Increased Intracranial Pressure, and Tremors Fluoroquinolones, including Levofloxacin in 5% Dextrose Injection, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (including pseudotumor cerebri), tremors, and lightheadedness. As with other fluoroquinolones, Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection, discontinue Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Post-marketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis.

Avoid

Levofloxacin in 5% Dextrose Injection in patients with a known history of myasthenia gravis [see Adverse Reactions ( 6.3 ) and 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 in 5% Dextrose Injection. 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 in 5% Dextrose Injection immediately at the first appearance of skin rash, jaundice, or any other sign of hypersensitivity and institute supportive measures [see Adverse Reactions ( 6 ) and Patient Counseling Information ( 17 )] .

5.7 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with fluoroquinolones, including Levofloxacin in 5% Dextrose Injection. These reactions often occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat, or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions. Levofloxacin in 5% Dextrose Injection should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 ) and Patient Counseling Information ( 17 )]</span> .

5.8 Hepatotoxicity Post-marketing reports of severe hepatotoxicity (including acute hepatitis and fatal events) have been received for patients treated with Levofloxacin in 5% Dextrose Injection. No evidence of serious drug-associated hepatotoxicity was detected in clinical trials of over 7,000 patients. Severe hepatotoxicity generally occurred within 14 days of initiation of therapy and most cases occurred within 6 days. Most cases of severe hepatotoxicity were not associated with hypersensitivity <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.6 )]</span> . The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. Levofloxacin in 5% Dextrose Injection should be discontinued immediately if the patient develops signs and symptoms of hepatitis <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 ) and Patient Counseling Information ( 17 )]</span> .

5.9 Risk of Aortic Aneurysm and Dissection Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients. The cause for the increased risk has not been identified. In patients with a known aortic aneurysm or patients who are at greater risk for aortic aneurysms, reserve Levofloxacin in 5% Dextrose Injection for use only when there are no alternative antibacterial treatments available.

5.10 Clostridium difficile -Associated Diarrhea Clostridium difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Levofloxacin in 5% Dextrose Injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 ) and Patient Counseling Information ( 17 )]</span> .

5.11 Prolongation of the QT Interval Some fluoroquinolones, including Levofloxacin in 5% Dextrose Injection, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsades de pointes have been spontaneously reported during post-marketing surveillance in patients receiving fluoroquinolones, including Levofloxacin in 5% Dextrose Injection. Levofloxacin should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.3 ), Use in Specific Populations ( 8.5 ) and Patient Counseling Information ( 17 )]</span> .

5.12 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals Levofloxacin in 5% Dextrose Injection is indicated in pediatric patients (6 months of age and older) only for the prevention of inhalational anthrax (post-exposure) and for plague <span class="opacity-50 text-xs">[see Indications and Usage ( 1.7 , 1.8 )]</span> . An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormality) compared to controls has been observed in pediatric patients receiving Levofloxacin in 5% Dextrose Injection <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4 )]</span> . In immature rats and dogs, the oral and intravenous administration of levofloxacin resulted in increased osteochondrosis. Histopathological examination of the weight-bearing joints of immature dogs dosed with levofloxacin revealed persistent lesions of the cartilage. Other fluoroquinolones also produce similar erosions in the weight-bearing joints and other signs of arthropathy in immature animals of various species <span class="opacity-50 text-xs">[see Animal Toxicology and/or Pharmacology ( 13.2 )]</span> .

5.13 Blood Glucose Disturbances Fluoroquinolones, including Levofloxacin in 5% Dextrose Injection, have been associated with disturbances of blood glucose, including symptomatic hyperglycemia and hypoglycemia, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. Severe cases of hypoglycemia resulting in coma or death have been reported. If a hypoglycemic reaction occurs in a patient being treated with Levofloxacin in 5% Dextrose Injection, discontinue Levofloxacin in 5% Dextrose Injection and initiate appropriate therapy immediately <span class="opacity-50 text-xs">[see Adverse Reactions (6.2), Drug Interactions (7.3) and Patient Counseling Information (17 )]</span>.

5.14 Photosensitivity/Phototoxicity Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of fluoroquinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if photosensitivity/phototoxicity occurs <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.3 ) and Patient Counseling Information ( 17 )]</span> .

5.15 Development of Drug-Resistant Bacteria Prescribing Levofloxacin in 5% Dextrose Injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria <span class="opacity-50 text-xs">[see Patient Counseling Information ( 17 )]</span> .

5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects Fluoroquinolones, including Levofloxacin in 5% Dextrose Injection, 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 in 5% Dextrose Injection. Patients of any age or without pre-existing risk factors have experienced these adverse reactions <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 , 5.3 , 5.4 )]</span> .

Discontinue

Levofloxacin in 5% Dextrose Injection immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including Levofloxacin in 5% Dextrose Injection, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

5.2 Tendinitis and Tendon Rupture Fluoroquinolones, including Levofloxacin in 5% Dextrose Injection have been associated with an increased risk of tendinitis and tendon rupture in all ages <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.2 )]</span> . 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 in 5% Dextrose Injection 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 usually 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 in 5% Dextrose Injection 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 5% Dextrose Injection in patients who have a history of tendon disorders or tendon rupture [see Adverse Reactions ( 6.3 ) and Patient Counseling Information ( 17 )] .

5.3 Peripheral Neuropathy Fluoroquinolones, including Levofloxacin in 5% Dextrose Injection, 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 in 5% Dextrose Injection. Symptoms may occur soon after initiation of Levofloxacin in 5% Dextrose Injection and may be irreversible in some patients <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 , 6.2 )]</span> .

Discontinue

Levofloxacin in 5% Dextrose Injection 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 5% Dextrose Injection, 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 in 5% Dextrose Injection, 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 in 5% Dextrose Injection, discontinue Levofloxacin in 5% Dextrose Injection and institute appropriate measures.

Central Nervous System Adverse

Reactions of Seizures, Increased Intracranial Pressure, and Tremors Fluoroquinolones, including Levofloxacin in 5% Dextrose Injection, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (including pseudotumor cerebri), tremors, and lightheadedness. As with other fluoroquinolones, Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection, discontinue Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Post-marketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis.

Avoid

Levofloxacin in 5% Dextrose Injection in patients with a known history of myasthenia gravis [see Adverse Reactions ( 6.3 ) and 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 in 5% Dextrose Injection. 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 in 5% Dextrose Injection immediately at the first appearance of skin rash, jaundice, or any other sign of hypersensitivity and institute supportive measures [see Adverse Reactions ( 6 ) and Patient Counseling Information ( 17 )] .

5.7 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with fluoroquinolones, including Levofloxacin in 5% Dextrose Injection. These reactions often occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat, or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions. Levofloxacin in 5% Dextrose Injection should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 ) and Patient Counseling Information ( 17 )]</span> .

5.8 Hepatotoxicity Post-marketing reports of severe hepatotoxicity (including acute hepatitis and fatal events) have been received for patients treated with Levofloxacin in 5% Dextrose Injection. No evidence of serious drug-associated hepatotoxicity was detected in clinical trials of over 7,000 patients. Severe hepatotoxicity generally occurred within 14 days of initiation of therapy and most cases occurred within 6 days. Most cases of severe hepatotoxicity were not associated with hypersensitivity <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.6 )]</span> . The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. Levofloxacin in 5% Dextrose Injection should be discontinued immediately if the patient develops signs and symptoms of hepatitis <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 ) and Patient Counseling Information ( 17 )]</span> .

5.10 Clostridium difficile -Associated Diarrhea Clostridium difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Levofloxacin in 5% Dextrose Injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 ) and Patient Counseling Information ( 17 )]</span> .

5.11 Prolongation of the QT Interval Some fluoroquinolones, including Levofloxacin in 5% Dextrose Injection, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsades de pointes have been spontaneously reported during post-marketing surveillance in patients receiving fluoroquinolones, including Levofloxacin in 5% Dextrose Injection. Levofloxacin should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.3 ), Use in Specific Populations ( 8.5 ) and Patient Counseling Information ( 17 )]</span> .

5.12 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals Levofloxacin in 5% Dextrose Injection is indicated in pediatric patients (6 months of age and older) only for the prevention of inhalational anthrax (post-exposure) and for plague <span class="opacity-50 text-xs">[see Indications and Usage ( 1.7 , 1.8 )]</span> . An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormality) compared to controls has been observed in pediatric patients receiving Levofloxacin in 5% Dextrose Injection <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4 )]</span> . In immature rats and dogs, the oral and intravenous administration of levofloxacin resulted in increased osteochondrosis. Histopathological examination of the weight-bearing joints of immature dogs dosed with levofloxacin revealed persistent lesions of the cartilage. Other fluoroquinolones also produce similar erosions in the weight-bearing joints and other signs of arthropathy in immature animals of various species <span class="opacity-50 text-xs">[see Animal Toxicology and/or Pharmacology ( 13.2 )]</span> .

5.13 Blood Glucose Disturbances Fluoroquinolones, including Levofloxacin in 5% Dextrose Injection, have been associated with disturbances of blood glucose, including symptomatic hyperglycemia and hypoglycemia, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. Severe cases of hypoglycemia resulting in coma or death have been reported. If a hypoglycemic reaction occurs in a patient being treated with Levofloxacin in 5% Dextrose Injection, discontinue Levofloxacin in 5% Dextrose Injection and initiate appropriate therapy immediately <span class="opacity-50 text-xs">[see Adverse Reactions (6.2), Drug Interactions (7.3) and Patient Counseling Information (17 )]</span>.

5.14 Photosensitivity/Phototoxicity Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of fluoroquinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if photosensitivity/phototoxicity occurs <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.3 ) and Patient Counseling Information ( 17 )]</span> .

5.15 Development of Drug-Resistant Bacteria Prescribing Levofloxacin in 5% Dextrose Injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria <span class="opacity-50 text-xs">[see Patient Counseling Information ( 17 )]</span> .

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 )]
• 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 in 5% Dextrose Injection. Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection. Therefore, adequate hydration of patients receiving Levofloxacin in 5% Dextrose Injection 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 5% Dextrose Injection in 7,537 patients in 29 pooled Phase 3 clinical trials. The population studied had a mean age of 50 years (approximately 74% of the population was &lt; 65 years of age), 50% were male, 71% were Caucasian, 19% were Black. Patients were treated with Levofloxacin in 5% Dextrose Injection for a wide variety of infectious diseases <span class="opacity-50 text-xs">[see Indications and Usage (1) ]</span> . Patients received Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation of Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection-treated patients and less common adverse reactions, occurring in 0.1 to &lt; 1% of Levofloxacin in 5% Dextrose Injection-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 System/Organ Class Adverse Reaction % (N = 7,537) Infections and Infestations moniliasis 1 Psychiatric Disorders insomnia* [see Warnings and Precautions ( 5.4 )] 4 Nervous System Disorders headache 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 * N = 7,274 † N = 3,758 (women)

Table

5: Less Common (0.1 to 1%)

Adverse Reactions

Reported in Clinical Trials with Levofloxacin (N=7,537)

System/Organ

Class Adverse Reaction Infections and Infestations genital moniliasis Blood and Lymphatic System Disorders anemia thrombocytopenia granulocytopenia [see Warnings and Precautions ( 5.6 )]

Immune System

Disorders allergic reaction [see Warnings and Precautions ( 5.6 , 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 )] * N = 7,274 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 Post-marketing Experience Table 6 lists adverse reactions that have been identified during post-approval use of Levofloxacin in 5% Dextrose Injection. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible.

Table

6: Post-marketing 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 suicide ideation, suicide attempt and completed suicide [see Warnings and Precautions ( 5.4 )]

Nervous System

Disorders exacerbation of myasthenia gravis [see Warnings and Precautions ( 5.2 )] anosmia ageusia parosmia dysgeusia peripheral neuropathy (may be irreversible) [see Warnings and Precautions ( 5.3 )] isolated reports of encephalopathy abnormal electroencephalogram (EEG) dysphonia pseudotumor cerebri [see Warnings and Precautions ( 5.4 )]

Eye

Disorders uveitis vision disturbance, including diplopia visual acuity reduced vision blurred scotoma Ear and Labyrinth Disorders hypoacusis tinnitus Cardiac Disorders isolated reports of torsades de pointes electrocardiogram QT prolonged [see Warnings and Precautions ( 5.11 )] tachycardia Vascular Disorders vasodilatation Respiratory, Thoracic and Mediastinal Disorders isolated reports of allergic pneumonitis [see Warnings and Precautions ( 5.6 )]

Hepatobiliary

Disorders hepatic failure (including fatal cases) hepatitis jaundice [see Warnings and Precautions ( 5.6 , 5.8 )] Skin and Subcutaneous Tissue Disorders bullous eruptions to include: Stevens-Johnson Syndrome toxic epidermal necrolysis Acute Generalized Exanthematous Pustulosis (AGEP) fixed drug eruptions erythema multiforme [see Warnings and Precautions ( 5.6 )] photosensitivity/phototoxicity reaction [see Warnings and Precautions ( 5.14 )] leukocytoclastic vasculitis Musculoskeletal and Connective Tissue Disorders tendon rupture [see Warnings and Precautions ( 5.2 )] muscle injury, including rupture rhabdomyolysis Renal and Urinary Disorders interstitial nephritis [see Warnings and Precautions ( 5.6 )]

General

Disorders and Administration Site Conditions multi-organ failure pyrexia Investigations prothrombin time prolonged international normalized ratio prolonged muscle enzymes increased

INTERACTIONS Interacting Drug Interaction Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. 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 ) Anti-diabetic agents Carefully monitor blood glucose ( 5.13 , 7.3 )

7.1 Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span>.

7.2 Warfarin No significant effect of Levofloxacin in 5% Dextrose Injection 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 post-marketing experience in patients that Levofloxacin in 5% Dextrose Injection enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent warfarin and Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.3 ) and Patient Counseling Information ( 17 )]</span>.

7.3 Anti-diabetic Agents Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with fluoroquinolones and an anti-diabetic agent. Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.13 ), Adverse Reactions (6.2) and Patient Counseling Information ( 17 )]</span>.

7.4 Non-Steroidal Anti-Inflammatory Drugs The concomitant administration of a non-steroidal anti-inflammatory drug with a fluoroquinolone, including Levofloxacin in 5% Dextrose Injection, may increase the risk of CNS stimulation and convulsive seizures <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span>.

7.5 Theophylline No significant effect of Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection is co-administered. Adverse reactions, including seizures, may occur with or without an elevation in serum theophylline levels <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span>.

7.6 Cyclosporine No significant effect of Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection or cyclosporine when administered concomitantly.

7.7 Digoxin No significant effect of Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection 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 ½ of levofloxacin were higher while CL/F and CL R were lower during concomitant treatment of Levofloxacin in 5% Dextrose Injection with probenecid or cimetidine compared to Levofloxacin in 5% Dextrose Injection alone. However, these changes do not warrant dosage adjustment for Levofloxacin in 5% Dextrose Injection when probenecid or cimetidine is co-administered.

7.9 Interactions with Laboratory or Diagnostic Testing Some fluoroquinolones, including Levofloxacin in 5% Dextrose Injection, 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.

7.1 Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span>.

7.2 Warfarin No significant effect of Levofloxacin in 5% Dextrose Injection 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 post-marketing experience in patients that Levofloxacin in 5% Dextrose Injection enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent warfarin and Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.3 ) and Patient Counseling Information ( 17 )]</span>.

7.3 Anti-diabetic Agents Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with fluoroquinolones and an anti-diabetic agent. Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.13 ), Adverse Reactions (6.2) and Patient Counseling Information ( 17 )]</span>.

7.4 Non-Steroidal Anti-Inflammatory Drugs The concomitant administration of a non-steroidal anti-inflammatory drug with a fluoroquinolone, including Levofloxacin in 5% Dextrose Injection, may increase the risk of CNS stimulation and convulsive seizures <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span>.

7.5 Theophylline No significant effect of Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection is co-administered. Adverse reactions, including seizures, may occur with or without an elevation in serum theophylline levels <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span>.

7.6 Cyclosporine No significant effect of Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection or cyclosporine when administered concomitantly.

7.7 Digoxin No significant effect of Levofloxacin in 5% Dextrose Injection 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 in 5% Dextrose Injection 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 ½ of levofloxacin were higher while CL/F and CL R were lower during concomitant treatment of Levofloxacin in 5% Dextrose Injection with probenecid or cimetidine compared to Levofloxacin in 5% Dextrose Injection alone. However, these changes do not warrant dosage adjustment for Levofloxacin in 5% Dextrose Injection when probenecid or cimetidine is co-administered.

7.9 Interactions with Laboratory or Diagnostic Testing Some fluoroquinolones, including Levofloxacin in 5% Dextrose Injection, 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.