LEVOFLOXACIN- levofloxacin tablet, film coated 
Clinical Solutions Wholesale, LLC

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use LEVOFLOXACIN TABLETS safely and effectively. See full prescribing information for LEVOFLOXACIN TABLETS.







LEVOFLOXACIN tablets, for oral use



Initial U.S. Approval: 1996

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS

See full prescribing information for complete boxed warning.

  • Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together ( 5.1), including:
    • Tendinitis and tendon rupture ( 5.2)
    • Peripheral neuropathy ( 5.3)
    • Central nervous system effects ( 5.4)

Discontinue levofloxacin immediately and avoid the use of fluoroquinolones, including levofloxacin, in patients who experience any of these serious adverse reactions ( 5.1)

  • Fluoroquinolones, including levofloxacin, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid levofloxacin in patients with a known history of myasthenia gravis [see Warnings and Precautions ( 5.5)].
  • Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions ( 5.1-5.14), reserve levofloxacin or use in patients who have no alternative treatment options for the following indications:
    • Uncomplicated urinary tract infection ( 1.12)
    • Acute bacterial exacerbation of chronic bronchitis ( 1.13)
    • Acute bacterial sinusitis ( 1.14)

INDICATIONS AND USAGE

Levofloxacin  is a fluoroquinolone antibacterial indicated in adults (18 years of age and older) with infections caused by designated, susceptible bacteria and in pediatric patients where indicated ( 1, 12.4).

  • Pneumonia: Nosocomial ( 1.1) and Community Acquired ( 1.2, 1.3)
  • Skin and Skin Structure Infections (SSSI): Complicated ( 1.4) and Uncomplicated ( 1.5)
  • Chronic bacterial prostatitis ( 1.6)
  • Inhalational Anthrax, Post-Exposure in adult and pediatric patients ( 1.7)
  • Plague in adult and pediatric patients ( 1.8)
  • Urinary Tract Infections (UTI): Complicated ( 1.9, 1.10) and Uncomplicated ( 1.12)
  • Acute Pyelonephritis ( 1.11)
  • Acute Bacterial Exacerbation of Chronic Bronchitis ( 1.13)
  • Acute Bacterial Sinusitis ( 1.14)

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of levofloxacin and other antibacterial drugs, levofloxacin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria ( 1.15).

DOSAGE AND ADMINISTRATION

  •   Administer levofloxacin tablets to pediatric patients weighing 30 kg and greater only ( 2.1, 2.2).
  •   Levofloxacin tablets cannot be administered to pediatric patients who weigh less than 30 kg because of the limitations of the available strengths. Alternative formulations of levofloxacin may be considered for pediatric patients who weigh less than 30 kg ( 2.2).

Dosage in Adult and Pediatric Patients with Creatinine Clearance greater than or equal to 50 mL/minute ( 2.1, 2.2)

Type of Infection

Dose Every 24 hours

Duration (days)

Nosocomial Pneumonia ( 1.1)

750 mg

7 to 14

Community Acquired Pneumonia ( 1.2)

500 mg

7 to 14

Community Acquired Pneumonia ( 1.3)

750 mg

5

Complicated Skin and Skin Structure Infections (SSSI) ( 1.4)

750 mg

7 to 14

Uncomplicated SSSI ( 1.5)

500 mg

7 to 10

Chronic Bacterial Prostatitis ( 1.6)

500 mg

28

Inhalational Anthrax (Post-Exposure) ( 1.7)

Adults and Pediatric Patients 50 kg or greater

500 mg

60

Pediatric Patients 30 kg to less than 50 kg (2.2)

250 mg every 12 hours

60

Plague ( 1.8)

Adults and Pediatric Patients 50 kg or greater

500 mg

10 to 14

Pediatric Patients 30 kg to less than 50 kg (2.2)

250 mg every 12 hours

10 to 14

Complicated UTI ( 1.9) or Acute Pyelonephritis ( 1.11)

750 mg

5

Complicated UTI ( 1.10) or Acute Pyelonephritis ( 1.11)

250 mg

10

Uncomplicated UTI ( 1.12)

250 mg

3

Acute Bacterial Exacerbation of Chronic Bronchitis ( 1.13)

500 mg

7

Acute Bacterial Sinusitis ( 1.14)

750 mg

5

500 mg

10 to 14

  •   Adjust dose for creatinine clearance less than 50 mL/minute ( 2, 8.6, 12.3)

DOSAGE FORMS AND STRENGTHS

Formulation ( 3)

Strength

Tablets

250 mg, 500 mg, and 750 mg

CONTRAINDICATIONS

Known hypersensitivity to levofloxacin  or other quinolones ( 4, 5.7)

WARNINGS AND PRECAUTIONS

  • Anaphylactic reactions and allergic skin reactions, serious, occasionally fatal, may occur after first dose ( 4, 5.7)
  • Hematologic (including agranulocytosis, thrombocytopenia), and renal toxicities may occur after multiple doses ( 5.6)
  • Hepatotoxicity: Severe, and sometimes fatal, hepatotoxicity has been reported. Discontinue immediately if signs and symptoms of hepatitis occur ( 5.8)
  • Clostridium difficile -associated colitis: evaluate if diarrhea occurs ( 5.9)
  • Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs that prolong the QT interval ( 5.10, 8.5)

ADVERSE REACTIONS

The most common reactions (≥ 3%) were nausea, headache, diarrhea, insomnia, constipation and dizziness ( 6.2).

To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS

Interacting Drug

Interaction

Multivalent cation-containing products including antacids, metal cations or didanosine

Absorption of levofloxacin is decreased when tablets taken within 2 hours of these products. ( 2.4, 7.1)

Warfarin

Effect may be enhanced. Monitor prothrombin time, INR and watch for bleeding ( 7.2)

Antidiabetic agents

Carefully monitor blood glucose (5.12, 7.3)

USE IN SPECIFIC POPULATIONS

  • Geriatrics: Severe hepatotoxicity has been reported. The majority of reports describe patients 65 years of age or older ( 5.8, 8.5, 17). May have increased risk of tendinopathy (including rupture), especially with concomitant corticosteroid use ( 5.2, 8.5, 17). May be more susceptible to prolongation of the QT interval. (5.10, 8.5, 17).
  • Pediatrics: Musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormality) seen in more levofloxacin-treated patients than in comparator. Shown to cause arthropathy and osteochondrosis in juvenile animals ( 5.11, 8.4, 13.2). Safety in pediatric patients treated for more than 14 days has not been studied. Risk-benefit appropriate only for the treatment of inhalational anthrax (post-exposure) ( 1.7, 2.2, 8.4, 14.9) and plague ( 1.8, 2.2, 8.4, 14.10)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 7/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS

1 INDICATIONS AND USAGE

1.1 Nosocomial Pneumonia

1.2 Community-Acquired Pneumonia: 7 to 14 day Treatment Regimen

1.3 Community-Acquired Pneumonia: 5-day Treatment Regimen

1.4 Complicated Skin and Skin Structure Infections

1.5 Uncomplicated Skin and Skin Structure Infections

1.6 Chronic Bacterial Prostatitis

1.7 Inhalational Anthrax (Post-Exposure)

1.8 Plague

1.9 Complicated Urinary Tract Infections: 5-day Treatment Regimen

1.10 Complicated Urinary Tract Infections: 10-day Treatment Regimen

1.11 Acute Pyelonephritis: 5 or 10-day Treatment Regimen

1.12 Uncomplicated Urinary Tract Infections

1.13 Acute Bacterial Exacerbation of Chronic Bronchitis

1.14 Acute Bacterial Sinusitis: 5-day and 10 to14 day Treatment Regimens

1.15 Usage

2 DOSAGE AND ADMINISTRATION

2.1 Dosage of Levofloxacin Tablets in Adult Patients with Creatinine Clearance ≥ 50 mL/minute

2.2 Dosage of Levofloxacin Tablets in Pediatric Patients with Inhalational Anthrax or Plague

2.3 Dosage Adjustment in Adults with Renal Impairment

2.4 Drug Interaction With Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins

2.5 Administration Instructions

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects

5.2 Tendinitis and Tendon Rupture

5.3 Peripheral Neuropathy

5.4 Central Nervous System Effects

5.5 Exacerbation of Myasthenia Gravis

5.6 Other Serious and Sometimes Fatal Adverse Reactions

5.7 Hypersensitivity Reactions

5.8 Hepatotoxicity

5.9 Clostridium difficile-Associated Diarrhea

5.10 Prolongation of the QT Interval

5.11 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals

5.12 Blood Glucose Disturbances

5.13 Photosensitivity/Phototoxicity

5.14 Development of Drug Resistant Bacteria

6 ADVERSE REACTIONS

6.1 Serious and Otherwise Important Adverse Reactions

6.2 Clinical Trial Experience

6.3 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins

7.2 Warfarin

7.3 Antidiabetic Agents

7.4 Non-Steroidal Anti-Inflammatory Drugs

7.5 Theophylline

7.6 Cyclosporine

7.7 Digoxin

7.8 Probenecid and Cimetidine

7.9 Interactions with Laboratory or Diagnostic Testing

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Nosocomial Pneumonia

14.2 Community-Acquired Pneumonia: 7 to 14 day Treatment Regimen

14.3 Community-Acquired Pneumonia: 5 day Treatment Regimen

14.4 Acute Bacterial Sinusitis: 5 day and 10 to 14 day Treatment Regimens

14.5 Complicated Skin and Skin Structure Infections

14.6 Chronic Bacterial Prostatitis

14.7 Complicated Urinary Tract Infections and Acute Pyelonephritis: 5-day Treatment Regimen

14.8 Complicated Urinary Tract Infections and Acute Pyelonephritis: 10-day Treatment Regimen

14.9 Inhalational Anthrax (Post-Exposure)

14.10 Plague

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 Levofloxacin Tablets

17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS

  • Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together [see Warnings and Precautions ( 5.1)] , including:
    • 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)]

Discontinue levofloxacin immediately and avoid the use of fluoroquinolones, including levofloxacin, in patients who experience any of these serious adverse reactions [see Warnings and Precautions ( 5.1)]

  • Fluoroquinolones, including levofloxacin , may exacerbate muscle weakness in patients with myasthenia gravis. Avoid levofloxacin in patients with a known history of myasthenia gravis [see Warnings and Precautions ( 5.5)] .
  • Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1-5.14)], reserve levofloxacin for use in patients who have no alternative treatment options for the following indications:
    • Uncomplicated urinary tract infection [see Indications and Usage ( 1.12)]
    • Acute bacterial exacerbation of chronic bronchitis [see Indications and Usage ( 1.13)]
    • Acute bacterial sinusitis [see Indications and Usage ( 1.14)].

1 INDICATIONS AND USAGE

1.1 Nosocomial Pneumonia

Levofloxacin tablet is indicated in adult patients for the treatment of nosocomial pneumonia due to methicillin-susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, 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 tablet is indicated in adult patients for the treatment of community-acquired pneumonia due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant Streptococcus pneumoniae [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae [see Dosage and Administration ( 2.1) and Clinical Studies ( 14.2)] .

MDRSP isolates are isolates resistant to two or more of the following antibacterials: penicillin (MIC ≥ 2 mcg/mL), 2 ndgeneration cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

 

1.3 Community-Acquired Pneumonia: 5-day Treatment Regimen

Levofloxacin tablet is indicated in adult patients for the treatment of community-acquired pneumonia due to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Dosage and Administration ( 2.1) and Clinical Studies ( 14.3)].

 

1.4 Complicated Skin and Skin Structure Infections

Levofloxacin tablet is indicated in adult patients for the treatment of complicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, or Proteus mirabilis [see Clinical Studies ( 14.5)].

1.5 Uncomplicated Skin and Skin Structure Infections

Levofloxacin tablet is indicated in adult patients for the treatment of uncomplicated skin and skin structure infections (mild to moderate) including abscesses, cellulitis, furuncles, impetigo, pyoderma, wound infections, due to methicillin-susceptible Staphylococcus aureus, or Streptococcus pyogenes.

1.6 Chronic Bacterial Prostatitis

Levofloxacin tablet is indicated in adult patients for the treatment of chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or methicillin-susceptible Staphylococcus epidermidis [see Clinical Studies ( 14.6)].

1.7 Inhalational Anthrax (Post-Exposure)

Levofloxacin tablet is indicated for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis in adults and pediatric patients, 6 months of age and older [see Dosage and Administration ( 2.2)]. The effectiveness of levofloxacin tablet is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin tablet has not been tested in humans for the post-exposure prevention of inhalation anthrax. The safety of levofloxacin tablets in adults for durations of therapy beyond 28 days or in pediatric patients for durations of therapy beyond 14 days has not been studied. Prolonged levofloxacin tablets therapy should only be used when the benefit outweighs the risk [see Clinical Studies ( 14.9)].

1.8 Plague

Levofloxacin tablet 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 [ see Dosage and Administration ( 2.2) ].

Efficacy studies of Levofloxacin tablets could not be conducted in humans with plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals [ see Clinical Studies ( 14.10) ].

1.9 Complicated Urinary Tract Infections: 5-day Treatment Regimen

Levofloxacin tablet is indicated in adult patients for the treatment of complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis [see Clinical Studies ( 14.7)].

1.10 Complicated Urinary Tract Infections: 10-day Treatment Regimen

Levofloxacin tablet is indicated in adult patients for the treatment of complicated urinary tract infections (mild to moderate) due to Enterococcus faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa [see Clinical Studies ( 14.8)] .

1.11 Acute Pyelonephritis: 5 or 10-day Treatment Regimen

Levofloxacin tablet is indicated in adult patients for the treatment of acute pyelonephritis caused by Escherichia coli, including cases with concurrent bacteremia [see Clinical Studies ( 14.7, 14.8)] .

1.12 Uncomplicated Urinary Tract Infections

Levofloxacin tablet  is indicated in adult patients for the treatment of uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae, or Staphylococcus saprophyticus.

Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1- 5.14)] and for some patients uncomplicated urinary tract infection is self-limiting, reserve levofloxacin for treatment of uncomplicated urinary tract infections in patients who have no alternative treatment options.

1.13 Acute Bacterial Exacerbation of Chronic Bronchitis

Levofloxacin tablet is indicated in adult patients for the treatment of acute bacterial exacerbation of chronic bronchitis (ABECB) due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis.

Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1- 5.14)] 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 to14 day Treatment Regimens

Levofloxacin tablet is indicated in adult patients for the treatment of acute bacterial sinusitis (ABS) due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis [see Clinical Studies ( 14.4)] .

Bcause fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1- 5.14)] and for some patients ABS is self-limiting, reserve levofloxacin for treatment of ABS in patients who have no alternative treatment options.

1.15 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of levofloxacin and other antibacterial drugs, levofloxacin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Culture and susceptibility testing

Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to levofloxacin [see Microbiology ( 12.4)] . Therapy with levofloxacin 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.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage of Levofloxacin Tablets in Adult Patients with Creatinine Clearance ≥ 50 mL/minute

The usual dose of levofloxacin tablets is 250 mg, 500 mg, or 750 mg administered orally every 24 hours, as indicated by infection and described in Table 1.

These recommendations apply to patients with creatinine clearance ≥ 50 mL/minute. For patients with creatinine clearance less than 50 mL/min, adjustments to the dosing regimen are required [see Dosage and Administration ( 2.3)] .

Table 1 Dosage of Levofloxacin Tablets in Adult Patients with Creatinine Clearance greater than or equal to 50 mL/minute
*Due to the designated pathogens [see Indications and Usage ( 1)] .
Sequential therapy (intravenous levofloxacin to oral levofloxacin tablets) may be instituted at the discretion of the healthcare provider.
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.
ÞDrug 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)] .
ßThe safety of levofloxacin tabletsin 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 ( 5.10), Use in Specific Populations ( 8.4), and Clinical Studies ( 14.9)] Prolonged levofloxacin tabletstherapy should only be used when the benefit outweighs the risk.
a Drug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis . Higher doses of levofloxacin tablet typically used for treatment of pneumonia can be used for treatment of plague, if clinically indicated.

Type of Infection * 

Dosed Every
24 hours

Duration (days)

Nosocomial Pneumonia

750 mg

7 to 14

Community Acquired Pneumonia  

500 mg

7 to 14

Community Acquired Pneumonia §  

750 mg

5

Complicated Skin and Skin Structure Infections (SSSI)

750 mg

7 to 14

Uncomplicated SSSI

500 mg

7 to 10

Chronic Bacterial Prostatitis

500 mg

28

Inhalational Anthrax (Post-Exposure), adult and pediatric patients weighing 50 kg Þ, ß or greater
Pediatric patients weighing 30 kg to less than 50 kg Þ, ß
 

500 mg
see Table 2 below (2.2)

60 ß
60 ß

Plague, adult and pediatric patients weighing 50 kg Þ, ß or greater
Pediatric patients weighing 30 kg to less than 50 kg Þ, ß

500 mg
see Table 2 below (2.2)

10 to 14
10 to 14

Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)  

750 mg

5

Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) #  

250 mg

10 #

Uncomplicated Urinary Tract Infection

250 mg

3

Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB)

500 mg

7

Acute Bacterial Sinusitis (ABS)

750 mg

5

500 mg

10 to 14

2.2 Dosage of Levofloxacin Tablets in Pediatric Patients with Inhalational Anthrax or Plague

The dosage of levofloxacin tablets for inhalational anthrax (post-exposure) and plague in pediatric patients who weigh 30 kg or greater is described below in Table 2. Levofloxacin tablets cannot be administered to patients who weigh less than 30 kg because of the limitations of the available strength. Alternative formulations of levofloxacin may be considered for pediatric patients who weigh less than 30 kg.

* Due to Bacillus anthracis [see Indications and Usage ( 1.13)] and Yersinia pestis [see Indications and Usage ( 1.14)].
 Sequential therapy (intravenous levofloxacin injection to oral levofloxacin tablets) may be instituted at the discretion of the healthcare provider.
Being levofloxacin tablets as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis .
§The safety of levofloxacin tabletsin pediatric patients for durations of therapy beyond 14 days has not been studied. [see Warnings and Precautions ( 5.10), Use in Specific Populations ( 8.4), and Clinical Studies ( 14.9)] .

Type of Infection *

Dose

Frequency

Duration

Inhalational Anthrax (post-exposure) ‡,§

Pediatric patients weighing 50 kg or greater

500 mg

every 24 hours

60 days §

Pediatric patients weighing 30 kg to less than 50 kg

250 mg

every 12 hours

60 days §

Plague

Pediatric patients weighing 50 kg or greater

500 mg

every 24 hours

10 to 14 days

Pediatric patients weighing 30 kg to less than 50 kg

250 mg

every 12 hours

10 to 14 days

2.3 Dosage Adjustment in Adults with Renal Impairment

Administer levofloxacin tablets  with caution in patients of renal impairment. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of levofloxacin may be reduced in these patients.

In patients with renal impairment (creatinine clearance less than 50 mL/min), adjustment of the dosage regimen is necessary to avoid the accumulation of levofloxacin due to decreased clearance [see Use in Specific Populations ( 8.6)] . No adjustment is necessary for patients with a creatinine clearance greater than or equal to 50 mL/minute.

Table 3 shows how to adjust dose based on creatinine clearance.

Table 3 Dosage Adjustment in Adult Patients with Renal Impairment Creatinine Clearance less than 50 mL/minute

Creatinine Clearance greater than or equal to 50 mL/minute

Creatinine Clearance 20 to 49 mL/minute

Creatinine Clearance 10 to 19 mL/minute

Hemodialysis or Chronic Ambulatory Peritoneal Dialysis (CAPD)

750 mg every 24 hours

750 mg every 48 hours

750 mg initial dose, then 500 mg every 48 hours

750 mg initial dose, then 500 mg every 48 hours

500 mg every 24 hours

500 mg initial dose, then 250 mg every 24 hours

500 mg initial dose, then 250 mg every 48 hours

500 mg initial dose, then 250 mg every 48 hours

250 mg every 24 hours

No dosage adjustment required

250 mg every 48 hours. If treating uncomplicated UTI, then no dosage adjustment is required

No information on dosing adjustment is available

2.4 Drug Interaction With Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins

Levofloxacin tablets should be administered at least two hours before or two hours after antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine chewable/buffered tablets [see Drug Interactions ( 7.1) and Patient Counseling Information ( 17)] .

2.5 Administration Instructions

Levofloxacin tablets can be administered without regard to food.

Hydration for Patients Receiving Levofloxacin  Tablets

Adequate hydration of patients receiving oral levofloxacin should be maintained to prevent the formation of highly concentrated urine. Crystalluria and cylindruria have been reported with quinolones [see Adverse Reactions ( 6.1) and Patient Counseling Information ( 17)].

3 DOSAGE FORMS AND STRENGTHS

Levofloxacin tablets, USP are white to off white, modified capsule-shaped, biconvex and film-coated

  • 250 mg tablets, debossed with logo of ‘ZC55’ on one side and plain on other side
  • 500 mg tablets, debossed with logo of ‘ZC56’ on one side and plain on other side
  • 750 mg tablets, debossed with logo of ‘ZC57’ on one side and plain on other side

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects

Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting levofloxacin. Patients of any age or without pre-existing risk factors have experienced these adverse reactions [see Warnings and Precautions ( 5.2, 5.3, 5.4)]. Discontinue levofloxacin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including levofloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

5.2 Tendinitis and Tendon Rupture

Fluoroquinolones, including levofloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages [see Warnings and Precautions ( 5.1) and Adverse Reactions ( 6.2)] . This adverse reaction most frequently involves the Achilles tendon and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites. Tendinitis or tendon rupture can occur within hours or days of starting levofloxacin or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally.

The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in those taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have been reported in patients taking fluoroquinolones who do not have the above risk factors. Discontinue levofloxacin immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. Avoid levofloxacin in patients who have a history of tendon disorders or tendon rupture [see Adverse Reactions ( 6.3)   and Patient Counseling Information ( 17)] .

5.3 Peripheral Neuropathy

Fluoroquinolones, including levofloxacin, have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including levofloxacin. Symptoms may occur soon after initiation of levofloxacin and may be irreversible in some patients [see Warnings and Precautions ( 5.1) and Adverse Reactions ( 6.1, 6.2)] .

Discontinue levofloxacin immediately if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation. Avoid fluoroquinolones, including levofloxacin, in patients who have previously experienced peripheral neuropathy [see Adverse Reactions ( 6) and Patient Counseling Information ( 17)] .

5.4 Central Nervous System Effects

Fluoroquinolones, including levofloxacin, have been associated with an increased risk of central nervous system (CNS) effects, including convulsions, toxic psychoses, increased intracranial pressure (including pseudotumor cerebri). Fluoroquinolones may also cause central nervous system stimulation which may lead to tremors, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, and insomnia. Suicidal thoughts, and attempted or completed suicide may also occur, especially in patients with a medical history of depression, or an underlying risk factor for depression. These reactions may occur following the first dose. If these reactions occur in patients receiving levofloxacin, discontinue levofloxacin and institute appropriate measures. As with other fluoroquinolones, levofloxacin  should be used with caution in patients with a known or suspected central nervous system (CNS) disorder that may predispose them to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose them to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction). [see Adverse Reactions ( 6),   Drug Interactions ( 7.4, 7.5) and Patient Counseling Information ( 17)] .

5.5 Exacerbation of Myasthenia Gravis

Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Avoid levofloxacin in patients with a known history of myasthenia gravis [see Adverse Reactions ( 6.3) 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. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:

  • fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome);
  • vasculitis; arthralgia; myalgia; serum sickness;
  • allergic pneumonitis;
  • interstitial nephritis; acute renal insufficiency or failure;
  • hepatitis; jaundice; acute hepatic necrosis or failure;
  • anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.

Discontinue levofloxacin immediately at the first appearance of skin rash, jaundice, or any other sign of hypersensitivity and institute supportive measures [see Adverse Reactions ( 6) 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. 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 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 [see Adverse Reactions ( 6) and Patient Counseling Information ( 17)].

5.8 Hepatotoxicity

Post-marketing reports of severe hepatotoxicity (including acute hepatitis and fatal events) have been received for patients treated with levofloxacin. 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 [see Warnings and Precautions (5.6)]. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. Levofloxacin should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Adverse Reactions ( 6) and Patient Counseling Information ( 17).]

5.9 Clostridium difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including levofloxacin, 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 [see Adverse Reactions ( 6.2) and Patient Counseling Information ( 17)].

5.10 Prolongation of the QT Interval

Some fluoroquinolones, including levofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving fluoroquinolones, including levofloxacin. 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 [see Adverse Reactions ( 6.3), Use in Specific Populations ( 8.5) and Patient Counseling Information ( 17)].

5.11 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals

Levofloxacin is indicated in pediatric patients (6 months of age and older) only for the prevention of inhalational anthrax (post-exposure) and for plague [see Indications and Usage ( 1.7, 1.8)]. An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormality) compared to controls has been observed in pediatric patients receiving levofloxacin [see Use in Specific Populations ( 8.4)].

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 [see Animal Toxicology and/or Pharmacology ( 13.2)].

5.12 Blood Glucose Disturbances

As with other fluoroquinolones, disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with levofloxacin, 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. If a hypoglycemic reaction occurs in a patient being treated with levofloxacin, levofloxacin should be discontinued and appropriate therapy should be initiated immediately [see Adverse Reactions ( 6.2); Drug Interactions ( 7.3) and Patient Counseling Information ( 17)].

 

5.13 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 [see Adverse Reactions ( 6.3) and Patient Counseling Information ( 17)].

 

5.14 Development of Drug Resistant Bacteria

Prescribing levofloxacin 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 [see Patient Counseling Information ( 17)].

 

6 ADVERSE REACTIONS

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 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 ( 5.9)]
  • Prolongation of the QT Interval [see Warnings and Precautions ( 5.10)]
  • Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions ( 5.11)]
  • Blood Glucose Disturbances [see Warnings and Precautions ( 5.12)]
  • Photosensitivity/Phototoxicity [see Warnings and Precautions ( 5.13)]
  • Development of Drug Resistant Bacteria [see Warnings and Precautions ( 5.14)]

Crystalluria and cylindruria have been reported with quinolones, including levofloxacin. Therefore, adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of a highly concentrated urine [see Dosage and Administration ( 2.5)].

6.2 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to levofloxacin  in 7537 patients in 29 pooled Phase 3 clinical trials. The population studied had a mean age of 50 years (approximately 74% of the population was < 65 years of age), 50% were male, 71% were Caucasian, 19% were Black. Patients were treated with levofloxacin  for a wide variety of infectious diseases [see Indications and Usage ( 1)] . Patients received levofloxacin doses of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. Treatment duration was usually 3 to 14 days, and the mean number of days on therapy was 10 days.

The overall incidence, type and distribution of adverse reactions was similar in patients receiving levofloxacin doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation of levofloxacin  due to adverse drug reactions occurred in 4.3% of patients overall, 3.8% of patients treated with the 250 mg and 500 mg doses and 5.4% of patients treated with the 750 mg dose. The most common adverse drug reactions leading to discontinuation with the 250 and 500 mg doses were gastrointestinal (1.4%), primarily nausea (0.6%); vomiting (0.4%); dizziness (0.3%); and headache (0.2%). The most common adverse drug reactions leading to discontinuation with the 750 mg dose were gastrointestinal (1.2%), primarily nausea (0.6%), vomiting (0.5%); dizziness (0.3%); and headache (0.3%).

Adverse reactions occurring in ≥ 1% of levofloxacin-treated patients and less common adverse reactions, occurring in 0.1 to < 1% of levofloxacin-treated patients, are shown in Table 4 and Table 5, respectively. The most common adverse drug reactions (≥ 3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness.

Table4 Common ( ≥ 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin #
*N = 7274
N=3758 (women)
# pool of studies included IV and oral administration

System/Organ Class

Adverse Reaction

%
(N=7537)

Infections and Infestations

moniliasis

1

Psychiatric Disorders

Insomnia *[see Warnings and Precautions ( 5.4)]

4

Nervous System Disorders

headache
dizziness [see Warnings and Precautions ( 5.4)]

6
3

Respiratory, Thoracic and Mediastinal Disorders

dyspnea [see Warnings and Precautions ( 5.7)]

1

Gastrointestinal Disorders

nausea
diarrhea
constipation
abdominal pain
vomiting
dyspepsia

7
5
3
2
2
2

Skin and Subcutaneous Tissue Disorders

rash [see Warnings and Precautions ( 5.7)]
pruritu

2
1

Reproductive System and Breast Disorders

vaginitis

1

General Disorders and Administration Site Conditions

edema
injection site reaction
chest pain

1
1
1

Table 5 Less Common (0.1 to 1%) Adverse Reactions Reported in Clinical Trials with levofloxacin (N=7537)
*N = 7274

System/Organ Class

Adverse Reaction

Infections and Infestations

genital moniliasis

Blood and Lymphatic System Disorders

anemia

thrombocytopenia

granulocytopenia

[see Warnings and Precautions ( 5.6)]

Immune System Disorders

allergic reaction [See Warnings and Precautions ( 5.6, 5.7)]

Metabolism and Nutrition Disorders

hyperglycemia

hypoglycemia

[see Warnings and Precautions ( 5.12)]

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 ( 5.9)]

Hepatobiliary Disorders

abnormal hepatic function

increased hepatic enzymes

increased alkaline phosphatase

Skin and Subcutaneous Tissue Disorders

urticaria [see Warnings and Precautions ( 5.7)]

Musculoskeletal and Connective Tissue Disorders

arthralgia

tendinitis

[see Warnings and Precautions ( 5.2)]

myalgia

skeletal pain

Renal and Urinary Disorders

abnormal renal function

acute renal failure [see Warnings and Precautions ( 5.6)]

In clinical trials using multiple-dose therapy, ophthalmologic abnormalities, including cataracts and multiple punctate lenticular opacities, have been noted in patients undergoing treatment with quinolones, including levofloxacin. The relationship of the drugs to these events is not presently established.

6.3 Postmarketing Experience

Table 6 lists adverse reactions that have been identified during post-approval use of levofloxacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Table 6 Postmarketing Reports Of Adverse Drug Reactions

System/Organ Class

Adverse Reaction

Blood and Lymphatic System Disorders

pancytopenia

aplastic anemia

leukopenia

hemolytic anemia

[see Warnings and Precautions ( 5.6)]

eosinophilia

Immune System Disorders

hypersensitivity reactions, sometimes fatal including:
   anaphylactic/anaphylactoid reactions
   anaphylactic shock
   angioneurotic edema
   serum sickness
[see Warnings and Precautions ( 5.6, 5.7)]

Psychiatric Disorders

psychosis

paranoia

isolated reports of suicidal ideation, suicide attempt and completed suicide

[see Warnings and Precautions ( 5.4)]

Nervous System Disorders

exacerbation of myasthenia gravis [see Warnings and Precautions ( 5.5)]
anosmia
ageusia
parosmia
dysgeusia
peripheral neuropathy (may be irreversible) 
  [see Warnings and 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 torsade de pointes
electrocardiogram QT prolonged
[see Warnings and Precautions ( 5.10)]
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 ( 5.13)]

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

7 DRUG INTERACTIONS

7.1 Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins

While the chelation by divalent cations is less marked than with other fluoroquinolones, concurrent administration of levofloxacin tablets with antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc may interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired. Tablets with antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamins preparations with zinc or didanosine may substantially interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired. These agents should be taken at least two hours before or two hours after oral levofloxacin  administration.

 

7.2 Warfarin

No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for R- and S- warfarin was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of warfarin on levofloxacin absorption and disposition was observed. However, there have been reports during the post-marketing experience in patients that levofloxacin  enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent warfarin and levofloxacin use have been associated with episodes of bleeding. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if levofloxacin is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Adverse Reactions ( 6.3) and Patient Counseling Information ( 17)].

 

7.3 Antidiabetic Agents

Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with fluoroquinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered [see Warnings and Precautions (5.12); Adverse Reactions ( 6.2) and Patient Counseling Information ( 17)].

7.4 Non-Steroidal Anti-Inflammatory Drugs

The concomitant administration of a non-steroidal anti-inflammatory drug with a fluoroquinolone, including levofloxacin, may increase the risk of CNS stimulation and convulsive seizures [see Warnings and Precautions ( 5.4)].

7.5 Theophylline

No significant effect of levofloxacin on the plasma concentrations, AUC, and other disposition parameters for theophylline was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of theophylline on levofloxacin absorption and disposition was observed. However, concomitant administration of other fluoroquinolones with theophylline has resulted in prolonged elimination half-life, elevated serum theophylline levels, and a subsequent increase in the risk of theophylline-related adverse reactions in the patient population. Therefore, theophylline levels should be closely monitored and appropriate dosage adjustments made when levofloxacin is co-administered. Adverse reactions, including seizures, may occur with or without an elevation in serum theophylline levels [see Warnings and Precautions ( 5.4)].

7.6 Cyclosporine

No significant effect of levofloxacin  on the peak plasma concentrations, AUC, and other disposition parameters for cyclosporine was detected in a clinical study involving healthy volunteers. However, elevated serum levels of cyclosporine have been reported in the patient population when co-administered with some other fluoroquinolones. Levofloxacin C max and k e were slightly lower while T max and t ½ were slightly longer in the presence of cyclosporine than those observed in other studies without concomitant medication. The differences, however, are not considered to be clinically significant. Therefore, no dosage adjustment is required for levofloxacin or cyclosporine when administered concomitantly.

7.7 Digoxin

No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for digoxin was detected in a clinical study involving healthy volunteers. Levofloxacin absorption and disposition kinetics were similar in the presence or absence of digoxin. Therefore, no dosage adjustment for levofloxacin or digoxin is required when administered concomitantly.

7.8 Probenecid and Cimetidine

No significant effect of probenecid or cimetidine on the C max of levofloxacin was observed in a clinical study involving healthy volunteers. The AUC and t ½ of levofloxacin were higher while CL/F and CL R were lower during concomitant treatment of levofloxacin with probenecid or cimetidine compared to levofloxacin alone. However, these changes do not warrant dosage adjustment for levofloxacin when probenecid or cimetidine is co-administered.

7.9 Interactions with Laboratory or Diagnostic Testing

Some fluoroquinolones, including levofloxacin, may produce false-positive urine screening results for opiates using commercially available immunoassay kits. Confirmation of positive opiate screens by more specific methods may be necessary.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C.

Levofloxacin was not teratogenic in rats at doses as high as 810 mg/kg/day which corresponds to 9.4 times the highest recommended oral human dose based upon relative body surface area. The oral dose of 810 mg/kg/day to rats caused decreased fetal body weight and increased fetal mortality. No teratogenicity was observed when rabbits were dosed orally as high as 50 mg/kg/day which corresponds to 1.1 times the highest recommended oral human dose based upon relative body surface area.

 

There are, however, no adequate and well-controlled studies in pregnant women. Levofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

 

8.3 Nursing Mothers

Based on data on other fluoroquinolones and very limited data on levofloxacin, it can be presumed that levofloxacin will be excreted in human milk. Because of the potential for serious adverse reactions from levofloxacin in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. [see Warnings and Precautions ( 5.11) and Animal Toxicology and/or Pharmacology ( 13.2)] .

 

Inhalational Anthrax (Post-Exposure)

Levofloxacin is indicated in pediatric patients 6 months of age and older, for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate. The safety of levofloxacin in pediatric patients treated for more than 14 days has not been studied [see Indications and Usage ( 1.7) , Dosage and Administration ( 2.2) and Clinical Studies ( 14.9)] .

 

Plague

Levofloxacin is indicated in pediatric patients, 6 months of age and older, for treatment of plague, including pneumonic and septicemic plague due to Yersinia pestis ( Y. pestis) and prophylaxis for plague. Efficacy studies of levofloxacin  could not be conducted in humans with pneumonic plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals. The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate [see Indications and Usage (1.8), Dosage and Administration ( 2.2) and Clinical Studies ( 14.10)].

Safety and effectiveness of levofloxacin in pediatric patients below the age of six months have not been established.

Pharmacokinetics following intravenous administration

The pharmacokinetics of levofloxacin following a single intravenous dose were investigated in pediatric patients ranging in age from six months to 16 years. Pediatric patients cleared levofloxacin faster than adult patients resulting in lower plasma exposures than adults for a given mg/kg dose [see Clinical Pharmacology ( 12.3) and Clinical Studies ( 14.9)] .

Dosage in Pediatric Patients with Inhalational Anthrax or Plague

For the recommended levofloxacin tablet dosage in pediatric patients with inhalational anthrax or plague, see Dosage and Administration ( 2.2). Levofloxacin tablets cannot be administered to pediatric patients who weigh less than 30 kg because of the limitations of the available strengths. Alternative formulations of levofloxacin may be considered for pediatric patients who weigh less than 30 kg.

Adverse Reactions

In clinical trials, 1534 pediatric patients (6 months to 16 years of age) were treated with oral levofloxacin. Pediatric patients 6 months to 5 years of age received levofloxacin 10 mg/kg twice a day and pediatric patients greater than 5 years of age received 10 mg/kg once a day (maximum 500 mg per day) for approximately 10 days. Levofloxacin tablets can only be administered to pediatric patients with inhalational anthrax (post-exposure) or plague who are 30 kg or greater due to the limitations of the available strengths [see Dosage and Administration ( 2.2)] .

 

A subset of pediatric patients in the clinical trials (1340 levofloxacin-treated and 893 non-fluoroquinolone-treated) enrolled in a prospective, long-term surveillance study to assess the incidence of protocol-defined musculoskeletal disorders (arthralgia, arthritis, tendinopathy, gait abnormality) during 60 days and 1 year following the first dose of the study drug. Pediatric patients treated with levofloxacin had a significantly higher incidence of musculoskeletal disorders when compared to the non-fluoroquinolone-treated children as illustrated in Table 7. Levofloxacin tablets can only be administered to pediatric patients with inhalational anthrax (post-exposure) or plague who are 30 kg or greater due to the limitations of the available strengths [see Dosage and Administration ( 2.2)].

Table 7 Incidence of Musculoskeletal Disorders in Pediatric Clinical Trial
* Non-Fluoroquinolone: ceftriaxone, amoxicillin/ clavulanate, clarithromycin
2-sided Fisher's Exact Test
There were 1199 levofloxacin-treated and 804 non-fluoroquinolone-treated pediatric patients who had a one year evaluation visit. However, the incidence of musculoskeletal disorders was calculated using all reported events during the specified period for all pediatric patients enrolled regardless of whether they completed the 1- year evaluation visit.

Follow-up Period

Levofloxacin
N = 1340

Non-Fluoroquinolone*
N = 893

p-value

60 days

28 (2.1%)

8 (0.9%)

p = 0.038

1 year

46 (3.4%)

16 (1.8%)

p = 0.025

Arthralgia was the most frequently occurring musculoskeletal disorder in both treatment groups. Most of the musculoskeletal disorders in both groups involved multiple weight-bearing joints. Disorders were moderate in 8/46 (17%) children and mild in 35/46 (76%) levofloxacin-treated pediatric patients and most were treated with analgesics. The median time to resolution was 7 days for levofloxacin-treated pediatric patients and 9 for non-fluoroquinolone-treated children (approximately 80% resolved within 2 months in both groups). No pediatric patient had a severe or serious disorder and all musculoskeletal disorders resolved without sequelae.

Vomiting and diarrhea were the most frequently reported adverse reactions, occurring in similar frequency in the levofloxacin-treated and non-fluoroqu inolone-treated pediatric patients.

In addition to the adverse reactions reported in pediatric patients in clinical trials, adverse reactions reported in adults during clinical trials or post-marketing experience [see Adverse Reactions ( 6)] may also be expected to occur in pediatric patients.

 

8.5 Geriatric Use

Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as levofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing levofloxacin  to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue levofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see Boxed Warning; Warnings and Precautions ( 5.2); and Adverse Reactions ( 6.3)] .

In Phase 3 clinical trials, 1,945 levofloxacin-treated patients (26%) were ≥ 65 years of age. Of these, 1,081 patients (14%) were between the ages of 65 and 74 and 864 patients (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Severe, and sometimes fatal, cases of hepatotoxicity have been reported post-marketing in association with levofloxacin. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. Levofloxacin should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Warnings and Precautions ( 5.8)].

Elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using levofloxacin with concomitant drugs that can result in prolongation of the QT interval (e.g., Class IA or Class III antiarrhythmics) or in patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia) [see Warnings and Precautions ( 5.10)].

The pharmacokinetic properties of levofloxacin in younger adults and elderly adults do not differ significantly when creatinine clearance is taken into consideration. However, since the drug is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology ( 12.3)] .

8.6 Renal Impairment

Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in patients with renal impairment (creatinine clearance < 50 mL/min), requiring dosage adjustment in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating that supplemental doses of levofloxacin are not required following hemodialysis or CAPD [see Dosage and Administration ( 2.3)].

 

8.7 Hepatic Impairment

Pharmacokinetic studies in patients with hepatic impairment have not been conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin are not expected to be affected by hepatic impairment.

 

10 OVERDOSAGE

In the event of an acute overdosage, the stomach should be emptied. The patient should be observed and appropriate hydration maintained. Levofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis.

Levofloxacin exhibits a low potential for acute toxicity. Mice, rats, dogs and monkeys exhibited the following clinical signs after receiving a single high dose of levofloxacin: ataxia, ptosis, decreased locomotor activity, dyspnea, prostration, tremors, and convulsions. Doses in excess of 1500 mg/kg orally and 250 mg/kg IV produced significant mortality in rodents.

11 DESCRIPTION

Levofloxacin tablets are synthetic antibacterial agents for oral 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

 

Structure product formula for Levofloxacin

Its molecular formula is C 18H 20FN 3O 4 • ½ H 2O and the molecular weight is 370.38. Levofloxacin, USP is a light yellowish–white to yellow–white crystals 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.

 

Each levofloxacin tablet, USP intended for oral administration contains levofloxacin hemihydrate equivalent to 250 mg or 500 mg or 750 mg of levofloxacin. In addition, each tablet contains the following inactive ingredients: crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 6000, talc and  titanium dioxide.

 

The product meets USP Dissolution Test 2.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

The mean ±SD pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following administration of the oral tablets, are summarized in Table 8.

 

Table 8 Mean ±SD Levofloxacin PK Parameters
1 clearance/bioavailability
2 volume of distribution/bioavailability
3 healthy males 18 to 53 years of age
4 healthy male and female subjects 18 to 54 years of age
5 healthy males 22 to 75 years of age
6 healthy females 18 to 80 years of age
7 young healthy male and female subjects 18 to 36 years of age
8 healthy elderly male and female subjects 66 to 80 years of age
* Absolute bioavailability; F=0.99 ± 0.08 from a 500 mg tablet and F=0.99 ± 0.06 from a 750 mg tablet;
ND=not determined.

Regimen

C max (mcg/mL)

T max (h)

AUC (mcg h/mL)

CL/F1 (mL/min)

Vd/F2
(L)

t 1/2 (h)

CL R (mL/min)

Single dose

250 mg oral tablet 3

2.8 ± 0.4

1.6 ± 1

27.2 ± 3.9

156 ± 20

ND

7.3 ± 0.9

142 ± 21

500 mg oral tablet 3*

5.1 ± 0.8

1.3 ± 0.6

47.9 ± 6.8

178 ± 28

ND

6.3 ± 0.6

103 ± 30

750 mg oral tablet 4*

9.3 ± 1.6

1.6 ± 0.8

101 ± 20

129 ± 24

83 ± 17

7.5 ± 0.9

ND

Multiple dose

500 mg every 24h oral tablet 3

5.7 ± 1.4

1.1 ± 0.4

47.5 ± 6.7

175 ± 25

102 ± 22

7.6 ± 1.6

116 ± 31

750 mg every 24h oral tablet 4

8.6 ± 1.9

1.4 ± 0.5

90.7 ± 17.6

143 ± 29

100 ± 16

8.8 ± 1.5

116 ± 28

500 mg oral tablet single dose, effects of gender and age:

Male 5

5.5 ± 1.1

1.2 ± 0.4

54.4 ± 18.9

166 ± 44

89 ± 13

7.5 ± 2.1

126 ± 38

Female 6

7 ± 1.6

1.7 ± 0.5

67.7 ± 24.2

136 ± 44

62 ± 16

6.1 ± 0.8

106 ± 40

Young 7

5.5 ± 1

1.5 ± 0.6

47.5 ± 9.8

182 ± 35

83 ± 18

6 ± 0.9

140 ± 33

Elderly 8

7 ± 1.6

1.4 ± 0.5

74.7 ± 23.3

121 ± 33

67 ± 19

7.6 ± 2

91 ± 29

500 mg oral single dose tablet, patients with renal impairment:

CLCR 50 to 80 mL/min

7.5 ± 1.8

1.5 ± 0.5

95.6 ± 11.8

88 ± 10

ND

9.1 ± 0.9

57 ± 8

CLCR 20 to 49 mL/min

7.1 ± 3.1

2.1 ± 1.3

182.1 ± 62.6

51 ± 19

ND

27 ± 10

26 ± 13

CLCR < 20 mL/min

8.2 ± 2.6

1.1 ± 1

263.5 ± 72.5

33 ± 8

ND

35 ± 5

13 ± 3

Hemodialysis

5.7 ± 1

2.8 ± 2.2

ND

ND

ND

76 ± 42

ND

CAPD

6.9 ± 2.3

1.4 ± 1.1

ND

ND

ND

51 ± 24

ND

Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral or IV dosing regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once-daily dosage regimen. The mean ± SD peak and trough plasma concentrations attained following multiple once-daily oral dosage regimens were approximately 5.7 ± 1.4 and 0.5 ± 0.2 mcg/mL after the 500 mg doses, and 8.6 ± 1.9 and 1.1 ± 0.4 mcg/mL after the 750 mg doses, respectively. The mean ± SD peak and trough plasma concentrations attained following multiple once-daily IV regimens were approximately 6.4 ± 0.8 and 0.6 ± 0.2 mcg/mL after the 500 mg doses, and 12.1 ± 4.1 and 1.3 ± 0.71 mcg/mL after the 750 mg doses, respectively.

Absorption

Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak plasma concentrations are usually attained one to two hours after oral dosing. The absolute bioavailability of levofloxacin from a 500 mg tablet and a 750 mg tablet of levofloxacin are both approximately 99%, demonstrating complete oral absorption of levofloxacin. Following a single intravenous dose of levofloxacin to healthy volunteers, the mean ± SD peak plasma concentration attained was 6.2 ± 1.0 mcg/mL after a 500 mg dose infused over 60 minutes and 11.5 ± 4.0 mcg/mL after a 750 mg dose infused over 90 minutes. Oral administration of a 500 mg dose of levofloxacin with food prolongs the time to peak concentration by approximately 1 hour and decreases the peak concentration by approximately 14% following tablet and approximately 25% following oral solution administration. Therefore, levofloxacin tablets can be administered without regard to food.

The plasma concentration profile of levofloxacin after IV administration is similar and comparable in extent of exposure (AUC) to that observed for levofloxacin tablets when equal doses (mg/mg) are administered. Therefore, the oral and IV routes of administration can be considered interchangeable .

 

Distribution

The mean volume of distribution of levofloxacin generally ranges from 74 to 112 L after single and multiple 500 mg or 750 mg doses, indicating widespread distribution into body tissues. Levofloxacin reaches its peak levels in skin tissues and in blister fluid of healthy subjects at approximately 3 hours after dosing. The skin tissue biopsy to plasma AUC ratio is approximately 2 and the blister fluid to plasma AUC ratio is approximately 1 following multiple once-daily oral administration of 750 mg and 500 mg doses of levofloxacin, respectively, to healthy subjects. Levofloxacin also penetrates well into lung tissues. Lung tissue concentrations were generally 2- to 5-fold higher than plasma concentrations and ranged from approximately 2.4 to 11.3 mcg/g over a 24 hour period after a single 500 mg oral dose.

In vitro, over a clinically relevant range (1 to 10 mcg/mL) of serum/plasma levofloxacin concentrations, levofloxacin is approximately 24 to 38% bound to serum proteins across all species studied, as determined by the equilibrium dialysis method. Levofloxacin is mainly bound to serum albumin in humans. Levofloxacin binding to serum proteins is independent of the drug concentration.

Elimination

Metabolism

Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to its enantiomer, D-ofloxacin. Levofloxacin undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. Following oral administration, approximately 87% of an administered dose was recovered as unchanged drug in urine within 48 hours, whereas less than 4% of the dose was recovered in feces in 72 hours. Less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans. These metabolites have little relevant pharmacological activity.

Excretion

Levofloxacin is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin given orally or intravenously. The mean apparent total body clearance and renal clearance range from approximately 144 to 226 mL/min and 96 to 142 mL/min, respectively. Renal clearance in excess of the glomerular filtration rate suggests that tubular secretion of levofloxacin occurs in addition to its glomerular filtration. Concomitant administration of either cimetidine or probenecid results in approximately 24% and 35% reduction in the levofloxacin renal clearance, respectively, indicating that secretion of levofloxacin occurs in the renal proximal tubule. No levofloxacin crystals were found in any of the urine samples freshly collected from subjects receiving levofloxacin.

Specific Populations

Geriatric Patients

There are no significant differences in levofloxacin pharmacokinetics between young and elderly subjects when the subjects' differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of levofloxacin to healthy elderly subjects (66 to 80 years of age), the mean terminal plasma elimination half-life of levofloxacin was about 7.6 hours, as compared to approximately 6 hours in younger adults. The difference was attributable to the variation in renal function status of the subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by age. levofloxacin dose adjustment based on age alone is not necessary [See Use in Specific Populations ( 8.5)] .

Pediatric Patients

The pharmacokinetics of levofloxacin following a single 7 mg/kg intravenous dose were investigated in pediatric patients ranging in age from 6 months to 16 years. Pediatric patients cleared levofloxacin faster than adult patients, resulting in lower plasma exposures than adults for a given mg/kg dose. Subsequent pharmacokinetic analyses predicted that a dosage regimen of 8 mg/kg every 12 hours (not to exceed 250 mg per dose) for pediatric patients 6 months to 17 years of age would achieve comparable steady state plasma exposures (AUC 0-24 and C max) to those observed in adult patients administered 500 mg of levofloxacin once every 24 hours. Levofloxacin tablets can only be administered to pediatric patients with inhalational anthrax (post-exposure) or plague who are 30 kg or greater due to the limitations of the available strengths [ see Dosage and Administration ( 2.2) ]

 

Male and Female Subjects   

There are no significant differences in levofloxacin pharmacokinetics between male and female subjects when subjects' differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of levofloxacin to healthy male subjects, the mean terminal plasma elimination half-life of levofloxacin was about 7.5 hours, as compared to approximately 6.1 hours in female subjects. This difference was attributable to the variation in renal function status of the male and female subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by the gender of the subjects. Dose adjustment based on gender alone is not necessary.

 

Racial or Ethnic Groups

The effect of race on levofloxacin pharmacokinetics was examined through a covariate analysis performed on data from 72 subjects: 48 white and 24 non-white. The apparent total body clearance and apparent volume of distribution were not affected by the race of the subjects.

 

Patients with Renal Impairment

Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in adult patients with impaired renal function (creatinine clearance < 50 mL/min), requiring dosage adjustment in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating that supplemental doses of levofloxacin are not required following hemodialysis or CAPD [see Dosage and Administration ( 2.3) and Use in Specific Populations ( 8.6)].

 

Patients with Hepatic Impairment

Pharmacokinetic studies in hepatically impaired patients have not been conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin are not expected to be affected by hepatic impairment [see Use in Specific Populations ( 8.7)] .

 

Patients with Bacterial Infection

The pharmacokinetics of levofloxacin in patients with serious community-acquired bacterial infections are comparable to those observed in healthy subjects.

 

Drug Interactions Studies

The potential for pharmacokinetic drug interactions between levofloxacin and antacids, warfarin, theophylline, cyclosporine, digoxin, probenecid, and cimetidine has been evaluated [see Drug Interactions ( 7)].

12.4 Microbiology

Mechanism of Action

Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair and recombination.

Resistance

Fluoroquinolone resistance can arise through mutations in defined regions of DNA gyrase or topoisomerase IV, termed the Quinolone-Resistance Determining Regions (QRDRs), or through altered efflux.

Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from aminoglycosides, macrolides and β-lactam antibiotics, including penicillins. Fluoroquinolones may, therefore, be active against bacteria resistant to these antimicrobials.

Resistance to levofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10 -9to 10 -10). Cross-resistance has been observed between levofloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to levofloxacin.

Antimicrobial Activity

Levofloxacin has in vitro activity against Gram-negative and Gram-positive bacteria.

Levofloxacin has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections as described in Indications and Usage ( 1):

Aerobic bacteria

Gram-Positive Bacteria

Enterococcus faecalis

Staphylococcus aureus (methicillin-susceptible isolates)

Staphylococcus epidermidis (methicillin-susceptible isolates)

Staphylococcus saprophyticus

Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP] 1)

Streptococcus pyogenes

1MDRSP (Multi-drug resistant Streptococcus pneumoniae) isolates are isolates resistant to two or more of the following antibiotics: penicillin (MIC ≥ 2 mcg/mL), 2nd generation cephalosporins, e.g., cefuroxime; macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

Gram-Negative Bacteria

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella pneumoniae

Legionella pneumophila

Moraxella catarrhalis

Proteus mirabilis

Pseudomonas aeruginosa

Serratia marcescens

Other microorganisms

Chlamydophila pneumoniae

Mycoplasma pneumoniae

The following in vitro data are available, but their clinical significance is unknown :

Levofloxacin exhibits in vitro minimum inhibitory concentrations (MIC values) of 2 mcg/mL or less against most (≥ 90%) isolates of the following microorganisms; however, the safety and effectiveness of levofloxacin in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Aerobic Bacteria

Gram-Positive Bacteria

Staphylococcus haemolyticus

β-hemolytic Streptococcus (Group C/F)

β-hemolytic Streptococcus (Group G)

Streptococcus agalactiae

Streptococcus milleri

Viridans group streptococci

Bacillus anthracis

Gram-Negative Bacteria

Acinetobacter baumannii

Acinetobacter lwoffii

Bordetella pertussis

Citrobacter koseri

Citrobacter freundii

Enterobacter aerogenes

Enterobacter sakazakii

Klebsiella oxytoca

Morganella morganii

Pantoea agglomerans

Proteus vulgaris

Providencia rettgeri

Providencia stuartii

Pseudomonas fluorescens

Yersinia pestis

Anaerobic Gram-Positive Bacteria

Clostridium perfringens

Susceptibility Tests

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a lifetime bioassay in rats, levofloxacin exhibited no carcinogenic potential following daily dietary administration for 2 years; the highest dose (100 mg/kg/day ) was 1.4 times the highest recommended human dose (750 mg) based upon relative body surface area. Levofloxacin did not shorten the time to tumor development of UV-induced skin tumors in hairless albino (Skh-1) mice at any levofloxacin dose level and was therefore not photo-carcinogenic under conditions of this study. Dermal levofloxacin concentrations in the hairless mice ranged from 25 to 42 mcg/g at the highest levofloxacin dose level (300 mg/kg/day) used in the photo-carcinogenicity study. By comparison, dermal levofloxacin concentrations in human subjects receiving 750 mg of levofloxacin averaged approximately 11.8 mcg/g at C max.

Levofloxacin was not mutagenic in the following assays: Ames bacterial mutation assay ( S. typhimurium and E. coli), CHO/HGPRT forward mutation assay, mouse micronucleus test, mouse dominant lethal test, rat unscheduled DNA synthesis assay, and the mouse sister chromatid exchange assay. It was positive in the in vitro chromosomal aberration (CHL cell line) and sister chromatid exchange (CHL/IU cell line) assays.

Levofloxacin caused no impairment of fertility or reproductive performance in rats at oral doses as high as 360 mg/kg/day, corresponding to 4.2 times the highest recommended human dose based upon relative body surface area and intravenous doses as high as 100 mg/kg/day, corresponding to 1.2 times the highest recommended human dose based upon relative body surface area.

13.2 Animal Toxicology and/or Pharmacology

Levofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see Warnings and Precautions ( 5.11)]. In immature dogs (4 to 5 months old), oral doses of 10 mg/kg/day for 7 days and intravenous doses of 4 mg/kg/day for 14 days of levofloxacin resulted in arthropathic lesions. Administration at oral doses of 300 mg/kg/day for 7 days and intravenous doses of 60 mg/kg/day for 4 weeks produced arthropathy in juvenile rats. Three month old beagle dogs dosed orally with levofloxacin at 40 mg/kg/day exhibited clinically severe arthrotoxicity resulting in the termination of dosing at Day 8 of a 14 day dosing routine. Slight musculoskeletal clinical effects, in the absence of gross pathological or histopathological effects, resulted from the lowest dose level of 2.5 mg/kg/day (approximately 0.2-fold the pediatric dose based upon AUC comparisons). Synovitis and articular cartilage lesions were observed at the 10 and 40 mg/kg dose levels (approximately 0.7-fold and 2.4-fold the pediatric dose, respectively, based on AUC comparisons). Articular cartilage gross pathology and histopathology persisted to the end of the 18 week recovery period for those dogs from the 10 and 40 mg/kg/day dose levels.

When tested in a mouse ear swelling bioassay, levofloxacin exhibited phototoxicity similar in magnitude to ofloxacin, but less phototoxicity than other quinolones.

While crystalluria has been observed in some intravenous rat studies, urinary crystals are not formed in the bladder, being present only after micturition and are not associated with nephrotoxicity.

In mice, the CNS stimulatory effect of quinolones is enhanced by concomitant administration of non-steroidal anti-inflammatory drugs.

In dogs, levofloxacin administered at 6 mg/kg or higher by rapid intravenous injection produced hypotensive effects. These effects were considered to be related to histamine release.

In vitro and in vivo studies in animals indicate that levofloxacin is neither an enzyme inducer nor inhibitor in the human therapeutic plasma concentration range; therefore, no drug metabolizing enzyme-related interactions with other drugs or agents are anticipated.

14 CLINICAL STUDIES

14.1 Nosocomial Pneumonia

Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a multicenter, randomized, open-label study comparing intravenous levofloxacin (750 mg once daily) followed by oral levofloxacin (750 mg once daily) for a total of 7 to 15 days to intravenous imipenem/cilastatin (500 to 1000 mg every 6 to 8 hours daily) followed by oral ciprofloxacin (750 mg every 12 hours daily) for a total of 7 to 15 days. levofloxacin-treated patients received an average of 7 days of intravenous therapy (range: 1 to 16 days); comparator-treated patients received an average of 8 days of intravenous therapy (range: 1 to 19 days).

Overall, in the clinically and microbiologically evaluable population, adjunctive therapy was empirically initiated at study entry in 56 of 93 (60.2%) patients in the levofloxacin arm and 53 of 94 (56.4%) patients in the comparator arm. The average duration of adjunctive therapy was 7 days in the levofloxacin arm and 7 days in the comparator. In clinically and microbiologically evaluable patients with documented Pseudomonas aeruginosa infection, 15 of 17 (88.2%) received ceftazidime (N=11) or piperacillin/tazobactam (N=4) in the levofloxacin arm and 16 of 17 (94.1%) received an aminoglycoside in the comparator arm. Overall, in clinically and microbiologically evaluable patients, vancomycin was added to the treatment regimen of 37 of 93 (39.8%) patients in the levofloxacin arm and 28 of 94 (29.8%) patients in the comparator arm for suspected methicillin-resistant S. aureus infection.

Clinical success rates in clinically and microbiologically evaluable patients at the posttherapy visit (primary study endpoint assessed on day 3 to 15 after completing therapy) were 58.1% for levofloxacin and 60.6% for comparator. The 95% CI for the difference of response rates (levofloxacin minus comparator) was [-17.2, 12]. The microbiological eradication rates at the posttherapy visit were 66.7% for levofloxacin and 60.6% for comparator. The 95% CI for the difference of eradication rates (levofloxacin minus comparator) was [-8.3, 20.3]. Clinical success and microbiological eradication rates by pathogen are detailed in Table 11.

Table 11Clinical Success Rates and Bacteriological Eradication Rates (Nosocomial Pneumonia)
Pathogen 
N
Levofloxacin No. (%) of Patients Microbiologic/ Clinical Outcomes
N
Imipenem/Cilastatin No. (%) of Patients Microbiologic/ Clinical Outcomes
*Methicillin-susceptible S. aureus
See above text for use of combination therapy
The observed differences in rates for the clinical and microbiological outcomes may reflect other factors that were not accounted for in the study

MSSA *

21

14 (66.7)/13 (61.9)

19

13 (68.4)/15 (78.9)

P. aeruginosa

17

10 (58.8)/11 (64.7)

17

5 (29.4)/7 (41.2)

S. marcescens 

11

9 (81.8)/7 (63.6)

7

2 (28.6)/3 (42.9)

E. coli 

12

10 (83.3)/7 (58.3)

11

7 (63.6)/8 (72.7)

K. pneumoniae

11

9 (81.8)/5 (45.5)

7

6 (85.7)/3 (42.9)

H. influenzae 

16

13 (81.3)/10 (62.5)

15

14 (93.3)/11 (73.3)

S. pneumoniae 

4

3 (75)/3 (75)

7

5 (71.4)/4 (57.1)

14.2 Community-Acquired Pneumonia: 7 to 14 day Treatment Regimen

Adult inpatients and outpatients with a diagnosis of community-acquired bacterial pneumonia were evaluated in 2 pivotal clinical studies. In the first study, 590 patients were enrolled in a prospective, multi-center, unblinded randomized trial comparing levofloxacin 500 mg once daily orally or intravenously for 7 to 14 days to ceftriaxone 1 to 2 grams intravenously once or in equally divided doses twice daily followed by cefuroxime axetil 500 mg orally twice daily for a total of 7 to 14 days. Patients assigned to treatment with the control regimen were allowed to receive erythromycin (or doxycycline if intolerant of erythromycin) if an infection due to atypical pathogens was suspected or proven. Clinical and microbiologic evaluations were performed during treatment, 5 to 7 days posttherapy, and 3 to 4 weeks posttherapy. Clinical success (cure plus improvement) with levofloxacin at 5 to 7 days posttherapy, the primary efficacy variable in this study, was superior (95%) to the control group (83%). The 95% CI for the difference of response rates (levofloxacin minus comparator) was [-6, 19]. In the second study, 264 patients were enrolled in a prospective, multi-center, non-comparative trial of 500 mg levofloxacin administered orally or intravenously once daily for 7 to 14 days. Clinical success for clinically evaluable patients was 93%. For both studies, the clinical success rate in patients with atypical pneumonia due to Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila were 96%, 96%, and 70%, respectively. Microbiologic eradication rates across both studies are presented in Table 12.

Table 12Bacteriological Eradication Rates Across 2 Community Acquired Pneumonia Clinical Studies
Pathogen 
No. Pathogens
Bacteriological Eradication Rate (%)

H. influenzae 

55

98

S. pneumoniae 

83

95

S. aureus 

17

88

M. catarrhalis 

18

94

H. parainfluenzae 

19

95

K. pneumoniae 

10

100

Community-Acquired Pneumonia Due to Multi-Drug Resistant Streptococcus pneumoniae

Levofloxacin was effective for the treatment of community-acquired pneumonia caused by multi-drug resistant Streptococcus pneumoniae (MDRSP). MDRSP isolates are isolates resistant to two or more of the following antibacterials: penicillin (MIC ≥ 2 mcg/mL), 2 ndgeneration cephalosporins (e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole). Of 40 microbiologically evaluable patients with MDRSP isolates, 38 patients (95%) achieved clinical and bacteriologic success at post-therapy. The clinical and bacterial success rates are shown in Table 13.

Table 13Clinical and Bacterial Success Rates for levofloxacin -Treated MDRSP in Community Acquired Pneumonia Patients (Population Valid for Efficacy)
Screening Susceptibility 
Clinical Success
Bacteriological Success *
*One patient had a respiratory isolate that was resistant to tetracycline, cefuroxime, macrolides and TMP/SMX and intermediate to penicillin and a blood isolate that was intermediate to penicillin and cefuroxime and resistant to the other classes. The patient is included in the database based on respiratory isolate.
n=the number of microbiologically evaluable patients who were clinical successes; N=number of microbiologically evaluable patients in the designated resistance group.
n=the number of MDRSP isolates eradicated or presumed eradicated in microbiologically evaluable patients; N=number of MDRSP isolates in a designated resistance group.

n/N

%

n/N

%

Penicillin-resistant 

16/17

94.1

16/17

94.1

2nd generation Cephalosporin resistant 

31/32

96.9

31/32

96.9

Macrolide-resistant 

28/29

96.6

28/29

96.6

Trimethoprim/ Sulfamethoxazole resistant 

17/19

89.5

17/19

89.5

Tetracycline-resistant 

12/12

100

12/12

100

Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in Table 14.

Table 14Clinical Success and Bacteriologic Eradication Rates for Resistant Streptococcus pneumoniae (Community Acquired Pneumonia)
Type of Resistance 
Clinical Success
Bacteriologic Eradication

Resistant to 2 antibacterials 

17/18 (94.4%)

17/18 (94.4%)

Resistant to 3 antibacterials 

14/15 (93.3%)

14/15 (93.3%)

Resistant to 4 antibacterials 

7/7 (100%)

7/7 (100%)

Resistant to 5 antibacterials 

0

0

Bacteremia with MDRSP 

8/9 (89%)

8/9 (89%)

14.3 Community-Acquired Pneumonia: 5 day Treatment Regimen

To evaluate the safety and efficacy of the higher dose and shorter course of levofloxacin, 528 outpatient and hospitalized adults with clinically and radiologically determined mild to severe community-acquired pneumonia were evaluated in a double-blind, randomized, prospective, multicenter study comparing levofloxacin 750 mg, IV or orally, every day for five days or levofloxacin  500 mg IV or orally, every day for 10 days.

 

Clinical success rates (cure plus improvement) in the clinically evaluable population were 90.9% in the levofloxacin  750 mg group and 91.1% in the levofloxacin  500 mg group. The 95% CI for the difference of response rates (levofloxacin 750 minus levofloxacin  500) was [-5.9, 5.4]. In the clinically evaluable population (31 to 38 days after enrollment) pneumonia was observed in 7 out of 151 patients in the levofloxacin  750 mg group and 2 out of 147 patients in the levofloxacin 500 mg group. Given the small numbers observed, the significance of this finding cannot be determined statistically. The microbiological efficacy of the 5 day regimen was documented for infections listed in Table 15.

Table 15Bacteriological Eradication Rates (Community-Acquired Pneumonia)
  S. pneumoniae 
 
19/20 (95%)

Haemophilus influenzae 

12/12 (100%)

Haemophilus parainfluenzae 

10/10 (100%)

Mycoplasma pneumoniae 

26/27 (96%)

Chlamydophila pneumoniae 

13/15 (87%)

14.4 Acute Bacterial Sinusitis: 5 day and 10 to 14 day Treatment Regimens

Levofloxacin is approved for the treatment of acute bacterial sinusitis (ABS) using either 750 mg by mouth x 5 days or 500 mg by mouth once daily x 10 to 14 days. To evaluate the safety and efficacy of a high dose short course of levofloxacin, 780 outpatient adults with clinically and radiologically determined acute bacterial sinusitis were evaluated in a double-blind, randomized, prospective, multicenter study comparing levofloxacin 750 mg by mouth once daily for five days to levofloxacin 500 mg by mouth once daily for 10 days.

 

Clinical success rates (defined as complete or partial resolution of the pre-treatment signs and symptoms of ABS to such an extent that no further antibiotic treatment was deemed necessary) in the microbiologically evaluable population were 91.4% (139/152) in the levofloxacin 750 mg group and 88.6% (132/149) in the levofloxacin 500 mg group at the test-of-cure (TOC) visit (95% CI [-4.2, 10] for levofloxacin 750 mg minus levofloxacin  500 mg).

Rates of clinical success by pathogen in the microbiologically evaluable population who had specimens obtained by antral tap at study entry showed comparable results for the five and ten day regimens at the test-of-cure visit 22 days post treatment (see Table 16).

Table 16Clinical Success Rate by Pathogen at the TOC in Microbiologically Evaluable Subjects Who Underwent Antral Puncture (Acute Bacterial Sinusitis)
Pathogen 
Levofloxacin
750 mg x 5 days
Levofloxacin
500 mg x 10 days
*Note: Forty percent of the subjects in this trial had specimens obtained by sinus endoscopy. The efficacy data for subjects whose specimen was obtained endoscopically were comparable to those presented in the above table

Streptococcus pneumoniae * 

25/27 (92.6%)

26/27 (96.3%)

Haemophilus influenzae

19/21 (90.5%)

25/27 (92.6%)

Moraxella catarrhalis

10/11 (90.9%)

13/13 (100%)

14.5 Complicated Skin and Skin Structure Infections

Three hundred ninety-nine patients were enrolled in an open-label, randomized, comparative study for complicated skin and skin structure infections. The patients were randomized to receive either levofloxacin 750 mg once daily (IV followed by oral), or an approved comparator for a median of 10 ± 4.7 days. As is expected in complicated skin and skin structure infections, surgical procedures were performed in the levofloxacin and comparator groups. Surgery (incision and drainage or debridement) was performed on 45% of the levofloxacin-treated patients and 44% of the comparator-treated patients, either shortly before or during antibiotic treatment and formed an integral part of therapy for this indication.

Among those who could be evaluated clinically 2 to 5 days after completion of study drug, overall success rates (improved or cured) were 116/138 (84.1%) for patients treated with levofloxacin and 106/132 (80.3%) for patients treated with the comparator.

Success rates varied with the type of diagnosis ranging from 68% in patients with infected ulcers to 90% in patients with infected wounds and abscesses. These rates were equivalent to those seen with comparator drugs.

14.6 Chronic Bacterial Prostatitis

Adult patients with a clinical diagnosis of prostatitis and microbiological culture results from urine sample collected after prostatic massage (VB 3) or expressed prostatic secretion (EPS) specimens obtained via the Meares-Stamey procedure were enrolled in a multicenter, randomized, double-blind study comparing oral levofloxacin 500 mg, once daily for a total of 28 days to oral ciprofloxacin 500 mg, twice daily for a total of 28 days. The primary efficacy endpoint was microbiologic efficacy in microbiologically evaluable patients. A total of 136 and 125 microbiologically evaluable patients were enrolled in the levofloxacin and ciprofloxacin groups, respectively. The microbiologic eradication rate by patient infection at 5 to 18 days after completion of therapy was 75% in the levofloxacin group and 76.8% in the ciprofloxacin group (95% CI [-12.58, 8.98] for levofloxacin  minus ciprofloxacin). The overall eradication rates for pathogens of interest are presented in Table 17.

Table 17Bacteriological Eradication Rates (Chronic Bacterial Prostatitis)
Levofloxacin (N=136)
Ciprofloxacin (N=125)
*Eradication rates shown are for patients who had a sole pathogen only;
mixed cultures were excluded.

Pathogen 

N

Eradication

N

Eradication

E. coli 

15

14 (93.3%)

11

9 (81.8%)

E. faecalis 

54

39 (72.2%)

44

33 (75%)

S. epidermidis

11

9 (81.8%)

14

11 (78.6%)

Eradication rates for S. epidermidis when found with other-copathogens are consistent with rates seen in pure isolates.

Clinical success (cure + improvement with no need for further antibiotic therapy) rates in microbiologically evaluable population 5 to 18 days after completion of therapy were 75% for levofloxacin-treated patients and 72.8% for ciprofloxacin-treated patients (95% CI [-8.87, 13.27] for levofloxacin minus ciprofloxacin). Clinical long-term success (24 to 45 days after completion of therapy) rates were 66.7% for the levofloxacin-treated patients and 76.9% for the ciprofloxacin-treated patients (95% CI [-23.40, 2.89] for levofloxacin minus ciprofloxacin).

14.7 Complicated Urinary Tract Infections and Acute Pyelonephritis: 5-day Treatment Regimen

To evaluate the safety and efficacy of the higher dose and shorter course of levofloxacin, 1109 patients with cUTI and AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the US from November 2004 to April 2006 comparing levofloxacin 750 mg IV or orally once daily for 5 days (546 patients) with ciprofloxacin 400 mg IV or 500 mg orally twice daily for 10 days (563 patients). Patients with AP complicated by underlying renal diseases or conditions such as complete obstruction, surgery, transplantation, concurrent infection or congenital malformation were excluded. Efficacy was measured by bacteriologic eradication of the baseline organism(s) at the post-therapy visit in patients with a pathogen identified at baseline. The post-therapy (test-of-cure) visit occurred 10 to 14 days after the last active dose of levofloxacin and 5 to 9 days after the last dose of active ciprofloxacin.

 

The bacteriologic cure rates overall for levofloxacin and control at the test-of-cure (TOC) visit for the group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the group of patients in the mITT population who closely followed the protocol (Microbiologically Evaluable) are summarized in Table 18.

Table 18Bacteriological Eradication at Test-of-Cure
Levofloxacin 750 mg orally or IV once daily for 5 days
Ciprofloxacin 400 mg IV/500 mg orally twice daily for 10 days
Overall Difference [95% CI]
*The mITT population included patients who received study medication and who had a positive (≥ 10 5CFU/mL) urine culture with no more than 2 uropathogens at baseline. Patients with missing response were counted as failures in this analysis.
The Microbiologically Evaluable population included patients with a confirmed diagnosis of cUTI or AP, a causative organism(s) at baseline present at ≥ 10 5CFU/mL, a valid test-of-cure urine culture, no pathogen isolated from blood resistant to study drug, no premature discontinuation or loss to follow-up, and compliance with treatment (among other criteria).

n/N

%

n/N

%

Levofloxacin-Ciprofloxacin

mITT Population *

Overall (cUTI or AP) 

252/333

75.7

239/318

75.2

0.5 (-6.1, 7.1) 

cUTI 

168/230

73

157/213

73.7

AP 

84/103

81.6

82/105

78.1

Microbiologically Evaluable Population

Overall (cUTI or AP) 

228/265

86

215/241

89.2

-3.2 [-8.9, 2.5] 

cUTI 

154/185

83.2

144/165

87.3

AP 

74/80

92.5

71/76

93.4

Microbiologic eradication rates in the Microbiologically Evaluable population at TOC for individual pathogens recovered from patients randomized to levofloxacin treatment are presented in Table 19.

Table 19Bacteriological Eradication Rates for Individual Pathogens Recovered From Patients Randomized to Levofloxacin750 mg QD for 5 Days Treatment
Pathogen
Bacteriological Eradication Rate (n/N)
%
*The predominant organism isolated from patients with AP was E. coli: 91% (63/69) eradication in AP and 89% (92/103) in patients with cUTI.

Escherichia coli * 

155/172

90

Klebsiella 
pneumoniae  

20/23

87

Proteus mirabilis 

12/12

100

14.8 Complicated Urinary Tract Infections and Acute Pyelonephritis: 10-day Treatment Regimen

To evaluate the safety and efficacy of the 250 mg dose, 10 day regimen of levofloxacin, 567 patients with uncomplicated UTI, mild-to-moderate cUTI, and mild-to-moderate AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the US from June 1993 to January 1995 comparing levofloxacin 250 mg orally once daily for 10 days (285 patients) with ciprofloxacin 500 mg orally twice daily for 10 days (282 patients). Patients with a resistant pathogen, recurrent UTI, women over age 55 years, and with an indwelling catheter were initially excluded, prior to protocol amendment which took place after 30% of enrollment. Microbiological efficacy was measured by bacteriologic eradication of the baseline organism(s) at 1 to 12 days post-therapy in patients with a pathogen identified at baseline.

The bacteriologic cure rates overall for levofloxacin and control at the test-of-cure (TOC) visit for the group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the group of patients in the mITT population who closely followed the protocol (Microbiologically Evaluable) are summarized in Table 20.

Table 20Bacteriological Eradication Overall (cUTI or AP) at Test-Of-Cure *
Levofloxacin
250 mg once daily for 10 days
Ciprofloxacin
500 mg twice daily for 10 days
*1 to 9 days posttherapy for 30% of subjects enrolled prior to a protocol amendment; 5 to 12 days posttherapy for 70% of subjects.
The mITT population included patients who had a pathogen isolated at baseline. Patients with missing response were counted as failures in this analysis.
The Microbiologically Evaluable population included mITT patients who met protocol-specified evaluability criteria.

n/N

%

n/N

%

mITT Population

174/209

83.3

184/219

84

Microbiologically Evaluable Population

164/177

92.7

159/171

93

14.9 Inhalational Anthrax (Post-Exposure)

The effectiveness of levofloxacin for this indication is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin has not been tested in humans for the post-exposure prevention of inhalation anthrax. The mean plasma concentrations of levofloxacin associated with a statistically significant improvement in survival over placebo in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage regimens [see Indications and Usage ( 1.13) and Dosage and Administration ( 2.1, 2.2)].

Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. The mean (± SD) steady state peak plasma concentration in human adults receiving 500 mg orally or intravenously once daily is 5.7 ± 1.4 and 6.4 ± 0.8 mcg/mL, respectively; and the corresponding total plasma exposure (AUC 0-24) is 47.5 ± 6.7 and 54.6 ± 11.1 mcg.h/mL, respectively. The predicted steady-state pharmacokinetic parameters in pediatric patients ranging in age from 6 months to 17 years receiving 8 mg/kg orally every 12 hours (not to exceed 250 mg per dose) were calculated to be comparable to those observed in adults receiving 500 mg orally once daily [see Clinical Pharmacology ( 12.3)] . Levofloxacin tablets can only be administered to pediatric patients with inhalational anthrax (post-exposure) or plague who are 30 kg or greater due to the limitations of the available strengths [see Dosage and Administration ( 2.2)].

In adults, the safety of levofloxacin for treatment durations of up to 28 days is well characterized. However, information pertaining to extended use at 500 mg daily up to 60 days is limited. Prolonged levofloxacin therapy in adults should only be used when the benefit outweighs the risk.

In pediatric patients, the safety of levofloxacin for treatment durations of more than 14 days has not been studied. An increased incidence of musculoskeletal adverse events (arthralgia, arthritis, tendinopathy, gait abnormality) compared to controls has been observed in clinical studies with treatment duration of up to 14 days. Long-term safety data, including effects on cartilage, following the administration of levofloxacin to pediatric patients is limited [see Warnings and Precautions ( 5.10) and Use in Specific Populations ( 8.4)].

A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 49 LD 50 (~2.7 X 10 6) spores (range 17 to 118 LD 50) of B. anthracis (Ames strain) was conducted. The minimal inhibitory concentration (MIC) of levofloxacin for the anthrax strain used in this study was 0.125 mcg/mL. In the animals studied, mean plasma concentrations of levofloxacin achieved at expected T max (1 hour post-dose) following oral dosing to steady state ranged from 2.79 to 4.87 mcg/mL. Steady state trough concentrations at 24 hours post-dose ranged from 0.107 to 0.164 mcg/mL. Mean (SD) steady state AUC 0-24 was 33.4 ± 3.2 mcg.h/mL (range 30.4 to 36 mcg.h/mL). Mortality due to anthrax for animals that received a 30 day regimen of oral levofloxacin beginning 24 hrs post exposure was significantly lower (1/10), compared to the placebo group (9/10) [P=0.0011, 2-sided Fisher's Exact Test]. The one levofloxacin treated animal that died of anthrax did so following the 30 day drug administration period.

14.10 Plague

Efficacy studies of levofloxacin could not be conducted in humans with pneumonic plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals.

 

The mean plasma concentrations of levofloxacin associated with a statistically significant improvement in survival over placebo in an African green monkey model of pneumonic plague are reached or exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage regimens [see Indications and Usage ( 1.14)   and  Dosage and Administration ( 2.1) , ( 2.2)] .

 

Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. The mean (± SD) steady state peak plasma concentration in human adults receiving 500 mg orally or intravenously once daily is 5.7 ± 1.4 and        6.4 ± 0.8 mcg/mL, respectively; and the corresponding total plasma exposure (AUC 0-24) is 47.5 ± 6.7 and 54.6 ± 11.1 mcg.h/mL, respectively. The predicted steady-state pharmacokinetic parameters in pediatric patients ranging in age from 6 months to 17 years receiving 8 mg/kg orally every 12 hours (not to exceed     250 mg per dose) were calculated to be comparable to those observed in adults receiving 500 mg orally once daily [see Clinical Pharmacology ( 12.3)] . Levofloxacin tablets can only be administered to pediatric patients with inhalational anthrax (post-exposure) or plague who are 30 kg or greater due to the limitations of the available strengths [see Dosage and Administration ( 2.2)].

 

A placebo-controlled animal study in African green monkeys exposed to an inhaled mean dose of 65 LD 50 (range 3 to 145 LD 50) of Yersinia pestis (CO92 strain) was conducted. The minimal inhibitory concentration (MIC) of levofloxacin for the Y. pestis strain used in this study was 0.03 mcg/mL. Mean plasma concentrations of levofloxacin achieved at the end of a single 30 min infusion ranged from 2.84 to 3.50 mcg/mL in African green monkeys. Trough concentrations at 24 hours post-dose ranged from < 0.03 to 0.06 mcg/mL. Mean (SD) AUC 0-24 was 11.9 (3.1) mcg.h/mL (range 9.50 to 16.86 mcg.h/mL). Animals were randomized to receive either a 10-day regimen of i.v. levofloxacin or placebo beginning within 6 hrs of the onset of telemetered fever (≥ 39 oC for more than 1 hour). Mortality in the levofloxacin group was significantly lower (1/17) compared to the placebo group (7/7) [p< 0.001, Fisher's Exact Test; exact 95% confidence interval (-99.9%, -55.5%) for the difference in mortality]. One levofloxacin-treated animal was euthanized on Day 9 post-exposure to Y. pestis due to a gastric complication; it had a blood culture positive for Y. pestis on Day 3 and all subsequent daily blood cultures from Day 4 through Day 7 were negative.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 Levofloxacin Tablets

Levofloxacin Tablets USP, 250 mg are white to off white, modified capsule-shaped, biconvex, film-coated tablets debossed with logo of 'ZC55' on one side and plain on other side and are supplied as follows:

NDC 68382-015-18 in bottles of 50 tablets

NDC 68382-015-01 in bottles of 100 tablets

NDC 68382-015-05 in bottles of 500 tablets

Levofloxacin Tablets USP, 500 mg are white to off white, modified capsule-shaped, biconvex, film-coated tablets debossed with logo of 'ZC56' on one side and plain on other side and are supplied as follows:

NDC 68382-016-18 in bottles of 50 tablets

NDC 68382-016-01 in bottles of 100 tablets

NDC 68382-016-05 in bottles of 500 tablets

NDC 68382-016-10 in bottles of 1000 tablets

NDC 58118-1016- in blister pack of 30 tablets

Levofloxacin Tablets USP, 750 mg are white to off white, modified capsule-shaped, biconvex, film-coated tablets debossed with logo of 'ZC57' on one side and plain on other side and are supplied as follows:

NDC 68382-017-18 in bottles of 50 tablets

NDC 68382-017-01 in bottles of 100 tablets

NDC 68382-017-05 in bottles of 500 tablets

Storage

Store at 20° to 25° C (68° to 77° F) [see USP Controlled Room Temperature]. Dispense in a well-closed container as described in the USP.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Serious Adverse Reactions

Advise patients to stop taking levofloxacin if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug.

Inform patients of the following serious adverse reactions that have been associated with levofloxacin or other fluoroquinolone use:

Antibacterial Resistance

Antibacterial drugs including levofloxacin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When levofloxacin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full

 

course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by levofloxacin or other antibacterial drugs in the future.

 

Administration with Food, Fluids, and Concomitant Medications

Patients should be informed that levofloxacin tablets may be taken with or without food. The tablets should be taken at the same time each day. Patients should drink fluids liberally while taking levofloxacin to avoid formation of a highly concentrated urine and crystal formation in the urine. Antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine should be taken at least two hours before or two hours after oral levofloxacin

administration.

 

Drug Interactions with Insulin, Oral Hypoglycemic Agents, and Warfarin

Patients should be informed that if they are diabetic and are being treated with insulin or an oral hypoglycemic agent and a hypoglycemic reaction occurs, they should discontinue levofloxacin and consult a physician. Patients should be informed that concurrent administration of warfarin and levofloxacin has been associated with increases of the International Normalized Ratio (INR) or prothrombin time and clinical episodes of bleeding. Patients should notify their physician if they are taking warfarin, be monitored for evidence of bleeding, and also have their anticoagulation tests closely monitored

while taking warfarin concomitantly.

 

Plague and Anthrax Studies

Patients given levofloxacin for these conditions should be informed that efficacy studies could not be conducted in humans for ethical and feasibility reasons. Therefore, approval for these conditions was based on efficacy studies conducted in animals.

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India.

Distributed by:

Zydus Pharmaceuticals (USA) Inc.

Pennington, NJ 08534

Rev: 07/18

Repackaged by:

Clinical Solutions Wholesale

Franklin, TN 37067

MEDICATION GUIDE

Levofloxacin (LEE voe FLOX a sin) Tablets, USP

What is the most important information I should know about levofloxacin? Levofloxacin, a fluoroquinolone antibiotic, can cause serious side effects. Some of these serious side effects can happen at the same time and could result in death.

If you have any of the following serious side effects while you take levofloxacin, get medical help right away.

1. Tendon rupture or swelling of the tendon (tendinitis). 

Some tendon problems include pain, swelling, tears, and swelling of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites.

The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can also happen with other tendons. You may need a different antibiotic that is not a fluoroquinolone to treat your infection.

2. Changes in sensation and possible nerve damage (Peripheral Neuropathy).

Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including levofloxacin. Stop taking levofloxacin immediately and talk to your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet:

The nerve damage may be permanent.

3. Central Nervous System (CNS) effects. 

Seizures have been reported in people who take fluoroquinolone antibacterial medicines, including levofloxacin. Tell your healthcare provider if you have a history of seizures before you start taking levofloxacin. CNS side effects may happen as soon as after taking the first dose of levofloxacin. Stop taking levofloxacin immediately and talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior:

4. Worsening of myasthenia gravis (a problem that causes muscle weakness).

Fluoroquinolones like levofloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Tell your healthcare provider if you have a history of myasthenia gravis before you start taking levofloxacin. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems.

What is levofloxacin ?

Levofloxacin is a fluoroquinolone antibiotic medicine used in adults age 18 years or older to treat certain infections caused by certain germs called bacteria. These bacterial infections include:

Studies of levofloxacin for use in the treatment of plague and anthrax were done in animals only, because plague and anthrax could not be studied in people.

 

Levofloxacin should not be used in patients with uncomplicated urinary tract infections, acute bacterial exacerbation of chronic bronchitis, or acute bacterial sinusitis if there are other treatment options available.

 

Levofloxacin tablets are also used to treat children who weigh at least 66 pounds (or at least 30 kilograms) and may have breathed in anthrax germs, have plague, or been exposed to plague germs.

 

It is not known if levofloxacin is safe and effective in children under 6 months of age.

 

The safety and effectiveness in children treated with levofloxacin for more than 14 days is not known.

 

Who should not take levofloxacin?

Do not take levofloxacin if you have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or if you are allergic to levofloxacin or any of the ingredients in levofloxacin tablets. See the end of this leaflet for a complete list of  ingredients in levofloxacin tablets.

 

Before you take levofloxacin, tell your healthcare provider about all of your medical conditions, including if you:

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

 

Levofloxacin and other medicines can affect each other causing side effects.

 

Especially tell your healthcare provider if you take:

Ask your healthcare provider if you are not sure if any of your medicines are listed above.

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take levofloxacin?

Taking all of your levofloxacin doses will help make sure that all of the bacteria are killed. Taking all of your levofloxacin doses will help you lower the chance that the bacteria will become resistant to levofloxacin. If your infection does not get better while you take levofloxacin, it may mean that the bacteria causing your infection may be resistant to levofloxacin. If your infection does not get better, call your healthcare provider. If your infection does not get better, levofloxacin and other similar antibiotic medicines may not work for you in the future.

What should I avoid while taking levofloxacin?

What are the possible side effects of levofloxacin?

Levofloxacin can cause serious side effects, including:.

Allergic reactions can happen in people taking fluoroquinolones, including levofloxacin, even after only 1 dose. Stop taking levofloxacin and get emergency medical help right away if you have any of the following symptoms of a severe allergic reaction:

Skin rash may happen in people taking levofloxacin, even after only 1 dose. Stop taking levofloxacin at the first sign of a skin rash and call your healthcare provider. Skin rash may be a sign of a more serious reaction to levofloxacin.

Hepatotoxicity can happen in people who take levofloxacin. Call your healthcare provider right away if you have unexplained symptoms such as:

Stop taking levofloxacin and tell your healthcare provider right away if you have yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to levofloxacin (a liver problem).

Pseudomembranous colitis can happen with many antibiotics, including levofloxacin. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic.

Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. Levofloxacin may cause a rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people:

Increased chance of problems with joints and tissues around joints in children can         happen. Tell your child’s healthcare provider if your child has any joint problems during or after treatment with levofloxacin.

People who take levofloxacin and other fluoroquinolone medicines with oral anti-diabetes medicines or with insulin can get low blood sugar (hypoglycemia) and high blood sugar (hyperglycemia). Follow your healthcare provider’s instructions for how often to check your blood sugar. If you have diabetes and you get low blood sugar while taking levofloxacin, stop taking levofloxacin and call your healthcare provider right away. Your antibiotic medicine may need to be changed.

See "What should I avoid while taking levofloxacin?"

The most common side effects of levofloxacin include:

In children 6 months and older who take levofloxacin to treat anthrax disease or plague, vomiting is also common.

 

Levofloxacin may cause false-positive urine screening results for opiates when testing is done with some commercially available kits. A positive result should be confirmed using a more specific test.

 

These are not all the possible side effects of levofloxacin.

 

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

 

How should I store levofloxacin?

General information about the safe and effective use of levofloxacin

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use levofloxacin for a condition for which it is not prescribed. Do not give levofloxacin to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about levofloxacin. If you would like more information about levofloxacin, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about levofloxacin that is written for healthcare professionals.

Please address medical inquiries to, MedicalAffairs@zydususa.com orTel.: 1-877-993-8779.

What are the ingredients in levofloxacin tablets, USP?

Active ingredients: levofloxacin, USP

Inactive ingredients: crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 6000, talc and titanium dioxide.

Trademarks are the property of their respective owners.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

This product's label may have been updated. For current full prescribing information, please visit www.zydususa.com.

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India.

Distributed by:

Zydus Pharmaceuticals (USA) Inc.

Pennington, NJ 08534

Rev.: 07/18

Repackaged by:

Clinical Solutions Wholesale

Franklin, TN 37067

Package/Label Display Panel

Levofloxacin 500mg tablets 30 count blister card
LEVOFLOXACIN 
levofloxacin tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:58118-1016(NDC:68382-016)
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
LEVOFLOXACIN (UNII: 6GNT3Y5LMF) (LEVOFLOXACIN ANHYDROUS - UNII:RIX4E89Y14) LEVOFLOXACIN ANHYDROUS500 mg
Inactive Ingredients
Ingredient NameStrength
HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
POLYETHYLENE GLYCOL 6000 (UNII: 30IQX730WE)  
TALC (UNII: 7SEV7J4R1U)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
CROSPOVIDONE, UNSPECIFIED (UNII: 2S7830E561)  
Product Characteristics
Colorwhite (WHITE TO OFF-WHITE) Scoreno score
ShapeCAPSULE (MODIFIED CAPSULE) Size19mm
FlavorImprint Code ZC56
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:58118-1016-830 in 1 BLISTER PACK; Type 0: Not a Combination Product10/23/2018
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA07765210/23/2018
Labeler - Clinical Solutions Wholesale, LLC (078710347)
Registrant - Clinical Solutions Wholesale, LLC (078710347)
Establishment
NameAddressID/FEIBusiness Operations
Clinical Solutions Wholesale, LLC078710347repack(58118-1016)

Revised: 7/2019
Document Id: 8d7e0add-0d02-1794-e053-2a95a90af82b
Set id: ecbbdb00-406e-49a1-86dd-d0f82b4680a0
Version: 2
Effective Time: 20190712
 
Clinical Solutions Wholesale, LLC