1 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 ).

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 nd generation 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 )] 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 )] 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 )] .

Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions ( 5 )] 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.

6 ADVERSE REACTIONS The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: Disabling and Potentially Irreversible Serious Adverse Reactions [see Warnings and Precautions ( 5.1 )] Tendinitis and Tendon Rupture [see Warnings and Precautions ( 5.2 )] Peripheral Neuropathy [see Warnings and Precautions ( 5.3 )] Central Nervous System Effects [see Warnings and Precautions ( 5.4 )] Exacerbation of Myasthenia Gravis [see Warnings and Precautions ( 5.5 )] Other Serious and Sometimes Fatal Reactions [see Warnings and Precautions ( 5.6 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] Hepatotoxicity [see Warnings and Precautions ( 5.8 )] Risk of Aortic Aneurysm and Dissection [see Warnings and Precautions ( 5.9 )] Clostridium difficile -Associated Diarrhea [see Warnings and Precautions ( 5.10 )] Prolongation of the QT Interval [see Warnings and Precautions ( 5.11 )] Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions ( 5.12 )] Blood Glucose Disturbances [see Warnings and Precautions ( 5.13 )] Photosensitivity/Phototoxicity [see Warnings and Precautions ( 5.14 )] Development of Drug Resistant Bacteria [see Warnings and Precautions ( 5.15 )] Crystalluria and cylindruria have been reported with quinolones, including levofloxacin.

Therefore, adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of a highly concentrated urine [see Dosage and Administration ( 2.5 )].

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

To report SUSPECTED ADVERSE REACTIONS, contact Viona Pharmaceuticals Inc.

at 1-888-304-5011 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 7,537 patients in 29 pooled Phase 3 clinical trials.

The population studied had a mean age of 50 years (approximately 74% of the population was < 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 = 7,274 † N=3,758 (women) # pool of studies included IV and oral administration System/Organ Class Adverse Reaction % (N=7,537) Infections and Infestations moniliasis 1 Psychiatric Disorders Insomnia * [see Warnings and Precautions ( 5.4 )] 4 Nervous System Disorders headache dizziness [see Warnings and Precautions ( 5.4 )] 6 3 Respiratory, Thoracic and Mediastinal Disorders dyspnea [see Warnings and Precautions ( 5.7 )] 1 Gastrointestinal Disorders nausea diarrhea constipation abdominal pain vomiting dyspepsia 7 5 3 2 2 2 Skin and Subcutaneous Tissue Disorders rash [see Warnings and Precautions ( 5.7 )] pruritus 2 1 Reproductive System and Breast Disorders vaginitis 1 † General Disorders and Administration Site Conditions edema injection site reaction chest pain 1 1 1 Table 5 Less Common (0.1 to 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin (N=7,537) * N = 7,274 System/Organ Class Adverse Reaction Infections and Infestations genital moniliasis Blood and Lymphatic System Disorders anemia thrombocytopenia granulocytopenia [see Warnings and Precautions ( 5.6 )] Immune System Disorders allergic reaction [see Warnings and Precautions ( 5.6 , 5.7 )] Metabolism and Nutrition Disorders hyperglycemia hypoglycemia [see Warnings and Precautions ( 5.13 )] hyperkalemia Psychiatric Disorders anxiety agitation confusion depression hallucination nightmare * [see Warnings and Precautions ( 5.4 )] sleep disorder * anorexia abnormal dreaming * Nervous System Disorders tremor convulsions [see Warnings and Precautions ( 5.4 )] paresthesia [see Warnings and Precautions ( 5.3 )] vertigo hypertonia hyperkinesias abnormal gait somnolence * syncope Respiratory, Thoracic and Mediastinal Disorders epistaxis Cardiac Disorders cardiac arrest palpitation ventricular tachycardia ventricular arrhythmia Vascular Disorders phlebitis Gastrointestinal Disorders gastritis stomatitis pancreatitis esophagitis gastroenteritis glossitis pseudomembranous/ C.

difficile colitis [see Warnings and Precautions ( 5.10 )] Hepatobiliary Disorders abnormal hepatic function increased hepatic enzymes increased alkaline phosphatase Skin and Subcutaneous Tissue Disorders urticaria [see Warnings and Precautions ( 5.7 )] Musculoskeletal and Connective Tissue Disorders arthralgia tendinitis [see Warnings and Precautions ( 5.2 )] myalgia skeletal pain Renal and Urinary Disorders abnormal renal function acute renal failure [see Warnings and Precautions ( 5.6 )] In clinical trials using multiple-dose therapy, ophthalmologic abnormalities, including cataracts and multiple punctate lenticular opacities, have been noted in patients undergoing treatment with quinolones, including levofloxacin.

The relationship of the drugs to these events is not presently established.

6.2 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 ( 5.11 )] tachycardia Acute myocardial ischemia with or without myocardial infarction occurring as part of an allergic reaction Vascular Disorders vasodilatation Respiratory, Thoracic and Mediastinal Disorders isolated reports of allergic pneumonitis [see Warnings and Precautions ( 5.6 )] Hepatobiliary Disorders hepatic failure (including fatal cases) hepatitis jaundice [see Warnings and Precautions ( 5.6 ), ( 5.8 )] Skin and Subcutaneous Tissue Disorders bullous eruptions to include: Stevens-Johnson Syndrome toxic epidermal necrolysis Acute Generalized Exanthematous Pustulosis (AGEP) fixed drug eruptions erythema multiforme [see Warnings and Precautions ( 5.6 )] photosensitivity/phototoxicity reaction [see Warnings and Precautions ( 5.14 )] leukocytoclastic vasculitis Musculoskeletal and Connective Tissue Disorders tendon rupture [see Warnings and Precautions ( 5.2 )] muscle injury, including rupture rhabdomyolysis Renal and Urinary Disorders interstitial nephritis [see Warnings and Precautions ( 5.6 )] General Disorders and Administration Site Conditions multi-organ failure pyrexia Investigations prothrombin time prolonged international normalized ratio prolonged muscle enzymes increased