Levofloxacin

1 INDICATIONS & 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 tablets are indicated in adult patients for the treatment of nosocomial pneumonia due to methicillin-susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, or Streptococcus pneumoniae. Adjunctive therapy should be used as clinically indicated. Where Pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with an anti-pseudomonal β-lactam is recommended [see Clinical Studies ( 14.1) ]. 1.2 Community-Acquired Pneumonia: 7 to 14 day Treatment Regimen Levofloxacin tablets are 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), 2nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole. 1.3 Community-Acquired Pneumonia: 5-day Treatment Regimen Levofloxacin tablets are 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 tablets are indicated in adult patients for the treatment of complicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, or Proteus mirabilis [see Clinical Studies ( 14.5)]. 1.5 Uncomplicated Skin and Skin Structure Infections Levofloxacin tablets are indicated in adult patients for the treatment of uncomplicated skin and skin structure infections (mild to moderate) including abscesses, cellulitis, furuncles, impetigo, pyoderma, wound infections, due to methicillin-susceptible Staphylococcus aureus, or Streptococcus pyogenes. 1.6 Chronic Bacterial Prostatitis Levofloxacin tablets are 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 tablets are 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 [

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

2 DOSAGE & 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 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 Pediatric Patients 30 kg to less than 50 kg (2.2) 500 mg 250 mg every 12 hours 60 60 Plague (1.8) Adults and Pediatric Patients 50 kg or greater Pediatric Patients 30 kg to less than 50 kg (2.2) 500 mg 250 mg every 12 hours 10 to 14 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 (2.3, 8.6, 12.3) 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) 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 à or greater Pediatric patients weighing 30 kg to less than 50 kg 500 mg see Table 2 below (2.2) 10 to 14 10 to 14 Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) ¶ 750 mg 5 Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) # 250 mg # 10 # Uncomplicated Urinary Tract Infection 250 mg 3 Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB) 500 mg 7 Acute Bacterial Sinusitis (ABS) 750 mg 5 500 mg 10 to 14 * Due to the designated pathogens [see Indications and Usage ( 1)]. † Sequential therapy (intravenous 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, Klebsiell

6 ADVERSE REACTIONS The most common reactions (≥3%) were nausea, headache, diarrhea, insomnia, constipation and dizziness ( 6.2 ). To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Serious and Otherwise Important Adverse Reactions The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: • Disabling and Potentially Irreversible Serious Adverse Reactions [ see Warnings and Precautions (5.1)] • Tendinitis and Tendon Rupture [see Warnings and Precautions ( 5.2)] • Peripheral Neuropathy [see Warnings and Precautions (5.3)] • Central Nervous System Effects [see Warnings and Precautions ( 5.4)] • Exacerbation of Myasthenia Gravis [see Warnings and Precautions ( 5.5)] • Other Serious and Sometimes Fatal 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 )]. 6.2 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to levofloxacin in 7537 patients in 29 pooled Phase 3 clinical trials. The population studied had a mean age of 50 years (approximately 74% of the population was < 65 years of age), 50% were male, 71% were Caucasian, 19% were Black. Patients were treated with levofloxacin for a wide variety of infectious diseases [see Indications and Usage (1)]. Patients received levofloxacin doses of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. Treatment duration was usually 3 to 14 days, and the mean number of days on therapy was 10 days. The overall incidence, type and distribution of adverse reactions was similar in patients receiving levofloxacin doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation of levofloxacin due to adverse drug reactions occurred in 4.3% of patients overall, 3.8% of patients treated with the 250 mg and 500 mg doses and 5.4% of patients treated with the 750 mg dose. The most common adverse drug reactions leading to discontinuation with the 250 and 500 mg doses were gastrointestinal (1.4%), primarily nausea (0.6%); vomiting (0.4%); dizziness (0.3%); and headache (0.2%). The most common adverse drug reactions leading to discontinuation with the 750 mg dose were gastrointestinal (1.2%), primarily nausea (0.6%), vomiting (0.5%); dizziness (0.3%); and headache (0.3%). Adverse reactions occurring in ≥1% of levofloxacin-treated patients and less common adverse reactions, occurring in 0.1 to <1% of levofloxacin-treated patients, are shown in Table 4 and Table 5, respectively. The most common adverse drug reactions (≥3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness. Table 4:Common (≥1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin System/Organ Class Adverse React

5 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, hepatoxicity has been reported. Discontinue immediately if signs and symptoms of hepatitis occur ( 5.8 ) Clostridium difficile -associated colitis: evaluate if diarrhea occurs ( 5.10 ) Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs that prolong the QT interval ( 5.11 , 8.5 ) 5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting levofloxacin. Patients of any age or without pre-existing risk factors have experienced these adverse reactions [see Warnings and Precautions (5.2 , 5.3 , 5.4 )]. Discontinue levofloxacin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including levofloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones. 5.2 Tendinopathy 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

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

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.