Levofloxacin

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

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 pneumonia

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, Klebsiella pneumoniae, Proteus mirabilis and AP due to E. coli, including cases with concurrent bacteremia. # This regimen is indicated for cUTI due to Enterococcus faecalis, Enterococcus cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa; and for AP due to E. coli. Þ Drug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis. This indication is based on a surrogate endpoint. Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit [see Clinical Studies ( 14.9 )]. ß The safety of levofloxacin tablets in adults for durations of therapy beyond 28 days or in pediatric patients for durations beyond 14 days has not been studied. An increased incidence of musculoskeletal adverse events compared to controls has been observed in pediatric patients [see Warnings and Precautions ( 5.12 ) , Use in Specific Populations ( 8.4), and Clinical Studies ( 14.9 )]. Pr

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 Reaction % (N=7537) Infections and Infestations moniliasis 1 Psychiatric Disorders insomnia * [see Warnings and Precautions ( 5.4 )] 4 Nervous System Disorders headache dizziness [see Warnings and Precautions ( 5.4 )] 6 3 Respiratory, Thoracic and Mediastinal Disorders dyspnea [see Warnings and Precautions ( 5.7 )] 1 Gastrointestinal Disorders nausea diarrhea constipation abdominal pain vomiting dyspepsia 7 5 3 2 2 2 Skin and Subcutaneous Tissue Disorders rash [see Warnings and Precautions ( 5.7 )] pruritus 2 1 Reproductive System and Breast Disorders vaginitis 1 † General Disorders and Administration Site Conditions edema injection site reaction chest pain 1 1 1 * N = 7274 † N=3758 (women) # pool of studies included IV and oral administration Table 5: Less Common (0.1 to 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin (N=7537) System/Organ Class Adverse Reaction Infections and Infestations genital moniliasis Blood and Lymphatic System Disorders anemiathrombocytopenia gr

7 DRUG INTERACTIONS Interacting Drug Interaction Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablets are 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 (5.13, 7.3) 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 multivitamin 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 postmarketing experience in patients that levofloxacin enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent warfarin and levofloxacin use have been associated with episodes of bleeding. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if levofloxacin is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Adverse Reactions ( 6.3) 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 ( 5.13 ), 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 t1/2 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 Cmax of levofloxacin was observed in a clini