Levofloxacin

1 INDICATIONS AND USAGE Levofloxacin Injection in 5% dextrose is indicated for the treatment of adults (≥18 years of age) with mild, moderate, and severe infections caused by susceptible isolates of the designated microorganisms in the conditions listed in this section. Levofloxacin Injection is indicated when intravenous administration offers a route of administration advantageous to the patient (e.g., patient cannot tolerate an oral dosage form). Levofloxacin is a fluoroquinolone antibacterial indicated in adults (≥18 years of age) with infections caused by designated, susceptible bacteria ( 1 , 12.4 ). Pneumonia: Nosocomial ( 1.1 ) and Community Acquired ( 1.2 , 1.3 ) Skin and Skin Structure Infections: Complicated ( 1.4 ) and Uncomplicated ( 1.5 ) Chronic bacterial prostatitis ( 1.6 ) Inhalational Anthrax, Post-Exposure ( 1.7 ) Plague ( 1.8 ) Urinary Tract Infections: Complicated ( 1.9 , 1.10 ) and Uncomplicated ( 1.12 ) Acute Pyelonephritis ( 1.11 ) Acute Bacterial Exacerbation of Chronic Bronchitis ( 1.13 ) Acute Bacterial Sinusitis ( 1.14 ) 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 is indicated for the treatment of nosocomial pneumonia due to methicillin susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, or Streptococcus pneumoniae . Adjunctive therapy should be used as clinically indicated. Where Pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with an antipseudomonal β-lactam is recommended [see Clinical Studies ( 14.1 )] . 1.2 Community-Acquired Pneumonia: 7 to 14 day Treatment Regimen Levofloxacin is indicated for the treatment of community-acquired pneumonia due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant Streptococcus pneumoniae [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae [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 is indicated for the treatment of community-acquired pneumonia due to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Dosage and Administration ( 2.1 ) and Clinical Studies ( 14.3 )]. 1.4 Complicated Skin and Skin Structure Infections Levofloxacin is indicated for the treatment of complicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, or Proteus mirabilis [see Clinical Studies ( 14.5 )]. 1.5 Uncomplicated Skin and Skin Structure Infections Levofloxacin is indicated for the treatment of uncomplicated skin and skin structure infections (mild to moderate) including abscesses, cellulitis, furuncles, impetigo, pyoderma, wound infections, due to methicillin-susceptible Staphylococcus aureus , or Streptococcus pyogenes . 1.6 Chronic Bacterial Prostatitis Levofloxacin is indicated 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 is indicated for inhalational anthrax (post-exposure) to reduce…

2 DOSAGE AND ADMINISTRATION Dosage in patients with normal renal function ( 2.1 ) Type of Infection Dose Every 24 hours Duration (days) Nosocomial Pneumonia ( 1.1 ) 750 mg 7 to 14 Community Acquired Pneumonia ( 1.2 ) 500 mg 7 to 14 Community Acquired Pneumonia ( 1.3 ) 750 mg 5 Complicated Skin and Skin Structure Infections (SSSI) ( 1.4 ) 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 Pediatric Patients < 50 kg and ≥ 6 months of age 500 mg 8mg/kg BID (not to exceed 250 mg/dose) 60 60 Plague ( 1.8 ) Adults and Pediatric Patients > 50 kg Pediatric Patients < 50 kg and ≥ 6 months of age 500 mg 8 mg/kg BID (not to exceed 250 mg/dose) 10 to 14 10 to 14 Complicated Urinary Tract Infection ( 1.9 ) or Acute Pyelonephritis ( 1.11 ) 750 mg 5 Complicated Urinary Tract Infection ( 1.10 ) or Acute Pyelonephritis ( 1.11 ) 250 mg 10 Uncomplicated Urinary Tract Infection ( 1.12 ) 250 mg 3 Acute Bacterial Exacerbation of Chronic Bronchitis ( 1.13 ) 500 mg 7 Acute Bacterial Sinusitis ( 1.14 ) 750 mg 5 500 mg 10 to 14 Adjust dose for creatinine clearance < 50 mL/min ( 2.3 , 8.6 , 12.3 ) IV Injection Premix: Slow IV infusion only, over 60 or 90 minutes depending on dose. Avoid rapid or bolus IV ( 2.5 ) Do not mix with other medications in IV line ( 2.6 ) 2.1 Dosage in Adult Patients with Normal Renal Function The usual dose of Levofloxacin Injection is 250 mg or 500 mg administered by slow infusion over 60 minutes every 24 hours or 750 mg administered by slow infusion over 90 minutes every 24 hours, as indicated by infection and described in Table 1 . These recommendations apply to patients with creatinine clearance ≥ 50 mL/min. For patients with creatinine clearance <50 mL/min, adjustments to the dosing regimen are required [see Dosage and Administration ( 2.3 )] . Table 1: Dosage in Adult Patients with Normal Renal Function (creatinine clearance ≥ 50 mL/min) 1 Due to the designated pathogens [see Indications and Usage ( 1 )] . 2 Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician. 3 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 )]. 4 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 )]. 5 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. 6 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. 7 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 )] . 8 The safety of levofloxacin in adults for durations of therapy beyond 28 days or in pediatric patients for durations beyond 14 days has not been studied. An increased incidence of musculoskeletal adverse events compared to controls has been observed in pediatric patients [see Warnings and Precautions ( 5.12 ), Use in Specific Populations ( 8.4 ), and Clinical Studies ( 14.9 )] . Prolonged levofloxacin therapy should only be used when the benefit outweighs the risk. 9 Drug administration should begin as soon as possible after suspected or confirmed exposure to Yer…

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, hepatotoxicity has been reported. Discontinue immediately if signs and symptoms of hepatitis occur ( 5.9 ) 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 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 ); 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 Reacti…

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

7 DRUG INTERACTIONS Interacting Drug Interaction Multivalent cation-containing products including antacids, metal cations or didanosine Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( 2.4 , 7.1 ) Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2 ) Antidiabetic agents Carefully monitor blood glucose ( 5.13 , 7.3 ) 7.1 Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins Levofloxacin Injection There are no data concerning an interaction of intravenous fluoroquinolones with oral antacids, sucralfate, multivitamins, didanosine, or metal cations. However, no fluoroquinolone should be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line [see Dosage and Administration ( 2.5 )] . 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 ); 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 ), 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 …

8.1 Pregnancy Pregnancy Category C. Levofloxacin was not teratogenic in rats at oral doses as high as 810 mg/kg/day which corresponds to 9.4 times the highest recommended human dose based upon relative body surface area, or at intravenous doses as high as 160 mg/kg/day corresponding to 1.9 times the highest recommended 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 human dose based upon relative body surface area, or when dosed intravenously as high as 25 mg/kg/day, corresponding to 0.5 times the highest recommended 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.

6 ADVERSE REACTIONS The most common reactions (≥ 3%) were nausea, headache, diarrhea, insomnia, constipation and dizziness ( 6.2 ). To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-4414100 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 )] Risk of Aortic Aneurysm and Dissection [see Warnings and Precautions ( 5.8 )] Hepatotoxicity [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 )] Hypotension has been associated with rapid or bolus intravenous infusion of levofloxacin. Levofloxacin should be infused slowly over 60 to 90 minutes, depending on dosage [see Dosage and Administration ( 2.5 )]. Crystalluria and cylindruria have been reported with quinolones, including levofloxacin. 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 (…