LEVOFLOXACIN

Levofloxacin Injection is a synthetic broad-spectrum antibacterial agent for intravenous 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 The empirical formula is C 18 H 20 FN 3 O 4 ● ½ H 2 O and the molecular weight is 370.38. Levofloxacin is a light yellowish-white to yellow-white crystal 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 per 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 per mL) and is considered freely soluble in this range. Above pH 6.7, the solubility decreases and reaches a minimum value (about 50 mg per 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 . Figure 1 Excipients and Description of Dosage Forms Levofloxacin Injection The appearance of Levofloxacin Injection may range from a clear yellow to a clear greenish-yellow solution. This does not adversely affect product potency. Levofloxacin Injection Premix in Single-Use Flexible Container is a sterile, preservative-free aqueous solution of levofloxacin with pH ranging from 3.8 to 5.8. This is a dilute, nonpyrogenic, nearly isotonic premixed solution that contains levofloxacin in 5% Dextrose (D 5 W). Solutions of hydrochloric acid and sodium hydroxide may have been added to adjust the pH. The flexible container is fabricated from a specially formulated non-plasticized, thermoplastic copolyolephine. The amount of water that can permeate from the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the flexible container can leach out certain of the container's chemical components in very small amounts within the expiration period. The suitability of the container material has been confirmed by tests in animals according to USP biological tests for plastic containers.

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 the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. The effectiveness of levofloxacin 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 safety of levofloxacin 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 therapy should only be used when the benefit outweighs the risk [see Dosage and Administration ( 2.1 , 2.2 ) and Clinical Studies ( 14.9 )]. 1.8 Plague Levofloxacin 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. Efficacy studies of levofloxacin 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 Dosage and Administration ( 2.1 , 2.2 ) and Clinical Studies ( 14.10 )] . 1.9 Complicated Urinary Tract Infections: 5-day Treatment Regimen Levofloxacin is indicated 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 is indicated 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 is indicated 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 is indicated 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 to 5.15 )] 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 is indicated 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 to 5.15 )] 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 to 14 day Treatment Regimens Levofloxacin is indicated 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 ( 5.1 to 5.15 )] 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.

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 Yersinia pestis . Higher doses of levofloxacin typically used for treatment of pneumonia can be used for treatment of plague, if clinically indicated. Type of Infection 1 Dosed Every 24 hours Duration (days) 2 Nosocomial Pneumonia 750 mg 7 to 14 Community Acquired Pneumonia 3 500 mg 7 to 14 Community Acquired Pneumonia 4 750 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 > 50 kg 7,8 Pediatric patients < 50 kg and ≥ 6 months of age 7,8 500 mg see Table 2 below ( 2.2 ) 60 8 60 8 Plague, adult and pediatric patients > 50 kg 9 Pediatric patients < 50 kg and ≥ 6 months of age 500 mg see Table 2 below ( 2.2 ) 10 to 14 10 to 14 Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) 5 750 mg 5 Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) 6 250 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 in Pediatric Patients The dosage in pediatric patients ≥ 6 months of age is described below in Table 2 . Table 2: Dosage in Pediatric Patients ≥ 6 months of age 1 Due to Bacillus anthracis [see Indications and Usage ( 1.7 )] and Yersinia pestis [see Indications and Usage ( 1.8 )] . 2 Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician. 3 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 )] 4 The safety of levofloxacin in pediatric patients for durations of therapy 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. 5 Drug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis . Type of Infection 1 Dose Freq. Once every Duration 2 Inhalational Anthrax (post-exposure) 3,4 Pediatric Patients > 50 kg 500 mg 24 hr 60 days 4 Pediatric Patients < 50 kg and ≥ 6 months of age 8 mg/kg (not to exceed 250 mg per dose) 12 hr 60 days 4 Plague 5 Pediatric Patients > 50 kg 500 mg 24 hr 10 to 14 days Pediatric Patients < 50 kg and ≥ 6 months of age 8 mg/kg (not to exceed 250 mg per dose) 12 hr 10 to 14 days 2.3 Dosage Adjustment in Adults with Renal Impairment Administer levofloxacin with caution in the presence of renal insufficiency. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of levofloxacin may be reduced. No adjustment is necessary for patients with a creatinine clearance ≥ 50 mL/min. In patients with impaired renal function (creatinine clearance < 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 )] . Table 3 shows how to adjust dose based on creatinine clearance. Table 3: Dosage Adjustment in Adult Patients with Renal Impairment (creatinine clearance < 50 mL/min) Dosage in Normal Renal Function Every 24 hours Creatinine Clearance 20 to 49 mL/min Creatinine Clearance 10 to 19 mL/min Hemodialysis or Chronic Ambulatory Peritoneal Dialysis (CAPD) 750 mg 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 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 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 Injection Levofloxacin Injection should not be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line [see Dosage and Administration ( 2.6 )] . 2.5 Administration Instructions Levofloxacin Injection Caution: Rapid or bolus intravenous infusion of levofloxacin has been associated with hypotension and must be avoided. Levofloxacin Injection should be infused intravenously slowly over a period of not less than 60 or 90 minutes, depending on the dosage. Levofloxacin Injection should be administered only by intravenous infusion. It is not for intramuscular, intrathecal, intraperitoneal, or subcutaneous administration. Hydration for Patients Receiving Levofloxacin Injection Adequate hydration of patients receiving intravenous 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 )]. 2.6 Preparation of Intravenous Product Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Because only limited data are available on the compatibility of Levofloxacin Injection with other intravenous substances, additives or other medications should not be added to Levofloxacin Injection Premix in Single-dose Flexible Containers, or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of Levofloxacin Injection with an infusion solution compatible with Levofloxacin Injection and with any other drug(s) administered via this common line. Levofloxacin Injection Premix in Single-Use Flexible Containers (5 mg per mL) Levofloxacin Injection is supplied in flexible containers within a foil overwrap. These contain a premixed, ready to use levofloxacin solution in 5% dextrose (D5W) for single-use. The 100 mL premixed flexible containers contain either 250 mg per 50 mL or 500 mg per 100 mL of levofloxacin solution. The 150 mL flexible container contains 750 mg per 150 mL of levofloxacin solution. The concentration of each container is 5 mg per mL. No further dilution of these preparations is necessary. Because the premix flexible containers are for single-use only, any unused portion should be discarded. Instructions for the Use of Levofloxacin Injection Premix in Flexible Containers: Tear outer wrap at the notch and remove solution container. Check the container for minute leaks by squeezing the inner bag firmly. If leaks are found, or if the seal is not intact, discard the solution, as the sterility may be compromised. Do not use if the solution is cloudy or a precipitate is present. Use sterile equipment. WARNING: Do not use flexible containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete. Preparation for Administration: Close flow control clamp of administration set. Remove cover from port at bottom of container. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. NOTE: See full directions on administration set carton. Suspend container from hanger. Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of Levofloxacin Injection Premix in Flexible Containers. Open flow control clamp to expel air from set. Close clamp. Regulate rate of administration with flow control clamp.

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 )

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 (≥3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness. Table 4: Common (≥ 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin a N = 7274 b N = 3758 (women) System/Organ Class Adverse Reaction % (N = 7537) Infections and Infestations moniliasis 1 Psychiatric Disorders insomnia a [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 1b 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) a 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 ( 5.13 )] hyperkalemia Psychiatric Disorders anxiety agitation confusion depression hallucination nightmare a [see Warnings and Precautions ( 5.4 )] sleep disorder a anorexia abnormal dreaming a Nervous System Disorders tremor convulsions [see Warnings and Precautions ( 5.4 )] paresthesia [see Warnings and Precautions ( 5.3 )] vertigo hypertonia hyperkinesias abnormal gait somnolence a 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. 6.3 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 ( 5.11 ) 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 ), ( 5.9 )] 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

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 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.