Levofloxacin

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 and Community Acquired ( 1.2 , 1.3 ) Skin and Skin Structure Infections (SSSI): Complicated and Uncomplicated Chronic bacterial prostatitis Inhalational Anthrax, Post-Exposure in adult and pediatric patients Plague in adult and pediatric patients Urinary Tract Infections (UTI): Complicated ( 1.9 , 1.10 ) and Uncomplicated Acute Pyelonephritis Acute Bacterial Exacerbation of Chronic Bronchitis Acute Bacterial Sinusitis 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.

1.1Nosocomial Pneumonia Levofloxacin

tablet is indicated in adult patients for the treatment of nosocomial pneumonia due to methicillin-susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, or Streptococcus pneumoniae . Adjunctive therapy should be used as clinically indicated. Where Pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with an anti-pseudomonal β-lactam is recommended .

1.2Community-Acquired Pneumonia:

7 to 14 day Treatment Regimen Levofloxacin tablet is indicated in adult patients for the treatment of community-acquired pneumonia due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant Streptococcus pneumoniae [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae . 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.

1.3Community-Acquired Pneumonia:

5-day Treatment Regimen Levofloxacin tablet is indicated in adult patients for the treatment of community-acquired pneumonia due to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae .

1.4Complicated Skin and Skin Structure Infections

Levofloxacin tablet is indicated in adult patients for the treatment of complicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, or Proteus mirabilis .

1.5Uncomplicated Skin and Skin Structure Infections

Levofloxacin tablet is indicated in adult patients for the treatment of uncomplicated skin and skin structure infections (mild to moderate) including abscesses, cellulitis, furuncles, impetigo, pyoderma, wound infections, due to methicillin-susceptible Staphylococcus aureus , or Streptococcus pyogenes .

1.6Chronic Bacterial Prostatitis Levofloxacin

tablet is indicated in adult patients for the treatment of chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or methicillin-susceptible Staphylococcus epidermidis .

1.7Inhalational Anthrax

(Post-Exposure) Levofloxacin tablet is indicated for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis in adults and pediatric patients, 6 months of age and older . The effectiveness of levofloxacin tablet is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin tablet has not been tested in humans for the post-exposure prevention of inhalation anthrax. The safety of levofloxacin tablets in adults for durations of therapy beyond 28 days or in pediatric patients for durations of therapy beyond 14 days has not been studied.

Prolonged levofloxacin tablets therapy should only be used when the benefit outweighs the risk .

1.8Plague Levofloxacin

tablet is indicated for treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis ( Y. pestis ) and prophylaxis for plague in adults and pediatric patients, 6 months of age and older . Efficacy studies of levofloxacin tablets could not be conducted in humans with plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals .

1.9Complicated Urinary Tract Infections:

5-day Treatment Regimen Levofloxacin tablet is indicated in adult patients for the treatment of complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis .

1.10Complicated Urinary Tract Infections:

10-day Treatment Regimen Levofloxacin tablet is indicated in adult patients for the treatment of complicated urinary tract infections (mild to moderate) due to Enterococcus faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa .

1.11Acute Pyelonephritis:

5 or 10-day Treatment Regimen Levofloxacin tablet is indicated in adult patients for the treatment of acute pyelonephritis caused by Escherichia coli , including cases with concurrent bacteremia .

1.12Uncomplicated Urinary Tract Infections Levofloxacin

tablet is indicated in adult patients for the treatment of uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae, or Staphylococcus saprophyticus . Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions 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.

1.13Acute Bacterial Exacerbation of Chronic Bronchitis

Levofloxacin tablet is indicated in adult patients for the treatment of acute bacterial exacerbation of chronic bronchitis (ABECB) due to methicillin-susceptible Staphylococcus aureus , Streptococcus pneumoniae , Haemophilus influenzae , Haemophilus parainfluenzae , or Moraxella catarrhalis . Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions and for some patients ABECB is self-limiting, reserve levofloxacin for treatment of ABECB in patients who have no alternative treatment options.

1.14Acute Bacterial Sinusitis:

5-day and 10 to14 day Treatment Regimens Levofloxacin tablet is indicated in adult patients for the treatment of acute bacterial sinusitis (ABS) due to Streptococcus pneumoniae , Haemophilus influenzae , or Moraxella catarrhalis . Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions and for some patients ABS is self-limiting, reserve levofloxacin for treatment of ABS in patients who have no alternative treatment options.

1.15Usage 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 . 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.

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. 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 750 mg 7 to 14 Community Acquired Pneumonia 500 mg 7 to 14 Community Acquired Pneumonia 750 mg 5 Complicated SSSI 750 mg 7 to 14 Uncomplicated SSSI 500 mg 7 to 10 Chronic Bacterial Prostatitis 500 mg 28 Inhalational Anthrax (Post-Exposure) Adults and Pediatric Patients 50 kg or greater 500 mg 60 Pediatric Patients 30 kg to less than 50 kg 250 mg every 12 hours 60 Plague Adults and Pediatric Patients 50 kg or greater 500 mg 10 to 14 Pediatric Patients 30 kg to less than 50 kg 250 mg every 12 hours 10 to 14 Complicated UTI or Acute Pyelonephritis 750 mg 5 Complicated UTI or Acute Pyelonephritis 250 mg 10 Uncomplicated UTI 250 mg 3 Acute Bacterial Exacerbation of Chronic Bronchitis 500 mg 7 Acute Bacterial Sinusitis 750 mg 5 500 mg 10 to 14 Adjust dose for creatinine clearance less than 50 mL/minute ( 2.3 , 8.6 , 12.3 )

2.1Dosage 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 . Table 1 Dosage of Levofloxacin Tablets in Adult Patients with Creatinine Clearance greater than or equal to 50 mL/minute * Due to the designated pathogens . † 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 . § Due to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae . ¶ 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 . 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 Prolonged levofloxacin tablets therapy should only be used when the benefit outweighs the risk. à Drug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis . Higher doses of levofloxacin tablet typically used for treatment of pneumonia can be used for treatment of plague, if clinically indicated. 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 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 à 500 mg see Table 2 below 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

2.2Dosage of Levofloxacin Tablets in Pediatric Patients

with Inhalational Anthrax or Plague The dosage of levofloxacin tablets for inhalational anthrax (post-exposure) and plague in pediatric patients who weigh 30 kg or greater is described below in Table 2. Levofloxacin tablets cannot be administered to patients who weigh less than 30 kg because of the limitations of the available strength. Alternative formulations of levofloxacin may be considered for pediatric patients who weigh less than 30 kg.

Table 2 Levofloxacin Tablets Dosage in Pediatric Patients Weighing 30 kg or greater with Inhalational Anthrax (Post-Exposure) and Plague* * Due to Bacillus anthracis and Yersinia pestis . † Sequential therapy (intravenous levofloxacin injection to oral levofloxacin tablets) may be instituted at the discretion of the healthcare provider. ‡ Begin levofloxacin tablets as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis . § The safety of levofloxacin tablets in pediatric patients for durations of therapy beyond 14 days has not been studied. . Begin levofloxacin tablets as soon as possible after suspected or confirmed exposure to Yersinia pestis . Type of Infection * Dose Frequency Duration † Inhalational Anthrax (post-exposure) ‡,§ Pediatric patients weighing 50 kg or greater 500 mg every 24 hours 60 days § Pediatric patients weighing 30 kg to less than 50 kg 250 mg every 12 hours 60 days § Plague ¶ Pediatric patients weighing 50 kg or greater 500 mg every 24 hours 10 to 14 days Pediatric patients weighing 30 kg to less than 50 kg 250 mg every 12 hours 10 to 14 days

2.3Dosage Adjustment in Adults with Renal Impairment

Administer levofloxacin tablets with caution in patients with renal impairment. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of levofloxacin may be reduced in these patients. In patients with renal impairment (creatinine clearance less than 50 mL/min), adjustment of the dosage regimen is necessary to avoid the accumulation of levofloxacin due to decreased clearance . No adjustment is necessary for patients with a creatinine clearance greater than or equal to 50 mL/minute.

Table 3 shows how to adjust dose based on creatinine clearance. Table 3 Dosage Adjustment in Adult Patients with Renal Impairment (Creatinine Clearance less than 50 mL/minute) Creatinine Clearance greater than or equal to 50 mL/minute Creatinine Clearance 20 to 49 mL/minute Creatinine Clearance 10 to 19 mL/minute Hemodialysis or Chronic Ambulatory Peritoneal Dialysis (CAPD) 750 mg every 24 hours 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 every 24 hours 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 every 24 hours 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

2.4Drug Interaction with Chelation Agents: Antacids,

Sucralfate, Metal Cations, Multivitamins Levofloxacin tablets should be administered at least two hours before or two hours after antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine chewable/buffered tablets or the pediatric powder for oral solution .

2.5Important Administration Instructions Levofloxacin

tablets can be administered without regard to food. If patients miss a dose, they should take it as soon as possible anytime up to 8 hours prior to their next scheduled dose. If less than 8 hours remain before the next dose, wait until their next scheduled dose.

2.6Hydration for Patients Receiving Levofloxacin Tablets

Adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of highly concentrated urine. Crystalluria and cylindruria have been reported with quinolones .

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 Hepatotoxicity: Severe, and sometimes fatal, hepatotoxicity has been reported. Discontinue immediately if signs and symptoms of hepatitis occur Clostridium difficile -associated colitis: evaluate if diarrhea occurs 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 )

5.1Disabling 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 . 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.

5.2Tendinitis and Tendon Rupture Fluoroquinolones,

including levofloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages . 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 .

5.3Peripheral 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 . Discontinue levofloxacin immediately if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation.

Avoid fluoroquinolones, including levofloxacin, in patients who have previously experienced peripheral neuropathy .

5.4Central Nervous System Effects Psychiatric

Adverse Reactions Fluoroquinolones, including levofloxacin, have been associated with an increased risk of psychiatric adverse reactions, including: toxic psychoses, hallucinations, or paranoia; depression, or suicidal thoughts; anxiety, agitation, restlessness, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; memory impairment. Attempted or completed suicide have been reported, especially in patients with a medical history of depression, or an underlying risk factor for depression. These reactions may occur following the first dose.

If these reactions occur in patients receiving levofloxacin tablets, discontinue levofloxacin tablets and institute appropriate measures. Central Nervous System Adverse Reactions Fluoroquinolones, including levofloxacin, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (including pseudotumor cerebri), tremors, and lightheadedness. As with other fluoroquinolones, levofloxacin tablets should be used with caution in patients with a known or suspected central nervous system (CNS) disorder that may predispose them to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose them to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction).

If these reactions occur in patients receiving levofloxacin tablets, discontinue levofloxacin tablets and institute appropriate measures .

5.5Exacerbation of Myasthenia Gravis Fluoroquinolones,

including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Avoid levofloxacin in patients with a known history of myasthenia gravis .

5.6Other Serious and Sometimes Fatal Adverse

Reactions Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with fluoroquinolones, including levofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome); vasculitis; arthralgia; myalgia; serum sickness; allergic pneumonitis; interstitial nephritis; acute renal insufficiency or failure; hepatitis; jaundice; acute hepatic necrosis or failure; anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.

Discontinue levofloxacin immediately at the first appearance of skin rash, jaundice, or any other sign of hypersensitivity and institute supportive measures .

5.7Hypersensitivity Reactions Serious and

occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with fluoroquinolones, including levofloxacin. These reactions often occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, acute myocardial ischemia with or without myocardial infarction, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat, or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions.

Levofloxacin should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated .

5.8Hepatotoxicity Post-marketing

reports of severe hepatotoxicity (including acute hepatitis and fatal events) have been received for patients treated with levofloxacin. No evidence of serious drug-associated hepatotoxicity was detected in clinical trials of over 7,000 patients. Severe hepatotoxicity generally occurred within 14 days of initiation of therapy and most cases occurred within 6 days.

Most cases of severe hepatotoxicity were not associated with hypersensitivity . The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. Levofloxacin should be discontinued immediately if the patient develops signs and symptoms of hepatitis .

5.9Risk of Aortic Aneurysm and Dissection Epidemiologic

studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients. The cause for the increased risk has not been identified. In patients with a known aortic aneurysm or patients who are at greater risk for aortic aneurysms, reserve levofloxacin for use only when there are no alternative antibacterial treatments available.

5.10Clostridium

difficile -Associated Diarrhea Clostridium difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including levofloxacin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated .

5.11Prolongation of the

QT Interval Some fluoroquinolones, including levofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving fluoroquinolones, including levofloxacin. Levofloxacin should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents.

Elderly patients may be more susceptible to drug-associated effects on the QT interval .

5.12Musculoskeletal Disorders in Pediatric Patients and Arthropathic

Effects in Animals Levofloxacin is indicated in pediatric patients (6 months of age and older) only for the prevention of inhalational anthrax (post-exposure) and for plague . An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormality) compared to controls has been observed in pediatric patients receiving levofloxacin . In immature rats and dogs, the oral and intravenous administration of levofloxacin resulted in increased osteochondrosis. Histopathological examination of the weight-bearing joints of immature dogs dosed with levofloxacin revealed persistent lesions of the cartilage. Other fluoroquinolones also produce similar erosions in the weight-bearing joints and other signs of arthropathy in immature animals of various species .

5.13Blood Glucose Disturbances Fluoroquinolones,

including levofloxacin, have been associated with disturbances of blood glucose, including symptomatic hyperglycemia and hypoglycemia, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. Severe cases of hypoglycaemia resulting in coma or death have been reported.

If a hypoglycemic reaction occurs in a patient being treated with levofloxacin tablets, discontinue levofloxacin tablets and initiate appropriate therapy immediately .

5.14Photosensitivity/Phototoxicity Moderate to

severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of fluoroquinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if photosensitivity/phototoxicity occurs .

5.15Development of Drug Resistant Bacteria Prescribing

levofloxacin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria .

Known hypersensitivity to levofloxacin or other quinolones ( 4 , 5.7 ) Levofloxacin tablet is contraindicated in persons with known hypersensitivity to levofloxacin, or other quinolone antibacterials .

8.1Pregnancy Risk Summary Published

information from case reports, case control studies and observational studies on levofloxacin administered during pregnancy have not identified any drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of levofloxacin to pregnant rats and rabbits during organogenesis at doses up to 9.4 times and 1.1 times the maximum recommended human dose (MRHD), respectively, did not result in teratogenicity. Fetal toxicity was seen in the rat study, but was absent at doses up to 1.2 times the maximum recommended human dose . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Levofloxacin was not teratogenic in an embryofetal development study in rats treated during organogenesis with oral doses as high as 810 mg/kg/day which corresponds to 9.4 times the MRHD (based upon doses normalized for total body surface area).

The oral dose of 810 mg/kg/day (high dose) to rats caused decreased fetal body weight and increased fetal mortality that was not seen at the next lower dose (mid-dose, 90 mg/kg/day, equivalent to 1.2 times the MRHD (based upon doses normalized for total body surface area). Maternal toxicity was limited to lower weight gain in the mid and high dose groups. No teratogenicity was observed in an embryofetal development study in rabbits dosed orally during organogenesis with doses as high as 50 mg/kg/day, which corresponds to 1.1 times the MRHD (based upon doses normalized for total body surface area).

Maternal toxicity at that dose consisted of lower weight gain and decreased food consumption relative to controls and abortion in four of sixteen dams.

8.2Lactation Risk Summary Published

literature reports that levofloxacin is present in human milk following intravenous and oral administration . There is no information regarding effects of levofloxacin on milk production or the breastfed infant. Because of the potential risks of serious adverse reactions, in breastfed infants, for most indications, a lactating woman may consider pumping and discarding breast milk during treatment with levofloxacin and an additional two days (five half-lives) after the last dose. Alternatively, advise a lactating woman that breastfeeding is not recommended during treatment with levofloxacin and for an additional two days (five half-lives) after the last dose . However, for inhalation anthrax (post exposure), during an incident resulting in exposure to anthrax, the risk-benefit assessment of continuing breastfeeding while the mother (and potentially the infant) is (are) on levofloxacin may be acceptable . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for levofloxacin and any potential adverse effects on the breastfed child from levofloxacin or from the underlying maternal condition.

Data A published literature reports that peak levofloxacin human milk concentration was 8.2 mg/L at 5 hours after dosing in a woman who received 500 mg of intravenous, followed by oral, levofloxacin daily. For an infant fed exclusively with human milk (approximately 900 ml/day), an estimated maximum daily dose of levofloxacin through breastfeeding is 5 mg (i.e., approximately 1% of maternal daily dose). The above data come from a single case and may not be generalizable to the general population of lactating women.

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 Tendinitis and Tendon Rupture Peripheral Neuropathy Central Nervous System Effects Exacerbation of Myasthenia Gravis Other Serious and Sometimes Fatal Reactions Hypersensitivity Reactions Hepatotoxicity Risk of Aortic Aneurysm and Dissection Clostridium difficile -Associated Diarrhea Prolongation of the QT Interval Musculoskeletal Disorders in Pediatric Patients Blood Glucose Disturbances Photosensitivity/Phototoxicity Development of Drug Resistant Bacteria 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 . The most common reactions (≥ 3%) were nausea, headache, diarrhea, insomnia, constipation and dizziness. To report SUSPECTED ADVERSE REACTIONS, contact Viona Pharmaceuticals Inc. at 1-888-304-5011 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trial Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to levofloxacin in 7,537 patients in 29 pooled Phase 3 clinical trials. The population studied had a mean age of 50 years (approximately 74% of the population was < 65 years of age), 50% were male, 71% were Caucasian, 19% were Black.

Patients were treated with levofloxacin for a wide variety of infectious diseases . Patients received levofloxacin doses of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. Treatment duration was usually 3 to 14 days, and the mean number of days on therapy was 10 days. The overall incidence, type and distribution of adverse reactions was similar in patients receiving levofloxacin doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily.

Discontinuation of levofloxacin due to adverse drug reactions occurred in 4.3% of patients overall, 3.8% of patients treated with the 250 mg and 500 mg doses and 5.4% of patients treated with the 750 mg dose. The most common adverse drug reactions leading to discontinuation with the 250 and 500 mg doses were gastrointestinal (1.4%), primarily nausea (0.6%); vomiting (0.4%); dizziness (0.3%); and headache (0.2%). The most common adverse drug reactions leading to discontinuation with the 750 mg dose were gastrointestinal (1.2%), primarily nausea (0.6%), vomiting (0.5%); dizziness (0.3%); and headache (0.3%).

Adverse reactions occurring in ≥ 1% of levofloxacin-treated patients and less common adverse reactions, occurring in 0.1 to < 1% of levofloxacin-treated patients, are shown in Table 4 and Table 5, respectively. The most common adverse drug reactions (≥ 3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness. Table4 Common ( ≥ 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin # * N = 7,274 † N=3,758 (women) # pool of studies included IV and oral administration System/Organ Class Adverse Reaction % (N=7,537) Infections and Infestations moniliasis 1 Psychiatric Disorders Insomnia * 4 Nervous System Disorders headache dizziness 6 3 Respiratory, Thoracic and Mediastinal Disorders dyspnea 1 Gastrointestinal Disorders nausea diarrhea constipation abdominal pain vomiting dyspepsia 7 5 3 2 2 2 Skin and Subcutaneous Tissue Disorders rash pruritus 2 1 Reproductive System and Breast Disorders vaginitis 1 † General Disorders and Administration Site Conditions edema injection site reaction chest pain 1 1 1 Table 5 Less Common (0.1 to 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin (N=7,537) * N = 7,274 System/Organ Class Adverse Reaction Infections and Infestations genital moniliasis Blood and Lymphatic System Disorders anemia thrombocytopenia granulocytopenia Immune System Disorders allergic reaction Metabolism and Nutrition Disorders hyperglycemia hypoglycemia hyperkalemia Psychiatric Disorders anxiety agitation confusion depression hallucination nightmare * sleep disorder * anorexia abnormal dreaming * Nervous System Disorders tremor convulsions paresthesia vertigo hypertonia hyperkinesias abnormal gait somnolence * syncope Respiratory, Thoracic and Mediastinal Disorders epistaxis Cardiac Disorders cardiac arrest palpitation ventricular tachycardia ventricular arrhythmia Vascular Disorders phlebitis Gastrointestinal Disorders gastritis stomatitis pancreatitis esophagitis gastroenteritis glossitis pseudomembranous/ C. difficile colitis Hepatobiliary Disorders abnormal hepatic function increased hepatic enzymes increased alkaline phosphatase Skin and Subcutaneous Tissue Disorders urticaria Musculoskeletal and Connective Tissue Disorders arthralgia tendinitis myalgia skeletal pain Renal and Urinary Disorders abnormal renal function acute renal failure 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.

6.2Postmarketing 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 eosinophilia Immune System Disorders hypersensitivity reactions, sometimes fatal including: anaphylactic/anaphylactoid reactions anaphylactic shock angioneurotic edema serum sickness Psychiatric Disorders psychosis paranoia isolated reports of suicidal ideation, suicide attempt and completed suicide Nervous System Disorders exacerbation of myasthenia gravis anosmia ageusia parosmia dysgeusia peripheral neuropathy (may be irreversible) isolated reports of encephalopathy abnormal electroencephalogram (EEG) dysphonia pseudotumor cerebri 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 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 Hepatobiliary Disorders hepatic failure (including fatal cases) hepatitis jaundice 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 photosensitivity/phototoxicity reaction leukocytoclastic vasculitis Musculoskeletal and Connective Tissue Disorders tendon rupture muscle injury, including rupture rhabdomyolysis Renal and Urinary Disorders interstitial nephritis General Disorders and Administration Site Conditions multi-organ failure pyrexia Investigations prothrombin time prolonged international normalized ratio prolonged muscle enzymes increased