Llevofloxacin

Levofloxacin is a fluoroquinolone antibacterial indicated in adults (18 years of age and older) with infections caused by designated, susceptible bacteria and in pediatric patients where indicated ( 1 , 12.4 ). Pneumonia: Nosocomial ( 1.1 ) and Community Acquired ( 1.2 , 1.3 ) Skin and Skin Structure Infections (SSSI): Complicated ( 1.4 ) and Uncomplicated ( 1.5 ) Chronic bacterial prostatitis ( 1.6 ) Inhalational Anthrax, Post-Exposure in adult and pediatric patients ( 1.7 ) Plague in adult and pediatric patients ( 1.8 ) Urinary Tract Infections (UTI): Complicated ( 1.9 , 1.10 ) and Uncomplicated ( 1.12 ) Acute Pyelonephritis ( 1.11 ) Acute Bacterial Exacerbation of Chronic Bronchitis ( 1.13 ) Acute Bacterial Sinusitis ( 1.14 ) Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of levofloxacin and other antibacterial drugs, levofloxacin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria ( 1.15 ).

1.1 Nosocomial Pneumonia Levofloxacin 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 [see Clinical Studies ( 14.1 )] .

1.2 Community-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 [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 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 [see Dosage and Administration ( 2.1 ) and Clinical Studies ( 14.3 )].

1.4 Complicated 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 [see Clinical Studies ( 14.5 )].

1.5 Uncomplicated 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 .

1.6 Chronic 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 [see Clinical Studies ( 14.6 )].

1.7 Inhalational 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 [see Dosage and Administration ( 2.2 )]. 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 [see Clinical Studies ( 14.9 )].

1.8 Plague 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 [ see Dosage and Administration ( 2.2 ) ]. 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 [ see Clinical Studies ( 14.10 ) ].

1.9 Complicated 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 [see Clinical Studies ( 14.7 )].

1.10 Complicated 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 [see Clinical Studies ( 14.8 )] .

1.11 Acute 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 [see Clinical Studies ( 14.7 , 14.8 )] .

1.12 Uncomplicated 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 [see Warnings and Precautions ( 5 )] 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 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 [see Warnings and Precautions ( 5 )] 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 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 [see Clinical Studies ( 14.4 )] . Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions ( 5 )] and for some patients ABS is self-limiting, reserve levofloxacin for treatment of ABS in patients who have no alternative treatment options. […]

Formulation ( 3 ) Strength Tablets 250 mg, 500 mg, and 750 mg Levofloxacin tablets, USP are white to off white, modified capsule-shaped, biconvex and film-coated 250 mg tablets, debossed with logo of ‘ZC55’ on one side and plain on other side 500 mg tablets, debossed with logo of ‘ZC56’ on one side and plain on other side 750 mg tablets, debossed with logo of ‘ZC57’ on one side and plain on other side

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 [see Warnings and Precautions ( 5.3 )].

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 ( 5.8 ) Clostridium difficile -associated colitis: evaluate if diarrhea occurs ( 5.10 ) Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs that prolong the QT interval ( 5.11 , 8.5 )

5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting levofloxacin. Patients of any age or without pre-existing risk factors have experienced these adverse reactions [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 )] . Discontinue levofloxacin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including levofloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

5.2 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 ) and Patient Counseling Information ( 17 )] .

5.3 Peripheral Neuropathy Fluoroquinolones, including levofloxacin, have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including levofloxacin. Symptoms may occur soon after initiation of levofloxacin and may be irreversible in some patients [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 , 6.2 )] . 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 [see Adverse Reactions ( 6 ) and Patient Counseling Information ( 17 )] .

5.4 Central 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 [see Adverse Reactions ( 6 ), Drug Interactions ( 7.4 , 7.5 ), and Patient Counseling Information ( 17 )] .

5.5 Exacerbation 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 [see Adverse Reactions ( 6.3 ) and Patient Counseling Information ( 17 )].

5.6 Other 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 [see Adverse Reactions ( 6 ) and Patient Counseling Information ( 17 )] . […]

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: Disabling and Potentially Irreversible Serious Adverse Reactions [see Warnings and Precautions ( 5.1 )] Tendinitis and Tendon Rupture [see Warnings and Precautions ( 5.2 )] Peripheral Neuropathy [see Warnings and Precautions ( 5.3 )] Central Nervous System Effects [see Warnings and Precautions ( 5.4 )] Exacerbation of Myasthenia Gravis [see Warnings and Precautions ( 5.5 )] Other Serious and Sometimes Fatal Reactions [see Warnings and Precautions ( 5.6 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] Hepatotoxicity [see Warnings and Precautions ( 5.8 )] Risk of Aortic Aneurysm and Dissection [see Warnings and Precautions ( 5.9 )] Clostridium difficile -Associated Diarrhea [see Warnings and Precautions ( 5.10 )] Prolongation of the QT Interval [see Warnings and Precautions ( 5.11 )] Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions ( 5.12 )] Blood Glucose Disturbances [see Warnings and Precautions ( 5.13 )] Photosensitivity/Phototoxicity [see Warnings and Precautions ( 5.14 )] Development of Drug Resistant Bacteria [see Warnings and Precautions ( 5.15 )] Crystalluria and cylindruria have been reported with quinolones, including levofloxacin. Therefore, adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of a highly concentrated urine [see Dosage and Administration ( 2.5 )]. The most common reactions (≥ 3%) were nausea, headache, diarrhea, insomnia, constipation and dizziness ( 6.2 ). 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.

6.1 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 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 [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. 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 * [see Warnings and Precautions ( 5.4 )] 4 Nervous System Disorders headache dizziness [see Warnings and Precautions ( 5.4 )] 6 3 Respiratory, Thoracic and Mediastinal Disorders dyspnea [see Warnings and Precautions ( 5.7 )] 1 Gastrointestinal Disorders nausea diarrhea constipation abdominal pain vomiting dyspepsia 7 5 3 2 2 2 Skin and Subcutaneous Tissue Disorders rash [see Warnings and Precautions ( 5.7 )] pruritus 2 1 Reproductive System and Breast Disorders vaginitis 1 † General Disorders and Administration Site Conditions edema injection site reaction chest pain 1 1 1 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 [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 * [see Warnings and Precautions ( 5.4 )] sleep disorder * anorexia abnormal dreaming * Nervous System Disorders tremor convulsions [see Warnings and Precautions ( 5.4 )] paresthesia [see Warnings and Precautions ( 5.3 )] 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 [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.

6.2 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. […]

Interacting Drug Interaction Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablets are taken within 2 hours of these products. ( 2.4 , 7.1 ) Warfarin Effect may be enhanced. Monitor prothrombin time, INR and watch for bleeding ( 7.2 ) Antidiabetic agents Carefully monitor blood glucose ( 5.13 , 7.3 )

7.1 Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins While the chelation by divalent cations is less marked than with other fluoroquinolones, concurrent administration of levofloxacin tablets with antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc may interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired. Tablets with antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamins preparations with zinc or didanosine may substantially interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired. These agents should be taken at least two hours before or two hours after oral levofloxacin administration.

7.2 Warfarin No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for R- and S- warfarin was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of warfarin on levofloxacin absorption and disposition was observed. However, there have been reports during the post-marketing experience in patients that levofloxacin enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent warfarin and levofloxacin use have been associated with episodes of bleeding. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if levofloxacin is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Adverse Reactions ( 6.3 ) and Patient Counseling Information ( 17 )].

7.3 Antidiabetic Agents Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with fluoroquinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered [see Warnings and Precautions ( 5.13 ), Adverse Reactions ( 6.2 ) and Patient Counseling Information ( 17 )].

7.4 Non-Steroidal Anti-Inflammatory Drugs The concomitant administration of a non-steroidal anti-inflammatory drug with a fluoroquinolone, including levofloxacin, may increase the risk of CNS stimulation and convulsive seizures [see Warnings and Precautions ( 5.4 )].

7.5 Theophylline No significant effect of levofloxacin on the plasma concentrations, AUC, and other disposition parameters for theophylline was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of theophylline on levofloxacin absorption and disposition was observed. However, concomitant administration of other fluoroquinolones with theophylline has resulted in prolonged elimination half-life, elevated serum theophylline levels, and a subsequent increase in the risk of theophylline-related adverse reactions in the patient population. Therefore, theophylline levels should be closely monitored and appropriate dosage adjustments made when levofloxacin is co-administered. Adverse reactions, including seizures, may occur with or without an elevation in serum theophylline levels [see Warnings and Precautions ( 5.4 )].

7.6 Cyclosporine No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for cyclosporine was detected in a clinical study involving healthy volunteers. However, elevated serum levels of cyclosporine have been reported in the patient population when co-administered with some other fluoroquinolones. Levofloxacin C max and k e were slightly lower while T max and 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.

Geriatrics: Severe hepatotoxicity has been reported. The majority of reports describe patients 65 years of age or older ( 5.8 , 8.5 , 17 ). May have increased risk of tendinopathy (including rupture), especially with concomitant corticosteroid use ( 5.2 , 8.5 , 17 ). May be more susceptible to prolongation of the QT interval. ( 5.11 , 8.5 , 17 ). Pediatrics: Musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormality) seen in more levofloxacin-treated patients than in comparator. Shown to cause arthropathy and osteochondrosis in juvenile animals ( 5.12 , 8.4 , 13.2 ). Safety in pediatric patients treated for more than 14 days has not been studied. Risk-benefit appropriate only for the treatment of inhalational anthrax (post-exposure) ( 1.7 , 2.2 , 8.4 , 14.9 ) and plague ( 1.8 , 2.2 , 8.4 , 14.10 ) Lactation : Breastfeeding is not recommended during treatment, but a lactating woman may pump and discard breastmilk during treatment and an additional 2 days after the last dose. In patients treated for inhalational anthrax (post exposure), consider the risks and benefits of continuing breastfeeding.

8.1 Pregnancy 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 (see Data). 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.

8.2 Lactation Risk Summary Published literature reports that levofloxacin is present in human milk following intravenous and oral administration (see Data). 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 [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)] . 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 [see Dosage and Administration (2.2), Pediatric Use (8.4), and Clinical Studies (14.2)]. 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.

8.4 Pediatric Use Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species [see Warnings and Precautions ( 5.12 ) and Animal Toxicology and/or Pharmacology ( 13.2 )] . Inhalational Anthrax (Post-Exposure) Levofloxacin is indicated in pediatric patients 6 months of age and older, for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate. The safety of levofloxacin in pediatric patients treated for more than 14 days has not been studied [see Indications and Usage ( 1.7 ) , Dosage and Administration ( 2.2 ) and Clinical Studies ( 14.9 )] . Plague Levofloxacin is indicated in pediatric patients, 6 months of age and older, for treatment of plague, including pneumonic and septicemic plague due to Yersinia pestis ( Y. pestis ) and prophylaxis for plague. Efficacy studies of levofloxacin could not be conducted in humans with pneumonic plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals. The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate [see Indications and Usage (1.8), Dosage and Administration ( 2.2 ) and Clinical Studies ( 14.10 )]. Safety and effectiveness of levofloxacin in pediatric patients below the age of six months have not been established. Pharmacokinetics following Intravenous Administration The pharmacokinetics of levofloxacin following a single intravenous dose were investigated in pediatric patients ranging in age from six months to 16 years. Pediatric patients cleared levofloxacin faster than adult patients resulting in lower plasma exposures than adults for a given mg/kg dose [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.9 )] . Dosage in Pediatric Patients with Inhalational Anthrax or Plague For the recommended levofloxacin tablet dosage in pediatric patients with inhalational anthrax or plague [see Dosage and Administration ( 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. Adverse Reactions In clinical trials, 1,534 pediatric patients (6 months to 16 years of age) were treated with oral and intravenous levofloxacin. Pediatric patients 6 months to 5 years of age received levofloxacin 10 mg/kg twice a day and pediatric patients greater than 5 years of age received 10 mg/kg once a day (maximum 500 mg per day) for approximately 10 days. […]

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