Levofloxacin

Levofloxacin tablets are fluoroquinolone antibacterial indicated in adults (18 years of age and older) with infections caused by designated, susceptible bacteria and in pediatric patients where indicated (

• Administer levofloxacin tablets to pediatric patients weighing 30 kg and greater only (

• Adjust dose for creatinine clearance less than 50 mL/minute (

Levofloxacin Tablets, USP

• 250 mg pink colored, capsule shaped, biconvex, film coated tablets, debossed 'T4' on one side and plain on other side
• 500 mg peach colored, capsule shaped, biconvex, film coated tablets, debossed 'T7' on one side and plain on other side
• 750 mg white colored, capsule shaped, biconvex, film coated tablets, debossed 'T5' on one side and plain on other side

• Geriatrics:
  Severe hepatotoxicity has been reported. The majority of reports describe patients 65 years of age or older (
  5.8 Hepatotoxicity

  
  
  

  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

  [see Warnings and Precautions ].

  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

  [see Adverse Reactions and Patient Counseling Information ].
  ,
  8.5 Geriatric Use

  Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as levofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing levofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue levofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur

  [see

  Boxed Warning

  ;

  Warnings and Precautions (

  5.2

  )

  ; and

  Adverse Reactions (

  6.3

  )

  ].

  
  
  

  In phase 3 clinical trials, 1,945 levofloxacin -treated patients (26%) were ≥ 65 years of age. Of these, 1,081 patients (14%) were between the ages of 65 and 74 and 864 patients (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

  Severe, and sometimes fatal, cases of hepatotoxicity have been reported post-marketing in association with levofloxacin. 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 [see

  Warnings and Precautions (

  5.8

  )

  ].
  
  Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients. [

  see Warnings and Precautions (

  5.9

  )

  ].

  Elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using levofloxacin with concomitant drugs that can result in prolongation of the QT interval (e.g., Class IA or Class III antiarrhythmics) or in patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia) [see

  Warnings and Precautions (

  5.11

  )

  ].

  
  
  

  The pharmacokinetic properties of levofloxacin in younger adults and elderly adults do not differ significantly when creatinine clearance is taken into consideration. However, since the drug is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function

  [see Clinical Pharmacology (

  12.3

  )]

  .
  ,
  17 PATIENT COUNSELING INFORMATION

  Advise the patient to read the FDA-approved patient labeling (Medication Guide).
  
  

  
  
  Serious Adverse Reactions

  
  
  

  Advise patients to stop taking levofloxacin tablets if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug.

  Inform patients of the following serious adverse reactions that have been associated with levofloxacin tablets or other fluoroquinolone use:

  • Disabling and Potentially Irreversible Serious Adverse Reactions That May Occur Together
    : Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of levofloxacin tablets and may occur together in the same patient. Inform patients to stop taking levofloxacin tablets immediately if they experience an adverse reaction and to call their healthcare provider.
  • Tendinitis and Tendon Rupture:
    Instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue levofloxacin tablets treatment. Symptoms may be irreversible. The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
  • Peripheral Neuropathies:
    Inform patients that peripheral neuropathies have been associated with levofloxacin use, symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, immediately discontinue levofloxacin tablets and tell them to contact their physician.
  • Central Nervous System Effects
    (for example, convulsions, dizziness, lightheadedness, increased intracranial pressure)
    :
    Inform patients that convulsions have been reported in patients receiving fluoroquinolones, including levofloxacin. Instruct patients to notify their physician before taking this drug if they have a history of convulsions. Inform patients that they should know how they react to levofloxacin tablets before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs.
  • Exacerbation of Myasthenia Gravis:
    Instruct patients to inform their physician of any history of myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties.
  • Hypersensitivity Reactions:
    Inform patients that levofloxacin can cause hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.
  • Hepatotoxicity:
    Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking levofloxacin tablets. Instruct patients to inform their physician if they experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light colored bowel movements or dark colored urine.
  • Aortic aneurysm and dissection:
    Inform patients to seek emergency medical care if they experience sudden chest, stomach, or back pain.
  • Diarrhea:
    Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, instruct patients to contact their physician as soon as possible.
  • Prolongation of the QT Interval:
    Instruct patients to inform their physician of any personal or family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia; if they are taking any Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Instruct patients to notify their physician if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness.
  • Musculoskeletal Disorders in Pediatric Patients:
    Instruct parents to inform their child’s physician if the child has a history of joint-related problems before taking this drug. Inform parents of pediatric patients to notify their child’s physician of any joint-related problems that occur during or following levofloxacin therapy
    [see Warnings and Precautions and Use in Specific Populations ].
  • Photosensitivity/Phototoxicity:
    Inform patients that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolones. Inform patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking fluoroquinolones. If patients need to be outdoors while using fluoroquinolones, instruct them to wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, instruct patients to contact their physician.
  • Lactation:
    Advise a lactating woman that she may pump and discard during treatment with levofloxacin and for an additional 2 days after the last dose. Alternatively, advise a lactating woman that breastfeeding is not recommended during treatment with levofloxacin and for an additional 2 days after the last dose [
    see Use in Specific Populations and Adverse Reactions ].
    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 ].
  ,
  8.5 Geriatric Use

  Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as levofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing levofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue levofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur

  [see

  Boxed Warning

  ;

  Warnings and Precautions (

  5.2

  )

  ; and

  Adverse Reactions (

  6.3

  )

  ].

  
  
  

  In phase 3 clinical trials, 1,945 levofloxacin -treated patients (26%) were ≥ 65 years of age. Of these, 1,081 patients (14%) were between the ages of 65 and 74 and 864 patients (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

  Severe, and sometimes fatal, cases of hepatotoxicity have been reported post-marketing in association with levofloxacin. 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 [see

  Warnings and Precautions (

  5.8

  )

  ].
  
  Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients. [

  see Warnings and Precautions (

  5.9

  )

  ].

  Elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using levofloxacin with concomitant drugs that can result in prolongation of the QT interval (e.g., Class IA or Class III antiarrhythmics) or in patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia) [see

  Warnings and Precautions (

  5.11

  )

  ].

  
  
  

  The pharmacokinetic properties of levofloxacin in younger adults and elderly adults do not differ significantly when creatinine clearance is taken into consideration. However, since the drug is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function

  [see Clinical Pharmacology (

  12.3

  )]

  .
  ,
  17 PATIENT COUNSELING INFORMATION

  Advise the patient to read the FDA-approved patient labeling (Medication Guide).
  
  

  
  
  Serious Adverse Reactions

  
  
  

  Advise patients to stop taking levofloxacin tablets if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug.

  Inform patients of the following serious adverse reactions that have been associated with levofloxacin tablets or other fluoroquinolone use:

  • Disabling and Potentially Irreversible Serious Adverse Reactions That May Occur Together
    : Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of levofloxacin tablets and may occur together in the same patient. Inform patients to stop taking levofloxacin tablets immediately if they experience an adverse reaction and to call their healthcare provider.
  • Tendinitis and Tendon Rupture:
    Instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue levofloxacin tablets treatment. Symptoms may be irreversible. The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
  • Peripheral Neuropathies:
    Inform patients that peripheral neuropathies have been associated with levofloxacin use, symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, immediately discontinue levofloxacin tablets and tell them to contact their physician.
  • Central Nervous System Effects
    (for example, convulsions, dizziness, lightheadedness, increased intracranial pressure)
    :
    Inform patients that convulsions have been reported in patients receiving fluoroquinolones, including levofloxacin. Instruct patients to notify their physician before taking this drug if they have a history of convulsions. Inform patients that they should know how they react to levofloxacin tablets before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs.
  • Exacerbation of Myasthenia Gravis:
    Instruct patients to inform their physician of any history of myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties.
  • Hypersensitivity Reactions:
    Inform patients that levofloxacin can cause hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.
  • Hepatotoxicity:
    Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking levofloxacin tablets. Instruct patients to inform their physician if they experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light colored bowel movements or dark colored urine.
  • Aortic aneurysm and dissection:
    Inform patients to seek emergency medical care if they experience sudden chest, stomach, or back pain.
  • Diarrhea:
    Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, instruct patients to contact their physician as soon as possible.
  • Prolongation of the QT Interval:
    Instruct patients to inform their physician of any personal or family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia; if they are taking any Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Instruct patients to notify their physician if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness.
  • Musculoskeletal Disorders in Pediatric Patients:
    Instruct parents to inform their child’s physician if the child has a history of joint-related problems before taking this drug. Inform parents of pediatric patients to notify their child’s physician of any joint-related problems that occur during or following levofloxacin therapy
    [see Warnings and Precautions and Use in Specific Populations ].
  • Photosensitivity/Phototoxicity:
    Inform patients that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolones. Inform patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking fluoroquinolones. If patients need to be outdoors while using fluoroquinolones, instruct them to wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, instruct patients to contact their physician.
  • Lactation:
    Advise a lactating woman that she may pump and discard during treatment with levofloxacin and for an additional 2 days after the last dose. Alternatively, advise a lactating woman that breastfeeding is not recommended during treatment with levofloxacin and for an additional 2 days after the last dose [
    see Use in Specific Populations and Patient Counseling Information ].
  ,
  8.5 Geriatric Use

  Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as levofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing levofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue levofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur

  [see

  Boxed Warning

  ;

  Warnings and Precautions (

  5.2

  )

  ; and

  Adverse Reactions (

  6.3

  )

  ].

  
  
  

  In phase 3 clinical trials, 1,945 levofloxacin -treated patients (26%) were ≥ 65 years of age. Of these, 1,081 patients (14%) were between the ages of 65 and 74 and 864 patients (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

  Severe, and sometimes fatal, cases of hepatotoxicity have been reported post-marketing in association with levofloxacin. 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 [see

  Warnings and Precautions (

  5.8

  )

  ].
  
  Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients. [

  see Warnings and Precautions (

  5.9

  )

  ].

  Elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using levofloxacin with concomitant drugs that can result in prolongation of the QT interval (e.g., Class IA or Class III antiarrhythmics) or in patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia) [see

  Warnings and Precautions (

  5.11

  )

  ].

  
  
  

  The pharmacokinetic properties of levofloxacin in younger adults and elderly adults do not differ significantly when creatinine clearance is taken into consideration. However, since the drug is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function

  [see Clinical Pharmacology (

  12.3

  )]

  .
  ,
  17 PATIENT COUNSELING INFORMATION

  Advise the patient to read the FDA-approved patient labeling (Medication Guide).
  
  

  
  
  Serious Adverse Reactions

  
  
  

  Advise patients to stop taking levofloxacin tablets if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug.

  Inform patients of the following serious adverse reactions that have been associated with levofloxacin tablets or other fluoroquinolone use:

  • Disabling and Potentially Irreversible Serious Adverse Reactions That May Occur Together
    : Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of levofloxacin tablets and may occur together in the same patient. Inform patients to stop taking levofloxacin tablets immediately if they experience an adverse reaction and to call their healthcare provider.
  • Tendinitis and Tendon Rupture:
    Instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue levofloxacin tablets treatment. Symptoms may be irreversible. The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
  • Peripheral Neuropathies:
    Inform patients that peripheral neuropathies have been associated with levofloxacin use, symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, immediately discontinue levofloxacin tablets and tell them to contact their physician.
  • Central Nervous System Effects
    (for example, convulsions, dizziness, lightheadedness, increased intracranial pressure)
    :
    Inform patients that convulsions have been reported in patients receiving fluoroquinolones, including levofloxacin. Instruct patients to notify their physician before taking this drug if they have a history of convulsions. Inform patients that they should know how they react to levofloxacin tablets before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs.
  • Exacerbation of Myasthenia Gravis:
    Instruct patients to inform their physician of any history of myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties.
  • Hypersensitivity Reactions:
    Inform patients that levofloxacin can cause hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.
  • Hepatotoxicity:
    Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking levofloxacin tablets. Instruct patients to inform their physician if they experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light colored bowel movements or dark colored urine.
  • Aortic aneurysm and dissection:
    Inform patients to seek emergency medical care if they experience sudden chest, stomach, or back pain.
  • Diarrhea:
    Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, instruct patients to contact their physician as soon as possible.
  • Prolongation of the QT Interval:
    Instruct patients to inform their physician of any personal or family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia; if they are taking any Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Instruct patients to notify their physician if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness.
  • Musculoskeletal Disorders in Pediatric Patients:
    Instruct parents to inform their child’s physician if the child has a history of joint-related problems before taking this drug. Inform parents of pediatric patients to notify their child’s physician of any joint-related problems that occur during or following levofloxacin therapy
    [see Warnings and Precautions and Use in Specific Populations ].
  • Photosensitivity/Phototoxicity:
    Inform patients that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolones. Inform patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking fluoroquinolones. If patients need to be outdoors while using fluoroquinolones, instruct them to wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, instruct patients to contact their physician.
  • Lactation:
    Advise a lactating woman that she may pump and discard during treatment with levofloxacin and for an additional 2 days after the last dose. Alternatively, advise a lactating woman that breastfeeding is not recommended during treatment with levofloxacin and for an additional 2 days after the last dose [
    see Use in Specific Populations , Use in Specific Populations , and Patient Counseling Information
    ].
    
    
    
    
    
  ,
  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 ].

  In immature dogs (4–5 months old), oral doses of 10 mg/kg/day for 7 days and intravenous doses of 4 mg/kg/day for 14 days of levofloxacin resulted in arthropathic lesions. Administration at oral doses of 300 mg/kg/day for 7 days and intravenous doses of 60 mg/kg/day for 4 weeks produced arthropathy in juvenile rats. Three-month old beagle dogs dosed orally with levofloxacin at 40 mg/kg/day exhibited clinically severe arthrotoxicity resulting in the termination of dosing at Day 8 of a 14-day dosing routine (dosing was terminated in the low and mid-dose groups on Day 9 due to similar findings at the mid-dose). Slight musculoskeletal clinical effects, in the absence of gross pathological or histopathological effects, resulted from the lowest dose level of 2.5 mg/kg/day (approximately 0.2-fold the pediatric dose based upon AUC comparisons). Synovitis and articular cartilage lesions were observed at the 10 and 40 mg/kg dose levels (approximately 0.7-fold and 2.4-fold the pediatric dose, respectively, based on AUC comparisons). Articular cartilage gross pathology and histopathology persisted to the end of the 18-week recovery period for those dogs from the 10 and 40 mg/kg/day dose levels. The low and mid-dose groups in that study were also evaluated by electron microscopy, revealing compound-related ultrastructural effects in articular cartilage chondrocytes at the end of treatment and at the end of recovery in both of those doses.
  
  
  
  When tested in a mouse ear swelling bioassay, levofloxacin exhibited phototoxicity similar in magnitude to ofloxacin, but less phototoxicity than other quinolones.
  
  
  
  While crystalluria has been observed in some intravenous rat studies, urinary crystals are not formed in the bladder, being present only after micturition and are not associated with nephrotoxicity.
  
  
  
  In mice, the CNS stimulatory effect of quinolones is enhanced by concomitant administration of non-steroidal anti-inflammatory drugs.
  
  
  
  In dogs, levofloxacin administered at 6 mg/kg or higher by rapid intravenous injection produced hypotensive effects. These effects were considered to be related to histamine release.

  
  
  
  
  In vitro

  and

  in vivo

  studies in animals indicate that levofloxacin is neither an enzyme inducer nor inhibitor in the human therapeutic plasma concentration range; therefore, no drug metabolizing enzyme-related interactions with other drugs or agents are anticipated.
  ). Safety in pediatric patients treated for more than 14 days has not been studied. Risk-benefit appropriate only for the treatment of inhalational anthrax (postexposure) (
  1.7 Inhalational Anthrax (Post-Exposure)

  Levofloxacin tablets are 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 ]. .

  The effectiveness of levofloxacin tablets are based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin tablets 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 ].

  
  
  
  ,
  2.2 Dosage 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*

  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 50kg	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

  
  
  

  * Due to Bacillus anthracis [see

  Indications and Usage ]

  and Yersinia pestis [see

  Indications and Usage

  ].
  
  
  
  † 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. [see

  Warnings and Precautions , Use in Specific Populations , and Clinical Studies

  ]. Begin levofloxacin tablets as soon as possible after suspected or confirmed exposure to Yersinia pestis.
  ,
  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 and Dosage and Administration ].

  Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. The mean (± SD) steady state peak plasma concentration in human adults receiving 500 mg orally or intravenously once daily is 5.7 ± 1.4 and 6.4 ± 0.8 mcg/mL, respectively; and the corresponding total plasma exposure (AUC_0-24) is 47.5 ± 6.7 and 54.6 ± 11.1 mcg.h/mL, respectively. The predicted steady-state pharmacokinetic parameters in pediatric patients ranging in age from 6 months to 17 years receiving 8 mg/kg orally every 12 hours (not to exceed 250 mg per dose) were calculated to be comparable to those observed in adults receiving 500 mg orally once daily [

  see Clinical Pharmacology

  ]. Levofloxacin tablets can only be administered to pediatric patients with inhalational anthrax (post-exposure) or plague who are 30 kg or greater due to the limitations of the available strengths [see

  Dosage and Administration (

  2.2 )].

  
  
  

  In adults, the safety of levofloxacin for treatment durations of up to 28 days is well characterized. However, information pertaining to extended use at 500 mg daily up to 60 days is limited. Prolonged levofloxacin therapy in adults should only be used when the benefit outweighs the risk.

  In pediatric patients, the safety of levofloxacin for treatment durations of more than 14 days has not been studied. An increased incidence of musculoskeletal adverse events (arthralgia, arthritis, tendinopathy, gait abnormality) compared to controls has been observed in clinical studies with treatment duration of up to 14 days. Long-term safety data, including effects on cartilage, following the administration of levofloxacin to pediatric patients is limited [

  see Warnings and Precautions (

  5.12

  ) and Use in Specific Populations (

  8.4

  )

  ].

  
  
  

  A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 49 LD₅₀(~2.7 X 10⁶) spores (range 17 - 118 LD₅₀) of

  B. anthracis

  (Ames strain) was conducted. The minimal inhibitory concentration (MIC) of levofloxacin for the anthrax strain used in this study was 0.125 mcg/mL. In the animals studied, mean plasma concentrations of levofloxacin achieved at expected T_max(1 hour post dose) following oral dosing to steady state ranged from 2.79 to 4.87 mcg/mL. Steady state trough concentrations at 24 hours post-dose ranged from 0.107 to 0.164 mcg/mL. Mean (SD) steady state AUC_0-24was 33.4 ± 3.2 mcg.h/mL (range 30.4 to 36.0 mcg.h/mL). Mortality due to anthrax for animals that received a 30 day regimen of oral levofloxacin beginning 24 hrs post exposure was significantly lower (1/10), compared to the placebo group (9/10) [P=0.0011, 2-sided Fisher's Exact Test]. The one levofloxacin treated animal that died of anthrax did so following the 30-day drug administration period.
  ) and plague (
  1.8 Plague

  
  
  

  Levofloxacin tablets are 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

  ].  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

  ].
  ,
  2.2 Dosage 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*

  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 50kg	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

  
  
  

  * Due to Bacillus anthracis [see

  Indications and Usage ]

  and Yersinia pestis [see

  Indications and Usage

  ].
  
  
  
  † 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. [see

  Warnings and Precautions , Use in Specific Populations , and Clinical Studies

  ]. Begin levofloxacin tablets as soon as possible after suspected or confirmed exposure to Yersinia pestis.
  ,
  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 and Dosage and Administration , ]

  .
  
  Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. The mean (± SD) steady state peak plasma concentration in human adults receiving 500 mg orally or intravenously once daily is 5.7 ± 1.4 and 6.4 ± 0.8 mcg/mL, respectively; and the corresponding total plasma exposure (AUC_0-24) is 47.5 ± 6.7 and 54.6 ± 11.1 mcg.h/mL, respectively. The predicted steady-state pharmacokinetic parameters in pediatric patients ranging in age from 6 months to 17 years receiving 8 mg/kg orally every 12 hours (not to exceed 250 mg per dose) were calculated to be comparable to those observed in adults receiving 500 mg orally once daily [

  see Clinical Pharmacology ]

  . Levofloxacin Tablets can only be administered to pediatric patients with inhalational anthrax (post-exposure) or plague who are 30 kg or greater due to the limitations of the available strengths [see

  Dosage and Administration (

  2.2) ].

  
  
  
  
  A placebo-controlled animal study in African green monkeys exposed to an inhaled mean dose of 65 LD₅₀(range 3 to 145 LD₅₀) of

  Yersinia pestis

  (CO92 strain) was conducted. The minimal inhibitory concentration (MIC) of levofloxacin for the

  Y. pestis

  strain used in this study was 0.03 mcg/mL. Mean plasma concentrations of levofloxacin achieved at the end of a single 30-min infusion ranged from 2.84 to 3.50 mcg/mL in African green monkeys. Trough concentrations at 24 hours post-dose ranged from <0.03 to 0.06 mcg/mL. Mean (SD) AUC_0-24was 11.9 (3.1) mcg.h/mL (range 9.50 to 16.86 mcg.h/mL). Animals were randomized to receive either a 10-day regimen of i.v. levofloxacin or placebo beginning within 6 hrs of the onset of telemetered fever (≥ 39^oC for more than 1 hour). Mortality in the levofloxacin group was significantly lower (1/17) compared to the placebo group (7/7) [p<0.001, Fisher's Exact Test; exact 95% confidence interval (-99.9%, -55.5%) for the difference in mortality]. One levofloxacin-treated animal was euthanized on Day 9 post-exposure to

  Y. pestis

  due to a gastric complication; it had a blood culture positive for

  Y. pestis

  on Day 3 and all subsequent daily blood cultures from Day 4 through Day 7 were negative.
  )
• 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.