LEVOFLOXACIN (levofloxacin 500 mg) Dailymed

2 Dosage And Administration

• 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 ( 2.2 ).

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 ( 1.1)	750 mg	7 to 14
Community Acquired Pneumonia ( 1.2)	500 mg	7 to 14
Community Acquired Pneumonia ( 1.3)	750 mg	5
Complicated (SSSI) ( 1.4)	750 mg	7 to 14
Type of Infection	Dose Every 24 hours	Duration (days)
Uncomplicated SSSI ( 1.5)	500 mg	7 to 10
Chronic Bacterial Prostatitis ( 1.6)	500 mg	28
Inhalational Anthrax (Post-Exposure) ( 1.7) Adults and Pediatric Patients 50 kg or greater Pediatric Patients 30 kg to less than 50 kg  ( 2.2)	500 mg 250 mg every 12 hours	60 60
Plague ( 1.8) Adults and Pediatric Patients 50 kg or greater Pediatric Patients 30 kg to less than 50 kg ( 2.2)	500 mg 250 mg every 12 hours	10 to 14 10 to 14
Complicated UTI ( 1.9) or Acute Pyelonephritis ( 1.11)	750 mg	5
Complicated UTI ( 1.10) or Acute Pyelonephritis ( 1.11)	250 mg	10
Uncomplicated UTI ( 1.12)	250 mg	3
Acute Bacterial Exacerbation of Chronic Bronchitis ( 1.13)	500 mg	7
Acute Bacterial Sinusitis ( 1.14)	750 mg	5
	500 mg	10 to 14

• Adjust dose for creatinine clearance less than 50 mL/minute ( 2.3 , 8.6 , 12.3 )

2.1 Dosage 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 [see Dosage and Administration ( 2.3)] .

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 [see Indications and Usage ( 1)] .
† 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 [see Indications and Usage ( 1.2)] .
§ Due to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Indications and Usage ( 1.3)] .
¶  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 [see Clinical Studies ( 14.9)] .
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 [see Warnings and Precautions ( 5.12), Use in Specific Populations ( 8.4), and Clinical Studies ( 14.9)]. Prolonged levofloxacin therapy should only be used when the benefit outweighs the risk.
à   Drug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis . Higher doses of levofloxacin tablets 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 to14
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 ( 2.2 )	60ß 60ß
Plague, adult and pediatric patients weighing 50 kg à or greater Pediatric patients weighing 30 kg to less than 50 kg	500 mg see Table 2 below ( 2.2 )	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

2.2 Dosage of levofloxacin tablets in Pediatric Patients with Inhalational Anthrax or Plaque

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 [see Indications and Usage ( 1.13)] and Yersinia pestis [see Indications and Usage ( 1.14)].
† 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 ( 5.12), Use in Specific Populations ( 8.4), and Clinical Studies ( 14.9)] .
¶ 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 day§
Pediatric patients weighing 30 kg to less than 50 kg	250 mg	every 12 hours	60 day§
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

2.3 Dosage 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 [see Use in Specific Populations ( 8.6)] . 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 hour	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 hour	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 hour	No dosage adjustment required	250 mg every 48 hours. If treating uncomplicated UTI, then no dosage adjustment is required	No information on dosing adjustment is available

2.4 Drug Interaction With Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins

Levofloxacin Tablets

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 [see Drug Interactions ( 7.1) and Patient Counseling Information ( 17)] .

2.5 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.

2.6 Hydration for Patients Receiving Levofloxacin Tablets

Adequate hydration of patients receiving levofloxacin tablets should be maintained to prevent the formation of highly concentrated urine. Crystalluria and cylindruria have been reported with quinolones [see Adverse Reactions ( 6.1) and Patient Counseling Information ( 17)].

• 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 tablets. 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 tablets 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 tablets 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, discontinue levofloxacin 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 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, 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)] .

5.7 Hypersensitivity 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, 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 [see Adverse Reactions ( 6) and Patient Counseling Information ( 17)] .

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 ( 5.6)] . 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 ( 6) and Patient Counseling Information ( 17)] .

5.9 Risk 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 tablets for use only when there are no alternative antibacterial treatments available.

5.10 Clostridium 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 [see Adverse Reactions ( 6.2) and Patient Counseling Information ( 17)] .

5.11 Prolongation 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 [see Adverse Reactions ( 6.3) , Use in Specific Populations ( 8.5) , and Patient Counseling Information ( 17)] .

5.12 Musculoskeletal 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 [see Indications and Usage ( 1.13, 1.14)] . An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormality) compared to controls has been observed in pediatric patients receiving levofloxacin [see Use in Specific Populations ( 8.4)] .

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 [see Animal Toxicology and/or Pharmacology ( 13.2)].

5.13 Blood 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 hypoglycemia resulting in coma or death have been reported. If a hypoglycemic reaction occurs in a patient being treated with levofloxacin, discontinue levofloxacin and initiate appropriate therapy immediately [see Adverse Reactions ( 6.2), Drug Interactions ( 7.3) and Patient Counseling Information ( 17)].

5.14 Photosensitivity/Phototoxicity

Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, bulering, 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 [see Adverse Reactions ( 6.3)  and Patient Counseling Information ( 17)] .

5.15 Development 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 [see Patient Counseling Information ( 17)] .

6 Adverse Reactions

The most common reactions (≥3%) were nausea, headache, diarrhea, insomnia, constipation and dizziness ( 6.2).

To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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)] .

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

Adverse reactions occurring in ≥1% of levofloxacin-treated patients and less common adverse reactions, occurring in 0.1 to <1% of levofloxacin-treated patients, are shown in Table 4 and Table 5, respectively. The most common adverse drug reactions (≥3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness.

Table 4: Common (≥1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin ^#

* 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)

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 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

Table 5: Less Common (0.1 to 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin (N = 7,537)

	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)]

*N = 7,274

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 uls 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 casual relationship to drug exposure.

Table 6:        Postmarketing Reports of Adverse Drug Reactions

System/Organ Class	Adverse Reaction
Blood and Lymphatic System Disorders	pancytopenia aplastic anemia leukopenia hemolytic anemia [see Warnings and Precautions ( 5.6)] eosinophilia
Immune System Disorders	hypersensitivity reactions, sometimes fatal including:     anaphylactic/anaphylactoid reactions     anaphylactic shock     angioneurotic edema     serum sickness [ see Warnings and Precautions ( 5.6) ,( 5.7)]
Psychiatric Disorders	psychosis paranoia isolated reports of suicidal ideation, suicide attempt and completed suicide  [see Warnings and Precautions ( 5.4)]
Nervous System Disorders	exacerbation of myasthenia gravis [see Warnings and Precautions ( 5.5)] anosmia ageusia parosmia dysgeusia peripheral neuropathy (may be irreversible) [see Warnings and Precautions ( 5.3)] isolated reports of encephalopathy abnormal electroencephalogram (EEG) dysphonia pseudotumor cerebri [see Warnings and Precautions ( 5.4)]
Eye Disorders	uveitis vision disturbance, including diplopia visual acuity reduced vision blurred scotoma
Ear and Labyrinth Disorders	hypoacusis tinnitus

Table 6:        Postmarketing Reports of Adverse Drug Reactions

Cardiac Disorders	isolated reports of torsade de pointes electrocardiogram QT prolonged [see Warnings and Precautions ( 5.11)] tachycardia
Vascular Disorders	vasodilatation
Respiratory, Thoracic and Mediastinal Disorders	isolated reports of allergic pneumonitis [see Warnings and Precautions ( 5.6)]
Hepatobiliary Disorders	hepatic failure (including fatal cases) hepatitis jaundice [see Warnings and Precautions ( 5.6), ( 5.8)]
Skin and Subcutaneous Tissue Disorders	bullous eruptions to include:      Stevens-Johnson Syndrome      toxic epidermal necrolysis        Acute Generalized Exanthematous Pustulosis  (AGEP)        fixed drug eruptions      erythema multiforme [see Warnings and Precautions ( 5.6)] photosensitivity/phototoxicity reaction [see Warnings and Precautions ( 5.14)] leukocytoclastic vasculitis
Musculoskeletal and Connective Tissue Disorders	tendon rupture [see Warnings and Precautions ( 5.2)] muscle injury, including rupture rhabdomyolysis
Renal and Urinary Disorders	interstitial nephritis [see Warnings and Precautions ( 5.6)]
General Disorders and Administration Site Conditions	multi-organ failure pyrexia
Investigations	prothrombin time prolonged international normalized ratio prolonged muscle enzymes increased