Levofloxacin (levofloxacin 750 mg) Dailymed

2 Dosage & 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 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 50mL/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)

Type of Infection*	Dosed Every 24 hours	Duration (days) †
Nosocomial Pneumonia	750 mg	7 to 14
Community Acquired Pneumonia ‡	500 mg ‡	7 to 14 ‡
Community Acquired Pneumonia §	750 mg §	5 §
Complicated Skin and Skin Structure Infections (SSSI)	750 mg	7 to 14
Uncomplicated SSSI	500 mg	7 to 10
Chronic Bacterial Prostatitis	500 mg	28
Inhalational Anthrax (Post-Exposure), adult and pediatric patients weighing 50 kg Þ,ß or greater Pediatric patients weighing 30 kg to less than 50 kg Þ,ß	500 mg   see Table 2 below (2.2)	60 ß   60 ß
Plague, adult and pediatric patients weighing 50 kg à or greater Pediatric patients weighing 30 kg to less than 50 kg	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

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

à  Drug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis. Higher doses of levofloxacin tablets typically used for treatment of pneumonia can be used for treatment of plague, if clinically indicated.

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 ( 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.

2.3 Dosage Adjustment in Adults with Renal Impairment

Administer levofloxacin 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 50mL/minute Table 3 shows how to adjust dose based on creatinine clearance. Table 3: Dosage Adjustment in Adult Patients with Renal Impairment (Creatinine Clearance  less than 50 mL/minute)   

Creatinine Clearance greater than or equal to 50 mL/ minute	Creatinine Clearance 20 to 49 mL/minute	Creatinine Clearance 10 to 19 mL/minute	Hemodialysis or Chronic Ambulatory Peritoneal Dialysis (CAPD)
750 mg every 24 hours	750 mg every 48 hours	750 mg initial dose, then 500 mg every 48 hours	750 mg initial dose,  then 500 mg every 48 hours
500 mg every 24 hours	500 mg initial dose, then 250 mg every 24 hours	500 mg initial dose, then 250 mg every 48 hours	500 mg initial dose,  then 250 mg every 48 hours
250 mg every 24 hours	No dosage adjustment required	250 mg every 48 hours. If treating uncomplicated UTI, then no dosage adjustment is required	No information on dosing adjustment is available

  

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

Levofloxacin Tablets should be administered at least two hours before or two hours after antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine chewable/buffered tablets or the pediatric powder for oral solution [see Drug Interactions ( 7.1) and Patient Counseling Information ( 17)] .

2.5 Important Administration Instructions

Levofloxacin 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 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. 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 <sup>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)].</sup>

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

5.10 - 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)].

5.11Prolongation of the QT Interval

Some fluoroquinolones, including levofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving fluoroquinolones, including levofloxacin. Levofloxacin should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval [ 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 ( 1.7, 1.8) ]. 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 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 Macleods Pharma USA, Inc., at 1-888-943-3210 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 7537 patients in 29 pooled Phase 3 clinical trials. The population studied had a mean age of 50 years (approximately 74% of the population was < 65 years of age), 50% were male, 71% were Caucasian, 19% were Black. Patients were treated with levofloxacin for a wide variety of infectious diseases [see Indications and Usage ( 1)]. Patients received levofloxacin doses of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. Treatment duration was usually 3–14 days, and the mean number of days on therapy was 10 days. The overall incidence, type and distribution of adverse reactions was similar in patients receiving levofloxacin doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation of levofloxacin due to adverse drug reactions occurred in 4.3% of patients overall, 3.8% of patients treated with the 250 mg and 500 mg doses and 5.4% of patients treated with the 750 mg dose. The most common adverse drug reactions leading to discontinuation with the 250 and 500 mg doses were gastrointestinal (1.4%), primarily nausea (0.6%); vomiting (0.4%); dizziness (0.3%); and headache (0.2%). The most common adverse drug reactions leading to discontinuation with the 750 mg dose were gastrointestinal (1.2%), primarily nausea (0.6%), vomiting (0.5%); dizziness (0.3%); and headache (0.3%). Adverse reactions occurring in ≥1% of levofloxacin -treated patients and less common adverse reactions, occurring in 0.1 to <1% of levofloxacin -treated patients, are shown in Table 4 and Table 5, respectively. The most common adverse drug reactions (≥3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness.

Table 4: Common (≥1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin# System/Organ ClassSystem/Organ Class Adverse ReactionAdverse Reaction % (N=7537)% (N=7537) System/Organ Class Adverse Reaction % (N=7537) Infections and Infestations moniliasis 1 Psychiatric Disorders insomnia 1 [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 2 General Disorders and Administration Site Conditions edema injection site reaction chest pain 1 1 1

# pool of studies included IV and oral administration

Table 5: Less Common (0.1 to 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin (N=7537) System/Organ ClassSystem/Organ Class Adverse ReactionAdverse Reaction 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 1 [see Warnings and Precautions ( 5.4) ] sleep disorder 1 anorexia abnormal dreaming 1 Nervous System Disorders tremor convulsions [see Warnings and Precautions ( 5.4) ] paresthesia [ see Warnings and Precautions ( 5.3 )] vertigo hypertonia hyperkinesias abnormal gait somnolence 1 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 pseudomembraneous/ 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=7274

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.

1 - N=7274 2 - N=3758 (women)

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 causal relationship to drug exposure. Table 6: Postmarketing Reports Of Adverse Drug Reactions

System/Organ ClassSystem/Organ Class	Adverse ReactionAdverse Reaction
System/Organ Class	Adverse Reaction
Blood and Lymphatic System Disorders	pancytopenia aplastic anemia leukopenia hemolytic anemia [see Warnings and Precautions ( 5.6) ] eosinophilia
Immune System Disorders	hypersensitivity reactions, sometimes fatal including:   anaphylactic/anaphylactoid reactions   anaphylactic shock   angioneurotic edema   serum sickness [see Warnings and Precautions ( 5.6, 5.7 ) ]
Psychiatric Disorders	psychosis paranoia isolated reports of suicidal ideation, suicide attempt and completed suicide [see Warnings and Precautions ( 5.4 ) ]
Nervous System Disorders	exacerbation of myasthenia gravis [see Warnings and Precautions ( 5.5 ) ] anosmia ageusia parosmia dysgeusia peripheral neuropathy  (may be irreversible) [see Warnings and Precautions ( 5.3 ) ] isolated reports of encephalopathy abnormal electroencephalogram (EEG) dysphonia pseudotumor cerebri [see Warnings and Precautions ( 5.4 ) ]
Eye Disorders	uveitis vision disturbance, including diplopia visual acuity reduced vision blurred scotoma
Ear and Labyrinth Disorders	hypoacusis tinnitus
Cardiac Disorders	isolated reports of torsade de pointes electrocardiogram QT prolonged [see Warnings and Precautions ( 5.11 ) ] tachycardia
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

7 Drug Interactions

Interacting Drug Interacting Drug	Interaction Interaction
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 multivitamin 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 postmarketing experience in patients that levofloxacin enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent warfarin and levofloxacin use have been associated with episodes of bleeding. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if levofloxacin is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Adverse Reactions ( 6.3) 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.

8 Use In Specific Populations

• 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 (postexposure) ( 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 2-4% and 15-20%, 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 )]

I nhalational 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 ) andClinical 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 tablets 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, 1534 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 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 subset of pediatric patients in the clinical trials (1340 levofloxacin-treated and 893 non-fluoroquinolone-treated) enrolled in a prospective, long-term surveillance study to assess the incidence of protocol-defined musculoskeletal disorders (arthralgia, arthritis, tendinopathy, gait abnormality) during 60 days and 1 year following the first dose of the study drug. Pediatric patients treated with levofloxacin had a significantly higher incidence of musculoskeletal disorders when compared to the non-fluoroquinolone-treated children as illustrated in Table 7. 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 )].

Table 7: Incidence of Musculoskeletal Disorders in Pediatric Clinical Trial 

Follow-up Period	Levofloxacin N = 1340	Non-Fluoroquinolone* N = 893	p-value†
60 days	28 (2.1%)	8 (0.9%)	p = 0.038
1 year‡	46 (3.4%)	16 (1.8%)	p = 0.025

* Non-Fluoroquinolone: ceftriaxone, amoxicillin/clavulanate, clarithromycin † 2-sided Fisher’s Exact Test ‡ There were 1199 levofloxacin-treated and 804 non-fluoroquinolone-treated pediatric patients who had a one-year evaluation visit. However, the incidence of musculoskeletal disorders was calculated using all reported events during the specified period for all pediatric patients enrolled regardless of whether they completed the 1-year evaluation visit. Arthralgia was the most frequently occurring musculoskeletal disorder in both treatment groups. Most of the musculoskeletal disorders in both groups involved multiple weight-bearing joints. Disorders were moderate in 8/46 (17%) children and mild in 35/46 (76%) levofloxacin-treated pediatric patients and most were treated with analgesics. The median time to resolution was 7 days for levofloxacin -treated pediatric patients and 9 for non-fluoroquinolone-treated children (approximately 80% resolved within 2 months in both groups). No pediatric patient had a severe or serious disorder and all musculoskeletal disorders resolved without sequelae. Vomiting and diarrhea were the most frequently reported adverse reactions, occurring in similar frequency in the levofloxacin -treated and non-fluoroquinolone-treated pediatric patients. In addition to the adverse reactions reported in pediatric patients in clinical trials, adverse reactions reported in adults during clinical trials or post-marketing experience [see Adverse Reactions ( 6 )] may also be expected to occur in pediatric patients.

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 )] .

8.6 Renal Impairment

Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in patients with renal impairment (creatinine clearance < 50 mL/min), requiring dosage adjustment in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating that supplemental doses of levofloxacin are not required following hemodialysis or CAPD [see Dosage and Administration ( 2.3) ].

8.7 Hepatic Impairment

Pharmacokinetic studies in patients with hepatic impairment have not been conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin are not expected to be affected by hepatic impairment.

Levofloxacin USP are synthetic antibacterial agents for oral administration. Chemically, levofloxacin, a chiral fluorinated carboxyquinolone, is the pure (-)-(S)-enantiomer of the racemic drug substance ofloxacin. The chemical name is (--(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hemihydrate. Figure 1: The Chemical Structure of Levofloxacin

The empirical formula is C ₁₈H ₂₀FN ₃O ₄•½ H ₂O and the molecular weight is 370.38. Levofloxacin USP is a light yellowish-white to yellow-white crystal or crystalline powder. The molecule exists as a zwitterion at the pH conditions in the small intestine.

The data demonstrate that from pH 0.6 to 5.8, the solubility of levofloxacin, USP is essentially constant (approximately 100 mg/mL). Levofloxacin USP is considered soluble to freely soluble in this pH range, as defined by USP nomenclature. Above pH 5.8, the solubility increases rapidly to its maximum at pH 6.7 (272 mg/mL) and is considered freely soluble in this range. Above pH 6.7, the solubility decreases and reaches a minimum value (about 50 mg/mL) at a pH of approximately 6.9.

Levofloxacin USP has the potential to form stable coordination compounds with many metal ions. This in vitro chelation potential has the following formation order: Al ⁺³>Cu ⁺²>Zn ⁺²>Mg ⁺²>Ca ⁺².

Levofloxacin USP is available as film-coated tablets and contain the following inactive ingredients:

• 250 mg (as expressed in the anhydrous form): hypromellose, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, titanium dioxide, polysorbate 80 and synthetic red iron oxide.
• 500 mg (as expressed in the anhydrous form): hypromellose, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, titanium dioxide, polysorbate 80 and synthetic red and yellow iron oxides.
• 750 mg (as expressed in the anhydrous form): hypromellose, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, titanium dioxide, polysorbate 80.

USP dissolution test 4.