PRINCEOXIN tablets are indicated for the treatment of adults with bacterial infections caused by susceptible strains of the designated microorganisms in the infections listed below.

Upper Respiratory Tract

Acute sinusitis (mild to moderate) due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella (Branhamella) catarrhalis.

“Restrict the use of PRINCEOXIN to settings where no other treatment options exist, and the clinical presentation meets the diagnostic criteria for acute bacterial sinusitis.”

Lower Respiratory Tract

Acute bacterial exacerbations of chronic bronchitis (mild to moderate) due to Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella (Branhamella) catarrhalis.

Community-acquired pneumonia (mild, moderate and severe infections) due to Staphylococcus aureus, Streptococcus pneumoniae (including penicillin-resistant strains), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella (Branhamella) catarrhalis, Chlamydia pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae (see DOSAGE AND ADMINISTRATION, and Product Monograph Part II: CLINICAL TRIALS).

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

PRINCEOXIN is not indicated for acute bronchitis.

PRINCEOXIN should not be prescribed to patients with acute bacterial exacerbations of simple/uncomplicated chronic obstructive pulmonary disease (ie. patients who have chronic obstructive pulmonary disease without underlying risk factors)

Skin and Skin Structure

Uncomplicated skin and skin structure infections (mild to moderate) due to Staphylococcus aureus or Streptococcus pyogenes.

Complicated skin and skin structure infections (mild to moderate), excluding burns, due to Enterococcus faecalis, methicillin-sensitive Staphylococcus aureus, Streptococcus pyogenes, Proteus mirabilis, or Streptococcus agalactiae.

Urinary Tract

Complicated urinary tract infections (mild to moderate) due to Enterococcus (Streptococcus) faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa (see DOSAGE AND ADMINISTRATION and Product Monograph Part II: CLINICAL TRIALS).

Uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae or Staphylococcus saprophyticus.

Acute pyelonephritis (mild to moderate) caused by Escherichia coli (see DOSAGE AND ADMINISTRATION and Product Monograph Part II: CLINICAL TRIALS).

Chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or Staphylococcus epidermidis.

Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify the organisms causing the infection, and to determine their susceptibility to levofloxacin. Therapy with levofloxacin may be initiated before the results of these tests are known; once results become available, appropriate therapy should be continued.

In cases of uncomplicated acute bacterial cystitis, limit the use of PRINCEOXIN to circumstances where no other treatment options are available. A urine culture should be obtained prior to treatment to ensure levofloxacin susceptibility.

As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with levofloxacin. Culture and susceptibility testing performed periodically during therapy, will reveal not only the therapeutic effect of the antimicrobial agent, but also the possible emergence of bacterial resistance.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of APO- LEVOFLOXACIN and other antibacterial drugs, PRINCEOXIN should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Geriatric (≥ 65 years of age):

Drug absorption appears to be unaffected by age. Dose adjustment based on age alone is not necessary (see WARNINGS AND PRECAUTIONS, Special Populations and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).

Pediatric Use (<18 years of age):

Safety and effectiveness in children under 18 years of age have not been established (see WARNINGS AND PRECAUTIONS, Special Populations).

Dosing Considerations

The dosage of PRINCEOXIN tablets for patients with normal renal function (i.e., ClCr,> 80 mL/min) is described in the following dosing chart. For patients with altered renal function (i.e., ClCr ≤ 80 mL/min), see Patients with Impaired Renal Function subsection.

Recommended Dose and Dosage Adjustment

Patients with Normal Renal Function

* DUE TO THE DESIGNATED PATHOGENS (see INDICATIONS AND CLINICAL USE).

** Efficacy of this alternative regimen has only been documented for infections caused by penicillin-susceptible Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophilia.

*** The efficacy of a regimen of 750 mg daily for 5 days has been demonstrated to be non-inferior to a regimen of 500 mg daily for 10 days. The 750 mg daily 5-day regimen has not been compared to a regimen of 500 mg daily for 11-14 days.

****The efficacy of this alternative regimen has been documented for infections caused by Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. Efficacy against infections caused by Enterococcus faecalis, Enterobacter cloacae, or Pseudomonas aeruginosa has not been demonstrated with this regimen.

Patients with Impaired Renal Function

On the basis of the altered levofloxacin disposition pharmacokinetics in subjects with impaired renal function, dose adjustment is recommended for patients with impaired renal function as given below (see WARNINGS AND PRECAUTIONS, Renal; ACTION AND CLINICAL

PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency and Product Monograph Part II: DETAILED PHARMACOLOGY, Factors Influencing the Pharmacokinetics, Special Populations, Renal Insufficiency).

Dosing recommendations for renally impaired patients are based on data collected from a clinical safety and pharmacokinetic study in renally impaired patients treated with a single 500 mg oral dose of levofloxacin. There is no clinical experience available in this patient population for the 250 mg dose or 750 mg dose. Pharmacokinetic modelling was used to determine a recommended dosing regimen which would provide equivalent drug exposures for which clinical efficacy has been demonstrated. The potential effects of levofloxacin associated with possible increased serum/tissue levels in renal-impaired patients, such as effect on QTc interval, have not been studied.

ClCr =  creatinine clearances

CAPD = chronic ambulatory peritoneal dialysis

When only the serum creatinine is known, the following formula may be used to estimate creatinine clearance.

Men:    Creatinine Clearance (mL/min)

=  Weight (kq) x (140 - age) x 1.2

     serum creatinine (mcmol/L)

Women: 0.85 x the value calculated for men.

The serum creatinine should represent a steady state of renal function.

Missed Dose

More than the prescribed dose of PRINCEOXIN should not be taken, even if a dose is missed.

Administration

Tablets

PRINCEOXIN can be administered without regard to food. Doses should be administered at least 2 hours before or 2 hours after antacids containing calcium, magnesium, aluminum, sucralfate, metal cations such as iron, multi-vitamin preparations with zinc, or products containing any of these components.

Epidemiologic studies report an increased risk of aortic aneurysm and dissection after intake of fluoroquinolones, particularly in the older population.

Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or in presence of other risk factors or conditions predisposing for aortic aneurysm and dissection (e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet's disease, hypertension, known atherosclerosis).

In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.

General

The administration of levofloxacin increased the incidence and severity of osteochondrosis in immature rats and dogs. Other quinolones also produce similar erosions in the weight-bearing joints and other signs of arthropathy in immature animals of various species. Consequently, levofloxacin should not be used in pre-pubertal patients (see Product Monograph Part II: TOXICOLOGY).

Although levofloxacin is soluble, adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of a highly concentrated urine. Crystalluria has been observed rarely in patients receiving other quinolones, when associated with high doses and an alkaline urine. Although crystalluria was not observed in clinical trials with levofloxacin,  patients are encouraged to remain adequately hydrated.

As with any antimicrobial drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy (see ADVERSE REACTIONS).

Use of levofloxacin with other drugs may lead to drug-drug interactions (see DRUG INTERACTIONS, Drug-Drug Interactions).

Sexually Transmitted Diseases

Levofloxacin is not indicated for the treatment of syphilis or gonorrhea. Levofloxacin is not effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with antimicrobial agents with limited or no activity against Treponema pallidum should have a follow- up serologic test for syphilis after 3 months.

Cardiovascular QT Prolongation

Some quinolones, including levofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. During post-marketing surveillance, very rare cases of torsades de pointes have been reported in patients taking levofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory. The risk of arrhythmias may be reduced by avoiding concurrent use with other drugs that prolong the QT interval including macrolide antibiotics, antipsychotics, tricyclic antidepressants, Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic agents, and cisapride. In addition, use of levofloxacin in the presence of risk factors for torsades de pointes such as hypokalemia, significant bradycardia, cardiomyopathy, patients with myocardial ischemia, and patients with congenital prolongation of the QT interval should be avoided (see Product Monograph Part II: DETAILED PHARMACOLOGY, Human Pharmacology, Studies Measuring Effects on QT and Corrected QT (QTc) Intervals).

Endocrine and Metabolism Disturbances of Blood Glucose

Disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with the use of quinolones, including levofloxacin. In patients treated with levofloxacin, some of these cases were serious. Blood glucose disturbances were usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide/glibenclamide) and/or with insulin. In these patients, careful monitoring of blood glucose is recommended. If a hypoglycemic reaction occurs in a patient being treated with levofloxacin, discontinue levofloxacin immediately and initiate appropriate therapy. Serious hypoglycemia and hyperglycemia have also occurred in patients without a history of diabetes (see ADVERSE REACTIONS and DRUG INTERACTIONS, Drug-Drug Interactions, Antidiabetic Agents).

Hypoglycemic coma has been observed in diabetic patients with the use of levofloxacin. Fatal outcomes have been reported. All cases of hypoglycemic coma had multiple confounding factors; a temporal relationship with the use of levofloxacin was identified (onset of altered consciousness occurred within 3 days in most cases). Caution should be exercised when using

levofloxacin in diabetic patients taking concomitant treatment with an oral hypoglycemic agent and/or insulin, especially those who are elderly or who have renal impairment (see WARNINGS AND PRECAUTIONS, Renal and DRUG INTERACTIONS, Drug-Drug Interactions, Antidiabetic Agents).

Gastrointestinal

Clostridium difficile-associated disease

Clostridium difficile-associated disease (CDAD) has been reported with use of many antibacterial agents, including levofloxacin. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of the colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.

If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated since surgical intervention may be required in certain severe cases (see ADVERSE REACTIONS).

Hepatic

Very rare post-marketing reports of severe hepatotoxicity (including acute hepatitis and fatal events) have been received for patients treated with levofloxacin. No evidence of serious drug- associated hepatotoxicity was detected in clinical trials of over 7,000 patients. Severe hepatotoxicity generally occurred within 14 days of initiation of therapy and most cases occurred within 6 days. Most cases of severe hepatotoxicity were not associated with hypersensitivity. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. Levofloxacin should be discontinued immediately if the patient develops signs and symptoms of hepatitis (see ADVERSE REACTIONS, Post- Market Adverse Drug Reactions).

Immune Hypersensitivity

Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with quinolones, 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).

Serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain etiology, have rarely been reported in patients receiving therapy with quinolones, 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, including acute 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. The administration of levofloxacin should be discontinued immediately, at the first appearance of a skin rash or any other sign of hypersensitivity, and supportive measures instituted (see ADVERSE REACTIONS).

Musculoskeletal Tendinitis

Rupture of the shoulder, hand and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including levofloxacin. Levofloxacin should be discontinued if the patient experiences pain, inflammation or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, 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 also occurred in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported.

Levofloxacin should be discontinued 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 (see ADVERSE REACTIONS).

Levofloxacin should not be used in patients with a history of tendon disease/disorder related to previous quinolone treatment (see CONTRAINDICATIONS).

Myasthenia Gravis

Fluoroquinolones have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post-marketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use (including levofloxacin) in persons with myasthenia gravis. Avoid levofloxacin in patients with a known history of myasthenia gravis (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions)  Neurologic

CNS and Psychiatric Effects

Convulsions, toxic psychoses and increased intracranial pressure (including pseudotumor cerebri) have been reported in patients receiving quinolones, including levofloxacin. Quinolones including levofloxacin, may also cause central nervous system stimulation which may lead to tremors, restlessness, anxiety, lightheadedness, dizziness, confusion and hallucinations, paranoia, depression, nightmares, insomnia and, rarely, suicidal thoughts or acts. These reactions may  occur following the first dose. If these reactions occur in patients receiving levofloxacin, the drug should be discontinued and appropriate measures instituted. As with all quinolones, levofloxacin should be used with caution in patients with a known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g., alcohol abuse, certain drug therapies such as NSAIDs and theophylline, renal dysfunction).

Levofloxacin should be used with caution in patients with unstable psychiatric illness (see DRUG INTERACTIONS and ADVERSE REACTIONS).

Peripheral Neuropathy

Rare 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 quinolones, including levofloxacin. Symptoms may occur soon after initiation of treatment and may be irreversible. Levofloxacin should be discontinued 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 in order to prevent the development of an irreversible condition.

Ophthalmologic Vision Disorders

Consult an eye specialist if vision disorder occurs in association with the use of APO-Levofloxacin.

Renal

Safety and efficacy of levofloxacin in patients with impaired renal function (creatinine clearance ≤ 80 mL/min) have not been studied. Since levofloxacin 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. The potential effects of levofloxacin associated with possible increased serum/tissue levels in renal impaired patients, such as effect on QTc interval, have not been studied.

Adjustment of the dosage regimen may be necessary to avoid the accumulation of levofloxacin due to decreased clearance. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy, since elimination of levofloxacin may be reduced.

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. Administer levofloxacin with caution in the presence of renal insufficiency (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Patients with Impaired Renal Function and Product Monograph Part II: DETAILED PHARMACOLOGY, Factors Influencing the Pharmacokinetics, Special Populations, Renal Insufficiency).

Skin Phototoxicity

Moderate to severe phototoxicity reactions have been observed in patients exposed to direct sunlight or ultraviolet (UV) light while receiving drugs in this class. Excessive exposure to sunlight or UV light should be avoided. However, in clinical trials with levofloxacin, phototoxicity has been observed in less than 0.1% of patients. Therapy should be discontinued if phototoxicity (e.g., skin eruption) occurs.

Susceptibility/Resistance

Development of Drug Resistant Bacteria

Prescribing PRINCEOXIN in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug- resistant bacteria.

Special Populations

The safety and efficacy of levofloxacin tablets in children, adolescents (under the age of 18 years), pregnant women and nursing mothers have not been established.

Pediatrics (<18 years of age): Levofloxacin is not indicated for the treatment of patients younger than 18 years of age. Quinolones, including levofloxacin, cause arthropathy in juvenile animals of several species (see Product Monograph Part II: TOXICOLOGY). The incidence of protocol-defined musculoskeletal disorders in a prospective long-term surveillance study was higher in children treated for approximately 10 days with levofloxacin than in children treated with non-fluoroquinolone antibiotics for approximately 10 days (see ADVERSE REACTIONS).

Geriatrics (≥65 years of age): 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. It may also be useful to monitor renal function.

Elderly patients may be more susceptible to drug-associated effects on the QT interval (see WARNINGS AND PRECAUTIONS, Cardiovascular).

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 (see WARNINGS AND PRECAUTIONS, Musculoskeletal).

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 (see WARNINGS AND PRECAUTIONS, Hepatic).

Overview

Levofloxacin undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. The P450 system is not involved in the levofloxacin metabolism, and is not affected by levofloxacin. Levofloxacin is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes. Disturbances of blood glucose have been reported in patients treated concomitantly with levofloxacin and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when these agents, including levofloxacin, are coadministered. As with all other quinolones, iron and antacids significantly reduced bioavailability of levofloxacin.

Drug-Drug Interactions

Table 1.4: Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Drug-Food Interactions

PRINCEOXIN may be taken with or without food.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Some quinolones, 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.

Pregnant Women: There are no adequate and well-controlled studies in pregnant women. Levofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see Product Monograph Part II: TOXICOLOGY).

Nursing Women: Levofloxacin has not been measured in human milk. Based upon data from ofloxacin, it can be presumed that levofloxacin can be excreted in human milk. Because of the potential for serious adverse reactions from levofloxacin in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see Product Monograph Part II: TOXICOLOGY).

Neurologic adverse effects such as dizziness and lightheadedness may occur. Therefore, patients should know how they react to levofloxacin before operating an automobile or machinery or engaging in other activities requiring mental alertness and coordination.

Adverse Drug Reaction Overview

In North American Phase III clinical trials involving 7537 subjects, the incidence of treatment- emergent adverse events in patients treated with levofloxacin tablets and injection was comparable to comparators. The majority of adverse events were considered to be mild to moderate, with 5.6% of patients considered to have severe adverse events. Among patients receiving multiple-dose therapy, 4.2% discontinued therapy with levofloxacin due to adverse experiences. The incidence of drug-related adverse reactions was 6.7%.

In clinical trials, the most frequently reported adverse drug reactions occurring in > 3% of the study population were nausea, headache, diarrhea, insomnia, dizziness and constipation.

Serious and otherwise important adverse drug reactions are discussed in greater detail in other sections (see WARNINGS AND PRECAUTIONS).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The data described below reflect exposure to levofloxacin in 7537 patients in 29 pooled Phase III clinical trials. The population studied had a mean age of 49.6 years (74.2% of the population was < 65 years), 50.1% were male, 71.0% were Caucasian, 18.8% were Black. Patients were treated with levofloxacin for a wide variety of infectious diseases (see INDICATIONS AND CLINICAL USE). Treatment duration was usually 3 to 14 days, the mean number of days on therapy was 9.6 days and the mean number of doses was 10.2. Patients received levofloxacin doses of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. The overall incidence, type and distribution of adverse reactions were similar in patients receiving levofloxacin doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily.

Adverse reactions (characterized as likely related to drug-therapy) occurring in ≥1% of levofloxacin-treated patients are shown in Table 1.1 below.

Table 1.1: Common (≥1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Less common adverse reactions occurring in 0.1 to <1% of levofloxacin-treated patients are shown in Table 1.2 below.

Table 1.2: Less Common (0.1 to ˂1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin

a N = 7274

Rare (<0.1%) adverse reactions from Phase III studies include dyspnea and rash maculopapular.

In clinical trials using multiple-dose therapy, ophthalmologic abnormalities, including cataracts and multiple punctate lenticular opacities, have been noted in patients undergoing treatment with other quinolones. The relationship of the drugs to these events is not presently established.

Crystalluria and cylindruria have been reported with other quinolones.

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory abnormalities seen in > 2% of patients receiving multiple doses of levofloxacin: decreased glucose 2.1%

It is not known whether this abnormality was caused by the drug or the underlying condition being treated.

Pediatric Data

In a group of 1534 pediatric patients (6 months to 16 years of age) treated with levofloxacin for respiratory infections, children 6 months to 5 years of age received 10 mg/kg of levofloxacin twice a day for approximately 10 days and children greater than 5 years of age received 10 mg/kg to a maximum of 500 mg of levofloxacin once a day for approximately 10 days. The adverse reaction profile was similar to that reported in adult patients. Vomiting and diarrhea were reported more frequently in children than reported in adults. However, the frequency of vomiting and diarrhea was similar in levofloxacin-treated and non-fluoroquinolone antibiotic comparator-treated children.

A subset of 1340 of these children treated with levofloxacin for approximately 10 days was enrolled in a prospective, long-term, surveillance study to assess the incidence of protocol- defined musculoskeletal disorders (arthralgia, arthritis, tendonopathy, gait abnormality) during 60 days and 1 year following the first dose of levofloxacin.

During the 60-day period following the first dose, the incidence of protocol-defined musculoskeletal disorders was greater in levofloxacin-treated children than in non- fluoroquinolone antibiotic comparator-treated children (2.1% vs. 0.9%, respectively [p=0.038]). In 22/28 (78%) of these children, reported disorders were characterized as arthralgia. A similar observation was made during the one-year period, with a greater incidence of protocol-defined musculoskeletal disorders in levofloxacin-treated children than in non-fluoroquinolone antibiotic comparator-treated children (3.4% vs. 1.8%, respectively [p=0.025]). The majority of these disorders occurring in children treated with levofloxacin were mild and resolved within 7 days. Disorders were moderate in 8 children and mild in 35 (76%) children.

Post-market Adverse Drug Reactions

Table 1.3 lists adverse reactions that have been identified during post-approval use of levofloxacin. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible.

Table 1.3: Post-marketing Reports of Adverse Drug Reactions

‐ To report any side effects:

In the event of an acute overdosage, activated charcoal may be administered to aid in the removal of unabsorbed drug. General supportive measures are recommended. The patient should be observed, including ECG monitoring (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, Studies Measuring Effects on QT and Corrected QT (QTc) Intervals), and appropriate hydration maintained. Treatment should be supportive. Levofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis.

Levofloxacin exhibits a low potential for acute toxicity. Mice, rats, dogs and monkeys exhibited the following clinical signs after receiving a single high dose of levofloxacin: ataxia, ptosis, decreased locomotor activity, dyspnea, prostration, tremors, and convulsions. Doses in excess of 1500 mg/kg orally produced significant mortality in rodents.

Studies Measuring Effects on QT and Corrected QT (QTc) Intervals

Two studies have been conducted to assess specifically the effect of levofloxacin on QT and corrected QT (QTc) intervals in healthy adult volunteers. In a dose escalation study (n=48) where the effect on average QTc, after single doses of 500, 1000, and 1500 mg of levofloxacin, was measured between the baseline QTc (calculated as the average QTc measured 24, 20, 16 hours and immediately before treatment) and the average post-dose QTc interval (calculated from measurements taken every half hour for two hours and at 4, 8, 12 and 24 hours after treatment), an effect on the average QTc (Bazett) was -1.84, 1.55 and 6.40 msec, respectively. In a study which compared the effect of 3 antimicrobials (n=48) where the difference was measured between the baseline QTc (calculated as the average QTc measured 24, 20, 16 hours and immediately before treatment) and the average post-dose QTc interval (calculated from measurements taken every half hour for four hours and at 8, 12 and 24 hours after treatment), an effect on the average QTc was an increase of 3.58 msec after the 1000 mg dose of levofloxacin. The mean increase compared to baseline of QTc at Cmax in these two trials was 7.82 msec and 5.32 msec after a single 1000 mg dose. In these trials, no effect on QT intervals compared to placebo was evident at any of the doses studied. The clinical relevance of the results of these studies is not known (see Product Monograph Part II: DETAILED PHARMACOLOGY, Human Pharmacology, Studies Measuring the Effects on QT and Corrected QT (QTc) Intervals).

The mean (± SD) pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following oral (p.o.) or intravenous (i.v.) doses of levofloxacin are summarized in Table 1.5.

a healthy males 18-53 years of age;

b 60 min infusion for 250 mg and 500 mg doses, 90 min infusion for 750 mg dose;

c healthy male subjects 32-46 years of age;

cc healthy male subjects 19-51 years of age;

d including 500 mg q48h for 8 patients with moderate renal impairment (ClCr20-50 mL/min) and infections of the respiratory tract or skin;

e healthy males 22-75 years of age;

f healthy females 18-80 years of age;

g young healthy male and female subjects 18-36 years of age;

h healthy elderly male and female subjects 66-80 years of age;

i dose-normalized values (to 500 mg dose), estimated by population pharmacokinetic modelling;

j AUC for 0-∞ reported, unless otherwise specified;

k male and female subjects 34-54 years of age;

x AUC 0-24 h;

* Absolute bioavailability; F = 0.99 ± 0.08 from a 500 mg tablet and F = 0.99 ± 0.06 from a 750 mg tablet.

ND = Not Determined

Absorption:

Oral

Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak plasma concentrations are usually attained 1 to 2 hours after oral dosing. The absolute bioavailability of a 500 mg tablet and a 750 mg tablet of levofloxacin is approximately 99% in both cases, demonstrating complete oral absorption of levofloxacin. Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral dosing regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once-daily dosage regimen. The peak and trough plasma concentrations attained following multiple once-daily oral dosage regimens were approximately 5.7 mcg/mL and 0.5 mcg/mL after the 500 mg doses, and 8.6 mcg/mL and 1.1 mcg/mL after the 750 mg doses, respectively.

There was no clinically significant effect of food on the extent of absorption of levofloxacin. Oral administration with food slightly prolongs the time to peak concentration by approximately 1 hour, and slightly decreases the peak concentration by approximately 14%. Therefore, levofloxacin can be administered without regard to food.

Distribution:

The mean volume of distribution of levofloxacin generally ranges from 74 to 112 L after single and multiple 500 mg or 750 mg doses, indicating widespread distribution into body tissues. Levofloxacin reaches its peak levels in skin tissues (11.7 mcg/g for a 750 mg dose) and in blister fluid (4.33 mcg/g for a 500 mg dose) at approximately 3 to 4 hours after dosing. The skin tissue biopsy to plasma AUC ratio is approximately 2. The blister fluid to plasma AUC ratio is approximately 1, following multiple once-daily oral administration of 750 mg and 500 mg levofloxacin to healthy subjects, respectively.

Levofloxacin also penetrates into lung tissues. Lung tissue concentrations were generally 2- to 5-fold higher than plasma concentrations, and ranged

from approximately 2.4 to 11.3 mcg/g over a 24-hour period after a single 500 mg oral dose. Levofloxacin is 24 to 38% bound to serum proteins across all species studied. Levofloxacin binding to serum proteins is independent of the drug concentration.

Metabolism:

Levofloxacin is stereochemically stable in plasma and urine, and does not invert metabolically to its enantiomer, D-ofloxacin. Levofloxacin undergoes limited metabolism in humans, and is primarily excreted as unchanged drug (87%) in the urine within 48 hours.

Excretion:

The major route of elimination of levofloxacin in humans is as unchanged drug in the urine. The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin given orally.

Special Populations and Conditions

Pediatrics: The pharmacokinetics of levofloxacin in pediatric patients have not been studied.

Geriatrics: There are no significant differences in levofloxacin pharmacokinetics between young and elderly subjects when the subjects’ differences in creatinine clearance are taken into consideration. Drug absorption appears to be unaffected by age. Levofloxacin dose adjustment based on age alone is not necessary.

Gender: There are no significant differences in levofloxacin pharmacokinetics between male and female subjects when the differences in creatinine clearance are taken into consideration. Dose adjustment based on gender alone is not necessary.

Race: The apparent total body clearance and apparent volume of distribution were not affected by race in a covariate analysis performed on data from 72 subjects.

Hepatic Insufficiency: Pharmacokinetic studies in hepatically impaired patients 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.

Renal Insufficiency: Pharmacokinetic parameters of levofloxacin following oral or intravenous doses of levofloxacin in patients with impaired renal function (creatinine clearance ≤80 mL/min) are presented in Table 1.5. Clearance of levofloxacin is reduced and plasma elimination half-life is prolonged in this patient population. Dosage adjustment may be required in such patients to avoid accumulation.

A dosage reduction is being recommended depending on the levels of renal insufficiency. Dosing recommendations are based on pharmacokinetic modelling of data collected from a clinical safety and pharmacokinetic study in renally impaired patients treated with a single 500 mg oral dose of levofloxacin (see WARNINGS AND PRECAUTIONS, Renal, and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Patients with Impaired Renal Function).

Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating supplemental doses of levofloxacin are not required following hemodialysis or CAPD.

Bacterial Infection: The pharmacokinetics of levofloxacin in patients with community-acquired bacterial infections are comparable to those observed in healthy subjects.

The potential toxicity of levofloxacin has been evaluated in acute, sub-chronic, carcinogenicity, mutagenicity, reproduction and teratology, and special toxicity studies.

Acute Toxicity

Table 2.49 - Summary of the acute toxicity studies

Signs of acute toxicity with metabolites (desmethyl and N-oxide) were similar to that of levofloxacin and were produced at doses significantly greater than would be encountered with therapeutic use.

Sub-Chronic Toxicity

Table 2.50 - Summary of the sub-chronic toxicity studies

Dosage = mg/kg/day; Clin Obs = clinical observations; Clin Path = clinical pathology; Micro = macroscopic and microscopic findings; NOAEL = No Observable Adverse Effect Level; NSF = No Significant Findings; TI =

Therapeutic Index – relationship of toxic dose to the projected human dose (calculation based on maximum daily dose of 500 mg and body weight of 70 kg); ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; A/G = albumin/globulin; fc = food consumption; wc = water consumption; bw = body weight; RBC = red blood cells; WBC = white blood cells; retic = reticulocyte; PMN = neutrophil; M:E = myeloid:erythroid; K+ = potassium; Cl- = chloride; P = phosphorus; Fe = iron.

Carcinogenicity

Levofloxacin exhibited no carcinogenic or tumorigenic potential after dietary administration of 10, 30 or 100 mg/kg/day for 2 years in a rat carcinogenicity study. The highest dose was 1.4 or 6.7 times the highest recommended human dose (750 mg) based on surface area or body weight, respectively. The mean levofloxacin plasma concentration in the 2-year rat bioassay (at 100 mg/kg/day) was 34% of the human steady-state concentration after 500 mg b.i.d. dosing. In a 2- stage multiple organ carcinogenesis model in rats, levofloxacin at a dosage level of approximately 668 mg/kg/day in diet for 16 weeks did not promote the development of preneoplastic or

neoplastic lesions after pretreatment with a number of wide spectrum carcinogens.

Mutagenicity

Levofloxacin was not mutagenic in the following assays: Ames bacterial mutation assays (S. typhimurium and E. coli), CHO/HGPRT forward mutation assay, mouse micronucleus test, mouse dominant lethal test, rat unscheduled DNA synthesis and the mouse sister chromatid exchange (SCE) assays. It was positive in the in vitro chromosomal aberration (CHL cell line) and SCE assays (CHL/IU cell line).

Reproduction and Teratology

Table 2.51 - Segment I: Fertility and Reproductive Performance Studies

wc = water consumption; bw = body weight; fc = food consumption

a In both studies, males (8 weeks old) were administered levofloxacin daily for 9 weeks prior to mating, throughout the mating period, and until necropsy. The females (11-12 weeks old) were treated daily for 2 weeks prior to mating, throughout the mating period, and for 7 days after copulation. NOAEL = No Observable Adverse Effect Levels.

Table 2.52 - Segment II: Teratogenicity

bw = body weight; wc = water consumption; fc = food consumption; inj. = injection

a In both rat studies, the rats were dosed from Day 7 to Day 17 of gestation. NOAEL = No Observable Adverse Effect Level

Table 2.53 - Segment III: Perinatal and Postnatal

NOAEL = No Observable Adverse Effect Level

Special Studies

Arthropathic Potential

Levofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested (see WARNINGS AND PRECAUTIONS). In juvenile rats, 7 days of oral administration of 300 mg/kg/day levofloxacin results in blister and cavity formation in articular cartilage. In juvenile dogs (4 months old), 7 days of oral administration of 10 mg/kg/day levofloxacin produces blister formation, cavitation, and increased synovial fluid of diarthroidal joints. In young immature dogs (13 months old), blister formation and cavitation of the arthritic joint were observed in 1/3 dogs following oral administration of 40 mg/kg/day levofloxacin for 7 days.

In long-term multidose studies, arthropathy in rats was observed after oral administration of 800 mg/kg/day for 4 weeks, after intravenous administration at 60 mg/kg/day for 4 weeks and 90 mg/kg/day for 13 weeks. Arthropathic lesions were observed in 4-month-old dogs following 4 mg/kg/day intravenous administration for 2 weeks and in 7 to 8 month-old dogs following 10 mg/kg/day intravenous administration for 4 weeks. No arthropathy was observed following 2-week intravenous dosing at dosages up to 30 mg/kg/day in young adult dogs (18 months old).

Three-month old beagle dogs dosed orally with up to 40 mg/kg/day levofloxacin for 8 or 9 consecutive days, with an 18-week recovery period, exhibited musculoskeletal clinical signs by the final dose at dose levels ≥2.5 mg/kg (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 (equivalent to and 3-fold greater than the potential therapeutic dose, respectively). All musculoskeletal clinical signs were resolved by week 5 of recovery; synovitis was resolved by the end of the 18-week recovery period; whereas, articular cartilage erosions and chondropathy persisted.

Phototoxicity

When tested in a mouse ear swelling bioassay, levofloxacin exhibited phototoxicity similar in magnitude to ofloxacin but less phototoxicity than some of the other quinolones tested. A single oral administration of 800 mg/kg levofloxacin followed by UVA exposure has been shown to result in ear erythema and swelling.

Crystalluria

When tested in rats with 20, 60, 120 or 180 mg/kg of levofloxacin, 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.

Cardiac Effects

Levofloxacin exhibits a weak interaction with the human HERG channel. The IC50 for levofloxacin in inhibiting human HERG K+ channel is 915 mcM. At therapeutic doses of 250, 500, and 750 mg levofloxacin, the peak unbound plasma concentrations ranged from 6 mcM for a single oral levofloxacin dose of 250 mg to 12 mcM and 15 mcM for 500 and 750 mg levofloxacin doses, respectively.

Studies in rabbit Purkinje fibers and studies in guinea pig right ventricular myocardium revealed no detectable effect on action potential duration with levofloxacin at concentrations up to 100 mcM.

The potential for levofloxacin to induce torsades de pointes was examined in a canine model of chronic high-degree atrioventricular block. Oral administration of levofloxacin at 6 and 60 mg/kg induced no ventricular arrhythmias. Monophasic action potential duration (MAP90) was not significantly affected by levofloxacin 0.3 and 3.0 mg/kg IV.

PRINCEOXIN(levofloxacin) Tablets are available as film-coated tablets and contain the following inactive ingredients:

250 mg: croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, methylcellulose, stearic acid, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, titanium dioxide, red ferric oxide.

500 mg: croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, methylcellulose, stearic acid, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, titanium dioxide, red ferric oxide, yellow ferric oxide.

750 mg: croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, methylcellulose, stearic acid, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, titanium dioxide.

None Applicable

Store below 30°C, protected from light.

None Applicable