Pro-Levofloxacin Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

RECENT MAJOR LABEL CHANGES ............................................................................................. 2

TABLE OF CONTENTS ................................................................................................................ 2

PART I: HEALTH PROFESSIONAL INFORMATION ........................................................................ 4

1 INDICATIONS ................................................................................................................ 4

1.1 Pediatrics ............................................................................................................... 5

1.2 Geriatrics ............................................................................................................... 6

2 CONTRAINDICATIONS ................................................................................................... 6

3 SERIOUS WARNINGS AND PRECAUTIONS BOX .............................................................. 6

4 DOSAGE AND ADMINISTRATION .................................................................................. 6

4.1 Dosing Considerations ........................................................................................... 6

4.2 Recommended Dose and Dosage Adjustment ....................................................... 7

4.4 Administration ....................................................................................................... 9

4.5 Missed Dose .......................................................................................................... 9

5 OVERDOSAGE ............................................................................................................... 9

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................ 10

7 WARNINGS AND PRECAUTIONS .................................................................................. 10

7.1 Special Populations .............................................................................................. 16

7.1.1 Pregnant Women ............................................................................................. 16

7.1.2 Breast-feeding .................................................................................................. 16

7.1.3 Pediatrics ......................................................................................................... 17

7.1.4 Geriatrics ......................................................................................................... 17

8 ADVERSE REACTIONS ................................................................................................. 17

8.1 Adverse Reaction Overview ................................................................................. 17

8.2 Clinical Trial Adverse Reactions ............................................................................ 18

8.2.1 Clinical Trial Adverse Reactions – Pediatrics..................................................... 19

8.3 Less Common Clinical Trial Adverse Reactions ..................................................... 19

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ............................................................................................................ 20

8.5 Post-Market Adverse Reactions ........................................................................... 21

9 DRUG INTERACTIONS ................................................................................................. 23

9.2 Drug Interactions Overview ................................................................................. 23

9.4 Drug-Drug Interactions ........................................................................................ 23

9.5 Drug-Food Interactions ........................................................................................ 26

9.6 Drug-Herb Interactions ........................................................................................ 26

9.7 Drug-Laboratory Test Interactions ....................................................................... 26

10 CLINICAL PHARMACOLOGY ........................................................................................ 26

10.1 Mechanism of Action ........................................................................................... 26

10.2 Pharmacodynamics ............................................................................................. 27

10.3 Pharmacokinetics ................................................................................................ 28

11 STORAGE, STABILITY AND DISPOSAL ........................................................................... 34

12 SPECIAL HANDLING INSTRUCTIONS ............................................................................ 34

PART II: SCIENTIFIC INFORMATION ........................................................................................ 35

13 PHARMACEUTICAL INFORMATION ............................................................................. 35

14 CLINICAL TRIALS ......................................................................................................... 36

14.1 Clinical Trials by Indication ................................................................................... 36

14.2 Comparative Bioavailability Studies ..................................................................... 52

15 MICROBIOLOGY .......................................................................................................... 53

16 NON-CLINICAL TOXICOLOGY ....................................................................................... 59

17 SUPPORTING PRODUCT MONOGRAPHS ..................................................................... 67

PATIENT MEDICATION INFORMATION .................................................................................... 68

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

PRO-LEVOFLOXACIN (levofloxacin tablets) is indicated for the treatment of adults with bacterial infections caused by susceptible strains of the designated microorganisms in the infections listed below.

• To reduce the development of drug-resistant bacteria and maintain the effectiveness of PRO-LEVOFLOXACIN and other antibacterial drugs, PRO-LEVOFLOXACIN 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.
• Upper Respiratory Tract

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

Restrict the use of PRO-LEVOFLOXACIN to settings where no other treatment options exist, and the clinical presentation meets the diagnostic criteria for acute bacterial sinusitis.¹

• 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. PRO-LEVOFLOXACIN should not be prescribed to patients with acute bacterial exacerbations of simple/uncomplicated chronic obstructive pulmonary disease (i.e., patients who have chronic obstructive pulmonary disease without underlying risk factors). ²

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 4 DOSAGE AND ADMINISTRATION, and 14 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.

¹ Canadian clinical practice guidelines for acute and chronic rhinosinusitis. Desrosiers et al. Allergy, Asthma and Clinical Immunology, 2011, 7:2

² Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease – 2008 update – highlights for primary care. O’Donnell et al. Can Respir J 2008; 15 (Suppl A): 1A-8A.

PRO-LEVOFLOXACIN is not indicated for acute bronchitis.

• 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 4 DOSAGE AND ADMINISTRATION and 14 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 4 DOSAGE AND ADMINISTRATION and 14 CLINICAL TRIALS).

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

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

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.

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.

1.1 Pediatrics

Pediatrics (<18 years of age): Safety and effectiveness in children under 18 years of age have not been established; therefore, Health Canada has not authorized an indication for pediatric use (see 7.1.3 Pediatrics).

1.2 Geriatrics

Geriatrics (≥ 65 years of age): Drug absorption appears to be unaffected by age. Dose adjustment based on age alone is not necessary (see 7.1.4 Geriatrics and 10 CLINICAL PHARMACOLOGY, Special Populations and Conditions).

2 CONTRAINDICATIONS

• PRO-LEVOFLOXACIN is contraindicated in persons with a history of hypersensitivity to levofloxacin, quinolone antimicrobial agents or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see the 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section.
• Levofloxacin is also contraindicated in persons with a history of tendinitis or tendon rupture associated with the use of any member of the quinolone group of antimicrobial agents.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

The dosage of PRO-LEVOFLOXACIN 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 4.2 Recommended Dose and Dosage Adjustment, Patients with Impaired Renal Function subsection.

4.2 Recommended Dose and Dosage Adjustment

Patients with Normal Renal Function

* DUE TO THE DESIGNATED PATHOGENS (see 1 INDICATIONS).

** 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 pneumophila.

*** 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 7 WARNINGS AND PRECAUTIONS, Renal; 10 CLINICAL PHARMACOLOGY, Special Populations and Conditions, 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.

Cl_Cr = 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 (kg) 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.

4.4 Administration

PRO-LEVOFLOXACIN 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.

4.5 Missed Dose

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

5 OVERDOSAGE

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 10 CLINICAL PHARMACOLOGY, 10.2 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.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Levofloxacin 250 mg film-coated tablets, containing 250 mg of levofloxacin (as levofloxacin hemihydrate), are terra cotta pink, octagonal, biconvex tablets, with imprint “LVF 250” on one side. Available in bottles of 50 tablets.

Levofloxacin 500 mg film-coated tablets, containing 500 mg of levofloxacin (as levofloxacin hemihydrate), are peach, octagonal biconvex tablets, with imprint “LVF 500” on one side. Available in bottles of 100 tablets.

Levofloxacin 750 mg film-coated tablets, containing 750 mg of levofloxacin (as levofloxacin hemihydrate), are white, octagonal biconvex tablets, with imprint “LVF 750” on one side. Available in bottles of 50 tablets.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

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 16 NON-CLINICAL 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 8 ADVERSE REACTIONS).

Use of levofloxacin with other drugs may lead to drug-drug interactions (see 9 DRUG INTERACTIONS, 9.4 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

Aortic Aneurysm and Aortic Dissection

Epidemiologic studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation after intake of fluoroquinolones. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones.

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 congenital heart valve disease, or in patients diagnosed with pre-existing aortic aneurysm and/or dissection or heart valve disease, or in presence of other risk factors or conditions predisposing for:

• Both aortic aneurysm and dissection and heart valve regurgitation/incompetence (e.g., connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behcet's disease, hypertension, rheumatoid arthritis) or additionally
• Aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren’s syndrome) or additionally
• Heart valve regurgitation/incompetence (e.g., infective endocarditis).

The risk of aortic aneurysm and dissection, and their rupture may also be increased in patients treated concurrently with systemic corticosteroids.

In case of sudden severe abdominal, chest or back pain, acute dyspnea, new onset of heart palpitations, or development of oedema of the abdomen or lower extremities, patients should be advised to immediately consult a physician in an emergency department.

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

10 CLINICAL PHARMACOLOGY, 10.2 Pharmacodynamics, Studies Measuring Effects on QT and Corrected QT (QTc) Intervals).

Driving and Operating Machinery

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.

Endocrine and Metabolism

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, discontinue PRO-LEVOFLOXACIN immediately and initiate appropriate therapy.

Serious hypoglycemia and hyperglycemia have also occurred in patients without a history of diabetes (see 8 ADVERSE REACTIONS and 9.4 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 7 WARNINGS AND PRECAUTIONS, Renal and 9 DRUG INTERACTIONS, 9.4 Drug-Drug Interactions, Antidiabetic Agents).

Gastrointestinal

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 8 ADVERSE REACTIONS).

Hepatic/Biliary/Pancreatic

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 8 ADVERSE REACTIONS, 8.5 Post-Market Adverse 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 8 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

8 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 8 ADVERSE REACTIONS).

Levofloxacin should not be used in patients with a history of tendon disease/disorder related to previous quinolone treatment (see 2 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 8 ADVERSE REACTIONS, 8.5 Post-Market Adverse Reactions).

Neurologic

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 light-headedness. As with other fluoroquinolones, PRO-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 PRO-LEVOFLOXACIN, discontinue PRO-LEVOFLOXACIN immediately and institute appropriate measures.

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 PRO-LEVOFLOXACIN.

Psychiatric

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; and memory impairment. Cases of 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 PRO-LEVOFLOXACIN, discontinue PRO-LEVOFLOXACIN and institute appropriate measures.

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 4 DOSAGE AND ADMINISTRATION, 4.2 Recommended Dose and Dosage Adjustment, Patients with Impaired Renal Function and 10 CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency).

Sensitivity/Resistance

Superinfection

The use of levofloxacin may result in overgrowth of non-susceptible organisms. If superinfection occurs during therapy, appropriate measures should be taken.

Development of Drug Resistant Bacteria

Prescribing PRO-LEVOFLOXACIN 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.

Methicillin-resistant Staphylococcus aureus (MRSA) is very likely to possess co-resistance to fluoroquinolones, including levofloxacin. Therefore, PRO-LEVOFLOXACIN is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to levofloxacin. In this case PRO-LEVOFLOXACIN can be used when commonly recommended antibacterial agents for the treatment of MRSA-infections are considered inappropriate.

Resistance of Escherichia coli, the most common pathogen involved in urinary tract infections, to fluoroquinolones varies. Prescribers are advised to take into account the local prevalence of resistance in E. coli to fluoroquinolones.

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.

7.1 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.

7.1.1 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 16 NON-CLINICAL TOXICOLOGY).

7.1.2 Breast-feeding

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

16 NON-CLINICAL TOXICOLOGY).

7.1.3 Pediatrics

Pediatrics (<18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of levofloxacin in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use. Quinolones, including levofloxacin, cause arthropathy in juvenile animals of several species (see 16 NON-CLINICAL 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 8 ADVERSE REACTIONS).

7.1.4 Geriatrics

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 7 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 7 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 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

8 ADVERSE REACTIONS

8.1 Adverse 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 7 WARNINGS AND PRECAUTIONS).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

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% were Caucasian and 18.8% were Black. Patients were treated with levofloxacin for a wide variety of infectious diseases (See 1 INDICATIONS). Treatment duration was usually 3-14 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 2 below.

Table 2 - Common (≥1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

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, tendinopathy, 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.

8.3 Less Common Clinical Trial Adverse Reactions

Less common adverse reactions occurring in 0.1 to <1% of levofloxacin-treated patients are shown in Table 3 below.

Table 3 - 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 maculo-papular.

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.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

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.

8.5 Post-Market Adverse Reactions

Table 4 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 4 - Post-Marketing Reports of Adverse Drug Reactions

9 DRUG INTERACTIONS

9.2 Drug Interactions 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 co-administered.

As with all other quinolones, iron and antacids significantly reduced bioavailability of levofloxacin.

The risk of aortic aneurysm and dissection, and their rupture may also be increased in patients treated concurrently with systemic corticosteroids.

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 5 - Established or Potential Drug-Drug Interactions

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

9.5 Drug-Food Interactions

Levofloxacin may be taken with or without food.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test 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.

Levofloxacin may interfere in the bacteriological diagnosis of tuberculosis and thus give false-negative results; therefore, tuberculosis diagnostic tests should be repeated on the patient after termination of PRO-LEVOFLOXACIN treatment.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Levofloxacin is a synthetic broad-spectrum antibacterial agent for oral administration and intravenous administration.

Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antibacterial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of levofloxacin and other quinolone antibacterials involves inhibition of bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Topoisomerases are essential in controlling the topological state of DNA, and are vital for DNA replication, transcription, repair and recombination.

Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from other classes of antimicrobial agents, such as β-lactam antibiotics, aminoglycosides, and macrolides. Therefore, microorganisms resistant to these latter classes of antimicrobial agents may be susceptible to fluoroquinolones. For example, β-lactamase production and alterations in penicillin-binding proteins have no effect on levofloxacin activity. Conversely, microorganisms resistant to fluoroquinolones may be susceptible to other classes of antimicrobial agents.

10.2 Pharmacodynamics

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

Two double-blind, placebo-controlled studies have been conducted to assess specifically the effect of levofloxacin on QT and corrected QT (QTc) intervals in healthy male and female volunteers 18-84 years of age. Each had a four-treatment crossover, single-dose study design. One study evaluated dose-response. The other was a comparative study that involved measuring the effects of doses of levofloxacin and two other fluoroquinolones. In this comparative study, subjects were given twice the doses of these antibiotics that are recommended for the treatment of otherwise healthy subjects with community-acquired pneumonia. 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 (top panels of figure A and figure B).

Dose escalation study (Figure A): 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. The change in QTc interval at C_max (calculated using the Bazett formula) after treatment with 500 mg of levofloxacin was not significantly different from that measured after treatment with placebo. In this trial, the mean change in the QTc (Bazett) at C_max from baseline QTc (calculated as the average QTc measured 24, 20, 16 hours and immediately before treatment) was -3.20 msec after treatment with 500 mg of levofloxacin, 7.82 msec after treatment with 1000 mg of levofloxacin and 10.58 msec after treatment with 1500 mg of levofloxacin.

Comparative, placebo-controlled study (Figure B; only levofloxacin and placebo data shown): 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. In this study, the change in the QTc (Bazett) at C_max from a baseline QTc (calculated as the average QTc measured 24, 20, 16 hours and immediately before treatment) was 5.32 msec after treatment with 1000 mg of levofloxacin.

10.3 Pharmacokinetics

The mean (± SD) pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following oral (PO) or intravenous (IV) doses of levofloxacin are summarized in Table 6.

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. After single oral doses of 250 to 1000 mg of levofloxacin to healthy subjects, plasma concentrations increase proportionally with the dose as shown (mean ± SD):

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 3-4 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 also penetrates into cortical and spongiosa bone tissues in both the femoral head and distal femur. Peak levofloxacin concentrations in these tissues ranging from 2.4 to 15 mcg/g were generally attained by 2 to 3 hours after a single 500 mg oral dose.

In vitro, over a clinically relevant range (1 to 10 mcg/mL) of serum/plasma levofloxacin concentrations, levofloxacin is 24 to 38% bound to serum proteins across all species studied, as determined by the equilibrium dialysis method. Levofloxacin is mainly bound (approximately 21 to 30%) to serum albumin in humans. 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 in the urine. Following oral administration, approximately 87% of an administered dose was recovered as unchanged drug in urine within 48 hours, whereas less than 4% of the dose was recovered in feces in 72 hours. Less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans. These metabolites have little relevant pharmacological activity.

Elimination

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 or intravenously. The mean apparent total body clearance and renal clearance range from approximately 144 to 226 mL/min and 96 to 142 mL/min, respectively. Renal clearance in excess of the glomerular filtration rate suggests that tubular secretion of levofloxacin occurs in addition to its glomerular filtration. Concomitant administration of either cimetidine or probenecid results in approximately 24% and 35% reduction in the levofloxacin renal clearance, indicating that secretion of levofloxacin occurs in the renal proximal tubule. No levofloxacin crystals were found in any of the urine samples freshly collected from subjects receiving levofloxacin.

Special Populations and Conditions

• Pediatrics: The pharmacokinetics of levofloxacin in pediatric patients have not been studied; therefore, Health Canada has not authorized an indication for pediatric use.
• 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. Following a 500 mg oral dose of levofloxacin to healthy elderly subjects (66-80 years of age), the mean terminal plasma elimination half-life of levofloxacin was about 7.6 hours, as compared to approximately 6 hours in younger adults. The difference was attributable to the variation in renal function status of the subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by age. Levofloxacin dose adjustment based on age alone is not necessary.
• Sex: There are no significant differences in levofloxacin pharmacokinetics between male and female subjects when the differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of levofloxacin to healthy male subjects, the mean terminal plasma elimination half-life of levofloxacin was about 7.5 hours, as compared to approximately 6.1 hours in female subjects. This difference was attributable to the variation in renal function status of the male and female subjects, and was not believed to be clinically significant. Drug absorption appears to be unaffected by the gender of the subjects. Dose adjustment based on gender alone is not necessary.
• Ethnic Origin: 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 6. 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 7 WARNINGS AND PRECAUTIONS, Renal, and 4 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.

  Plasma Ratio

  Comparison of the expected steady-state AUC values^a in renally impaired patients relative to those in patients with normal renal function:

^a Values were extrapolated from the mean levofloxacin plasma concentration-time data in subjects with normal renal function (n=23) and subjects with impaired renal function (n=3 for Cl_Cr 50-80 mL/min, n=8 for Cl_Cr 20-49 mL/min, and n=6 for Cl_Cr <20 mL/min).

Urine Concentrations

The mean ± SD concentrations (mcg/mL) of levofloxacin in the urine following a 500 mg PO dose of levofloxacin in subjects with impaired renal function are summarized as follows^a:

^a limit of quantitation = 25 mcg/mL

^b N= number of subjects

Expected steady-state urinary concentrations (mcg/mL) of levofloxacin in renally impaired patients with the recommended adjusted dose regimen in the treatment of complicated UTI and acute pyelonephritis^a:

^a Values were extrapolated from the mean pharmacokinetic profiles in subjects with impaired renal function (n=12 for Cl_Cr 50-80 mL/min, n=8 for Cl_Cr 20-49 mL/min, and n=6 for Cl_Cr <20 mL/min).

• Bacterial Infection: The pharmacokinetics of levofloxacin in patients with community-acquired bacterial infections are comparable to those observed in healthy subjects.
• HIV Infection: The pharmacokinetics of levofloxacin in HIV seropositive subjects (with CD4 cell counts ranging from 17 to 772) are comparable to those observed in healthy subjects.

11 STORAGE, STABILITY AND DISPOSAL

PRO-LEVOFLOXACIN tablets should be stored at controlled room temperature between 15°C and 30°C in well closed containers. Protect from moisture.

12 SPECIAL HANDLING INSTRUCTIONS

None.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Levofloxacin hemihydrate

Chemical name: (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

Molecular formula and molecular mass: C₁₈H₂₀FN₃O₄ . ½ H₂O, 370.4 g/mol (levofloxacin hemihydrate)

Structural formula:

Physicochemical properties: Light yellowish powder, odourless.

Solubility: Sparingly soluble in water and in methanol.

Solubility of Levofloxacin in water depends on pH

(PDR): -pH 2-5, solubility 100 mg/ml

-pH 5.8, solubility 272 mg/ml

-pH 7 and more, solubility 30-50 mg/ml pKa: pKa₁: 6

pKa₂: 8.2 (4, 5, 6)

Partition Coefficient: log P: - 0.4 (3)

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Acute Sinusitis

Study demographics and trial design

Table 7 - Summary of patient demographics for clinical trials in Acute Sinusitis

^a Subjects enrolled and randomized to treatment

^b 780 outpatient adults with clinically and radiologically determined acute maxillary sinusitis (ITT population)

Study Results

5 Day Treatment Regimen

Table 8 - Results of study CAPSS-232 in Acute Sinusitis

^a Test-of-Cure visit 17 to 22 days after first dose of active study drug (7-12 days after last dose for 500 mg arm, 12-17 days after last dose for 750 mg arm) in microbiologically clinically evaluable population (subset of 462 patients where sinus samples were taken by sinus puncture)

^b Clinical success was defined as complete (cured) or partial (improved) resolution of pre-treatment signs and symptoms of ABS to such extent that no further antibiotic treatment was deemed necessary ^c Two-sided 95% CIs (with continuity correction) around the difference in response rates

^d Microbiologically evaluable population

Table 9 - Clinical Success Rates^a for Microbiologically Evaluable Population^b (CAPSS-232)

^a Eradication rate for the three pathogens was the same as clinical success rate because microbiological success was presumed based on clinical success

^b Subset of 462 patients where sinus samples were taken by sinus puncture

10-14 Day Treatment Regimen

Table 10 – Clinical Success^a in Pivotal Acute Sinusitis Studies – Clinically Evaluable Subjects

^a cured plus improved

Table 11– Microbiologic Eradication in Pivotal Acute Sinusitis Studies – Microbiologically Evaluable Subjects

Table 12 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable

Population (N93-006)

Community Acquired Pneumonia

Study demographics and trial design

Table 13 - Summary of patient demographics for clinical trials in Community Acquired Pneumonia

^a Subjects enrolled and randomized to treatment

^b 528 outpatient and hospitalized adults with clinically and radiologically determined mild to severe community-acquired pneumonia

Study Results

5 Day Treatment Regimen

Table 14 - Results of study CAPSS-150 in Community Acquired Pneumonia

^a 7-14 days after last dose of active study medication for clinically evaluable population

^b success rates include the clinical response category of cured and improved

^c two-sided 95% CIs (with continuity correction) around the difference in response rates

^d 7-14 days after last dose of active study medication for microbiologically evaluable population

In the clinically evaluable population (31-38 days after enrollment) pneumonia was observed in 7 out of 151 patients in the levofloxacin 750 mg group and 2 out of 147 patients in the levofloxacin 500 mg group. Given the small numbers observed, the significance of this finding cannot be determined statistically.

Table 15 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable

Population (5-day regimen)

7 to 14 Day Treatment Regimen

In three North American clinical studies, of 655 patients treated with levofloxacin for community-acquired pneumonia, 45 clinically and microbiologically evaluable patients were defined as severely ill by study criteria and met American Thoracic Society criteria for severe community-acquired pneumonia (American Thoracic Society, 1993). Clinical success (cure and improvement) was achieved in 98% of these 45 patients. Data on the treatment of patients with severe Legionella pneumonia is limited to one patient.

Data on the treatment of community-acquired pneumonia due to penicillin-resistant S. pneumoniae is limited to 12 evaluable patients from the combined clinical trials database. Of these, 4 were considered to have been severe. All 12 patients achieved clinical success (see 15 MICROBIOLOGY).

The following tables describe the results from the two pivotal trials for community-acquired pneumonia (7-14 day treatment regimen).

Table 16 – Clinical Success^a in Pivotal Community Acquired Pneumonia Studies – Clinically Evaluable Subjects

^a cured plus improved

Table 17 – Microbiologic Eradication in Pivotal Community Acquired Pneumonia Studies -Microbiologically Evaluable Subjects

Table 18 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (K90-071)

Table 19 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (M92-075)

Acute Bacterial Exacerbation of Chronic Bronchitis

Study demographics and trial design

Table 20 - Summary of patient demographics for clinical trials in Acute Bacterial Exacerbation of Chronic Bronchitis

^a Subjects enrolled and randomized to treatment

^b From ITT population. Study subjects were characterized by FEV₁<50% predicted, or FEV₁ between 50% and 65% predicted, with ≥4 exacerbations in the preceding 12 months and/or the presence of significant co-morbidity. About half (48.2%) of the subjects were current smokers, with a mean pack-year history of 42.4

Study Results

5 Day Treatment Regimen

Table 21 - Results of Study CAPSS-197 in Acute Bacterial Exacerbation of Chronic Bronchitis

^a 17 to 26 days after the first dose of study drug for clinical evaluable subjects

^b Success rates include the clinical response category of cured and improved

^c Difference in success rates

^d Two-sided 95% CIs (with continuity correction) around the difference (amoxicillin/clavulanate minus levofloxacin) in clinical success rates

^e Microbiologically evaluable population

Table 22 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population

7 Day Treatment Regimen

Table 23– Clinical Success^a in Pivotal Acute Bacterial Exacerbation of Chronic Bronchitis Studies – Clinically Evaluable Subjects

^a Cured plus improved

Table 24 – Microbiologic Eradication in Pivotal Acute Bacterial Exacerbation of Chronic Bronchitis Studies – Microbiologically Evaluable Subjects

Table 25 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (K90-070)

Table 26 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (M92-024)

Nosocomial Pneumonia

Study demographics and trial design

Table 27 - Summary of patient demographics for clinical trials in Nosocomial Pneumonia

^a Subjects enrolled and randomized to treatment

Table 28 - Results of study CAPSS-117 in Nosocomial Pneumonia

^a Success includes Cured and Improved; clinically evaluable population

^b overall microbiologic eradication rates by subject for microbiologically evaluable population

Table 29 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (CAPSS-117)

Uncomplicated Skin and Skin Structure Infections

Study demographics and trial design

Table 30 - Summary of patient demographics for clinical trials in Uncomplicated Skin and Skin Structure Infections

^a Subjects enrolled and randomized to treatment

Study Results

Table 31 – Clinical Success^a in Pivotal Uncomplicated Skin and Skin Structure Infection Studies – Clinically Evaluable Subjects

^a cured plus improved

Table 32 – Microbiologic Eradication in Pivotal Uncomplicated Skin and Skin Structure Infection Studies – Microbiologically Evaluable Subjects

Table 33 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (K90-075)

Table 34 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (L91-031)

Complicated Skin and Skin Structure Infections

Study demographics and trial design

Table 35 - Summary of patient demographics for clinical trial in Complicated Skin and Skin Structure Infections

^a Subjects enrolled and randomized to treatment

Table 36 - Results of study LOFBIV-SSS-040 in Complicated Skin and Skin Structure Infections

^a Success includes Cured and Improved; clinically evaluable population

^b overall microbiologic eradication rates by subject for microbiologically evaluable population

Table 37 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (LOFBIV-SSS-040)

Complicated Urinary Tract Infection and Acute Pyelonephritis

Study demographics and trial design

Table 38 - Summary of patient demographics for clinical trials in Complicated Urinary Tract Infection (cUTI) and Acute Pyelonephritis (AP)

^a Subjects enrolled and randomized to treatment

^b Intent-to-treat population. Patients with AP complicated by underlying renal diseases or conditions such as complete obstruction, surgery, transplantation, concurrent infection or congenital malformation were excluded.

Study results

5 Day Treatment Regimen

Table 39 – Clinical Success^a in Complicated Urinary Tract Infection (cUTI) and Acute Pyelonephritis (AP) – Microbiologically Evaluable Subjects

^a Clinical success includes subjects who were cured or improved at the Posttherapy Visit

^b Two-sided 95% confidence interval around the difference (comparator minus levofloxacin)

Table 40 - Results of Study CAPSS-349 in Complicated Urinary Tract Infection (cUTI) and Acute Pyelonephritis (AP)

750 mg once daily for 5

days

Microbiologic Eradication^a

mITT Population ^b,c

Overall (cUTI or

AP) 240/317 (75.7)

0.1 (-6.6, 6.9)

^a At posttherapy visit (10-14 days after last active dose of levofloxacin and 5-9 days after last active dose of ciprofloxacin).

^b The mITT population included patients who had a clinical diagnosis of AP or cUTI and who had a positive (≥10⁵ CFU/mL) urine culture with no more than 2 uropathogens at Study Entry.

^c In the mITT population there were a limited number of patients treated with IV therapy (levofloxacin-8, comparator-9), with catheters (levofloxacin-4, comparator-5) and with bacteremia (levofloxacin-13, comparator-12).

^d The microbiologically evaluable population included patients with a confirmed diagnosis of cUTI or AP according to the protocol-specified inclusion criteria and with a known uropathogen with adequate growth (≥ 10⁵ CFU/mL) who met all other microbiologic evaluability criteria.

^e In the microbiologically evaluable population there were a limited number of patients treated with IV therapy (levofloxacin-4, comparator-3), with catheters (levofloxacin-3, comparator-3) and with bacteremia (levofloxacin-10, comparator-8).

^f Difference in eradication rates (comparator minus levofloxacin).

^g Two-sided 95% confidence interval around the difference (comparator minus levofloxacin) in microbiologic eradication rates.

Table 41 - Microbiologic Eradication Rates by Pathogen at Posttherapy Visit

Table 42 - Relapse Rates at Post-Study Visit^a

^a 33-40 days after the last active dose of levofloxacin and 28-35 days after the last active dose of ciprofloxacin

10 Day Treatment Regimen

Table 43 – Clinical Success^a in Pivotal cUTI and AP Studies – Microbiologically Evaluable Subjects

^a cured plus improved

Table 44 – Microbiologic Eradication in Pivotal cUTI and AP Studies – Microbiologically Evaluable Subjects

Table 45 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (L91-058)

Table 46 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (L91-059)

Uncomplicated Urinary Tract Infections

Study demographics and trial design

Table 47 - Summary of patient demographics for clinical trials in Uncomplicated Urinary Tract Infections

^a Subjects enrolled and randomized to treatment

Study Results

Table 48 - Results of study LOFBO-UTI-060 in Uncomplicated Urinary Tract Infections

^a Success includes Cured and Improved; microbiologically evaluable population

^b Overall microbiologic eradication rates by subject for microbiologically evaluable population

Table 49 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (LOFBO-UTI-060)

Chronic Bacterial Prostatitis

Study demographics and trial design

Table 50 - Summary of patient demographics for clinical trials in Chronic Bacterial Prostatitis

^a Subjects enrolled and randomized to treatment

Study Results

Table 51 - Results of study CAPSS-101 in Chronic Bacterial Prostatitis

^a Success includes Cured and Improved; mITT

^b Overall microbiologic eradication rates by subject for microbiologically evaluable population

Table 52 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (CAPSS-101)

14.2 Comparative Bioavailability Studies

Comparative bioavailability AA05476 employed a randomized, single dose two-way crossover bioavailability study of Pro Doc Ltée. and Ortho-McNeil Pharmaceutical, USA (Levaquin^®) 750 mg Levofloxacin tablets in eight healthy male and ten healthy nonpregnant female subjects under fasting conditions. The following table presents a summary of the comparative bioavailability data demonstrating bioequivalence of the test and reference tablets.

Summary Table of the Comparative Bioavailability Data

^* Levofloxacin 750 mg tablets manufactured for Pro Doc Ltée.

^† Levaquin^® (levofloxacin) 750 mg tablets manufactured by Ortho-McNeil Pharmaceutical, USA were purchased in USA.

^§ Expressed as the arithmetic mean (CV %) only.

15 MICROBIOLOGY

Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antibacterial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of levofloxacin and other quinolone antibacterials involves inhibition of bacterial topoisomerase II (DNA gyrase) and topoisomerase IV, enzymes required for DNA replication, transcription, repair, and recombination. In this regard, the L-isomer produces more hydrogen bonds and therefore, more stable complexes with DNA gyrase than does the D-isomer. Microbiologically, this translates into a 25- to 40-fold greater antibacterial activity for the L-isomer, levofloxacin, over the D-isomer. Quinolones rapidly and specifically inhibit bacterial DNA synthesis.

Levofloxacin has in vitro activity against a broad spectrum of gram-positive and gram-negative aerobic and anaerobic bacteria. Levofloxacin is often bactericidal at concentrations equal to or greater than the Minimum Inhibitory Concentrations (MIC). The in vitro activity of levofloxacin against clinical isolates is summarized in Table 53.

Table 53 - In Vitro Activity of Levofloxacin Against Clinical Isolates

* As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with levofloxacin.

** Data obtained for isolates from Complicated Skin and Skin Structure clinical studies, and literature, indicate the MIC value has increased for MRSA (see 1 INDICATIONS for approved organisms).

^† Based on NCCLS classification

Levofloxacin is not active against Treponema pallidum (see 7 WARNINGS AND PRECAUTIONS, General, Sexually Transmitted Diseases).

Resistance

Resistance to levofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10^-9 to 10^-10). Although cross-resistance has been observed between levofloxacin and other fluoroquinolones, some organisms resistant to other quinolones, including ofloxacin, may be susceptible to levofloxacin.

Susceptibility Tests

Susceptibility testing for levofloxacin should be performed, as it is the optimal predictor of activity.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method*¹ (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of levofloxacin powder. The MIC values should be interpreted according to the following criteria:

For testing aerobic microorganisms other than Haemophilus influenzae, Haemophilus parainfluenzae, and Streptococcus pneumoniae:

MIC (mcg/mL) Interpretation

≤2 Susceptible (S)

4 Intermediate (I)

≥8 Resistant (R)

For testing Haemophilus influenzae and Haemophilus parainfluenzae:^a

MIC (mcg/mL) Interpretation

≤2 Susceptible (S)

^a These interpretive standards are applicable only to broth microdilution susceptibility testing with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium*¹.

The current absence of data on resistant strains precludes defining any categories other than “Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

For testing Streptococcus pneumoniae:^b

MIC (mcg/mL) Interpretation

≤2 Susceptible (S)

4 Intermediate (I)

≥8 Resistant (R)

^b These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard levofloxacin powder should give the following MIC values:

^c This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution procedure using Haemophilus Test Medium (HTM)*¹.

^d This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a broth microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure*² requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg levofloxacin to test the susceptibility of microorganisms to levofloxacin. Reports from the laboratory, providing results of the standard single-disk susceptibility test with a 5 mcg levofloxacin disk, should be interpreted according to the following criteria:

For aerobic microorganisms other than Haemophilus influenzae, Haemophilus parainfluenzae, Streptococcus pneumoniae and Neisseria gonorrhoeae:

Zone diameter (mm) Interpretation

≥17 Susceptible (S)

14-16 Intermediate (I)

≤13 Resistant (R)

For Haemophilus influenzae and Haemophilus parainfluenzae:^e

Zone diameter (mm) Interpretation

≥17 Susceptible (S)

^e These interpretive standards are applicable only to disk diffusion susceptibility testing with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium* (HTM) ².

The current absence of data on resistant strains precludes defining any categories other than “Susceptible”. Strains yielding zone diameter results suggestive of a “Nonsusceptible” category should be submitted to a reference laboratory for further testing.

For Streptococcus pneumoniae:^f

Zone diameter (mm) Interpretation

≥17 Susceptible (S)

14-16 Intermediate (I)

≤13 Resistant (R)

^f These zone diameter standards for Streptococcus pneumoniae apply only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO₂.

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for levofloxacin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5 mcg levofloxacin disk should provide the following zone diameters in these laboratory test quality control strains

^g This quality control range is applicable to only H. influenzae ATCC 49247 tested by a disk diffusion procedure using Haemophilus Test Medium (HTM)* ².

^h This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a disk diffusion procedure using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO₂.

* References

1. 1. National Committee for Clinical Laboratory Standards: Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, Fourth Edition, 1997.
2. 2. National Committee for Clinical Laboratory Standards: Performance Standards for Antimicrobial Disk Susceptibility Tests, Sixth Edition,1997.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

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

Acute Toxicity

Table 54 - 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 55 – 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 tumourigenic 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.

Genotoxicity:

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).

Reproductive and Developmental Toxicology:

Table 56 - 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 Level.

Table 57 - 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 58 - Segment III: Perinatal and Postnatal

NOAEL = No Observable Adverse Effect Level

Special Toxicology:

Arthropathic Potential

Levofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested (see 7 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 7-8-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 mg/kg IV.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. TEVA-LEVOFLOXACIN^® (levofloxacin tablets and Injection), Submission control 226600, Product Monograph, Teva Canada Limited. (JUL 17, 2019).
2. 2. LEVAQUIN^®, Product Monograph, Janssen Inc., Canada. (AUG 13, 2014).
3. 3. LEVOFLOXACIN IN 5% DEXTROSE INJECTION (levofloxacin, 5 mg / mL Sterile solution for intravenous infusion), submission control 279109, Product Monograph, Pfizer Canada ULC. (FEB 13, 2024).
4. 4. APO-LEVOFLOXACIN® (levofloxacin tablets, 250 mg, 500 mg, 750 mg), submission control 289861, Product Monograph, Apotex Inc. (FEB 14, 2025)