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Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 10 DRUG INTERACTIONS 14 DOSAGE AND ADMINISTRATION 16 OVERDOSAGE 20 ACTION AND CLINICAL PHARMACOLOGY 20 STORAGE AND STABILITY 25 DOSAGE FORMS, COMPOSITION AND PACKAGING 25

PART II: SCIENTIFIC INFORMATION 27

PHARMACEUTICAL INFORMATION 27 CLINICAL TRIALS 28 DETAILED PHARMACOLOGY 44 MICROBIOLOGY 51 TOXICOLOGY 57 REFERENCES 64

PART III: CONSUMER INFORMATION. 66

Pr LEVAQUIN * levofloxacin

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

LEVAQUIN levofloxacin Tablets and Injection are contraindicated in persons with a history of hypersensitivity to levofloxacin, quinolone antimicrobial agents, or any other components of this product. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph. 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.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

LEVAQUIN (levofloxacin) has been shown to prolong the QT interval of the electrocardiogram in some patients (see WARNINGS AND PRECAUTIONS; Cardiovascular).

Serious hypersensitivity and/or anaphylactic reactions have been reported in patients receiving quinolone therapy, including LEVAQUIN (see WARNINGS AND PRECAUTIONS;

Sensitivity/Resistance).

Seizures may occur with quinolone therapy. LEVAQUIN should be used with caution in patients with known or suspected CNS disorders which may predispose to seizures or lower the seizure threshold (see WARNINGS AND PRECAUTIONS; Neurologic).

LEVAQUIN should not be used in pregnant women unless the potential benefits outweigh the potential risk to the fetus (see WARNINGS AND PRECAUTIONS; Special Populations).

For nursing mothers, a decision should be made to either discontinue nursing or discontinue the administration of LEVAQUIN, taking into account the importance of LEVAQUIN therapy to the mother and the possible risk to the infant (see WARNINGS AND PRECAUTIONS; Special Populations).

LEVAQUIN is not recommended for children under the age of 18 years (see WARNINGS AND PRECAUTIONS; Special Populations).

General

The oral and intravenous 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 TOXICOLOGY). Although levofloxacin is soluble, adequate hydration of patients receiving LEVAQUIN 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).

Musculoskeletal Effects

Ruptures of the shoulder, hand, Achilles tendon, or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including levofloxacin. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially the elderly. 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 tendonitis or tendon rupture has been confidently excluded. Tendon rupture can occur during or after therapy with quinolones, including levofloxacin (see CONTRAINDICATIONS).

I.V. Administration

Because rapid or bolus intravenous injection may result in hypotension, LEVOFLOXACIN INJECTION SHOULD ONLY BE ADMINISTERED BY SLOW INTRAVENOUS INFUSION OVER A PERIOD OF 60 MINUTES FOR A 500 MG DOSE, AND 90 MINUTES FOR A 750 MG DOSE (see DOSAGE AND ADMINISTRATION).

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

DETAILED PHARMACOLOGY; Human Pharmacology; Studies Measuring Effects on QT and Corrected QT (QTc) Intervals

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

).

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 LEVAQUIN. In patients treated with LEVAQUIN, 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) 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 (see DRUG INTERACTIONS, and ADVERSE REACTIONS). Serious hypoglycaemia and hyperglycemia have also occurred in patients without a history of diabetes.

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

DOSAGE AND ADMINISTRATION; Recommended Dose and Dosage Adjustment, Patients with Impaired Renal FunctionDETAILED PHARMACOLOGY; Special Populations, Renal Insufficiency

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

, and

).

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.

Special Populations

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

Pregnant Women: TOXICOLOGY

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

).

Nursing Women: TOXICOLOGY

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

).

Pediatrics (<18 years of age): TOXICOLOGYADVERSE REACTIONS

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

). 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

).

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).

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.

Drug-Drug Interactions

Table 4- Established or Potential Drug-Drug Interactions

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

Drug-Food Interactions

LEVAQUIN 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.

DOSAGE AND ADMINISTRATION

Dosing Considerations

The dosage of LEVAQUIN levofloxacin Tablets and Injection 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 the Patients with Impaired Renal Function subsection. The 250 mg and 500 mg doses of LEVAQUIN Injection should be administered by slow infusion over 60 minutes every 24 hours while the 750 mg dose is administered by slow infusion over 90 minutes every 24 hours.

Recommended Dose and Dosage Adjustment

Patients with Normal Renal Function

Infection * Dose Freq. Duration * *

Acute Bacterial Exacerbation of Chronic Bronchitis

500 mg q24h 7 days

750 mg q24h 5 days

Comm.- Acquired Pneumonia 500 mg q24h 7-14 days (10-14 days for

severe infections)

750 mg * * * q24h 5 days

Sinusitis 500 mg q24h 10-14 days

750 mg * * * * q24h 5 days Nosocomial Pneumonia 750 mg q24h 7-14 days Uncomplicated SSSI 500 mg q24h 7-10 days Complicated SSSI 750 mg q24h 7-14 days Chronic Bacterial Prostatitis 500 mg q24h 28 days Complicated UTI 250 mg q24h 10 days

750 mg++ q24h 5 days

Acute Pyelonephritis 250 mg q24h 10 days

750 mg q24h 5 days

Uncomplicated UTI 250 mg q24h 3 days

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

* * TOTAL THERAPY DURATION. When appropriate, patients may be converted from LEVAQUIN Injection to an equivalent dose of LEVAQUIN Tablets.

* * * 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 750mg daily for 5 days has been demonstrated to be non-inferior to a regimen of 500mg daily for 10 days. The 750mg daily 5 day regimen has not been compared to a regimen of 500mg 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 ACTION AND CLINICAL PHARMACOLOGY, DETAILED PHARMACOLOGY; Special Populations, Renal Insufficiency and WARNINGS AND PRECAUTIONS; Renal). 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 modeling 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.

Renal Status Initial Dose Subsequent Dose Acute Sinusitis / Acute Bacterial Exacerbation of Chronic Bronchitis / Community

Acquired Pneumonia / Uncomplicated SSSI / Chronic Bacterial Prostatitis

ClCr >= 20 mL/min No dosage adjustment required

ClCr from 10 to 19 mL/min 250 mg 250 mg q48h

Complicated SSSI / Nosocomial Pneumonia / Community Acquired Pneumonia/Acute Bacterial Exacerbation of Chronic Bronchitis/Acute Sinusitis/Complicated UTI/Acute Pyelonephritis

Uncomplicated UTI No dosage adjustment required 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 (kg) x (140 - age) x 1.2 serum creatinine (umol/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 LEVAQUIN should not be taken, even if a dose is missed.

Administration

Tablets

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.

Injection

CAUTION: RAPID OR BOLUS INTRAVENOUS INFUSION MUST BE AVOIDED.

Levofloxacin injection should be infused intravenously, slowly over a period of not less than 60 minutes for a 250 mg or a 500 mg dose, and not less than 90 minutes for a 750 mg dose. LEVAQUIN Injection should only be administered by intravenous infusion. It is not for intramuscular, intrathecal, intraperitoneal, or subcutaneous administration (see WARNINGS AND PRECAUTIONS).

LEVAQUIN Injection Premix in single-use flexible containers does not require further dilution. Consequently, each 50 mL, 100 mL and 150 mL of PREMIXED solution contains the equivalent of 250 mg, 500 mg and 750 mg of levofloxacin (5mg/mL), respectively in 5% Dextrose (D5W).

This parenteral drug product should be inspected visually for clarity, discoloration, particulate matter, precipitate, and leakage prior to administration. Samples containing visible particles should be discarded.

Since the premix flexible containers are for single use only, any unused portion should be discarded.

Since only limited data are available on the compatibility of levofloxacin intravenous injection with other intravenous substances, additives or other medications should not be added to LEVAQUIN Injection or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of LEVAQUIN Injection with an infusion solution compatible with LEVAQUIN Injection and with any other drug(s) administered via this common line.

Instructions for the Use of LEVAQUIN Injection PREMIX in flexible containers

To open Tear outer wrap at the notch and remove solution container. Check the container for minute leaks by squeezing the inner bag firmly. If leaks are found, or if the seal is not intact, discard the solution, as the sterility may be compromised. Do not use if the solution is cloudy or a precipitate is present. Use sterile equipment.

WARNING: Do not use flexible containers in series connections.

Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

Preparation for administration Close flow control clamp of administration set. Remove cover from port at bottom of container. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated.

NOTE: See full directions on administration set carton.

Suspend container from hanger. Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of LEVAQUIN Injection in PREMIX flexible containers. Open flow control clamp to expel air from set. Close clamp. Regulate rate of administration with flow control clamp.

OVERDOSAGE

In the event of an acute overdosage, the stomach should be emptied. The patient should be observed, including ECG monitoring (see ACTION AND CLINICAL PHARMACOLOGY; 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. The administration of activated charcoal as soon as possible after oral overdose may prevent excessive increase of systemic levofloxacin exposure. LEVAQUIN exhibits a low potential for acute toxicity. Mice, rats, dogs and monkeys exhibited the following clinical signs after receiving a single high dose of LEVAQUIN: ataxia, ptosis, decreased locomotor activity, dyspnea, prostration, tremors, and convulsions. Doses in excess of 1500 mg/kg orally and 250 mg/kg IV produced significant mortality in rodents. For management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

LEVAQUIN levofloxacin is a synthetic broad-spectrum antibacterial agent for oral 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 b-lactam antibiotics, aminoglycosides, and macrolides. Therefore, microorganisms resistant to these latter classes of antimicrobial agents may be susceptible to fluoroquinolones. For example, b-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.

Pharmacodynamics

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 DETAILED PHARMACOLOGY; Human Pharmacology; Studies Measuring the Effects on QT and Corrected QT (QTc) Intervals).

Pharmacokinetics

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 the following table.

Table 1.2 - Summary of Pharmacokinetic Parameters (mean +- SD)

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 AUC0-24 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

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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 ug/mL and 0.5 ug/mL after the 500 mg doses, and 8.6 ug/mL and 1.1 ug/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.

I.V.

Following a single intravenous dose of levofloxacin to healthy volunteers, the mean peak plasma concentration attained was 6.2 ug/mL after a 500 mg dose infused over 60 minutes, and 7.99 ug/mL after a 750 mg dose infused over 90 minutes. Levofloxacin pharmacokinetics are linear and predictable after single and multiple i.v. dosing regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once-daily dosing regimen. The peak and trough plasma concentrations attained following multiple once-daily i.v. regimens were approximately 6.4 ug/mL and 0.6 ug/mL after the 500 mg doses, and 7.92 ug/mL and 0.85 ug/mL after the 750 mg doses, respectively. The plasma concentration profile of levofloxacin after i.v. administration is similar and comparable in extent of exposure (AUC) to that observed for levofloxacin tablets when equal doses (mg/mg) are administered. Therefore, the oral and i.v. routes of administration can be considered interchangeable (see following figure).

Mean Levofloxacin Plasma Concentration:Time Profiles

Plasma Concentration (ug/mL)

500 mg p.o.

500 mg i.v.

0 6 12 18 24 30 36

Time (h)

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 ug/g for a 750 mg dose) and in blister fluid (4.33 ug/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 ug/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 or intravenously.

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 1.2. 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 modeling 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.

STORAGE AND STABILITY

Tablets

LEVAQUIN Tablets should be stored at controlled room temperature (15-30degC) in well-closed containers.

Injection

When stored under recommended conditions, LEVAQUIN Injection, as supplied in flexible containers, is stable through the expiration date printed on the label. LEVAQUIN Injection PREMIX in flexible containers should be stored at 2-25degC; however, brief exposure up to 40degC does not adversely affect the product. Avoid excessive heat and protect from freezing and light. Store with protective overwrap and use immediately once removed from the overwrap.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Tablets

LEVAQUIN levofloxacin 250 mg Tablets are supplied as modified rectangular, film-coated, terra cotta pink tablets embossed "LEVAQUIN" on one side and "250" on the other. LEVAQUIN levofloxacin 500 mg Tablets are supplied as modified rectangular, film-coated, peach tablets embossed "LEVAQUIN" on one side and "500" on the other. LEVAQUIN levofloxacin 750 mg Tablets are supplied as modified rectangular, film-coated, white tablets embossed "LEVAQUIN" on one side and "750" on the other. LEVAQUIN Tablets are packaged in bottles of 50 tablets. LEVAQUIN levofloxacin Tablets contain the following inactive ingredients: 250 mg: hydroxypropyl methylcellulose, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, titanium dioxide, polysorbate 80, and synthetic red iron oxide. 500 mg: hydroxypropyl methylcellulose, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, titanium dioxide, polysorbate 80, and synthetic red and yellow iron oxides. 750 mg: hydroxypropyl methylcellulose, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, titanium dioxide, and polysorbate 80.

LEVAQUIN Injection

LEVAQUIN Injection in Premix flexible containers is a sterile, preservative-free, non-pyrogenic premixed solution that contains levofloxacin, at 5 mg/mL in 5% dextrose (D5W). The solution has a pH ranging from 3.8 to 5.8. Solutions of hydrochloric acid and/or sodium hydroxide may have been added to adjust the pH. The flexible container is fabricated from a specially formulated non-plasticized, thermoplastic copolyester (CR3). The amount of water that can permeate from the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the flexible container can leach out certain of the container's chemical components in very small amounts within the expiration period. The suitability of the container material has been confirmed by tests in animals according to USP biological tests for plastic containers. LEVAQUIN Injection is supplied in single-use flexible containers containing a premixed, ready- to-use levofloxacin solution in D5W in the following formats: containers of 100 mL capacity containing 50 or 100 mL of PREMIXED solution containers of 150 mL capacity containing 150 mL of PREMIXED solution Supplied in cases of 12 flexible containers

NO FURTHER DILUTION OF THESE PREPARATIONS ARE NECESSARY.

Consequently, each 50 mL, 100 mL and 150 mL of PREMIXED solution contains the equivalent of 250 mg, 500 mg and 750 mg of levofloxacin (5 mg/mL), respectively in 5% Dextrose (D5W).

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: levofloxacin 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: C18H20FN3O4 * 1/2 H2O Molecular mass: 370.38 Structural formula:

O F

N N

O

COOH

* 1/2 H20 Physicochemical Properties: Levofloxacin is a light yellowish white to yellow-white crystal or crystalline powder with a melting point of 226-227degC. The pKa values for levofloxacin are 5.33 and 8.07 for pKa1 and pKa2, respectively. The molecule exists as a zwitterion at the pH conditions in the small intestine. The data demonstrate that, from pH 0.6 to 5.8, the solubility of levofloxacin is essentially constant (approximately 100 mg/mL). Levofloxacin is considered soluble to freely soluble in this pH range, as defined by USP nomenclature. Above pH 5.8, the solubility increases rapidly to its maximum at pH 6.7 (272 mg/mL), and is considered freely soluble in this range. Above pH 6.7, the solubility decreases and reaches a minimum value (about 50 mg/mL) at a pH of approximately 6.9. Levofloxacin is considered freely soluble to soluble at the pH range of 6.7 to 7.7, beyond which the solubility begins to increase again. Levofloxacin has the potential to form stable co-ordination compounds with many metal ions. This in vitro chelation potential has the following formation order: Al+3 >Cu+2 >Zn+2 >Mg+2 >Ca+2.

CLINICAL TRIALS

Acute Sinusitis

Study demographics and trial design

Table 2.1 - 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 2.2 - Results of study CAPSS-232 in Acute Sinusitis

1. 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).

2. 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

3. Two-sided 95% CIs (with continuity correction) around the difference in response rates

4. Microbiologically evaluable population

Table 2.3 - Clinical Success Ratesa for Microbiologically Evaluable Populationb (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 2.4 - Clinical Successa in Pivotal Acute Sinusitis Studies - Clinically Evaluable Subjects

a

cured plus improved

Table 2.5 - Microbiologic Eradication in Pivotal Acute Sinusitis Studies - Microbiologically Evaluable Subjects

Table 2.6 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (N93-006)

Community Acquired Pneumonia

Study demographics and trial design

Table 2.7 - 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 2.8 - Results of study CAPSS-150 in Community Acquired Pneumonia

1. 7-14 days after last dose of active study medication for clinically evaluable population

2. success rates include the clinical response category of cured and improved

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

4. 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 2.9 - 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 MICROBIOLOGY). The following tables describe the results from the two pivotal trials for community-acquired pneumonia (7-14 day treatment regimen).

Table 2.10 - Clinical Successa in Pivotal Community Acquired Pneumonia Studies - Clinically Evaluable Subjects

a

cured plus improved

Table 2.11 - Microbiologic Eradication in Pivotal Community Acquired Pneumonia Studies - Microbiologically Evaluable Subjects

Table 2.12 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (K90-071)

Table 2.13 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (M92-075)

Acute Bacterial Exacerbation of Chronic Bronchitis

Study demographics and trial design

Table 2.14 - 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 2.15 - Results of Study CAPSS-197 in Acute Bacterial Exacerbation of Chronic Bronchitis

1. 17 to 26 days after the first dose of study drug for clinical evaluable subjects

2. Success rates include the clinical response category of cured and improved

3. Difference in success rates

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

e

Microbiologically evaluable population

Table 2.16 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population

7 Day Treatment Regimen

Table 2.17 - Clinical Successa in Pivotal Acute Bacterial Exacerbation of Chronic Bronchitis Studies - Clinically Evaluable Subjects

a

Cured plus improved

Table 2.18 - Microbiologic Eradication in Pivotal Acute Bacterial Exacerbation of Chronic Bronchitis Studies

Microbiologically Evaluable Subjects

Table 2.19 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (K90-070)

Table 2.20 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (M92-024)

Nosocomial Pneumonia

Study demographics and trial design

Table 2.21 - Summary of patient demographics for clinical trials in Nosocomial Pneumonia

a

Subjects enrolled and randomized to treatment

Table 2.22 - 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 2.23 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (CAPSS-117)

Uncomplicated Skin and Skin Structure Infections

Study demographics and trial design

Table 2.24 - Summary of patient demographics for clinical trials in Uncomplicated Skin and Skin Structure Infections

a

Subjects enrolled and randomized to treatment

Study Results

Table 2.25 - Clinical Successa in Pivotal Uncomplicated Skin and Skin Structure Infection Studies - Clinically Evaluable Subjects

a

cured plus improved

Table 2.26 - Microbiologic Eradication in Pivotal Uncomplicated Skin and Skin Structure Infection Studies - Microbiologically Evaluable Subjects

Table 2.27 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (K90-075)

Table 2.28 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (L91-031)

Complicated Skin and Skin Structure Infections

Study demographics and trial design

Table 2.29 - Summary of patient demographics for clinical trial in Complicated Skin and Skin Structure Infections

a

Subjects enrolled and randomized to treatment

Table 2.30 - 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 2.31 - 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 2.32 - 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 2.33 - Clinical Successa 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 2.34 - Results of Study CAPSS-349 in Complicated Urinary Tract Infection (cUTI) and Acute Pyelonephritis (AP)

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 2.35 - Microbiologic Eradication Rates by Pathogen at Posttherapy Visit

Table 2.36 - Relapse Rates at Post-Study Visita

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 2.37 - Clinical Successa in Pivotal cUTI and AP Studies - Microbiologically Evaluable Subjects

a

cured plus improved

Table 2.38 - Microbiologic Eradication in Pivotal cUTI and AP Studies - Microbiologically Evaluable Subjects

Table 2.39 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (L91-058)

Table 2.40 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (L91-059)

Uncomplicated Urinary Tract Infections

Study demographics and trial design

Table 2.41 - Summary of patient demographics for clinical trials in Uncomplicated Urinary Tract Infections

a

Subjects enrolled and randomized to treatment

Study Results

Table 2.42 - 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 2.43 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (LOFBO-UTI-060)

Chronic Bacterial Prostatitis

Study demographics and trial design

Table 2.44 - Summary of patient demographics for clinical trials in Chronic Bacterial Prostatitis

a

Subjects enrolled and randomized to treatment

Study Results

Table 2.45 - 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 2.46 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable Population (CAPSS-101)

DETAILED PHARMACOLOGY

Animal Pharmacology

Pharmacodynamics

A summary of the major findings obtained from animal pharmacology studies with levofloxacin is presented below:

Table 2.47 - Summary of Major Nonclinical Pharmacological Effects of Levofloxacin

In mice, the CNS stimulatory effect of quinolones is enhanced by concomitant administration of non-steroidal anti-inflammatory drugs. In vitro and in vivo studies in animals indicate that levofloxacin is neither an enzyme inducer nor inhibitor in the human therapeutic plasma concentration range; therefore, no drug metabolizing enzyme-related interactions with other drugs or agents are anticipated.

Human Pharmacology

Pharmacodynamics

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

Two double-blind, placebo-controlled studies assessing the effect of levofloxacin on QTc intervals in healthy male and female volunteers 18-84 years of age were conducted. 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 both trials, no effect on QT intervals compared to placebo was evident at any of the doses of levofloxacin studied (top panels of figure A and figure B).

Dose escalation study (Figure A):

In this trial, the mean change in the average QTc interval (calculated from measurements taken every half hour for two hours and at 4, 8, 12 and

24 hours after treatment) from the baseline QTc (calculated as the average QTc measured 24, 20, 16 hours and immediately before treatment) was a decrease of 1.84 msec after treatment with 500 mg, an increase of 1.55 msec after treatment with 1000 mg of levofloxacin and an increase of 6.40 msec after treatment with 1500 mg. The change in QTc interval at Cmax (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 Cmax 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 this study, the mean change in the average QTc interval (calculated from measurements taken every half hour for four hours and at 8, 12 and 24 hours after treatment) from the baseline QTc (calculated as the average QTc measured 24, 20, 16 hours and immediately before treatment) was 3.58 msec after treatment with 1000 mg levofloxacin. In this study, the change in the QTc (Bazett) at Cmax 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.

FIGURE A

Mean QT and QTc Bazett versus Time after Dose of Placebo, 500 mg, 1000 mg or

1500 mg Levofloxacin (Dose Escalation Study n=48)

FIGURE B

Mean QT and QTc Bazett versus Time after Dose of Placebo

or 1000 mg of Levofloxacin

(Comparative Study n=48)

Mean QT (not corrected)

Mean QTc (Bazett)

Placebo

500 mg Levofloxacin

1000 mg Levofloxacin

1500 mg Levofloxacin

Mean QT (not corrected)

Mean QTc (Bazett)

Placebo

Levofloxacin (1000 mg)

0 4 8 12 16 20 24

Time after dose

0 4 8 12 16 20 24

Time after dose

Pharmacokinetics

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): Oral Dose Peak Plasma Concentration Area Under the Curve

(mg) n (ug/mL) 0-[?]

(AUC

, ug.h/mL)

Steady-state conditions are reached within 48 hours following 500 mg or 750 mg once-daily dosage regimens. The peak and trough plasma concentrations attained following multiple once- daily oral dosage regimens were approximately 5.7 and 0.5 ug/mL after the 500 mg doses, and 8.6 and 1.1 ug/mL after the 750 mg doses, respectively. Oral administration with food slightly prolongs the time to peak concentration by approximately 1 hour and slightly decreases the peak concentration by approximately 14%.

Intravenous

Levofloxacin pharmacokinetics are linear and predictable after single and multiple i.v. dosing regimens. Following a single intravenous dose of levofloxacin to healthy volunteers, the mean peak plasma concentration attained was 6.2 ug/mL after a 500 mg dose infused over 60 minutes and 7.99 ug/mL after a 750 mg dose infused over 90 minutes. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once-daily dosing regimen. The peak and trough plasma concentrations attained following multiple once-daily i.v. regimens were approximately 6.4 ug/mL and 0.6 ug/mL after the 500 mg doses, and 7.92 ug/mL and 0.85 ug/mL after the 750 mg doses, respectively. The plasma concentration profile of levofloxacin after i.v. administration is similar and comparable in extent of exposure (AUC) to that observed for levofloxacin tablets when equal doses (mg/mg) are administered. Therefore, the oral and i.v. routes of administration can be considered interchangeable.

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 ug/g for a 750 mg dose) and in blister fluid (4.33 ug/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 range from approximately 2.4 to 11.3 ug/g over a 24-hour period after a single 500 mg 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 ug/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 ug/mL) of serum/plasma levofloxacin concentrations, levofloxacin is approximately 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.

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 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.

Factors Influencing the Pharmacokinetics

Special Populations

Elderly

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.

Pediatric

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

Gender

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.

Race

The effect of race on levofloxacin pharmacokinetics was examined through a covariate analysis performed on data from 72 subjects: 48 white and 24 nonwhite. The apparent total body clearance and apparent volume of distribution were not affected by the race of the subjects.

Renal Insufficiency

Clearance of levofloxacin is reduced and plasma elimination half-life is prolonged in patients with impaired renal function (creatinine clearance <=80 mL/min). Dosage adjustment may be required in such patients to avoid levofloxacin accumulation. 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 (see ACTION AND CLINICAL PHARMACOLOGY; Pharmacokinetics, WARNINGS AND PRECAUTIONS; Renal, and DOSAGE AND ADMINISTRATION).

Plasma Ratio

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

Creatinine Clearance 50-80 mL/min receiving

500 mg q24h

Creatinine Clearance 20-49 mL/min receiving

250 mg q24h

Creatinine Clearance

<20 mL/min receiving

250 mg q48h

AUC value relative to patients with normal renal function receiving 500 mg q24h

AUC value relative to patients with normal renal function receiving 500 mg q12h

172% 183% 139%

89% 94% 71%

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 ClCr 50 - 80 mL/min, n = 8 for ClCr 20

- 49 mL/min, and n = 6 for ClCr <20 mL/min).

Urine Concentrations

The mean +- SD concentrations (ug/mL) of levofloxacin in the urine following a 500 mg p.o. dose of levofloxacin in subjects with impaired renal function are summarized as followsa:

Collection Interval

ClCr 50-80 mL/min

nb = 3

ClCr 20-49 mL/min

n = 8

ClCr <20 mL/min

n = 6

0__6 h 185+-61.7 98.1+-48.1 66.5+-27.3

6__12 h 91.6+-24.4 75.2+-22.1 39.0+-23.1

12 24 h 156+-183 58.6+-31.1 29.5+-20.7

24 36 h 49.7+-16.2 44.1+-10.6 <25

36 48 h <25 <25 <25

a

Limit of quantitation = 25 ug/mL

b

n = number of subjects

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

Collection Interval

ClCr 50-80 mL/min

receiving 250 mg

q24 h

ClCr 20-49 mL/min

receiving 250 mg

q24h

ClCr <20 mL/min

receiving 250 mg

q48h

0__6 h 161 103 54

6 12 h 61 76 29

12 24 h 40 58 24

24 36 h - - 23

36 48 h - - 16

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

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.

Bacterial Infection

The pharmacokinetics of levofloxacin in patients with serious 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.

Drug-Drug Interactions

The potential for pharmacokinetic drug interactions between levofloxacin and theophylline, warfarin, cyclosporine, digoxin, probenecid, cimetidine, sucralfate, zidovudine and antacids has been evaluated (see DRUG INTERACTIONS).

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 the following table.

Table 2.48 - 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 INDICATIONS AND CLINICAL USE for approved organisms).

++

Based on NCCLS classification

Levofloxacin is not active against Treponema pallidum (see WARNINGS AND PRECAUTIONS; 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 (ug/mL) Interpretation

<=2 Susceptible (S) 4 Intermediate (I) >=8 Resistant (R) For testing Haemophilus influenzae and Haemophilus parainfluenzae:a

MIC (ug/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 (ug/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:

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

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 ug 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 ug levofloxacin disk, should be interpreted according to the following criteria: For aerobic microorganisms other than Haemophilus influenzae, Haemophilus parainfluenzae, Streptococcus pneumoniae and Nisseria 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)

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)

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 ug levofloxacin disk should provide the following zone diameters in these laboratory test quality control strains:

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

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

2. National Committee for Clinical Laboratory Standards: Performance Standards for Antimicrobial Disk Susceptibility Tests, Sixth Edition, 1997.

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 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 Level.

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 7-8-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 mM. At therapeutic doses of 250, 500, and 750 mg levofloxacin, the peak unbound plasma concentrations ranged from 6 mM for a single oral levofloxacin dose of 250 mg to 12 mM and 15 mM 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 mM. 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.

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