JAMP LEVOFLOXACIN TABLET

Canada - English - Health Canada

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Active ingredient:
LEVOFLOXACIN (LEVOFLOXACIN HEMIHYDRATE)
Available from:
JAMP PHARMA CORPORATION
ATC code:
J01MA12
INN (International Name):
LEVOFLOXACIN
Dosage:
500MG
Pharmaceutical form:
TABLET
Composition:
LEVOFLOXACIN (LEVOFLOXACIN HEMIHYDRATE) 500MG
Administration route:
ORAL
Units in package:
100
Prescription type:
Prescription
Therapeutic area:
QUINOLONES
Product summary:
Active ingredient group (AIG) number: 0131663004; AHFS: 08:12.18
Authorization status:
APPROVED
Authorization number:
02508451
Authorization date:
2020-11-24

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JAMP Levofloxacin

Page 1 of 68

PRODUCT MONOGRAPH

Pr

JAMP Levofloxacin

Levofloxacin Tablets, USP

250 mg, 500 mg and 750 mg Levofloxacin

as Levofloxacin Hemihydrate

Antibacterial Agent

JAMP Pharma Corporation

Date of Approval: November 23, 2020

1310, rue Nobel

Boucherville, Québec

J4B 5H3

Submission Control No: 232133

JAMP Levofloxacin

Page 2 of 68

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 ........................................................................................................ 12

DRUG INTERACTIONS ........................................................................................................ 16

DOSAGE AND ADMINISTRATION ........................................................................................ 18

OVERDOSAGE ..................................................................................................................... 20

ACTION AND CLINICAL PHARMACOLOGY ......................................................................... 21

STORAGE AND STABILITY .................................................................................................. 25

DOSAGE FORMS, COMPOSITION AND PACKAGING ........................................................ 25

PART II: SCIENTIFIC INFORMATION...................................................................................... 27

PHARMACEUTICAL INFORMATION .................................................................................... 27

CLINICAL TRIALS ................................................................................................................. 28

DETAILED PHARMACOLOGY .............................................................................................. 41

MICROBIOLOGY .................................................................................................................. 47

TOXICOLOGY ...................................................................................................................... 51

REFERENCES ...................................................................................................................... 57

PATIENT MEDICATION INFORMATION ................................................................................. 60

JAMP Levofloxacin

Page 3 of 68

Pr

JAMP Levofloxacin

Levofloxacin Tablets, USP

250 mg, 500 mg and 750 mg

as levofloxacin hemihydrate

Antibacterial Agent

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage

Form/

Strength

All Nonmedicinal

Ingredients

Oral

Tablet/ 250 mg,

500 mg and 750 mg

microcrystalline cellulose, crospovidone,

hypromellose, magnesium stearate, ferric

oxide yellow (500 mg strengths only),

ferric

oxide red (250 mg and 500 mg strengths

only), polysorbate 80, polyethylene glycol and

titanium dioxide.

INDICATIONS AND CLINICAL USE

JAMP 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.

Upper Respiratory Tract

Acute sinusitis (mild to moderate) due to Streptococcus pneumoniae, Haemophilus influenzae, or

Moraxella (Branhamella) catarrhalis.

“Restrict the use of JAMP Levofloxacin to settings where no other treatment options exist, and

the clinical presentation meets the diagnostic criteria for acute bacterial sinusitis

.”

Lower Respiratory Tract

Acute bacterial exacerbations of chronic bronchitis (mild to moderate) due to Staphylococcus

aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or

Moraxella (Branhamella) catarrhalis.

Community-acquired pneumonia (mild, moderate and severe infections) due to Staphylococcus

aureus, Streptococcus pneumoniae (including penicillin-resistant strains), Haemophilus

influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella (Branhamella)

catarrhalis, Chlamydia pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae (see

Canadian clinical practice guidelines for acute and chronic rhinosinusitis. Desrosiers et al.

Allergy, Asthma and

Clinical Immunology, 2011, 7:2

JAMP Levofloxacin

Page 4 of 68

DOSAGE AND ADMINISTRATION, and 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.

JAMP Levofloxacin is not indicated for acute bronchitis.

JAMP Levofloxacin should not be prescribed to patients with acute bacterial exacerbations of

simple/uncomplicated chronic obstructive pulmonary disease (ie. patients who have chronic

obstructive pulmonary disease without underlying risk factors)

Skin and Skin Structure

Uncomplicated skin and skin structure infections (mild to moderate) due to Staphylococcus

aureus or Streptococcus pyogenes.

Complicated skin and skin structure infections (mild to moderate), excluding burns, due to

Enterococcus faecalis, methicillin-sensitive Staphylococcus aureus, Streptococcus pyogenes,

Proteus mirabilis, or Streptococcus agalactiae.

Urinary Tract

Complicated urinary tract infections (mild to moderate) due to Enterococcus (Streptococcus)

faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or

Pseudomonas aeruginosa (see DOSAGE AND ADMINISTRATION and CLINICAL TRIALS).

Uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella

pneumoniae or Staphylococcus saprophyticus.

Acute pyelonephritis (mild to moderate) caused by Escherichia coli (see DOSAGE AND

ADMINISTRATION and CLINICAL TRIALS).

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

epidermidis.

Appropriate culture and susceptibility tests should be performed before treatment in order to

isolate and identify the organisms causing the infection, and to determine their susceptibility to

levofloxacin. Therapy with JAMP Levofloxacin may be initiated before the results of these tests

known; once results become available, appropriate therapy should be continued.

In cases of uncomplicated acute bacterial cystitis, limit the use of JAMP Levofloxacin to

circumstances where no other treatment options are available. A urine culture should be

obtained

prior to treatment to ensure levofloxacin susceptibility.

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

JAMP Levofloxacin

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As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop

resistance fairly rapidly during treatment with JAMP Levofloxacin. Culture and susceptibility

testing

performed periodically during therapy, will reveal not only the therapeutic effect of the

antimicrobial agent, but also the possible emergence of bacterial resistance.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of JAMP

Levofloxacin and other antibacterial drugs, JAMP 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.

Geriatrics (≥65 years of age):

Drug absorption appears to be unaffected by age. Dose adjustment based on age alone is not

necessary (see WARNINGS AND PRECAUTIONS, Special Populations and ACTION AND

CLINICAL PHARMACOLOGY, Special Populations and Conditions).

Pediatric Use (<18 years of age):

Safety and effectiveness in children under 18 years of age have not been established (see

WARNINGS AND PRECAUTIONS, Special Populations).

CONTRAINDICATIONS

JAMP Levofloxacin is contraindicated in persons with a history of hypersensitivity to

levofloxacin,

quinolone antimicrobial agents, or to any components of this product. For a

complete listing, see

the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the

Product

Monograph.

JAMP 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

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 levofloxacin (see WARNINGS AND

PRECAUTIONS, Immune).

Seizures may occur with quinolone therapy. JAMP Levofloxacin 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).

JAMP Levofloxacin

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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 TOXICOLOGY).

Although levofloxacin is soluble, adequate hydration of patients receiving levofloxacin should be

maintained to prevent the formation of a highly concentrated urine. Crystalluria has been

observed rarely in patients receiving other quinolones, when associated with high doses and an

alkaline urine. Although crystalluria was not observed in clinical trials with levofloxacin, patients

are encouraged to remain adequately hydrated.

As with any antimicrobial drug, periodic assessment of organ system functions, including renal,

hepatic, and hematopoietic, is advisable during prolonged therapy (see ADVERSE

REACTIONS).

Use of JAMP Levofloxacin with other drugs may lead to drug-drug interactions (see DRUG

INTERACTIONS, Drug-Drug Interactions).

Sexually Transmitted Diseases

JAMP Levofloxacin is not indicated for the treatment of syphilis or gonorrhea. Levofloxacin is not

effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of

time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with

gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with

antimicrobial agents with limited or no activity against Treponema pallidum should have a

follow-

up serologic test for syphilis after 3 months.

Cardiovascular

QT Prolongation

Some quinolones, including levofloxacin, have been associated with prolongation of the QT

interval on the electrocardiogram and infrequent cases of arrhythmia. During post-marketing

surveillance, very rare cases of torsades de pointes have been reported in patients taking

levofloxacin. These reports generally involved patients with concurrent medical conditions or

concomitant medications that may have been contributory. The risk of arrhythmias may be

reduced by avoiding concurrent use with other drugs that prolong the QT interval including

macrolide antibiotics, antipsychotics, tricyclic antidepressants, Class IA (e.g., quinidine,

procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic agents, and cisapride. In

addition, use of levofloxacin in the presence of risk factors for torsades de pointes such as

hypokalemia, significant bradycardia, cardiomyopathy, patients with myocardial ischemia, and

Fluoroquinolones, including JAMP Levofloxacin, may exacerbate muscle weakness in

persons with myasthenia gravis. Avoid JAMP Levofloxacin in patients with a known history

of myasthenia gravis (see WARNINGS AND PRECAUTIONS, Musculoskeletal).

Fluoroquinolones, including levofloxacin, have been associated with disabling and

potentially persistent adverse reactions which to date include, but are not limited to:

tendonitis, tendon rupture, peripheral neuropathy and neuropsychiatric effects.

JAMP Levofloxacin

Page 7 of 68

patients with congenital prolongation of the QT interval should be avoided (see DETAILED

PHARMACOLOGY, Human Pharmacology, Studies Measuring Effects on QT and Corrected

QT (QTc) Intervals).

Aortic Aneurysm and Aortic Dissection

Epidemiologic studies report an increased risk of aortic aneurysm and dissection after intake of

fluoroquinolones, particularly in the older population.

Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after

consideration of other therapeutic options in patients with positive family history of aneurysm

disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or

presence of other risk factors for aortic aneurysm and dissection (e.g., Marfan syndrome,

vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet's disease,

hypertension, atherosclerosis).

In case of sudden severe abdominal, chest or back pain, patients should be advised to

immediately consult a physician in an emergency department.

Endocrine and Metabolism

Blood Glucose Disturbances

Fluoroquinolones, including levofloxacin, have been associated with disturbances of blood

glucose, including symptomatic hyperglycemia and hypoglycemia, usually in diabetic patients

receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with

insulin. In these patients, careful monitoring of blood glucose is recommended. SEVERE

CASES OF HYPOGLYCEMIA RESULTING IN COMA OR DEATH HAVE BEEN

REPORTED. If a hypoglycemic reaction occurs, discontinue JAMP Levofloxacin

immediately and initiate appropriate therapy.

Disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been

reported with the use of quinolones, including levofloxacin. In patients treated with levofloxacin,

some of these cases were serious. Blood glucose disturbances were usually in diabetic patients

receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide/glibenclamide)

and/or with insulin. In these patients, careful monitoring of blood glucose is recommended. If a

hypoglycemic reaction occurs in a patient being treated with JAMP Levofloxacin, discontinue

JAMP Levofloxacin immediately and initiate appropriate therapy. Serious hypoglycemia and

hyperglycemia have also occurred in patients without a history of diabetes (see ADVERSE

REACTIONS and DRUG INTERACTIONS, Drug-Drug Interactions, Antidiabetic Agents).

Hypoglycemic coma has been observed in diabetic patients with the use of levofloxacin. Fatal

outcomes have been reported. All cases of hypoglycemic coma had multiple confounding

factors; a temporal relationship with the use of levofloxacin was identified (onset of altered

consciousness occurred within 3 days in most cases). Caution should be exercised when using

JAMP Levofloxacin in diabetic patients taking concomitant treatment with an oral hypoglycemic

agent

and/or insulin, especially those who are elderly or who have renal impairment (see

WARNINGS AND PRECAUTIONS, Renal and DRUG INTERACTIONS, Drug-Drug

Interactions, Antidiabetic Agents).

JAMP Levofloxacin

Page 8 of 68

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

initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not

directed against Clostridium difficile. In moderate to severe cases, consideration should be given

to management with fluids and electrolytes, protein supplementation, and treatment with an

antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be

instituted as clinically indicated since surgical intervention may be required in certain severe

cases (see ADVERSE REACTIONS).

Hepatic

Very rare post-marketing reports of severe hepatotoxicity (including acute hepatitis and fatal

events) have been received for patients treated with levofloxacin. No evidence of serious drug-

associated hepatotoxicity was detected in clinical trials of over 7000 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.

majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and

most

were not associated with hypersensitivity. JAMP Levofloxacin should be discontinued

immediately if

the patient develops signs and symptoms of hepatitis (see ADVERSE

REACTIONS, Post-

Market Adverse Drug Reactions).

Immune

Hypersensitivity

Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported

in patients receiving therapy with quinolones, including levofloxacin. These reactions often

occur following the first dose. Some reactions have been accompanied by cardiovascular

collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including

tongue, laryngeal, throat or facial edema/swelling), airway obstruction (including bronchospasm,

shortness of breath, and acute respiratory distress), dyspnea, urticaria, itching, and other serious

skin reactions. JAMP 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

JAMP Levofloxacin

Page 9 of 68

indicated (see ADVERSE REACTIONS).

Serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain

etiology, have rarely been reported in patients receiving therapy with quinolones, including

levofloxacin. These events may be severe, and generally occur following the administration of

multiple doses. Clinical manifestations may include one or more of the following: fever; rash or

severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome);

vasculitis; arthralgia; myalgia; serum sickness; allergic pneumonitis; interstitial nephritis; acute

renal insufficiency or failure; hepatitis, including acute hepatitis; jaundice; acute hepatic necrosis

or failure; anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic

thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic

abnormalities. The administration of JAMP Levofloxacin should be discontinued immediately, at

the first

appearance of a skin rash or any other sign of hypersensitivity, and supportive

measures instituted (see ADVERSE REACTIONS).

Musculoskeletal

Tendinitis

Rupture of the shoulder, hand and Achilles tendons that required surgical repair or

resulted in prolonged disability have been reported in patients receiving quinolones,

including levofloxacin. JAMP Levofloxacin should be discontinued if the patient experiences

pain,

inflammation or rupture of a tendon. Patients should rest and refrain from exercise until

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. JAMP Levofloxacin should be

discontinued if

the patient experiences pain, swelling, inflammation or rupture of a tendon.

Patients should be

advised to rest at the first sign of tendinitis or tendon rupture, and to contact

their healthcare

provider regarding changing to a non-quinolone antimicrobial drug (see

ADVERSE

REACTIONS).

JAMP Levofloxacin should not be used in patients with a history of tendon disease/disorder

related to

previous quinolone treatment (see CONTRAINDICATIONS).

Myasthenia Gravis

Fluoroquinolones have neuromuscular blocking activity and may exacerbate muscle weakness

persons with myasthenia gravis. Postmarketing serious adverse events, including deaths

requirement for ventilatory support, have been associated with fluoroquinolone use

(including levofloxacin) in persons with myasthenia gravis. Avoid levofloxacin in patients with a

known

history of myasthenia gravis (see ADVERSE REACTIONS, Post-Market Adverse Drug

Reactions).

JAMP Levofloxacin

Page 10 of 68

Neurologic

CNS and Psychiatric Effects

Convulsions, toxic psychoses and increased intracranial pressure (including pseudotumor

cerebri) have been reported in patients receiving quinolones, including levofloxacin. Quinolones

including levofloxacin, may also cause central nervous system stimulation which may lead to

tremors, restlessness, anxiety, lightheadedness, dizziness, confusion and hallucinations,

paranoia,

depression, nightmares, insomnia, and rarely, suicidal thoughts or acts. These

reactions may occur following the first dose. If these reactions occur in patients receiving JAMP

Levofloxacin, the drug should be discontinued and appropriate measures instituted. As with all

quinolones, JAMP Levofloxacin

should be used with caution in patients with a known or

suspected CNS disorder that may predispose to seizures or lower the seizure threshold (e.g.,

severe cerebral arteriosclerosis,

epilepsy), or in the presence of other risk factors that may

predispose to seizures or lower the

seizure threshold (e.g., alcohol abuse, certain drug therapies

such as NSAIDs and theophylline,

renal dysfunction). JAMP Levofloxacin should be used with

caution in patients with unstable

psychiatric illness (see DRUG INTERACTIONS and ADVERSE

REACTIONS).

Peripheral Neuropathy

Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large

axons

resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been

reported in

patients receiving quinolones, including levofloxacin. Symptoms may occur soon

after initiation of treatment and may be irreversible. JAMP 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.

Central Nervous System Effects

Psychiatric Adverse Reactions

Fluoroquinolones, including levofloxacin, have been associated with an increased risk of

psychiatric adverse reactions, including: toxic psychoses, hallucinations, or paranoia;

depression,

or suicidal thoughts; anxiety, agitation, restlessness, or nervousness; confusion,

delirium,

disorientation, or disturbances in attention; insomnia or nightmares; 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 JAMP Levofloxacin,

discontinue JAMP Levofloxacin and institute appropriate measures.

Central Nervous System Adverse Reactions

Fluoroquinolones, including levofloxacin, have been associated with an increased risk of

seizures (convulsions), increased intracranial pressure (including pseudotumor cerebri),

tremors, and light-headedness. As with other fluoroquinolones, JAMP 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 JAMP Levofloxacin, discontinue JAMP

Levofloxacin immediately and institute appropriate

measures

JAMP Levofloxacin

Page 11 of 68

Ophthalmologic

Vision Disorders

Consult an eye specialist if vision disorder occurs in association with the use of JAMP

Levofloxacin.

Renal

Safety and efficacy of levofloxacin in patients with impaired renal function (creatinine clearance

≤ 80 mL/min) have not been studied. Since levofloxacin is known to be substantially excreted by

the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal

function. The potential effects of levofloxacin associated with possible increased serum/tissue

levels in renal impaired patients, such as effect on QTc interval, have not been studied.

Adjustment of the dosage regimen may be necessary to avoid the accumulation of levofloxacin

due to decreased clearance. Careful clinical observation and appropriate laboratory studies

should be performed prior to and during therapy, since elimination of levofloxacin may be

reduced. Because elderly patients are more likely to have decreased renal function, care

should be taken in dose selection and it may be useful to monitor renal function. Administer

JAMP Levofloxacin with caution in the presence of renal insufficiency (see DOSAGE AND

ADMINISTRATION, Recommended Dose and Dosage Adjustment, Patients with Impaired

Renal Function and DETAILED PHARMACOLOGY, Factors Influencing the

Pharmacokinetics, Special Populations, Renal Insufficiency).

Skin

Phototoxicity

Moderate to severe phototoxicity reactions have been observed in patients exposed to direct

sunlight or ultraviolet (UV) light while receiving drugs in this class. Excessive exposure to

sunlight or UV light should be avoided. However, in clinical trials with levofloxacin,

phototoxicity

has been observed in less than 0.1% of patients. Therapy should be discontinued if

phototoxicity (e.g., skin eruption) occurs.

Susceptibility/Resistance

Development of Drug Resistant Bacteria

Prescribing JAMP 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.

Special Populations

The safety and efficacy of levofloxacin in children, adolescents (under the age of 18

years), pregnant women, and nursing mothers have not been established.

Pregnant Women: There are no adequate and well-controlled studies in pregnant women.

JAMP

Levofloxacin should be used during pregnancy only if the potential benefit justifies the

potential

risk to the fetus (see TOXICOLOGY).

Nursing Women: Levofloxacin has not been measured in human milk. Based upon data from

ofloxacin, it can be presumed that levofloxacin can be excreted in human milk. Because of the

potential for serious adverse reactions from levofloxacin in nursing infants, a decision should be

JAMP Levofloxacin

Page 12 of 68

made whether to discontinue nursing or to discontinue the drug, taking into account the

importance of the drug to the mother (see TOXICOLOGY).

Pediatrics (<18 years of age): JAMP 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 TOXICOLOGY). The incidence of protocol-defined

musculoskeletal disorders in a prospective long-term surveillance study was higher in children

treated for approximately 10 days with levofloxacin than in children treated with non-

fluoroquinolone antibiotics for approximately 10 days (see ADVERSE REACTIONS).

Geriatrics (≥65 years of age): The pharmacokinetic properties of levofloxacin in younger adults

and elderly adults do not differ significantly when creatinine clearance is taken into

consideration. However, since the drug is known to be substantially excreted by the kidney, the

risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken

dose selection. It may also be useful to monitor renal function.

Elderly patients may be more susceptible to drug-associated effects on the QT interval (see

WARNINGS AND PRECAUTIONS, Cardiovascular).

Geriatric patients are at increased risk for developing severe tendon disorders including tendon

rupture when being treated with a fluoroquinolone such as levofloxacin. This risk is further

increased in patients receiving concomitant corticosteroid therapy (see WARNINGS AND

PRECAUTIONS, Musculoskeletal).

Severe and sometimes fatal cases of hepatotoxicity have been reported post-marketing in

association with levofloxacin. The majority of fatal hepatotoxicity reports occurred in patients 65

years of age or older and most were not associated with hypersensitivity (see WARNINGS AND

PRECAUTIONS, Hepatic).

Effects on Ability to Drive and Use Machines

Neurologic adverse effects such as dizziness and lightheadedness may occur. Therefore,

patients

should know how they react to JAMP Levofloxacin before operating an automobile or

machinery or

engaging in other activities requiring mental alertness and coordination.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

In North American Phase III clinical trials involving 7537 subjects, the incidence of treatment-

emergent adverse events in patients treated with levofloxacin tablets and injection was

comparable to comparators. The majority of adverse events were considered to be mild to

moderate, with 5.6%of patients considered to have severe adverse events. Among patients

receiving multiple-dose therapy, 4.2% discontinued therapy with levofloxacin due to adverse

experiences. The incidence of drug-related adverse reactions was 6.7%.

JAMP Levofloxacin

Page 13 of 68

In clinical trials, the most frequently reported adverse drug reactions occurring in > 3% of the

study population were nausea, headache, diarrhea, insomnia, dizziness and constipation.

Serious and otherwise important adverse drug reactions are discussed in greater detail in other

sections (see WARNINGS AND PRECAUTIONS).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates

observed in the clinical trials may not reflect the rates observed in practice and should not be

compared to the rates in the clinical trials of another drug. Adverse drug reaction information

from clinical trials is useful for identifying drug-related adverse events and for approximating

rates.

The data described below reflect exposure to levofloxacin in 7537 patients in 29 pooled Phase

III clinical trials. The population studied had a mean age of 49.6 years (74.2% of the population

< 65 years), 50.1% were male, 71.0% were Caucasian and 18.8% were Black. Patients were

treated with levofloxacin for a wide variety of infectious diseases (See INDICATIONS AND

CLINICAL USE). Treatment duration was usually 3-14 days, the mean number of days on

therapy was 9.6 days and the mean number of doses was 10.2. Patients received levofloxacin

doses of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. The overall

incidence, type and distribution of adverse reactions were similar in patients receiving

levofloxacin doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily.

Adverse reactions (characterized as likely related to drug-therapy) occurring in ≥1% of

levofloxacin-treated patients are shown in Table 1.1 below.

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

System/Organ Class

Adverse Reaction

%

(N=7537)

Infections and Infestations

Moniliasis

Psychiatric Disorders

Insomnia

Nervous System Disorders

headac

dizzines

Respiratory, Thoracic

and

Mediastinal

Disorders

Dyspnea

Gastrointestinal Disorders

nausea

diarrhea

constipation

abdominal

pain

vomiting

dyspepsia

Skin and Subcutaneous

Tissue

Disorders

rash

pruritu

Reproductive System and

Breast

Disorders

Vaginitis

General Disorders and

Administration Site

Conditions

edema

injection site

reaction

chest pain

JAMP Levofloxacin

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System/Organ Class

Adverse Reaction

%

(N=7537)

N = 7274

N = 3758 (women)

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

Less common adverse reactions occurring in 0.1 to <1% of levofloxacin-treated patients are

shown in Table 1.2 below.

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

System/Organ Class

Adverse Reaction

Infections and Infestations

genital moniliasis

Blood and Lymphatic

System

Disorders

anemia, thrombocytopenia, granulocytopenia

Immune System Disorders

allergic reaction

Metabolism and Nutrition

Disorders

hyperglycemia, hypoglycemia, hyperkalemia

Psychiatric Disorders

anxiety, agitation, confusion, depression, hallucination,

nightmare

sleep disorder

, anorexia, abnormal dreaming

Nervous System Disorders

tremor, convulsions, paresthesia, vertigo, hypertonia,

hyperkinesias,

abnormal gait, somnolence

, syncope

Respiratory, Thoracic

and

Mediastinal

Disorders

epistaxis

Cardiac Disorders

cardiac arrest, palpitation, ventricular tachycardia,

ventricular

arrhythmia

Vascular Disorders

phlebitis

Gastrointestinal Disorders

gastritis, stomatitis, pancreatitis, esophagitis, gastroenteritis,

glossitis,

pseudomembranous/ C.difficile colitis

Hepatobiliary Disorders

abnormal hepatic function, increased hepatic enzymes,

increased

alkaline phosphatase

Skin and Subcutaneous

Tissue

Disorders

urticaria

Musculoskeletal and

Connective

Tissue

Disorders

tendinitis, arthralgia, myalgia, skeletal pain

Renal and Urinary Disorders

abnormal renal function, acute renal failure

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.

Abnormal Hematologic and Clinical Chemistry Findings

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

decreased glucose 2.1%

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

being treated.

JAMP Levofloxacin

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Pediatric Data

In a group of 1534 pediatric patients (6 months to 16 years of age) treated with levofloxacin for

respiratory infections, children 6 months to 5 years of age received 10 mg/kg of levofloxacin

twice a day for approximately 10 days and children greater than 5 years of age received

10 mg/kg to a maximum of 500 mg of levofloxacin once a day for approximately 10 days. The

adverse reaction profile was similar to that reported in adult patients. Vomiting and diarrhea

were reported more frequently in children than reported in adults. However, the frequency of

vomiting and diarrhea was similar in levofloxacin-treated and non-fluoroquinolone antibiotic

comparator-treated children.

A subset of 1340 of these children treated with levofloxacin for approximately 10 days was

enrolled in a prospective, long-term, surveillance study to assess the incidence of protocol-

defined musculoskeletal disorders (arthralgia, arthritis, 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.

Post-Market Adverse Drug Reactions

Table 1.3 lists adverse reactions that have been identified during post-approval use of

levofloxacin. Because these reactions are reported voluntarily from a population of uncertain

size, reliably estimating their frequency or establishing a causal relationship to drug exposure is

not always possible.

JAMP Levofloxacin

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Table 1.3: Post-Marketing Reports of Adverse Drug Reactions

System Organ Class

Adverse Reaction

Blood and Lymphatic

System

Disorders

pancytopenia, aplastic anemia, leucopenia, hemolytic anemia,

eosinophilia, thrombocytopenia including thrombotic

thrombocytopenic

purpura, agranulocytosis

Immune System Disorders

hypersensitivity reactions, sometimes fatal including:

anaphylactic/anaphylactoid reactions, anaphylactic shock,

angioneurotic

edema, serum sickness

Psychiatric Disorders

psychosis, paranoia, isolated reports of suicide attempt and

suicidal

ideation

Nervous System Disorders

anosmia, ageusia, parosmia, dysgeusia, peripheral neuropathy

(may be

irreversible), isolated reports of encephalopathy,

abnormal EEG,

dysphonia, exacerbation of myasthenia gravis,

amnesia, pseudotumor

cerebri

Eye Disorders

uveitis, vision disturbance (including diplopia), visual acuity

reduced,

vision blurred, scotoma

Ear and Labyrinth Disorders

hypoacusis, tinnitus

Cardiac Disorders

isolated reports of torsades de pointes, electrocardiogram QT

prolonged,

tachycardia

Vascular Disorders

vasodilation, vasculitis, DIC

Respiratory, Thoracic

and

Mediastinal

Disorders

isolated reports of allergic pneumonitis, interstitial pneumonia,

laryngeal

edema, apnea

Hepatobiliary Disorders

hepatic failure (including fatal cases), hepatitis, jaundice, hepatic

necrosis

Skin and Subcutaneous

Tissue

Disorders

bullous eruptions to include: Stevens-Johnson Syndrome, toxic

epidermal

necrolysis, erythema multiforme,

photosensitivity/phototoxicity reaction,

leukocytoclastic vasculitis

Musculoskeletal and

Connective

Tissue

Disorders

tendon rupture, muscle injury (including rupture),

rhabdomyolysis,

myositis, myalgia

Renal and Urinary Disorders

interstitial nephritis, nephrosis, glomerulonephritis

General Disorders and

Administration Site

Conditions

multi-organ failure, pyrexia, rash

Investigations

prothrombin time prolonged, international normalized ratio

(INR)

prolonged, muscle enzymes increased (CPK)

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

JAMP Levofloxacin

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Table 1.4: Established or Potential Drug-Drug Interactions

Proper name

Ref

Effect

Clinical comment

Antidiabeti

Agents

Disturbances of blood glucose, including

hyperglycemia and hypoglycemia, have

been

reported in patients treated

concomitantly with

levofloxacin and an

antidiabetic agent. Some of

these cases

were serious including hypoglycemic

coma.

Careful monitoring of blood

glucose

is recommended when

these agents,

including

levofloxacin, are co-

administered.

Antacids,

Sucralfate,

Metal

Cations,

Multi-Vitamins

Tablets: Due to the chelation of levofloxacin

multivalent cations, concurrent

administration of

levofloxacin tablets with

antacids containing

calcium, magnesium, or

aluminum, as well as

sucralfate, metal

cations such as iron, multi-

vitamin

preparations with zinc, or any products

containing any of these components may

interfere

with the gastrointestinal absorption

levofloxacin, resulting in systemic levels

considerably lower than desired.

These agents should be taken at

least

2 hours before or 2 hours

after

levofloxacin tablet

administration.

Cyclosporine

No significant effect of levofloxacin on the

peak

plasma concentrations, AUC, and other

disposition

parameters for cyclosporine was

detected in a

clinical study involving healthy

volunteers.

However, elevated serum levels of

cyclosporine

have been reported in the

patient population when

co-administered with

some other quinolones.

Levofloxacin C

and k

were slightly lower,

while T

and t

were slightly longer in the

presence of cyclosporine, than those

observed in

other studies without

concomitant medication. The

differences,

however, are not considered to be

clinically

significant.

No dosage adjustment is required

levofloxacin or cyclosporine

when

administered

concomitantly.

Digoxin

No significant effect of levofloxacin on the

peak

plasma concentrations, AUC, and, other

disposition parameters for digoxin was

detected in

a clinical study involving healthy

volunteers.

Levofloxacin absorption and disposition

kinetics

were similar in the presence or

absence of digoxin.

No dosage adjustment for

levofloxacin or digoxin is

required

when administered

concomitantly.

Digoxin levels

should be closely

monitored in

patients receiving

concomitant

therapy with digoxin.

Non-

Steroidal

Anti-

Inflammator

Drugs

(NSAIDs)

Although not observed with levofloxacin in

clinical trials, some quinolones have been

reported

to have proconvulsant activity that is

exacerbated

with concomitant use of

NSAIDs.

The concomitant administration of

non-steroidal anti-inflammatory

drug

with a quinolone, including

levofloxacin, may increase the

risk

of CNS stimulation and

convulsive

seizures (see

WARNINGS AND

PRECAUTIONS, Neurologic and

DETAILED PHARMACOLOGY,

Animal Pharmacology).

JAMP Levofloxacin

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Proper name

Ref

Effect

Clinical comment

Probenecid

Cimetidine

No significant effect of probenecid or

cimetidine

on the rate and extent of

levofloxacin absorption

was observed in a

clinical study involving healthy

volunteers.

The AUC and t

of levofloxacin were

27-38%

and 30% higher, respectively, while CL/F

were 21-35% lower during concomitant

treatment with probenecid or cimetidine

compared

to levofloxacin alone.

.No dosage adjustment for

levofloxacin is required when

administered concomitantly with

probenecid or cimetidine except

dosage adjustment for

levofloxacin

may be required

based on the renal

function of

the patient.

Theophylline

CT/T

No significant effect of levofloxacin on the

plasma

concentrations, AUC, and other

disposition

parameters for theophylline was

detected in a

clinical study involving 14

healthy volunteers.

Similarly, no apparent effect of theophylline on

levofloxacin absorption and disposition was

observed. However, concomitant

administration of

other quinolones with

theophylline has resulted in

prolonged

elimination, elevated serum theophylline

levels, and a subsequent increase in the

risk of theophylline-related adverse reactions

in the patient population.

Theophylline levels should be

closely monitored, and

theophylline

dosage adjustments

made if

appropriate, when

levofloxacin is co-

administered.

Adverse reactions,

including

seizures, may occur with

without an elevation in serum

theophylline level (see

WARNINGS

PRECAUTIONS, Neurologic).

Warfarin

Certain quinolones, including levofloxacin,

enhance the effects of oral

anticoagulant warfarin

or its derivatives.

When these products are

administered concomitantly,

prothrombin time, International

Normalized Ratio (INR), or other

suitable coagulation tests

should be

monitored closely,

especially in

elderly patients.

Zidovudine

Levofloxacin absorption and disposition in

HIV-

infected subjects, with or without

concomitant

zidovudine treatment, were

similar. The effect of

levofloxacin on

zidovudine pharmacokinetics has

not been

studied.

No dosage adjustment for

levofloxacin appears to be

required

when co-administered

with

zidovudine.

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

Drug-Food Interactions

JAMP Levofloxacin 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.

JAMP Levofloxacin

Page 19 of 68

DOSAGE AND ADMINISTRATION

Dosing Considerations

The dosage of JAMP Levofloxacin tablets for patients with normal renal function (i.e.,

> 80 mL/min) is described in the following dosing chart. For patients with altered renal

function (i.e., Cl

≤ 80 mL/min), see Patients with Impaired Renal Function subsection.

Recommended Dose and Dosage Adjustment

Patients with Normal Renal Function

Infection*

Dose

Freq.

Duration

Acute Bacterial Exacerbation

Chronic Bronchitis

500 mg

750 mg

7 days

5 days

Comm.-Acquired Pneumonia

500 mg

750 mg**

q24h

q24h

7-14 days (10-14 days

severe infections)

5 days

Sinusitis

500 mg

750 mg***

10-14 days

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

750 mg

10 days

5 days

Acute Pyelonephritis

250 mg

750 mg

10 days

5 days

Uncomplicated UTI

250 mg

q24h

3 days

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

Efficacy of this alternative regimen has only been documented for infections caused by penicillin-

susceptible

Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae,

Mycoplasma pneumoniae,

Chlamydia pneumoniae, and Legionella 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 WARNINGS AND PRECAUTIONS, Renal; ACTION AND CLINICAL

PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency and DETAILED

PHARMACOLOGY, Factors Influencing the Pharmacokinetics, Special Populations, Renal

Insufficiency).

Dosing recommendations for renally impaired patients are based on data collected from a

clinical

safety and pharmacokinetic study in renally impaired patients treated with a single 500

mg oral

dose of levofloxacin. There is no clinical experience available in this patient population

for the

250 mg dose or 750 mg dose. Pharmacokinetic modelling was used to determine a

recommended dosing regimen which would provide equivalent drug exposures for which clinical

efficacy has been demonstrated. The potential effects of levofloxacin associated with possible

increased serum/tissue levels in renal impaired patients, such as effect on QTc interval, have

JAMP Levofloxacin

Page 20 of 68

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

from 50 to 80 mL/min

No dosage adjustment required

from 20 to 49 mL/min

500 mg

250 mg q24h

from 10 to 19 mL/min

500 mg

250 mg q48h

Hemodialysis

500 mg

250 mg q48h

CAPD

500 mg

250 mg q48h

Complicated UTI/Acute Pyelonephritis

≥20 mL/min

No dosage adjustment required

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

from 50 to 80 mL/min

No dosage adjustment required

from 20 to 49 mL/min

750 mg

750 mg q48h

from 10 to 19 mL/min

750 mg

500 mg q48h

Hemodialysis

750 mg

500 mg q48h

CAPD

750 mg

500 mg q48h

Uncomplicated UTI

No dosage adjustment required

= creatinine clearances

CAPD = continuous 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.

Missed Dose

More than the prescribed dose of JAMP Levofloxacin should not be taken, even if a dose is

missed.

Administration

JAMP 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.

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

observed, including ECG monitoring (see ACTION AND CLINICAL PHARMACOLOGY,

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

For management of a suspected drug overdose, contact your regional Poison Control Centre.

JAMP Levofloxacin

Page 21 of 68

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.

ACTION AND CLINICAL PHARMACOLOGY

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

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

JAMP Levofloxacin

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steady-state conditions following oral (PO) or intravenous (IV) doses of levofloxacin are

summarized in Table 1.5.

JAMP Levofloxacin

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Table 1.5: Summary of Pharmacokinetic Parameters (mean ± SD)

Regimen

N

Cmax

(mcg/mL)

Tmax (h)

AUC

j

(mcgh/mL)

CL/F

(mL/min)

Vd/F

t

½

Cl

r

(mL/min)

Single dose

250 mg PO

500 mg PO

500 mg IV

750 mg PO

750 mg IV

2.8 ± 0.4

5.1 ± 0.8

6.2 ± 1.0

7.1 ± 1.4

7.99 ± 1.2

1.6 ± 1.0

1.3 ± 0.6

1.0 ± 0.1

1.9 ± 0.7

27.2 ± 3.9

47.9 ± 6.8

48.3 ± 5.4

82.2 ± 14.3

74.4 ± 8.0

156 ± 20

178 ± 28

175 ± 20

157 ± 28

170 ± 19

90 ± 11

90 ± 14

97.0 ± 14.8

7.3 ± 0.9

6.3 ± 0.6

6.4 ± 0.7

7.7 ± 1.3

7.5 ± 1.9

142 ± 21

103 ± 30

112 ± 25

118 ± 28

Multiple dose

500 mg q24h

500 mg

q24h IV

500 mg or 250 mg q24h IV patients with bacterial

infections

750 mg q24h PO

750 mg q24h IV

5.7 ± 1.4

6.4 ± 0.8

8.7 ± 4.0

8.6 ± 1.9

7.92 ± 0.91

1.1 ± 0.4

1.4 ± 0.5

47.5 ± 6.7

54.6 ± 11.1

72.5

51.2

90.7 ± 17.6

72.5 ± 0.8

175 ± 25

158 ± 29

154 ± 72

143 ± 29

172 ± 2

102 ± 22

91 ± 12

111 ± 58

100 ± 16

111 ± 12

7.6 ± 1.6

7.0 ± 0.8

8.8 ± 1.5

8.1 ± 2.1

116 ± 31

99 ± 28

116 ± 28

500 mg PO single dose, effects of gender and age:

male

female

young

elderly

5.5 ± 1.1

7.0 ± 1.6

5.5 ± 1.0

7.0 ± 1.6

1.2 ± 0.4

1.7 ± 0.5

1.5 ± 0.6

1.4 ± 0.5

54.4 ± 18.9

67.7 ± 24.2

47.5 ± 9.8

74.7 ± 23.3

166 ± 44

136 ± 44

182 ± 35

121 ± 33

89 ± 13

62 ± 16

83 ± 18

67 ± 19

7.5 ± 2.1

6.1 ± 0.8

6.0 ± 0.9

7.6 ± 2.0

126 ± 38

106 ± 40

140 ± 33

91 ± 29

500 mg PO single dose, patients with renal

insufficiency:

50-80 mL/min

20-49

mL/min

< 20

mL/min

Hemodialysis

CAPD

7.5 ± 1.8

7.1 ± 3.1

8.2 ± 2.6

5.7 ± 1.0

6.9 ± 2.3

1.5 ± 0.5

2.1 ± 1.3

1.1 ± 1.0

2.8 ± 2.2

1.4 ± 1.1

95.6 ± 11.8

182.1 ± 62.6

263.5 ± 72.5

88 ± 10

51 ± 19

33 ± 8

9.1 ± 0.9

27 ± 10

35 ± 5

76 ± 42

51 ± 24

57 ± 8

26 ± 13

13 ± 3

750 mg IV single dose and multiple dose, patients

with renal

insufficiency:

Single dose - Cl

50-80 mL/min

Multiple q24h dose - Cl

50-80

mL/min

13.3 ± 3.6

14.3 ± 3.2

128 ± 37

145 ± 36

104 ± 25

103 ± 20

62.7 ± 15.1

64.2 ± 16.9

7.5 ± 1.5

7.8 ± 2.0

healthy males 18-53 years of age;

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

healthy male subjects 32-46 years of age;

healthy male subjects 19-51 years of age;

including 500 mg q48h for 8 patients with moderate renal impairment (Cl

20-50 mL/min) and infections of the respiratory tract or skin;

healthy males 22-75 years of age;

healthy females 18-80 years of age;

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

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

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

AUC for 0-∞ reported, unless otherwise specified;

male and female subjects 34-54 years of age;

0-24 h

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

ND = Not Determined

JAMP Levofloxacin

Page 23 of 68

JAMP Levofloxacin

Page 24 of 68

Absorption: Levofloxacin is rapidly and essentially completely absorbed after oral

administration. Peak plasma concentrations are usually attained 1 to 2 hours after oral dosing.

The absolute bioavailability of a 500 mg tablet and a 750 mg tablet of levofloxacin is

approximately 99% in both cases, demonstrating complete oral absorption of levofloxacin.

Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral dosing

regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg

once-daily dosage regimen. The peak and trough plasma concentrations attained following

multiple once-daily oral dosage regimens were approximately 5.7 mcg/mL and 0.5 mcg/mL after

the 500 mg doses, and 8.6 mcg/mL and 1.1 mcg/mL after the 750 mg doses, respectively.

There was no clinically significant effect of food on the extent of absorption of levofloxacin.

Oral administration with food slightly prolongs the time to peak concentration by approximately

1 hour, and slightly decreases the peak concentration by approximately 14%. Therefore,

levofloxacin can be administered without regard to food.

Distribution: The mean volume of distribution of levofloxacin generally ranges from 74 to

112 L after single and multiple 500 mg or 750 mg doses, indicating widespread distribution into

body tissues. Levofloxacin reaches its peak levels in skin tissues (11.7 mcg/g for a 750 mg dose)

and in blister fluid (4.33 mcg/g for a 500 mg dose) at approximately 3-4 hours after dosing. The

skin tissue biopsy to plasma AUC ratio is approximately 2. The blister fluid to plasma AUC ratio

is approximately 1, following multiple once-daily oral administration of 750 mg and 500 mg

levofloxacin to healthy subjects, respectively. Levofloxacin also penetrates into lung tissues.

Lung tissue concentrations were generally 2- to 5-fold higher than plasma concentrations, and

ranged from approximately 2.4 to 11.3 mcg/g over a 24-hour period after a single 500 mg oral

dose.

Levofloxacin is 24 to 38% bound to serum proteins across all species studied. Levofloxacin

binding to serum proteins is independent of the drug concentration.

Metabolism: Levofloxacin is stereochemically stable in plasma and urine, and does not invert

metabolically to its enantiomer, D-ofloxacin. Levofloxacin undergoes limited metabolism in

humans, and is primarily excreted as unchanged drug (87%) in the urine within 48 hours.

Excretion: The major route of elimination of levofloxacin in humans is as unchanged drug in the

urine. The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6

to 8 hours following single or multiple doses of levofloxacin given orally 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.

JAMP Levofloxacin

Page 25 of 68

Dose adjustment based on gender alone is not necessary.

Race: The apparent total body clearance and apparent volume of distribution were not affected

by race in a covariate analysis performed on data from 72 subjects.

Hepatic Insufficiency: Pharmacokinetic studies in hepatically impaired patients have not been

conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of

levofloxacin are not expected to be affected by hepatic impairment.

Renal Insufficiency: Pharmacokinetic parameters of levofloxacin following oral or intravenous

doses of levofloxacin in patients with impaired renal function (creatinine clearance ≤ 80

mL/min) are presented in Table 1.5. Clearance of levofloxacin is reduced and plasma elimination

half-life is prolonged in this patient population. Dosage adjustment may be required in such

patients to avoid accumulation.

A dosage reduction is being recommended depending on the levels of renal insufficiency.

Dosing

recommendations are based on pharmacokinetic modelling of data collected from a

clinical

safety and pharmacokinetic study in renally impaired patients treated with a single 500

mg oral

dose of levofloxacin (see WARNINGS AND PRECAUTIONS, Renal, and DOSAGE

AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Patients with Impaired

Renal Function).

Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in

removal of levofloxacin from the body, indicating supplemental doses of levofloxacin are not

required following hemodialysis or CAPD.

Bacterial Infection: The pharmacokinetics of levofloxacin in patients with community-acquired

bacterial infections are comparable to those observed in healthy subjects.

STORAGE AND STABILITY

JAMP Levofloxacin tablets should be stored at controlled room temperature between 15°C and

30°C in well closed containers. Protect from moisture.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Form

JAMP Levofloxacin 250 mg film coated tablets, containing 250 mg of levofloxacin (as

levofloxacin hemihydrate), are pink colored, capsule shaped, biconvex tablets debossed with

‘250’ on one side and “JP” on the other side.

JAMP Levofloxacin 500 mg film coated tablets, containing 500 mg of levofloxacin (as

levofloxacin hemihydrate), are peach colored, capsule shaped, biconvex tablets debossed with

‘500’ on one side and “JP” on the other side.

JAMP Levofloxacin 750 mg film coated tablets, containing 750 mg of levofloxacin (as

levofloxacin hemihydrate), are white colored, capsule shaped, biconvex tablets debossed with

‘750’ on one side and “JP” on the other side.

Packaging

JAMP Levofloxacin

Page 26 of 68

JAMP Levofloxacin tablets 250 mg, 500 mg and 750 mg are available in bottles of 50 and 100

tablets.

Composition

JAMP Levofloxacin film-coated tablets contains the following nonmedicinal ingredients:

microcrystalline cellulose, crospovidone, hypromellose, magnesium stearate ferric oxide yellow

(500 mg strengths only),

ferric oxide red (250 mg and 500 mg strengths only), polysorbate 80,

polyethylene glycol and titanium dioxide.

JAMP Levofloxacin

Page 27 of 68

PART II: SCIENTIFIC INFORMATION

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

Structural Formula:

Molecular Mass: 370.4 g/mol (levofloxacin hemihydrate)

Molecular Formula:

. ½ H

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 7.0 and more, solubility 30-50 mg/ml

pKa:

: 6.0

: 8.2 (4, 5, 6)

Partition Coefficient: log P: - 0.4 (3)

JAMP Levofloxacin

Page 28 of 68

CLINICAL TRIALS

Comparative Bioavailability Study

A double blind, balanced, randomized, two-treatment, two-sequence, two-period, crossover, single

dose oral bioequivalence study comparing JAMP Levofloxacin Tablets, 750 mg (JAMP Pharma

Corporation) to

Sandoz Levofloxacin Tablets, 750 mg (Sandoz Canada Inc.) was conducted in

24 healthy adult human male subjects under fasting conditions. A summary of the comparative

bioavailability data from the 23 subjects who completed the study is presented in following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

Levofloxacin

(1 x 750 mg)

From measured data

Geometric Mean**

Arithmetic Mean (%CV)

Parameter

TEST*

REFERENCE

% Ratio of

Geometric Means

90% Confidence

Interval

(hr*ng/mL)

106338.35

107575.36 (16.45)

104924.05

105937.39 (14.71)

101.3

99.2 -103.5

(hr*ng/mL)

108438.17

109817.96 (17.33)

106953.22

108071.39 (15.38)

101.4

99.2 -103.6

(ng/mL)

9864.26

10141.60 (26.58)

9685.72

9854.86 (20.83)

101.8

95.0 -109.2

(hr)

1.50 (0.50-3.00)

0.75 (0.50-2.67)

@

(hr)

8.19 (13.76)

8.22 (12.48)

** Expressed as geometric least square mean.

* JAMP Levofloxacin Tablets, 750 mg (JAMP Pharma Corporation).

Sandoz

Levofloxacin Tablets, 750 mg (Sandoz Canada Inc.) were purchased in Canada

§

Expressed as the median (range) only.

@

Expressed as the arithmetic mean (%CV) only

Acute Sinusitis

Study demographics and trial design

Table 2.1 - Summary of patient demographics for clinical trials in Acute Sinusitis

Study #

Trial design

Dosage, route of

administration

and

duration

Study subjects

(n = number)

a

Mean

age

(Range)

Gender

Male/female

CAPSS-232

Double-

blind,

randomized,

prospective,

multicentre

oral levofloxacin

750 mg once daily

5 days

n=389

41.7

(18-86)

152/237

oral levofloxacin

500 mg once daily

10 days

n=391

42.2

(18-85)

173/218

M92-040

Randomized,

open-label,

active-

controlled

oral levofloxacin

500 mg once daily

10-14 days

n=306

39.2

(18-85)

115/191

oral amoxicillin

mg/clavulanate

mg three times

daily for

10-14 days

n=309

38.6

(18-84)

110/199

JAMP Levofloxacin

Page 29 of 68

N93-006

Open-label,

non-

comparative

oral levofloxacin

500 mg once daily

10-14 days

n=329

41.6

(18-89)

137/192

Subjects enrolled and randomized to treatment

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

Endpoints

Levofloxacin

n/N (%)

Comparator

n/N (%)

95%

Confidence

Interval

c

Clinical Success Rate

81/90 (90.0)

(45.6% cured; 44.4% improved)

89/95 (93.7)

(55.8% cured; 37.9% improved)

(-4.8, 12.1)

Microbiologic

Eradication

Rate

140/152 (92.1)

133/149 (89.3)

(-9.7, 4.1)

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)

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

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

Microbiologically evaluable population

Table 2.3 - Clinical Success Rates

a

for Microbiologically Evaluable Population

b

(CAPSS-232)

Pathogen

Levofloxacin 750 mg x 5 days

n/N

(%)

Comparator

n/N (%)

Streptococcus pneumoniae

25/27 (92.6)

26/27 (96.3)

Haemophilus influenzae

19/21 (90.5)

25/27 (92.6)

Moraxella catarrhalis

10/11 (90.9)

13/13 (100.0)

Eradication rate for the three pathogens was the same as clinical success rate because microbiological

success

was presumed based on clinical success

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

10-14 Day Treatment Regimen

Table 2.4 – Clinical Success

a

in Pivotal Acute Sinusitis Studies – Clinically Evaluable Subjects

Study Number

Levofloxacin

n/N (%)

Comparator

n/N (%)

95% Confidence

Interval

M92-040

236/267 (88.4)

234/268 (87.3)

(-6.8, 4.6)

N93-006

265/300 (88.3)

cured plus improved

Table 2.5 – Microbiologic Eradication in Pivotal Acute Sinusitis Studies – Microbiologically

Evaluable

Subjects

Study Number

Levofloxacin

n/N (%)

Comparator

n/N (%)

95% Confidence

Interval

M92-040

N93-006

127/138 (92.0)

JAMP Levofloxacin

Page 30 of 68

Table 2.6 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable

Population (N93-006)

Pathogen

Levofloxaci

n

n/N (%)

Haemophilus influenzae

35/36 (97.2)

Streptococcus pneumoniae

32/32 (100.0)

Staphylococcus aureus

31/33 (93.9)

Moraxella (Branhamella) catarrhalis

14/15 (93.3)

Community Acquired Pneumonia

Study demographics and trial design

Table 2.7 - Summary of patient demographics for clinical trials in Community Acquired Pneumonia

Study #

Trial design

Dosage, route of

administration and

duration

Study

subjects

(n

= number)

a

Mean

age

(Range)

Gender

Male/femal

e

CAPSS-150

Double-

blind,

randomized,

prospective,

multicenter

oral or IV levofloxacin 750

once daily for 5 days

n=256

53.1

(18-86)

148/108

oral or IV levofloxacin 500

once daily for 10 days

n=272

55.3

(18-89)

162/110

K90-071

Open-

label,

randomized

active-

controlled

levofloxacin oral 488 mg or

500 mg once daily for 7-

days

n=295

49.0

(18-87)

162/133

oral cefuroxime axetil 500

twice daily or IV

ceftriaxone

sodium 1 to 2 g

once daily or

in equally

divided doses given

twice

daily for 7-14 days

n=295

50.3

(18-96)

163/132

M92-075

Open-

label,

non-

comparativ

oral or IV levofloxacin 500

once daily for 7-14 days

n=264

51.9

(18-93)

146/118

Subjects enrolled and randomized to treatment

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

Endpoints

Levofloxacin 750 mg

once

daily for 5 days

n/N (%)

Comparator

n/N

(%)

95%

Confidence

Interval

c

Clinical Success Rate

183/198 (92.4)

175/192 (91.1)

(-7.0, 4.4)

Microbiologic Eradication Rate

96/103 (93.2)

85/92 (92.4)

(-8.6, 7.0)

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

success rates include the clinical response category of cured and improved

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

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.

JAMP Levofloxacin

Page 31 of 68

Table 2.9 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable

Population (5-day regimen)

Pathogen

Levofloxacin 750

mg

n/N (%)

Penicillin susceptible S. pneumoniae

19/22 (86.4)

Haemophilus influenzae

12/13 (92.3)

Haemophilus parainfluenzae

12/12 (100.0)

Mycoplasma pneumoniae

32/34 (94.1)

Chlamydia pneumoniae

20/22 (90.9)

Legionella pneumophila

12/12 (100.0)

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 Success

a

in Pivotal Community Acquired Pneumonia Studies – Clinically

Evaluable

Subjects

Study Number

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

95%

Confidenc

e

Interval

K90-071

218/226 (96.5)

208/230 (90.4)

(-10.7, -1.3)

M92-075

222/234 (94.9)

cured plus improved

Table 2.11 – Microbiologic Eradication in Pivotal Community Acquired Pneumonia Studies -

Microbiologically Evaluable Subjects

Study Number

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

95%

Confidenc

e

Interval

K90-071

126/128 (98.4)

126/144 (87.5)

(-17.1, -4.7)

M92-075

155/163 (95.1)

JAMP Levofloxacin

Page 32 of 68

Table 2.12 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable

Population

(K90-071)

Pathogen

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

Chlamydia pneumoniae

46/47 (97.9)

49/53 (92.5)

Streptococcus pneumoniae

39/39 (100.0)

39/40 (97.5)

Haemophilus influenzae

30/30 (100.0)

19/24 (79.2)

Mycoplasma pneumoniae

19/19 (100.0)

22/22 (100.0)

Staphylococcus aureus

10/10 (100.0)

9/9 (100.0)

Haemophilus parainfluenzae

7/8 (87.5)

15/21 (71.4)

Moraxella (Branhamella) catarrhalis

7/7 (100.0)

6/7 (85.7)

Legionella pneumophila

5/5 (100.0)

3/4 (75.0)

Klebsiella pneumonia

3/3 (100.0)

8/8 (100.0)

Table 2.13 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable

Population

(M92-075)

Pathogen

Levofloxaci

n

n/N (%)

Chlamydia pneumoniae

71/75 (94.7)

Streptococcus pneumoniae

43/44 (97.7)

Haemophilus influenzae

38/39 (97.4)

Staphylococcus aureus

10/12 (83.3)

Moraxella (Branhamella) catarrhalis

11/11 (100.0)

Mycoplasma pneumoniae

10/10 (100.0)

Haemophilus parainfluenzae

8/9 (88.9)

Klebsiella pneumonia

7/7 (100.0)

Legionella pneumophila

4/5 (80.0)

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

Study #

Trial design

Dosage, route of

administration and

duration

Study

subjects

(n=number)

a

Mean

age

(Range)

Gender

male/femal

e

CAPSS-197

Multicentre

randomized

blinded,

non-inferiority

oral levofloxacin 750 mg

once

daily for 5 days

n=187

(18-91)

93/94

oral amoxicillin

875 mg/clavulanate 125

twice daily for 10

days

n=182

(20-85)

88/94

K90-070

Open-

label,

randomized

active-

controlled

oral levofloxacin 488 mg

once

daily for 5-7 days

n=187

59.8

(21-89)

107/80

oral cefaclor 250 mg

three

times daily for 7-

10 days

n=186

61.2

(19-89)

108/78

M92-024

Open-

label,

randomized

active-

controlled

oral levofloxacin 500 mg

once

daily for 5-7 days

n=248

51.7

(18-97)

124/124

oral cefuroxime axetil 250

twice daily for 10 days

n=244

53.1

(18-87)

140/104

Subjects enrolled and randomized to treatment

From ITT population. Study subjects were characterized by FEV

<50% predicted, or FEV

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

JAMP Levofloxacin

Page 33 of 68

Study Results

5 Day Treatment Regimen

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

Endpoints

Levofloxacin 750 mg

once

daily for 5 days

n/N (%)

Comparator

n/N

(%)

Difference

c

95%

Confidence

Interval

d

Clinical Success Rate

Success

95/120

(79.2)

Non-

success:

25/120

(20.8)

Success

103/126

(81.7)

Non-

success:

23/126

(18.3)

(-7.8, 12.9)

Microbiologic

Eradication

Rate

70/86 (81.4)

71/89 (79.8)

-1.6

(-13.9, 10.7)

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

Success rates include the clinical response category of cured and improved

Difference in success rates

Two-sided 95% CIs (with continuity correction) around the difference (amoxicillin/clavulanate

minus

levofloxacin) in clinical success rates

Microbiologically evaluable population

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

Pathogen

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

Staphylococcus aureus

4/5 (80.0)

3/5 (60.0)

Streptococcus pneumoniae

16/18 (88.9)

10/13 (76.9)

Haemophilus influenzae

25/30 (83.3)

20/20 (100.0)

Haemophilus parainfluenzae

18/20 (90.0)

15/18 (83.3)

Moraxella catarrhalis

10/12 (83.3)

16/19 (84.2)

7 Day Treatment Regimen

Table 2.17 – Clinical Success

a

in Pivotal Acute Bacterial Exacerbation of Chronic Bronchitis

Studies –

Clinically Evaluable Subjects

Study Number

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

95%

Confidenc

e

Interval

K90-070

141/154 (91.6%)

142/155 (91.6%)

(-6.5, 6.6)

M92-024

210/222 (94.6%)

212/229 (92.6%)

(-6.8, 2.7)

Cured plus improved

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

Studies

Microbiologically Evaluable Subjects

Study Number

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

95%

Confidenc

e

Interval

K90-070

97/103 (94.2)

77/89 (86.5)

(-16.6, 1.3)

M92-024

129/134 (96.3)

137/147 (93.2)

(-8.6, 2.5)

Table 2.19 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable

Population

(K90-070)

Pathogen

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

Haemophilus influenzae

21/21 (100.0)

17/24 (70.8)

Moraxella (Branhamella) catarrhalis

18/19 (94.7)

8/8 (100.0)

Haemophilus parainfluenzae

14/15 (93.3)

7/7 (100.0)

Pseudomonas aeruginosa

8/10 (80.0)

11/14 (78.6)

JAMP Levofloxacin

Page 34 of 68

Pathogen

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

Streptococcus pneumoniae

9/10 (90.0)

6/7 (85.7)

Staphylococcus aureus

8/9 (88.9)

2/3 (66.7)

Table 2.20 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable

Population

(M92-024)

Pathogen

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

Haemophilus influenzae

42/44 (95.5)

29/31 (93.5)

Haemophilus parainfluenzae

27/27 (100.0)

30/32 (93.8)

Moraxella (Branhamella) catarrhalis

25/25 (100.0)

29/32 (90.6)

Streptococcus pneumoniae

14/16 (87.5)

10/10 (100.0)

Staphylococcus aureus

10/10 (100.0)

34/35 (97.1)

Pseudomonas aeruginosa

9/10 (90.0)

8/9 (88.9)

Nosocomial Pneumonia

Study demographics and trial design

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

Study #

Trial design

Dosage, route of

administration

and

duration

Study

subjects (n

=

number)

a

Mean

age

(Range)

Gender

Male/femal

e

CAPSS-117

Open-label,

randomized,

active-

controlled

multicentre

IV levofloxacin 750 mg

once daily for ≥ 24

hours

with switch to

oral

levofloxacin 750

mg once

daily at

investigator

discretion

(7-15 days total)

n=220

55.8

(19-93)

161/59

IV imipenem/cilastatin

0.5-1 g q6-8h for ≥3

days

with switch to

oral

ciprofloxacin 750 mg

q12h

at investigator

discretion (7-

15 days

total)

n=218

55.5

(18-93)

154/64

Subjects enrolled and randomized to treatment

Table 2.22 - Results of study CAPSS-117 in Nosocomial Pneumonia

Endpoints

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

95%

Confidenc

e

Interval

Clinical Success Rate

70/118 (59.3%)

70/112 (62.5%)

(-9.9, 16.2)

Microbiologic Eradication Rate

62/93 (66.7%)

57/94 (60.6%)

(-20.3, 8.3)

Success includes Cured and Improved; clinically evaluable population

overall microbiologic eradication rates by subject for microbiologically evaluable population

Table 2.23 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable

Population

(CAPSS-117)

Pathogen

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

Staphylococcus aureus

14/21 (66.7)

13/19 (68.4)

Pseudomonas aeruginosa

10/17 (58.8)

5/17 (29.4)

Haemophilus influenzae

13/16 (81.3)

14/15 (93.3)

Escherichia coli

10/12 (83.3)

7/11 (63.6)

JAMP Levofloxacin

Page 35 of 68

Pathogen

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

Klebsiella pneumoniae

9/11 (81.8)

6/7 (85.7)

Serratia marcescenes

9/11 (81.8)

2/7 (28.6)

Streptococcus pneumoniae

3/4 (75.0)

5/7 (71.4)

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

Study #

Trial design

Dosage, route of

administration and

duration

Study

subjects

(n=number)

a

Mean

age

(Range)

Gender

male/femal

e

K90-075

Open-

label,

randomized

active-

controlled

oral levofloxacin 488 mg

once

daily for 7-10 days

n=231

42.8

(15-85)

124/107

oral ciprofloxacin HCl 500

twice daily for 7-10

days

n=238

45.2

(18-88)

118/120

L91-031

Double-

blind,

randomized,

active-

controlled

oral levofloxacin 500 mg

once

daily for 7 days

n=136

43.0

(16-79)

67/69

oral ciprofloxacin HCl 500

twice daily for 10 days

n=136

44.3

(15-81)

78/58

Subjects enrolled and randomized to treatment

Study Results

Table 2.25 – Clinical Success

a

in Pivotal Uncomplicated Skin and Skin Structure Infection Studies

– Clinically

Evaluable Subjects

Study Number

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

95% Confidence Interval

K90-075

178/182 (97.8)

182/193 (94.3)

(-7.7, 0.7)

L91-031

124/129 (96.1)

116/124 (93.5)

(-8.4, 3.3)

cured plus improved

Table 2.26 – Microbiologic Eradication in Pivotal Uncomplicated Skin and Skin Structure Infection

Studies –

Microbiologically Evaluable Subjects

Study Number

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

95% Confidence Interval

K90-075

153/157 (97.5)

135/152 (88.8)

(-14.5, -2.7)

L91-031

93/100 (93.0)

87/97 (89.7)

(-11.7, 5.1)

Table 2.27 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable

Population (K90-

075)

Pathogen

Levofloxac

in

n/N

(%)

Comparato

r

n/N (%)

Staphylococcus aureus

87/87 (100.0)

76/87 (87.4)

Streptococcus pyogenes

14/14 (100.0)

18/20 (90.0)

Pseudomonas aeruginosa

7/8 (87.5)

10/10 (100.0)

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Page 36 of 68

Table 2.28 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable

Population

(L91-031)

Pathogen

Levofloxac

in

n/N

(%)

Comparato

r

n/N (%)

Staphylococcus aureus

66/70 (94.3)

70/75 (93.3)

Streptococcus pyogenes

17/18 (94.4)

12/13 (92.3)

Pseudomonas aeruginosa

5/5 (100.0)

5/5 (100.0)

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

Study #

Trial design

Dosage, route of

administration

and

duration

Study

subjects

(n=number)

a

Mean

age

(Range)

Gender

male/femal

e

LOFBIV-

SSS-

Multicentre

open-

label,

randomize

comparativ

oral or IV levofloxacin

mg once daily for 7-

14 days

n=200

51.9

(18-90)

126/74

IV ticarcillin/clavulanate

g every 4-6 hours

alone or

followed by

amoxicillin/clavulanate

mg twice daily (7-14

days

total)

n=199

49.8

(18-90)

117/82

Subjects enrolled and randomized to treatment

Table 2.30 - Results of study LOFBIV-SSS-040 in Complicated Skin and Skin Structure Infections

Endpoints

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

95%

Confidenc

e

Interval

Clinical Success Rate

116/138 (84.1)

106/132 (80.3)

(-13.3, 5.8)

Microbiologic Eradication Rate

82/98 (83.7)

70/98 (71.4)

(-24.3, -0.2)

Success includes Cured and Improved; clinically evaluable population

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)

Pathogen

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

Staphylococcus aureus

50/56 (89.3)

35/49 (71.4)

Streptococcus faecalis

8/10 (80.0)

6/11 (54.5)

Streptococcus pyogenes

5/6 (83.3)

6/7 (85.7)

Proteus mirabilis

9/10 (90.0)

7/12 (58.3)

Streptococcus agalactiae

9/12 (75.0)

9/13 (69.2)

Pseudomonas aeruginosa

4/7 (57.1)

5/6 (83.3)

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Page 37 of 68

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)

Study #

Trial design

Dosage, route of

administration

and

duration

Study

subjects

(n=number)

a

Mean

age

(Range)

Gender

male/femal

e

CAPSS-349

Multicentre

randomize

double-

blind

IV levofloxacin 750 mg and

/or oral levofloxacin 750

once daily for 5 days

n=537

b

54.0

(18-94)

207/330

IV ciprofloxacin 400 mg

and/or oral ciprofloxacin

mg twice daily for 10

days

n=556

b

54.4

(18-93)

220/336

L91-058

Double-

blind,

randomized

active-

controlled

oral levofloxacin 250

once daily for 10

days

n=285

51.7

(18-95)

117/168

oral ciprofloxacin 500

twice daily for 10

days

n=282

49.7

(18-93)

112/170

L91-059

Open-

label,

randomized

active-

controlled

oral levofloxacin 250

once daily for 7-10

days

n=326

62.5

(19-92)

124/202

oral lomefloxacin HCl

400 mg once-daily for

days

n=324

59.9

(18-91)

105/219

Subjects enrolled and randomized to treatment

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 Success

a

in Complicated Urinary Tract Infection (cUTI) and Acute Pyelonephritis

(AP)

Microbiologically Evaluable Subjects

Study Number

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

95% Confidence Interval

b

CAPSS-349

229/265 (86.4)

213/241 (88.4)

(-3.8, 7.7)

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

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)

Primary

Endpoin

t

Diagnosis

Levofloxacin

750 mg once

daily

for 5 days

Comparator

Difference

f

95%

Confidence

Interval

g

Microbiologi

Eradication

mITT Population

b,c

Overall (cUTI or AP)

240/317 (75.7)

229/302 (75.8)

(-6.6, 6.9)

cUTI

162/223 (72.6)

151/204 (74.0)

(-7.0, 9.8)

78/94 (83.0)

78/98 (79.6)

-3.4

(-14.4, 7.6)

Microbiologically Evaluable Population

d,e

Overall (cUTI or AP)

228/265 (86.0%)

215/241 (89.2%)

(-2.5, 8.9)

cUTI

154/185 (83.2%)

144/165 (87.3%)

(-3.4, 11.4)

74/80 (92.5%)

71/76 (93.4%)

(-7.1, 8.9)

At posttherapy visit (10-14 days after last active dose of levofloxacin and 5-9 days after last active dose

of ciprofloxacin)

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Page 38 of 68

The mITT population included patients who had a clinical diagnosis of AP or cUTI and who had a positive

(≥10

CFU/mL) urine culture with no more than 2 uropathogens at Study Entry.

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).

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 (≥ 10

CFU/mL) who met all other microbiologic evaluability criteria

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)

Difference in eradication rates (comparator minus levofloxacin)

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

Pathogen

Levofloxacin 750 mg x 5

days

n/N (%)

Comparator n/N (%)

mITT Population

Overall

AP

cUTI

Overall

AP

cUTI

Escherichia coli

165/20

(80.1)

67/8

(82.7

98/12

(78.4)

158/21

(73.1)

70/8

(78.7

88/12

(69.3)

Klebsiella

pneumoniae

21/29

19/26

26/29

22/25

(72.4)

(73.1)

(89.7)

(88.0)

Proteus mirabilis

13/13

(100.0

10/10

(100.0

(85.7

(85.7

Escherichia coli with

7/12

8/12

Bacteremia

(58.3)

(66.7)

Microbiologically Evaluable Population

Overall

AP

cUTI

Overall

AP

cUTI

Escherichia coli

155/172

63/69

92/103

148/168

63/67

85/101

(90.1)

(91.3)

(89.3)

(88.1)

(94.0)

(84.2)

Klebsiella

pneumoniae

20/23

18/21

24/26

21/23

(87.0)

(85.7)

(92.3)

(91.3)

Proteus mirabilis

12/12

(100.0

(100.0

(100.0

(100.0

Escherichia coli with

Bacteremia

(66.7)

(87.5)

Table 2.36 - Relapse Rates at Post-Study Visit

a

Levofloxacin 750 mg x 5

days

n/N (%)

Comparato

r

n/N (%)

mITT Population

Overall (cUTI or AP)

13/207 (6.3)

11/204 (5.4)

cUTI

8/136 (5.9)

10/139 (7.2)

5/71 (7.0)

1/65 (1.5)

Microbiologically Evaluable Population

Overall (cUTI or AP)

12/199 (6.0)

11/195 (5.6)

cUTI

7/131 (5.3)

10/135 (7.4)

5/68 (7.4)

1/60 (1.7)

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

ciprofloxacin

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Page 39 of 68

10 Day Treatment Regimen

Table 2.37 – Clinical Success

a

in Pivotal cUTI and AP Studies – Microbiologically Evaluable Subjects

Study Number

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

95%

Confidenc

e

Interval

L91-058

163/177 (92.1)

155/171 (90.6)

(-7.6, 4.7)

L91-059

195/209 (93.3)

183/204 (89.7)

(-9.2, 2.0)

cured plus improved

Table 2.38 – Microbiologic Eradication in Pivotal cUTI and AP Studies – Microbiologically

Evaluable

Subjects

Study Number

Levofloxacin n/N (%)

Comparator n/N (%)

95% Confidence Interval

L91-058

164/177 (92.7)

159/171 (93.0)

(-5.4, 6.0)

L91-059

198/209 (94.7)

189/204 (92.6)

(-7.0, 2.8)

Table 2.39 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable

Population

(L91-058)

Pathogen

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

Escherichia coli

88/92 (95.7)

96/99 (97.0)

Klebsiella pneumonia

31/32 (96.9)

22/23 (95.7)

Streptococcus faecalis

8/9 (88.9)

6/11 (54.5)

Proteus mirabilis

13/14 (92.9)

5/5 (100.0)

Pseudomonas aeruginosa

7/12 (58.3)

7/7 (100.0)

Enterobacter cloacae

9/9 (100.0)

4/4 (100.0)

Table 2.40 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable

Population

(L91-059)

Pathogen

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

Escherichia coli

118/119 (99.2)

116/118 (98.3)

Klebsiella pneumonia

29/31 (93.5)

23/25 (92.0)

Proteus mirabilis

11/11 (100.0)

9/9 (100.0)

Streptococcus faecalis

4/8 (50.0)

6/8 (75.0)

Pseudomonas aeruginosa

8/9 (88.9)

4/6 (66.7)

Enterobacter cloacae

6/7 (85.7)

4/6 (66.7)

Uncomplicated Urinary Tract Infections

Study demographics and trial design

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

Infections

Study #

Trial design

Dosage, route of

administration

and

duration

Study subjects

(n = number)

a

Mean

age

(Range)

Gender

Male/female

LOFBO

UTI-

Double-

blind,

randomized,

active-

controlled,

multi-centre

oral levofloxacin 250

once daily for 3

days

n=298

31.3

(18-57)

0/298

oral ofloxacin 200

twice daily for 3

days

n=296

32.0

(18-71)

0/296

Subjects enrolled and randomized to treatment

JAMP Levofloxacin

Page 40 of 68

Study Results

Table 2.42 - Results of study LOFBO-UTI-060 in Uncomplicated Urinary Tract Infections

Endpoints

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

95%

Confidenc

e

Interval

Clinical Success Rate

154/157 (98.1)

160/165 (97.0)

(-4.8, 2.6)

Microbiologic Eradication Rate

151/157 (96.2)

153/165 (92.7)

(-8.7, 1.8)

Success includes Cured and Improved; microbiologically evaluable population

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)

Pathogen

Levofloxaci

n

n/N (%)

Comparato

r

n/N (%)

Escherichia coli

125/127 (98.4)

131/138 (94.9)

Klebsiella pneumoniae

10/11 (90.9)

8/8 (100.0)

Staphylococcus saprophyticus

8/8 (100.0)

3/3 (100.0)

Staphylococcus aureus

5/5 (100.0)

3/3 (100.0)

Chronic Bacterial Prostatitis

Study demographics and trial design

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

Study #

Trial design

Dosage, route of

administration

and

duration

Study

subjects (n

=

number)

Mean

age

(Range)

Gender

Male/femal

e

CAPSS-101

Double-blind,

randomized,

active-

controlled,

comparative

oral levofloxacin 500

once daily for 28

days

n=197

50.9

(18-81)

197/0

oral ciprofloxacin 500

twice daily for 28

days

n=180

51.5

(19-83)

180/0

Subjects enrolled and randomized to treatment

Study Results

Table 2.45 - Results of study CAPSS-101 in Chronic Bacterial Prostatitis

Endpoints

Levofloxaci

n

n/N (%)

Comparator

n/N (%)

95% Confidence

Interval

Clinical Success Rate

122/170 (71.8)

107/151 (70.9)

(-11.15, 9.34)

Microbiologic Eradication Rate

102/136 (75.0)

96/125 (76.8)

(-8.98, 12.58)

Success includes Cured and Improved; mITT

Overall microbiologic eradication rates by subject for microbiologically evaluable population

Table 2.46 - Microbiologic Eradication Rates by Pathogen for Microbiologically Evaluable

Population

(CAPSS-101)

Pathogen

Levofloxacin

n/N (%)

Comparator

n/N (%)

Escherichia coli

14/15 (93.3)

9/11 (81.8)

Enterococcus faecalis

39/54 (72.2)

34/45 (75.6)

Staphylococcus epidermis

20/24 (83.3)

26/29 (89.7)

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Page 41 of 68

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

System

Specie

s

Major Findings

Central

Nervous

System

mouse

rabbi

≥600 mg/kg, PO, decreased spontaneous locomotor activity, CNS

depression,

decreased pinna reflex, decreased writhing response to

acetic acid; increased

incidences of strychnine-, pentylenetetrazol- and

caffeine-induced convulsions;

≥200 mg/kg, IV, convulsions after rapid injection, decreased spontaneous

motor

activity, muscle tone, posture, body temperature; increased

respiratory rate;

prolonged hexobarbital sleep time

At 200 mg/kg, IV inhibition of conditioned-avoidance response;

At 200 mg/kg, IP, increased spontaneous motor activity, lowered body

posture,

increased restlessness

At 200 mg/kg, PO, decrease in body temperature

≥6 mg/kg, IV, decreased spinal reflex;

≥30 mg/kg, IV, increased EEG awake stage, seizure discharges

Autonomic

Nervous

System

At 20 mg/kg, IV, reduced contractile response of nictitating membrane to

pre- and

postganglionic stimulation; suppression of acetylcholine

depressor response

Cardiopulmonar

System

≥6 mg/kg, IV bolus, decreases in blood pressure, left ventricular pressure,

respiration depth; ≤10 mg/kg, IV infusion, no effect on blood pressure; ≥20

mg/kg,

IV infusion, decrease in blood pressure, decrease in cardiac output

and stroke

volume; increase in serum histamine concentrations

Gastrointestin

System

mous

At 200 mg/kg, IV, inhibition of gastric propulsion

≥200 mg/kg, PO, decrease in gastric fluid volume, total acidity, pepsin

output;

increase in gastric fluid pH; at 600 mg/kg, decrease in gastric

emptying; at

200 mg/kg, IV, decrease in gastric fluid volume, acid and

pepsin output and

gastric emptying; increase in gastric pH

Urinary Tract

≥200 mg/kg, PO, decrease in urinary volume and electrolyte

excretion; at

200 mg/kg, IV, decrease in urinary volume

Inflammation

At 600 mg/kg, PO, inhibition of carrageenan-induced foot edema

Isolated

Smooth

Muscle

On dog mesenteric, renal, femoral, and basilar arteries, inhibition of

norepinephrine-induced contractions ≥10 x 10

M; competitive

inhibition of

phenylephrine-induced contractions of rabbit thoracic

artery

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.

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Page 42 of 68

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

four-treatment crossover, single-dose study design. One study evaluated dose-response.

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 C

(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 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.

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Page 43 of 68

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

(mg)

n

Peak Plasma Concentration

(mcg/mL)

Area Under the Curve

(AUC

0-∞

, mcg·h/mL)

2.8 ± 0.4

27.2 ± 3.9

5.1 ± 0.8

47.9 ± 6.8

7.1 ± 1.4

82.2 ± 14.3

1000

8.9 ± 1.9

111.0 ± 20.8

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 mcg/mL after the 500 mg doses,

and 8.6 and 1.1 mcg/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%.

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Page 44 of 68

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

range from approximately 2.4 to 11.3 mcg/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 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 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

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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

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 non-white. 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 values

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

172%

183%

139%

AUC value relative to

patients with normal

renal

function receiving

500 mg

q12h

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

50-80 mL/min, n=8 for

49 mL/min, and n=6 for Cl

<20 mL/min).

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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

Collection Interval

Cl

Cr

50-80

mL/min

n

b

=3

Cl

Cr

20-49

mL/min

n=8

Cl

Cr

<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

limit of quantitation = 25 mcg/mL

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

Collection Interval

Cl

Cr

50-80 mL/min

receiving 250

mg

q24h

Cl

Cr

20-49 mL/min

receiving 250

mg

q24h

Cl

Cr

<20 mL/min

receiving 250

mg

q48h

0-6 h

6-12 h

12-24 h

24-36 h

36-48 h

Values were extrapolated from the mean pharmacokinetic profiles in subjects with impaired renal function

(n=12

for Cl

50-80 mL/min, n=8 for Cl

20-49 mL/min, and n=6 for Cl

<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).

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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 2.48.

Table 2.48 - In Vitro Activity of Levofloxacin Against Clinical Isolates

Organism

(# of

isolate

s)

MIC (mcg/mL)

50%

90%

Range

Acinetobacter baumannii

(57)

0.120

16.000

0.060->16.000

Acinetobacter calcoaceticus

(48)

0.250

0.250

0.030-64.000

Chlamydia pneumoniae

(10)

0.250

0.250

0.125-0.500

Citrobacter diversus

(20)

0.030

0.030

0.015-0.060

Citrobacter freundii

(50)

0.060

1.000

0.015-8.000

Enterobacter spp.

(200)

0.060

0.500

≤0.008->16.000

Enterobacter aerogenes

(44)

0.250

0.500

0.060-2.000

Enterobacter agglomerans

(13)

0.250

0.250

0.060-0.500

Enterobacter cloacae

(97)

0.250

0.500

0.025-16.000

Enterococcus spp.

(162)

1.000

>16.000

0.500->16.000

Enterococcus (Streptococcus) faecalis

(122)

1.000

16.000

0.250-64.000

Escherichia coli

(817)

0.030

0.060

≤0.008->16.000

Haemophilus influenzae

(94)

0.015

0.015

≤0.008-0.030

Haemophilus parainfluenzae

(127)

0.250

0.250

0.015-1.000

Haemophilus parahemolyticus

(12)

0.250

0.250

0.008-0.250

Klebsiella spp.

(345)

0.060

1.000

0.015-16.000

Klebsiella oxytoca

(43)

0.250

0.250

0.030-2.000

Klebsiella pneumoniae

(225)

0.250

0.500

0.060-18.000

Legionella pneumophila

(10)

0.030

0.0079-0.030

Moraxella (Branhamella) catarrhalis

(110)

0.250

0.250

0.0150-1.000

Morganella morganii

(43)

0.060

1.000

0.0150->16.000

Mycoplasma pneumoniae

(60)

0.250

0.500

0.250-0.500

Neisseria gonorrhoeae

(47)

≤ 0.008

0.016

≤0.008-0.060

Neisseria meningitidis

(13)

0.250

0.250

0.250-0.500

Proteus and Providencia spp.

(36)

0.060

1.000

0.015->16.000

Proteus mirabilis

(123)

0.060

0.120

0.015-4.000

Proteus vulgaris

(14)

0.250

0.250

0.250-0.500

Pseudomonas aeruginosa*

(378)

1.000

8.000

0.030->16.000

Pseudomonas maltophilia

(17)

0.500

2.000

0.250-4.000

Salmonella spp.

(10)

0.060

0.060

0.060-0.250

Serratia spp.

(65)

0.120

0.500

0.030->16.000

Serratia marcescens

(42)

0.250

1.000

0.125-4.000

Staphylococcus aureus

(565)

0.250

0.500

0.125-32.000

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(# of

MIC (m cg/mL)

Organism

isolates)

50%

90%

Range

Staphylococcus aureus, methicillin-

resistant

(MRSA)**

(25)

0.250

0.500

0.120-1.000

Staphylococcus aureus, methicillin-

susceptible

(MSSA)

(25)

0.250

0.500

0.120-0.500

Staphylococcus aureus, oxacillin-resistant

(62)

8.000

>16.000

0.120->16.000

Staphylococcus aureus, oxacillin-susceptible

(367)

0.120

0.500

0.030-16.000

Staphylococcus epidermidis

(47)

0.250

8.000

0.250-32.000

Staphylococcus epidermidis, methicillin-

resistant

(MRSE)

(14)

0.250

0.250

0.120-0.500

Staphylococcus epidermidis, methicillin-

susceptible

(MSSE)

(12)

0.250

1.000

0.250-1.000

Staphylococcus saprophyticus

(16)

0.500

1.000

0.250-2.000

Stenotrophomonas maltophilia

(43)

2.000

16.000

0.250-16.000

Streptococcus (Viridans group)

0.750

1.000

0.250-1.000

Streptococcus (Group C)

(28)

0.500

1.000

0.250-2.000

Streptococcus (Group G)

(34)

0.500

1.000

0.250-2.000

Streptococcus agalactiae

(96)

1.000

2.000

0.500-2.000

Streptococcus milleri

(35)

0.500

1.000

0.250-4.000

Streptococcus pneumoniae

(99)

1.000

1.000

0.500-2.000

Streptococcus pneumoniae, penicillin-

susceptible

(MIC ≤0.06 mcg/mL)

(2699)

0.500

1.000

≤0.004->8.000

Streptococcus pneumoniae, penicillin-resistant

(MIC ≥2.0 mcg/mL)

(538)

0.500

1.000

≤0.004-2.000

Streptococcus pneumoniae,

clarithromycin-

susceptible (MIC≤0.25

mcg/mL)

(502)

0.500

1.000

0.250->16.000

Streptococcus pneumoniae, clarithromycin-

resistant

(MIC ≥1.0 mcg/mL)

(136)

1.000

2.000

0.12-16.000

Streptococcus pneumoniae, erythromycin-

resistant

(MIC ≥1.0 mcg/mL)

(27)

1.000

1.000

0.500-16.000

Streptococcus pyogenes

(87)

0.500

1.000

0.250-2.000

Streptococcus sanguis

(19)

1.000

2.000

0.250-2.000

* 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

to 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

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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*

(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)

Intermediate (I)

≥8

Resistant (R)

For testing Haemophilus influenzae and Haemophilus parainfluenzae:

MIC (mcg/mL)

Interpretation

≤2

Susceptible (S)

These interpretive standards are applicable only to broth microdilution susceptibility testing with

Haemophilus

influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium*

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:

MIC (mcg/mL)

Interpretation

≤2

Susceptible (S)

Intermediate (I)

≥8

Resistant (R)

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:

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Microorganism

Enterococcus faecalis

ATCC 29212

MIC (mcg/mL)

0.25-2

Escherichia coli

ATCC 25922

0.008-0.06

Escherichia coli

ATCC 35218

0.015-0.06

Pseudomonas aeruginosa

ATCC 27853

0.5-4

Staphylococcus aureus

ATCC 29213

0.06-0.5

Haemophilus influenzae

ATCC 49247

0.008-0.03

Streptococcus pneumoniae

ATCC 49619

0.5-2

This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth

microdilution

procedure using Haemophilus Test Medium (HTM)*

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*

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:

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)

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:

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

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using Mueller-

Hinton agar supplemented with 5% sheep blood and incubated in 5% CO

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:

Microorganism

Escherichia coli

ATCC 25922

Zone Diameter (mm)

29-37

Pseudomonas aeruginosa

ATCC 27853

19-26

Staphylococcus aureus

ATCC 25923

25-30

Haemophilus influenzae

ATCC 49247

32-40

Streptococcus pneumoniae

ATCC 49619

20-25

This quality control range is applicable to only H. influenzae ATCC 49247 tested by a disk diffusion

procedure

using Haemophilus Test Medium (HTM)*

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% CO

* References

National Committee for Clinical Laboratory Standards: Methods for Dilution Antimicrobial Susceptibility

Tests

for Bacteria That Grow Aerobically, Fourth Edition, 1997.

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

STRAIN/

SPECIES

# ANIMAL/

GROUP

ROUTE

LD

50

mg/kg

SUMMARY TOXIC SIGNS

Mouse

M-10

F-10

1881

1803

↓ locomotor activity, ptosis, respiratory depression,

tremor,

convulsion

Mouse

M-10

1943

↓ locomotor activity, ptosis, prostration, tremor,

convulsion

M-10

F-10

1478

1507

Salivation, ptosis, ↓ locomotor activity, tremor,

convulsion,

respiratory depression

M-10

1754

Monkey

>250

Soft stool, transient ↓ platelet count and ↑ bw at 250

mg/kg,

transient ↑ bilirubin, ↓ bw, and emesis at 500

mg/kg

Mouse

M-10

F-10

↓ locomotor activity, ptosis, abnormal posture,

tachypnea,

convulsion, dyspnea

Mouse

Symptoms prior to death: tachypnea, collapse,

dyspnea,

convulsions, respiratory arrest. In

survivors, ↓ locomotor

activity and collapse

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M-10

F-10

↓ locomotor activity, prostration followed by

respiratory

depression, tachypnea, dyspnea,

convulsion, tremor, salivation

Salivation, dyspnea, tonic and clonic convulsion,

death

from respiratory arrest at 200 mg/kg,

lacrimation, vomiting,

lethargy, and tremors. ↑

RBC, WBC, ALT and ALP, and ↓

P on Day 2.

Values returned to normal by Day 8

Monkey

>200

At 200 mg/kg – ptosis, vomiting, ↓ locomotor

activity,

prostration and anorexia, ketone urine,

proteinuria, ↓

glucose. Ptosis and emesis at 100

mg/kg

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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

Species,

Age/Grp/No.

,

Sex/Grp

Route,

Dosage,

Duratio

n

Results

4-6 wk old

4 grp

10 ♀ & 10♂ /grp

0, 50, 200, 800

4 weeks

Lethality: No treatment-related deaths. Clin Obs: Salivation, body

staining,

transient pallor and hypothermia at 800 mg/kg. Transient ↓ fc

in treated ♂ and

↓ bw gain during week 1 in ♂ at 800 mg/kg. Clin Path: ↑ WBC due to

↑ in

lymphocytes at 800 mg/kg. PMNs ↓ in treated ♀ and at 50 and

200 mg/kg in

♂. ↓ K

, Cl

, and urea and ↑ P and ALT (primarily at 800 mg/kg). Higher

ratio at 800 mg/kg. Micro: ↓ relative heart weights at 800 mg/kg

and ↑ cecal

weights at 200 and 800 mg/kg. Slight vacuolization and

minimal hypertrophy

of hepatocytes at 800 mg/kg and arthropathy

(minor) at 800 mg/kg.

NOAEL = 200 mg/kg/day. TI= 2.8

4-5 wk old

4 grp

20 ♀ & 20 ♂ /grp

0, 20, 80, 320

26 wk

Lethality: No treatment-related deaths. Clin Obs: Salivation, ↑ large

fecal

pellets, and stained haircoat mainly at 320 mg/kg. ↑ fc at 80 and

320 mg/kg,

↑ food conversion ratios in ♀ at 320 mg/kg. Clin Path: ↓ PMNs in all

treated

rats, ↑ glucose (treated ♂ ), ↓ triglycerides (320 mg/kg ♀), ↓ ß-

globulin

(treated rats), ↓ α-globulin (treated ♀), ↓ Cl

(320 mg/kg rats

and 80 mg/kg ♀),

↓ total protein (80 and 320 mg/kg ♂), and ↑ urinary pH at 80 and 320

mg/kg.

Micro: Dosage-related ↑ cecal weight, elongated and/or

distended ceca and

engorged goblet cells of the cecal mucosa.

Changes in intestinal flora and

lower nutrient absorption in the

intestines probably responsible for most

changes. No arthropathy.

NOAEL = 20 mg/kg/day. TI = 2.8

6 wk old

5 grp

10 ♀ & 10 ♂ /grp

Diet

0, 100, 200,

400,

13 wk

Lethality: No deaths. Clin Obs:↓ bw at 400 and 800 mg/kg. Clin Path:

↓ total protein (≥200 mg/kg), globulin, and triglycerides (at 800

mg/kg ♂

only). ↑ ALP at 800 mg/kg (♀). Micro: ↓ absolute liver

weight ≥400 (♂),

↑ cecal weight and cecal distension (≥100). No

arthropathy.

NOAEL = 100 mg/kg/day. TI = 14

4 wk old

3 grp, 5 ♂ /grp

0, 20, 100

10 days

4 wk old

4 grp, 4 ♂ /grp

0, 10, 40, 160

2 wk

Lethality: No mortality. Clin Obs: NSF. Clin Path and Micro:

Crystalluria,

↑ cecal weight and ↓ (mild) AST and ALT at 160 mg/kg. No

arthropathy.

NOAEL = 40 mg/kg/day. TI= 5.6

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5 wk old

4 grp

10 ♀ & 10 ♂ /grp

0, 20, 60, 180

4 wk

Lethality: No mortality, Clin Obs: Transient ↓ spontaneous

activity,

blepharoptosis (♂), ↓ bw gain and fc, and swelling at the

injection site at

180 mg/kg. Clin Path: ↓ total protein, albumin, A/G

ratio, cholinesterase

activity, urinary protein, and RBC. ↑ WBC,

retic, and fibrinogen at

180 mg/kg. Crystalluria. Micro: ↓ weights of thymus, liver, heart,

ovaries, and

brain due to ↓ bw gain. ↑ cecal weight at 60 and 180

mg/kg. Arthropathy at 60

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Species,

Age/Grp/No.

,

Sex/Grp

Route,

Dosage,

Duratio

n

Results

and 180 mg/kg.

NOAEL = 20 mg/kg/day, TI = 2.8.

6 wk old

4 grp

10 ♀ & 10♂ /grp

0, 10, 30, 90

13 wk

Lethality: None. Clin Obs: Slight ↓ fc at 30 and 90 mg/kg (♂). Clin

Path:

Mild ↓ total protein, phospholipids, and cholesterol at 90 mg/kg (♂)

due to↓ fc. Mild ↑ A/G and albumin at 30 and 90 mg/kg (♂).

Crystalluria at 30 and

90 (♂) and 90 mg/kg (♀). Micro: ↑ cecal

weight, arthropathy (mild) at 90 mg/kg. NOAEL = 30 mg/kg/day. TI =

4-5 mo old

5 grp

3 ♂ /grp

0, 2, 4, 15, 60

2 wk

Lethality: None. Clin Obs: Histamine-like effects at 15 and 60 mg/kg,

↓ bw

gain and fc at 60 mg/kg. Clin Path: ↑ plasma fibrinogen and

urine specific

gravity; ↓ serum Fe. Micro: ↓ absolute liver weight at 60

mg/kg and ↓

absolute and relative testes weight at 4, 15, and 60

mg/kg; and thrombus

formation in injected vessels at 60 mg/kg,

arthropathy and delayed testicular

maturation at ≥4 mg/kg.

NOAEL = 2 mg/kg/day. TI= 0.28

18 mo old

3 grp

3 ♂/grp

0, 10, 30

2 wk

Lethality: None. Clin Obs: Histamine-like effects and ↓ activity at 10

30 mg/kg. Signs subsided by 30 min post-administration except

↓ activity.

Clin Path: NSF. Micro: NSF.

NOAEL for arthropathy = 30 mg/kg/day. TI=4.2

7-8 mo old

4 grp

3 ♀ & 3 ♂/grp

Infusion

0, 3, 10, 30

4 wk

Lethality: None. Clin Obs: Histamine-like effects in a dosage-

related

manner. Clin Path: NSF. Micro: Arthropathy at ≥10

mg/kg/day.

NOAEL = 3 mg/kg/day. TI=0.42

Monkey

2-4 yr

4 grp

3 ♀ & 3♂/grp

0, 10, 30, 100

4 wk

Lethality: None. Clin Obs and Clin Path: Salivation and diarrhea at

100 mg/kg. Some animals occasionally had what appeared to be blood

in the

urine. Slight bw losses, unusually large adrenal glands in one

monkey and low

urinary pH in two monkeys at 100 mg/kg/day. Micro:

NSF.

NOAEL = 30 mg/kg/day. TI= 4.2

Monkey

2-4 yr

4 grp

4 ♀ & 4 ♂/grp

0, 10, 25, 62.5

26 wk

Lethality: None. Clin Obs: ↓ fc in one high-dosage male during the

first half

of the study. Clin Path and Micro: NSF.

NOAEL = 62.5 mg/kg/day. TI = 8.75

Monkey

2-4 yr

4 grp

3 ♀ & 3 ♂/grp

0, 10, 25, 63

4 wk

Lethality: None. Clin Obs: Loose stools and slightly ↓ wc at 25 and 63

mg/kg and ptosis, occasional quietness, and ↓ fc ( ♀) at 63 mg/kg. Clin

Path:

NSF. Micro: NSF.

NOAEL = 10 mg/kg/day. TI= 1.4

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;

= 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

JAMP Levofloxacin

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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

Study

a

Parental Toxicity

Embryo/Fetal Toxicity

Teratogenicit

y

Oral gavage,

0, 10, 60,

mg/kg/day

24/sex/grou

salivation (at 60 mg/kg mostly ♂ and at

360 mg/kg ♀ & ♂ ) and soft stool at 360

mg/kg;

↑ wc at 360 mg/kg for ♂ and ≥60 mg/kg for ♀

↓ in placental weights at 360

mg/kg.

No effect on mating

performance.

No effect on

intrauterine

survival or

fetal

development.

None

Intravenous,

0, 10, 30,

mg/kg/day

24/sex/grou

swollen tail, soft feces, and urinary

incontinence

at 100 mg/kg in ♂ and ♀. In

females, ↓ bw gain

and fc (wk 1 only) at

100 mg/kg. In males, ↓ bw

gain ≥30 and

slight ↓ fc at all levels, enlarged

cecum ≥30

mg/kg.

No effect on reproductive

performance.

NOAEL = 10

mg/kg/day for ♂ rats,

30 mg/kg/day for ♀ rats.

No effect on intrauterine

survival or development.

Slight non-dose-related ↑

resorptions.

NOAEL = 100 mg/kg/day

for in utero exposure for

fetuses.

None

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

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

Study

a

Maternal Toxicity

Embryo/Fetal Toxicity

Teratogenicit

y

Oral gavage,

0, 10, 90,

810 mg/kg/day

36 ♀ /group

salivation, piloerection, alopecia,

poor hair coat, soft stool,

hyperuresis

and/or watery eyes

at 90 mg/kg and

810 mg/kg. ↓ bw

gain at 810 mg/kg,

↓ fc ≥90 mg/kg,

↑ wc at 810 mg/kg,

enlarged cecum ≥90

mg/kg.

NOAEL = 10

mg/kg.

No effect on survival and weaning

rate,

sexual maturation,

development or

reproductive

performance of F

generation. ↓

mean bw for pups at birth

(♂ and

♀) on Days 63-77 postpartum

(♀)

at 810 mg/kg. ↑ fetal mortality, and

↓ fetal weight at 810 mg/kg.

Maternal

toxicity at 810 mg/kg led

to delayed

ossification of sternum,

metatarsal,

proximal phalange,

and caudal

vertebrae.

None

Intravenous,

0, 10, 40,

mg/kg/day

36 ♀

/group

↓ fc at 40 mg/kg (Days 7-12

only)

and at 160 mg/kg. Swollen

tails (inj.

site) and ↑ wc at 160

mg/kg.

NOAEL= 10 mg/kg for dams.

Maternal toxicity led to delayed

ossification of sternum and caudal

vertebrae. No effect other than

delayed

ossification was observed.

NOAEL = 40 mg/kg for fetuses,

≥160

mg/kg for pups.

None

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Study

a

Maternal Toxicity

Embryo/Fetal Toxicity

Teratogenicit

y

Oral gavage,

rabbit

0, 5, 16,

mg/kg/day

16 ♀ /group

↓ fc and bw gain at 50 mg/kg,

transient ↓ fc at 16 mg/kg, ↑

number

placental remnants at

50 mg/kg, 4

dams aborted.

NOAEL = 5 mg/kg/day for dams.

No adverse effects.

NOAEL = 50 mg/kg/day for fetuses.

None

Intravenous,

rabbit

0, 6.25,

12.5, 25

mg/kg/day

20 ♀

/group

transient ↓ bw and fc at 25

mg/kg

early in gestation (Days

6-9).

NOAEL = 12.5 mg/kg/day

maternal toxicity.

No adverse effects.

NOAEL = 25 mg/kg/day

developmental

toxicity.

None

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

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

Study

Maternal Toxicity

Embryo/Fetal

Toxicity

Parturition

/

Neonatal

Growth

and

Survival

Oral gavage, rat

0, 10, 60, 360 mg/kg/day

24 ♀ /group

Dosed daily from Day 17

gestation to Day 21 of

lactation

salivation, diarrhea and soft

feces at

360 mg/kg, salivation in

some at

60 mg/kg, ↓ fc at 60 mg/kg during

gestation and lactation (Days 14-

18), ↓

fc during gestation and ↑ fc

during

lactation at 360 mg/kg, ↓wc

on 2 days

during gestation and ↑

wc during

lactation at 360 mg/kg.

NOAEL = 10 mg/kg for dams.

No effects on either F

generation.

NOAEL = 360 mg/kg for

pups.

No effects

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

JAMP Levofloxacin

Page 58 of 68

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 IC

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 (MAP

was not significantly affected by levofloxacin 0.3 and 3.0 mg/kg IV.

JAMP Levofloxacin

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REFERENCES

Watanabe K, Kato N, Muto Y, Bandou K, Ueno K. Antibacterial activity of levofloxacin,

isomer of ofloxacin, against anaerobic bacteria. Chemotherapy (Japan) 1992; 40:57-63.

Gough AW, Kasali OB, Sigler RE, Baragi V. Quinolone arthropathy - acute toxicity to

immature articular cartilage. Toxicol Path 1992; 20(3):436-449.

Niederman MS, Bass JB Jr, Campbell GD, Fein AM, Grossman RF, Mandell LA, Marrie

TJ, Sarosi GA, Torres A, Yu VL. Guidelines for the initial management of adults with

community-acquired pneumonia: diagnosis, assessment of severity, and initial

antimicrobial therapy. Amer Thoracic Soc, Med Section, Amer Lung Assoc. Amer Review

of Respiratory Disease Nov 1993; 148(5): 1418-1426.

Tanaka M, Kurata T, Fujisawa C. Mechanistic study of inhibition of levofloxacin

absorption by aluminum hydroxide. Antimicrobial Agents and Chemotherapy 1993;

37(10):2173-2178.

Yamane N, Jones RN, Frei R, Hoban DJ, Pignatari AC, Marco F. Levofloxacin in vitro

activity: results from an international comparative study with ofloxacin and ciprofloxacin.

Chemotherapy 1994; 6:83-91.

Peterson LR, Cooper I, Willard KE, et al. Activity of twenty-one antimicrobial agents

including L-ofloxacin against quinolone-sensitive and –resistant, and methicillin-sensitive

and -resistant Staphylococcus aureus. Chemotherapy 1994; 40:21-25.

Child J, Mortiboy D, Andrews JM, Chow AT, Wise R. Open-label crossover study to

determine pharmacokinetics and penetration of two dose regimens of levofloxacin into

inflammatory fluid. Antimicrobial Agents and Chemotherapy 1995; 39(12):2749-2751.

Fuch PC, Barry AL, Brown SD. The AST Surveillance Group. Prevalence of resistance to

three fluoroquinolones: assessment of levofloxacin disk test error rates and surrogate

predictors of levofloxacin susceptibility. Antimicrobial Agents and Chemotherapy 1996;

40(7):1633-1639.

DeAbate CA, Russell M, McElvaine P, Faris H, Upchurch J, Fowler CL, Polak EM,

Morgan NS. Safety and efficacy of oral levofloxacin versus cefuroxime axetil in acute

bacterial exacerbation of chronic bronchitis. Respiratory Care 1997; 42(2): 206-213.

Fish DN, Chow AT. Levofloxacin clinical pharmacokinetics. Clinical Pharmacokinetics

1997; 32(2):101-119.

Isaacson DM, Fernandez JA, Frosco M, Foleno BD, Goldschmidt RM, Amararunga D,

Manolz A, Lawrence LE, Wira E, Barrett JF. Levofloxacin: A review of its antibacterial

activity. Recent Res Devel in Antimicrob Agents and Chemother 1996; 1:391-439.

Lee L-J, Sha X, Gotfried MH, Howard JR, Dix RK, Fish DN. Penetration of levofloxacin

into

lung tissue after oral administration to subjects undergoing lung biopsy or lobectomy.

Pharmacotherapy 1998; 18(1): 35-41.

JAMP Levofloxacin

Page 60 of 68

Sydnor TA, Kopp EJ, Anthony KE, LoCoco JM, Kim SS, Fowler CL. An open-label

assessment of the activity of levofloxacin for the treatment of acute community-acquired

bacterial sinusitis in adults. Annals of Allergy, Asthma & Immunology 1998; 80:357-362.

Nichols RL, Smith JW, Gentry LO, Gezon J, Campbell T, Sokol P, Williams RR.

Multicenter, randomized study comparing levofloxacin and ciprofloxacin for

uncomplicated skin and skin structure infections. Southern Medical Journal 1997; 90(12):

1193-1200.

File TM Jr, Segreti J, Dunbar L, Player R, Kohler R, Williams RR, Kojak C, Rubin A. A

multicenter, randomized study comparing the efficacy and safety of iv/oral levofloxacin

versus ceftriaxone/cefuroxime axetil in the treatment of adults with community-acquired

pneumonia. Antimicrobial Agents and Chemotherapy 1997; 41(9):1965-1972.

Habib MP, Gentry LO, Rodriguez-Gomez G, Morowitz W, Polak E, Rae JK, Morgan NS,

Williams RR. Multicenter, randomized study comparing efficacy and safety of oral

levofloxacin and cefaclor in treatment of acute bacterial exacerbations of chronic

bronchitis. Infectious Diseases in Clinical Practice 1998; 7:101-109.

Nicodemo AC, Robledo JA, Jasovich A, Neto W. A multicentre, double-blind, randomised

study comparing the efficacy and safety of oral levofloxacin versus ciprofloxacin in the

treatment of uncomplicated skin and skin structure infections. International Journal of

Clinical Practice 1998; 52(2):69-74.

Noel GJ, Natarajan J, Chien S, Hunt TL, Goodman DB, Abels R. Effects of three

fluoroquinolones on QT intervals in healthy adults after single doses. Clinical

Pharmacology and Therapeutics 2003; 73: 292-303.

West M, Boulanger BR, Fogarty C, Tennenberg A, Wiesinger B, Oross M, Wu S-C,

Fowler C, Morgan N, Kahn JB. Levofloxacin compared with imipenem/cilastatin followed

by ciprofloxacin in adult patients with nosocomial pneumonia: A multicenter, prospective,

randomized, open-label study. Clinical Therapeutics 2003; 25(2): 485-506

Bundrick W, Heron SP, Ray P, Schiff WM, Tennenberg AM, Wiesinger BA, Wright PA,

Wu S-C, Zadeikis N, Kahn JB. Levofloxacin versus ciprofloxacin in the treatment of

chronic bacterial prostatitis: A randomized double-blind multicenter study. Urology 2003;

62: 537-541

Dunbar LM, Wunderlink RG, Habib MP, Smith LG, Tennenberg AM, Khashab MM,

Wiesinger BA, Xiang JX, Zadeikis N, Kahn JB. High-dose, short-course levofloxacin for

community-acquired pneumonia: a new treatment paradigm. Clinical Infectious Diseases

2003; 37:752-760

Janssen-Ortho Inc., Levaquin Product Monograph, Control No: 175523, Date of revision:

August 13, 2014.

Canadian clinical practice guidelines for acute and chronic rhinosinusitis. Desrosiers et al.

Allergy, Asthma and Clinical Immunology, 2011, 7:2.

JAMP Levofloxacin

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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.

Teva Canada Limited, TEVA-LEVOFLOXACIN Product Monograph, Control No:

226600, Date of Revision: July 17, 2019

Sandoz Canada Inc., Sandoz LEVOFLOXACIN Product Monograph, Control No:

231592, Date of Revision: September 17, 2019

JAMP Levofloxacin

Page 62 of 68

READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE

PATIENT MEDICATION INFORMATION

Pr

JAMP Levofloxacin

Levofloxacin tablets, USP

Read this carefully before you start taking JAMP Levofloxacin and each time you get a refill.

This leaflet is a summary and will not tell you everything about this drug. Talk to your

healthcare

professional about your medical condition and treatment and ask if there is any

new information about JAMP Levofloxacin.

What is JAMP Levofloxacin used for?

JAMP Levofloxacin is used to treat bacterial infections in the:

Skin.

Kidneys.

Urinary tract (bladder or prostate).

Sinuses.

Lungs.

How does JAMP Levofloxacin work?

JAMP Levofloxacin is in a group of antibiotics called quinolones (kwin-o-lones) that:

Stop growth of bacteria.

Kill the bacteria.

Reduce the infection.

Some infections are caused by viruses, such as the common cold. JAMP Levofloxacin does not

kill viruses.

Serious Warnings and Precautions

Talk to your doctor, if you:

Have serious allergic reaction to levofloxacin or similar antibiotics such as ciprofloxacin,

moxifloxacin, and others.

Have seizures (convulsions). Tell your doctor if you have any problems in the brain, including

epilepsy. Your doctor will tell you whether you should use this medication.

Have muscle problems (e.g. weakness, joint problems). Do not use JAMP Levofloxacin

if

you have or have had myasthenia gravis.

Have previous history of inflamed tendon (fiber that connects bones to muscles in the body)

and tendon rupture. Your risk for tendon problem is greater, if you are over 60 years of age,

and if you are taking steroid medication, or if you have had kidney, heart or lung transplant.

Have family history of long QT syndrome (prolongation of the heartbeat on an

electrocardiogram test.

JAMP Levofloxacin

Page 63 of 68

What are the ingredients in JAMP Levofloxacin?

Medicinal ingredients: Levofloxacin (levofloxacin hemihydrate).

Non-medicinal ingredients: microcrystalline cellulose, crospovidone, hypromellose, magnesium

stearate ferric oxide yellow (500 mg strengths only),

ferric oxide red (250 mg and 500 mg

strengths only), polysorbate 80, polyethylene glycol and titanium dioxide.

JAMP Levofloxacin comes in the following dosage forms:

JAMP Levofloxacin tablets are pink for the 250 mg tablet, peach coloured for the

500 mg

tablet, or white for the 750 mg tablet.

Do not use JAMP Levofloxacin:

you have allergic reaction to this drug or to other quinolone antibiotics (such as

ciprofloxacin, moxifloxacin)

you have a history of tendinitis (inflammation of tendon or tendon rupture). This

condition causes pain and tenderness just outside of joint in shoulders, elbows,

wrists, knees, heels, etc.

To help avoid side effects and ensure proper use, talk to your healthcare professional

before you take JAMP Levofloxacin. Talk about any health conditions or problems you

may have, including if you:

have kidney problems.

have epilepsy.

have or have had seizures (convulsions).

have had any problems with your heart rhythm, heart rate, or problems with low

potassium.

have diabetes and are taking anti-diabetic medications (it may interfere with blood sugar

levels).

have a disease that causes muscle weakness (myasthenia gravis).

experience any symptoms of muscle weakness, including breathing difficulties (e.g.,

shortness of breath).

have a history of tendon problems associated with antibiotics.

are pregnant or plan to become pregnant.

are breastfeeding or plan to breastfeed. Talk to your doctor about how to feed your

baby while you are taking JAMP Levofloxacin.

Have an aortic aneurysm which is an abnormal bulge in a large blood vessel called

aorta.

Have or if anyone in your family has a condition called aneurysm disease which is an

abnormal bulge in any large blood vessel in the body.

Have an aortic dissection which is a tear in the wall of the aorta.

Have any of the following conditions: Marfan syndrome, vascular Ehlers-Danlos

JAMP Levofloxacin

Page 62 of 68

syndrome, Takayasu arteritis, giant cell arteritis or Behcet's disease.

Have high blood pressure.

Have atherosclerosis, which is a hardening of your blood vessels.

Other warnings you should know about:

Blood Sugar Changes

Medicines like JAMP Levofloxacin can cause blood sugar levels to rise and drop in patients

with

diabetes. Serious cases of hypoglycemia (low blood sugar levels) that caused coma or death

have been seen with medicines like JAMP Levofloxacin. If you have diabetes, check your blood

sugar levels often while taking JAMP Levofloxacin.

If you have diabetes, you may develop a hypoglycemic reaction (low blood sugar) with

common symptoms such as:

-Dizziness.

-Excessive hunger.

-Lack of coordination.

-Headache.

-Fatigue.

-Fainting.

Or a hyperglycemic reaction (high blood sugar) with common symptoms such as:

-Excessive thirst.

-Excessive urination.

Quinolones, including levofloxacin, have been associated with an enlargement or

"bulge"

of a large blood vessel (aortic aneurysm or large vessel peripheral aneurysm) and

aortic

dissection (a tear in the aorta wall)

The risk of these problems is higher if you:

are elderly

have or anyone in your family has had aneurysm disease

have an aortic aneurysm or an aortic dissection

have any of the following conditions: Marfan syndrome, vascular Ehlers-Danlos

syndrome, Takayasu arteritis or giant cell arteritis or Behcet's disease

have high blood pressure or atherosclerosis

If you experience sudden, severe pain in your abdomen, chest or back, a pulsating

sensation in your abdomen, dizziness or loss of consciousness, get immediate

medical

help.

What are possible side effects (from using JAMP Levofloxacin)?

Self-Limiting Side Effects

-Feeling lightheaded

-Insomnia (difficulty sleeping)

-Nightmares

JAMP Levofloxacin

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You should call your doctor if you experience any of these symptoms.

Allergic reaction:

If you develop one of the following:

-Hives.

-Itching.

-Skin rash.

-Difficulty breathing or swallowing.

-Swelling in the face, tongue or throat.

-Other symptoms of an allergic reaction.

You should stop taking this medication and call your doctor.

Operating Heavy Machinery:

You should know that use of JAMP Levofloxacin may cause dizziness. Please make sure that

you know how to react if you are:

-driving a car.

-operate any machinery at working place.

-perform work that needs mental alertness or coordination.

Exposure to sunlight:

You should not expose yourself to sunlight or artificial ultraviolet light while you are taking

JAMP Levofloxacin. Use sunscreen and wear protective clothing if out in the sun

Tell your healthcare professional about all the medicines you take, including any drugs,

vitamins, minerals, natural supplements or alternative medicines.

The following may interact with JAMP Levofloxacin:

antiacids, multi-vitamins, or products containing metals (such as aluminium, calcium,

iron, magnesium or zinc). See How to take JAMP Levofloxacin.

medicines used for ulcers (such as sucralfate). See How to take JAMP Levofloxacin.

medicines used for heartburn or gout (such as probenecid, cimetidine, etc).

medicines used for treatment of asthma or chronic obstructive pulmonary

disease (COPD) (such as theophylline)

medications for arthritis (nonsteroidal anti-inflammatory drugs (NSAIDs) such as

ibuprofen, naproxen).

blood sugar medicines (such as metformin, gliclazide, insulin, etc).

medicines used for any heart conditions.

blood thinner medications (such as warfarin, etc.) that used to thin the blood and

prevent

clots – may predispose you to the development of bleeding problems.

This medication may interfere with certain laboratory tests (such as urine screening for

opiates), possibly causing false test results.

How to take JAMP Levofloxacin:

JAMP Levofloxacin

Page 64 of 68

If you think you have taken too much JAMP Levofloxacin, contact your healthcare

professional,

hospital emergency department or regional Poison Control Centre immediately, even if there are

no symptoms.

You should swallow the whole tablet with or without food.

Try to take the tablet at the same time and drink plenty of fluids while taking this medicine

unless otherwise directed by your doctor.

Do not share your medicine with anyone.

Antibacterial drugs like JAMP Levofloxacin treat only bacterial infections. They do not treat

viral infections. Although you may feel better early in the treatment, JAMP Levofloxacin

should

be used exactly as directed. Misuse or overuse of JAMP Levofloxacin could lead to the

growth

of bacterial that will not be killed by JAMP Levofloxacin (resistance). This means that

JAMP

Levofloxacin may not work in the future.

Ask your pharmacist about the other products you take. Some medicines will affect the way

that

your body absorbs JAMP Levofloxacin. Take JAMP Levofloxacin at least 2 hours before

or 2 hours after taking these medicines. Some examples include: vitamins/minerals (including

iron

and zinc supplements), and products containing magnesium, aluminum, or calcium (such

antacids, calcium supplements).

Usual Adult Dose:

You should take this medication by mouth as directed by your doctor.

The dosage and length of the treatment depends on your kidney function, medical condition, and

response to treatment. It may last for 3, 5, 7, 10, 14 or 28 days depending on your condition.

Tell your doctor if your condition does not improve.

Overdose:

Symptoms of overdose may include: severe dizziness.

Missed dose:

If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip

the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

What are possible side effects from using JAMP Levofloxacin?

These are not all the possible side effects you may feel when taking JAMP Levofloxacin. If you

experience any side effects not listed here, contact your healthcare professional.

JAMP Levofloxacin

Page 65 of 68

Serious side effects and what to do about them

Symptom/Effect

Talk to your healthcare

professional

Stop taking drug

and get

immediate

medical help

Only if

sever

In all cases

VERY COMMON

Nausea

Headache

Diarrhea (have slightly soft to watery

stool)

Insomnia (lack of sleep)

Dizziness (drowsiness, light headedness)

Constipation (hard to pass stool)

COMMON

Abdominal or stomach pain or discomfort

Vomiting

Dyspepsia (discomfort or pain in the upper

abdomen)

Dyspnea (shortness of breath)

Moniliasis (yeast infection of the mouth

and throat)

Skin rash

Pruritus (itching)

Vaginal itching and discharge

Edema (swelling caused by excess fluid in

your body)

Chest pain

RARE

Stomach cramps or pain (severe)

Agitation (purposeless movements)

Blisters

Confusion

Diarrhea (watery and severe) which may

also be bloody

Feeling that others can hear your

thoughts

or control your behavior

Fever

Pain, inflammation, or swelling in the

calves of the legs, shoulders, or hands,

including tendon rupture or swelling of the

tendon (tendinitis)

Redness and swelling of the skin

Seeing, hearing, or feeling things that are

JAMP Levofloxacin

Page 66 of 68

Serious side effects and what to do about them

Symptom/Effect

Talk to your healthcare

professional

Stop taking drug

and get

immediate

medical help

Only if

sever

In all cases

not there

Sensation of burning on the skin

Severe mood or mental changes

Neuropathy (problems in the nerves such

as pain, burning, tingling, numbness or

weakness)

Skin rash, itching, or redness – sun

sensitivity (photosensitivity), which can

appear as skin eruption or severe

Trembling

Unusual behavior

Severe/persistent headache

Vision changes

Shaking (tremors), seizures (convulsions)

Severe dizziness, fainting

Fast/irregular heartbeat

Mental Health Problems:

Anxiety

Confusion

Depression

Feeling agitated

Restless or nervous

Suicidal thoughts or actions

Hallucinations

Inability to

think clearly or

pay attention

Memory loss

Paranoia or loss of touch with reality

Neurological Problems:

Seizures (convulsions)

Tremor

Rise in the pressure within your skull:

Blurred or double vision

Headaches

Nausea

Hypoglycemia (Low blood sugar):

Change in mood

JAMP Levofloxacin

Page 67 of 68

Serious side effects and what to do about them

Symptom/Effect

Talk to your healthcare

professional

Stop taking drug

and get

immediate

medical help

Only if

sever

In all cases

Change in vision

Confusion

Dizziness

Fast heartbeat

Feeling faint

Headache

Hunger

Shaking

Sweating

Weakness

Signs of liver problems (such as persistent

nausea/vomiting, stomach abdominal pain,

unusual tiredness, yellowing eyes/skin,

dark urine)

Aortic aneurysm (abnormal bulge in

large blood vessel called the aorta)

/Aortic

dissection (tear in the wall of

the aorta):

dizziness, loss of

consciousness, pulsating sensation

in the abdomen, sudden, severe

pain in abdomen, chest or back.

If you have a troublesome symptom or side effect that is not listed here or becomes bad

enough to interfere with your daily activities, talk to your healthcare professional.

Reporting Side Effects

You can report any suspected side effects associated with the use of health products to

Health Canada by:

Visiting the Web page on Adverse Reaction Reporting

(https://www.canada.ca/en/health-canada/services/drugs-health-

products/medeffect-canada/adverse-reaction-reporting.html)

information

on how to report online, by mail or by fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need information about how to manage

your side effects.

The Canada Vigilance Program does not provide medical advice.

JAMP Levofloxacin

Page 68 of 68

Storage:

JAMP Levofloxacin tablets should be stored in a well-closed container between 15°C and

30°C. Protect from moisture.

Keep out of reach and sight of children.

Do not use after the expiry date. Generally, all expired medications should be returned to your

pharmacist.

If you want more information about JAMP Levofloxacin:

Talk to your healthcare professional.

Find the full Product Monograph that is prepared for

healthcare professionals and includes

this Patient Medication Information by visiting the Health Canada website

(https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-

products/drug-product-database.html

or by calling

the manufacturer, JAMP Pharma

Corporation, at: 1-866-399-9091.

This leaflet was prepared by JAMP Pharma Corporation

1310, rue Nobel

Boucherville, Québec

J4B 5H3

Last Approved: November 23, 2020

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