• In adults with infections of mild or moderate severity, Levox tablets are indicated for
the treatment of the following infections when due to levofloxacin-susceptible
microorganisms:
• Acute bacterial sinusitis (adequately diagnosed according to national and/or local
guidelines on the treatment of respiratory tract infections)
• Acute bacterial exacerbations of chronic bronchitis (adequately diagnosed according to
national and/or local guidelines on the treatment of respiratory tract infections)
• Community-acquired pneumonia
• Uncomplicated urinary tract infections
• Complicated urinary tract infections including pyelonephritis
• Chronic bacterial prostatitis.
• Skin and soft tissue infections.
Before prescribing Levox, consideration should be given to national and/or local guidance
on the appropriate use of fluoroquinolones.
- Not recommended for children under 12 years.
 

• Levox tablets are administered once or twice daily. The dosage depends on the type and

severity of the infection and the sensitivity of the presumed causative pathogen.
• Duration of treatment
The duration of treatment varies according to the course of the disease (see table below).
As with antibiotic therapy in general, administration of Levox tablets should be continued
for a minimum of 48 to 72 hours after the patient has become afebrile or evidence of
bacterial eradication has been obtained.
• Method of administration
Levox tablets should be swallowed without crushing and with sufficient amount of liquid.
The tablets may be taken during meals or between meals. Levox tablets should be taken at
least two hours before or after iron salts, antacids and sucralfate administration since
reduction of absorption can occur (see section 4.5).
Inhalation anthrax (post exposure)
The effectiveness of Levox® for this indication is based on plasma concentrations achieved in
humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levox® has not been
tested in humans for the post-exposure prevention of inhalation anthrax. The mean plasma
concentrations of Levox® associated with a statistically significant improvement in survival
over placebo in the rhesus monkey model of inhalational anthrax are reached or exceeded in
adult and pediatric patients receiving the recommended oral and intravenous dosage regimens
Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. The mean
(± SD) steady state peak plasma concentration in human adults receiving 500 mg orally or
intravenously once daily is 5.7 ± 1.4 and 6.4 ± 0.8 mcg/mL, respectively; and the
corresponding total plasma exposure (AUC0–24) is 47.5 ± 6.7 and 54.6 ± 11.1 mcg.h/mL,
respectively. The predicted steady-state pharmacokinetic parameters in pediatric patients
ranging in age from 6 months to 17 years receiving 8 mg/kg orally every 12 hours (not to
exceed 250 mg per dose) were calculated to be comparable to those observed in adults
receiving 500 mg orally once daily.
In adults, the safety of Levox® for treatment durations of up to 28 days is well characterized.
However, information pertaining to extended use at 500 mg daily up to 60 days is limited.
Prolonged Levox® therapy in adults should only be used when the benefit outweighs the risk.
In pediatric patients, the safety of levofloxacin for treatment durations of more than 14 days
has not been studied. An increased incidence of musculoskeletal adverse events (arthralgia,
arthritis, tendonopathy, gait abnormality) compared to controls has been observed in clinical
studies with treatment duration of up to 14 days. Long-term safety data, including effects on
cartilage, following the administration of levofloxacin to pediatric patients is limited.
Posology
The following dose recommendations can be given for Levox:
Dosage in patients with normal renal function (creatinine clearance > 50 ml/min)

Indication	Daily dose regimen (according to severity)	Duration of treatment (according to severity)
Acute sinusitis	500 mg once daily	10 - 14 days
Acute  exacerbations of chronic bronchitis	250 to 500 mg once daily	7 - 10 days
Community-acquired pneumonia	500 mg once or twice daily	7 - 14 days
Uncomplicated urinary tract infection	250 mg once daily	3 days
Complicated urinary tract infections including pyelonephritis	250 mg once daily	7 - 10 days
Chronic bacterial prostatitis.	500 mg once daily	28 days
Skin and soft tissue infections	250 mg once daily or 500 mg once or twice daily	7 - 14 days

Special populations
Impaired renal function (creatinine clearance ≤50ml/min)

	Dose regimen
	250 mg/24 h	500 mg/24 h	500 mg/12 h
Creatinine clearance	first dose: 250 mg	first dose: 500 mg	first dose: 500 mg
50-20 ml/min	then: 125 mg/24 h	then : 250 mg/24 h	then : 250 mg/12 h
19-10 ml/min	then: 125 mg/48 h	then : 125 mg/ 24 h	then : 125 mg/12 h
< 10 ml/min (including haemodialysis and CAPD) 1	then: 125 mg/48 h	then: 125 mg/24 h	then: 125 mg/24 h

¹ No additional doses are required after haemodialysis or continuous ambulatory peritoneal dialysis (CAPD).

Impaired liver function
No adjustment of dosage is required since levofloxacin is not metabolised to any relevant
extent by the liver and is mainly excreted by the kidneys.
In the elderly
No adjustment of dosage is required in the elderly, other than that imposed by consideration of
renal function. (See section 4.4 QT interval prolongation).
In children
Levox is contraindicated in children and growing adolescents (see section 4.3).
Inhalational Anthrax (Post-Exposure)
Levofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The
risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is

appropriate. The safety of levofloxacin in pediatric patients treated for more than 14 days has
not been studied. The pharmacokinetics of levofloxacin following a single intravenous dose
were investigated in pediatric patients ranging in age from six months to 16 years. Pediatric
patients cleared levofloxacin faster than adult patients resulting in lower plasma exposures than
adults for a given mg/kg dose.

Levox tablets must not be used: • In patients hypersensitive to levofloxacin or other quinolones or any of the excipients, • In patients with epilepsy, • In patients with history of tendon disorders related to fluoroquinolone administration, • In children or growing adolescents, • During pregnancy, • In breast-feeding women.

In the most severe cases of pneumococcal pneumonia Levox may not be the optimal therapy.
Nosocomial infections due to P. aeruginosa may require combination therapy.
Tendinitis and tendon rupture
Tendinitis may rarely occur. It most frequently involves the Achilles tendon and may lead to
tendon rupture. The risk of tendinitis and tendon rupture is increased in the elderly and in
patients using corticosteroids. Close monitoring of these patients is therefore necessary if they
are prescribed Levox. All patients should consult their physician if they experience symptoms
of tendinitis. If tendinitis is suspected, treatment with Levox must be halted immediately, and
appropriate treatment (e.g. immobilisation) must be initiated for the affected tendon.
Clostridium difficile-associated disease
Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with Levox
tablets, may be symptomatic of Clostridium difficile-associated disease, the most severe form
of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, Levox
tablets must be stopped immediately and patients should be treated with supportive measures ±
specific therapy without delay (e.g. oral vancomycin). Products inhibiting the peristalsis are
contraindicated in this clinical situation.
Patients predisposed to seizures
Levox tablets are contraindicated in patients with a history of epilepsy and, as with other
quinolones, should be used with extreme caution in patients predisposed to seizures, such as
patients with pre-existing central nervous system lesions, concomitant treatment with fenbufen
and similar non-steroidal anti-inflammatory drugs or with drugs which lower the cerebral

seizure threshold, such as theophylline (see section 4.5). In case of convulsive seizures,
treatment with levofloxacin should be discontinued.
Patients with G-6- phosphate dehydrogenase deficiency
Patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity may be
prone to haemolytic reactions when treated with quinolone antibacterial agents, and so
levofloxacin should be used with caution.
Patients with renal impairment
Since levofloxacin is excreted mainly by the kidneys, the dose of Levox should be adjusted in
patients with renal impairment (see section 4.2).
Hypersensitivity reactions
Levofloxacin can cause serious, potentially fatal hypersensitivity reactions (e.g. angioedema up
to anaphylactic shock), occasionally following the initial dose (see section 4.8). Patients should
discontinue treatment immediately and contact their physician or an emergency physician, who
will initiate appropriate emergency measures.
Hypoglycemia
As with all quinolones, hypoglycemia has been reported, usually in diabetic patients receiving
concomitant treatment with an oral hypoglycemic agent (e.g., glibenclamide) or with insulin. In
these diabetic patients, careful monitoring of blood glucose is recommended. (See section 4.8).
Prevention of photosensitisation
Although photosensitisation is very rare with levofloxacin, it is recommended that patients
should not expose themselves unnecessarily to strong sunlight or to artificial UV rays (e.g.
sunray lamp, solarium), in order to prevent photosensitisation.
Patients treated with Vitamin K antagonists
Due to possible increase in coagulation tests (PT/INR) and/or bleeding in patients treated with
Levox in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be
monitored when these drugs are given concomitantly (see section 4.5).
Psychotic reactions
Psychotic reactions have been reported in patients receiving quinolones, including
levofloxacin. In very rare cases these have progressed to suicidal thoughts and selfendangering
behaviour- sometimes after only a single dose of levofloxacin (see section 4.8). In
the event that the patient develops these reactions, levofloxacin should be discontinued and
appropriate measures instituted. Caution is recommended if levofloxacin is to be used in
psychotic patients or in patients with history of psychiatric disease.
QT interval prolongation
Caution should be taken when using fluoroquinolones, including levofloxacin, in patients with
known risk factors for prolongation of the QT interval such as, for example:
- Congenital long QT syndrome
- Concomitant use of drugs that are known to prolong the QT interval (e.g. Class IA and III
antiarrhythmics, tricyclic antidepressants, macrolides).
- Uncorrected electrolyte imbalance (e.g. hypokalemia, hypomagnesemia)
- Elderly
- Cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)
(See section 4.2 Elderly, section 4.5, section 4.8, section 4.9).

Peripheral neuropathy
Sensory or sensorimotor peripheral neuropathy has been reported in patients receiving
fluoroquinolones, including levofloxacin, which can be rapid in its onset. Levofloxacin should
be discontinued if the patient experiences symptoms of neuropathy in order to prevent the
development of an irreversible condition.
Opiates
In patients treated with levofloxacin, determination of opiates in urine may give false-positive
results. It may be necessary to confirm positive opiate screens by more specific method.
Hepatobiliary disorders
Cases of hepatic necrosis up to life threatening hepatic failure have been reported with
levofloxacin, primarily in patients with severe underlying diseases, e.g. sepsis (see section 4.8).
Patients should be advised to stop treatment and contact their doctor if signs and symptoms of
hepatic disease develop such as anorexia, jaundice, dark urine, pruritus or tender abdomen.
Levox® is indicated in pediatric patients (≥6 months of age) only for the prevention of
inhalational anthrax (post-exposure). An increased incidence of musculoskeletal disorders
(arthralgia, arthritis, tendonopathy, and gait abnormality) compared to controls has been
observed in pediatric patients receiving Levox®.

Effect of other medicinal products on Levox
Iron salts, magnesium- or aluminium-containing antacids
Levofloxacin absorption is significantly reduced when iron salts, or magnesium- or aluminiumcontaining
antacids are administered concomitantly with Levox tablets. It is recommended that
preparations containing divalent or trivalent cations such as iron salts, or magnesium- or
aluminium-containing antacids should not be taken 2 hours before or after Levox tablet
administration (see section 4.2). No interaction was found with calcium carbonate.
Sucralfate
The bioavailability of Levox tablets is significantly reduced when administered together with
sucralfate. If the patient is to receive both sucralfate and Levox, it is best to administer
sucralfate 2 hours after the Levox tablet administration (see section 4.2).
Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs
No pharmacokinetic interactions of levofloxacin were found with theophylline in a clinical
study. However a pronounced lowering of the cerebral seizure threshold may occur when
quinolones are given concurrently with theophylline, non-steroidal anti-inflammatory drugs, or
other agents, which lower the seizure threshold.
Levofloxacin concentrations were about 13% higher in the presence of fenbufen than when
administered alone.
Probenecid and cimetidine
Probenecid and cimetidine had a statistically significant effect on the elimination of
levofloxacin. The renal clearance of levofloxacin was reduced by cimetidine (24%) and
probenecid (34%). This is because both drugs are capable of blocking the renal tubular

secretion of levofloxacin. However, at the tested doses in the study, the statistically significant
kinetic differences are unlikely to be of clinical relevance.
Caution should be exercised when levofloxacin is coadministered with drugs that affect the
tubular renal secretion such as probenecid and cimetidine, especially in renally impaired
patients.
Other relevant information
Clinical pharmacology studies have shown that the pharmacokinetics of levofloxacin were not
affected to any clinically relevant extent when levofloxacin was administered together with the
following drugs: calcium carbonate, digoxin, glibenclamide, ranitidine.
Effect of Levox on other medicinal products
Ciclosporin
The half-life of ciclosporin was increased by 33% when coadministered with levofloxacin.
Vitamin K antagonists
Increased coagulation tests (PT/INR) and/or bleeding, which may be severe, have been
reported in patients treated with levofloxacin in combination with a vitamin K antagonist (e.g.
warfarin). Coagulation tests, therefore, should be monitored in patients treated with vitamin K
antagonists (see section 4.4).
Drugs known to prolong QT interval
Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving
drugs known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic
antidepressants, macrolides). (See section 4.4 QT interval prolongation).
Other forms of interactions
Meals
There is no clinically relevant interaction with food. Levox tablets may therefore be
administered regardless of food intake.

Pregnancy
Reproductive studies in animals did not raise specific concern. However, in the absence of
human data and due to the experimental risk of damage by fluoroquinolones to the weightbearing
cartilage of the growing organism, Levox tablets must not be used in pregnant women.
(see sections 4.3 and 5.3)
Lactation
In the absence of human data and due to the experimental risk of damage by fluoroquinolones
to the weight-bearing cartilage of the growing organism, Levox tablets must not be used in
breast-feeding women. (see sections 4.3 and 5.3)

Some undesirable effects (e.g. dizziness/vertigo, drowsiness, and visual disturbances) may
impair the patient's ability to concentrate and react, and therefore may constitute a risk in
situations where these abilities are of special importance (e.g. driving a car or operating
machinery).

 

The information given below is based on data from clinical studies on Levofloxacin in more
than 5000 patients and on extensive post marketing experience.
The adverse reactions are described according to the MedDRA system organ class below.
Frequencies are defined using the following convention: very common (≥ 1/10), common (≥
1/100, <1/10), uncommon (≥ 1/1000, ≤1/100), rare ( ≥1/10000, ≤1/1000), very rare (
1/10000), not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
Infections and infestations
Uncommon: Fungal infection (and proliferation of other resistant microorganisms)
Blood and lymphatic system disorders
Uncommon: Leukopenia, eosinophilia
Rare: Thrombocytopenia, neutropenia
Very rare: Agranulocytosis
Not Known: Pancytopenia, haemolytic anaemia
Immune system disorders
Very rare: Anaphylactic shock (see section 4.4)
Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose
Not known: Hypersensitivity (see section 4.4)
Metabolism and nutrition disorders
Uncommon: Anorexia
Very rare: Hypoglycemia, particularly in diabetic patients (see section 4.4)
Psychiatric disorders
Uncommon: Insomnia, nervousness
Rare: Psychotic disorder, Depression, confusional state, agitation, anxiety
Very rare: Psychotic reactions with self-endangering behaviour including suicidal ideation or
acts (see section 4.4), hallucination
Nervous system disorders
Uncommon: Dizziness, headache, somnolence
Rare: Convulsion, tremor, paraesthesia,
Very rare: sensory or sensorimotor peripheral neuropathy, dysgeusia including ageusia,
parosmia including anosmia
Eye disorders
Very rare: Visual disturbance
Ear and Labyrinth disorders
Uncommon: Vertigo
Very rare: Hearing impaired
Not known: Tinnitus
Cardiac disorders
Rare: Tachycardia
Not Known: Electrocardiogram QT prolonged (see section 4.4 QT interval prolongation and
section 4.9)

Vascular disorders
Rare: Hypotension
Respiratory, thoracic and mediastinal disorders
Rare: Bronchospasm, dyspnoea
Very rare: Pneumonitis allergic
Gastrointestinal disorders
Common: Diarrhoea, nausea
Uncommon: Vomiting, abdominal pain, dyspepsia, flatulence, constipation
Rare: Diarrhoea –haemorrhagic, which in very rare cases may be indicative of enterocolitis,
including pseudomembranous colitis
Hepatobiliary disorders
Common: Hepatic enzyme increased (ALT/AST, alkaline phosphatase, GGT)
Uncommon: Blood bilirubin increased
Very rare: Hepatitis
Not known: Jaundice and severe liver injury, including cases with acute liver failure, has been
reported with levofloxacin, primarily in patients with severe underlying diseases (see section
4.4).
Skin and subcutaneous tissue disorders
Uncommon: Rash, pruritus
Rare: Urticaria
Very rare: Angioneurotic oedema, photosensitivity reaction
Not Known: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme,
hyperhidrosis
Mucocutaneous reactions may sometimes occur even after the first dose
Musculoskeletal and Connective tissue disorders
Rare: Tendon disorder (see section 4.4) including tendinitis (e.g. Achilles tendon), arthralgia,
myalgia
Very rare: Tendon ruptures (see section 4.4). This undesirable effect may occur within 48
hours of starting treatment and may be bilateral, muscular weakness which may be of special
importance in patients with myasthenia gravis
Not Known: Rhabdomyolysis
Renal and urinary disorders
Uncommon: Blood creatinine increased
Very rare: Renal failure acute (e.g. due to nephritis interstitial)
General disorders and administration site conditions
Uncommon: Asthenia
Very rare: Pyrexia
Not known: Pain (including pain in back, chest, and extremities)
Other undesirable effects that have been associated with fluoroquinolone administration
include:
• Extrapyramidal symptoms and other disorders of muscular coordination,
• Hypersensitivity vasculitis,
• Attacks of porphyria in patients with porphyria.

According to toxicity studies in animals or clinical pharmacology studies performed with
supra-therapeutic doses, the most important signs to be expected following acute overdosage of
Levofloxacin tablets are central nervous system symptoms such as confusion, dizziness,
impairment of consciousness, and convulsive seizures, increases in QT interval as well as
gastro-intestinal reactions such as nausea and mucosal erosions.
In the event of overdose, symptomatic treatment should be implemented. ECG monitoring
should be undertaken, because of the possibility of QT interval prolongation. Antacids may be
used for protection of gastric mucosa. Haemodialysis, including peritoneal dialysis and CAPD,
are not effective in removing levofloxacin from the body. No specific antidote exists.

- Anatomical Therapeutical Chemical (ATC): J01MA12.
- Pharmacotherapeutic group:
Quinolone antibacterial, fluoroquinolones
Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class and is the S (-)
enantiomer of the racemic drug substance ofloxacin.
Mechanism of action
As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA-DNA-gyrase complex
and topoisomerase IV.
PK/PD relationship
The degree of the bactericidal activity of levofloxacin depends on the ratio of the maximum
concentration in serum (Cmax) or the area under the curve (AUC) and the minimal inhibitory
concentration (MIC).
Mechanism of resistance
The main mechanism of resistance is due to a gyr-A mutation. In vitro, there is a crossresistance
between levofloxacin and other fluoroquinolones.
Due to the mechanism of action, there is generally no cross-resistance between levofloxacin
and other classes of antibacterial agents.
Breakpoints
The EUCAST recommended MIC breakpoints for levofloxacin, separating susceptible from
intermediately susceptible organisms and intermediately susceptible from resistant organisms
are presented in the below table for MIC testing (mg/L).
EUCAST clinical MIC breakpoints for levofloxacin (2006-06-20):

Pathogen	Susceptible	Resistant
Enterobacteriacae	≤1 mg/L	>2 mg/L
Pseudomonas spp.	≤1 mg/L	>2 mg/L
Acinetobacter spp.	≤1 mg/L	>2 mg/L
Staphylococcus spp.	≤1 mg/L	>2 mg/L
S.pneumoniae 1	≤2 mg/L	>2 mg/L
Streptococcus A,B,C,G	≤1 mg/L	>2 mg/L
H.influenzae, M.catarrhalis2	≤1 mg/L	>1 mg/L
Non-species related breakpoints3	≤1 mg/L	>2 mg/L
1 the S/I-breakpoint was increased from 1.0 to 2.0 to avoid dividing the wild type MIC distribution. The breakpoints relate to high dose therapy. 2 Strains with MIC values above the S/I breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory. 3 Non-species related breakpoints have been determined mainly based on pharmacokinetic/pharmacodynamic data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific breakpoint and are not for use with species where susceptibility testing is not recommended or for which there is insufficient evidence that the species in question is a good target (Enterococcus, Neisseria, Gram negative anaerobes)

The CLSI (Clinical And Laboratory Standards Institute, formerly NCCLS) recommended MIC
breakpoints for levofloxacin, separating susceptible from intermediately susceptible organisms
and intermediately susceptible from resistant organisms are presented in the below table for
MIC testing (μg/mL) or disc diffusion testing (zone diameter [mm] using a 5 μg levofloxacin
disc).
CLSI recommended MIC and disc diffusion breakpoints for levofloxacin (M100-S17, 2007):

Pathogen	Susceptible	Resistant
Enterobacteriaceae	≤2 μg/mL ≥17 mm	≥8 μg/mL ≤13 mm
Non-Enterobacteriaceae.	≤2 μg/mL ≥17 mm	≥8 μg/mL ≤13 mm
Acinetobacter spp.	≤2 μg/mL ≥17 mm	≥8 μg/mL ≤13 mm
Stenotrophomonas maltophilia	≤2 μg/mL ≥17 mm	≥8 μg/mL ≤13 mm
Staphylococcus spp.	≤1 μg/mL ≥19 mm	≥4 μg/mL ≤15 mm
Enterococcus spp.	≤2 μg/mL ≥17 mm	≥8 μg/mL ≤13 mm
H.influenzae M.catarrhalis 1	≤2 μg/mL ≥17 mm
Streptococcus pneumoniae	≤2 μg/mL ≥17 mm	≥8 μg/mL ≤13 mm
beta-hemolytic Streptococcus	≤2 μg/mL ≥17 mm	≥8 μg/mL ≤13 mm
1 The absence or rare occurrence of resistant strains precludes defining any results categories other than « susceptible ». For strains yielding results suggestive of a « nonsuceptible » category, organism identification and antimicrobial susceptibility test results should be confirmed by a reference laboratory using CLSI reference dilution method.

Antibacterial spectrum
The prevalence of resistance may vary geographically and with time for selected species and
local information on resistance is desirable, particularly when treating severe infections. As
necessary, expert advice should be sought when the local prevalence of resistance is such that
the utility of the agent in at least some types of infections is questionable

Commonly susceptible species
Aerobic Gram-positive bacteria
Staphylococcus aureus* methicillin-susceptible
Staphylococcus saprophyticus
Streptococci, group C and G
Streptococcus agalactiae
Streptococcus pneumoniae *
Streptococcus pyogenes *
Aerobic Gram- negative bacteria
Burkholderia cepacia$
Eikenella corrodens
Haemophilus influenzae *
Haemophilus para-influenzae *
Klebsiella oxytoca
Klebsiella pneumoniae *
Moraxella catarrhalis *
Pasteurella multocida
Proteus vulgaris

Providencia rettgeri
Anaerobic bacteria
Peptostreptococcus
Other
Chlamydophila pneumoniae *
Chlamydophila psittaci
Chlamydia trachomatis
Legionella pneumophila*
Mycoplasma pneumoniae *
Mycoplasma hominis
Ureaplasma urealyticum
Species for which acquired resistance may be a problem
Aerobic Gram-positive bacteria
Enterococcus faecalis*
Staphylococcus aureus methicillin-resistant
Staphylococcus coagulase spp
Aerobic Gram- negative bacteria
Acinetobacter baumannii *
Citrobacter freundii *
Enterobacter aerogenes
Enterobacter agglomerans
Enterobacter cloacae *
Escherichia coli *
Morganella morganii *
Proteus mirabilis *
Providencia stuartii
Pseudomonas aeruginosa*
Serratia marcescens *
Anaerobic bacteria
Bacteroides fragilis
Bacteroides ovatus$
Bacteroides thetaiotamicron$
Bacteroides vulgatus$
Clostridium difficile$
* Clinical efficacy has been demonstrated for susceptible isolates in the approved clinical
indications.
$ Natural intermediate susceptibility
Other information
Nosocomial infections due to P. aeruginosa may require combination therapy.

 

Absorption
Orally administered levofloxacin is rapidly and almost completely absorbed with peak plasma
concentrations being obtained within 1h. The absolute bioavailability is approximately 100 %.
Food has little effect on the absorption of levofloxacin.
Distribution
Approximately 30 - 40 % of levofloxacin is bound to serum protein. 500 mg once daily
multiple dosing with levofloxacin showed negligible accumulation. There is modest but
predictable accumulation of levofloxacin after doses of 500 mg twice daily. Steady state is
achieved within 3 days.
Penetration into tissues and body fluids:
Penetration into Bronchial Mucosa, Epithelial Lining Fluid (ELF)
Maximum levofloxacin concentrations in bronchial mucosa and epithelial lining fluid after 500
mg p.o. were 8.3 μg/g and 10.8 μg/ml respectively. These were reached approximately one
hour after administration.
Penetration into Lung Tissue
Maximum levofloxacin concentrations in lung tissue after 500 mg p.o. were approximately
11.3 μg/g and were reached between 4 and 6 hours after administration. The concentrations in
the lungs consistently exceeded those in plasma.
Penetration into Blister Fluid
Maximum levofloxacin concentrations of about 4.0 and 6.7 μg/ml in the blister fluid were
reached 2 - 4 hours after administration following 3 days dosing at 500 mg once or twice daily,
respectively.
Penetration into Cerebro-Spinal Fluid
Levofloxacin has poor penetration into cerebro-spinal fluid.
Penetration into prostatic tissue
After administration of oral 500mg levofloxacin once a day for three days, the mean
concentrations in prostatic tissue were 8.7 μg/g, 8.2 μg/g and 2.0 μg/g respectively after 2
hours, 6 hours and 24 hours; the mean prostate/plasma concentration ratio was 1.84.
Concentration in urine
The mean urine concentrations 8 -12 hours after a single oral dose of 150 mg, 300 mg or 500
mg levofloxacin were 44 mg/L, 91 mg/L and 200 mg/L, respectively.
Biotransformation
Levofloxacin is metabolised to a very small extent, the metabolites being desmethyllevofloxacin
and levofloxacin N-oxide. These metabolites account for < 5 % of the dose
excreted in urine. Levofloxacin is stereo chemically stable and does not undergo chiral
inversion.
Elimination
Following oral and intravenous administration of levofloxacin, it is eliminated relatively slowly
from the plasma (t½: 6 - 8 h). Excretion is primarily by the renal route (> 85 % of the
administered dose).
There are no major differences in the pharmacokinetics of levofloxacin following intravenous
and oral administration, suggesting that the oral and intravenous routes are interchangeable.
Linearity

Levofloxacin obeys linear pharmacokinetics over a range of 50 to 600 mg.
Subjects with renal insufficiency
The pharmacokinetics of levofloxacin is affected by renal impairment. With decreasing renal
function, renal elimination and clearance are decreased, and elimination half-lives increased as
shown in the table below:

Clcr [ml/min]	< 20	20 - 49	50 - 80
ClR [ml/min]	13	26	57
t1/2 [h]	35	27	9

 

Elderly subjects
There are no significant differences in levofloxacin pharmacokinetics between young and
elderly subjects, except those associated with differences in creatinine clearance.
Gender differences
Separate analysis for male and female subjects showed small to marginal gender differences in
levofloxacin pharmacokinetics. There is no evidence that these gender differences are of
clinical relevance.

Acute toxicity
The median lethal dose (LD50) values obtained in mice and rats after oral administration of
levofloxacin were in the range 1500-2000 mg/kg.
Administration of 500 mg/kg p.o. to monkeys induced little effect apart from vomiting.
Repeated dose toxicity
Studies of one and six month's duration by gavages have been carried out in the rat and
monkey. Doses were 50, 200, 800 mg/kg/day and 20, 80, 320 mg/kg/day for 1 and 6 months in
the rat and 10, 30, 100 mg/kg/day and 10, 25, 62.5 mg/kg/day for 1 and 6 months in the
monkey.
Signs of reaction to treatment were minor in the rat with slight effects principally at 200
mg/kg/day and above in reducing food consumption and slightly altering haematological and
biochemical parameters. The No Observed Adverse Effect Levels (NOELs) in these studies
were concluded to be 200 and 20 mg/kg/day after 1 and 6 months respectively.
Toxicity after oral dosing in the monkey was minimal with reduced body weight at 100
mg/kg/day together with salivation, diarrhoea and decreased urinary pH in some animals at this
dose. No toxicity was seen in the 6-month study. The NOELs were concluded to be 30 and
62.5 mg/kg/day after 1 and 6 months respectively.

The NOELs in the six-month studies were concluded to be 20 and 62.5 mg/kg/day in the rat
and monkey respectively.
Reproductive toxicity
Levofloxacin caused no impairment of fertility or reproductive performance in rats at oral
doses as high as 360 mg/kg/day or intravenous doses up to 100 mg/kg/day.
Levofloxacin was not teratogenic in rats at oral doses as high as 810 mg/kg /day or at
intravenous doses as high as 160 mg/kg/day. No teratogenicity was observed when rabbits
were dosed orally with up to 50 mg/kg/day or intravenously with up to 25 mg/kg/day.
Levofloxacin had no effect on fertility and its only effect on foetuses was delayed maturation
as a result of maternal toxicity.
Genotoxicity
Levofloxacin did not induce gene mutations in bacterial or mammalian cells but did induce
chromosome aberrations in Chinese hamster lung cells in vitro at or above 100 μg/ml, in the
absence of metabolic activation. In vivo tests (micronucleus, sister chromatid exchange,
unscheduled DNA synthesis, dominant lethal tests) did not show any genotoxic potential.
Phototoxic potential
Studies in the mouse after both oral and intravenous dosing showed levofloxacin to have
phototoxic activity only at very high doses. Levofloxacin did not show any genotoxic potential
in a photomutagenicity assay, and it reduced tumour development in a photocarcinogenicity
assay.
Carcinogenic potential
No indication of carcinogenic potential was seen in a two year study in the rat with dietary
administration (0, 10, 30 and 100 mg/kg/day).
Toxicity to joints
In common with other fluoroquinolones, levofloxacin showed effects on cartilage (blistering
and cavities) in rats and dogs. These findings were more marked in young animals.

Active Ingredient:
Levofloxacin Hemihydrate (equivalent to Levofloxacin…250 mg).
Excipients for Core:
Hydroxypropyl Methylcellulose EP.
Crospovidone NF.
Silicified Microcrystalline Cellulose (Prosolv SMCC 50).
Magnesium Stearate.
Excipients for Film Coating:
Polysorbate 80 EP.
Titanium Dioxide EP.
Purified Talc EP.
Polyethylene Glycol MW 6000 EP.
Hydroxypropyl Methylcellulose EP.
Iron Oxide Yellow.

Not Applicable.

2 Years.

- Do not store above 30°C.

Blister Pack.
Lidding material: Aluminum Foil
Forming Film: PVC/PVDC.
(PVC: polyvinyl chloride, PVDC polyvinylidene chloride)

None.